TAP Vol 5 Issue 19

CAR T-Cell Therapy

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| Focused Ultrasound

53

| Hazards of Overscreening

128

| Letters to the Editor

VOLUME 5, ISSUE 19

139

DECEMBER 1, 2014

Editor-in-Chief, James O. Armitage, MD | ASCOPost.com

Chemotherapy Foundation Symposium

Optimizing HER2 Therapy in Early and Advanced Breast Cancers

When Should We Stop Prescribing?

By Alice Goodman

By John F. Smyth, MD

T

rastuzumab (Herceptin) has been the cornerstone of therapy for HER2-positive tumors, which comprise about 20% of all breast tumors. Additional therapies targeted to other HER2 pathways or other targets to be used in combination with trastuzumab are being explored in both the adjuvant and metastatic settings. At the 2014 Chemotherapy Foundation Symposium, experts reviewed new approaches to HER2-positive breast cancer in these settings.

Adjuvant Therapy Several drugs are now approved or under in-

tensive study for adjuvant therapy of HER2-positive breast cancer: trastuzumab, pertuzumab (Perjeta), adotrastuzumab emtansine (formerly known as T-DM1 [Kadcyla]), lapatinib (Tykerb), and the investigational tyrosine kinase inhibitor neratinib. These treatments act differently, explained José Baselga, MD, Physicianin-Chief at Memorial Sloan Kettering Cancer Center

and President-Elect of the American Association for Cancer Research.1 “Trastuzumab has aged extremely well,” Dr. Baselga told the audience. Overall survival and disease-free survival benefits of trastuzumab are well established José Baselga, MD in the adjuvant setting. It has also been established that 2 years of trastuzumab is not better than 1 year, and 1 year should be the standard of care at present. “But we are not sure that 12 months is a magic number,” Dr. Baselga noted.

The CLEOPATRA trial showed that dual blockade of HER2 with docetaxel and pertuzumab plus trastuzumab achieved an overall survival improvement of 16 months compared with docetaxel and trastuzumab in continued on page 5

Quality Care Symposium

CancerLinQ: Building a Data Infrastructure to Improve Quality and Reduce Cost

By Ronald Piana

I

n November 2013, ASCO initiated the development of CancerLinQ, a learning health system designed to transform cancer care and improve outcomes. At this year’s Quality Care Symposium in Boston, ASCO President Peter Paul Yu, MD, FACP, FASCO, Director of Cancer Research at the Palo Alto Medical Foundation, highlighted the work that has been done on the project and outlined future plans.

“So far at the meeting, we’ve heard a lot about

different data repositories on the national, state, federal, and hospital levels. They all represent different collection sources in our data ecosystem. However, CancerLinQ represents the data collected from electronic health records in practitioners’ offices,” said Dr. Yu. He added that the CancerLinQ data “are vitally important because we practitioners are the main interface between patients and the health-care system, and the information in our health records constitutes the foundational data that other data sources are deOur pilot program shows that such a rived from.”

He explained that allearning health system will work. Based though CancerLinQ on our platform development work this endeavors to provide a mechanism to aggregate year, we plan to debut a functioning massive amounts of data CancerLinQ system in 2015. from electronic health —Peter Paul Yu, MD, FACP, FASCO records across the coun-

T

his year’s European Society for Medical Oncology (ESMO) meeting held in Madrid was attended by 19,000 delegates, and it was encouraging to see among that number so many young oncologists being given time off for education and discussion. There has never before been a time when so much new information has become available so rapidly, showing positive results in many common cancers, and where science is driving the agenda. Keeping abreast of all this information is hard enough for all of us, but there are special challenges for less experienced oncologists or those in training. One example of this is the issue of knowing when to stop active anticancer treatment—that continued on page 55

Dr. Smyth is Emeritus Professor of Medical Oncology, University of Edinburgh, United Kingdom.

Disclaimer: This commentary represents the views of the author and may not necessarily reflect the views of ASCO.

MORE IN THIS ISSUE Oncology Meetings Coverage Chemotherapy Foundation ������������������� 3–9 Thoracic Oncology Symposium ��������11–12 Quality Care Symposium ��������� 15, 19–25 AACR Conference �����������������������������������30 Palliative Care in Oncology ����������������������85 Best of ASCO ������������������������������������������� 90 Maha Hussain, MD, FACP, FASCO, on Metastatic Prostate Cancer ������������������49 Direct From ASCO �������������������������� 57–60 Robert S. Miller, MD, FACP, FASCO, on Quality of Care �������������������������������������� 61 Tracy Batchelor, MD, on Treating Brain Cancer in 2014 ����������������������������������70

continued on page 15

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PAGE 3

Chemotherapy Foundation Symposium Hematology

New Agents and Novel Targets for Multiple Myeloma

By Alice Goodman

N

ew therapies for multiple myeloma have dramatically improved life expectancy, but despite these advances, 5-year overall survival still remains below 50%. Investigators are in hot pursuit of new therapies that will extend remissions and improve survival. Thus far, monoclonal antibodies, immunotherapy, histone deacetylase inhibitors, and the new proteasome inhibitor ixazomib show promise.

“There is still room for improvement. Multiple myeloma is treatable but not necessarily considered curable.

Monoclonal antibodies are likely to play a key role in progress in treating the disease, and immunotherapy may be a key for refractory myeloma with high-risk genetics. There are a number of new targets and agents in the pipe-

onstrate value across multiple lines of therapy.

“Multiple myeloma has many different treatment options and the path patients follow is different depending on response. A new therapy would need to show efficacy across different lines of therapy,” he told listeners.

About 15% to 29% of patients with multiple myeloma die within 3 years, even with novel agents. “For these highrisk groups, we want drugs that are genome neutral. This leads us to monoclonal antibodies,” he said.

Promising Approaches Three monoclonal antibodies show promise in multiple myeloma: daratumumab, SAR650984, and an older drug called elotuzumab. All three drugs improve response rates as single agents in

Right now in multiple myeloma, there is no molecularly targeted therapy. This is an area where progress has to be made.

—Sundar Jagannath, MD

line, and this is where personalized medicine may play a role,” said Sundar Jagannath, MD, Icahn School of Medicine at Mt. Sinai, New York. At the recent 2014 Chemotherapy Foundation Symposium, Dr. Jagannath updated listeners about promising new drugs for multiple myeloma.1 Ultimately, all patients become refractory to current treatments, he continued, attributing this mainly to the genetic complexity of the disease.

“At diagnosis, five different clones have been identified. With treatment, different clones emerge over time.

There is selection of mutations, and this tells us that combination therapy is better than single-agent therapy,” Dr. Jagannath said.

“Right now in multiple myeloma, there is no molecularly targeted therapy. This is an area where progress has to be made,” he stated.

For a treatment to be considered an advance, it would have to boost complete and partial remission and achieve molecularly defined remission. Ideally, new agents should be well tolerated without causing cytopenias and dem-

multiple myeloma and show encouraging activity when combined with standard drugs used in multiple myeloma, such as lenalidomide (Revlimid) and dexamethasone.

Based on the success of rituximab (Rituxan) in lymphoma and the fact that CD38 is highly expressed in multiple myeloma cells, developing an antiCD38 monoclonal antibody is an active area of study in multiple myeloma. Daratumumab and SAR650984 are both anti-CD38 monoclonal antibodies in phase III testing, he continued.

Daratumumab as a single agent achieved excellent response rates in relapsed multiple myeloma.2 Responses were more robust when daratumumab is combined with lenalidomide/dexa-

methasone, Dr. Jagannath explained. In one phase II study, the combination of daratumumab plus lenalidomide/dexamethasone achieved responses in 15 of 20 patients.3 SAR650984 as a single agent achieved a 33% response rate in patients with relapsed/refractory multiple myeloma, similar to that seen with daratumumab. In a small study of 31 patients with relapsed/refractory multiple myeloma, overall benefit for the combination of SAR650984 plus lenalidomide/ dexamethasone was 65%, overall response rate was 58%, very good partial response was 23%, and partial response was 35%.4 “Anti-CD38 monoclonal antibodies are very exciting. They currently have breakthrough designation from the U.S. Food and Drug Administration [FDA].

We hope to have these drugs available sooner rather than later,” Dr. Jagannath stated.

“Elotuzumab is another monoclonal antibody that has been around for a while, but the newer drugs stole its thunder,” he continued.

This drug targets SLAMF7, which is highly expressed in multiple myeloma cells and natural killer cells. This enables targeting multiple myeloma cells via natural killer cell–mediated mechanisms, Dr. Jagannath explained.

In phase II studies, elotuzumab did not have impressive single-agent activity, but dramatic responses were seen in the phase II ELOQUENT-2 trial, when elotuzumab was combined with lenalidomide/dexamethasone. The median duration of response was 11 to 15 months.5 “Immunotherapy is an area of intense interest in all of oncology, and this may be where future progress lies,” he continued. Checkpoint inhibitors, chimeric antigen receptor T cells, and approaches to stimulating innate immunity may hold promise in multiple myeloma.

Panobinostat, a pan histone deacetylase inhibitor, has showed promising

New Therapies for Multiple Myeloma ■■ Almost all patients with multiple myeloma ultimately become refractory to treatment, and new approaches are needed.

■■ Newer therapies will need to be used in combination, due to the genetic heterogeneity of multiple myeloma.

■■ Monoclonal antibodies, immunotherapy, and histone deacetylase inhibitors (HDAC1) are among the most promising strategies.

results with a 4-month improvement in progression-free survival when combined with bortezomib (Velcade)/dexamethasone vs bortezomib/dexamethasone alone: median of 12 months progressionfree survival vs 8.1 months, respectively.6 Subgroup analysis of progression-free survival revealed a strong benefit in poor-risk patients. [Editor’s note: During the 2014 Chemotherapy Foundation Symposium meeting, the FDA’s Oncology Drug Advisory Committee recommended against the approval of panobinostat based on results of the PANORAMA-1 trial. FDA is not obligated to follow the committee’s vote, but it generally does.]

The histone deacetylase inhibitor 6 inhibitor ACY-1215 showed encouraging activity alone and in combination with bortezomib in patients with relapsed/refractory multiple myeloa, he said. In these heavily pretreated patients, the response rate was 25%, and the clinical benefit rate was 60%. Responses were seen in bortezomib-refractory patients.7

Other Targets Other targets in the pipeline include kinesin spindle protein inhibitors (ie, filanesib); AKT inhibitors (ie, afuresertib); CDK inhibitors (ie, dinaciclib); nuclear transport inhibitors; PI3K inhibitors; Bruton’s tyrosine kinase inhibitors; and BCL2 inhibitors.

“Dr. Jagannath has given us an excellent educational session about what to expect in the future for treatment of multiple myeloma,” said Kanti Rai, MD, session moderator. n

Disclosure: Dr. Jagannath reported no potential conflicts of interest.

References 1. Jagannath S: New drugs in multiple myeloma. 2014 Chemotherapy Foundation Symposium. Presented November 5, 2014.

2. Lokhorst HM, Laubach J, Nahi H, et al: Dose-dependent efficacy of daratumumab as monotherapy in patients with relapsed or refractory multiple myeloma. 2014 ASCO Annual Meeting. Abstract 8513.

3. Plesner T, Arkenau H-T, Lokhorst HM, et al: Safety and efficacy of daratumumab with lenalidomide and dexamethasone in relapsed or relapsed, refractory multiple myeloma. 2014 ASCO Annual Meeting. Abstract 8533.

4. Martin TG, Hsu K, Charpentier E, et al: A phase 1b dose escalation trial of continued on page 4

The ASCO Post | DECEMBER 1, 2014

PAGE 4

Chemotherapy Foundation Symposium Breast Cancer

Hormonal Therapy for Early Breast Cancer: Do We Learn From Past Mistakes?

By Alice Goodman the NSABP 14 protocol, which evaluated the use of adjuvant tamoxifen for 5 years vs 10 years for breast cancer. At 7 years, 5 years looked like it was superior, but this analysis failed to account for the rebound effect that continues after stopping tamoxifen. The study was stopped because it crossed futility limits.

“What a mistake!” he exclaimed.

“This set us back a decade.”

More recently, data from the AT-

©ASCO/Zach Boyden-Holmes

G

uidelines can be incorrect if they are not based on incontrovertible evidence. Such was the case with the National Cancer Institute (NCI) 1995 guidelines recommending 5 years of tamoxifen adjuvant therapy for stage I to III hormone receptor–positive breast cancer. With more definitive evidence, ASCO issued 2014 guidelines recommending 10 years of tamoxifen as the new standard.

In 2015, new guidelines on aromatase inhibitors and gonadotropinreleasing hormone agonists are expected, and these guidelines could fall into a similar trap as the NCI 1995 guidelines for tamoxifen, according to Norman Wolmark, MD, Chairman of the National Surgical Adjuvant Breast and Bowel Project (NSABP) and Professor and Chairman of Human Oncology at the Drexel University School of Medicine, Philadelphia.

He stated that the new guidelines should incorporate genomic profiling; otherwise they will miss the mark.

“Hormonal management of adjuvant therapy of breast cancer justifies a reprise. Are we destined to learn from the mistakes of the past, or are we going to repeat them?” was the challenge Dr.

5. Richardson PG, Jagannath S, Moreau P, et al: A phase 2 study of elotuzumab in combination with lenalidomide and low-dose dexamethasone in patients with relapsed/refractory multiple myeloma: Updated results. 2012 ASH Annual Meeting. Abstract 202.

6. Richardson PG, Hungria VTM, Yoon S-S, et al: Panorama 1: A randomized, double-blind phase 3 study of panobinostat or placebo plus bortezomib and dexamethasone in relapsed or relapsed and refractory multiple myeloma. 2014 ASCO Annual Meeting. Abstract 8510.

■■ The upcoming 2015 guidelines for hormonal therapy could fall into the same trap as the 1995 guidelines. To avoid this, they should be based on incontrovertible evidence and incorporate genomic profiling.

Multiple Myeloma continued from page 3

SAR650984 (Anti-CD38 mAb) in combination with lenalidomide and dexamethasone in relapsed/refractory multiple myeloma. 2014 ASCO Annual Meeting.

Abstract 8512.

— Norman Wolmark, MD

standard,” he stated. The new ASCO guidelines recommend 10 years of total tamoxifen therapy.

Dr. Wolmark suggested that the new guidelines may be “authoritarian,” and there may be cohorts for whom 10 years of hormonal therapy is not desirable. Perhaps these cohorts could be identified by genomic signatures such as Oncotype DX

■■ Based on results of the ATLAS and aTTOM trials, the new standard of care is 10 years of tamoxifen in that setting.

The 1995 NCI guidelines for adjuvant tamoxifen, distributed to every oncologist at every U.S. hospital, were based on results of a 7-year interim analysis of

“New data that have emerged in the past 2 years exacerbate the dilemma of how to address the enigma of the ovary.

Some of these therapeutic strategies are competing and mutually exclusive,” Dr.

Wolmark told listeners. “We may be deluding ourselves if we have conflicting data and think that we will find a Rosetta stone,” he said.

Several trials suggest that gonadotropin-releasing hormone agonist analogs and luteinizing hormone-releasing hormone analogs can reduce the risk of tumor recurrence in premenopausal women with hormone receptor–positive breast cancer.

“These agents are making a comeback in premenopausal women. They have been tried before. It’s like being on a roller coaster,” Dr. Wolmark said. “2014 is the year of resurgence of luteinizing hormone-releasing hormone agonists.”

Data are conflicting about whether tamoxifen plus ovarian function suppression (ie, with gonadotropin-releasing hormone agonist or luteinizing hormonereleasing hormone agonists) or aromatase inhibitor plus ovarian function suppression has a greater effect on reducing tumor recurrence in premenopausal women.

Updated results of a joint analysis of the TEXT and SOFT salvage trials should provide further evidence of this question. These results will be presented at the 2014 San Antonio Breast Cancer

LAS and aTTOM trials showed a 4% incremental benefit for 10 years of tamoxifen compared with 5 years (hazard ratio = 0.80).2,3 “The ATLAS and aTTOM trials were unencumbered by interim analyses—they plotted on and went forward.

This refuted the NSABP 5-year gold

■■ The 1995 guidelines recommending 5 years of tamoxifen adjuvant therapy for hormone receptor–positive early breast cancer were based on flawed evidence from an interim analysis.

Mistakes of the Past

Resurgence of Luteinizing Hormone-Releasing Hormone Agonists

If the guidelines don’t take into account genomic profiling, you may miss the mark. You can run the risk of paying an enormous price and setting back the field by at least a decade.

Update on Hormonal Therapy for Early Breast Cancer

Wolmark issued in his Keynote Address at the 2014 Chemotherapy Foundation Symposium.1

that determine which patients are at risk for early or late tumor recurrence.

Symposium. A previous joint analysis favored ovarian function suppression plus exemestane over tamoxifen plus ovarian function suppression, with a 5% absolute difference in disease-free survival at 5.7 years of follow-up.4 “Are we going to think this is a home run? I’m not holding my breath,” he said.

Hypothetically, the 2015 guidelines could state that premenopausal women should be offered an aromatase inhibitor with gonadotropin-releasing hormone agonist for 5 years. He questions this, as well as the duration of therapy beyond 5 years whether they remain premenopausal or become postmenopausal.

He suggested there may be premenopausal cohorts who can benefit from 5 vs 10 years of this type of therapy. Additional trials will show the optimal duration of aromatase inhibitors (NSABP-42) and disease-free survival with ovarian function suppression (MA17R).

“Strap yourselves into that roller coaster,” he said.

Take-Home Message “The take-home message is that if the data are definitive and incontrovertible, go ahead and formulate guidelines.

On the other hand, we are in the era of genomic profiling. Do the guidelines apply to every patient, in this age of molecular genomics? If the guidelines don’t take into account genomic profiling, you may miss the mark. You can run the risk of paying an enormous price and setting back the field by at least a decade,” Dr. Wolmark stated. n

Disclosure: Dr. Wolmark reported no potential conflicts of interest.

References 1. Wolmark N: 2014 Chemotherapy Foundation Symposium. Presented November 5, 2014.

2. Davies C, et al: Lancet 381:805-816, 2013.

3. Gray RG, et al: 2013 ASCO Annual Meeting. Abstract 5.

4. Pagani O, et al: 2014 ASCO Annual Meeting. Abstract LBA1.

7. Raje N, Vogl DT, Parameswaran NH, et al: ACY-1215, a selective histone deacetylase (HDAC) 6 inhibitor: Interim results of combination therapy with bortezomib in patients with multiple myeloma. 2013 ASH Annual Meeting.

Abstract 759.

ASCOPost.com | DECEMBER 1, 2014

PAGE 5

Chemotherapy Foundation Symposium Breast Cancer

HER2 Therapy continued from page 1

metastatic HER2-positive breast cancer.2 “This represents great progress, and now there are studies of trastuzumab/ pertuzumab in the adjuvant setting,” he said. They included the phase II NEOSPHERE trial, which showed a doubling of pathologic complete response

trastuzumab emtansine vs 14 cycles of trastuzumab, and 50% of planned enrollment is completed. The primary endpoint is disease-free survival.7 KAITLIN, the phase III registration trial for ado-trastuzumab emtansine, will randomize patients (after surgery and anthracycline-based chemotherapy) to ado-trastuzumab emtansine vs taxane/

Trastuzumab has aged extremely well.

But we are not sure that 12 months is a magic number [for duration of therapy].

—José Baselga, MD

rate with the combination of pertuzumab/trastuzumab plus docetaxel compared with trastuzumab/docetaxel (39.3% vs 21.5%).3 The randomized, double-blind, placebo-controlled, two-arm APHINITY trial is evaluating adjuvant pertuzumab plus chemotherapy plus trastuzumab vs chemotherapy with trastuzumab plus placebo for 1 year after surgery.4 Neoadjuvant trastuzumab/lapatinib has been studied in four trials, and all of them have shown an advantage for the combination, he continued. However, in the large ALTTO trial, the combination failed to improve disease-free survival in the adjuvant setting, which was disappointing, he added.5 Another approach—sequential therapy with 1 year of trastuzumab followed by 1 year of neratinib—appears to be effective in the extended adjuvant setting, according to preliminary data from the ExteNET study showing improved disease-free survival.6 “We look forward to hearing more about this sequential therapy,” Dr. Baselga said.

Moving on, he noted, “There is tremendous excitement about [ado-trastuzumab emtansine] in the adjuvant setting.”

The phase II KATHERINE study is comparing 14 cycles of adjuvant ado-

trastuzumab.8 The study is designed to determine how much chemotherapy is

needed, Dr. Baselga said.

Advanced HER2-Positive Breast Cancer Kimberly Blackwell, MD, Duke Cancer Institute, Durham, North Carolina, brought attendees up to date on targeting HER2-positive advanced breast cancer for first-line treatment (de novo or metastatic tumor recurrence) and beyond the first-line setting.9 “The introduction of trastuzumab is one of the most important breakthroughs in the treatment of breast cancer with its improvement in overall survival. This survival bar has now been raised to over 15 months with the combination of pertuzumab plus trastuzu­mab,” she said.

“One important study showed us what not to do for first-line metastatic breast cancer,” she continued. The MA-31 trial compared lapatinib/taxane followed by lapatinib vs trastuzumab/taxane followed by trastuzumab in 600 patients and found a progression-free survival detriment for lapatinib/taxane at the interim analysis.10 Moreover, the combination was associated with increased febrile neutropenia and grade 3 or higher diarrhea.

“We need to remember these data [ie,

Therapeutic Update on HER2-Positive Breast Cancer ■■ Trastuzumab continues to be the cornerstone of treatment for HER2positive breast cancer.

■■ Dual HER2 blockade with pertuzumab and trastuzumab achieves improved survival in HER2-positive metastatic breast cancer.

■■ In the adjuvant setting, new trastuzumab-based approaches are being explored.

■■ Lapatinib/taxane should not be used in the first-line setting for metastatic breast cancer.

■■ Ado-trastuzumab emtansine and lapatinib are second- and third-line options for metastatic breast cancer.

■■ mTOR inhibitors and PI3K inhibitors are being explored in combination with HER2-directed therapy in the metastatic setting.

negative findings for lapatinib/taxane] in clinical decision-making when lining up our therapeutic options for women facing this disease,” she emphasized.

Another very important study, CLEOPATRA,2 showed the power of adding a second antibody to trastuzu­mab as first-line treatment in the metastatic setting [see above]. Final results showed improved progression-free and overall survival with pertuzumab/­trastuzumab.

“CLEOPATRA showed that it is important to first give six cycles of docetaxel [with antibody],” she said.

“Getting the chemotherapy out of the way allows the targeted agents to work in this scenario without the chemotherapy toxicity.”

“With limited toxicity, pertuzumab/ trastuzumab has become the preferred treatment regimen in patients diagnosed with de novo advanced or recur-

yond.12 In this study, patients with at least two prior lines of HER2-directed therapy were randomized to receive ado-trastuzumab emtansine or physician’s choice of chemotherapy. Ado-trastuzumab emtansine produced a 2.7-month advantage in progression-free survival, and overall survival has not yet been reached.

A phase III study provided additional support for dual HER2 blockade, this time with lapatinib/trastuzumab vs lapatinib alone, showing that patients with HER2-driven metastatic breast cancer derived a survival benefit from HER2 combination therapy.13 The median overall survival was 51 weeks for the combination vs 39 months for lapatinib alone.

“Choice of third-line therapy should be based on patient characteristics and toxicity,” Dr. Blackwell said.

“Several ongoing trials will tell us about new options once trastuzumab,

The introduction of trastuzumab is one of the most important breakthroughs in the treatment of breast cancer with its improvement in overall survival. This survival bar has now been raised to over 15 months with the combination of pertuzumab plus trastuzumab.

—Kimberly Blackwell, MD

rent HER2-positive breast cancer,” Dr. Blackwell stated.

Second- and Third-Line Options Once patients progress on this regimen, therapeutic options include adotrastuzumab emtansine and lapatinib.

In the EMILIA trial, ado-trastuzumab emtansine offered significantly superior survival compared with lapatinib/ capecitabine in the second- and thirdline settings (P < .001), with a favorable toxicity profile.11 When EMILIA was designed, the standard of care was lapatinib/capecitabine, Dr. Blackwell explained. Ado-trastuzumab emtansine achieved a median overall survival of 30.9 months vs 25.1 months with lapatinib/capecitabine (P = .0007).

“This survival benefit is similar to what we saw initially with trastuzumab.

This study, plus CLEOPATRA, show how far we have come,” she stated.

Ado-trastuzumab emtansine has different toxicities than chemotherapy, she said, mainly elevated liver enzymes and grade 3 and 4 cytopenias.

Based on the TH3RESA trial, adotrastuzumab emtansine is a reasonable choice for third-line therapy and be-

pertuzumab, [ado-trastuzumab emtansine], and lapatinib have been optimally utilized. Promising approaches include mTOR inhibitors [everolimus (Afinitor), the MARIANNE, BOLERO 1, and BOLERO 3 trials], and PI3 kinase inhibitors,” she said. n Disclosure: Drs. Baselga and Blackwell reported no potential conflicts of interest.

References 1. Baselga J: Adjuvant therapy for HER2-positive breast cancer. 2014 Chemotherapy Foundation Symposium. Presented November 6, 2014.

2. Swain SM, Kim SB, Cortés J, et al: Pertuzumab, trastuzumab, and docetaxel for HER2-positive metastatic breast cancer (CLEOPATRA study): Overall survival results from a randomised, double-blind, placebo-controlled, phase 3 study. Lancet Oncol 14:461-471, 2013.

3. Gianni L, Pienkowski T, Im YH, et al: Efficacy and safety of neoadjuvant pertuzumab and trastuzumab in women with locally advanced, inflammatory, or early HER2-positive breast cancer (neoSphere): A randomised, open-label, phase 2 trial.

Lancet Oncol 13:25-32, 2012. continued on page 8

First-line Treatment for CLL ARZERRA® (ofatumumab) is indicated, in combination with chlorambucil, for previously untreated patients with CLL for whom fludarabine-based therapy is considered inappropriate

An Effective Combination to Extend PFS*

1

*Assessed by a blinded Independent Review Committee (IRC) using the International Workshop for Chronic Lymphocytic Leukemia (IWCLL) updated National Cancer Institute–sponsored Working Group (NCI-WG) guidelines (2008).

CLL=chronic lymphocytic leukemia; PFS=progression-free survival; AR=adverse reaction; IR=infusion reaction.

Indications

Hepatitis B Virus Reactivation Hepatitis B virus (HBV) reactivation, in some cases resulting in ARZERRA (ofatumumab) is indicated: fulminant hepatitis, hepatic failure and death, has occurred • In combination with chlorambucil, for the treatment of previously in patients treated with ARZERRA. Cases have been reported untreated patients with chronic lymphocytic leukemia (CLL) for in patients who are hepatitis B surface antigen (HBsAg) positive whom fludarabine-based therapy is considered inappropriate and also in patients who are HBsAg negative but are hepatitis B • For the treatment of patients with CLL refractory to core antibody (anti-HBc) positive. Reactivation also has occurred fludarabine and alemtuzumab in patients who appear to have resolved hepatitis B infection (ie, HBsAg negative, anti-HBc positive, and hepatitis B surface Important Safety Information for ARZERRA antibody [anti-HBs] positive).

WARNING: HEPATITIS B VIRUS REACTIVATION AND HBV reactivation is defined as an abrupt increase in HBV PROGRESSIVE MULTIFOCAL LEUKOENCEPHALOPATHY replication manifesting as a rapid increase in serum HBV DNA level or detection of HBsAg in a person who was previously • Hepatitis B Virus (HBV) reactivation can occur in HBsAg negative and anti-HBc positive. Reactivation of HBV patients receiving CD20-directed cytolytic antibodies, replication is often followed by hepatitis, ie, increase in including ARZERRA, in some cases resulting in transaminase levels and, in severe cases, increase in bilirubin fulminant hepatitis, hepatic failure, and death levels, liver failure, and death. [see Warnings and Precautions (5.2)].

• Progressive Multifocal Leukoencephalopathy (PML) Screen all patients for HBV infection by measuring HBsAg and resulting in death can occur in patients receiving anti-HBc before initiating treatment with ARZERRA. For CD20-directed cytolytic antibodies, including ARZERRA patients who show evidence of hepatitis B infection (HBsAg [see Warnings and Precautions (5.4)]. positive [regardless of antibody status] or HBsAg negative but anti-HBc positive), consult physicians with expertise in managing Infusion Reactions hepatitis B regarding monitoring and consideration for HBV ARZERRA can cause serious, including fatal, infusion reactions antiviral therapy. manifesting as bronchospasm, dyspnea, laryngeal edema, pulmonary edema, flushing, hypertension, hypotension, syncope, Monitor patients with evidence of current or prior HBV cardiac events (eg, myocardial ischemia/infarction, acute coronary infection for clinical and laboratory signs of hepatitis or HBV reactivation during and for several months following treatment syndrome, arrhythmia, bradycardia), back pain, abdominal pain, with ARZERRA. HBV reactivation has been reported for at least pyrexia, rash, urticaria, angioedema, cytokine release syndrome, 12 months following completion of therapy. and anaphylactoid/anaphylactic reactions. Infusion reactions In patients who develop reactivation of HBV while receiving occur more frequently with the first 2 infusions. These reactions may result in temporary interruption or withdrawal of treatment. ARZERRA, immediately discontinue ARZERRA and any concomitant chemotherapy, and institute appropriate Administer ARZERRA in an environment where facilities to treatment. Resumption of ARZERRA in patients whose HBV adequately monitor and treat infusion reactions are available. reactivation resolves should be discussed with physicians with Premedicate with acetaminophen, an antihistamine, and a corticosteroid. Infusion reactions may occur despite premedication. expertise in managing hepatitis B. Insufficient data exist regarding the safety of resuming ARZERRA in patients who Interrupt infusion with ARZERRA for infusion reactions of any develop HBV reactivation. severity. Institute medical management for severe infusion Hepatitis B Virus Infection reactions including angina or other signs and symptoms Fatal infection due to hepatitis B in patients who have not been of myocardial ischemia. If an anaphylactic reaction occurs, previously infected has been observed with ARZERRA. Monitor immediately and permanently discontinue ARZERRA and patients for clinical and laboratory signs of hepatitis. initiate appropriate medical treatment. ®

ARZERRA Plus Chlorambucil Demonstrated a Median PFS of 22.4 Months vs 13.1 Months With Chlorambucil Alone1 Probability of Progression-free Survival

1.0

ARZERRA + chlorambucil (n=221) Chlorambucil (n=226)

0.9 0.8

(HR 0.57 [95% CI: 0.45, 0.72] P<0.001)

0.7

22.4

0.6

13.1

0.4

• 67% incidence of IRs (all grades), including Grade ≥3, serious, or those that led to interruption or discontinuation; majority were Grade 1-2 and decreased after Cycle 1

Months

0.3 0.2 0.1 0.0 0

4

8

Number at risk ARZERRA plus 221 192 169 Chlorambucil 173 130 Chlorambucil 226

12

• 10% incidence of Grade ≥3 IRs; occurred most frequently during Cycle 1 — 6% on Day 1 — 3% on Day 8

Months

0.5

The Most Common ARs (≥10%) Were IRs and Neutropenia1

16

20

24

28

32

36

40

44

48

Time of Progression-free Survival (Months) 148

125

104

70

46

28

15

9

92

67

52

33

17

6

1

1

3

1

ARZERRA in combination with chlorambucil vs chlorambucil alone was studied in a randomized, open-label, parallel-arm, multicenter trial of 447 patients with previously untreated CLL for whom fludarabine-based therapy was considered inappropriate. The population for safety analysis comprised 444 patients.1 HR=hazard ratio; CI=confidence interval.

Important Safety Information for ARZERRA (cont’d) Progressive Multifocal Leukoencephalopathy Progressive multifocal leukoencephalopathy (PML) resulting in death has occurred with ARZERRA. Consider PML in any patient with new onset of or changes in pre-existing neurological signs or symptoms. If PML is suspected, discontinue ARZERRA and initiate evaluation for PML including neurology consultation.

Tumor Lysis Syndrome Tumor lysis syndrome (TLS), including the need for hospitalization, has occurred in patients treated with ARZERRA. Patients with high tumor burden and/or high circulating lymphocyte counts (>25 x 109/L) are at greater risk for developing TLS. Consider tumor lysis prophylaxis with anti-hyperuricemics and hydration beginning 12 to 24 hours prior to infusion of ARZERRA. For treatment of TLS, administer aggressive intravenous hydration and anti-hyperuricemic agents, correct electrolyte abnormalities, and monitor renal function.

Cytopenias Severe cytopenias, including neutropenia, thrombocytopenia, and anemia, can occur with ARZERRA. Pancytopenia, agranulocytosis, and fatal neutropenic sepsis have occurred in patients who received ARZERRA in combination with chlorambucil. Grade 3 or 4 late-onset neutropenia (onset at least 42 days after last treatment dose) and/or prolonged neutropenia (not resolved between 24 and 42 days after last treatment dose) were reported in patients who received ARZERRA. Monitor complete blood counts at regular intervals during and after conclusion of therapy, and increase the frequency of monitoring in patients who develop Grade 3 or 4 cytopenias.

52

— 56% on Day 1 — 23% on Day 8 • No patients in the chlorambucilalone arm experienced IRs • 3% of IRs led to discontinuation of ARZERRA • 27% incidence of neutropenia with ARZERRA plus chlorambucil vs 18% with chlorambucil alone

Immunizations The safety of immunization with live viral vaccines during or following administration of ARZERRA has not been studied. Do not administer live viral vaccines to patients who have recently received ARZERRA. The ability to generate an immune response to any vaccine following administration of ARZERRA has not been studied.

Most Common Adverse Reactions In the previously untreated CLL clinical trial, the most common adverse reactions (≥10%, all grades) were infusion reactions (67% for ARZERRA plus chlorambucil vs 0% for chlorambucil) and neutropenia (27% vs 18%).

In the single-arm refractory CLL clinical trial, the most common adverse reactions (≥10%, all grades) were neutropenia, pneumonia (23%), pyrexia (20%), cough (19%), diarrhea (18%), anemia (16%), fatigue (15%), dyspnea (14%), rash (14%), nausea (11%), bronchitis (11%), and upper respiratory tract infections (11%). The most common serious adverse reactions were infections (including pneumonia and sepsis), neutropenia, and pyrexia. Infections were the most common adverse reactions leading to drug discontinuation.

Laboratory Abnormalities In the previously untreated CLL clinical trial, post-baseline hematologic laboratory abnormalities (all grades) occurring with ≥5% incidence in patients receiving ARZERRA plus chlorambucil and also ≥2% more than patients receiving chlorambucil were leukopenia (67% for ARZERRA plus chlorambucil vs 28% for chlorambucil), neutropenia (66% vs 56%), and lymphopenia (52% vs 20%).

Reference: 1. ARZERRA (ofatumumab) [package insert].

Research Triangle Park, NC: GSK; 2014.

Please see Brief Summary of Prescribing Information, including Boxed Warning, for ARZERRA on the following pages.

ARZERRA J-Code: J9302 To learn more, please visit www.ARZERRAhcp.com.

www.GSKSource.com ©2014 GSK group of companies.

All rights reserved. Printed in USA. AZA522R0 October 2014

The ASCO Post | DECEMBER 1, 2014

PAGE 8

Chemotherapy Foundation Symposium HER2 Therapy continued from page 5

4. U.S. National Institutes of Health: A study of pertuzumab in addition to chemotherapy and Herceptin (trastuzumab) as adjuvant therapy in patients with HER2positive primary breast cancer. Available at ClinicalTrials.gov/show/NCT01358877.

Accessed November 17, 2014.

5. Piccart-Gebhart MJ, Holmes MP, Baselga J, et al: First results from the phase III ALTTO trial (BIG 2-06; NCCTG [Alliance] N063D) comparing one year of anti-HER2 therapy with lapatinib alone, trastuzumab alone, their sequence, or their combination in the adjuvant treatment of HER2-positive early breast cancer. 2014 ASCO Annual Meeting.

Abstract LBA4. Presented June 1, 2014.

BRIEF SUMMARY ARZERRA® (ofatumumab) Injection, for intravenous infusion The following is a brief summary only; see full prescribing information, including Boxed Warning, for complete product information.

WARNING: HEPATITIS B VIRUS REACTIVATION AND PROGRESSIVE MULTIFOCAL LEUKOENCEPHALOPATHY • Hepatitis B Virus (HBV) reactivation can occur in patients receiving CD20-directed cytolytic antibodies, including ARZERRA®, in some cases resulting in fulminant hepatitis, hepatic failure, and death [see Warnings and Precautions (5.2)].

• Progressive Multifocal Leukoencephalopathy (PML) resulting in death can occur in patients receiving CD20-directed cytolytic antibodies, including ARZERRA [see Warnings and Precautions (5.4)].

1 INDICATIONS AND USAGE 1.1 Previously Untreated Chronic Lymphocytic Leukemia ARZERRA (ofatumumab) is indicated, in combination with chlorambucil, for the treatment of previously untreated patients with chronic lymphocytic leukemia (CLL) for whom fludarabine-based therapy is considered inappropriate [see Clinical Studies (14.1) of full prescribing information]. 1.2 Refractory CLL ARZERRA is indicated for the treatment of patients with CLL refractory to fludarabine and alemtuzumab [see Clinical Studies (14.2) of full prescribing information].

4 CONTRAINDICATIONS None.

5 WARNINGS AND PRECAUTIONS 5.1 Infusion Reactions ARZERRA can cause serious, including fatal, infusion reactions manifesting as bronchospasm, dyspnea, laryngeal edema, pulmonary edema, flushing, hypertension, hypotension, syncope, cardiac events (e.g., myocardial ischemia/infarction, acute coronary syndrome, arrhythmia, bradycardia), back pain, abdominal pain, pyrexia, rash, urticaria, angioedema, cytokine release syndrome, and anaphylactoid/anaphylactic reactions. Infusion reactions occur more frequently with the first 2 infusions.

These reactions may result in temporary interruption or withdrawal of treatment [see Adverse Reactions (6.1)]. Premedicate with acetaminophen, an antihistamine, and a corticosteroid [see Dosage and Administration (2.1, 2.4) of full prescribing information]. Infusion reactions may occur despite premedication. Interrupt infusion with ARZERRA for infusion reactions of any severity. Institute medical management for severe infusion reactions including angina or other signs and symptoms of myocardial ischemia [see Dosage and Administration (2.3) of full prescribing information]. If an anaphylactic reaction occurs, immediately and permanently discontinue ARZERRA and initiate appropriate medical treatment. 5.2 Hepatitis B Virus Reactivation Hepatitis B virus (HBV) reactivation, in some cases resulting in fulminant hepatitis, hepatic failure, and death, has occurred in patients treated with ARZERRA. Cases have been reported in patients who are hepatitis B surface antigen (HBsAg) positive and also in patients who are HBsAg negative but are hepatitis B core antibody (anti-HBc) positive.

Reactivation also has occurred in patients who appear to have resolved hepatitis B infection (i.e., HBsAg negative, anti-HBc positive, and hepatitis B surface antibody [anti-HBs] positive). HBV reactivation is defined as an abrupt increase in HBV replication manifesting as a rapid increase in serum HBV DNA level or detection of HBsAg in a person who was previously HBsAg negative and anti-HBc positive. Reactivation of HBV replication is often followed by hepatitis, i.e., increase in transaminase levels and, in severe cases, increase in bilirubin levels, liver failure, and death. Screen all patients for HBV infection by measuring HBsAg and anti-HBc before initiating treatment with ARZERRA. For patients who show evidence of hepatitis B infection (HBsAg positive [regardless of antibody status] or HBsAg negative but anti-HBc positive), consult physicians with expertise in managing hepatitis B regarding monitoring and consideration for HBV antiviral therapy.

Monitor patients with evidence of current or prior HBV infection for clinical and laboratory signs of hepatitis or HBV reactivation during and for several months following treatment with ARZERRA. HBV reactivation has been reported for at least 12 months following completion of therapy. In patients who develop reactivation of HBV while receiving ARZERRA, immediately

6. U.S. National Institutes of Health: Study evaluating the effects of neratinib after adjuvant trastuzumab in women with early stage breast cancer (ExteNET). Available at ClinicalTrials.gov/show/ NCT00878709.

Accessed November 17, 2014.

7. U.S. National Institutes of Health: A study of trastuzumab emtansine versus trastuzumab as adjuvant therapy in pa-

tients with HER2-positive breast cancer who have residual tumor in the breast or axillary lymph nodes following preoperative therapy (KATHERINE). Available at ClinicalTrials.gov/show/ NCT01772472.

Accessed November 17, 2014.

8. U.S. National Institutes of Health: A study of Kadcyla (trastuzumab emtansine) plus Perjeta (pertuzumab) following an-

discontinue ARZERRA and any concomitant chemotherapy, and institute appropriate treatment. Resumption of ARZERRA in patients whose HBV reactivation resolves should be discussed with physicians with expertise in managing hepatitis B. Insufficient data exist regarding the safety of resuming ARZERRA in patients who develop HBV reactivation. 5.3 Hepatitis B Virus Infection Fatal infection due to hepatitis B in patients who have not been previously infected has been observed with ARZERRA. Monitor patients for clinical and laboratory signs of hepatitis. 5.4 Progressive Multifocal Leukoencephalopathy Progressive multifocal leukoencephalopathy (PML) resulting in death has occurred with ARZERRA. Consider PML in any patient with new onset of or changes in pre-existing neurological signs or symptoms.

If PML is suspected, discontinue ARZERRA and initiate evaluation for PML including neurology consultation. 5.5 Tumor Lysis Syndrome Tumor lysis syndrome (TLS), including the need for hospitalization, has occurred in patients treated with ARZERRA. Patients with high tumor burden and/or high circulating lymphocyte counts (>25 x 109/L) are at greater risk for developing TLS. Consider tumor lysis prophylaxis with anti-hyperuricemics and hydration beginning 12 to 24 hours prior to infusion of ARZERRA. For treatment of TLS, administer aggressive intravenous hydration and anti-hyperuricemic agents, correct electrolyte abnormalities, and monitor renal function.

5.6 Cytopenias Severe cytopenias, including neutropenia, thrombocytopenia, and anemia, can occur with ARZERRA. Pancytopenia, agranulocytosis, and fatal neutropenic sepsis have occurred in patients who received ARZERRA in combination with chlorambucil. Grade 3 or 4 late-onset neutropenia (onset at least 42 days after last treatment dose) and/or prolonged neutropenia (not resolved between 24 and 42 days after last treatment dose) were reported in patients who received ARZERRA [see Adverse Reactions (6.1)]. Monitor complete blood counts at regular intervals during and after conclusion of therapy, and increase the frequency of monitoring in patients who develop Grade 3 or 4 cytopenias. 5.7 Immunizations The safety of immunization with live viral vaccines during or following administration of ARZERRA has not been studied. Do not administer live viral vaccines to patients who have recently received ARZERRA. The ability to generate an immune response to any vaccine following administration of ARZERRA has not been studied.

6 ADVERSE REACTIONS The following serious adverse reactions are discussed in greater detail in other sections of the labeling: • Infusion Reactions [see Warnings and Precautions (5.1)] • Hepatitis B Virus Reactivation [see Warnings and Precautions (5.2)] • Hepatitis B Virus Infection [see Warnings and Precautions (5.3)] • Progressive Multifocal Leukoencephalopathy [see Warnings and Precautions (5.4)] • Tumor Lysis Syndrome [see Warnings and Precautions (5.5)] • Cytopenias [see Warnings and Precautions (5.6)] Previously Untreated CLL: The most common adverse reactions (≥10%) were infusion reactions and neutropenia (Table 1). Refractory CLL: The most common adverse reactions (≥10%) were neutropenia, pneumonia, pyrexia, cough, diarrhea, anemia, fatigue, dyspnea, rash, nausea, bronchitis, and upper respiratory tract infections (Table 3). The most common serious adverse reactions were infections (including pneumonia and sepsis), neutropenia, and pyrexia. Infections were the most common adverse reactions leading to drug discontinuation. 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared with rates in the clinical trials of another drug and may not reflect the rates observed in practice. Previously Untreated CLL: The safety of ARZERRA was evaluated in an open-label, parallel-arm, randomized trial (Study 1) in 444 patients with previously untreated CLL. Patients were randomized to receive either ARZERRA as an intravenous infusion every 28 days in combination with chlorambucil (n = 217) or chlorambucil as a single agent (n = 227). In both arms, patients received chlorambucil 10 mg/m2 orally on Days 1 to 7 every 28 days. The infusion schedule for ARZERRA was 300 mg administered on Cycle 1 Day 1, 1,000 mg administered on Cycle 1 Day 8, and 1,000 mg administered on Day 1 of subsequent 28-day cycles. The median number of cycles of ARZERRA completed was 6. The data described in Table 1 include relevant adverse reactions occurring up to 60 days after the last dose of study medication; Table 2 includes relevant hematologic laboratory abnormalities.

(cont’d)

ASCOPost.com | DECEMBER 1, 2014

PAGE 9

Chemotherapy Foundation Symposium thracyclines in comparison with Herceptin (trastuzumab) plus Perjeta and a taxane following anthracyclines as adjuvant therapy in patients with operable HER2-positive primary breast cancer. Available at ClinicalTrials.gov/show/ NCT01966471. Accessed November 17, 2014.

9. Blackwell K: New agents for advanced HER2-positive breast cancer. Chemotherapy

Foundation Symposium. Presented November 6, 2014.

10. Gelmon KA, Boyle F, Kaufman B, et al: Open-label phase III randomized controlled trial comparing taxane-based chemotherapy with lapatinib or trastuzumab as firstline therapy for women with HER2-positive metastatic breast cancer: Interim analysis of NCIC CTG MA.31/GSK EGF 108919. 2012

Table 1. Adverse Reactions With ≥5% Incidence in Patients Receiving ARZERRA Plus Chlorambucil and Also ≥2% More Than Patients Receiving Chlorambucil ARZERRA Plus Chlorambucil (N = 217)

Chlorambucil (N = 227)

All Grades %

Grade ≥3 %

All Grades %

Grade ≥3 %

Infusion reactionsa

67

10

0

0

Neutropenia

27

26

18

14

Asthenia

8

<1

5

0

Headache

7

<1

3

0

6

3

2

<1

6

0

4

<1

Lower respiratory tract infection

5

1

3

<1

Arthralgia

5

<1

3

Adverse Reactions

Leukopenia Herpes simplex

b

Upper abdominal pain

5

0

3

ASCO Annual Meeting. Abstract LBA671.

11. Verma S, Miles D, Gianni L, et al: Trastuzumab emtansine for HER2-positive advanced breast cancer. N Engl J Med 367:1783-1791, 2012.

12. Krop IE, Kim SB, González-Martin A, et al: Trastuzumab emtansine versus treatment of physician’s choice for pretreated HER2-positive advanced breast cancer

and 55% received all 12 infusions. The median age was 63 years (range: 41 to 86 years), 72% were male, and 97% were white.

Table 3. Incidence of All Adverse Reactions Occurring in ≥5% of Patients and in the Fludarabine- and Alemtuzumab-refractory Subset

Total Population (N = 154) Adverse Reaction Pneumoniaa

All Grades %

Grade ≥3 %

All Grades %

Grade ≥3 %

23

14

25

15

Pyrexia

20

3

25

5

Cough

19

0

19

0

Diarrhea

18

0

19

0

16

5

17

8

Fatigue

15

0

15

0

0

Dyspnea

14

2

19

5

0

Rashb

14

<1

17

2

Bronchitis

11

<1

19

2

Nausea

11

0

12

0

Upper respiratory tract infection

11

0

3

0

Edema peripheral

9

<1

8

2

Includes events which occurred on the day of an infusion or within 24 hours of the end of an infusion and resulted in an interruption or discontinuation of treatment. Infusion reactions may include, but are not limited to, chills, dyspnea, flushing, hypotension, nausea, pain, pruritus, pyrexia, rash, and urticaria. b Includes oral herpes, herpes, herpes virus infection, genital herpes, and herpes simplex.

Table 2. Post-baseline Hematologic Laboratory Abnormalities Occurring With ≥5% Incidence in Patients Receiving ARZERRA Plus Chlorambucil and Also ≥2% More Than Patients Receiving Chlorambucil

Leukopenia

Fludarabine- and Alemtuzumabrefractory (N = 59)

Anemia

a

ARZERRA Plus Chlorambucil (N = 217)

(TH3RESA): A randomised, open-label, phase 3 trial. Lancet Oncol 15:689-699, 2014.

13. Blackwell KL, Burstein HJ, Storniolo AM, et al: Overall survival benefit with lapatinib in combination with trastuzumab for human epidermal growth factor receptor 2-positive metastatic breast cancer: Final results from the EGF104900 study. J Clin Oncol 30:2585-2592, 2012.

Chlorambucil (N = 227)

All Grades %

Grade ≥3 %

All Grades %

Grade ≥3 %

67

23

28

4

Neutropenia

66

29

56

24

Lymphopenia

52

29

20

7

Infusion Reactions: Overall, 67% of patients who received ARZERRA in combination with chlorambucil experienced one or more symptoms of infusion reactions (10% were Grade 3 or greater; none were fatal). Infusion reactions that were either Grade 3 or greater, serious, or led to treatment interruption or discontinuation occurred most frequently during Cycle 1 (56% on Day 1 [6% were Grade 3 or greater] and 23% on Day 8 [3% were Grade 3 or greater]) and decreased with subsequent infusions. Infusion reactions led to discontinuation of treatment in 3% of patients. Serious adverse events of infusion reactions occurred in 2% of patients. Neutropenia: Overall, 3% of patients had neutropenia as a serious adverse event, reported up to 60 days after the last dose. One patient died with neutropenic sepsis and agranulocytosis. Prolonged neutropenia occurred in 6% of patients receiving ARZERRA in combination with chlorambucil compared with 4% of patients receiving chlorambucil. Late-onset neutropenia occurred in 6% of patients receiving ARZERRA in combination with chlorambucil compared with 1% of patients receiving chlorambucil alone. Refractory CLL: The safety of monotherapy with ARZERRA was evaluated in 181 patients with relapsed or refractory CLL in 2 open-label, non-randomized, single-arm studies. In these studies, ARZERRA was administered at 2,000 mg beginning with the second dose for 11 doses (Study 2 [n = 154]) or 3 doses (Study 3 [n = 27]). The data described in Table 3 and other sections below are derived from 154 patients in Study 2. All patients received 2,000 mg weekly from the second dose onward. Ninety percent of patients received at least 8 infusions of ARZERRA

Back pain

8

1

12

2

Chills

8

0

10

0

Nasopharyngitis

8

0

8

0

Sepsisc

8

8

10

10

Urticaria

8

0

5

0

Insomnia

7

0

10

0

Headache

6

0

7

0

Herpes zoster

6

1

7

2

Hyperhidrosis

5

0

5

0

Hypertension

5

0

8

0

Hypotension

5

0

3

0

Muscle spasms

5

0

3

0

Sinusitis

5

2

3

2

Tachycardia

5

<1

7

2

Includes pneumonia, lung infection, lobar pneumonia, and bronchopneumonia. b Includes rash, rash macular, and rash vesicular. c Includes sepsis, neutropenic sepsis, bacteremia, and septic shock. a

Infusion Reactions: Infusion reactions occurred in 44% of patients on the day of the first infusion (300 mg), 29% on the day of the second infusion (2,000 mg), and less frequently during subsequent infusions. Infections: A total of 108 patients (70%) experienced bacterial, viral, or fungal infections. A total of 45 patients (29%) experienced Grade 3 or greater infections, of which 19 (12%) were fatal. The proportion of fatal infections in the fludarabine- and alemtuzumab-refractory group was 17%. Neutropenia: Of 108 patients with normal neutrophil counts at baseline, 45 (42%) developed Grade 3 or greater neutropenia. Nineteen (18%) developed Grade 4 neutropenia. Some patients experienced new onset Grade 4 neutropenia >2 weeks in duration.

6.2 Immunogenicity There is a potential for immunogenicity with therapeutic proteins such as ofatumumab. Serum samples from more than 300 patients with CLL were tested during and after treatment for antibodies to ARZERRA. (cont’d)

The ASCO Post | DECEMBER 1, 2014

PAGE 10

FDA Update Gynecologic Oncology

FDA Approves Bevacizumab Plus Chemotherapy for Platinum-Resistant, Recurrent Ovarian Cancer

T

he U.S. Food and Drug Administration (FDA) approved bevacizumab (Avastin) in combination with paclitaxel, pegylated liposomal doxorubicin, or topotecan for the treatment of patients with plati-

num-resistant, recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer.

The approval is based on the results of an international, randomized, twoarm trial (AURELIA) with the primary

There was no formation of anti-ofatumumab antibodies in patients with CLL after treatment with ofatumumab. Immunogenicity assay results are highly dependent on several factors including assay sensitivity and specificity, assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of incidence of antibodies to ARZERRA with the incidence of antibodies to other products may be misleading. 6.3 Postmarketing Experience The following adverse reactions have been identified during post-approval use of ARZERRA. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Infusion-related Cardiac Events: Cardiac arrest. Mucocutaneous Reactions: Stevens-Johnson syndrome, porphyria cutanea tarda.

7 DRUG INTERACTIONS Coadministration of ARZERRA with chlorambucil did not result in clinically relevant effects on the pharmacokinetics of chlorambucil or its active metabolite, phenylacetic acid mustard.

8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Pregnancy Category C: There are no adequate or wellcontrolled studies of ofatumumab in pregnant women. A reproductive study in pregnant cynomolgus monkeys that received ofatumumab at doses up to 3.5 times the maximum recommended human dose (2,000 mg) of ofatumumab did not demonstrate maternal toxicity or teratogenicity.

Ofatumumab crossed the placental barrier, and fetuses exhibited depletion of peripheral B cells and decreased spleen and placental weights. ARZERRA should be used during pregnancy only if the potential benefit to the mother justifies the potential risk to the fetus. There are no human or animal data on the potential short- and long-term effects of perinatal B-cell depletion in offspring following in utero exposure to ofatumumab. Ofatumumab does not bind normal human tissues other than B lymphocytes. It is not known if binding occurs to unique embryonic or fetal tissue targets. In addition, the kinetics of B-lymphocyte recovery are unknown in offspring with B-cell depletion [see Nonclinical Toxicology (13.3)]. 8.3 Nursing Mothers It is not known whether ofatumumab is secreted in human milk; however, human IgG is secreted in human milk. Published data suggest that neonatal and infant consumption of breast milk does not result in substantial absorption of these maternal antibodies into circulation. Because the effects of local gastrointestinal and limited systemic exposure to ofatumumab are unknown, caution should be exercised when ARZERRA is administered to a nursing woman. 8.4 Pediatric Use Safety and effectiveness of ARZERRA have not been established in children. 8.5 Geriatric Use In Study 1, 68% of patients (148/217) receiving ARZERRA plus chlorambucil were 65 years and older.

Patients age 65 years and older experienced a higher incidence of the following Grade 3 or greater adverse reactions compared with patients younger than 65 years of age: neutropenia (30% versus 17%) and pneumonia (5% versus 1%) [see Adverse Reactions (6.1)]. In patients 65 years and older, 29% experienced serious adverse events compared with 13% of patients younger than 65 years. No clinically meaningful differences in the effectiveness of ARZERRA plus chlorambucil were observed between older and younger patients [see Clinical Studies (14.1) of full prescribing information]. In refractory CLL, clinical studies of ARZERRA did not include sufficient numbers of subjects aged 65 years and older to determine whether they respond differently from younger subjects [see Clinical Pharmacology (12.3) of full prescribing information]. 8.6 Renal Impairment No formal studies of ARZERRA in patients with renal impairment have been conducted [see Clinical Pharmacology (12.3) of full prescribing information].

8.7 Hepatic Impairment No formal studies of ARZERRA in patients with hepatic impairment have been conducted.

10 OVERDOSAGE No data are available regarding overdosage with ARZERRA. 13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility No carcinogenicity or mutagenicity studies of ofatumumab have been conducted.

In a repeat-dose toxicity study, no tumorigenic or unexpected mitogenic responses were noted in cynomolgus monkeys treated for 7 months with up to 3.5 times the maximum human dose (2,000 mg) of ofatumumab. Effects on male and female fertility have not been evaluated in animal studies.

comparison of investigator-assessed progression-free survival. This trial compared bevacizumab plus chemotherapy vs chemotherapy alone. The trial enrolled 361 patients: 179 patients

13.3 Reproductive and Developmental Toxicology Pregnant cynomolgus monkeys dosed with 0.7 or 3.5 times the maximum human dose (2,000 mg) of ofatumumab weekly during the period of organogenesis (gestation days 20 to 50) had no maternal toxicity or teratogenicity. Both dose levels of ofatumumab depleted circulating B cells in the dams, with signs of initial B cell recovery 50 days after the final dose. Following Caesarean section at gestational day 100, fetuses from ofatumumab-treated dams exhibited decreases in mean peripheral B-cell counts (decreased to approximately 10% of control values), splenic B-cell counts (decreased to approximately 15% to 20% of control values), and spleen weights (decreased by 15% for the low-dose and by 30% for the high-dose group, compared with control values). Fetuses from treated dams exhibiting anti-ofatumumab antibody responses had higher B cell counts and higher spleen weights compared with the fetuses from other treated dams, indicating partial recovery in those animals developing anti-ofatumumab antibodies. When compared with control animals, fetuses from treated dams in both dose groups had a 10% decrease in mean placental weights. A 15% decrease in mean thymus weight compared with the controls was also observed in fetuses from dams treated with 3.5 times the human dose of ofatumumab. The biological significance of decreased placental and thymic weights is unknown. The kinetics of B-lymphocyte recovery and the potential long-term effects of perinatal B-cell depletion in offspring from ofatumumab-treated dams have not been studied in animals.

17 PATIENT COUNSELING INFORMATION Advise patients to contact a healthcare professional for any of the following: • Signs and symptoms of infusion reactions including fever, chills, rash, or breathing problems within 24 hours of infusion [see Warnings and Precautions (5.1), Adverse Reactions (6.1)] • Symptoms of hepatitis including worsening fatigue or yellow discoloration of skin or eyes [see Warnings and Precautions (5.2, 5.3)] • New neurological symptoms such as confusion, dizziness or loss of balance, difficulty talking or walking, or vision problems [see Warnings and Precautions (5.4)] • Bleeding, easy bruising, petechiae, pallor, worsening weakness, or fatigue [see Warnings and Precautions (5.6)] • Signs of infections including fever and cough [see Warnings and Precautions (5.6), Adverse Reactions (6.1)] • Pregnancy or nursing [see Use in Specific Populations (8.1, 8.3)] Advise patients of the need for: • Monitoring and possible need for treatment if they have a history of hepatitis B infection (based on the blood test) [see Warnings and Precautions (5.2)] • Periodic monitoring for blood counts [see Warnings and Precautions (5.6)] • Avoiding vaccination with live viral vaccines [see Warnings and Precautions (5.7)] ARZERRA is a registered trademark of the GSK group of companies.

Manufactured by: GLAXO GROUP LIMITED Brentford, Middlesex, TW8 9GS, United Kingdom U.S. License 1809 Distributed by:

GlaxoSmithKline Research Triangle Park, NC 27709 ©2014, the GSK group of companies. All rights reserved.

Revised: 04/2014 ARZ:8BRS ©2014 GSK group of companies.

All rights reserved. Printed in USA. AZA522R0 October 2014

were assigned to receive bevacizumab plus chemotherapy, and 182 patients were assigned to receive chemotherapy alone. The chemotherapy included paclitaxel, pegylated liposomal doxorubicin, or topotecan.

Treatment continued until disease progression, unacceptable toxicity, and/ or consent withdrawal. All enrolled patients had received no more than two prior chemotherapy regimens, had an ECOG performance status of 0 to 2, and had recurred within less than 6 months from the most recent platinum-based therapy.

The progression-free survival assessment demonstrated a statistically significant improvement in patients who received bevacizumab plus chemotherapy compared to those who received chemotherapy alone (hazard ratio [HR] = 0.38, 95% confidence interval [CI] = 0.30– 0.49, P < .0001, stratified log-rank test).

The median progression-free survival of patients who received bevacizumab plus chemotherapy was 6.8 months (95% CI = 5.6–7.8) compared to 3.4 months (95% CI = 2.1–3.8) for those receiving chemotherapy alone. There was no significant difference in overall survival (16.6 vs 13.3 months; HR = 0.89, 95% CI = 0.69–1.14).

Exploratory Analyses The trial was stratified by chemotherapy regimen. Exploratory analyses were performed by comparing the addition of bevacizumab to each chemotherapy regimen.

The addition of bevacizumab to paclitaxel provided the largest improvement, resulting in a 5.7-month improvement in median progression-free survival (9.6 vs 3.9 months; HR = 0.47, 95% CI = 0.31–0.72), an improvement in the overall response rate of 23% (53% vs 30%), and a 9.2-month improvement in median overall survival (22.4 vs 13.2 months; HR = 0.64, 95% CI = 0.41–1.01).

Ninety-seven per cent of patients in the paclitaxel regimen had received paclitaxel with previous chemotherapy regimens. These exploratory analyses suggest that patients who have received prior treatment with paclitaxel may benefit from bevacizumab plus weekly paclitaxel. n

ASCOPost.com | DECEMBER 1, 2014

PAGE 11

Chicago Multidisciplinary Symposium in Thoracic Oncology Thoracic Oncology

Top 5 Breakthroughs in the Treatment of Advanced Lung Cancer

By Charlotte Bath

A

countdown of the top 5 breakthrough therapies in the treatment of advanced lung cancer was presented

by D. Ross Camidge, MD, PhD, at the 2014 Chicago Multidisciplinary Symposium in Thoracic Oncology.1 Dr. Camidge is Director, Thoracic Oncology Clinical and Clinical Research Programs, and Associate Director for Clinical Research, University of Colorado Comprehensive Cancer Center, Aurora. He singled out the following molecular therapies:

#5. Crizotinib Dr. Camidge chose crizotinib (Xalkori) as a breakthrough therapy “because of how it has exemplified the philosophy of one size does not fit all,” he said.

“Before the phase I study, preclinical work had already clarified that crizotinib had particular activity only in some cell lines, which could be characterized by their evidence of either MET or ALK activation,” Dr. Camidge stated.

Clinical trial results showing overall response rates exceeding 60% among patients with ALK-positive non–small cell lung cancer (NSCLC) “led to the initial licensing of crizotinib and the defining of ALK-positive lung cancer as a clinically relevant subtype of disease,” he added.

This was followed by publication a few months ago of the ROS1-positive lung cancer cohort data “showing equally impressive efficacy,” Dr. Camidge noted. “And at this year’s ASCO Annual Meeting, we saw data for the first time on crizotinib’s activity in the METamplified lung cancer cohorts showing a 67% response rate and a median duration of response of over a year in the highest amplified cohort.”

#4. Second-Generation ALK Inhibitors The second-generation ALK inhibitors were chosen “not because of their activity postcrizotinib, but because of their progress in accurately defining how we capture data on benefit in central nervous system (CNS) disease,” Dr. Camidge explained.

The benefit of crizotinib in the central nervous system is limited, Dr. Camidge noted. “Patients with ALKpositive disease who receive or never receive crizotinib have very similar lifetime incidences of brain metastases; nearly 50% of patients on crizotinib

have a first progression within the brain, with it being the sole site of progression in most cases,” he said.

Second-generation ALK inhibitors shown to be clinically active following an initial tyrosine kinase inhibitor include ceritinib (Zykadia), which has been approved by the U.S. Food and Drug Administration (FDA) for use in patients with metastatic NSCLC, and alectinib and AP26113, which have both received Breakthrough Therapy designations from the FDA for use in patients with metastatic NSCLC who have had disease progression on crizotinib. Magnetic resonance imaging (MRI) has shown responses of CNS lesions occurring with secondgeneration ALK inhibitors, but Dr. Camidge cautioned that hard data are still lacking on the proportion of patients with CNS responses to these

drugs “could not achieve tolerable enough levels to inhibit T790M due to their lower IC50 [half maximal inhibitory concentration] for the wild-type form of the EGFR. The third-generation drugs were not screened against the wild-type form of the enzyme, but rather, against the mutant forms present in the cancer,” he said.

“The two most notable third-generation drugs, AZD9291 and CO-1686 (now called rociletinib), both have significant activity against the standard activating EGFR mutations and T790M while relatively sparing the wild-type EGFR.” Both rociletinib and AZD9291 “are now showing robust response rates in known T790M-positive disease,” Dr. Camidge added, with skin and gut toxicity appearing to be significantly less than with earlier generation drugs.

We might need to look at our back catalogues for treatments we could retrospectively explore for effective predictive biomarkers with our more modern approaches.

—D. Ross Camidge, MD, PhD

newer agents and the duration of the responses.

“The good news is that the brain is now achieving appropriate recognition as a relevant battleground, and robust CNS data are now being generated prospectively,” Dr. Camidge said. The ongoing ALEX study is “comparing alectinib head-to-head with crizotinib in the [tyrosine kinase inhibitor]–naive setting, with time to CNS progression as a prominent secondary endpoint in the study,” he reported.

#3. Third-Generation EGFR Inhibitors Dr. Camidge chose the third-generation EGFR inhibitors “because of what they are teaching us about understanding acquired resistance in order to effectively treat it,” he said.

“From multiple elegant rebiopsy series we know that the T790M exon 20 mutation drives acquired resistance in 50% to 60% of cases. But inhibiting T790M has been a problem,” according to Dr. Camidge. Second-generation

#2. PD-1/PD-L1 Antagonists Dr. Camidge singled out the inhibitors of programmed death protein 1 (PD-1) and its ligand (PD-L1) with the open question of whether they will be a panacea or whether they have the potential to become a truly personalized medicine.

“From the earliest nivolumab data it was clear that responses could be very long lasting in lung cancer, but benefit doesn’t occur in everyone,” Dr. Camidge said. Objective response rates have been relatively modest and progression-free survival short. Low median progression-free survival has also been seen with pembrolizumab (Keytruda) in the pretreated population, although treatment-naive patients may do well. The rate of response to MPDL3280A has been higher among those with a smoking history and among those with specific mutations. “Who exactly is deriving benefit from these agents and why remain a work in progress,” Dr. Camidge stated.

“Perhaps the biggest challenge to

the idea of PD-1/PD-L1 inhibitors as a panacea is the recognition that the PD-1/PD-L1 axis is only one of multiple immune stimulatory and inhibitory pathways that will be exploited as drug targets in the next few years,” he added.

The excitement about PD-1 and PD-L1 inhibitors needs to be tempered “with the reality that they don’t work in everyone, and many new immune modulatory agents are on the horizon, suggesting the one-size-does-not-fit-all philosophy will also extend into the realm of immunotherapies.”

#1. Three Possible Future Breakthroughs Dr. Camidge’s number 1 spot was shared by three “mini-fantasies” about what future breakthroughs might be, based on the concepts of mining the past, intraoncogene heterogeneity, and affordable incremental benefit.

Explaining his interest in mining the past, Dr. Camidge said, “We have walked away from a large number of targeted agents because they didn’t work when given to otherwise unselected lung cancer populations. However, in almost all of these cases, no attempt at robustly exploring predictive biomarkers was conducted,” he noted.

“Consequently, the classes of drugs may not truly be ineffective, and there may have been evidence of hypersensitive subpopulations ripe for re-exploration,” he continued. “We might need to look at our back catalogues for treatments we could retrospectively explore for effective predictive biomarkers with our more modern approaches.”

As an example, he cited the class of drugs known as death receptor agonists. These drugs “which directly stimulate apoptosis and worked exceptionally well in various preclinical models, were all dropped when a series of randomized phase II studies adding these agents to first-line chemotherapy failed to show an advantage.” But the nonprogressors in the experimental arms approached 15% of the population in several of the studies, he said.

“Unfortunately little or no tissue was collected in these studies so no predictive biomarkers could really be explored at the time.”

Dr. Camidge used KRAS as an example of intraoncogene heterogeneity. The most common mutation among adenocarcinomas of the lung, KRAS has been continued on page 12

The ASCO Post | DECEMBER 1, 2014

PAGE 12

Health-Care Policy

ASCO Calls for Major Medicaid Reform to Improve Quality Cancer Care for Low-Income Americans

By Jo Cavallo

A

SCO issued its new Policy Statement on Medicaid Reform on November 17, which calls for major

Blase N. Polite, MD, MPP

changes to the program to ensure access to high-quality cancer care for all low-income individuals. The Society’s

Top 5 Breakthroughs continued from page 11

shown in preclinical and clinical studies to have tremendous heterogeneity. The trial design for the FAK inhibitor VS6063 in KRAS-mutant lung cancer is “at least starting to address this heterogeneity by exploring its benefit in four KRAS-mutant cohorts that have also been characterized with regard to their INK4a and p53 status to see if these contexts alter the response to the drug,

recommendations call for Medicaid expansion in all 50 states to close coverage gaps, improve cancer screening and prevention services, and end coverage restrictions that prevent Medicaid enrollees from receiving high-quality cancer care, among others. The Policy Statement on Medicaid Reform is published in the Journal of Clinical Oncology.1 “People with cancer, for whom the costs of evaluation and treatment can be extraordinarily high, are particularly in need of insurance coverage to allow for timely diagnosis and high-quality treatment,” wrote statement authors Blase N. Polite, MD, MPP, of the University of Chicago, and colleagues. Currently,

67.9 million Americans are enrolled in Medicaid. Of them, an estimated 2.1 million beneficiaries, including those

added under the Affordable Care Act, have had a cancer diagnosis, and many more depend on Medicaid for routine

based on relevant preclinical data,” Dr. Camidge said.

To explain affordable incremental benefit, Dr. Camidge cited the REVEL study, which looked at the addition of ramucirumab (Cyramza), an antibody against VEGFR2, to standard secondline docetaxel. “The addition of ramucirumab increased the response rate from 14% to 30% and the disease control rate from 53% to 64%, increased the progression free survival from 3.0

to 4.5 months, and increased the overall survival from 9.1 to 10.5 months,” Dr. Camidge reported.

“So with an unequivocally positive phase III study, adding a little to all major endpoints, we might want to be using this drug. But only if it, and drugs like it, are affordable, as one recurring problem has been in pricing a breakthrough as if it’s a game-changer and not just a way of offering a little incremental benefit to everyone.” If not af-

fordable, “these minor breakthroughs will never be practical to use in the real world,” he said. n

ASCO Policy Statement on Medicaid Reform ■■ ASCO calls for Medicaid reform to close major gaps in coverage to ensure access to life-saving screening, treatment, and prevention services for lowincome Americans with cancer.

■■ ASCO’s policy recommendations include expanding Medicaid eligibility to all 50 states, parity for oral cancer drugs, adequate physician reimbursement, reform of the 340B Drug Pricing Program, full coverage for cancer screening and genetic testing, guaranteed coverage for clinical trials, adherence to quality metrics, and oncology medical home designations.

■■ Low-income patients with cancer are in particular need of insurance coverage to allow for timely diagnosis and high-quality treatment.

Disclosure: Dr. Camidge has received honoraria from Pfizer, Genentech/Roche, Clovis, Aria, and Eli Lilly.

Reference 1. Camidge DR: The top five most promising molecular therapies on the horizon. Chicago Multidisciplinary Symposium in Thoracic Oncology. Presented October 31, 2014.

Don’t Miss These Important Reports in This Issue of The ASCO Post Aline Charabaty, MD, on colorectal cancer screening see page 47

Maha Hussain, MD, FACP, FASCO, on metastatic castration-resistant prostate cancer see page 49

Neal F. Kassell, MD, on focused ultrasound see page 53

Jesus F. San-Miguel, MD, on panobinostat for relapsed/ refractory myeloma see page 65

Sagar Lonial, MD, on HDAC inhibitors in myeloma see page 66

Tracy Batchelor, MD, on treating brain cancer in 2014 see page 70

Camilla Zimmermann, MD, PhD, FRCPC, on earlier introduction of palliative care see page 78

Arif H. Kamal, MD, on survivorship care see page 90

H. Gilbert Welch, MD, MPH, on the hazards of overscreening see page 128

Visit The ASCO Post online at ASCOPost.com

ASCOPost.com | DECEMBER 1, 2014

PAGE 13

Health-Care Policy

cancer screenings and prevention services. Twenty-seven states and the District of Columbia have already expanded their Medicaid programs under the Affordable Care Act, 21 have not, and the remaining 2 states are in “open debate.”

In releasing its policy statement, ASCO noted that the November midterm elections are unlikely to significantly change the outlook for state expansion under the Affordable Care Act. But other opportunities exist for improving access to cancer-related care among Medicaid beneficiaries, and unexpanded states, according to the ASCO policy statement, “should come up with an alternative strategy that provides comprehensive

ASCO strongly believes the Society should, first, draw attention to the critical issues facing cancer patients under Medicaid and, second, make recommendations for strengthening this program to assure that our most vulnerable citizens receive needed health care.

—Peter Paul Yu, MD, FACP, FASCO

subsidized health coverage that ensures, among other benefits, access to highquality cancer care, measured by cancerspecific quality metrics, delivered by a cancer specialist.”

Critical Health-Care Disparities During a news conference announcing the policy statement, Peter Paul Yu, MD, FACP, FASCO, ASCO President and Director of Cancer Research at Palo Alto Medical Foundation, explained why ASCO has decided to issue recommendations for Medicaid reform.

“The evidence shows that uninsured patients are significantly more likely to be diagnosed with advanced cancer than are insured patients. Further, Medicaid’s low reimbursement rates are a disincentive for physician participation, making it increasingly difficult for patients to access care from specialists,” said Dr. Yu. “As oncologists, we believe it is our responsibility to advocate for policies that expand and improve the care of all people with cancer regardless of financial means. We also believe that no individual diagnosed with cancer should be

without insurance that guarantees access to high-quality cancer care delivered by a cancer specialist. Therefore, patients with cancer who have Medicaid should receive the same timely and high-quality cancer care as patients with private insurance. Lastly, Medicaid payments should be sufficient to ensure that Medicaid patients have access to quality cancer care.

“For these and other reasons, ASCO strongly believes that the Society should, first, draw attention to the critical issues facing cancer patients under Medicaid and, second, make concrete, constructive recommendations for strengthening this program to assure that our most vulnerable citizens receive needed health care. The ASCO Policy Statement on

Medicaid Reform is designed to achieve both of those objectives,” said Dr. Yu. The recommendations ASCO presented in its policy statement offer several ways Medicaid could be reformed to expand access to cancer care and remove barriers to key elements of quality cancer care for enrollees. They include: continued on page 14

The ASCO Post | DECEMBER 1, 2014

PAGE 14

Health-Care Policy Medicaid Reform continued from page 13

• Expanding insurance coverage for individuals below the federal poverty level in all 50 states • Ensuring oral parity for patients with Medicaid coverage and including oral and intravenous cancer therapies, as

well as supportive care medications, as exempt services for cost-sharing purposes • Extending clinical trial participation included in the Affordable Care Act to patients with Medicaid coverage, and allowing patients to cross state lines to participate in those trials

• Eliminating artificial barriers between current Medicaid beneficiaries and newly eligible ones, and applying Affordable Care Act final-rule mandates for cancer screening and diagnostic follow-up without copay for all Medicaid beneficiaries • Requiring coverage for genetic testing,

•

•

•

•

without deductibles or copays, in any patient deemed at high risk for an inheritable cancer-risk syndrome Improving the 340B Drug Pricing Program to incentivize care for uninsured and underinsured patients regardless of care setting Eliminating variation between Medicare and Medicaid physician payment rates for cancer diagnosis and treatment by raising Medicaid payment to Medicare rates Tying state flexibility in running Medicaid programs to the requirement to meet predefined cancer quality metrics Allowing oncology practices to be designated as medical homes, and developing expanded reimbursement for care coordination and patient education for oncology practices n

Disclosure: Coauthor Nefertiti C. duPont reported a consultant or advisory role with Genentech, honoraria from DySIS Medical, and research funding from Genentech.

Reference 1. Polite BN, Griggs JJ, Moy B, et al: J Clin Oncol. November 17, 2014 (early release online).

The ASCO Post Wants to Hear From You

We encourage readers to share their opinions and thoughts on issues of interest to the oncology community.

Write to The ASCO Post at editor@ASCOPost.com Harborside Press 37 Main Street Cold Spring Harbor, NY 11724 Phone: 631.692.0800 Fax: 631.692.0805 www.ASCOPost.com

ASCOPost.com | DECEMBER 1, 2014

PAGE 15

Quality Care Symposium Technology

CancerLinQ continued from page 1

try into one repository, that goal alone would not be enough justification for ASCO to take on such an ambitious and difficult project. “CancerLinQ is really a rapid-learning health system. The concept is to upload data from the point of care into CancerLinQ and allow the data to be aggregated and studied by and on behalf of the provider. This generates insights and, ultimately, new learning that yields services to the provider and patient in the form of reports and clinical decision support tools. This process helps to power quality improvement in real time,” said Dr. Yu. Moreover, CancerLinQ allows data exploration of real-world clinical issues and may offer new understanding of treatment variations. “Clinical trials data are very important and granular but often don’t represent patient populations in the real world. This process will accelerate our development of guidelines and other clinical decision support tools,” noted Dr. Yu.

Could Such a System Work?

Dr. Yu explained that to test the concept, ASCO built a prototype 2 years ago. “Frankly, we didn’t know if this system was actually doable. No one had approached this type of rapid-learning health system before. It was a challenge that came out of the Institute of Medi-

cine, and we took it up,” said Dr. Yu. He explained that while building the prototype, the team decided to limit its work to one disease site—breast cancer.

He continued, “We populated the prototype with more than 170,000 deidentified cases of breast cancer from the electronic health records of five different practices. This first step showed us that we could ingest data from multiple electronic sources. After that, we began to conduct preliminary analyses of the data, which showed us that not only could we collect data, we could make observations from it as well.”

FDA Testing Grounds The ASCO team next went to the U.S. Food and Drug Administration (FDA) and presented its work. “The FDA felt our work was intriguing since they really don’t have a lot of data on drugs they approve once they’re released into the real world. They asked us to tell them about the use of erythropoietin-stimulating agents after the Agency changed its policy on their indication,” said Dr. Yu. “We analyzed the use of [erythropoietin-stimulating agents] in 8,300 breast cancer cases, and we could see that there was a trend developing even before the FDA changed its labeling and guidance on their use. Use of [erythropoietinstimulating agents] declined markedly once the FDA’s labeling change went

public. We also looked at the hemoglobin level that doctors were targeting before and after the FDA’s labeling change on these drugs, and that, too, dropped considerably after the FDA’s new labeling change went public,” said Dr. Yu. “So using CancerLinQ analysis, we were indeed able to tell the FDA about [erythropoietin-stimulating agent] usage in the real world.”

The Next Step On the merit of this early success, the ASCO Board was encouraged enough to move to a production model. “The first step was an extensive requirementgathering process to find out exactly what information would be useful to clinicians. To that end, more than 1,000 ‘user stories’ were submitted by ASCO members, who told us what they wanted from CancerLinQ. We then distilled these data into 13 detailed user scenarios, from which we crafted a request for proposal that we issued to the technology industry, asking if they could build a platform with this information and how much it would cost,” said Dr. Yu. The ASCO team received 10 consortia responses involving 50 technology companies. “We also needed to talk to oncologists and see if they’d be willing to work with us. At this point, we have a memorandum of understanding signed by 15 vanguard practices across the country that will share their data in

CancerLinQ,” said Dr. Yu. The CancerLinQ team was advised by volunteers on several committees including data governance, technology, physician practice, patient advocate, and business development. “The concept is to collect the [electronic medical record] and practice management data from the 15 vanguard practices, which will comprise both structured fields and unstructured fields (such as physician notes). We can then analyze this wealth of clinical information,” said Dr. Yu.

Clinical Decision Support Dr. Yu stressed that one ultimate goal of CancerLinQ is to provide realtime clinical decision support. By having the capability to process specific patient characteristics and compare them to outcomes from comparable patients, CancerLinQ will allow the practitioner to offer a personalized diagnosis and treatment plan based on real-world evidence in addition to published clinical trial data. CancerLinQ can also offer prompts to improve quality, such as oncology drug-related interactions.

“Our pilot program shows that such a learning health system will work.

Based on our platform development work this year, we plan to debut a functioning CancerLinQ system in 2015,” concluded Dr. Yu. n

Disclosure: Dr. Yu is the President of ASCO for 2014–2015.

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The ASCO Post | DECEMBER 1, 2014

PAGE 16

Announcements

ASH Pairs Hematologists From Developing and Developed Nations for Global Training Program

T

he American Society of Hematology (ASH) recently announced the 20 hematologists and other medical professionals selected to participate in the 2014 ASH Visitor Training Program. This program provides talented hematologists, scientists, and laboratory staff from developing countries the opportunity to receive training on a specific area of hematology from an ASH member located anywhere in the world for up to 12 weeks. The goal of this program is to build hematology capacity in developing countries and ultimately improve the care of patients with blood diseases worldwide.

The ASH Visitor Training Program is offered to hematologists and scientists from developing countries at any level of their careers. The availability of program mentors from any institution and country around the world allows participants to select an expert in the specific area of hematology in which they are interested. Hematologists selected for the ASH Visitor Training Program are also paired with a member of the ASH International Members Committee, who is charged with helping participants prepare for and evaluate their training program experience.

“The exchange of knowledge and best practices among hematologists around the world is critical to continue to move the field of hematology forward,” said ASH President Linda J. Burns, MD, of the University of

• Renate Asare, BSc (Ghana) and mentor Alok Srivastava, MD (Christian Medical College, Vellore, India) • Adriana Bello, MD (Venezuela) and mentor Sergio Giralt, MD (Memo-

rial Sloan Kettering Cancer Center, New York) S:6.75” • Jorge Luis Contreras Saavedra, MD (Peru) and mentor Monica Thakar, MD (Children’s Hospital of

COMETRIQ® (cabozantinib) is indicated for the treatment of patients with progressive, metastatic medullary thyroid cancer (MTC)

Attack from multiple angles COMETRIQ® has been shown to inhibit the activity of MET; VEGFR-1, -2, and -3; RET; and other receptor tyrosine kinases, in vitro • These tyrosine kinases are involved in both normal cellular function and pathologic processes such as oncogenesis, metastasis, tumor angiogenesis, and maintenance of the tumor microenvironment MET=hepatocyte growth factor receptor; VEGFR=vascular endothelial cell growth factor receptor; RET=rearranged during transfection.

Important Safety Information WARNING: PERFORATIONS AND FISTULAS, and HEMORRHAGE

• Perforations and Fistulas: Gastrointestinal perforations occurred in 3% and fistula formation in 1% of COMETRIQ®treated patients. Discontinue COMETRIQ in patients with perforation or fistula.

• Hemorrhage: Severe, sometimes fatal, hemorrhage including hemoptysis and gastrointestinal hemorrhage occurred in 3% of COMETRIQ-treated patients. Monitor patients for signs and symptoms of bleeding. Do not administer COMETRIQ to patients with severe hemorrhage.

Linda J. Burns, MD

Minnesota. “The ASH Visitor Training Program aims to facilitate that exchange, helping participants bring their new knowledge back to their home institutions to ultimately expand research opportunities and improve the care of patients with blood disorders.”

2014 Participants The 2014 Visitor Training Program participants are:

Wisconsin, Milwaukee) • Reynaldo Angelo De Castro, BSc (Philippines) and mentor Carolyn C. Hoppe, MD (Children’s Hospital and Research Center,

Perforations and Fistulas: Serious gastrointestinal (GI) perforations and fistulas were reported, of which one GI fistula was fatal. Non-GI fistulas including tracheal/esophageal were reported in 4% of COMETRIQ-treated patients. Two of these were fatal. Monitor patients for symptoms of perforations and fistulas.

Hemorrhage: Serious and sometimes fatal hemorrhage occurred with COMETRIQ. Events ≥ Grade 3 occurred in 3% of COMETRIQ patients vs 1% receiving placebo. Do not administer COMETRIQ to patients with a recent history of hemorrhage or hemoptysis.

Thrombotic Events: COMETRIQ treatment results in an increased incidence vs placebo of venous thromboembolism (6% vs 3%) and arterial thromboembolism (2% vs 0%).

Discontinue COMETRIQ in patients who develop an acute myocardial infarction or any other clinically significant arterial thromboembolic complication.

Wound Complications: Wound complications have been reported with COMETRIQ. Stop treatment with COMETRIQ at least 28 days prior to scheduled surgery. Resume COMETRIQ therapy after surgery based on clinical judgment of adequate wound healing. Withhold COMETRIQ in patients with dehiscence or wound healing complications requiring medical intervention.

Hypertension: COMETRIQ treatment results in an increased incidence of treatment-emergent hypertension vs placebo (61% vs 30%). Monitor blood pressure prior to initiation and regularly during COMETRIQ treatment. Withhold COMETRIQ for hypertension that is not adequately controlled with medical management; when controlled, resume COMETRIQ at a reduced dose. Discontinue COMETRIQ for severe hypertension that cannot be controlled with anti-hypertensive therapy.

Osteonecrosis of the Jaw (ONJ): ONJ occurred in 1% of COMETRIQ-treated patients. ONJ can manifest as jaw pain, osteomyelitis, osteitis, bone erosion, tooth or periodontal infection, toothache, gingival ulceration or erosion, persistent jaw pain or slow healing of the mouth or jaw after dental surgery. Perform an oral examination prior to initiation of COMETRIQ and periodically during COMETRIQ therapy. Advise patients regarding good oral hygiene practices. For invasive dental procedures, withhold COMETRIQ treatment for at least 28 days prior to scheduled surgery, if possible.

Palmar-Plantar Erythrodysesthesia Syndrome (PPES): PPES occurred in 50% of patients treated with COMETRIQ and was severe in 13% of patients. Withhold COMETRIQ in patients who develop intolerable Grade 2 PPES or Grade 3-4 PPES until improvement to Grade 1; resume COMETRIQ at a reduced dose.

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Oakland, California) • Ahmet Emre Eskazan, MD (Turkey) and mentor Jorge Cortes, MD (The University of Texas MD Anderson Cancer Center, Houston) • Pamela Fajardo, MD (Philippines) and mentor David Williams, MD (Boston Children’s Hospital, Harvard Medical School, Boston)

• Toman Tua Julian, MD (Indonesia) and mentor Wee Joo Chng, MD (National University Cancer Institute, Singapore) • Sehar Khaliq, MBBS, FCPS (Pakistan) and mentor Suthat Fucharoen, MD (MahidolS:6.75” University, Bangkok) • Pedro Lovato, MD (Peru) and mentor Rizwan Romee, MD (Washing-

ton University School of Medicine, St. Louis) • Aime Mbaya, MD (Democratic Republic of the Congo) and mentor Lekidelu Taddesse-Heath, MD (Howard University Hospital, Washington, DC) • Magdalene Namuwonge, Nursing Officer Diplomat (Uganda) and

mentor Jeannie Callum, MD, FRCP (Sunnybrook Health and Sciences Centre and University Health Network, Toronto) • Onsongo Simon Nyangena, MMed (Kenya) and mentor Nigel Key, MB, ChB (University of North Carolina, Chapel Hill) continued on page 18

Statistically significant efficacy in patients with progressive, metastatic MTC • COMETRIQ® significantly prolonged progression-free survival (PFS) vs placebo in patients with metastatic MTC with radiographically confirmed disease progression — Patients were required to have radiographic evidence of actively progressive disease within 14 months prior to study entry PROD

• Partial response rate was 27% with COMETRIQ® vs 0% with placebo (P<0.0001) • Median duration of response (DOR) was 14.7 months with COMETRIQ® (95% CI: 11.1,19.3)

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• No significant difference in overall survival (OS) was seen with COMETRIQ® vs placebo at the planned interim analysis

PFS

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Proteinuria: Proteinuria was observed in 2% of patients receiving COMETRIQ (vs 0% receiving placebo), including 1 with nephrotic syndrome. Monitor urine protein regularly during COMETRIQ treatment. Discontinue COMETRIQ in patients who develop nephrotic syndrome.

Reversible Posterior Leukoencephalopathy Syndrome (RPLS): RPLS occurred in 1 patient. Perform an evaluation for RPLS in any patient presenting with seizures, headache, visual disturbances, confusion, or altered mental function.

Discontinue COMETRIQ in patients who develop RPLS. Drug Interactions: Avoid administration of COMETRIQ with agents that are strong CYP3A4 inducers or inhibitors.

Hepatic Impairment: COMETRIQ is not recommended for use in patients with moderate or severe hepatic impairment.

Embryo-fetal Toxicity: COMETRIQ can cause fetal harm when administered to a pregnant woman. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus.

Adverse Reactions: The most commonly reported adverse drug reactions (≥25% and ≥5% difference from placebo) were diarrhea (63% vs 33%), stomatitis (51% vs 6%), PPES (50% vs 2%), decreased weight (48% vs 10%), decreased appetite (46% vs 16%), nausea (43% vs 21%), fatigue (41% vs 28%), oral pain (36% vs 6%), hair color changes (34% vs 1%), dysgeusia (34% vs 6%), hypertension (33% vs 4%), abdominal pain (27% vs 13%), and constipation (27% vs 6%). The most common laboratory abnormalities (≥25%) were increased AST (86% vs 35%), increased ALT (86% vs 41%), lymphopenia (53% vs 51%),

Results of the international, multicenter, randomized, double-blind EXAM study in patients with progressive, metastatic MTC (N=330).

Primary endpoint: PFS; secondary endpoints included: objective response rate (ORR) and OS.1

increased ALP (52% vs 35%), hypocalcemia (52% vs 27%), neutropenia (35% vs 15%), thrombocytopenia (35% vs 4%), hypophosphatemia (28% vs 10%), and hyperbilirubinemia (25% vs 14%).

Increased levels of thyroid stimulating hormone (TSH) were observed in 57% of patients receiving COMETRIQ (vs 19% receiving placebo).

In clinical trials, the dose was reduced in 79% of patients receiving COMETRIQ compared to 9% of patients receiving placebo. The median number of dosing delays was one in patients receiving COMETRIQ compared to none in patients receiving placebo. Adverse reactions led to study treatment discontinuation in 16% of patients receiving COMETRIQ and in 8% of patients receiving placebo.

Please see accompanying brief summary of Prescribing Information, including Boxed Warnings.

You are encouraged to report negative side effects of prescription drugs to the FDA. Visit www.FDA.gov/medwatch or call 1-800-FDA-1088.

Reference: 1. Elisei R, Schlumberger MJ, Müller SP, et al. Cabozantinib in progressive medullary thyroid cancer. J Clin Oncol. 2013;31:3639-3646.

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Announcements Global Training Program continued from page 17

• Sunday Ocheni, MBBS, FMCPath (Nigeria) and mentor Ayman Saad, MD (Evelina London Children’s Hospital, London) • Emmanuel Okakpu, MBBS (Nigeria) and mentor Jean-Jacques Kiladjan, MD, PhD (Saint-Louis Centre

D’Investigations Clinique, Paris) • Ekarat Rattarittamrong, MD (Thailand) and mentor Jean-Jacques Kiladjan, MD, PhD (Saint-Louis Centre D’Investigations Clinique, Paris) • Eloísa Riva, MD (Uruguay) and mentor Giampaolo Merlini, MD (Amyloidosis Research and Treatment Center at the University

of Pavia, Italy) • Ninoska Rojas Soto, MD (Peru) and mentor Heather Symons, MD (The Johns Hopkins University, Baltimore) • Yuliya Shestovska, MD (Ukraine) and mentors Sergio S:6.75” Giralt, MD, and Miguel-Angel Perales, MD (Memorial Sloan Kettering Cancer

COMETRIQ® (cabozantinib) capsules BRIEF SUMMARY OF PRESCRIBING INFORMATION Initial U.S. Approval: 2012 WARNING: PERFORATIONS AND FISTULAS, and HEMORRHAGE See full prescribing information for complete boxed warning.

Perforations and Fistulas: Gastrointestinal perforations occurred in 3% and fistula formation in 1% of COMETRIQ-treated patients. Discontinue COMETRIQ in patients with perforation or fistula. (5.1) Hemorrhage: Severe, sometimes fatal, hemorrhage including hemoptysis and gastrointestinal hemorrhage occurred in 3% of COMETRIQ-treated patients. Monitor patients for signs and symptoms of bleeding. Do not administer COMETRIQ to patients with severe hemorrhage. (5.2)

1. INDICATIONS AND USAGE COMETRIQ is indicated for the treatment of patients with progressive, metastatic medullary thyroid cancer (MTC).

2. DOSAGE AND ADMINISTRATION 2.1 Recommended Dose: The recommended daily dose of COMETRIQ is 140 mg (one 80-mg and three 20-mg capsules). Do not administer COMETRIQ with food. Instruct patients not to eat for at least 2 hours before and at least 1 hour after taking COMETRIQ. Continue treatment until disease progression or unacceptable toxicity occurs. Swallow COMETRIQ capsules whole. Do not open COMETRIQ capsules.

Do not take a missed dose within 12 hours of the next dose. Do not ingest foods (e.g., grapefruit, grapefruit juice) or nutritional supplements that are known to inhibit cytochrome P450 during COMETRIQ. 2.2 Dosage Adjustments: For Adverse Reactions : Withhold COMETRIQ for NCI CTCAE Grade 4 hematologic adverse reactions, Grade 3 or greater non-hematologic adverse reactions or intolerable Grade 2 adverse reactions.

Upon resolution/improvement of the adverse reaction (i.e., return to baseline or resolution to Grade 1), reduce the dose as follows: • If previously receiving 140-mg daily dose, resume treatment at 100 mg daily (one 80-mg and one 20-mg capsule) • If previously receiving 100-mg daily dose, resume treatment at 60 mg daily (three 20-mg capsules) • If previously receiving 60-mg daily dose, resume at 60 mg if tolerated, otherwise, discontinue COMETRIQ Permanently discontinue COMETRIQ for any of the following: development of visceral perforation or fistula formation; severe hemorrhage; serious arterial thromboembolic event (e.g., myocardial infarction, cerebral infarction); nephrotic syndrome; malignant hypertension, hypertensive crisis, persistent uncontrolled hypertension despite optimal medical management; osteonecrosis of the jaw; or reversible posterior leukoencephalopathy syndrome. In Patients With Hepatic Impairment : COMETRIQ is not recommended for use in patients with moderate and severe hepatic impairment.

In Patients Taking CYP3A4 Inhibitors : Avoid the use of concomitant strong CYP3A4 inhibitors (e.g., ketoconazole, itraconazole, clarithromycin, atazanavir, nefazodone, saquinavir, telithromycin, ritonavir, indinavir, nelfinavir, voriconazole) in patients receiving COMETRIQ. For patients who require treatment with a strong CYP3A4 inhibitor, reduce the daily COMETRIQ dose by 40 mg (for example, from 140 mg to 100 mg daily or from 100 mg to 60 mg daily). Resume the dose that was used prior to initiating the CYP3A4 inhibitor 2 to 3 days after discontinuation of the strong inhibitor.

In Patients Taking Strong CYP3A4 Inducers : Avoid the chronic use of concomitant strong CYP3A4 inducers (e.g., phenytoin, carbamazepine, rifampin, rifabutin, rifapentine, phenobarbital) if alternative therapy is available. Do not ingest foods or nutritional supplements (e.g., St. John’s Wort [Hypericum perforatum]) that are known to induce cytochrome P450 activity. For patients who require treatment with a strong CYP3A4 inducer, increase the daily COMETRIQ dose by 40 mg (for example, from 140 mg to 180 mg daily or from 100 mg to 140 mg daily) as tolerated. Resume the dose that was used prior to initiating the CYP3A4 inducer 2 to 3 days after discontinuation of the strong inducer. The daily dose of COMETRIQ should not exceed 180 mg.

4. CONTRAINDICATIONS None.

5. WARNINGS AND PRECAUTIONS 5.1 Perforations and Fistulas: Gastrointestinal (GI) perforations and fistulas were reported in 3% and 1% of COMETRIQ-treated patients, respectively.

All were serious and one GI fistula was fatal (<1%). Non-GI fistulas including tracheal/esophageal were reported in 4% of COMETRIQ-treated patients.

Two (1%) of these were fatal. Monitor patients for symptoms of perforations and fistulas. Discontinue COMETRIQ in patients who experience a perforation or a fistula.

5.2 Hemorrhage: Serious and sometimes fatal hemorrhage occurred with COMETRIQ. The incidence of Grade ≥3 hemorrhagic events was higher in COMETRIQ-treated patients compared with placebo (3% vs. 1%). Do not administer COMETRIQ to patients with a recent history of hemorrhage or hemoptysis.

5.3 Thrombotic Events: COMETRIQ treatment results in an increased incidence of thrombotic events (venous thromboembolism: 6% vs. 3% and arterial thromboembolism: 2% vs. 0% in COMETRIQ-treated and placebo-treated patients, respectively). Discontinue COMETRIQ in patients who develop an acute myocardial infarction or any other clinically significant arterial thromboembolic complication.

Center, New York) • Zsofia Varady, MD, PhD (Romania) and mentor Richard Jones, MD ( Johns Hopkins Kimmel Cancer Center, Baltimore) • Tamunomieibi Wakama, MBBS, FMCPath (Nigeria) and mentor Vishalla Neppalli, MD (Roswell Park Cancer Center, Buffalo) n

5.4 Wound Complications: Wound complications have been reported with COMETRIQ. Stop treatment with COMETRIQ at least 28 days prior to scheduled surgery. Resume COMETRIQ therapy after surgery based on clinical judgment of adequate wound healing. Withhold COMETRIQ in patients with dehiscence or wound healing complications requiring medical intervention.

5.5 Hypertension: COMETRIQ treatment results in an increased incidence of treatment-emergent hypertension with Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (modified JNC criteria) stage 1 or 2 hypertension identified in 61% of COMETRIQ-treated patients compared with 30% of placebo-treated patients in the randomized trial. Monitor blood pressure prior to initiation and regularly during COMETRIQ treatment. Withhold COMETRIQ for hypertension that is not adequately controlled with medical management; when controlled, resume COMETRIQ at a reduced dose. Discontinue COMETRIQ for severe hypertension that cannot be controlled with anti-hypertensive therapy.

5.6 Osteonecrosis of the Jaw (ONJ): Osteonecrosis of the jaw (ONJ) occurred in 1% of COMETRIQ-treated patients. ONJ can manifest as jaw pain, osteomyelitis, osteitis, bone erosion, tooth or periodontal infection, toothache, gingival ulceration or erosion, persistent jaw pain or slow healing of the mouth or jaw after dental surgery. Perform an oral examination prior to initiation of COMETRIQ and periodically during COMETRIQ therapy. Advise patients regarding good oral hygiene practices. For invasive dental procedures, withhold COMETRIQ treatment for at least 28 days prior to scheduled surgery, if possible.

5.7 Palmar-Plantar Erythrodysesthesia Syndrome: Palmar-plantar erythrodysesthesia syndrome (PPES) occurred in 50% of patients treated with cabozantinib and was severe (≥Grade 3) in 13% of patients. Withhold COMETRIQ in patients who develop intolerable Grade 2 PPES or Grade 3-4 PPES until improvement to Grade 1; resume COMETRIQ at a reduced dose.

5.8 Proteinuria: Proteinuria was observed in 4 (2%) patients receiving COMETRIQ, including one with nephrotic syndrome, as compared to none of the patients receiving placebo. Monitor urine protein regularly during COMETRIQ treatment. Discontinue COMETRIQ in patients who develop nephrotic syndrome.

5.9 Reversible Posterior Leukoencephalopathy Syndrome: Reversible Posterior Leukoencephalopathy Syndrome (RPLS), a syndrome of subcortical vasogenic edema diagnosed by characteristic finding on MRI, occurred in one (<1%) patient. Perform an evaluation for RPLS in any patient presenting with seizures, headache, visual disturbances, confusion or altered mental function. Discontinue COMETRIQ in patients who develop RPLS. 5.10 Drug Interactions: Avoid administration of COMETRIQ with agents that are strong CYP3A4 inducers or inhibitors.

5.11 Hepatic Impairment: COMETRIQ is not recommended for use in patients with moderate or severe hepatic impairment.

5.12 Embryo-Fetal Toxicity: COMETRIQ can cause fetal harm when administered to a pregnant woman. Cabozantinib was embryolethal in rats at exposures below the recommended human dose, with increased incidences of skeletal variations in rats and visceral variations and malformations in rabbits. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus.

6. ADVERSE REACTIONS 6.1 Clinical Trial Experience: Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The safety of COMETRIQ was evaluated in 330 patients with progressive, metastatic medullary thyroid cancer randomized to receive 140 mg of COMETRIQ (n=214) or placebo (n=109) administered daily until disease progression or intolerable toxicity occurred in a randomized, double-blind, controlled trial. The data described below reflect a median exposure to COMETRIQ for 204 days.

The population exposed to COMETRIQ was 70% male, 90% white, and had a median age of 55 years. Adverse reactions which occurred in ≥25% of COMETRIQ-treated patients occurring more frequently in the COMETRIQ arm with a between-arm difference of ≥5% included, in order of decreasing frequency: diarrhea, stomatitis, palmar-plantar erythrodysesthesia syndrome (PPES), decreased weight, decreased appetite, nausea, fatigue, oral pain, hair color changes, dysgeusia, hypertension, abdominal pain, and constipation. The most common laboratory abnormalities (>25%) were increased AST, increased ALT, lymphopenia, increased alkaline phosphatase, hypocalcemia, neutropenia, thrombocytopenia, hypophosphatemia, and hyperbilirubinemia.

Grade 3-4 adverse reactions and laboratory abnormalities which occurred in ≥5% of COMETRIQ-treated patients occurring more frequently in the COMETRIQ arm with a between-arm difference of ≥2% included, in order of decreasing frequency: diarrhea, PPES, lymphopenia, hypocalcemia, fatigue, hypertension, asthenia, increased ALT, decreased weight, stomatitis, and decreased appetite (see Table 1, Table 2). Fatal adverse reactions occurred in 6% of patients receiving COMETRIQ and resulted from hemorrhage, pneumonia, septicemia, fistulas, cardiac arrest, respiratory failure, and unspecified death. Fatal adverse reactions occurred in 5% of patients receiving placebo and resulted from septicemia, pneumonia, and general deterioration. The dose was reduced in 79% of patients receiving COMETRIQ compared to 9% of patients receiving placebo. The median number of dosing delays was one in patients receiving COMETRIQ compared to none in patients receiving placebo. Adverse reactions led to study treatment discontinuation in 16% of patients receiving COMETRIQ and in 8% of patients receiving placebo. The most frequent adverse reactions leading to permanent discontinuation in patients treated with COMETRIQ were: hypocalcemia, increased lipase, PPES, diarrhea, fatigue, hypertension, nausea, pancreatitis, tracheal fistula formation, and vomiting. Increased levels of thyroid stimulating hormone (TSH) were observed in 57% of patients receiving COMETRIQ after the first dose compared to 19% of patients receiving placebo (regardless of baseline value). Ninety-two percent (92%) of patients on the COMETRIQ arm had a prior thyroidectomy, and 89% were taking thyroid hormone replacement prior to the first dose.

Table 1. Per-Patient Incidence of Selected Adverse Reactions in Protocol XL184-301 Occurring at a Higher Incidence in COMETRIQ-Treated Patients [Between-Arm Difference of ≥5% (All Grades)1 or ≥2% (Grades 3-4)] Cabozantinib Placebo (n=214) (n=109) MedDRA System Organ Class/ Preferred Terms All Grades All Grades Grades 3-4 Grades 3-4 GASTROINTESTINAL DISORDERS DIARRHEA 63 16 33 2 STOMATITIS2 51 5 6 0 NAUSEA 43 1 21 0 ORAL PAIN3 36 2 6 0 CONSTIPATION 27 0 6 0 ABDOMINAL PAIN4 27 3 13 1 VOMITING 24 2 2 1 DYSPHAGIA 13 4 6 1 DYSPEPSIA 11 0 0 0 HEMORRHOIDS 9 0 3 0 GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS FATIGUE 41 9 28 3 ASTHENIA 21 6 15 1 INVESTIGATIONS DECREASED WEIGHT 48 5 10 0 METABOLISM AND NUTRITION DISORDERS DECREASED APPETITE 46 5 16 1 DEHYDRATION 7 2 2 1 MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS ARTHRALGIA 14 1 7 0 MUSCLE SPASMS 12 0 5 0 MUSCULOSKELETAL CHEST PAIN 9 1 4 0 NERVOUS SYSTEM DISORDERS DYSGEUSIA 34 0 6 0 HEADACHE 18 0 8 0 DIZZINESS 14 0 7 0 PARESTHESIA 7 0 2 0 PERIPHERAL SENSORY 7 0 0 0 NEUROPATHY PERIPHERAL NEUROPATHY 5 0 0 0 PSYCHIATRIC DISORDERS ANXIETY 9 0 2 0 RESPIRATORY, THORACIC, AND MEDIASTINAL DISORDERS DYSPHONIA 20 0 9 0 SKIN AND SUBCUTANEOUS TISSUE DISORDERS PPES5 50 13 2 0 HAIR COLOR CHANGES/ 34 0 1 0 DEPIGMENTATION, GRAYING RASH 19 1 10 0 DRY SKIN 19 0 3 0 ALOPECIA 16 0 2 0 ERYTHEMA 11 1 2 0 HYPERKERATOSIS 7 0 0 0 VASCULAR DISORDERS HYPERTENSION 33 8 4 0 HYPOTENSION 7 1 0 0 National Cancer Institute Common Terminology Criteria for Adverse Events Version 3.0.

Includes the following terms: stomatitis, aphthous stomatitis, mouth ulceration, mucosal inflammation.

3 Includes the following terms: oral pain, oropharyngeal pain, glossitis, burning mouth syndrome, glossodynia.

4 Includes the following terms: abdominal pain, abdominal pain lower, abdominal pain upper, abdominal rigidity, abdominal tenderness, esophageal pain.

5 Palmar-plantar erythrodysesthesia syndrome.

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Quality Care Symposium Medicare Part D Low-Income Subsidy Program Improves Adherence to Hormone Therapy After Breast Cancer Surgery

PROD ED AE/AS CW CD

Disclosure: The study authors reported no potential conflicts of interest.

Reference 1. Biggers A, et al: Medicare Part D lowincome subsidy and disparities in breast cancer treatment. Quality Care Symposium.

Abstract 2. Presented October 17, 2014.

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Hormone therapy can reduce risk of breast cancer recurrence and improve chances for long-term survival. In this study, data were collected from a national sample of 23,299 Medicare Part D enrollees with early-stage breast cancer who received hormone therapy within 1 year of surgery. Overall, 27% of the women were enrolled in the Extra Help low-income subsidy program, which eliminated or reduced out-of-pocket costs for the hormone therapy. The out-of-pocket costs ranged from $155 to $428 per year, on average. Racial minorities were more likely to be enrolled in the program.

In the first year of hormone therapy, overall adherence rates were similar across all races (64% for white women, 63% for black women, and 67%for Hispanic women). However, racial/ethnic disparities in adherence were evident among the subgroup of women who were not enrolled in the Extra Help program, with white women having significantly higher adherence rates (62%) compared to black and Hispanic women (55%).

In all racial/ethnic groups, adherence rates were higher among women who received the low-income subsidy, compared to those who did not. In addition, although hormone therapy adherence rates declined in years 2 and 3, adherence rate reductions were smaller among those who used the Extra Help program, and this trend was observed in all racial/ethnic groups. n S:9.75”

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Per-Patient Incidence of Hypertension in Protocol XL184-301 COMETRIQ HYPERTENSION, JNC1 STAGE N=2113 (%) Normal: Grade 0: Systolic 4 <120 mmHg and Diastolic <80 mmHg Pre-hypertension: Systolic 34 ≥120 mmHg or Diastolic ≥80 mmHg Stage 1: Systolic ≥140 mmHg or 46 Diastolic ≥90 mmHg

7. DRUG INTERACTIONS 7.1 Effect of CYP3A4 Inhibitors: Administration of a strong CYP3A4 inhibitor, ketoconazole (400 mg daily for 27 days) to healthy subjects increased single-dose plasma cabozantinib exposure (AUC0-inf) by 38%. Avoid taking a strong CYP3A4 inhibitor (e.g., ketoconazole, itraconazole, clarithromycin, atazanavir, indinavir, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin, voriconazole) when taking COMETRIQ. 7.2 Effect of CYP3A4 Inducers: Administration of a strong CYP3A4 inducer, rifampin (600 mg daily for 31 days) to healthy subjects decreased single-dose plasma cabozantinib exposure (AUC0-inf) by 77%. Avoid chronic coadministration of strong CYP3A4 inducers (e.g., dexamethasone, phenytoin, carbamazepine, rifampin, rifabutine, rifapentine, phenobarbital, St. John’s Wort) with COMETRIQ. 8. USE IN SPECIFIC POPULATIONS 8.1 Pregnancy: Pregnancy Category D. Risk Summary : Based on its mechanism of action, COMETRIQ can cause fetal harm when administered to a pregnant woman. Cabozantinib was embryolethal in rats at exposures below the recommended human dose, with increased incidences of skeletal variations in rats and visceral variations and malformations in rabbits. If this drug is used during pregnancy or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus. Animal Data: In an embryo-fetal development study in which pregnant rats were administered daily doses of cabozantinib during organogenesis, increased loss of pregnancy compared to controls was observed at doses as low as 0.03 mg/kg (less than 1% of the human exposure by AUC at the recommended dose). Findings included delayed ossifications and skeletal variations at doses equal to or greater than 0.01 mg/kg/day (approximately 0.03% of the human exposure by AUC at the recommended dose). In pregnant rabbits administered cabozantinib daily during organogenesis, there were findings of visceral malformations and variations including reduced splenic size and missing lung lobe at 3 mg/kg (approximately 11% of the human exposure by AUC at the recommended dose).

8.2 Nursing Mothers: It is unknown whether cabozantinib or its metabolites are excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from COMETRIQ, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.

8.3 Pediatric Use: The safety and effectiveness of COMETRIQ in pediatric patients have not been studied.

8.4 Geriatric Use: Clinical studies of COMETRIQ did not include sufficient numbers of patients aged 65 years and over to determine whether they respond differently from younger patients.

8.5 Females and Males of Reproductive Potential: Contraception: Use effective contraception during treatment with COMETRIQ and up to 4 months after completion

of therapy. Infertility : There are no data on the effect of COMETRIQ on human fertility.

Cabozantinib impaired male and female fertility in animal studies.

8.6 Hepatic Impairment: Cabozantinib pharmacokinetics has not been studied in patients with hepatic impairment. There are limited data in patients with liver impairment (serum bilirubin greater than 1.5 times the upper limit of normal).

COMETRIQ is not recommended for use in patients with moderate or severe hepatic impairment, as safety and efficacy have not been established.

8.7 Renal Impairment: No dose adjustment is recommended for patients with mild or moderate renal impairment. There is no experience with COMETRIQ in patients with severe renal impairment.

10. OVERDOSAGE One case of overdosage was reported in a patient who inadvertently took twice the intended dose (200 mg daily) for nine days. The patient suffered Grade 3 memory impairment, Grade 3 mental status changes, Grade 3 cognitive disturbance, Grade 2 weight loss, and Grade 1 increase in BUN. The extent of recovery was not documented.

17. PATIENT COUNSELING INFORMATION See FDA-approved patient labeling (Patient Information and Instructions for Use).

Inform patients of the following: • COMETRIQ often causes diarrhea which may be severe in some cases. Inform patients of the need to contact their healthcare provider if severe diarrhea occurs during treatment with COMETRIQ. • COMETRIQ often causes palmar-plantar erythrodysesthesia syndrome. Advise patients to contact their healthcare provider for progressive or intolerable rash.

• COMETRIQ often causes sores in the mouth, oral pain, changes in taste, nausea or vomiting. Advise patients to contact their healthcare provider if any of these symptoms are severe or prevent patients from eating and drinking.

• COMETRIQ often causes weight loss which may be significant in some cases. Advise patients to report significant weight loss.

• To contact their healthcare provider before any planned surgeries, including dental procedures.

• COMETRIQ may interact with other drugs; advise patients to inform their healthcare provider of all prescription or nonprescription medication or herbal products that they are taking.

• Patients of childbearing potential must use effective contraception during therapy and for at least four months following their last dose of COMETRIQ. • Breast-feeding mothers must discontinue nursing while receiving COMETRIQ therapy.

• COMETRIQ should not be taken with food. Instruct patients not to eat for at least 2 hours before and at least 1 hour after taking COMETRIQ. COMETRIQ capsules should not be opened or crushed but should be taken with a full glass (at least 8 ounces) of water.

• Patients should not consume grapefruits or grapefruit juice while taking COMETRIQ treatment.

Reference ID: 3223542 Distributed by Exelixis, Inc. 11/2012

medications if they are able to afford them,” said lead study author Alana Biggers, MD, MPH, Assistant Professor of Clinical Medicine at the University of Illinois, Chicago. “Our study shows that federal policy interventions that help cover out-of-pocket costs have the potential to reduce the breast cancer outcome gap by race and ethnicity.”

While breast cancer predominantly affects white women, breast cancer outcomes are worse among black women. In fact, black women are more likely to die of breast cancer than any other group.

Breast cancer death rates are also higher among women with low socioeconomic status, regardless of race/ethnicity.

TC

Nearly all COMETRIQ-treated patients (96% vs. 84% placebo) experienced elevated blood pressure and there was a doubling in the incidence of overt hypertension in COMETRIQ-treated patients over placebo-treated patients (61% vs. 30%) according to modified Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC) staging criteria. No patients developed malignant hypertension.

Malignant: Diastolic 0 0 ≥120 mmHg 1 Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure, JAMA 2003:289:2560. Criteria applied were modified, as multiple readings were not available per timepoint, and therefore not averaged.

2 Subjects classified by highest category based on all recorded blood pressure readings beginning after the first dose through 30 days after last dose.

3 Subjects with at least two blood pressure measurements after the first dose.

that overcoming economic barriers to medication access may ultimately help reduce breast cancer outcome disparities, especially among racial minorities.

“Patients are more likely to take their

QC

Table 2. Percent-Patient Incidence of Laboratory Abnormalities Occurring at a Higher Incidence in COMETRIQ-Treated Patients in Protocol XL184-301 [Between- Arm Difference of ≥5% (All Grades) or ≥2% (Grades 3-4)] COMETRIQ (n=214) Placebo (n=109) ADVERSE EVENT All Grade 3-4 All Grades Grade 3-4 Grades CHEMISTRIES INCREASED AST 86 3 35 2 INCREASED ALT 86 6 41 2 INCREASED ALP 52 3 35 3 HYPOCALCEMIA 52 12 27 3 HYPOPHOSPHATEMIA 28 3 10 1 HYPERBILIRUBINEMIA 25 2 14 5 HYPOMAGNESEMIA 19 1 4 0 HYPOKALEMIA 18 4 9 3 HYPONATREMIA 10 2 5 0 HEMATOLOGIC LYMPHOPENIA 53 16 51 11 NEUTROPENIA 35 3 15 2 THROMBOCYTOPENIA 35 0 4 3 ALT, alanine aminotransferase; ALP, alkaline phosphatase; AST, aspartate aminotransferase

to hormone therapy after breast cancer surgery in all racial/ethnic groups and reduces S:6.75” racial/ethnic disparities.

The study, reported at the 2014 ASCO Quality Care Symposium,1 suggests

PG

F

indings from a study of more than 23,000 women suggest that the Medicare Part D Extra Help program, which provides low-income subsidies for medications, improves adherence

PharmaGraphics

5”

PAGE 19

S&H

.5”

ASCOPost.com | DECEMBER 1, 2014

The ASCO Post | DECEMBER 1, 2014

PAGE 20

Quality Care Symposium Checklists: Simple Tools That Enhance Quality

By Ronald Piana

E

vidence indicates that the use of surgical safety checklists results in marked improvements in patient outcomes. Unfortunately, their adoption in the field of medicine has largely been limited to equipment operations or parts of specific treatment algorithms. Yet they have tremendous potential to improve patient outcomes by democratizing knowledge and helping ensure that all patients receive evidence-based best practices and safe high-quality care.

That said, not all checklists are created equal, and the development and use of this simple tool are more complicated than it would appear. The value and proper use of checklists were fully examined at this year’s Quality Care Symposium by William Berry, MD, MPA, MPH, FACS, Principal Research Scientist, Department of Health Policy and Management, Harvard School of Public Health, Boston.1 “I want to spend time talking about a decades-long journey I’ve been on with several colleagues, which has led to a better understanding about how to use checklists for quality improvement. And I believe there is a place for a checklist or a standardized protocol when delivering chemotherapy, especially in the oral administration setting,” said Dr. Berry.

Learning From Disaster To illustrate the potential consequences of missing a protocol step, Dr. Berry took the audience back to the early 1930s. At that time, the U.S. Army Air Corps was looking for a multiengine bomber that had greater capacity and range to replace the old Martin B-10.

Boeing won the contract and designed and built the B-17 bomber, known as the Flying Fortress. On October 30, 1935, with Boeing’s two best test pilots at the controls, the B-17 rolled down the runway on its second test flight before a crowd of reporters.

When the huge plane lifted off the runway, it stalled, nosed over, and crashed in a ball of fire, killing the

two pilots. It was discovered that the crew had forgotten to disengage the “gust locks,” a system of devices that are locked in place while the aircraft is parked on the ground but must be unlocked before takeoff to avoid the kind of disaster that befell the B-17. Subsequently, the use of preflight checklists became standard procedure by military pilots and was later adopted by all commercial pilots.

Enhanced Patient Outcomes The checklist didn’t stop with the airline industry. Dr. Berry pointed to the famous intensive care checklist developed by Peter J. Pronovost, MD, PhD, of Johns Hopkins Hospital, Balti-

“If a task has a lot of important steps, which increases the possibility of accidently omitting one, a checklist becomes an important tool. Moreover, tasks that are performed under stress can benefit from a checklist because people working under stress are more likely to forget an important item, which can prove fatal in certain patient care settings. Checklists are also useful for reminding people to do new things that have recently been integrated into the patient care path,” said Dr. Berry.

Dr. Berry explained that there are places where checklists should not be used. “Checklists aren’t particularly valuable as a learning tool since we don’t absorb complex information in

If you want people to change their behavior in the clinic, it is important to have a personal conversation with them.

—William Berry, MD, MPA, MPH, FACS

more, that experts say has saved countless thousands of lives and hundreds of millions of health-care dollars. “Checklists are now spreading more broadly throughout medicine, particularly for certain settings where they are very useful and enhance patient outcomes,” said Dr. Berry.

He continued, “I think you can use checklists to change workplace policies, improve your patient care process, enhance teamwork and communication, and help guide a conversation among your colleagues.” He added that checklists standardize and improve the reliable translation of information so that the same knowledge is available to doctors, nurses, and patients.

Know When and Where to Use Checklists Dr. Berry then drilled down to the specific strongpoints of the checklist.

that kind of linear fashion. Also, checklists by their very nature are designed for simplicity; they don’t take the place of algorithms or procedure guides that are needed in highly complex scenarios,” said Dr. Berry.

He explained that there are two basic kinds of checklists. “There is a read-do checklist, which means that you read through the checklist while you’re doing the task. And there is the read-confirm checklist, in which one party of the medical team reads a point off the list, and it is verbally confirmed by another team member,” said Dr. Berry.

“I look at checklist development in several major phases and virtually every quality improvement measure addresses these phases. In the first phase, you need to be focused on the steps you want integrated into your tool. Then comes the tool-making part, when you actually draft the document. The most

Using Checklists in the Clinic ■■ Respect the workflow.

■■ Keep them simple.

■■ Create a multidisciplinary team.

■■ Test before you use them with patients.

■■ Train people how to use them.

■■ Engage everyone individually.

important step here is to keep it as simple as possible. No one should have to work off a six-page checklist. And probably the most important aspect of making a checklist is to test it in the clinical setting it’s designed for before finalizing it as a document,” stressed Dr. Berry.

Practice Is Needed Dr. Berry noted that a checklist by itself is just a piece of paper, and proper training is essential to making it a valuable tool in the clinic. “Actual practice using the checklist away from the patient setting is the best way for people to learn. Repetitive workshops during which the checklist is used also creates a good communication base for the care team,” said Dr. Berry, adding, “Collecting feedback and learning about what works well is essential for long-term use.”

Dr. Berry’s presentation concluded with a simple takeaway message. “The one idea I want to leave you with, which might seem patently obvious, is that if you want someone to use this tool, have a one-on-one conversation with him.

Don’t send out e-mails or tweet about it. That works for some ideas but not this kind of hands-on tool. If you want people to change their behavior in the clinic, it is important to have a personal conversation with them.” n

Disclosure: Dr. Berry reported no potential conflicts of interest.

Reference 1. Berry W: Patient safety across disciplines: Checklists (surgery). Quality Care Symposium. Presented October 18, 2014.

Visit The ASCO Post website at ASCOPost.com

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From innovative biotechnology to extensive experience in biologic manufacturing, see how Amgen strives to deliver on its commitment to your patients.

Take a deeper look at our reliability and quality visit biotechnologybyamgen.com Download the LAYAR app on your smartphone and scan this page. Š2014 Amgen Inc. All rights reserved. 80012-R2-V1

Our Roots Go Deep

The ASCO Post | DECEMBER 1, 2014

PAGE 22

Quality Care Symposium Technology

A National Cancer Database and Cancer Care Quality Improvement

By Ronald Piana

A

t this year’s Quality Care Symposium, Lawrence N. Shulman, MD, Chief of Staff and Director of the Center for Global Cancer Medicine at Dana-Farber Cancer Institute, Boston, looked at the issue of quality infrastructure development through the prism of several tools developed by the American College of Surgeons’ Commission on Cancer. Dr. Shulman is one of two ASCO representatives to that consortium and Chair of the Commission on Cancer’s Quality Committee.

“The Commission on Cancer was established by the American College of Surgeons in 1922, at a time when surgery was the only available cancer treatment. It is a now a broad-based consortium of professional organizations dedicated to improving survival and quality of life for cancer patients in hospitals. There are currently about 1,500 U.S. hospitals that are accredited by the Commission,” said Dr. Shulman.

Dr. Shulman explained that the National Cancer Data Base was formed in 1988 as a joint venture of the American College of Surgeons and the American Cancer Society. “Approximately 70% of newly diagnosed cancer patients have their records in the [National Cancer Data Base]. We currently have about 30 million records from hospital cancer registries across the country,” said Dr. Shulman.

Web-Based Tools He then described the Rapid Quality Reporting System (RQRS), a fairly new Web-based data collection tool from the National Cancer Data Base.

“All case information reported to the system is collected by cancer registries at participating programs and entered into their registry database. The system makes it easier for us to deliver evidence-based care in real clinical time. We do case tracking and ongoing reporting of quality metrics,” said Dr. Shulman.

“Another important component of the reporting system is that we can give feedback to clinicians if their

patients have not had their recommended treatment in the appropriate time frame,” he continued. “So, if you have a patient who has had breastconserving surgery, and after a certain period of time—I believe it should be about 180 days—she hasn’t received breast radiation therapy, the system pings the cancer program about the need for the treatment,” said Dr. Shulman. He added, “This is a voluntary program, and about 900 of the 1,500 hospital programs are participating in the RQRS. We feel that within a year or two, all hospital programs will be enrolled.”

Another Web-based tool is the Cancer Program Practice Profile Report,

a relatively easy three-page application for research data. In 2014, we received 227 applications and approved 194.

The main reason for not approving a submission is that the data they were requesting didn’t exist.”

Dr. Shulman then discussed the very important initiative, the Cancer Quality Improvement Program, which was launched in 2013, and the first reports were delivered in February 2014.

“We’re currently preparing the 2014 report and we hope to deliver them to the [Commission on Cancer] institutions by the end of the calendar year.

This program is a data-driven, process and outcomes-based quality improvement program that generates individ-

Approximately 70% of newly diagnosed cancer patients have their records in the [National Cancer Data Base]. We currently have about 30 million records from hospital cancer registries across the country.

—Lawrence N. Shulman, MD

which hospitals can use to measure their compliance rates in a number of different quality metrics in the treatment of breast, colon, and rectal cancers. “This tool helps cancer programs gauge their intrafacility trends over time and compare the results to other facilities. It empowers clinicians, administrators, and other hospital staff to work cooperatively and diminish care disparities,” noted Dr. Shulman.

Other Initiatives Dr. Shulman discussed another benefit of being a College of Surgeons’ accredited institution. “The Participant User File Research Program allows external researchers from any of the 1,500 member hospitals to conduct outcomes research utilizing the 30 million cancer patient records in the [National Cancer Data Base]. It’s

ual facility level quality reports with a side-by-side comparison to other [Commission on Cancer] hospitals,” said Dr. Shulman.

He explained that the annual reports are in PowerPoint format that analyzes patient demographics, quality measures, survival data, and patients’ migration into and out of the system.

“We think the target audience for these reports includes the hospital’s cancer committee, the individual oncologists, and the hospital’s executives and administration. So this data tool has value across the full spectrum of the hospital,” said Dr. Shulman.

Report Features In the 2014 report, there will be data on 12 quality metrics. “Before we develop quality measures, we look into the [National Cancer Data Base]

to identify the most important initiatives we should approach. For instance, one of the new measures is to have at least 10 regional lymph nodes removed and pathologically examined for staging IA, IB, IIA, and IIB resected non–small cell lung cancer.

In 2012, the baseline adherence to this measure was only 39%, so there’s a lot of room for quality improvement there,” commented Dr. Shulman.

The report shows the individual hospital’s performance rate in each disease and also against the state, the region, and all Commission on Cancer programs, giving hospital leaders and doctors a good overall picture of their performance rate. “We’re also looking at survival data, both riskadjusted and unadjusted. Beginning with breast, colon, and lung disease sites, these stage-specific data will be adjusted for age, race, gender, insurance status, and comorbidities,” explained Dr. Shulman.

Dr. Shulman noted that the program automatically produces reports on a yearly basis, so no chart abstractions are required, and it includes all cases from the participating institution. Moreover, there are a growing number of quality metrics being ­d eveloped.

“There are a couple of disadvantages to the system. For example, specific systemic drugs are not included in the report and the information on tumor biomarkers is not yet complete,” said Dr. Shulman, adding, “The [Commission on Cancer] is dedicated to improving quality of life for patients through evidence-based care, and these tools that I’ve been discussing are an integral part of that effort.” n Disclosure: Dr. Shulman reported no potential conflicts of interest.

Reference 1. Shulman LN: National Cancer Database and the Cancer Quality Improvement Program for the Commission On Cancer.

Quality Care Symposium. Presented October 18, 2014.

ASCOPost.com | DECEMBER 1, 2014

PAGE 23

Quality Care Symposium Having Dependent Children Motivates Parents With Advanced Cancer to Pursue More Aggressive, Life-Extending Treatments

F

indings from a pilot study of 42 parents with advanced cancer indicate that parental status is an important factor in treatment decision-making. When asked how having children influences their treatment decisions, the majority of parents (64%) responded that being a parent motivates them to pursue life-extending treatments, largely out of a desire to have more time with their children. A smaller proportion of parents (15%) identified preserving parental functioning as a treatment priority, and 12% mentioned the importance of receiving treatment close to their families, vs traveling for a second opinion, or pursuing treatment that may require long hospital stays.

Parenting concerns identified in this study will inform further research in this understudied patient population. The study findings were reported at the 2014 ASCO Quality Care Symposium.1 “Numerous psychosocial factors influence patients’ decisions about cancer treatment. It’s important for patients with dependent children to discuss their treatment priorities with their oncologist, who may not know, for example, how important it is for a patient with children to preserve their functioning at home,” said lead author Devon Check, a PhD student at the University of North Carolina, Chapel Hill. “We hope that our study can help oncologists engage patients with children in shared decisionmaking and promote alignment of the treatment plan with the patients’ priorities.”

Study Details Prior studies suggested that patients with advanced cancer who are parents prefer aggressive treatments for their illness more often than patients who are not parents. The present study, which focused solely on patients with dependent children, is the first to directly ask parents if and how having children affects their treatment preferences, beyond serving as a motivator for aggressive treatment. It is also the first to include qualitative methods, which helped elucidate more nuanced factors influencing decision-making.

Researchers interviewed 42 patients with metastatic cancer who have children younger than 18 years. Parents had an average age of 44, and the average age of their children was 12. When queried about preferences for palliative care and hospice, 52% of parents indicated an interest in using hospice services. Of these parents, many recognized hospice as a supportive resource for their family. Others were spe-

cifically interested in institutional vs home hospice care, due to a desire to protect their children from the dying experience. Twenty-four percent of parents reported an interest in receiving palliative care concurrent

with their cancer treatment, although several parents seemed to conflate palliative care with end-of-life care. n

Disclosure: The study authors reported no potential conflicts of interest.

Now

OAK

Reference 1. Check D, et al: How does parental status influence preferences for cancer treatment and palliative care? Quality Care Symposium.

Abstract 65. Presented October 18, 2014.

Enrolling

A Randomized Phase III Study of MPDL3280A (an Engineered Anti-PDL1 Antibody) Compared to Docetaxel in Patients with Locally Advanced or Metastatic Non-small Cell Lung Cancer Who Have Failed Platinum Therapy (NCT02008227, Study ID GO28915)

MPDL3280A1 Patients with locally advanced or metastatic NSCLC who have failed platinum-containing chemotherapy

(an engineered anti-PDL1 antibody)

N=850

Randomized 1:1

Docetaxel

Primary Endpoint:

Secondary Endpoints:

• Objective survival

• Safety: incidence of adverse events • Overall response rate • Progression-free survival • Duration of response

Key Inclusion Criteria 2:

Key Exclusion Criteria 2:

• Locally advanced or metastatic NSCLC • • • •

• History of autoimmune disease

(stage IIIB, stage IV, or recurrent) Representative FFPE tumor specimens Disease progression during or following platinum-containing treatment regimen Measurable disease, defined by RECIST v1.1 ECOG performance status of 0-1

• Active hepatitis B or hepatitis C • Prior treatment with docetaxel, CD137 agonists,

anti-CTLA4, anti-PD1, anti-PDL1 antibodies, or pathway-targeting agents

For more information Visit: clinicaltrials.gov or antiPDL1ClinicalTrials.com/hcp

Call: Genentech Trial Information Support Line: 1-888-662-6728 (US only)

E-mail: global.rochegenentechtrials@roche.com

1. Product under investigation has not been approved for use outside of the clinical trial setting. This information is presented only for the purpose of providing an overview of the clinical trial and should not be construed as a recommendation for use of any product for unapproved purposes.

2. For more information on trial inclusion and exclusion criteria, visit clinicaltrials.gov or antiPDL1ClinicalTrials.com/hcp.

© 2014 Genentech USA, Inc. All rights reserved. BIO0002588200 Printed in USA.

The ASCO Post | DECEMBER 1, 2014

PAGE 24

Quality Care Symposium Tumor Board Participation Associated With Improved Survival in Stage IV Lung and Colorectal Cancers

By Alice Goodman

A

large, population-based, observational study suggests that participation in weekly tumor boards can improve outcomes in oncologic care.

Specifically, oncologist participation in weekly tumor board meetings was associated with improved survival in patients with stage IV small cell lung cancer and stage IV colorectal cancers. Weekly tumor board participation was also associated with an increased likelihood of patient enrollment in clinical trials and increased the likelihood of guidelinebased curative surgery for patients with early-stage non–small cell lung cancer (NSCLC).

“Prior single-center studies suggest that tumor boards often change treatment recommendations. These findings from a larger study are exploratory and will be the basis of future research. Patients with lung cancer and colorectal cancer may want to ask their doctors if

This study supports our belief that multidisciplinary communication improves outcomes and enrollment in clinical trials. Tumor boards represent one tool that can improve care for cancer patients, and the effect is difficult to measure.

—Kenneth L. Kehl, MD

their cases will be discussed by a tumor board that includes multidisciplinary experts,” said lead author Kenneth L. Kehl, MD, a fellow in cancer medicine at The University of Texas MD Anderson Cancer Center, Houston.

Study Details The study utilized data from the Cancer Care Outcomes Research and Surveillance Consortium (CanCORS), with a total of 9,732 patients diagnosed

EXPERT POINT OF VIEW

F

ormal discussant of the Quality Care Symposium presentation on the impact of tumor boards, Deborah Schrag, MD, MPH, Dana-Farber Cancer Institute, Boston, commended the authors for the collaborative use of data to improve quality of care. “For this study, Dr. Kehl and coauthors leveraged the considerable strengths of the Cancer Care Outcomes Research and Surveillance Consortium (CanCORS) and linked unique physicians caring for particular patients. This is as powerful an observational study as we

The upshot is that tumor board participation does seem to be associated with higher quality clinical care.

—Deborah Schrag, MD, MPH

are likely to see on this topic. The upshot is that tumor board participation does seem to be associated with higher quality clinical care,” she said.

“The study shows an association but no causal link, but physicians who practice at sites that have the wherewithal to hold tumor boards have the training, colleagues, and expertise to deliver high-quality care. In other words, the tumor boards could be an ancillary effect, not a cause, of the better outcomes seen in this study,” she continued.

This issue needs to be further studied to identify what works and what doesn’t, Dr. Schrag said. She cautioned that patients and entrepreneurs are in the wings inviting doctors to spend a half-hour on the phone participating in tumor boards. “If we don’t get our act together, companies are going to get ahead of us,” she stated. n Disclosure: Dr. Schrag reported no potential conflicts of interest.

with lung or colorectal cancer from 2003 to 2005. Of them, a cohort of 4,620 patients were included in this study, as well as 1,601 physicians who reported on their tumor board participation; of them, 1,198 were linked directly to the patients in the cohort. Physicians were asked how often they participated in tumor board meetings, whether the meetings were educational or helped in treatment-planning, whether they reviewed challenging cases only, and whether tumor board meetings focused on more than one cancer site.

Patients had a mean age of 68 years, 51% were male, 62% were married, and stage at diagnosis was evenly distributed between both types of cancers. Among physicians, 33% were medical oncologists, 15% were radiation oncologists, 37% were general surgeons, and 15% were subspecialty surgeons. Physicians treated a mean of eight lung cancer patients and eight colorectal cancer patients per month. Twenty-seven percent of physicians worked at a National Cancer Institute–designated cancer center.

Among those who ever participated in a tumor board, 83% said their tumor board primarily served a pretreatment planning function, 92% said it included evaluation of treatment decisions, 59% reviewed only challenging cases, 87% reviewed multiple tumor sites, and 12% were for educational purposes only.

Among physicians, radiation oncologists were more likely to participate in tumor boards, while surgeons and surgery subspecialists were less likely to participate. Those who worked at a Veteran’s Administration/government facility were more likely to participate, whereas those in solo or group practices were less likely.

Tumor board participation in challenging cases only was associated with lower mortality rates, and participation in educational tumor boards was associated with higher mortality.

Note of Caution Dr. Kehl cautioned that this was not a randomized trial, so one should not leap to the conclusion that tumor board participation directly improves survival. The study identifies associations rather than direct effects.

“This study supports our belief that multidisciplinary communication improves outcomes and enrollment in clinical trials. Tumor boards represent one tool that can improve care for cancer patients, and the effect is difficult to measure,” Dr. Kehl noted. n

Patterns of Participation

Disclosure: Dr. Kehl reported no potential conflicts of interest.

The study revealed different patterns of oncologist participation in multidisciplinary tumor boards. About 54% participated weekly, 26% monthly, 8% quarterly, 8% less than quarterly, and 4% said they never participated in tumor boards.

Reference 1. Kehl KL: Tumor boards among physicians caring for lung and colorectal cancer patients. Quality Care Symposium.

Abstract 179. Presented October 17, 2014.

Impact of Tumor Boards on Cancer Care

A

large observational study suggested that weekly tumor board participation by oncologists improves survival in advanced lung and colorectal cancers, increases participation in clinical trials, and leads to greater use of guideline-based curative care for early non–small cell lung cancer.

This is an observational study only, and it is difficult to quantify the direct effect of tumor board participation.

It is likely that facilities that sponsor tumor boards have improved expertise to deliver high-quality care, so participation may not be directly related to improved outcomes. n

ASCOPost.com | DECEMBER 1, 2014

PAGE 25

Quality Care Symposium Assessing the Nature of Unplanned Emergency Cancer Care Situations

By Ronald Piana

U

nplanned cancer care—emergency department presentations and other unanticipated events—can result in poor outcomes that are potentially preventable. Suzanne Tamang, PhD, Stanford University, Stanford, California, addressed this important issue in her presentation at this year’s Quality Care Symposium in Boston.1 “Avoiding unplanned care is in the interest of many health-care stakeholders. Not only is it unpleasant for patients and their caregivers, it can compromise the ability to achieve expected outcomes and can also disrupt carefully planned cancer treatments.

And as we move toward value-based payment systems, unplanned cancer care is of increasing interest to payers and providers,” said Dr. Tamang.

Goals and Methods Dr. Tamang and her colleagues conducted a study to identify and reduce unplanned episodes of unplanned care. She explained that although cancer care teams document each patient’s care trajectory in freetext notes, care outcomes are typically measured from structured patient record data and do not contain key information necessary for quality improvement efforts, such as the etiology of emergent events, or events that occur outside the facility.

“We conducted our study with the Clinical Effectiveness Council at Stanford’s Cancer Institute, looking at emergency department visits and unplanned hospitalizations. Our data-driven approach used electronic health records and captured emergent events coded in the Stanford Cancer Institute electronic health record and non-Stanford episodes, which were documented in clinician notes,” said Dr. Tamang. She continued, “After the data were captured, we combined the information from both data sources and used the emergency department presentations to

characterize their symptomatology.”

Dr. Tamang explained that the team’s quality improvement goal was to achieve a reduction in unplanned episodes of cancer care among the cohorts. “Quality measurement supports high-value care. And in order to assess the quality, we needed a benchmark to establish a better baseline, which helped inform the design of new interventions and provide continued learning for established protocols,” noted Dr. Tamang.”

Reducing Unplanned Care “The best models we have now are built from administrative data and oth-

there’s a bulk of data in the [electronic health record], of which only a small percentage is structured-based. And for the most part, a lot of this very rich clinically oriented information, much of which contains quality measures, is being left to gather dust,” stressed Dr. Tamang.

Text-Mining Pipeline The research team conducted a retrospective study of unplanned care among 3,318 patients with a new diagnosis of breast, gastrointestinal, or thoracic cancer during the years 2010 to 2013. Dr. Tamang gave a brief overview of the team’s text-mining pipeline and how they integrated structured and un-

These information extraction applications have broad implications for improved cancer quality care measures and quality improvement efforts.

—Suzanne Tamang, PhD

er structured sources for quality measures, which are fairly limited in their ability to report quality measures and patient characteristics. For instance, at Stanford we see only a partial trajectory of care. There may be other episodes of unplanned care occurring at other inpatient facilities or urgent care centers. In terms of chief-complaint analyses, one chief symptom may be unable to describe a more complex symptomatology of cancer patients who are presenting to the emergency room,” said Dr. Tamang.

Dr. Tamang explained that their innovation goal is to leverage both the structured and unstructured data that are in the electronic health record. “It’s clear that care teams document so much more data in the [electronic health record], especially in terms of quality indicators, process measures, and outcomes. So

structured data for information extraction purposes.

“The first two steps involve concept recognition during which we need to establish a terminology to annotate the note. For that we used California’s OSHPD [Office of Statewide Health Planning and Development] as our resource to find a list of the urgent care centers and other facilities with emergency departments. From the National Library of Medicine’s UMLS [Unified Medical Language System], we can extract clinical terminologies for the text-mining algorithm,” said Dr. Tamang.

The OSHPD and UMLS resources, in effect, served the team as a large dictionary of clinical terms and locations used for annotating clinician notes. “There were more than 300,000 clinician notes on patient

care for two tasks and we tagged them, which is part of the conceptrecognition process. The third step is the event detection, where we construct a patient event matrix in order to further filter and process candidate events,” said Dr. Tamang.

For all cancer patients, text mining detected more than 400 unplanned events at outside facilities with high positive predictive value. “Among breast cancer patients, pain, nausea and vomiting are documented in combination in 34% of documented emergency department presentations, and pain and infection in 29%.

Pain is consistently the most prevalent symptom up to 1 year after diagnosis, and the most common type documented is abdominal pain,” said Dr. Tamang.

Potential Benefits She noted that the application of text-mining methods could improve the quantification of morbidity outcomes by improving the estimation of unplanned care rates and by providing continued learning for symptom-driven interventions to mitigate preventable emergent care.

“Structured and unstructured [electronic health record] data sources are technically feasible to implement and beneficial for profiling symptoms and disorders associated with emergency department presentations,” said Dr. Tamang.

She concluded, “These information extraction applications have broad implications for improved cancer quality care measures and quality improvement efforts.” n

Disclosure: Dr. Tamang reported no potential conflicts of interest.

Reference 1. Tamang S, Patel MI, Finlayson S, et al: Assessing the true nature of unplanned cancer care. Quality Care Symposium. Abstract 183. Presented October 18, 2014.

IMBRUVICA® demonstrated single-agent survival in previously treated CLL INDICATIONS: IMBRUVICA® is a first-in-class Bruton’s tyrosine kinase (BTK) inhibitor indicated for the treatment of patients with: • Chronic lymphocytic leukemia (CLL) who have received at least one prior therapy • CLL with 17p deletion

Superior overall survival (OS) with IMBRUVICA® vs ofatumumab—secondary endpoint (HR=0.43; 95% CI: 0.24, 0.79); P<0.05 • 57% statistically significant reduction in the risk of death for patients in the IMBRUVICA® arm • Median OS not yet reached in either treatment arm

Superior progression-free survival (PFS) with IMBRUVICA® vs ofatumumab— primary endpoint • Median PFS not yet reached with IMBRUVICA® vs 8.1 months with ofatumumab

(HR for progression or death: 0.22; 95% CI: 0.15, 0.32); P<0.0001

78% statistically significant reduction in the risk of death or progression (independent review) 100

PFS (%)

80 60 40 20 0

Ofatumumab

P<0.0001 by log-rank test 0

3

6

Number at risk IMBRUVICA® 195 Ofatumumab 196

183 161

116 83

Months

9

12

15

Results from the randomized, multicenter, open-label, Phase 3 RESONATE™ trial of IMBRUVICA® vs ofatumumab in patients with previously treated CLL. Patients (N=391) were randomized 1:1 to receive either IMBRUVICA® 420 mg orally daily until disease progression or unacceptable toxicity or IV ofatumumab at an initial dose of 300 mg, followed 1 week later by a dose of 2000 mg weekly for 7 doses, and then every 4 weeks for 4 additional doses. Fifty-seven patients randomized to ofatumumab crossed over following Independent Review Committee (IRC)-confirmed progression to receive IMBRUVICA®. Primary endpoint: PFS as assessed by an IRC according to modified International Workshop on CLL Criteria.

HR=hazard ratio.

38 15

7 1

0 0

In patients with previously treated del 17p CLL, IMBRUVICA® demonstrated a 75% reduced risk of progression or death (HR=0.25; 95% CI: 0.14, 0.45) • Median PFS not reached with IMBRUVICA® (n=63) vs 5.8 months with ofatumumab (n=64)

Oral, once-daily dosing In CLL studies, approximately 5% of patients discontinued due to adverse events Please review the Important Safety Information on adjacent page.

IMPORTANT SAFETY INFORMATION WARNINGS AND PRECAUTIONS Hemorrhage - Grade 3 or higher bleeding events (subdural hematoma, gastrointestinal bleeding, hematuria, and post-procedural hemorrhage) have occurred in up to 6% of patients. Bleeding events of any grade, including bruising and petechiae, occurred in approximately half of patients treated with IMBRUVICA®.

The mechanism for the bleeding events is not well understood.

IMBRUVICA® may increase the risk of hemorrhage in patients receiving anti-platelet or anti-coagulant therapies. Consider the benefit-risk of withholding IMBRUVICA® for at least 3 to 7 days pre- and post-surgery depending upon the type of surgery and the risk of bleeding.

Infections - Fatal and non-fatal infections have occurred with IMBRUVICA®. Twenty-six percent of patients with CLL had infections Grade 3 or greater NCI Common Terminology Criteria for Adverse Events (CTCAE). Monitor patients for fever and infections and evaluate promptly.

Cytopenias - Treatment-emergent Grade 3 or 4 cytopenias including neutropenia (range, 23 to 29%), thrombocytopenia (range, 5 to 17%), and anemia (range, 0 to 9%) occurred in patients treated with IMBRUVICA®. Monitor complete blood counts monthly.

Atrial Fibrillation - Atrial fibrillation and atrial flutter (range, 6 to 9%) have occurred in patients treated with IMBRUVICA®, particularly in patients with cardiac risk factors, acute infections, and a previous history of atrial fibrillation.

Periodically monitor patients clinically for atrial fibrillation.

Patients who develop arrhythmic symptoms (eg, palpitations, lightheadedness) or new-onset dyspnea should have an ECG performed. If atrial fibrillation persists, consider the risks and benefits of IMBRUVICA® treatment and dose modification.

Second Primary Malignancies - Other malignancies (range, 5 to 10%) including carcinomas (range, 1 to 3%) have occurred in

© Pharmacyclics, Inc. 2014 © Janssen Biotech, Inc. 2014 11/14 PRC-00659

patients treated with IMBRUVICA®. The most frequent second primary malignancy was non-melanoma skin cancer (range, 4 to 8%).

Embryo-Fetal Toxicity - Based on findings in animals, IMBRUVICA® can cause fetal harm when administered to a pregnant woman. Advise women to avoid becoming pregnant while taking IMBRUVICA®. If this drug is used during pregnancy or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to a fetus.

ADVERSE REACTIONS The most common adverse reactions (≥20%) in the clinical trials were thrombocytopenia (56%), neutropenia (51%), diarrhea (51%), anemia (37%), fatigue (28%), musculoskeletal pain (28%), upper respiratory tract infection (28%), rash (26%), nausea (25%), and pyrexia (24%). Approximately 5% of patients receiving IMBRUVICA® discontinued treatment due to adverse events. These included infections, subdural hematomas, and diarrhea. Adverse events leading to dose reduction occurred in approximately 6% of patients.

DRUG INTERACTIONS CYP3A Inhibitors - Avoid concomitant administration with strong or moderate inhibitors of CYP3A. If a moderate CYP3A inhibitor must be used, reduce the IMBRUVICA® dose.

CYP3A Inducers - Avoid co-administration with strong CYP3A inducers.

SPECIFIC POPULATIONS Hepatic Impairment - Avoid use in patients with baseline hepatic impairment.

Please review the Brief Summary of full Prescribing Information on the following page.

To learn more, visit us at

www.IMBRUVICA.com

Brief Summary of Prescribing Information for IMBRUVICA® (ibrutinib) IMBRUVICA® (ibrutinib) capsules, for oral use See package insert for Full Prescribing Information

IMBRUVICA® (ibrutinib) capsules

INDICATIONS AND USAGE Mantle Cell Lymphoma: IMBRUVICA is indicated for the treatment of patients with mantle cell lymphoma (MCL) who have received at least one prior therapy.

Accelerated approval was granted for this indication based on overall response rate. Improvements in survival or disease-related symptoms have not been established. Continued approval for this indication may be contingent upon verification of clinical benefit in confirmatory trials [see Clinical Studies (14.1) in full Prescribing Information].

Chronic Lymphocytic Leukemia: IMBRUVICA is indicated for the treatment of patients with chronic lymphocytic leukemia (CLL) who have received at least one prior therapy [see Clinical Studies (14.2) in full Prescribing Information].

Chronic Lymphocytic Leukemia with 17p deletion: IMBRUVICA is indicated for the treatment of patients with chronic lymphocytic leukemia (CLL) with 17p deletion [see Clinical Studies (14.2) in full Prescribing Information].

CONTRAINDICATIONS None WARNINGS AND PRECAUTIONS Hemorrhage: Grade 3 or higher bleeding events (subdural hematoma, gastrointestinal bleeding, hematuria and post procedural hemorrhage) have occurred in up to 6% of patients. Bleeding events of any grade, including bruising and petechiae, occurred in approximately half of patients treated with IMBRUVICA. The mechanism for the bleeding events is not well understood.

IMBRUVICA may increase the risk of hemorrhage in patients receiving antiplatelet or anticoagulant therapies.

Consider the benefit-risk of withholding IMBRUVICA for at least 3 to 7 days pre and post-surgery depending upon the type of surgery and the risk of bleeding [see Clinical Studies (14) in full Prescribing Information].

Infections: Fatal and non-fatal infections have occurred with IMBRUVICA therapy. Twenty-five percent of patients with MCL and 26% of patients with CLL had infections Grade 3 or greater NCI Common Terminology Criteria for Adverse Events (CTCAE) [See Adverse Reactions]. Monitor patients for fever and infections and evaluate promptly.

Cytopenias: Treatment-emergent Grade 3 or 4 cytopenias including neutropenia (range, 23 to 29%), thrombocytopenia (range, 5 to 17%), and anemia (range, 0 to 9%) occurred in patients treated with IMBRUVICA. Monitor complete blood counts monthly.

Atrial Fibrillation: Atrial fibrillation and atrial flutter (range, 6 to 9%) have occurred in patients treated with IMBRUVICA, particularly in patients with cardiac risk factors, acute infections, and a previous history of atrial fibrillation. Periodically monitor patients clinically for atrial fibrillation.

Patients who develop arrhythmic symptoms (e.g., palpitations, lightheadedness) or new onset dyspnea should have an ECG performed. If atrial fibrillation persists, consider the risks and benefits of IMBRUVICA treatment and dose modification [see Dosage and Administration (2.3) in full Prescribing Information].

Second Primary Malignancies: Other malignancies (range, 5 to 10%) including carcinomas (range, 1 to 3%) have occurred in patients treated with IMBRUVICA. The most frequent second primary malignancy was non-melanoma skin cancer (range, 4 to 8%).

Embryo-Fetal Toxicity: Based on findings in animals, IMBRUVICA can cause fetal harm when administered to a pregnant woman. Ibrutinib caused malformations in rats at exposures 14 times those reported in patients with MCL and 20 times those reported in patients with CLL, receiving the ibrutinib dose of 560 mg per day and 420 mg per day, respectively. Reduced fetal weights were observed at lower exposures. Advise women to avoid becoming pregnant while taking IMBRUVICA. If this drug is used during pregnancy or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to a fetus [see Use in Specific Populations].

ADVERSE REACTIONS The following adverse reactions are discussed in more detail in other sections of the labeling: • Hemorrhage [see Warnings and Precautions] • Infections [see Warnings and Precautions] • Cytopenias [see Warnings and Precautions] • Atrial Fibrillation [see Warnings and Precautions] • Second Primary Malignancies [see Warnings and Precautions] Because clinical trials are conducted under widely variable conditions, adverse event rates observed in clinical trials of a drug cannot be directly compared with rates of clinical trials of another drug and may not reflect the rates observed in practice.

Mantle Cell Lymphoma: The data described below reflect exposure to IMBRUVICA in a clinical trial that included 111 patients with previously treated MCL treated with 560 mg daily with a median treatment duration of 8.3 months.

The most commonly occurring adverse reactions (≥ 20%) were thrombocytopenia, diarrhea, neutropenia, anemia, fatigue, musculoskeletal pain, peripheral edema, upper respiratory tract infection, nausea, bruising, dyspnea, constipation, rash, abdominal pain, vomiting and decreased appetite (see Tables 1 and 2).

The most common Grade 3 or 4 non-hematological adverse reactions (≥ 5%) were pneumonia, abdominal pain, atrial fibrillation, diarrhea, fatigue, and skin infections.

Fatal and serious cases of renal failure have occurred with IMBRUVICA therapy. Increases in creatinine 1.5 to 3 times the upper limit of normal occurred in 9% of patients.

Adverse reactions from the MCL trial (N=111) using single agent IMBRUVICA 560 mg daily occurring at a rate of ≥ 10% are presented in Table 1.

Table 1: Non-Hematologic Adverse Reactions in ≥ 10% of Patients with MCL (N=111) System Organ Class Gastrointestinal disorders

Infections and infestations

Preferred Term Diarrhea Nausea Constipation Abdominal pain Vomiting Stomatitis Dyspepsia Upper respiratory tract infection Urinary tract infection Pneumonia Skin infections Sinusitis

All Grades (%) 51 31 25 24 23 17 11

Grade 3 or 4 (%) 5 0 0 5 0 1 0

34 14 14 14 13

0 3 7 5 1

Table 1: Non-Hematologic Adverse Reactions in ≥ 10% of Patients with MCL (N=111) (continued) System Organ Class

Preferred Term

General disorders and administrative site conditions

Fatigue Peripheral edema Pyrexia Asthenia Bruising Rash Petechiae Musculoskeletal pain Muscle spasms Arthralgia Dyspnea Cough Epistaxis Decreased appetite Dehydration Dizziness Headache

Skin and subcutaneous tissue disorders Musculoskeletal and connective tissue disorders Respiratory, thoracic and mediastinal disorders Metabolism and nutrition disorders Nervous system disorders

All Grades (%)

Grade 3 or 4 (%)

41 35 18 14 30 25 11 37 14 11 27 19 11 21 12 14 13

5 3 1 3 0 3 0 1 0 0 4 0 0 2 4 0 0

Table 2: Treatment-Emergent* Decrease of Hemoglobin, Platelets, or Neutrophils in Patients with MCL (N=111) Percent of Patients (N=111) All Grades Grade 3 or 4 (%) (%) 57 17 47 29 41 9

Platelets Decreased Neutrophils Decreased Hemoglobin Decreased

* Based on laboratory measurements and adverse reactions Ten patients (9%) discontinued treatment due to adverse reactions in the trial (N=111). The most frequent adverse reaction leading to treatment discontinuation was subdural hematoma (1.8%).

Adverse reactions leading to dose reduction occurred in 14% of patients.

Patients with MCL who develop lymphocytosis greater than 400,000/mcL have developed intracranial hemorrhage, lethargy, gait instability, and headache. However, some of these cases were in the setting of disease progression.

Forty percent of patients had elevated uric acid levels on study including 13% with values above 10 mg/dL. Adverse reaction of hyperuricemia was reported for 15% of patients.

Chronic Lymphocytic Leukemia: The data described below reflect exposure to IMBRUVICA in an open label clinical trial (Study 1) that included 48 patients with previously treated CLL and a randomized clinical trial (Study 2) that included 391 randomized patients with previously treated CLL or SLL. The most commonly occurring adverse reactions in Study 1 and Study 2 (≥ 20%) were thrombocytopenia, neutropenia, diarrhea, anemia, fatigue, musculoskeletal pain, upper respiratory tract infection, rash, nausea, and pyrexia.

Approximately five percent of patients receiving IMBRUVICA in Study 1 and 2 discontinued treatment due to adverse events. These included infections, subdural hematomas and diarrhea.

Adverse events leading to dose reduction occurred in approximately 6% of patients.

Study 1: Adverse reactions and laboratory abnormalities from the CLL trial (N=48) using single agent IMBRUVICA 420 mg daily occurring at a rate of ≥ 10% are presented in Tables 3 and 4.

Table 3: Non-Hematologic Adverse Reactions in ≥ 10% of Patients with CLL (N=48) in Study 1 System Organ Class Gastrointestinal disorders

Infections and infestations

General disorders and administrative site conditions

Skin and subcutaneous tissue disorders Respiratory, thoracic and mediastinal disorders Musculoskeletal and connective tissue disorders Nervous system disorders

Preferred Term Diarrhea Constipation Nausea Stomatitis Vomiting Abdominal pain Dyspepsia Upper respiratory tract infection Sinusitis Skin infection Pneumonia Urinary tract infection Fatigue Pyrexia Peripheral edema Asthenia Chills Bruising Rash Petechiae Cough Oropharyngeal pain Dyspnea Musculoskeletal pain Arthralgia Muscle spasms Dizziness Headache Peripheral neuropathy Decreased appetite

Metabolism and nutrition disorders Neoplasms benign, malignant, Second malignancies* unspecified Injury, poisoning and Laceration procedural complications Psychiatric disorders Anxiety Insomnia Vascular disorders Hypertension *One patient death due to histiocytic sarcoma.

All Grades (%) 63 23 21 21 19 15 13

Grade 3 or 4 (%) 4 2 2 0 2 0 0

48 21 17 10 10 31 25 23 13 13 54 27 17 19 15 10 27 23 19 21 19 10 17

2 6 6 8 0 4 2 0 4 0 2 0 0 0 0 0 6 0 2 0 2 0 2

10*

0

10

2

10 10 17

0 0 8

IMBRUVICA® (ibrutinib) capsules

IMBRUVICA® (ibrutinib) capsules Avoid concomitant use of strong CYP3A inducers (e.g., carbamazepine, rifampin, phenytoin and St. John’s Wort). Consider alternative agents with less CYP3A induction [see Clinical Pharmacology (12.3) in full Prescribing Information].

Table 4: Treatment-Emergent* Decrease of Hemoglobin, Platelets, or Neutrophils in Patients with CLL (N=48) in Study 1 Percent of Patients (N=48) All Grades Grade 3 or 4 (%) (%) 71 10 54 27 44 0

Platelets Decreased Neutrophils Decreased Hemoglobin Decreased

* Based on laboratory measurements per IWCLL criteria and adverse reactions Study 2: Adverse reactions and laboratory abnormalities described below in Tables 5 and 6 reflect exposure to IMBRUVICA with a median duration of 8.6 months and exposure to ofatumumab with a median of 5.3 months in Study 2.

Table 5: Non-Hematologic Adverse Reactions ≥ 10% Reported in Study 2

System Organ Class ADR Term Gastrointestinal disorders Diarrhea Nausea Stomatitis* Constipation Vomiting General disorders and administration site conditions Fatigue Pyrexia Infections and infestations Upper respiratory tract infection Pneumonia* Sinusitis* Urinary tract infection Skin and subcutaneous tissue disorders Rash* Petechiae Bruising* Musculoskeletal and connective tissue disorders Musculoskeletal Pain* Arthralgia Nervous system disorders Headache Dizziness Injury, poisoning and procedural complications Contusion Eye disorders Vision blurred

IMBRUVICA (N=195) All Grades Grade 3 or 4 (%) (%)

Ofatumumab (N=191) All Grades Grade 3 or 4 (%) (%)

48 26 17 15 14

4 2 1 0 0

18 18 6 9 6

2 0 1 0 1

28 24

2 2

30 15

2 1

16 15 11 10

1 10 1 4

11 13 6 5

2 9 0 1

24 14 12

3 0 0

13 1 1

0 0 0

28 17

2 1

18 7

1 0

14 11

1 0

6 5

0 0

11

0

3

0

10

0

3

0

Subjects with multiple events for a given ADR term are counted once only for each ADR term.

The system organ class and individual ADR terms are sorted in descending frequency order in the IMBRUVICA arm. * Includes multiple ADR terms Table 6: Treatment-Emergent* Decrease of Hemoglobin, Platelets, or Neutrophils in Study 2

Neutrophils Decreased Platelets Decreased Hemoglobin Decreased

IMBRUVICA (N=195) All Grades Grade 3 or 4 (%) (%) 51 23 52 5 36 0

Ofatumumab (N=191) All Grades Grade 3 or 4 (%) (%) 57 26 45 10 21 0

* Based on laboratory measurements per IWCLL criteria DRUG INTERACTIONS Ibrutinib is primarily metabolized by cytochrome P450 enzyme 3A. CYP3A Inhibitors: In healthy volunteers, co-administration of ketoconazole, a strong CYP3A inhibitor, increased Cmax and AUC of ibrutinib by 29- and 24-fold, respectively. The highest ibrutinib dose evaluated in clinical trials was 12.5 mg/kg (actual doses of 840 – 1400 mg) given for 28 days with single dose AUC values of 1445 ± 869 ng • hr/mL which is approximately 50% greater than steady state exposures seen at the highest indicated dose (560 mg).

Avoid concomitant administration of IMBRUVICA with strong or moderate inhibitors of CYP3A. For strong CYP3A inhibitors used short-term (e.g., antifungals and antibiotics for 7 days or less, e.g., ketoconazole, itraconazole, voriconazole, posaconazole, clarithromycin, telithromycin) consider interrupting IMBRUVICA therapy during the duration of inhibitor use. Avoid strong CYP3A inhibitors that are needed chronically. If a moderate CYP3A inhibitor must be used, reduce the IMBRUVICA dose. Patients taking concomitant strong or moderate CYP3A4 inhibitors should be monitored more closely for signs of IMBRUVICA toxicity [see Dosage and Administration (2.4) in full Prescribing Information].

Avoid grapefruit and Seville oranges during IMBRUVICA treatment, as these contain moderate inhibitors of CYP3A [see Dosage and Administration (2.4), and Clinical Pharmacology (12.3) in full Prescribing Information].

CYP3A Inducers: Administration of IMBRUVICA with rifampin, a strong CYP3A inducer, decreased ibrutinib Cmax and AUC by approximately 13- and 10-fold, respectively.

USE IN SPECIFIC POPULATIONS Pregnancy: Pregnancy Category D [see Warnings and Precautions].

Risk Summary: Based on findings in animals, IMBRUVICA can cause fetal harm when administered to a pregnant woman. If IMBRUVICA is used during pregnancy or if the patient becomes pregnant while taking IMBRUVICA, the patient should be apprised of the potential hazard to the fetus.

Animal Data: Ibrutinib was administered orally to pregnant rats during the period of organogenesis at oral doses of 10, 40 and 80 mg/kg/day. Ibrutinib at a dose of 80 mg/kg/day was associated with visceral malformations (heart and major vessels) and increased post-implantation loss. The dose of 80 mg/kg/day in animals is approximately 14 times the exposure (AUC) in patients with MCL and 20 times the exposure in patients with CLL administered the dose of 560 mg daily and 420 mg daily, respectively. Ibrutinib at doses of 40 mg/kg/day or greater was associated with decreased fetal weights. The dose of 40 mg/kg/day in animals is approximately 6 times the exposure (AUC) in patients with MCL administered the dose of 560 mg daily.

Nursing Mothers: It is not known whether ibrutinib is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from IMBRUVICA, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.

Pediatric Use: The safety and effectiveness of IMBRUVICA in pediatric patients has not been established.

Geriatric Use: Of the 111 patients treated for MCL, 63% were 65 years of age or older. No overall differences in effectiveness were observed between these patients and younger patients. Cardiac adverse events (atrial fibrillation and hypertension), infections (pneumonia and cellulitis) and gastrointestinal events (diarrhea and dehydration) occurred more frequently among elderly patients.

Of the 391 patients randomized in Study 2, 61% were ≥ 65 years of age. No overall differences in effectiveness were observed between age groups. Grade 3 or higher adverse events occurred more frequently among elderly patients treated with IMBRUVICA (61% of patients age ≥ 65 versus 51% of younger patients) [see Clinical Studies (14.2) in full Prescribing Information].

Renal Impairment: Less than 1% of ibrutinib is excreted renally. Ibrutinib exposure is not altered in patients with Creatinine clearance (CLcr) > 25 mL/min. There are no data in patients with severe renal impairment (CLcr < 25 mL/min) or patients on dialysis [see Clinical Pharmacology (12.3) in full Prescribing Information].

Hepatic Impairment: Ibrutinib is metabolized in the liver and significant increases in exposure of ibrutinib are expected in patients with hepatic impairment. Patients with serum aspartate transaminase (AST/SGOT) or alanine transaminase (ALT/SGPT) ≥ 3.0 x upper limit of normal (ULN) were excluded from IMBRUVICA clinical trials. There is insufficient data to recommend a dose of IMBRUVICA in patients with baseline hepatic impairment [see Clinical Pharmacology (12.3) in full Prescribing Information].

Females and Males of Reproductive Potential: Advise women to avoid becoming pregnant while taking IMBRUVICA because IMBRUVICA can cause fetal harm [see Use in Specific Populations].

PATIENT COUNSELING INFORMATION See FDA-approved patient labeling (Patient Information) • Hemorrhage: Inform patients of the possibility of bleeding, and to report any signs or symptoms (blood in stools or urine, prolonged or uncontrolled bleeding). Inform the patient that IMBRUVICA may need to be interrupted for medical or dental procedures [see Warnings and Precautions].

• Infections: Inform patients of the possibility of serious infection, and to report any signs or symptoms (fever, chills) suggestive of infection [see Warnings and Precautions].

• Atrial Fibrillation: Counsel patients to report any signs of palpitations, lightheadedness, dizziness, fainting, shortness of breath, and chest discomfort [see Warnings and Precautions].

• Second primary malignancies: Inform patients that other malignancies have occurred in patients who have been treated with IMBRUVICA, including skin cancers and other carcinomas [see Warnings and Precautions].

• Embryo-fetal toxicity: Advise women of the potential hazard to a fetus and to avoid becoming pregnant [see Warnings and Precautions].

• Inform patients to take IMBRUVICA orally once daily according to their physician’s instructions and that the capsules should be swallowed whole with a glass of water without being opened, broken, or chewed at approximately the same time each day [see Dosage and Administration (2.1) in full Prescribing Information].

• Advise patients that in the event of a missed daily dose of IMBRUVICA, it should be taken as soon as possible on the same day with a return to the normal schedule the following day. Patients should not take extra capsules to make up the missed dose [see Dosage and Administration (2.5) in full Prescribing Information].

• Advise patients of the common side effects associated with IMBRUVICA [see Adverse Reactions].

Direct the patient to a complete list of adverse drug reactions in PATIENT INFORMATION. • Advise patients to inform their health care providers of all concomitant medications, including prescription medicines, over-the-counter drugs, vitamins, and herbal products [see Drug Interactions].

• Advise patients that they may experience loose stools or diarrhea, and should contact their doctor if their diarrhea persists. Advise patients to maintain adequate hydration.

Active ingredient made in China.

Distributed and Marketed by: Pharmacyclics, Inc. Sunnyvale, CA USA 94085 and Marketed by: Janssen Biotech, Inc. Horsham, PA USA 19044 Patent http://www.imbruvica.com IMBRUVICA® is a registered trademark owned by Pharmacyclics, Inc. © Pharmacyclics, Inc. 2014 © Janssen Biotech, Inc. 2014 PRC-00526 07/14

The ASCO Post | DECEMBER 1, 2014

PAGE 30

AACR Conference on Cancer Prevention Hematology

Childhood Obesity and Leukemia: Is It Time to Intervene?

By Meg Barbor

“O

besity is associated with cancer mortality,” said Steven D. Mittelman, MD, PhD, at the recent American Association for Cancer Research (AACR) International Conference on Frontiers in Cancer Prevention Research.1 Dr. Mittelman presented a wealth of data to explain the link between obesity and cancer, focusing on leukemia, and suggested there may be a variety of opportunities for intervention to improve survival.

A landmark study by Calle et al2 found that obesity is responsible for more than 90,000 cancer deaths per year in the United States, and according to the American Institute for Cancer Research (AICR), more than 100,000

(ALL) have a significantly higher risk of relapse than their leaner counterparts.

“Leukemia is the most common type of cancer in children, and relapsed leukemia is about the number 6 or 7 cancer in children, so there is a lot of work to be done,” he explained.

Underlying Mechanisms “Obesity is not a simple phenotype,” said Dr. Mittelman. Hence, the sheer number of associations and internal and external factors associated with obesity make it difficult to elucidate mechanisms in humans, stressing the need for animal models.

Using mouse models, Dr. Mittelman and colleagues found that obesity

Looking at the clinical outcomes, looking at the mouse data, and knowing what we know about adipose tissue-protecting leukemia cells, I think that some interventions in kids would certainly be justified to see if we can reduce their obesity, slow their gain in body fat, and maybe even improve their survival.

—Steven D. Mittelman, MD, PhD

cancers each year are linked to excess body fat, said Dr. Mittelman, who is Director of the Diabetes and Obesity Program at Children’s Hospital Los Angeles and Associate Professor of Pediatrics and Physiology & Biophysics at Keck School of Medicine, University of Southern California, Los Angeles.

Obesity has been shown to increase cancer incidence, and obese cancer patients experience worse outcomes than lean patients. Retrospective studies have confirmed that children who were obese at the time of diagnosis of high-risk acute lymphoblastic leukemia

accelerates the onset of spontaneous leukemia. Additionally, obese mice implanted with leukemia cells experienced poorer survival after being treated with either vincristine or asparaginase (Elspar), and adipocytes appeared to be at the root of this worse outcome.

Adipocytes attract ALL cells to migrate closer to fat cells. The fat cells absorb the chemotherapy, making the treatment unable to reach the ALL cells and less available in the leukemia microenvironment. Adipocytes also secrete asparagine, glutamine, fatty acids, and other fuels that help leukemia

cells survive, allowing them to proliferate and avoid apoptosis. “We think fat cells might be protecting nearby leukemia cells from oxidative stress, which may be part of how they’re protecting them from chemotherapies,” he ­explained.

Ultimately, Dr. Mittelman and colleagues concluded that adipocytes may contribute to a poorer prognosis in obese patients with ALL and impair their leukemia-related survival. This is cause for particular concern, considering the high prevalence of overweight and obese pediatric cancer patients, particularly among those with leukemia, suggested Dr. Mittelman.

Childhood Obesity and Leukemia About one-third of children in the United States are overweight or obese.

“We’re in Los Angeles, and almost half of our children were overweight or obese at the time of cancer diagnosis,” Dr. Mittelman said.

To further compound this problem, cancer treatment typically leads to weight gain. “In the first month of treatment, these kids’ body fat goes up by 25%,” he observed. This is due to steroid treatment intended to kill the leukemia, which also increases appetite and causes fat accumulation. As a result, high-risk ALL patients experience a sizable and cumulative burden of adipose tissue, which will likely hinder their leukemia treatment and lessen their chances of survival.

Opportunities for Intervention Evidence suggests that the consequences of obesity may be reversible.

A recently published retrospective analysis3 cited by Etan Orgel, MD, also from Children’s Hospital Los Angeles, found that those who were obese at diagnosis but lost weight and became nonobese for more than half the duration of their treatment experienced better outcomes, comparable

to their counterparts who were never overweight or obese.

“This implies that the effect of obesity to impair survival is not fixed at diagnosis,” suggested Dr. Mittelman.

“The data seem to suggest that intervening might actually help survival.

If we were to intervene to try to improve leukemia outcome, at the same time, we would likely (or hopefully) be improving some of these long-term ­complications.”

In additional laboratory experiments, Dr. Mittelman and his colleagues also found that switching obese mice to a low-fat diet at the onset of ALL treatment greatly improved their survival, giving them better outcomes than the control mice who had been raised on that same low-fat diet.

“Considering these data, looking at the clinical outcomes, looking at the mouse data, and knowing what we know about adipose tissue-protecting leukemia cells, I think that some interventions in kids would certainly be justified to see if we can reduce their obesity, slow their gain in body fat, and maybe even improve their survival,” he suggested.” n Disclosure: Dr. Mittelman reported no potential conflicts of interest.

References 1. Mittelman SD: Childhood obesity and leukemia: Opportunities for intervention. AACR International Conference on Frontiers in Cancer Prevention Research.

Presented September 30, 2014.

2. Calle EE, Rodriguez C, Walker-Thurmond K, et al: Overweight, obesity, and mortality from cancer in a prospectively studied cohort of U.S. adults. N Engl J Med 348:1625-1638, 2003.

3. Orgel E, Sposto R, Malvar J, et al: Impact on survival and toxicity by duration of weight extremes during treatment for pediatric acute lymphoblastic leukemia: A report from the Children’s Oncology Group.

J Clin Oncol 32:1331-1337, 2014.

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ASCOPost.com | DECEMBER 1, 2014

PAGE 31

EORTC-NCI-AACR Symposium Genitourinary Oncology

Patients With Advanced Papillary Kidney Cancer Respond Well to Bevacizumab/Erlotinib Combination Therapy

R

esearchers have found that patients with an advanced form of kidney cancer, for which there is no standard treatment and a very poor prognosis, respond well to a combination of two existing anticancer drugs. The combination of bevacizumab (Avastin) and erlotinib (Tarceva) produced excellent response rates with tolerable side effects in patients with advanced papillary renal cell carcinoma and in those with hereditary leiomyomatosis and renal cell cancer, a highly aggressive form of the disease. The findings were presented at the 26th EORTC-NCI-AACR Symposium on Molecular Targets and Cancer Therapeutics in Barcelona.1 “The genetic and biochemical events that lead to papillary renal cell carci-

cell carcinoma. Some forms of papillary renal cell carcinoma, particularly those associated with hereditary leiomyomatosis and renal cell cancer, are characterized by altered cellular metabolism; the tumor cells obtain energy from a process called aerobic glycolysis, and they require high levels of glucose to survive.

We believe the combination of erlotinib and bevacizumab may target this particular weakness, at least partly, by impairing glucose delivery to the tumor cells,” Dr. Srinivasan said.

Study Details This phase II clinical trial included 41 patients with advanced papillary renal cell carcinoma (20 with advanced hereditary leiomyomatosis and renal cell can-

The combination of erlotinib and bevacizumab for treating patients with advanced papillary renal cell carcinoma shows excellent response rates with tolerable side effects. This is particularly true of patients with hereditary leiomyomatosis and renal cell cancer.

—Ramaprasad Srinivasan, MD, PhD

noma are different to those that lead to the more common form of kidney cancer, clear cell renal carcinoma,” said Ramaprasad Srinivasan, MD, PhD, Head of the Molecular Cancer Therapeutics Section, Urologic Oncology Branch, of the National Cancer Institute in Bethesda, Maryland.

“Treatments that are effective in clear cell renal cell carcinoma are not particularly effective in papillary renal

cer and 21 with advanced sporadic papillary renal cell carcinoma). Nineteen of the patients had received at least one previous systemic therapy, such as sunitinib (Sutent), that had not been successful in preventing their disease progressing. Patients received bevacizumab 10 mg/kg given intravenously once every 2 weeks, combined with erlotinib 150 mg taken orally every day. Treatment was continued until disease progression or unac-

ceptable toxic side effects.

“Almost all the patients with hereditary leiomyomatosis and renal cell cancer responded with their tumours either shrinking or remaining stable and not progressin,” Dr. Srinivasan said.

The overall response rate was 65%, with 13 patients showing tumor shrinkage of more than 30% and 7 patients with stable disease. “Many of the responses were long-lasting; some of patients have remained on the study for 3 years or more, which is a significant since metastatic hereditary leiomyomatosis and renal cell cancer is uniformly fatal and patients usually die within a year or so,” he added.

Among the patients with sporadic papillary renal cell carcinoma, approximately one-third demonstrated very good, often durable, partial responses.

The overall response rate as 29%, 6 patients showed tumor shrinkage, and 12 patients had stable disease.

The median progression-free survival in the hereditary leiomyomatosis and renal cell cancer cohort was 24.2 months, while for sporadic papillary renal cell carcinoma cohort it was 7.4 months. This compares well with existing survival times for patients on other treatments. “The median progression-free survival for metastatic papillary renal cell carcinoma appears to be less than 6 months with most regimens commonly used today,” Dr. Srinivasan said. “This is also true for patients with metastatic hereditary leiomyomatosis and renal cell cancer, who generally demonstrate rapidly progressive fatal disease.

Manageable Side Effects Treatment was well tolerated, and most patients reported a good quality of life. Side effects were mostly mild or moderate and included high blood pressure, acne, proteinuria, and fatigue, which could be managed effectively with drugs or other supportive measures. One patient died from a gastrointestinal hemorrhage, which may have been related to the bevacizumab.

“The combination of erlotinib and bevacizumab for treating patients with advanced papillary renal cell carcinoma shows excellent response rates with tolerable side effects. This is particularly true of patients with hereditary leiomyomatosis and renal cell cancer,” Dr. Srinivasan concluded. “The current data are sufficiently encouraging for this combination to be explored further in larger trials as a possible standard-of-care treatment for papillary renal cell carcinoma patients. We are in the process of designing these studies.

It is also important to try and identify specific subgroups of patients most likely to benefit from this regimen and our group is working on this issue.” n

Disclosure: The study authors reported no potential conflicts of interest.

Reference 1. Srinivasan R, et al: Mechanism based targeted therapy for hereditary leiomyomatosis and renal cell cancer (HLRCC) and sporadic papillary renal cell carcinoma: interim results from a phase 2 study of bevacizumab and erlotinib. EORTC-NCI-AACR Symposium on Molecular Targets and Cancer Therapeutics. Abstract 5. Presented November 19, 2014.

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The ASCO Post | DECEMBER 1, 2014

PAGE 32

Journal Spotlight Hematology

CD19-Directed CAR T Cells Produce Sustained Remission in Relapsed/Refractory Acute Lymphoblastic Leukemia

By Matthew Stenger

I

n a study reported in The New England Journal of Medicine, Shannon L. Maude, MD, PhD, of Children’s Hospital of Philadelphia, and Noelle Frey, MD, of the Perelman School of Medicine, University of Pennsylvania, and colleagues reported achieving sustained remissions in children and adults with

With a follow-up period of 2 to 24 months, sustained remissions were observed in 19 patients, with 15 receiving no further treatment; these remissions were associated with persistence of CTL019 and B-cell aplasia, which continued for up to 2 years. Six-month event-free survival was 67% (95% con-

CTL019 was associated with a high remission rate, even among patients for whom stem cell transplantation had failed, and durable remissions up to 24 months were observed.

—Shannon L. Maude, MD, PhD, and Noelle Frey, MD

relapsed/refractory acute lymphoblastic leukemia (ALL) using autologous CD19-targeted chimeric antigen receptor (CAR)–modified T cells.1

Study Details In the study, 25 patients aged 5 to 22 years at Children’s Hospital of Philadelphia and 5 patients aged 26 to 60 years at Hospital of the University of Pennsylvania with relapsed or refractory ALL received infusions of autologous T cells transduced with a CD19-directed CAR (CTL019) lentiviral vector at doses of 0.76×106 to 20.6×106 CTL019 cells/kg.

Of the 30 patients, 26 had B-cell ALL in first to fourth relapse, 3 had primary refractory B-cell ALL, and 1 had relapsed T-cell ALL expressing CD19; 18 had relapsed disease after allogeneic stem cell transplantation and 3 had disease previously shown to be refractory to blinatumomab, a bispecific antibody that binds to both CD3 on T cells and CD19.

Remissions Complete remission was achieved in 27 patients (90%), including 2 of the 3 patients with blinatumomab-refractory disease and 15 of 18 patients who had undergone stem cell transplantation.

fidence interval [CI] = 51%–88%), and overall survival was 78% (95% CI = 65%–95%).

Relapses Seven patients with complete remission had relapse between 6 weeks and 8.5 months after infusion, with 3 developing relapses after early loss of CTL019modified T cells at 2 weeks to 3 months and the relapsed ALL remaining CD19positive in each case. After recovery of normal B cells at 2 to 3 months, one relapse occurred rapidly at 3 months, and two were delayed, occurring at 6 and 8.5 months. One patient, who had minimal residual disease (0.22%) at 1 month, had relapse with CD19-positive ALL at 6 weeks, which progressed rapidly and resulted in death; this patient had highly refractory disease in fourth relapse at baseline and was not eligible for stem cell transplantation. Loss of expression of CD19 in leukemia cells resulted in

relapse in three patients, including one who had received blinatumomab therapy; CTL019 cells were not lost at the time of relapse in these patients.

Expansion and Persistence of CTL019 Detection of CTL019 cells by flow cytometry showed in vivo proliferation.

The median peak proportion in blood was 39.8% of CTL019-positive cells in CD3-positive cells (range 4.4%–69.3%) in responders compared with 0.2%, 0.6%, and 8.2% of CD3-positive cells at peak levels in the three nonresponders.

CTL019 cells were detectable in blood for up to 11 months, with a probability of persistence at 6 months of 68% (95% CI = 50%–92%).

Further, CTL019 sequences remained detectable by quantitative polymerase chain reaction (PCR) assay until 2 years in patients with sustained remissions.

PCR showed high levels of proliferation, with all patients having peak levels > 5,000 copies/µg of genomic DNA and 26 having peak levels > 15,000 copies/µg.

Persistence of CTL019 was observed in one patient after reinfusion at 3 months and 6 months due to early loss of CTL019 cells with B-cell recovery. The patient with the longest remission (2 years) exhibited B-cell aplasia (absence of CD19-positive cells) for 1 year after CTL019 cells were no longer detectable on flow cytometry; this finding suggests functional persistence of CTL019 cells below flow cytometry limits of detection but at levels detectable by means of quantitative PCR. Overall, the probability of relapse-free B-cell aplasia at 6 months was 73% (95% CI = 57%–94%).

Cytokine-Release Syndrome No deaths appeared to be related to the study treatment. Seven patients died after disease progression or relapse, including one who died of myelodysplastic syndrome that developed during ALL remission and withdrew from the study to receive other treatment.

All patients exhibited cytokine-release syndrome. Severe cytokine-release syndrome, requiring intensive care with

Update on CTL019 Therapy ■■ CTL019 treatment resulted in complete remission in 90% of 30 patients.

■■ Sustained remissions of up to 2 years were observed in 19 patients, with 15 receiving no further treatment.

varying degrees of respiratory support, developed in eight patients (27%), with all requiring vasopressor support for hypotension. These patients also exhibited coagulopathy, with clinical bleeding observed in three (10%).

Severe cytokine-release syndrome started a median of 1 day after infusion, compared with a median of 4 days in patients with nonsevere syndrome (P = .005). Inflammatory markers, including C-reactive protein and ferritin, were elevated in all patients; patients with severe reactions had higher peak levels of interleukin-6 (P < .001), C-reactive protein (P = .02), ferritin (P = .005), interferon-γ (P < .001), and soluble interleukin-2 receptor (P < .001). Higher disease burden at baseline (percentage of blast cells in marrow before infusion) was significantly associated with an increased risk of severe cytokine-release syndrome (P = .002), and severity was also associated with higher levels of CTL019-positive CD8 cells (P = .012) and CTL019-positive CD3 cells (P = .026).

Nine patients with severe reactions received the anti–interleukin-6 receptor antibody tocilizumab, which produced rapid reduction of fever and stabilization of blood pressure over 1 to 3 days. Six patients also received short glucocorticoid course and four received a second dose of tocilizumab (Actemra) for recurrence of the cytokine-release syndrome after transient improvement with the first dose. All patients recovered fully, with complete reversal of symptoms and normalization of lab results.

Relapses were observed in two of the nine patients who received immunosuppressive therapy for cytokine-release syndrome.

The investigators concluded: “Chimeric antigen receptor–modified T-cell therapy against CD19 was effective in treating relapsed and refractory ALL. CTL019 was associated with a high remission rate, even among patients for whom stem cell transplantation had failed, and durable remissions up to 24 months were observed.” n

Disclosure: The study was funded by Novartis and others. For full disclosures of the study authors, visit www.nejm.org.

Reference 1. Maude SL, Frey N, Shaw PA, et al: Chimeric antigen receptor T cells for sustained remissions in leukemia. N Engl J Med 371:1507-1517, 2014.

See commentary by Andrew Evens, DO, MSc, on page 33.

ASCOPost.com | DECEMBER 1, 2014

PAGE 33

Perspective Hematology

CAR T-Cell Therapy in Cancer: Driving Toward the Clinic

By Andrew Evens, DO, MSc

C

himeric antigen receptor (CAR) T-cell therapy represents a novel and promising therapeutic advance in cancer.1,2 It constitutes a form of personalized therapy that harnesses adoptive cell transfer through genetic engineering of autologous T cells. The initial step in this therapeutic paradigm involves leukapheresis of the patient’s peripheral T cells; this is followed by ex vivo transduction (by retrovirus or lentivirus), which encodes components of a chimeric T-cell receptor. These components include a fragment of a monoclonal antibody that targets the desired tumor antigen as well as signaling domains, the latter being responsible for activation, proliferation, survival, and cytokine production of T cells; cells are then reinfused into the patient. An important advance that has helped make this therapeutic platform more convenient is the relatively straightforward manufacturing process of the peripheral blood-derived re-engineered T cells.

Collectively, these gene-modified immune cells combine the specificity of B cells (via antibody binding) with the proliferative and cytotoxic capabilities of T cells. Binding via a chimeric antibody confers several advantages over classic T-cell–receptor activation, namely the ability to bind to the specific target of interest independent of major histocompatibility complex (MHC) restriction and immune tolerance of the T-cell repertoire. An MHC-independent process may be leveraged to target a multitude of cell-surface markers.

To date, CAR T-cells recognizing the B-cell–associated molecule CD19 have emerged as the most prominent treatment strategy.3 CD19 is a cellsurface protein that is expressed in the majority of B-cell lymphoid malignancies, thus representing an attractive therapeutic approach in these cancers. CTL019 (formerly known as CART19) is one of the most developmentally advanced constructs in this class of personalized immunotherapies. CTL019 is a secondgeneration CAR T cell that combines an extracellular anti-CD19 antibody Dr. Evens is Director of Tufts Cancer Center and Chief of the Division of Hematology/Oncology at Tufts Medical Center and Tufts University School of Medicine

fragment with costimulatory intracellular signaling domains, CD3-zeta and CD137 (4-1BB).

‘Unparalleled’ Results in the Refractory Setting As reviewed in this issue of The ASCO Post, Maude and colleagues conducted pilot clinical trials at the University of Pennsylvania to assess the safety and feasibility of CTL019 CAR T-cell therapy in patients with relapsed and refractory CD19-positive cancers.4 Over an approximate 2-year period, 30 patients were treated (25 children and

sion and subsequently experienced progressive disease, relapse was associated with early loss of CTL019-modified T cells in three patients, and there was absence of CD19 expression in the leukemic cells of three other patients.

This remarkable clinical efficacy was tempered by the development of cytokine-release syndrome, a serious and potentially life-threatening toxicity.

Although there were no deaths attributed to CTL019 therapy, 8 of 30 patients (27%) required intensive care support, including vasopressors for hypotension.

Nine patients were treated with the

These rapid responses and overall highly efficacious results [with CTL019 CAR T-cell therapy] are unparalleled in this refractory and difficult-to-treat patient population.

—Andrew Evens, DO, MSc

5 adults); all patients had relapsed/refractory acute lymphoblastic leukemia (ALL), with all but the one having B-cell disease (one patient had T-cell ALL that expressed CD19). Furthermore, 18 of 30 patients (60%) had relapsed disease after prior allogeneic stem cell transplantation and 3 additional patients had primary refractory disease.

Impressively, 27 (90%) of 30 patients experienced morphologic complete remission 1 month after CTL019 infusion. Further, 22 of 30 ALL patients (73%) had no evidence of minimal residual disease, as measured by multiparametric flow cytometry. These rapid responses and overall highly efficacious results are unparalleled in this refractory and difficult-to-treat patient population.

Of the 27 patients who entered complete remission, 19 (70%) remained in remission, although followup is relatively short (ie, median follow-up of 7 months). The probability of persistence of CTL019 at 6 months was 68%, and CTL019 sequences remained detectable by quantitative polymerase chain reaction through 2 years in patients with sustained remissions. Moreover, all remissions were associated with persistence of CTL019.

Among patients who achieved remis-

anti–interleukin-6 receptor antibody tocilizumab (Actemra), which produced prompt reduction of fever and stabilization of blood pressure; four patients required a second dose of tocilizumab.

All patients in this study ultimately recovered from this cytokine storm, with complete reversal of symptoms and normalization of laboratory data.

Despite the universal occurrence of the aforementioned cytokine release syndrome toxicity, the clinical efficacy of CTL019 CAR T-cell therapy is unprecedented in this patient population. On July 7, 2014, the U.S. Food and Drug Administration granted breakthrough therapy status to CTL019 CAR T-cell therapy for the treatment of adult and pediatric relapsed/refractory ALL.

Challenges Still Ahead Despite the early success of CAR T-cell therapy, there are a number of roadblocks that must be navigated.5 They include optimization of dosing and mitigation of toxicity along with ongoing legal proceedings regarding intellectual property. In addition, it will be important to manage scalability and cost to ensure accessibility and affordability. These issues and others must be

addressed to expand the utility of this innovative therapy to other hematologic malignancies as well as solid tumors.

Solid tumor studies are ongoing with CAR T-cell therapy (eg, via CA19-9 and carcinoembryonic antigen constructs), although tumor bulk, tumor heterogeneity, and off-target effects are challenges that need to be overcome.6,7 A strategy being examined to potentially enhance efficacy is a treatment platform using T cells redirected for universal cytokine killing (TRUCK).8 TRUCKs are CAR T cells that are engineered with the additional capacity to induce IL-12 production in the tumor. Release of IL-12 attracts an innate immune response, including macrophages and natural killer cells, which may subsequently augment the antitumor response. Other potential rational treatment approaches that may augment the efficacy of CAR T-cell therapy, include use in combination with other immunology-based therapeutics such as programmed cell death protein 1 (PD-1) blockade.9 Altogether, CAR T-cell therapy represents a significant and exciting advance in the treatment of cancer.

Furthermore, CTL019 represents a likely first-in-class personalized T-cell immunotherapeutic that may soon be available to patients in the clinic. Continued study of these agents in clinical trials will be critical in helping to define the most optimal role for this highly novel and personalized therapy. n Disclosure: Dr. Evens reported no potential conflicts of interest.

References 1. Corrigan-Curay J, Kiem HP, Baltimore D, et al: T-cell immunotherapy: Looking forward. Mol Ther 22:1564-1574, 2014.

2. Maus MV, Grupp SA, Porter DL, June CH: Antibody-modified T cells: CARs take the front seat for hematologic malignancies. Blood 123:2625-2635, 2014.

3. Lee DW, Kochenderfer JN, StetlerStevenson M, et al: T cells expressing CD19 chimeric antigen receptors for acute lymphoblastic leukaemia in children and young adults: A phase 1 doseescalation trial. Lancet. October 10, 2014 (early release online).

4. Maude SL, Frey N, Shaw PA, et al: Chimeric antigen receptor T cells for sustained remissions in leukemia. N Engl J continued on page 37

Continue treatment.* 1-4 Extend survival.

For patients with advanced nonsquamous† NSCLC Median Overall Survival: 13.9 months with ALIMTA single agent vs 11.0 months with placebo; HR: 0.78 (95% CI: 0.64-0.96); P=0.02 * Only patients with stable disease or better are eligible for continuation maintenance with ALIMTA single agent.

After initial treatment with ALIMTA/cisplatin, patients who achieve stable disease or better may be eligible for continued therapy with single-agent ALIMTA

ALIMTA continuation maintenance showed extended overall survival with a safety profile consistent with previously reported ALIMTA single-agent trials

† Includes adenocarcinoma, large cell carcinoma, and other histologies except those with squamous cell type.

ALIMTA is indicated in combination with cisplatin therapy for the initial treatment of patients with locally advanced or metastatic nonsquamous non-small cell lung cancer.

ALIMTA is indicated for the maintenance treatment of patients with locally advanced or metastatic nonsquamous non-small cell lung cancer whose disease has not progressed after four cycles of platinum-based first-line chemotherapy.

Limitations of Use: ALIMTA is not indicated for the treatment of patients with squamous cell non-small cell lung cancer.

Myelosuppression is usually the dose‐limiting toxicity with ALIMTA therapy.

Select Important Safety Information Contraindication ALIMTA is contraindicated in patients who have a history of severe hypersensitivity reaction to pemetrexed.

Warnings and Precautions Premedication regimen: Prior to treatment with ALIMTA, initiate supplementation with oral folic acid and intramuscular vitamin B12 to reduce the severity of hematologic and gastrointestinal toxicity of ALIMTA. Do not substitute oral vitamin B12 for intramuscular vitamin B12. Administer dexamethasone the day before, the day of, and the day after ALIMTA administration.

Why consider maintenance therapy*?

After completion of first-line therapy, several studies have shown that 50% of patients with advanced NSCLC off active treatment will experience rapid disease progression (within 3 months)‡2,5-8 You may have patients* with advanced nonsquamous† NSCLC who are eligible for continuation maintenance with single-agent ALIMTA

57%% 57

57% (n=539) of patients in the PARAMOUNT trial were eligible for continuation maintenance therapy (ALIMTA or placebo) from the 939 patients who received ALIMTA/cisplatin induction therapy1,4

PARAMOUNT PARAMOUNT PARAMOUNT PARAMOUNT

SAFETY SAFETY PP rr oo ff ii ll ee

The safety profile of ALIMTA continuation maintenance in patients with advanced nonsquamous NSCLC was consistent with the safety profile of single-agent ALIMTA in previously reported phase III trials1-4

of patients patients of

2.9 2.9

months months months months

Median OS OS Median

2.9 months’ median overall survival advantage was demonstrated with single-agent ALIMTA following induction with ALIMTA/cisplatin compared with placebo in patients* with advanced nonsquamous NSCLC1,4 Median overall survival (months) (95% CI): ALIMTA + BSC (n=359): 13.9 (12.8-16.0); Placebo + BSC (n=180): 11.0 (10.0-12.5); Unadjusted HRa,b: 0.78 (95% CI: 0.64-0.96); P=0.02

NCCN NCCN Guidelines®®®® Guidelines

NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for NSCLC Category 1§: NCCN Guidelines® recommend continuation of pemetrexed for injection (ALIMTA) after 4-6 cycles of cisplatin and pemetrexed chemotherapy in the absence of disease progression for patients with advanced or metastatic nonsquamous NSCLC9

‡ The median PFS for the referenced studies was less than 3 months. § Based upon high-level evidence, there is uniform National Comprehensive Cancer Network® (NCCN®) consensus that the intervention is appropriate. a OS was calculated from time of randomization, after completion of 4 cycles of ALIMTA/cisplatin induction therapy. b An HR <1.0 indicates that the maintenance treatment with ALIMTA is associated with lower risk of death compared to treatment with placebo.

Select Important Safety Information

Common Terminology Criteria for Adverse Events Drug-related Toxicities (Version 3.0) Adverse Reactions: Grades 3-4 In the PARAMOUNT trial, grades 3-4 adverse reactions occurring more frequently (≥2%) with ALIMTA as a single agent (n=333) versus placebo (n=167), respectively, were anemia (4.8% vs 0.6%), neutropenia (3.9% vs 0%), and fatigue (4.5% vs 0.6%).

Adverse Reactions: All Grades In the PARAMOUNT trial, adverse reactions of any severity (all grades) occurring more frequently (≥5%) with ALIMTA as a single agent (n=333) versus placebo (n=167), respectively, were anemia (15% vs 4.8%), neutropenia (9% vs 0.6%), fatigue (18% vs 11%), nausea (12% vs 2.4%), vomiting (6% vs 1.8%), mucositis/stomatitis (5% vs 2.4%), and edema (5% vs 3.6%).

See the complete data at ALIMTAhcp.com/data See the Important Safety Information and Brief Summary for ALIMTA on the following pages.

References: 1. ALIMTA (pemetrexed for injection) [package insert]. Indianapolis, IN: Eli Lilly and Company; 2013.

2. Ciuleanu T, et al. Lancet. 2009;374(9699):1432‐1440. 3. Hanna N, et al. J Clin Oncol. 2004;22(9):1589‐1597.

4. Paz-Ares LG, et al. J Clin Oncol. 2013;31(23):2895-2902. 5. Fidias PM, et al. J Clin Oncol. 2009;27(4):591-598.

6. Paz-Ares L, et al. Lancet Oncol. 2012;13(3):247-255. 7. Cappuzzo F, et al. Lancet Oncol. 2010;11(6):521-529.

8. Zhang L, et al. Lancet Oncol. 2012;13(5):466-475. 9. Referenced with permission from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Non-Small Cell Lung Cancer V.4.2014. © National Comprehensive Cancer Network, Inc 2014. All rights reserved. Accessed August 18, 2014. To view the most recent and complete version of the guidelines, go online to NCCN.org. NATIONAL COMPREHENSIVE CANCER NETWORK®, NCCN®, NCCN GUIDELINES®, and all other NCCN content are trademarks owned by the National Comprehensive Cancer Network, Inc.

Indications for ALIMTA ALIMTA is indicated in combination with cisplatin therapy for the initial treatment of patients with locally advanced or metastatic nonsquamous non-small cell lung cancer.

ALIMTA is indicated for the maintenance treatment of patients with locally advanced or metastatic nonsquamous non-small cell lung cancer whose disease has not progressed after four cycles of platinum-based first-line chemotherapy.

Limitations of Use: ALIMTA is not indicated for the treatment of patients with squamous cell non-small cell lung cancer.

Important Safety Information for ALIMTA Myelosuppression is usually the dose-limiting toxicity with ALIMTA therapy.

Contraindication ALIMTA is contraindicated in patients who have a history of severe hypersensitivity reaction to pemetrexed.

Warnings and Precautions Prior to treatment with ALIMTA, patients must be instructed to initiate supplementation with oral folic acid. Additionally, intramuscular injections of vitamin B12 are also required prior to ALIMTA treatment. Folic acid and vitamin B12 supplementation should be continued throughout treatment as they may reduce the severity of treatment-related hematologic and GI toxicities.

Dexamethasone or its equivalent should be administered the day before, the day of, and the day after ALIMTA treatment.

ALIMTA can suppress bone marrow function, as manifested by neutropenia, thrombocytopenia, and anemia (or pancytopenia). Reduce doses for subsequent cycles based on hematologic and nonhematologic toxicities.

ALIMTA should not be administered to patients with a creatinine clearance <45 mL/min. One patient with severe renal impairment (creatinine clearance 19 mL/min) who did not receive folic acid and vitamin B12 died of drug-related toxicity following administration of ALIMTA alone.

Caution should be used when administering NSAIDs concurrently with ALIMTA to patients with mild to moderate renal insufficiency (creatinine clearance from 45 to 79 mL/min). Patients with mild to moderate renal insufficiency should avoid taking NSAIDs with short elimination half-lives for a period of 2 days before, the day of, and 2 days following administration of ALIMTA. In the absence of data regarding potential interaction between ALIMTA and NSAIDs with longer half-lives, all patients taking these NSAIDs should interrupt dosing for at least 5 days before, the day of, and 2 days following ALIMTA administration. If concomitant administration of NSAIDs is necessary, patients should be monitored closely for toxicity, especially myelosuppression, renal, and gastrointestinal toxicity. No dose adjustment of ALIMTA is needed with concomitant NSAIDs in patients with normal renal function.

Do not initiate a cycle of treatment in patients unless the ANC is ≥1500 cells/mm3, the platelet count is ≥100,000 cells/mm3, and creatinine clearance is ≥45 mL/min.

Abbreviated Adverse Reactions (% incidence) – 1st-line advanced nonsquamous non-small cell lung cancer (NS NSCLC) The most severe adverse reactions (grades 3-4) with ALIMTA in combination with cisplatin versus gemcitabine in combination with cisplatin, respectively, for the 1st-line treatment of patients with advanced nonsquamous non-small cell lung cancer (NSCLC) were neutropenia (15% vs 27%); leukopenia (5% vs 8%); thrombocytopenia (4% vs 13%); anemia (6% vs 10%); fatigue (7% vs 5%); nausea (7% vs 4%); vomiting (6% vs 6%); anorexia (2% vs 1%); creatinine elevation (1% vs 1%); and diarrhea (1% vs 2%).

Common adverse reactions (all grades) with ALIMTA in combination with cisplatin versus gemcitabine in combination with cisplatin, respectively, were nausea (56% vs 53%); fatigue (43% vs 45%); vomiting (40% vs 36%); anemia (33% vs 46%); neutropenia (29% vs 38%); anorexia (27% vs 24%); constipation (21% vs 20%); leukopenia (18% vs 21%); stomatitis/pharyngitis (14% vs 12%); alopecia (12% vs 21%); diarrhea (12% vs 13%); thrombocytopenia (10% vs 27%); neuropathy/sensory (9% vs 12%); taste disturbance (8% vs 9%); rash/desquamation (7% vs 8%); dyspepsia/heartburn (5% vs 6%); and creatinine elevation (10% vs 7%).

Abbreviated Adverse Reactions (% incidence) – Maintenance in advanced NS NSCLC following non-ALIMTA containing, platinum-based induction therapy The most severe adverse reactions (grades 3-4) with ALIMTA as a single agent versus placebo, respectively, for the maintenance treatment of patients with locally advanced nonsquamous non-small cell lung cancer (NS NSCLC) following non-ALIMTA containing platinum-based induction therapy were anemia (3% vs 1%); neutropenia (3% vs 0%); leukopenia (2% vs 1%); fatigue (5% vs 1%); nausea (1% vs 1%); anorexia (2% vs 0%); mucositis/stomatitis (1% vs 0%); diarrhea (1% vs 0%); infection (2% vs 0%); and neuropathy-sensory (1% vs 0%).

Common adverse reactions (all grades) with ALIMTA as a single agent versus placebo, respectively, after non-ALIMTA containing platinum-based induction therapy were anemia (15% vs 6%); neutropenia (6% vs 0%); leukopenia (6% vs 1%); increased ALT (10% vs 4%); increased AST (8% vs 4%); fatigue (25% vs 11%); nausea (19% vs 6%); anorexia (19% vs 5%); vomiting (9% vs 1%); mucositis/stomatitis (7% vs 2%); diarrhea (5% vs 3%); infection (5% vs 2%); neuropathy-sensory (9% vs 4%); and rash/ desquamation (10% vs 3%).

Abbreviated Adverse Reactions (% incidence) – Maintenance in advanced NS NSCLC following ALIMTA plus cisplatin induction therapy The most severe adverse reactions (grades 3-4) with ALIMTA as a single agent versus placebo, respectively, for the maintenance treatment of patients with locally advanced nonsquamous non-small cell lung cancer (NS NSCLC) following ALIMTA plus cisplatin induction therapy were anemia (4.8% vs 0.6%); neutropenia (3.9% vs 0%); and fatigue (4.5% vs 0.6%).

Common adverse reactions (all grades) with ALIMTA as a single agent versus placebo, respectively, following ALIMTA plus cisplatin induction therapy were anemia (15% vs 4.8%); neutropenia (9% vs 0.6%); fatigue (18% vs 11%); nausea (12% vs 2.4%); vomiting (6% vs 1.8%); mucositis/stomatitis (5% vs 2.4%); and edema (5% vs 3.6%).

Pregnancy Category D—ALIMTA may cause fetal harm when administered to a pregnant woman. Women should be apprised of the potential hazard to the fetus and should be advised to use effective contraceptive measures to prevent pregnancy during treatment with ALIMTA.

For safety and dosing guidelines, see complete Warnings and Precautions, Adverse Reactions, and Dosage and Administration sections in the Brief Summary of Prescribing Information on the adjacent page.

Drug Interactions See Warnings and Precautions for specific information regarding NSAID administration in patients with renal insufficiency.

PM_HCP_ISI_NSCLC1M_17OCT2012

Concomitant administration of nephrotoxic drugs or substances that are tubularly secreted could result in delayed clearance of ALIMTA. Use in Specific Patient Populations It is recommended that nursing be discontinued if the mother is being treated with ALIMTA or discontinue the drug, taking into account the importance of the drug for the mother.

Efficacy of ALIMTA in pediatric patients has not been demonstrated. The most common toxicities reported in the studied pediatric patients were hematological (leukopenia, neutropenia/granulocytopenia, anemia, thrombocytopenia, and lymphopenia), liver function abnormalities (increased ALT/AST), fatigue, and nausea.

Dosage and Administration Guidelines Complete blood cell counts, including platelet counts and periodic chemistry tests, which include renal and hepatic function tests, should be performed on all patients receiving ALIMTA. Dose adjustments at the start of a subsequent cycle should be based on nadir hematologic counts or maximum nonhematologic toxicity from the preceding cycle of therapy. Modify or suspend therapy according to the Dosage Reduction Guidelines in the full Prescribing Information.

PM92674

09/2014 PRINTED IN USA © Lilly USA, LLC 2014. ALL RIGHTS RESERVED. ALIMTA® is a registered trademark of Eli Lilly and Company.

ASCOPost.com | DECEMBER 1, 2014

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Perspective

Andrew Evens, DO, MSc continued from page 33

Med 371:1507-1517, 2014.

5. Amos SM, Duong CP, Westwood JA, et al: Autoimmunity associated with immunotherapy of cancer. Blood 118:499-509, 2011.

6. Junghans RP: Strategy escalation: An emerging paradigm for safe clinical development of T cell gene therapies. J Transl Med 8:55, 2010.

7. Moon EK, Wang LC, Dolfi DV, et al: Multifactorial T-cell hypofunction that is reversible can limit the efficacy of chime-

ALIMTA® (pemetrexed for injection) BRIEF SUMMARY. For complete safety, please consult the full Prescribing Information.

1 INDICATIONS AND USAGE 1.1 Nonsquamous Non-Small Cell Lung Cancer — Combination with Cisplatin ALIMTA® is indicated in combination with cisplatin therapy for the initial treatment of patients with locally advanced or metastatic nonsquamous non-small cell lung cancer.

1.2 Nonsquamous Non-Small Cell Lung Cancer — Maintenance ALIMTA is indicated for the maintenance treatment of patients with locally advanced or metastatic nonsquamous non-small cell lung cancer whose disease has not progressed after four cycles of platinum-based first-line chemotherapy.

1.5 Limitations of Use ALIMTA is not indicated for the treatment of patients with squamous cell non-small cell lung cancer [see Clinical Studies (14.1, 14.2, 14.3) in the full Prescribing Information].

2 DOSAGE AND ADMINISTRATION 2.1 Combination Use with Cisplatin for Nonsquamous Non-Small Cell Lung Cancer or Malignant Pleural Mesothelioma The recommended dose of ALIMTA is 500 mg/m2 administered as an intravenous infusion over 10 minutes on Day 1 of each 21-day cycle. The recommended dose of cisplatin is 75 mg/m2 infused over 2 hours beginning approximately 30 minutes after the end of ALIMTA administration. See cisplatin package insert for more information.

2.2 Single-Agent Use as Maintenance Following First-Line Therapy, or as a Second-Line Therapy The recommended dose of ALIMTA is 500 mg/m2 administered as an intravenous infusion over 10 minutes on Day 1 of each 21-day cycle.

2.3 Premedication Regimen and Concurrent Medications Vitamin Supplementation Instruct patients to initiate folic acid 400 mcg to 1000 mcg orally once daily beginning 7 days before the first dose of ALIMTA. Continue folic acid during the full course of therapy and for 21 days after the last dose of ALIMTA [see Warnings and Precautions (5.1)].

Administer vitamin B12 1 mg intramuscularly 1 week prior to the first dose of ALIMTA and every 3 cycles thereafter. Subsequent vitamin B12 injections may be given the same day as treatment with ALIMTA [see Warnings and Precautions (5.1)].

Corticosteroids Administer dexamethasone 4 mg by mouth twice daily the day before, the day of, and the day after ALIMTA administration [see Warnings and Precautions (5.1)].

2.4 Laboratory Monitoring and Dose Reduction/Discontinuation Recommendations Monitoring Complete blood cell counts, including platelet counts, should be performed on all patients receiving ALIMTA. Patients should be monitored for nadir and recovery, which were tested in the clinical study before each dose and on days 8 and 15 of each cycle.

Patients should not begin a new cycle of treatment unless the ANC is ≥1500 cells/mm3, the platelet count is ≥100,000 cells/mm3, and creatinine clearance is ≥45 mL/min. Periodic chemistry tests should be performed to evaluate renal and hepatic function [see Warnings and Precautions (5.5)].

Dose Reduction Recommendations Dose adjustments at the start of a subsequent cycle should be based on nadir hematologic counts or maximum nonhematologic toxicity from the preceding cycle of therapy. Treatment may be delayed to allow sufficient time for recovery. Upon recovery, patients should be retreated using the guidelines in Tables 1-3, which are suitable for using ALIMTA as a single-agent or in combination with cisplatin.

Table 1: Dose Reduction for ALIMTA (single-agent or in combination) and Cisplatin — Hematologic Toxicities Nadir ANC <500/mm3 and nadir platelets ≥50,000/mm3.

75% of previous dose (pemetrexed and cisplatin).

Nadir platelets <50,000/mm3 without bleeding 75% of previous dose regardless of nadir ANC. (pemetrexed and cisplatin).

Nadir platelets <50,000/mm3 with bleedinga, 50% of previous dose regardless of nadir ANC. (pemetrexed and cisplatin). a These criteria meet the CTC version 2.0 (NCI 1998) definition of ≥CTC Grade 2 bleeding.

If patients develop nonhematologic toxicities (excluding neurotoxicity) ≥Grade 3, treatment should be withheld until resolution to less than or equal to the patient’s pre-therapy value. Treatment should be resumed according to guidelines in Table 2.

Table 2: Dose Reduction for ALIMTA (single-agent or in combination) and Cisplatin — Nonhematologic Toxicitiesa,b Dose of ALIMTA Dose of Cisplatin (mg/m2) (mg/m2) Any Grade 3 or 4 toxicities except mucositis 75% of previous 75% of previous dose dose Any diarrhea requiring hospitalization (irrespective 75% of previous 75% of previous of Grade) or Grade 3 or 4 diarrhea dose dose ALIMTA® (pemetrexed for injection)

PV 8927 AMP

ric antigen receptor-transduced human T cells in solid tumors. Clin Cancer Res 20:4262-4273, 2014.

8. Chmielewski M, Hombach AA, Abken H: Of CARs and TRUCKs: Chimeric antigen receptor (CAR) T cells engineered with an inducible cytokine

Table 2: Dose Reduction for ALIMTA (single-agent or in combination) and Cisplatin — Nonhematologic Toxicitiesa,b (Cont.)

Grade 3 or 4 mucositis

50% of previous dose

100% of previous dose

a

NCI Common Toxicity Criteria (CTC).

Excluding neurotoxicity (see Table 3).

In the event of neurotoxicity, the recommended dose adjustments for ALIMTA and cisplatin are described in Table 3. Patients should discontinue therapy if Grade 3 or 4 neurotoxicity is experienced.

Table 3: Dose Reduction for ALIMTA (single-agent or in combination) and Cisplatin — Neurotoxicity b

Dose of ALIMTA Dose of Cisplatin CTC Grade (mg/m2) (mg/m2) 0-1 100% of previous dose 100% of previous dose 2 100% of previous dose 50% of previous dose Discontinuation Recommendation ALIMTA therapy should be discontinued if a patient experiences any hematologic or nonhematologic Grade 3 or 4 toxicity after 2 dose reductions or immediately if Grade 3 or 4 neurotoxicity is observed.

Renally Impaired Patients In clinical studies, patients with creatinine clearance ≥45 mL/min required no dose adjustments other than those recommended for all patients. Insufficient numbers of patients with creatinine clearance below 45 mL/min have been treated to make dosage recommendations for this group of patients [see Clinical Pharmacology (12.3) in the full Prescribing Information]. Therefore, ALIMTA should not be administered to patients whose creatinine clearance is <45 mL/min [see Laboratory Monitoring and Dose Reduction/ Discontinuation Recommendations (2.4) in the full Prescribing Information]. Caution should be exercised when administering ALIMTA concurrently with NSAIDs to patients whose creatinine clearance is <80 mL/min [see Drug Interactions (7.1)].

3 DOSAGE FORMS AND STRENGTHS ALIMTA, pemetrexed for injection, is a white to either light-yellow or green-yellow lyophilized powder available in sterile single-use vials containing 100 mg or 500 mg pemetrexed.

4 CONTRAINDICATIONS ALIMTA is contraindicated in patients who have a history of severe hypersensitivity reaction to pemetrexed.

5 WARNINGS AND PRECAUTIONS 5.1 Requirement for Premedication and Concomitant Medication to Reduce Toxicity Vitamin Supplementation Prior to treatment with ALIMTA, initiate supplementation with oral folic acid and intramuscular vitamin B12 to reduce the severity of hematologic and gastrointestinal toxicity of ALIMTA [see Dosage and Administration (2.3)]. Do not substitute oral vitamin B12 for intramuscular vitamin B12. In clinical studies, the incidence of the following Grade 3-4 toxicities were higher in patients with mesothelioma who were never supplemented as compared to patients who were fully supplemented with folic acid and vitamin B12 prior to and throughout ALIMTA treatment: neutropenia [38% versus 23%], thrombocytopenia [9% versus 5%], febrile neutropenia [9% versus 0.6%], and infection with neutropenia [6% versus. 0].

Corticosteroids Administer dexamethasone the day before, the day of, and the day after ALIMTA administration [see Dosage and Administration (2.3)].

5.2 Bone Marrow Suppression ALIMTA can suppress bone marrow function, as manifested by neutropenia, thrombocytopenia, and anemia (or pancytopenia) [see Adverse Reactions (6.1)]; myelosuppression is usually the dose-limiting toxicity. Dose reductions for subsequent cycles are based on nadir ANC, platelet count, and maximum nonhematologic toxicity seen in the previous cycle [see Dosage and Administration (2.4)].

5.3 Decreased Renal Function ALIMTA is primarily eliminated unchanged by renal excretion. No dosage adjustment is needed in patients with creatinine clearance ≥45 mL/min. Insufficient numbers of patients have been studied with creatinine clearance <45 mL/min to give a dose recommendation.

Therefore, ALIMTA should not be administered to patients whose creatinine clearance is <45 mL/min [see Dosage and Administration (2.4)].

One patient with severe renal impairment (creatinine clearance 19 mL/min) who did not receive folic acid and vitamin B12 died of drug-related toxicity following administration of ALIMTA alone.

5.4 Use with Non-Steroidal Anti-Inflammatory Drugs (NSAIDs) with Mild to Moderate Renal Insufficiency Caution should be used when administering NSAIDs concurrently with ALIMTA to patients with mild to moderate renal insufficiency (creatinine clearance from 45 to 79 mL/min) [see Drug Interactions (7.1)].

5.5 Required Laboratory Monitoring Obtain a complete blood count and renal function tests at the beginning of each cycle and as needed. Do not initiate a cycle of treatment unless the ANC is ≥1500 cells/mm3, the ALIMTA® (pemetrexed for injection)

PV 8927 AMP

to modulate the tumor stroma. Immunol Rev 257:83-90, 2014.

9. John LB, Devaud C, Duong CP, et al: Anti-PD-1 antibody therapy potently enhances the eradication of established tumors by gene-modified T cells. Clin Cancer Res 19:5636-5646, 2013.

The ASCO Post | DECEMBER 1, 2014

PAGE 38

Journal Spotlight Molecular Oncology

Power Behind ‘Master’ Gene for Cancer Discovered

A

study at The University of Texas MD Anderson Cancer Center, Houston, led by Mong-Hong Lee, PhD, Professor of Molecular and Cellular Oncology, has demonstrated the significance of CSN6 in regulating Myc which may well open up a new pathway for treat-

ing and killing tumors. The study results are published in a recent issue of Nature Communications.1 “We have discovered that CSN6 is a strong oncogene that is frequently overexpressed and significantly speeds up tumor growth in many types of cancer,” said Dr.

Lee. “Furthermore, CSN6 also affects the expression of Myc in tumors.”

Myc is a proto-oncogene or master cancer gene that spurs tumor growth in a variety of cancers including breast, lung, colon, brain, skin, leukemia, prostate, pancreas, stomach, and bladder.

Dr. Lee said that the study findings are important because targeting Myc is a challenging task due to its unique protein structure. Even though it has been studied for decades, no effective inhibitor for Myc has been successfully developed. His team’s study found that inhibiting CSN6

3 3 platelet count is ≥100,000 cells/mm platelet , and count creatinine is ≥100,000 cells/mm clearance is ≥45 mL/min , and creatinine [see Dosage clearance is ≥45 mL/min Incidence [see1% Dosage to 5% Incidence 1% to 5% Body as a Whole — febrile neutropenia, Body as ainfection, Whole —pyrexia febrile neutropenia, infection, pyrexia and Administration (2.4)]. and Administration (2.4)]. lacrimati General Disorders — dehydration General Disorders — dehydration In 5.6 Pregnancy Category D 5.6 Pregnancy Category D Metabolism and Nutrition — increased AST,and increased Metabolism NutritionALT— increased AST, increased ALT Based on its mechanism of action, Based ALIMTA on itscan mechanism cause fetal of action, harm when ALIMTA administered can cause fetal harm when administered Renal — creatinine renal failureclearance decrease, renal failure Renal — creatinine to a pregnant woman. Pemetrexed to a pregnant administered woman.intraperitoneally Pemetrexed administered to mice during intraperitoneally to mice during clearance decrease, Special organogenesis was embryotoxic, organogenesis fetotoxic andwas teratogenic embryotoxic, in mice fetotoxic at greater and than teratogenic 1/833rdin mice at greater thanSenses 1/833rd— conjunctivitisSpecial Senses — conjunctivitis than 1% Incidence Less than 1% the recommended human dose. the Ifrecommended ALIMTA is used human during dose. pregnancy, If ALIMTAor isif used the patient during pregnancy,Incidence or if theLess patient becomes pregnant while takingbecomes this drug,pregnant the patient whileshould takingbethis apprised drug, the of the patient potential should be apprisedCardiovascular of the potential— arrhythmia Cardiovascular — arrhythmia Disorders — chest painGeneral Disorders — chest pain C hazard to the fetus. Women of childbearing hazard to thepotential fetus. Women shouldofbechildbearing advised to avoid potential becoming should be advised toGeneral avoid becoming Metabolism and Nutrition — increased GGTand Nutrition — increased GGT Metabolism In pregnant. Women should be advised pregnant. to use Women effective shouldcontraceptive be advised to measures use effective to prevent contraceptive measures to prevent Neurology — motor neuropathyNeurology — motor neuropathy Ta pregnancy during treatment with pregnancy ALIMTA [see during Usetreatment in Specificwith Populations ALIMTA [see (8.1)].

Use in Specific Populations (8.1)].

Non-Small Cell Lung Cancer (NSCLC) – Maintenance Non-Small Cell Lung Cancer (NSCLC) – Maintenance of the 50 6 ADVERSE REACTIONS 6 ADVERSE REACTIONS ALIMTA Maintenance FollowingALIMTA Non-ALIMTA Containing, Platinum-Based Maintenance Following Non-ALIMTAInduction Containing, Platinum-Based In maintena Therapy Therapy T 6.1 Clinical Trials Experience 6.1 Clinical Trials Experience Table 5 provides the frequency Table 5 and severity of adverse reactions of reactions reported provides the frequency andreported severityinof>5% adverse doses in of Because clinical trials are conducted Because under clinicalwidely trials varying are conducted conditions, underadverse widely varying conditions, adverse the 438trials patients ALIMTA the 218 patients with the received 438 patients withmaintenance NSCLC who and received ALIMTA maintenance and the 218 patie reduction reactions rates cannot be directly reactions compared rates tocannot rates be in other directlyclinical compared trials toandrates mayinnot other clinical andwith mayNSCLC not who NSCLC who received placebo following a platinum-based induction therapy.

NSCLC who received placebo following a platinum-based induction therapy. the place reflect the rates observed in clinical reflectpractice. the rates observed in clinical practice.

All patients immediately following cycles of platinum-based All patients received study4therapy immediately following 4 cycles ofarm platinum and In clinical trials, the most common In clinical adverse trials,reactions the most(incidence common ≥20%) adverseduring reactions (incidence ≥20%)received during study therapy for locally advanced or metastatic NSCLC.advanced Patients inorboth study arms were fully in both studyacid treatment for locally metastatic NSCLC. Patients armsandw therapy with ALIMTA as a single-agent therapy with were ALIMTA fatigue, as nausea, a single-agent and anorexia. were fatigue, Additional nausea,treatment and anorexia.

Additional supplemented withused folic in acid and vitamin B12. with folic acid and vitamin B12. supplemented common adverse reactions (incidence common≥20%) adverseduring reactions therapy (incidence with ALIMTA ≥20%)when during used therapy in with ALIMTA when Tabl combination with cisplatin included combination vomiting,with neutropenia, cisplatin included leukopenia, vomiting, anemia, neutropenia, stomatitis/leukopenia, Table anemia, stomatitis/Reactions inTable 5: Adverse Patients 5: Adverse Receiving Reactions ALIMTAinversus Patients Placebo Receiving ALIMTA versusALIMTA Placeb a a pharyngitis, thrombocytopenia, pharyngitis, and constipation. thrombocytopenia, and constipation. in NSCLC Following Platinum-Based in NSCLCInduction Following Therapy Platinum-Based Induction Therapy Non-Small Cell Lung Cancer (NSCLC) Non-Small – ALIMTA Cell Lung in Combination Cancer (NSCLC) with Cisplatin – ALIMTA in Combination with Cisplatin ALIMTA Placebo ALIMTA Placebo Advers Table 4 provides the frequencyTable and 4severity provides of the adverse frequency reactions and that severity haveofbeen adverse reactions that have been (N=438) (N=438) (N=218) (N=218)Sys Reactionb Reactionb reported in >5% of 839 patients reported with NSCLC in >5% who of were 839 patients randomized with toNSCLC studywho and were received randomized to study and received ALIMTA plus cisplatin and 830ALIMTA patientsplus withcisplatin NSCLC and who830 werepatients randomized with NSCLC to studywho andwere randomized to study and All Grades Grade 3-4 All Grades Grade 3-4 All Grades Grad received gemcitabine plus cisplatin. received All patients gemcitabine received plus study cisplatin. therapy All patients as initialreceived treatment study therapy as initial treatment Toxicity (%) Toxicity (%) Toxicity (%) Toxicity (%) Toxicity (%) AllToxic Adv for locally advanced or metastatic for locally NSCLCadvanced and patients or metastatic in both treatment NSCLC and groups patients were infully both treatment groups were fully All Adverse Reactions All66 Adverse Reactions 16 37 66 16 4 37 Labora supplemented with folic acid and supplemented vitamin B12. with folic acid and vitamin B12.

Laboratory Laboratory Hema Table 4: Adverse Reactions inTable Fully 4:Supplemented Adverse Reactions in Fully Supplemented Hematologic Hematologic Anem a a Patients Receiving ALIMTA plus Patients Cisplatin Receiving in NSCLC ALIMTA plus Cisplatin in NSCLC 13 6 6 3 15 15 Anemia Anemia Neut 03 06 0 3 6 Neutropenia Neutropenia ALIMTA/cisplatin Gemcitabine/cisplatin ALIMTA/cisplatin Gemcitabine/cisplatin Clinica 1 1 1 2 2 6 6 Leukopenia Leukopenia (N=839) (N=839) (N=830) (N=830) Reactionb Reactionb Const Hepatic Grade 3-4 Hepatic Symp All Grades Grade 3-4 All Grades Grade 3-4 All Grades Increased ALT Increased 10 ALT 0 10 4 0 4 Fatig Toxicity (%) Toxicity (%) Toxicity (%) Toxicity (%) Toxicity (%) Toxicity (%) Increased AST Increased 8 AST 0 48 0 4 Gastr All Adverse Reactions All90 Adverse Reactions 37 91 90 53 37 91 53 Clinical Clinical Naus Laboratory Laboratory Constitutional Constitutional Vom Hematologic Hematologic Symptoms Symptoms Muco 10 10 46 46 6 6 33 33 Anemia Anemia Fatigue Fatigue 25 5 11 25 15 11 Gener 27 27 38 38 15 15 29 29 Neutropenia Neutropenia Gastrointestinal Gastrointestinal Edem 85 8 21 21 5 18 18 Leukopenia Leukopenia 1 6 6 1 19 19 Nausea Nausea a 13 13 27 27 4 4 10 10 Thrombocytopenia Thrombocytopenia Adverse 02 5 5 2 19 19 Anorexia Anorexia adverse Renal Renal 0 19 1 0 9 Vomiting Vomiting to those Creatinine elevation Creatinine 10 elevation 1 10 7 1 7 1 01 27 2 1 7 Mucositis/stomatitis Mucositis/stomatitis b NCI CT 01 35 3 1 5 Diarrhea Diarrhea Clinical Clinical A Constitutional Constitutional Infection Infection 5 2 25 02 2 erythropo Symptoms Symptoms Neurology Neurology factors (6 Fatigue Fatigue 43 7 45 43 57 45 5 Neuropathy-sensory Neuropathy-sensory 9 1 49 01 4 T Gastrointestinal Gastrointestinal frequent Dermatology/Skin Dermatology/Skin 47 4 53 53 7 56 56 Nausea Nausea In Rash/Desquamation Rash/Desquamation 10 0 10 3 0 3 6 6 36 36 6 40 40 Vomiting Vomiting a 24 12 1 this table aacut 24 2 27 27 Anorexia Anorexia For the purpose of Foroff theofpurpose 5% wasofused this for table inclusion a cut offofofall5% events was where used fortheinclusion of all events w 01 0 a possible relationship 20 20 1 21 21 Constipation Constipation reporter considered reporter considered to ALIMTA. a possible relationship to ALIMTA. In b 12 b 01 0 Criteria version 12 1 14 14 Stomatitis/Pharyngitis Stomatitis/Pharyngitis Refer to NCI CTCAE Refer3.0 to NCI for each CTCAE Grade Criteria of toxicity. version 3.0 for each Grade of toxicity.

21 13 13 No clinically2 relevant differencesNoin clinically 1 12 12 Diarrhea Diarrhea Grade 3/4relevant adversedifferences reactions were in Grade seen3/4 in patients adverse reactions were seen in 0 0 ethnic origin, 65 6 on age, gender, 0 5 Dyspepsia/Heartburn Dyspepsia/Heartburn based based or on histology age, gender, except ethnic a higher origin,incidence or histology of Grade except3/4 a higher incidence of Gr fatigue for Caucasian patients compared fatigue fortoCaucasian non-Caucasian patientspatients compared (6.5% to versus non-Caucasian 0.6%). patients (6.5% versus 0 Neurology Neurology Safetyforwas patients assessed who by received exposure at least for patients one dosewho of received at least one Neuropathy-sensory Neuropathy-sensory 9 0 9 01 12 12 Safety was1 assessed by exposure ALIMTA (N=438).0cThe incidence ALIMTA of adverse (N=438). reactions The incidence was evaluated of adverse for patients reactionswho was evaluated for patien Taste disturbance Taste 8 disturbance0c 89 0c 9 received ≤6 cycles of ALIMTA, and received compared ≤6 cycles to patients of ALIMTA, who received and compared >6 cycles to patients of ALIMTA. who received >6 cycles of N Dermatology/Skin Dermatology/Skin Increases in adverse Increases grades)inwere adverse observed reactions with(all longer grades) exposure; were observed however no with longer exposure; how c reactions (all Alopecia Alopecia 12 0c 12 21 10c 21 1 clinically relevant differences inclinically Grade 3/4 relevant adverse differences reactions inwere Grade seen.

3/4 adverse reactions were seen. increase Rash/Desquamation Rash/Desquamation 7 0 87 01 8 Consistent 1with the higher incidence Consistent of anemia with the (allhigher grades)incidence on the ALIMTA of anemia arm,(all usegrades) on the ALIMTAAa Se a For the purpose of this table aacut Foroff theofpurpose 5% wasofused this for table inclusion a cut offofofall5% events was where used fortheinclusion of all events (mainly where the of transfusions RBC) and of transfusions erythropoiesis (mainly stimulating RBC) and agents erythropoiesis (ESAs; erythropoietin stimulating agents (ESAs; erythr reporter considered a possible relationship reporter considered to ALIMTA. a possible relationship to ALIMTA. and darbepoetin) were higher inand thedarbepoetin) ALIMTA arm compared were highertointhetheplacebo ALIMTAarm arm(transfusions compared to the placebo arm (tranE b b Refer to NCI CTC Criteria version Refer 2.0 for to NCI eachCTC Grade Criteria of toxicity. version 2.0 for each Grade of toxicity. 9.5% versus 3.2%, ESAs 5.9% 9.5% 6.2 P versusversus 1.8%).3.2%, ESAs 5.9% versus 1.8%). c c T According to NCI CTC Criteria version According 2.0, to thisNCIadverse CTC Criteria event term version should 2.0, this onlyadverse be reported event term should be reported Theonly following additional adverseThe reactions following were additional observed adverse in patients reactions with were non-small observed in patients with no ALIMTA. as Grade 1 or 2. as Grade 1 or 2. cell lung cancer who received ALIMTA. cell lung cancer who received ALIMTA. size, it i No clinically relevant differences Noinclinically adverserelevant reactionsdifferences were seenininadverse patientsreactions based were seenIncidence in patients1%based to 5% Incidence 1% to 5% relations on histology. on histology.

Dermatology/Skin — alopecia, Dermatology/Skin pruritus/itching — alopecia, pruritus/itching Gastrointestinal T In addition to the lower incidence In addition of hematologic to the lower toxicityincidence on the ALIMTA of hematologic and cisplatin toxicity on the ALIMTA and cisplatin— constipationGastrointestinal — constipation General General (in the Disorders absence—ofedema, neutropenia) fever (in the absence of neutropenia) combina arm, use of transfusions (RBC and arm,platelet) use of transfusions and hematopoietic (RBC and growth platelet) factors andwas hematopoietic lower in growth factors was Disorders lower in — edema, fever Hematologic — thrombocytopenia Hematologic — thrombocytopenia B the ALIMTA and cisplatin arm compared the ALIMTA to and the gemcitabine cisplatin armand compared cisplatintoarm. the gemcitabine and cisplatin arm.

— decreased creatinine Renalclearance, — decreased increased creatinine creatinine, clearance, decreased increased creatinine, de G The following additional adverseThe reactions following were additional observed adverse in patients reactions with were non-small observed in patientsRenal with non-small glomerular filtration rate glomerular filtration rate G cell lung cancer randomly assigned cell lung to receive cancerALIMTA randomly plusassigned cisplatin.to receive ALIMTA plus cisplatin.

ALIMTA® (pemetrexed for injection) ALIMTA® (pemetrexed for injection) PV 8927 AMP

019517_elalns_PM92674_OT_fa.indd 2

ALIMTA®PV (pemetrexed 8927 AMP for injection) ALIMTA® (pemetrexed for injection) PV 8927 AMP

9/26/14 1:32 PM

ALIMTA PV 892

ASCOPost.com | DECEMBER 1, 2014

PAGE 39

Journal Spotlight

quickly destabilizes Myc, greatly impairing metastasis and tumor growth.

“This has the potential to unlock a promising and completely new door to effectively eliminating tumors and suppressing cancers that overexpress Myc,” said Dr. Lee. n Disclosure: The study was funded by the National Institutes of Health, the Fidelity

Foundation, and the Susan G. Komen Breast Cancer Foundation. The authors reported no potential conflicts of interest.

Reference 1. Chen J, et al: CSN6 drives carcinogenesis by positively regulating Myc stability. Nat Commun. November 14, 2014 (early release online).

The ASCO Post Wants to Hear From You

Injury, poisoning, Injury,complications poisoning, and — procedural Radiation recall complications has been— Radiation recall has been Special Senses — ocular surface Special disease Senses(including — ocular conjunctivitis), surface disease increased (including conjunctivitis), increasedand procedural reported in patients who have previously reported inreceived patientsradiotherapy. who have previously received radiotherapy. ion lacrimation Respiratory — interstitial pneumonitis Respiratory — interstitial pneumonitis ncidence Less than 1% Incidence Less than 1% Skin — Bullous conditions, including Skin — Stevens-Johnson Bullous conditions, syndrome including andStevens-Johnson toxic epidermal syndrome and toxic epidermal Cardiovascular — supraventricular Cardiovascular arrhythmia— supraventricular arrhythmia necrolysis. Some cases were fatal. necrolysis. Some cases were fatal.

Dermatology/Skin — erythemaDermatology/Skin multiforme — erythema multiforme General Disorders — febrile neutropenia, General Disorders allergic — reaction/hypersensitivity febrile neutropenia, allergic reaction/hypersensitivity 7 DRUG INTERACTIONS 7 DRUG INTERACTIONS Neurology — motor neuropathyNeurology — motor neuropathy 7.1 Non-Steroidal Anti-Inflammatory 7.1 Non-Steroidal Drugs (NSAIDs) Anti-Inflammatory Drugs (NSAIDs) Renal — renal failure Renal — renal failure Although four timesibuprofen a day) can (400 decrease mg four the times clearance a day) ofcan decrease the clearance of Continuation of ALIMTA as Continuation Maintenance ofFollowing ALIMTA ALIMTA as Maintenance Plus Platinum Following ALIMTA Plus ibuprofen Platinum (400 mg Although pemetrexed, it can be administered pemetrexed, with ALIMTA it can be in patients administered with normal with ALIMTA renal infunction patients with normal renal function nduction Therapy Induction Therapy (creatinine clearance ≥80 mL/min). (creatinine No doseclearance adjustment ≥80 mL/min). of ALIMTA isNo needed dose adjustment with concomitant of ALIMTA is needed with concomitant Table 6 provides the frequencyTable 6 and severity provides of adverse the frequency reactions andreported severity inof >5% adverse reactions reported in >5% NSAIDs in patients with normal renal NSAIDs function in patients [see Clinical with normal Pharmacology renal function (12.3)]. [see Clinical Pharmacology (12.3)].

00 patients with non-squamous of the 500NSCLC patients whowith received non-squamous at least one NSCLC cyclewho of ALIMTA received at least one cycle of ALIMTA Caution should be used whenCaution administering should be NSAIDs used concurrently when administering with ALIMTA NSAIDs concurrently with ALIMTA nduction ance (n=333) or placebo maintenance (n=167) on(n=333) the continuation or placebo maintenance (n=167) ontrial. the continuation maintenance trial. to patients with mild to moderate to patients renal insufficiency with mild to (creatinine moderate renal clearance insufficiency from 45(creatinine to clearance from 45 to The median of maintenance cycles The median administered of maintenance to patientscycles receiving administered one or more to patients receiving one or more 79 mL/min).

79 mL/min). nf >5% of maintenance therapydoses was 4ofonmaintenance both the pemetrexed therapy was and4 placebo on both arms. the pemetrexed Dose and placebo arms.

Dose NSAIDs with short eliminationNSAIDs half-lives with(e.g., shortdiclofenac, eliminationindomethacin) half-lives (e.g., should diclofenac, indomethacin) should ents ns forwith adverse events occurred reductions in for 3.3% adverse of patients eventsinoccurred the ALIMTA in 3.3% arm and of patients 0.6% inin thebe avoided ALIMTA armforand 0.6% in a period of 2 days be avoided before, the for aday period of, and of 2 days 2 days before, following theadministration day of, and 2 days following administration ebo arm. Dose delays for theadverse placeboevents arm. Dose occurred delays in 22% for adverse of patients events in the occurred ALIMTAin 22%ofofALIMTA. patients in the ALIMTA of ALIMTA. dm-based 16% in the placebo arm. armPatients and 16% in both in thestudy placebo armsarm. werePatients supplemented in both study with folic arms were supplemented withoffolic In the absence data regardingInpotential the absence interaction of databetween regarding ALIMTA potential andinteraction NSAIDs withbetween ALIMTA and NSAIDs with were fully 12. d vitamin B acid and vitamin B12. longer half-lives (e.g., meloxicam, longer nabumetone), half-lives patients (e.g., meloxicam, taking these nabumetone), NSAIDs should patients interrupt taking these NSAIDs should interrupt a b a b dosing for atReceiving least 5 days before, dosing the day for at of, least and 2 days 5 days following before, theALIMTA day of,administration. and 2 days following If ALIMTA administration. If le 6: Selected Adverse Reactions Table 6: Selected OccurringAdverse in ≥5% Reactions of Patients Occurring Receiving in ≥5% of Patients concomitant administration concomitant is necessary, administration patientsofshould NSAIDsbeismonitored necessary,closely patients for should be monitored closely for Aboin Nonsquamous NSCLC ALIMTA Following in Nonsquamous ALIMTA PlusNSCLC Cisplatin Following Induction ALIMTA Therapy Plus Cisplatin Induction Therapy of NSAIDs toxicity, especially myelosuppression, toxicity,renal, especially and gastrointestinal myelosuppression, toxicity. renal, and gastrointestinal toxicity.

ALIMTA Placebo ALIMTA Placebo 7.2 Nephrotoxic Drugs 7.2 Nephrotoxic Drugs (N=333) (N=167) (N=333) (N=167) se Reaction Organ Adverse Reaction Organ ALIMTA is primarily eliminated ALIMTA unchanged is primarily renally aseliminated a result ofunchanged glomerularrenally filtration as a result of glomerular filtration a and Term a stem and Term System All Grades Grade 3-4 All Gradesa Grades Grade 3-4 3-4aa All Gradesa Grades 3-4a and tubular secretion. Concomitant and tubular administration secretion.ofConcomitant nephrotoxic administration drugs could result of nephrotoxic in drugs could result in de 3-4 Toxicity (%) Toxicity (%) Toxicity (%) Toxicity (%) Toxicity (%) Toxicity (%) delayed clearance of ALIMTA.delayed Concomitant clearance administration of ALIMTA.ofConcomitant substances administration that are also of substances that are also city (%) verse Reactions All53 Adverse Reactions 17 34 53 4.8 17 34 tubularly secreted4.8 (e.g., probenecid) tubularly couldsecreted potentially (e.g.,result probenecid) in delayed could clearance potentially of ALIMTA. result in delayed clearance of ALIMTA. 4 atory Laboratory 8 USE IN SPECIFIC POPULATIONS 8 USE IN SPECIFIC POPULATIONS atologic Hematologic 8.1 Pregnancy 8.1 Pregnancy mia Anemia 15 4.8 4.8 15 0.6 4.8 4.8 0.6 Teratogenic Effects - PregnancyTeratogenic Category DEffects [see Warnings - Pregnancy and Precautions Category D [see (5.6)].Warnings and Precautions (5.6)].

1 tropenia Neutropenia 9 3.9 0.6 9 3.9 0 0.6 0 Based on its mechanism of action, Based ALIMTA on itscan mechanism cause fetal of action, harm when ALIMTA administered can cause fetal harm when administered 0 al1 Clinical to a pregnant woman. There are to anopregnant adequatewoman. and well There controlled are no studies adequateof and ALIMTA well incontrolled studies of ALIMTA in titutional Constitutional pregnant women. Pemetrexedpregnant was embryotoxic, women. Pemetrexed fetotoxic, and wasteratogenic embryotoxic, in mice. fetotoxic, In and teratogenic in mice. In ptoms Symptoms mice, repeated intraperitonealmice, dosesrepeated of pemetrexed intraperitoneal when given dosesduring of pemetrexed organogenesis when given during organogenesis 0 gue Fatigue 18 4.5 11 18 0.6 4.5 11 fetal malformations 0.6 caused (incomplete caused fetal ossification malformations of talus(incomplete and skull bone; ossification about 1/833rd of talus and skull bone; about 1/833rd 0 2 the recommended intravenousthe human recommended dose on a intravenous mg/m2 basis), human on a mg/m and dose cleft palate (1/33rd basis), and cleft palate (1/33rd rointestinal Gastrointestinal the recommended dose on intravenous a mg/m2 basis). humanEmbryotoxicity dose on a mg/m was 2 basis). Embryotoxicity was 0 2.4 2.4recommended0 intravenousthehuman 0.3 0.3 12 12 sea Nausea characterized by increased embryo-fetal characterized deaths by increased and reduced embryo-fetal litter sizes.deaths If ALIMTA andisreduced used litter sizes. If ALIMTA is used 0 0 1.8 1.8 0 6 6 miting Vomiting during duringbecomes pregnancy, pregnant or if the while patient takingbecomes this drug, pregnant the patient while taking this drug, the patient 0 2.4 2.4 pregnancy,0or if the patient 0.3 0.3 5 5 ositis/stomatitis Mucositis/stomatitis 1 should be apprised of the potential shouldhazard be apprised to the fetus. of the Women potentialofhazard childbearing to the potential fetus. Women of childbearing potential ral Disorders General Disorders should be advised to use effective should contraceptive be advisedmeasures to use effective to prevent contraceptive pregnancymeasures during theto prevent pregnancy during the ma Edema 5 0 3.6 5 0 3.6 0 treatment with ALIMTA. treatment with ALIMTA. 1 a e0reactions of any severity Adverse (all grades) reactions occurring of anymore severity frequently (all grades) (≥5%)occurring or Grademore 3-4 frequently (≥5%) or Mothers Grade 3-4 8.3 Nursing 8.3 Nursing Mothers e0 reactions occurring more adverse frequently reactions (≥2%) occurring in ALIMTA-treated more frequently patients (≥2%) compared in ALIMTA-treated Itpatients is notcompared known whether ALIMTA It is not or its known metabolites whether are ALIMTA excreted or itsin metabolites human are excreted in human e0 receiving placebo to those receiving placebo milk. Because many drugs aremilk. Because excreted in human many milk, drugsand arebecause excretedofinthe human potential milk,for and because of the potential for b TCAE 0 Criteria version 3.0 NCI CTCAE Criteria version 3.0 serious adverse reactions in nursing seriousinfants adversefrom reactions ALIMTA,in anursing decisioninfants shouldfrom be ALIMTA, made to a decision should be made to Administration of RBC (13% versus Administration 4.8%) and platelet of RBC(1.5% (13% versus 4.8%) 0.6%) and transfusions, platelet (1.5%discontinue versus 0.6%)nursing transfusions, or discontinue discontinue the drug,nursing taking or intodiscontinue account thetheimportance drug, taking of into the drug account the importance of the drug 0 oiesis stimulating agents erythropoiesis (12% versus stimulating 7%), andagents granulocyte (12% colony versus stimulating 7%), and granulocyte colony stimulating for the mother. for the mother.

6% versus 0) were higher factors in the(6% ALIMTA versus arm0) compared were higher to inthetheplacebo ALIMTAarm. arm compared to the placebo arm.

8.4 Pediatric Use 8.4 Pediatric Use 0 following additional GradeThe3 following The or 4 adverse additional reactions Gradewere 3 orobserved 4 adverse morereactions were observed more Efficacy of ALIMTA in pediatricEfficacy patientsofhas ALIMTA not been in pediatric demonstrated. patientsALIMTA has notwas been demonstrated. ALIMTA was tly in the ALIMTA arm. frequently in the ALIMTA arm. administered as an intravenousadministered infusion overas10anminutes intravenous on Day infusion 1 of aover 21 10 dayminutes cycle toon Day 1 of a 21 day cycle to ncidence 1% to 5% Incidence 1% to 5% 0 pediatric patients with recurrentpediatric solid tumors patients in awith Phase recurrent 1 studysolid (32 patients) tumors inand a Phase a Phase 1 study (32 patients) and a Phase Blood/Bone Marrow — thrombocytopenia Blood/Bone Marrow — thrombocytopenia 2 study (72 patients). All patients 2 study received (72 patients). pretreatment All patients with vitamin received B12 pretreatment and folic acidwith vitamin B12 and folic acid where the General Disorders — febrile neutropenia General Disorders — febrile neutropenia supplementation and dexamethasone. supplementation The dose escalation and dexamethasone. in the PhaseThe 1 study dose escalation determinedin the Phase 1 study determined ncidence Less than 1% Incidence Less than 1% 2 the maximum tolerated dose was the maximum 1910 mg/m tolerated dose was(or1910 mg/m2forandpatients and this dose 60 mg/kg this dose (or 60 mg/kg for patients Cardiovascular — ventricular tachycardia, Cardiovascular syncope — ventricular tachycardia, syncope <12 months old) was evaluated<12 months in the Phaseold) 2 study was evaluated of patientsinwith the relapsed Phase 2 study or refractory of patients with relapsed or refractory n patients General Disorders — pain General Disorders — pain osteosarcoma, Ewing sarcoma/peripheral osteosarcoma,PNET, Ewingrhabdomyosarcoma, sarcoma/peripheral neuroblastoma, PNET, rhabdomyosarcoma, neuroblastoma, rade 3/4 Gastrointestinal — gastrointestinal Gastrointestinal obstruction — gastrointestinal obstruction ependymoma, medulloblastoma/supratentorial ependymoma, medulloblastoma/supratentorial PNET, or nonbrainstem high grade PNET,glioma. or nonbrainstem high grade glioma.

0.6%).

Neurologic — depression Neurologic — depression No responses were observed among No responses the 72 patients were observed in this Phase among 2 trial. the 72 Thepatients most common in this Phase 2 trial. The most common dose of Renal Renal — renal failure toxicities reported were hematological toxicities(leukopenia, reported were neutropenia/granulocytopenia, hematological (leukopenia, anemia, neutropenia/granulocytopenia, anemia, nts who— renal failure Vascular — pulmonary embolism Vascular — pulmonary embolism thrombocytopenia, and lymphopenia), thrombocytopenia, liver function and abnormalities lymphopenia),(increased liver function ALT/AST), abnormalities (increased ALT/AST), ALIMTA. No relevant No relevant due to effect genderfororALIMTA race was safety identified, due to except genderan or racefatigue, was identified, except an fatigue, and nausea. and nausea. wever no effect for ALIMTA safety ed incidence of rash in men (24%) increased incidence comparedoftorash women (16%). in men (24%) compared to women (16%). The single dose pharmacokinetics The single of ALIMTA dose pharmacokinetics administered in doses of ALIMTA ranging administered in doses ranging Additional Additional TrialsExperience Across Clinical Trials from 400 to 2480 mg/m2 werefrom 400 to mg/m12 were evaluated in2480 the Phase trial inevaluated 22 patients in the (13Phase males1and trial in 22 patients (13 males and arm, use Experience Across Clinical epsis, which in some cases was Sepsis, fatal, which occurred in some in approximately cases was fatal, 1% of occurred patients. in approximately 1% of patients.

9 females) aged 4 to 18 years9 (average females) age aged124 years). to 18 years Pemetrexed (averageexposure age 12 (AUC years).andPemetrexed exposure (AUC and ropoietin Esophagitis Esophagitis 1% of patients. occurred in less than 1% of patients.

Cmax) appeared to increase proportionally Cmax) appeared withtodose. increase The average proportionally pemetrexed with dose. clearance The average pemetrexed clearance nsfusions occurred in less than 2 2 (2.30 L/h/m ) and half-life (2.3(2.30 L/h/m hours) in pediatric ) and half-life patients (2.3were hours) comparable in pediatric to values patients were comparable to values Postmarketing Experience 6.2 Postmarketing Experience reported in adults. use of reported in adults.

The following adverse reactionsThehave following been identified adverse reactions during post-approval have been identified use of during post-approval on-small Because these reactions ALIMTA. are reported Becausevoluntarily these reactions from aare population reported ofvoluntarily uncertainfrom 8.5 a population of Use uncertain 8.5 Geriatric Use Geriatric is not always possible size, to reliably it is not estimate alwaystheir possible frequency to reliably or establish estimatea their causalfrequency or ALIMTA establishis known a causalto be substantially ALIMTA excreted is known by to thebekidney, substantially and theexcreted risk of adverse by the kidney, and the risk of adverse ship to drug exposure. relationship to drug exposure. reactions to this drug may be greater reactions in patients to this drug with may impaired be greater renal function. in patients Renal withfunction impaired renal function. Renal function These reactions occurred with These ALIMTA reactions when occurred used as with a single-agent ALIMTA when and used in asmonitoring a single-agent and in with is recommended monitoring administration is recommended of ALIMTA. with No dose administration reductions ofother ALIMTA. than No dose reductions other than ation therapies. combination therapies. those recommended for all patients thoseare recommended necessary forforpatients all patients 65 years are necessary of age or older for patients [see 65 years of age or older [see Dosage and Administration (2.4)].

Dosage and Administration (2.4)].

Blood and Lymphatic System –Blood Immune-mediated and Lymphatichemolytic System –anemia Immune-mediated hemolytic anemia ecreased Of 3,946 patients (34.0% ≥65)Ofstudied 3,946 patients across the (34.0% five clinical ≥65) studied trials [see across Clinical the five clinical trials [see Clinical Gastrointestinal — colitis, pancreatitis Gastrointestinal — colitis, pancreatitis Studies (14.1, 14.2, 14.3, and 14.4)], Studiesthe(14.1, effect14.2, of ALIMTA 14.3, and on survival 14.4)], the waseffect similar of ALIMTA in patients on survival was similar in patients General Disorders and Administration GeneralSite Disorders Conditions and — Administration edema Site Conditions — edema

® A27 (pemetrexed AMP for injection) ALIMTA® (pemetrexed for injection) PV 8927 AMP

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We encourage readers to share their opinions and thoughts on issues of interest to the oncology community.

Write to The ASCO Post at editor@ASCOPost.com

The ASCO Post | DECEMBER 1, 2014

PAGE 40

FDA Update

FDA Grants Orphan Drug Designation to BGB324 for Acute Myeloid Leukemia

T

he U.S. Food and Drug Administration (FDA) has granted orphan drug designation to BGB324 for the treatment of acute myeloid leukemia (AML). BGB324 is a first-in-class, highly selective small-molecule inhibitor of the Axl receptor tyrosine kinase.

It blocks the epithelial-mesenchymal transition (EMT), which is a key driver in drug-resistance and metastasis.

Earlier this month BerGenBio announced that the first patient has been dosed in its multicenter phase Ib trial of BGB324 in patients with AML. The

two-part trial will primarily investigate the safety and tolerability of BGB324 when administered as a single agent and in combination with a standard-of-care drug (cytarabine). Secondary endpoints will also explore evidence of clinical response and assess novel biomarkers.

<65 compared to ≥65 years of age. There were no differences in safety with the exception of the following Grade 3-4 adverse reactions, which were noted in at least one of the five trials to be greater in patients 65 years of age and older as compared to younger patients: anemia , fatigue, thrombocytopenia, hypertension, and neutropenia.

8.6 Patients with Hepatic Impairment There was no effect of elevated AST, ALT, or total bilirubin on the pharmacokinetics of pemetrexed. However, no formal studies have been conducted to examine the pharmacokinetics of pemetrexed in patients with hepatic impairment [see Clinical Pharmacology (12.3)].

8.7 Patients with Renal Impairment ALIMTA is known to be primarily excreted by the kidneys. Decreased renal function will result in reduced clearance and greater exposure (AUC) to ALIMTA compared with patients with normal renal function [see Dosage and Administration (2.4) and Clinical Pharmacology (12.3) in the full Prescribing Information]. Cisplatin coadministration with ALIMTA has not been studied in patients with moderate renal impairment.

8.8 Gender Of 3,946 patients (Male 70.5% ) studied across the five registration studies for ALIMTA indications [see Clinical Studies (14.1, 14.2, 14.3, and 14.4)], the effect of ALIMTA on survival was similar in female and male patients.

8.9 Race Of 3,946 patients (Caucasian 78.6%) studied across the five registration studies for ALIMTA indications [see Clinical Studies (14.1, 14.2, 14.3, and 14.4)], the effect of ALIMTA on survival was similar in the Caucasian and non-Caucasian patients.

10 OVERDOSAGE There have been few cases of ALIMTA overdose. Reported toxicities included neutropenia, anemia, thrombocytopenia, mucositis, and rash. Anticipated complications of overdose include bone marrow suppression as manifested by neutropenia, thrombocytopenia, and anemia. In addition, infection with or without fever, diarrhea, and mucositis may be seen. If an overdose occurs, general supportive measures should be instituted as deemed necessary by the treating physician.

In clinical trials, leucovorin was permitted for CTC Grade 4 leukopenia lasting ≥3 days, CTC Grade 4 neutropenia lasting ≥3 days, and immediately for CTC Grade 4 thrombocytopenia, bleeding associated with Grade 3 thrombocytopenia, or Grade 3 or 4 mucositis. The following intravenous doses and schedules of leucovorin were recommended for intravenous use: 100 mg/m2, intravenously once, followed by leucovorin, 50 mg/m2, intravenously every 6 hours for 8 days.

The ability of ALIMTA to be dialyzed is unknown.

13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility No carcinogenicity studies have been conducted with pemetrexed. Pemetrexed was clastogenic in the in vivo micronucleus assay in mouse bone marrow but was not mutagenic in multiple in vitro tests (Ames assay, CHO cell assay). Pemetrexed administered at i.v. doses of 0.1 mg/kg/day or greater to male mice (about 1/1666 the recommended human dose on a mg/m2 basis) resulted in reduced fertility, hypospermia, and testicular atrophy.

17 PATIENT COUNSELING INFORMATION See FDA-Approved Patient Labeling (PPI) Instruct patients to read the patient package insert before initiating ALIMTA. • Instruct patients on the need for folic acid and vitamin B12 supplementation to reduce treatment-related hematologic and gastrointestinal toxicity and of the need for corticosteroids to reduce treatment-related dermatologic toxicity [see Dosage and Administration (2.3) and Warnings and Precautions (5.1)].

• Inform patients of the risk of low blood cell counts and instruct them to immediately contact their physician for signs of infection, including fever, bleeding or symptoms of anemia.

• Instruct patients to contact their physician if persistent vomiting, diarrhea, or signs of dehydration appear.

• Instruct patients to inform their physician of all concomitant prescription or over-the-counter medications they are taking, particularly those for pain or inflammation such as non-steroidal anti-inflammatory drugs [see Drug Interactions (7.1)].

To report SUSPECTED ADVERSE REACTIONS, contact Eli Lilly and Company at 1-800-LillyRx (1-800-545-5979) or FDA at 1-800-FDA-1088, or http://www.fda.gov/medwatch.

Additional information can be found at www.AlimtaHCP.com

The FDA grants Orphan Drug designation to development-stage novel therapeutics that are intended for use in treating rare diseases and medical conditions that affect fewer than 200,000 patients in the United States. n

Contact

The ASCO Post Editorial Correspondence James O. Armitage, MD Editor-in-Chief e-mail: Editor@ASCOPost.com Cara H. Glynn Director of Editorial e-mail: Cara@harborsidepress.com Phone: 631.935.7654 Andrew Nash Assoc. Director of Editorial e-mail: Andrew@harborsidepress.com Phone: 631.935.7657

Rights & Permissions e-mail: Permissions@harborsidepress.com

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Rates, reprints, or supplements Leslie Dubin e-mail: Leslie@harborsidepress.com Phone: 631.935.7660

Editorial Office Harborside Press 37 Main Street Cold Spring Harbor, NY 11724 Phone: 631.692.0800 Fax: 631.692.0805 ASCOPost.com HarborsidePress.com

Marketed by: Lilly USA, LLC Indianapolis, IN 46285, USA Copyright © 2004, 2013, Eli Lilly and Company. All rights reserved.

PM HCP BS NSCLC1M 18Nov2013 ALIMTA® (pemetrexed for injection)

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PAGE 41

Expert’s Corner Health-Care Disparities

The Harvard Global Equity Initiative: From Research to Policy A Conversation With Felicia Knaul, PhD

By Ronald Piana

Goals of the Global Task Force

Felicia Knaul, PhD

T

he Harvard Global Equity Initiative is a research program at Harvard University that is dedicated to promoting equitable global development, with a strong emphasis on health-care issues.

This initiative brings together scholars, policymakers, advocates, and practitioners from around the world to address global-equity challenges by contributing evidence and research.

The ASCO Post recently spoke with the Harvard Global Equity Initiative Director, Felicia Knaul, PhD, about her research in breast cancer in low- and middle-income countries and her work in enhancing access to pain control in resourcechallenged areas of the world. Dr. Knaul is a breast cancer survivor.

Cancer Survivor’s Perspective Does being a breast cancer survivor affect the way you approach the work you’re currently engaged in?

Yes, profoundly. In 2007, I was diagnosed with breast cancer in a small clinic in Cuernavaca, the capital and largest city of the state of Morelos in Mexico, which is my home. At the time, I was 41-years-old, with no history of the disease; the diagnosis gave me a deeper understanding of the shock and sense of helplessness one has after a cancer diagnosis. But in my case, I was fortunate enough to have great medical, personal, and financial support during my treatment and survivorship, which is not the case in much of Mexico, where large portions of the population live in poverty.

After my diagnosis, I dedicated my personal and professional life to confronting the inequity and cancer divide of preventable and treatable cancers that exists between rich and poor countries.

In 2008, I founded the Mexican nonprofit organization, Cáncer de Mama: Tómatelo a Pecho, which promotes research, advocacy, awareness, and earlydetection initiatives.

Another collaborative enterprise that the Harvard Global Equity Initiative is part of is the Global Task Force on Expanded Access to Cancer Care and Control in Developing Countries. There are some shocking figures that put the inequity problem into perspective. For instance, of the 7 million cancer deaths per year worldwide, more than 70% occur in the developing world. And despite this enormous burden, only 5% of global cancer resources are spent in the developing world.

In October 2011, the Harvard Global Equity Initiative released the report Closing the Cancer Divide: A Blueprint to Expand Access in Low and Middle Income Countries. The report has been disseminated worldwide, describing innovative models for achieving expanded access and supplying a well-drawn plan for future action in resource-constrained areas.

Moreover, the Global Task Force will focus on areas that have largely been neglected. Working from the standpoint of health-system strengthening, we will specifically target ways to implement cancer care pathways and expand medical coverage of existing vaccines; detect and treat cancers early, where cure and significant life expectant are likely; and increase services for palliation of cancer symptoms to reduce unnecessary human suffering.

Enhancing Cancer Services Can you discuss a specific strategy that you feel will make a meaningful impact on cancer care services in a poor region?

To promote and increase the level of cancer care in the poorer areas of the world, you first must assess the primary needs of the population to develop a strategy. For example, my colleagues and I recently completed a report in Mexico looking at breast cancer knowledge among health-care promoters before and after focused training.

It’s important to note that breast cancer is the leading cause of death in adult women, and the mortality rates are rising, now exceeding the mortality rates of cervical cancer. Like in most poor countries, in Mexico, breast cancers are typically diagnosed at an advanced stage, making the outlook for positive outcomes dismal. On the positive side, as part of Mexico’s health reform, in 2003 the Popular Health Insurance program was established, covering about 50 million Mexicans who were otherwise uninsured. And since 2007, breast cancer care

is included in Popular Health Insurance coverage. However, access to screening services for early detection remains limited in the poor sections of the country.

In our report, we assessed the effectiveness of a train-the-trainer program in two states in Mexico, where community health workers are a vital part of the health-care force. Realizing the opportunity to expand care, Mexico is committed to increasing the number of these workers to promote early detection of breast cancer and improve outcomes. We worked with local organizations to develop and implement the train-the-trainer program to improve breast cancer knowledge among community health-care workers. We then surveyed the workers before and after the 3-month training period, which included one-onone classes and online classes.

We found that the trained workers had significantly increased their knowledge of breast cancer in areas including early de-

It was largely the memory of my father’s struggle with horrible cancer pain that later fueled my passion to help close the pain divide that exists between the rich and poor sections of the world. To that end, as Director of the Harvard Global Equity Initiative, I’m pleased that we’ve created the Harvard Global Equity Initiative–Lancet Commission on Global Access to Pain Control and Palliative Care.

The raw data on this issue are nothing short of startling. The difference in opioid consumption per cancer death is close to 600-fold between the poorest 20% and the richest 20% of countries. For example, the United States and Canada consume about 300,000 mg per pain-related cancer death, compared with 450 mg in Uganda and 47 mg in Haiti. The World Health Organization estimates that about 5.5 million terminal cancer patients are suffering in severe pain because they do not have access to opioid medications.

Frankly, denial of pain medication is a form of torture. Living pain free is a human right that can be met, even in our poorest areas.

—Felicia Knaul, PhD

tection screening, risk factors, treatments, and insurance coverage. So in low-income areas of the world, easy-to-implement training programs can enhance cancer services markedly and cost-effectively.

Closing the Pain Divide Can you discuss your role as Director of the Harvard Global Equity Initiative in addressing untreated cancer pain in low- and middle-income countries.

Similar to my approach to breast cancer, I approach the issue of cancer pain through the lens of personal experience. In 1984, my father Sigmund Knaul, who was a Holocaust survivor, died of stomach cancer at the age of 60. My father’s cancer was swift and deadly; he died within 4 months of his diagnosis. I was 18 at the time, and his suffering from inadequately treated cancer pain left a lasting impression on me.

During his final days in the hospital, when he desperately needed better pain control, I had to struggle with the medical staff, who were reluctant to prescribe more morphine. In the end, I was the one who gave him the extra medication. When I administered the final dose of morphine, I did it with peace of mind, because he was in such severe, uncontrolled pain.

Ironically, global and national health systems have the ability to close this divide of needless suffering. A huge part of the problem is caused by archaic drug regulations, which need to be addressed through lobbying and education.

For instance, in Mexico not only does a doctor have to have a special prescription pad for pain meds, but also those prescription pads are only available in major cities. Making matters worse, they only produce a limited amount of these special pads. This makes it almost impossible for young physicians working in rural areas to prescribe adequate pain medications for their cancer patients. And Mexico is a middle-income country with a solvent economy. Lack of access to opioids in other parts of the world, such as sub-Saharan Africa, is catastrophic.

Frankly, denial of pain medication is a form of torture. Unfortunately, far too few are willing to acknowledge this human crisis. Living pain free is a human right that can be met, even in our poorest areas.

This terrible pain divide can be closed, and it’s a cause that the health-care community needs to rally around. n

Disclosure: Dr. Knaul reported no potential conflicts of interest.

Kyprolis速 (carfilzomib) for Injection Now Has a Permanent J Code: J9047 For the treatment of patients with multiple myeloma who have received at least 2 prior therapies including bortezomib and an immunomodulatory agent and have demonstrated disease progression on or within 60 days of completion of last therapy. Approval is based on response rate.

Clinical benefit, such as improvement in survival or symptoms, has not been verified.

THE POWER OF SECOND-GENERATION PROTEASOME INHIBITION TAKES FLIGHT

Important Safety Information CONTRAINDICATIONS None.

WARNINGS AND PRECAUTIONS The safety of KYPROLIS was evaluated in clinical studies of 526 patients with relapsed and/or refractory multiple myeloma.

Cardiac Arrest, Congestive Heart Failure, Myocardial Ischemia: Death due to cardiac arrest has occurred within a day of KYPROLIS administration. New onset or worsening of pre-existing congestive heart failure with decreased left ventricular function or myocardial ischemia have occurred following administration of KYPROLIS. Cardiac failure events (e.g., cardiac failure congestive, pulmonary edema, ejection fraction decreased) were reported in 7% of patients. Monitor for cardiac complications and manage promptly. Withhold KYPROLIS for Grade 3 or 4 cardiac events until recovery and consider whether to restart KYPROLIS based on a benefit/risk assessment. Patients with New York Heart Association Class III and IV heart failure, myocardial infarction in the preceding 6 months, and conduction abnormalities uncontrolled by medications may be at greater risk for cardiac complications.

Pulmonary Hypertension: Pulmonary arterial hypertension (PAH) was reported in 2% of patients treated with KYPROLIS and was Grade 3 or greater in less than 1% of patients.

Evaluate with cardiac imaging and/or other tests as indicated.

Withhold KYPROLIS for pulmonary hypertension until resolved or returned to baseline and consider whether to restart KYPROLIS based on a benefit/risk assessment.

Pulmonary Complications: Dyspnea was reported in 35% of patients enrolled in clinical trials. Grade 3 dyspnea occurred in 5%; no Grade 4 events, and 1 death (Grade 5) was reported.

Monitor and manage dyspnea immediately; interrupt KYPROLIS until symptoms have resolved or returned to baseline.

Infusion Reactions: Infusion reactions were characterized by a spectrum of systemic symptoms including fever, chills, arthralgia, myalgia, facial flushing, facial edema, vomiting, weakness, shortness of breath, hypotension, syncope, chest tightness, or angina. These reactions can occur immediately following infusion or up to 24 hours after administration of KYPROLIS. Administer dexamethasone prior to KYPROLIS to reduce the incidence and severity of reactions. Inform patients of the risk and symptoms, and to contact physician if symptoms of an infusion reaction occur.

Tumor Lysis Syndrome: Tumor lysis syndrome (TLS) occurred following KYPROLIS administration in < 1% of patients. Patients with multiple myeloma and a high tumor burden should be considered to be at greater risk for TLS. Prior to receiving KYPROLIS, ensure that patients are well hydrated. Monitor for evidence of TLS during treatment, and manage promptly. Interrupt KYPROLIS until TLS is resolved.

KYPROLIS is engineered for selective inhibition1 • Single-agent KYPROLIS phase 2 study results2,* - Overall response rate (ORR) of 22.9% in PX-171-003 study (95% CI: 18.0, 28.5) - Median duration of response of 7.8 months (95% CI: 5.6, 9.2) • Most patients across all phase 2 studies (85%) did not need to discontinue therapy due to an adverse event - Adverse reactions leading to discontinuation included congestive heart failure (2%), cardiac arrest, dyspnea, increased blood creatinine, and acute renal failure (1% each) ADVERSE REACTIONS The safety of KYPROLIS was evaluated in clinical trials of 526 patients with relapsed and/or refractory multiple myeloma.

• Serious adverse reactions were reported in 45% of patients. The most common were pneumonia (10%), acute renal failure (4%), pyrexia (3%), and congestive heart failure (3%) • The most common adverse reactions (incidence ≥ 30%) were fatigue (56%), anemia (47%), nausea (45%), thrombocytopenia (36%), dyspnea (35%), diarrhea (33%), and pyrexia (30%) *Study PX-171-003 was a single-arm, multicenter clinical trial of KYPROLIS in 266 patients with relapsed multiple myeloma and whose disease had a ≤ 25% response to the most recent therapy or had disease progression during or within 60 days of the most recent therapy. At the time of study entry, patients had received a median of 5 prior lines of therapy. The primary endpoint was ORR. Response was determined by Independent Review Committee assessment using International Myeloma Working Group criteria.

References: 1. Demo SD, Kirk CJ, Aujay MA, et al. Antitumor activity of PR-171, a novel irreversible inhibitor of the proteasome. Cancer Res. 2007;67(13):6383-6391.

2. KYPROLIS [prescribing information]. South San Francisco, CA: Onyx Pharmaceuticals, Inc.; 2012.

Thrombocytopenia: KYPROLIS causes thrombocytopenia with platelet nadirs occurring around Day 8 of each 28-day cycle and recovery to baseline by the start of the next 28-day cycle.

In patients with multiple myeloma, 36% of patients experienced thrombocytopenia, including Grade 4 in 10%. Thrombocytopenia following KYPROLIS administration resulted in a dose reduction in 1% of patients and discontinuation of treatment with KYPROLIS in < 1% of patients. Monitor platelet counts frequently during treatment with KYPROLIS. Reduce or interrupt dose as clinically indicated.

Hepatic Toxicity and Hepatic Failure: Cases of hepatic failure, including fatal cases, have been reported (< 1%).

KYPROLIS can cause elevations of serum transaminases and bilirubin. Withhold KYPROLIS in patients experiencing Grade 3 or greater elevations of transaminases, bilirubin, or other liver enzyme abnormalities until resolved or returned to baseline. After resolution, consider if restarting KYPROLIS is appropriate. Monitor liver enzymes frequently.

Embryo-fetal Toxicity: KYPROLIS can cause fetal harm when administered to a pregnant woman based on its mechanism of action and findings in animals. There are no adequate and well-controlled studies in pregnant women using KYPROLIS. Carfilzomib caused embryo-fetal toxicity in pregnant rabbits at doses that were lower than in patients receiving the recommended dose. Females of reproductive potential should be advised to avoid becoming pregnant while being treated with KYPROLIS.

ADVERSE REACTIONS Serious adverse reactions were reported in 45% of patients. The most common serious adverse reactions were pneumonia (10%), acute renal failure (4%), pyrexia (3%), and congestive heart failure (3%). Adverse reactions leading to discontinuation of KYPROLIS occurred in 15% of patients and included congestive heart failure (2%), cardiac arrest, dyspnea, increased blood creatinine, and acute renal failure (1% each).

The most common adverse reactions (incidence ≥ 30%) were fatigue (56%), anemia (47%), nausea (45%), thrombocytopenia (36%), dyspnea (35%), diarrhea (33%), and pyrexia (30%).

USE IN SPECIFIC POPULATIONS Since dialysis clearance of KYPROLIS concentrations has not been studied, the drug should be administered after the dialysis procedure.

Please see Brief Summary of the full Prescribing Information on adjacent pages.

Onyx, Onyx Pharmaceuticals, Onyx Pharmaceuticals logo, Kyprolis and Kyprolis logo are all trademarks of Onyx Pharmaceuticals, Inc. ©2014 Onyx Pharmaceuticals, Inc., South San Francisco, CA TROPIC-KYPR-100603 October 2014

The ASCO Post | DECEMBER 1, 2014

PAGE 44

Journal Spotlight Technology

New Imaging Technique Identifies Receptors for Targeted Cancer Therapy

D

artmouth researchers have developed a fluorescence imaging technique that can more accurately identify receptors for targeted cancer therapies without a tissue biopsy. They report on their findings in a recently published article in Cancer Research.1

“Protein overexpression is a hallmark of certain cancers and is used in clinical oncology to personalize treatment through tumor detection, molecular therapies, and therapeutic monitoring,” said lead author Kimberley S. Samkoe, PhD, Assistant

Professor of Surgery at the Geisel School of Medicine and Adjunct Assistant Professor at Thayer School of Engineering. “Protein expression is currently measured through a total protein analysis of tumor tissue. This new technique allows us to accurately

KYPROLIS™ (carfilzomib) for Injection Brief Summary of Prescribing Information. Please see the KYPROLIS package insert for full prescribing information.

INDICATIONS AND USAGE: KYPROLIS is indicated for the treatment of patients with multiple myeloma who have received at least two prior therapies including bortezomib and an immunomodulatory agent and have demonstrated disease progression on or within 60 days of completion of the last therapy. Approval is based on response rate [see Clinical Studies section of full PI]. Clinical benefit, such as improvement in survival or symptoms, has not been verified.

DOSAGE AND ADMINISTRATION: Dosing Guidelines. KYPROLIS is administered intravenously over 2 to 10 minutes, on two consecutive days, each week for three weeks (Days 1, 2, 8, 9, 15, and 16), followed by a 12‑day rest period (Days 17 to 28). Each 28‑day period is considered one treatment cycle (Table 1). In Cycle 1, KYPROLIS is administered at a dose of 20 mg/m2. If tolerated in Cycle 1, the dose should be escalated to 27 mg/m2 beginning in Cycle 2 and continued at 27 mg/m2 in subsequent cycles. Treatment may be continued until disease progression or until unacceptable toxicity occurs [see Dosage and Administration]. The dose is calculated using the patient’s actual body surface area at baseline. Patients with a body surface area greater than 2.2 m2 should receive a dose based upon a body surface area of 2.2 m2. Dose adjustments do not need to be made for weight changes of less than or equal to 20%.

Table 1: KYPROLIS Dosage Regimen for Patients with Multiple Myeloma Cycle 1 Week 1 Week 2 Week 3 Week 4 Day Day Days Day Day Days Day Day Days Days 2 3–7 8 9 10–14 15 16 17–21 22–28 1 KYPROLIS No 20 20 20 No 20 20 No No 20 (20 mg/m2): Dosing Dosing Dosing Dosing a Cycles 2 and Beyond Week 1 Week 2 Week 3 Week 4 Day Day Days Day Day Days Day Day Days Days 2 3–7 8 9 10–14 15 16 17–21 22–28 1 KYPROLIS 27 No 27 27 No 27 27 No No 27 Dosing Dosing Dosing Dosing (27 mg/m2): a If

previous cycle dosage is tolerated.

Hydration and Fluid Monitoring. Hydrate patients to reduce the risk of renal toxicity and of tumor lysis syndrome (TLS) with KYPROLIS treatment [see Warnings and Precautions]. Maintain adequate fluid volume status throughout treatment and monitor blood chemistries closely. Prior to each dose in Cycle 1, give 250 mL to 500 mL of intravenous normal saline or other appropriate intravenous fluid.

Give an additional 250 mL to 500 mL of intravenous fluids as needed following KYPROLIS administration. Continue intravenous hydration, as needed, in subsequent cycles. Also monitor patients during this period for fluid overload [see Warnings and Precautions]. Dexamethasone Premedication. Pre‑medicate with dexamethasone 4 mg orally or intravenously prior to all doses of KYPROLIS during Cycle 1 and prior to all KYPROLIS doses during the first cycle of dose escalation to 27 mg/m2 to reduce the incidence and severity of infusion reactions [see Warnings and Precautions].

Reinstate dexamethasone premedication (4 mg orally or intravenously) if these symptoms develop or reappear during subsequent cycles. Dose Modifications based on Toxicities. Recommended actions and dose modifications are presented in Table 2.

Table 2: Dose Modifications for Toxicitya during KYPROLIS Treatment Hematologic Toxicity • Grade 3a or 4 Neutropenia • Grade 4 Thrombocytopenia [see Warnings and Precautions]

Recommended Action • Withhold dose.

• If fully recovered before next scheduled dose, continue at same dose level.

• If recovered to Grade 2 neutropenia or Grade 3 thrombocytopenia, reduce dose by one dose level (from 27 mg/m2 to 20 mg/m2, OR from 20 mg/m2 to 15 mg/m2).

• If tolerated, the reduced dose may be escalated to the previous dose at the discretion of the physician.

Non-Hematologic Toxicity Recommended Action • Withhold until resolved or returned to baseline.

Cardiac Toxicity Grade 3 or 4, new onset or worsening of: • After resolution, consider if restarting KYPROLIS at a reduced dose is appropriate (from 27 mg/m2 to • congestive heart failure; 20 mg/m2, OR from 20 mg/m2 to 15 mg/m2).

• decreased left ventricular • If tolerated, the reduced dose may be escalated to the function; previous dose at the discretion of the physician.

• or myocardial ischemia

[see Warnings and Precautions] Pulmonary Hypertension [see Warnings and Precautions]

Pulmonary Complications • Grade 3 or 4 [see Warnings and Precautions]

Hepatic Toxicity • Grade 3 or 4 elevation of transaminases, bilirubin or other liver abnormalities [see Warnings and Precautions)]

• Withhold until resolved or returned to baseline.

• Restart at the dose used prior to the event or reduced dose (from 27 mg/m2 to 20 mg/m2, OR from 20 mg/m2 to 15 mg/m2), at the discretion of the physician.

• If tolerated, the reduced dose may be escalated to the previous dose at the discretion of the physician.

• Withhold until resolved or returned to baseline.

• Consider restarting at the next scheduled treatment with one dose level reduction (from 27 mg/m2 to 20 mg/m2, OR from 20 mg/m2 to 15 mg/m2).

• If tolerated, the reduced dose may be escalated to the previous dose at the discretion of the physician.

• Withhold until resolved or returned to baseline.

• After resolution, consider if restarting KYPROLIS is appropriate; may be reinitiated at a reduced dose (from 27 mg/m2 to 20 mg/m2, OR from 20 mg/m2 to 15 mg/m2) with frequent monitoring of liver function.

• If tolerated, the reduced dose may be escalated to the previous dose at the discretion of the physician. (continued)

determine the amount of protein receptors available for binding a drug without invasive biopsy.”

T:16

S:14.

Study Details The researchers developed a dualtracer in vivo receptor concentra-

Table 2: Dose Modifications for Toxicitya during KYPROLIS Treatment (continued) • Withhold until renal function has recovered to Grade 1 Renal Toxicity or to baseline and monitor renal function.

• Serum creatinine equal to or • If attributable to KYPROLIS, restart at the next scheduled greater than 2 × baseline treatment at a reduced dose (from 27 mg/m2 to [see Adverse Reactions] 20 mg/m2, OR from 20 mg/m2 to 15 mg/m2).

• If not attributable to KYPROLIS, restart at the dose used prior to the event.

• If tolerated, the reduced dose may be escalated to the previous dose at the discretion of the physician.

• Withhold until resolved or returned to baseline.

Peripheral Neuropathy • Restart at the dose used prior to the event or reduced • Grade 3 or 4 dose (from 27 mg/m2 to 20 mg/m2, OR from 20 mg/m2 [see Adverse Reactions] to 15 mg/m2), at the discretion of the physician.

• If tolerated, the reduced dose may be escalated to the previous dose at the discretion of the physician.

• Withhold until resolved or returned to baseline.

Other • Grade 3 or 4 non‑hematological • Consider restarting at the next scheduled treatment with one dose level reduction (from 27 mg/m2 to toxicities 20 mg/m2, OR from 20 mg/m2 to 15 mg/m2).

• If tolerated, the reduced dose may be escalated to the previous dose at the discretion of the physician.

National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) Version 3.0.

a

Administration Precautions. The quantity of KYPROLIS contained in one single‑use vial (60 mg carfilzomib) may exceed the required dose. Caution should be used in calculating the quantity delivered to prevent overdosing. Do not mix KYPROLIS with or administer as an infusion with other medicinal products. The intravenous administration line should be flushed with normal saline or 5% Dextrose Injection, USP immediately before and after KYPROLIS administration. KYPROLIS should not be administered as a bolus. KYPROLIS should be administered over 2 to 10 minutes. Reconstitution and Preparation for Intravenous Administration. KYPROLIS vials contain no antimicrobial preservatives and are intended only for single use. Unopened vials of KYPROLIS are stable until the date indicated on the package when stored in the original package at 2°C to 8°C (36°F to 46°F). The reconstituted solution contains carfilzomib at a concentration of 2 mg/mL. Read the complete preparation instructions prior to reconstitution. Reconstitution/Preparation Steps: 1. Remove vial from refrigerator just prior to use. 2. Aseptically reconstitute each vial by slowly injecting 29 mL Sterile Water for Injection, USP, directing the solution onto the INSIDE WALL OF THE VIAL to minimize foaming. 3. Gently swirl and/or invert the vial slowly for about 1 minute, or until complete dissolution of any cake or powder occurs. DO NOT SHAKE to avoid foam generation. If foaming occurs, allow solution to rest in vial for about 2 to 5 minutes, until foaming subsides. 4. After reconstitution, KYPROLIS is ready for intravenous administration. The reconstituted product should be a clear, colorless solution. If any discoloration or particulate matter is observed, do not use the reconstituted product. 5. When administering in an intravenous bag, withdraw the calculated dose [see Dosage and Administration] from the vial and dilute into 50 mL 5% Dextrose Injection, USP intravenous bag.

6. Immediately discard the vial containing the unused portion. The stabilities of reconstituted KYPROLIS under various temperature and container conditions are shown in Table 3.

Table 3: Stability of Reconstituted KYPROLIS Storage Conditions of Reconstituted KYPROLIS

a

B:16

Stabilitya per Container Vial

Syringe

IV Bag (D5Wb)

Refrigerated (2°C to 8°C; 36°F to 46°F)

24 hours

24 hours

24 hours

Room Temperature (15°C to 30°C; 59°F to 86°F)

4 hours

4 hours

4 hours

Total time from reconstitution to administration should not exceed 24 hours. b 5% Dextrose Injection, USP.

WARNINGS AND PRECAUTIONS: Cardiac Arrest, Congestive Heart Failure, Myocardial Ischemia. Death due to cardiac arrest has occurred within a day of KYPROLIS administration. New onset or worsening of pre‑existing congestive heart failure with decreased left ventricular function or myocardial ischemia have occurred following administration of KYPROLIS. Cardiac failure events (e.g., cardiac failure congestive, pulmonary edema, ejection fraction decreased) were reported in 7% of patients. Monitor for cardiac complications and manage promptly. Withhold KYPROLIS for Grade 3 or 4 cardiac events until recovery and consider whether to restart KYPROLIS based on a benefit/risk assessment [see Dosage and Administration]. Patients with New York Heart Association Class III and IV heart failure, myocardial infarction in the preceding 6 months, and conduction abnormalities uncontrolled by medications were not eligible for the clinical trials. These patients may be at greater risk for cardiac complications. Pulmonary Hypertension. Pulmonary arterial hypertension (PAH) was reported in 2% of patients treated with KYPROLIS and was Grade 3 or greater in less than 1% of patients. Evaluate with cardiac imaging and/or other tests as indicated. Withhold KYPROLIS for pulmonary hypertension until resolved or returned to baseline and consider whether to restart KYPROLIS based on a benefit/risk assessment [see Dosage and Administration]. Pulmonary Complications. Dyspnea was reported in 35% of patients enrolled in clinical trials. Grade 3 dyspnea occurred in 5%; no Grade 4 events, and 1 death (Grade 5) was reported. Monitor and manage dyspnea immediately; interrupt KYPROLIS until symptoms have resolved or returned to baseline [see Dosage and Administration and Adverse Reactions]. Infusion Reactions. Infusion reactions were characterized by a spectrum of systemic symptoms including fever, chills, arthralgia, myalgia, facial flushing, facial edema, vomiting, weakness, shortness of breath, hypotension, syncope, chest tightness, or angina. These reactions can occur immediately following or up to 24 hours after administration of KYPROLIS. Administer dexamethasone prior to KYPROLIS to reduce the incidence and severity of reactions [see Dosage and Administration]. Inform patients of the risk and symptoms and to contact physician if symptoms of an infusion reaction occur [see Patient Counseling Information]. Tumor Lysis Syndrome. Tumor lysis syndrome (TLS) occurred following KYPROLIS administration in < 1% of patients. Patients with multiple myeloma and a high tumor burden should be considered to be at greater risk for TLS. Prior to receiving KYPROLIS, ensure that patients are well hydrated [see Dosage and Administration]. Monitor for evidence of TLS during treatment, and manage promptly. Interrupt KYPROLIS until TLS is resolved [see Dosage and Administration].Thrombocytopenia. KYPROLIS causes thrombocytopenia with platelet nadirs occurring around Day 8 of each 28‑day cycle and recovery to baseline by the start of the next 28‑day cycle. In patients with multiple myeloma, 36% of patients experienced thrombocytopenia, including Grade 4 in 10%. Thrombocytopenia following KYPROLIS administration resulted in a dose reduction in 1% of patients and discontinuation of treatment with KYPROLIS in < 1% of patients. Monitor platelet counts frequently during treatment with KYPROLIS. Reduce or interrupt dose as clinically indicated [see Dosage and Administration].

Hepatic Toxicity and Hepatic Failure. Cases of hepatic failure, including fatal cases, have been

6.75”

6.25”

.625”

ASCOPost.com | DECEMBER 1, 2014

PAGE 45

Journal Spotlight

tion imaging technique that involves the simultaneous injection of both a targeted and a nontargeted imaging agent. They then studied the protein expression of five tumors, comparing the receptor concentration imaging data to that determined by clinical immunohistochemistry, either scored by a pathologist (as performed in the

clinic) or analyzed independently by a computer.

They found that the protein expression determined by receptor concentration imaging strongly correlated to that determined by tissue analysis.

They also found that commonly used techniques of measuring protein expression, such as Western blots or flow

cytometry, did not correlate to the receptor concentration imaging values, and in fact overpredicted the number of receptors available for therapeutic or diagnostic targeting.

Potential Impact on Outcomes “Accurately determining the population of protein receptors in a tumor

Our in vivo receptor concentration imaging technique is a novel approach for fluorescence imaging that can potentially impact clinical assessment of tumor status and malignant tissue classification.

—Kimberley S. Samkoe, PhD

Event

All Gradesa

Patients (N = 526) [n (%)] Grade 3 Events

Grade 4 Events

B:11.25”

S:10”

T:10.875”

available for targeting by molecular therapies or diagnostic imaging agents can greatly impact oncology patient outcomes,” said Dr. Samkoe.

“Our in vivo receptor concentration imaging technique is a novel approach for fluorescence imaging that can potentially impact clinical assessment of tumor status and malignant tissue classification,” she added.

Dr. Samkoe noted that this study looks at the average receptor expression within the tumor. The next step will be to look at tumors on a microscopic level in order to correlate receptor expression to distinct physiological features such as cellular viability, cellular type, vascularity, and overall tumor architecture.

The study was a collaboration between Geisel School of Medicine at Dartmouth College, the Thayer School of Engineering, members of the Norris Cotton Cancer Center, and the Wellman Center for Photomedicine at Massachusetts General Hospital. n

Disclosure: The study was supported by NIH grants R01CA156177, U54CA151662 and P01CA84203. For full disclosures of the study authors, visit cancerres.aacrjournals.org.

Reference 1. Samkoe KS, Tichauer KM, Gunn JR, et al: Quantitative in vivo immunohistochemistry of epidermal growth factor receptor using a receptor concentration imaging approach. Cancer Res. October 24, 2014 (early release online).

The ASCO Post | DECEMBER 1, 2014

PAGE 46

Journal Spotlight Gastrointestinal Oncology

NORCCAP Trial Shows Reduced Colorectal Cancer Incidence and Mortality With Flexible Sigmoidoscopy Screening at 11 Years

By Matthew Stenger

T

he Norwegian Colorectal Cancer Prevention (NORCCAP) trial comparing colorectal cancer screening with flexible sigmoidoscopy vs no screening showed no reduction in colorectal cancer incidence or mortality after 7 years of follow-up. As reported by Øyvind Holme, MD, of Sorlandet Hospital Kristiansand, and colleagues in JAMA, the 11-year follow-up shows significant reductions in both incidence and mortality with screening.1

Study Details In the trial, individuals aged 50 to 64 years were randomly assigned to no screening (usual care) or once-only flexible sigmoidoscopy screening with or without fecal occult blood testing.

Those randomized to screening were invited to undergo screening, performed in 1999 to 2000 in the 55- to 64-year age group and in 2001 in the

ing group and 56 years in the control group, with 34% and 47% aged 50 to 54 years and 66% and 53% aged 55 to 64 years. Half the participants in each group were women. The screening adherence rate was 63%.

Colorectal Cancer Incidence Colorectal cancer was diagnosed in 253 participants in the screening group vs 1,086 in the control group, yielding age-standardized rates of 112.6 vs 141.0 cases per 100,000 person-years (absolute rate difference = 28.4, 95% confidence interval [CI] = 12.1–44.7, hazard ratio [HR] = 0.80, 95% CI = 0.70– 0.92). The number needed to invite for screening to prevent 1 colorectal cancer case over 10 years was 498.

Hazard ratios were 0.68 (95% CI = 0.49–0.94) in the 50- to 54-year age group and 0.83 (95% CI = 0.71–0.96) in the 55- to 64-year age group (P = .27 for

In Norway, once-only flexible sigmoidoscopy screening or flexible sigmoidoscopy and [fecal occult blood testing] reduced colorectal cancer incidence and mortality on a population level compared with no screening.

—Øyvind Holme, MD, and colleagues

50- to 54-year age group. Participants with positive screening tests, consisting of cancer, adenoma, polyp ≥ 10 mm, or positive fecal occult blood test, were offered colonoscopy.

A total of 98,792 participants were included in the intention-to-screen analyses, consisting of 78,220 in the no-screening control group and 20,572 in the screening group. Of those in the screening group, 10,283 were randomly assigned to receive flexible sigmoidoscopy and 10,289 to receive flexible sigmoidoscopy and fecal occult blood testing.

Mean age was 57 years in the screen-

heterogeneity), 0.73 (95% CI = 0.60– 0.89) in men and 0.87 (95% CI = 0.72– 1.06) in women (P = .26 for heterogeneity), and 0.76 (95% CI = 0.63–0.92) for distal colorectal cancer and 0.90 (95% CI = 0.73–1.10) for proximal colorectal cancer. Hazard ratios were 0.72 (95% CI = 0.59–0.87) for sigmoidoscopy alone and 0.88 (95% CI = 0.74-1.05) for sigmoidoscopy plus fecal occult blood testing (P = .11 for heterogeneity). Screendetected colorectal cancer was more frequently diagnosed at an earlier stage.

Overall, 19.5% of participants undergoing screening sigmoidoscopy

Colorectal Cancer Screening ■■ Invitation to screening with flexible sigmoidoscopy with or without fecal occult blood testing was associated with a significant 20% reduction in colorectal cancer incidence.

■■ Invitation to screening was associated with a 27% reduction in colorectal cancer mortality.

and 21.3% of those who also had fecal occult blood testing were referred for colonoscopy, with 18.7% and 20.3% undergoing the procedure. Perforation or hospital admission for postpolypectomy bleeding occurred in none of the participants after sigmoidoscopy and in 10 after colonoscopy.

Colorectal Cancer Mortality After a median of 10.9 years of follow-up, death due to colorectal cancer had occurred in 71 screening group participants and 330 control group participants, yielding age-standardized rates of 31.4 vs 43.1 deaths per 100,000 personyears (absolute rate difference = 11.7, 95% CI = 3.0–20.4, HR = 0.73, 95% CI = 0.56–0.94). The number needed to invite for screening to prevent 1 colorectal cancer death over 10 years was 1,547.

Hazard ratios for colorectal cancer mortality were 0.74 (95% CI = 0.40– 1.35) in the 50- to 54-year age group and 0.73 (95% CI = 0.55–0.97) in the 55- to 64-year age group, 0.58 (95% CI = 0.40– 0.85) in men and 0.91 (95% CI, 0.64– 1.30) in women (P = .10 for heterogeneity), and 0.79 (95% CI = 0.55–1.11) for distal colorectal cancer and 0.73 (95% CI = 0.49–1.09) for proximal colorectal cancer. Hazard ratios were 0.84 (95% CI = 0.61–1.17) for flexible sigmoidoscopy and 0.62 (95% CI = 0.42–0.90) with sigmoidoscopy plus fecal occult blood testing (P = .20 for heterogeneity).

There was no difference between groups in all-cause mortality (HR = 0.97, 95% CI = 0.93–1.02).

Adjustment for Nonadherence The intention-to-screen 10-year risk absolute difference was −0.22% (95% CI = −0.38% to −0.06%) for colorectal cancer incidence and −0.06% (95% CI = −0.14% to 0.03%) for colorectal cancer death in the entire population.

After adjustment for nonadherence, the 10-year risk differences were −0.42% (95% CI = −0.69% to −0.15%) for incidence and −0.10% (95% CI = −0.25% to 0.05%) for death.

The investigators concluded: “In Norway, once-only flexible sigmoidoscopy screening or flexible sigmoidoscopy and [fecal occult blood testing] reduced colorectal cancer incidence and mortality on a population level compared with no screening.

Screening was effective both in the 50- to 54-year and the 55- to 64-year age groups.” n

Disclosure: NORCCAP was funded by grants from the Norwegian government and Norwegian Cancer Society. Work on the JAMA article was funded by grants from the Norwegian Cancer Society, Research Council of Norway, South-East Regional Health Authority of Norway, Fulbright Foundation, Sorlandet Hospital Kristiansand, and National Institutes of Health. For full disclosures of the study authors, visit jama.jamanetwork.com.

Reference 1. Holme Ø, Løberg M, Kalager M, et al: Effect of flexible sigmoidoscopy screening on colorectal cancer incidence and mortality: A randomized clinical trial. JAMA 312:606-615, 2014.

See commentary by Aline Charabaty, MD, on page 47.

The ASCO Post

Wants to Hear From You We encourage readers to share their opinions and thoughts on issues of interest to the oncology community.

Write to The ASCO Post at editor@ASCOPost.com

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ASCOPost.com | DECEMBER 1, 2014

PAGE 47

Perspective Colorectal Cancer

Sigmoidoscopy or Colonoscopy for Colorectal Cancer Screening: Is It Still the Question?

By Aline Charabaty, MD

M

ortality from colorectal cancer remains a public-health concern, being the second leading cause of cancerrelated death for men and women combined. The major preventive measure for colorectal cancer is to screen for and remove adenomatous polyps. Average-risk individuals (ie, those who do not have a hereditary colorectal syndrome) are offered several screening options starting at age 50 at regular intervals: colonoscopy every 10 years, flexible sigmoidoscopy every 5 years, fecal occult blood test yearly, and computed tomographic colonography every 5 years.

Sigmoidoscopy Study As reviewed in this issue of The ASCO Post, Holme and colleagues recently reported the results of a large randomized trial of colorectal cancer screening in Norway, comparing the effect of a one-time flexible sigmoidoscopy (with or without fecal occult blood test) with no screening on the incidence and mortality of colorectal cancer after 11 years of follow-up.1 Participants with an abnormal screening result were offered a colonoscopy. In an intentionto-treat analysis (ie, including the onethird of patients who were invited to be screened but did not participate), flexible sigmoidoscopy screening reduced this incidence and mortality by 20% and 27%, respectively. It is estimated that the absolute reduction of colorectal cancer risk at 10 years would double if all patients adhered to the screening recommendations. Fecal occult blood test did not improve outcomes beyond flexible sigmoidoscopy alone.

Practice Implications and Limitations The results of this study are in accordance with those reported in three prior large randomized trials of flexible sigmoidoscopy screening (UK FlexiScope Trial, Italian SCORE Trial, and U.S. PLCO trial),2-4 highlighting the effectiveness and safety of this relatively inexpensive method to prevent colorectal cancer and decrease cancerassociated mortality. However, despite these results, flexible sigmoidoscopy screening is underutilized in the UnitDr. Charabaty is Director of the Center for Inflammatory Bowel Diseases at Georgetown University Hospital, Washington, DC.

ed States, and colonoscopy has become the most recommended and performed procedure for colorectal cancer screening. Other screening methods are usually offered to patients who decline colonoscopy, who have severe comorbidities, who do not have access to colonoscopy, or who are underinsured or uninsured. Several factors have contributed to colonoscopy becoming the preferred screening method.

In 2001, Medicare began paying for colonoscopy to screen average-risk individuals, and private insurers followed.

Gastroenterologists now had an economic incentive to recommend colonoscopy over other screening tests, and training in flexible sigmoidoscopy by nongastroenterologists (primary-care physicians and internists) has sharply declined. Even though the American College of Physicians and the U.S. Preventive Task Force do not favor one screening

noscopy with that of mammography on one breast) and is both diagnostic and therapeutic. However, one of the most important arguments for colonoscopy are data from large cohort average-risk patients (mainly males, in the Veterans Affairs Cooperative Study), suggesting that approximately 50% of advanced neoplasia (adenomas larger than 1 cm, villous adenomas, adenomas with highgrade dysplasia, or colorectal cancer) proximal to the splenic flexure would be missed if the initial screening strategy relied on sigmoidoscopy (with colonoscopy only performed if a distal adenoma is detected on sigmoidoscopy).

The issue seems to be even more relevant in women. A large cohort study of screening colonoscopy for averagerisk women showing that up to 65% of proximal advanced neoplasia would have been missed if the initial screening test was limited to sigmoidoscopy.10,11

The debate between screening sigmoidoscopy followed by colonoscopy only if a distal adenoma is found vs initial screening colonoscopy might soon become a thing of the past, with the recent FDA approval of stool DNA testing for colorectal cancer screening.

—Aline Charabaty, MD

method over another, several specialty societies such as the American College of Gastroenterology recommend colonoscopy as the preferred colorectal cancer screening test.5-8 Although the National Polyp Study group showed that colonoscopic polypectomy provided a 53% reduction in cancer mortality compared with the general population (Surveillance, Epidemiology, and End Results database),9 there is no randomized trial level evidence that screening colonoscopy of the general population reduces cancer-related mortality.

The perception of the superiority of colonoscopy as a screening test by the public and health-care providers is largely based on the fact that it is a procedure that allows the visualization of the entire colon (with experts comparing the performance of a screening sigmoidoscopy as opposed to a full colo-

Further Considerations What we are certain of is that any screening is better than no screening at all and that there might not be a gold standard test that applies to all patients.

Beyond defining which screening tool is optimal in decreasing the incidence and related mortality of colorectal cancer, a more important issue to be addressed is the fact that colorectal cancer screening rates remain low (less than 50% of average-risk individuals undergo screened) despite the many test options available to patients.12 A screening test that examines the entire colon, that is not invasive like an endoscopy, that is easy to perform and not time-consuming, and that is cost-effective would be an ideal screening tool for patients and physicians alike. The multitarget stool DNA test (which also includes a hemoglobin immunoassay) has

the potential to become such a screening tool. Compared with colonoscopy, stool DNA testing has a sensitivity of 92% and 42% for detecting colorectal cancer and advanced adenomas, respectively.13 Hence, the debate between screening sigmoidoscopy followed by colonoscopy only if a distal adenoma is found vs initial screening colonoscopy might soon become a thing of the past, with the recent U.S. Food and Drug Administration approval of stool DNA testing for colorectal cancer screening.

Physicians and professional societies will need to define the role of this new technology and include it in our strategy to improve colorectal cancer screening compliance and reduce the incidence and mortality of colorectal cancer. n Disclosure: Dr. Charabaty reported no potential conflicts of interest.

References 1. Holme Ø, et al: Effect of flexible sigmoidoscopy screening on colorectal cancer incidence and mortality. JAMA 312:606615, 2014.

2. Atkin WS, et al: Lancet 375:16241633, 2010.

3. Segnan N, et al: Once-only sigmoidoscopy in colorectal cancer screening. J Natl Cancer Inst 103:1310-1322, 2011.

4. Schoen RE, et al: Colorectal-cancer incidence and mortality with screening flexible sigmoidoscopy. N Engl J Med 366:2345-2357, 2012.

5. Qaseem A, et al: Screening for colorectal cancer. Ann Intern Med 156:378-386, 2012.

6. U.S. Preventive Services Task Force: Screening for colorectal cancer. Ann Intern Med 149:627-637, 2008.

7. Rex DK, et al: American College of Gastroenterology guidelines for colorectal cancer screening 2009 [corrected]. Am J Gastroenterol 104:739-750, 2009.

8. Levin B, et al: Screening and surveillance for the early detection of colorectal cancer and adenomatous polyps, 2008. Gastroenterology 134:1570-1595, 2008.

9. Zauber AG, et al: Colonoscopic polypectomy and long-term prevention of colorectal-cancer death. N Engl J Med 366:687-696, 2012.

10. Lieberman DA, et al: Use of colonoscopy to screen asymptomatic adults for colorectal cancer. N Engl J Med 343:162168, 2000.

11. Schoenfeld P, et al: Colonoscopic screening of average-risk women for colorectal neoplasia. N Engl J Med 352:2061-2068, 2005.

12. Swan J, et al: Progress in cancer screening practices in the United States.

Cancer 97:1528-1540, 2003.

13. Imperiale TF, et al: Multitarget stool DNA testing for colorectal-cancer screening. N Engl J Med 370:1287-1297, 2014.

The ASCO Post | DECEMBER 1, 2014

PAGE 48

Journal Spotlight Genitourinary Oncology

Systemic Therapy in Men With Metastatic Castration-Resistant Prostate Cancer: ASCO/CCO Clinical Practice Guideline

By Matthew Stenger

T

he ASCO Clinical Practice Guidelines Committee and the Cancer Care Ontario (CCO) program in evidence-based care have released a clinical practice guideline on systemic therapy in men with metastatic castration-resistant prostate cancer. The guideline was published in the Journal of Clinical Oncology.1 The guideline is the result of efforts of a multidisciplinary ASCO/CCO expert

ing that quality-of-life benefits are not shown and high levels of toxicities have been reported.

Mitoxantrone can be offered accompanied by discussion of limited clinical benefit and toxicity risk, and ketoconazole or antiandrogens (eg, bicalutamide, flutamide, and nilutamide [Nilandron]) may be offered, accompanied by discussion of unknown clinical benefit amidst known toxicities. Bevacizumab (Avas-

Patients may place a higher importance on quality of life than length of life. Treatment decisions require understanding of individual patient values and preferences.

—Ethan Basch, MD, MSc, and colleagues

panel, which developed evidence-based recommendations through a systematic review of the literature guided by the question: “Which systemic therapies improve outcomes in men with metastatic [castration-resistant prostate cancer]?”

The evidentiary basis of the guideline consists of 26 randomized controlled ­trials identified through a 2012 CCO systematic review2 and an updated literature search through June 2014.

The panel was chaired by Ethan Basch, MD, MSc, Director of the Cancer Outcomes Research Program and Associate Professor of Medicine and Public Health at the Lineberger Comprehensive Cancer Center, The University of North Carolina at Chapel Hill.

In Brief In brief, the guideline recommends that androgen deprivation be continued indefinitely. Systemic therapy that should be offered includes abiraterone acetate (Zytiga)/prednisone, enzalutamide (Xtandi), and radium-223 (Xofigo) for men with predominantly bone metastases, with docetaxel/prednisone also being offered accompanied by discussion of toxicity risk. Sipuleucel-T (Provenge) may be offered to asymptomatic/minimally symptomatic men, with an understanding that quality-oflife outcomes data are not available.

Cabazitaxel ( Jevtana) may be offered to patients experiencing disease progression on docetaxel, with an understand-

tin), estramustine (Emcyt), and sunitinib (Sutent) should not be used.

There is insufficient evidence to identify optimal sequences or combinations of therapies. Palliative care should be offered to all patients.

Individual recommendations are summarized below.

Androgen-Deprivation Therapy • Continuous androgen deprivation (pharmaceutical or surgical) should be continued indefinitely regardless of additional therapies (benefit = moderate; harm = moderate; evidence strength = weak; recommendation strength = moderate).

Therapies in Addition to Androgen-Deprivation Therapy Therapy with survival and quality-oflife benefits • Abiraterone acetate and prednisone (benefit = moderate; harm = low; evidence strength = strong; recommendation strength = strong).

• Enzalutamide (benefit = moderate; harm = low; evidence strength = strong; recommendation strength = strong).

• Radium-223 should be offered to men with bone metastases (benefit = moderate; harm = low; evidence quality = strong; recommendation strength = strong).

• Docetaxel and prednisone (benefit = moderate; harm = moderate; evidence strength = strong; recommendation strength = moderate). Recent data suggest a substantial survival benefit with addition of a limited course of docetaxel to androgen-deprivation therapy in newly diagnosed metastatic androgen-sensitive prostate cancer, primarily in patients with high burden of metastatic disease (ie, visceral disease or more than four bone metastatic lesions). The additive benefits or toxicities associated with subsequent docetaxel retreatment of such patients in the castration-resistant setting are unknown.

Therapy with survival benefit and unclear quality-of-life benefit • Sipuleucel-T may be offered to asymptomatic or minimally symptomatic men (benefit = moderate; harm = low; evidence strength = moderate; recommendation strength = weak).

• Cabazitaxel and prednisone may be offered to patients with disease progression on docetaxel (benefit = moderate; harm = moderate to high; evidence strength = strong; recommendation strength = moderate).

Therapy with quality-of-life benefit without demonstrated survival benefit • Mitoxantrone plus prednisone (benefit = low; harm = high; evidence strength = weak; recommendation strength = weak).

Therapy with biologic activity and unknown survival or quality-of-life benefit • Antiandrogens—eg, bicalutamide, flutamide, and nilutamide (benefit = low; harm = low; evidence strength = weak; recommendation strength = weak).

• Ketoconazole (benefit = low; harm = moderate; evidence strength = weak; recommendation strength = weak).

• Low-dose corticosteroid monotherapy (benefit = low; harm = low; evidence strength = weak; recommendation strength = weak).

Therapy with no demonstrated survival or quality-of-life benefit • Bevacizumab, estramustine, and sunitinib should not be offered (for each: benefit = none; harm = high; evidence strength = moderate; recommendation strength = strong).

Palliative Care Services • Palliative care should be offered to all patients, particularly to those exhibit-

ing symptoms or quality-of-life decreases, regardless of treatment type (benefit = moderate; harm = none; evidence strength = moderate; recommendation strength = strong).

Qualifying Statements • Clinicians should review the published regimens discussed in the guideline for use in appropriate patient populations and for dose selections/modifications.

• There is insufficient published evidence to recommend specific sequencing or combinations of recommended therapies (except as otherwise noted in full guideline).

• A distinction made in some clinical trials between pre- and post-docetaxel treatment contexts should not play a role in selecting therapies for individual patients (unless otherwise noted).

• Patients may place a higher importance on quality of life than length of life. Treatment decisions require understanding of individual patient values and preferences. Many patients with incurable metastatic disease believe the goals of care to be curative; clear communication about goals and potential benefits and harms of care is necessary.

• Cost and availability may influence treatment decisions, and these factors must be discussed with patients.

• Most phase III clinical trials have included patients with good baseline performance status. Choices of treatment for patients with diminished performance status are not clearly established by existing evidence in most cases. n

Disclosure: For full disclosures of the guideline authors, visit jco.ascopubs.org.

References 1. Basch E, Loblaw DA, Oliver, TK, et al: Systemic therapy in men with metastatic castration-resistant prostate cancer: American Society of Clinical Oncology and Cancer Care Ontario Clinical Practice Guideline. J Clin Oncol. September 8, 2014 (early release online).

2. Loblaw DA, Walker-Dilks C, Winquist E, et al: Systemic therapy in men with metastatic castration-resistant prostate cancer: A systematic review. Clin Oncol (R Coll Radiol) 25:406-430, 2013.

See commentary by Maha Hussain, MD, FACP, on page 49.

ASCOPost.com | DECEMBER 1, 2014

PAGE 49

Perspective

From ‘Clinical Judgment’ to Evidence-Based Medicine: Thoughts on the ASCO/CCO Guideline in Metastatic Castration-Resistant Prostate Cancer

By Maha Hussain, MD, FACP, FASCO

W

e are witnessing unprecedented progress in the development of therapy for patients with metastatic castration-resistant prostate cancer. The U.S. Food and Drug Administration (FDA) has issued 13 approvals since 1996 for agents that have demonstrated an impact on overall survival, pain, or skeletal-related events—all very clearly clinical benefit outcomes relevant for managing this group of patients. In a similar time period, more phase III trials proved negative despite some very promising biologic, preclinical, and randomized phase II trials data. In the previous era, when there were no established effective therapies to manage metastatic castration-resistant prostate cancer, oncologists based their decision on judgment, prior experience, and phase II clinical trials data.

The need to reduce the morbidity of bone metastasis resulted in the early FDA approvals for agents that reduce pain or minimize skeletal-related events, beginning with the approval of mitoxantrone/prednisone in 1996, followed by strontium, samarium-153 (Quadramet), and zoledronic acid.

However, the major landmark occurred in 2004 with the approval of docetaxel, which is the first agent to demonstrate a survival impact in this disease setting.

With the limited number of agents available then, clinical decisions as to what to use first were relatively simple.

Now, the great news is that we have several agents with impact on survival in both docetaxel-naive patients (sipuleucel-T [Provenge], abiraterone [Zytiga]/prednisone, radium-223 [Xofigo], enzalutamide [Xtandi]) and docetaxel-treated patients (cabazitaxel [ Jevtana]/prednisone, abiraterone, enzalutamide, radium-223).

Need for Guidelines?

Now that we have level 1 evidence for these approaches, one may ask: Why do we need clinical practice guidelines?

The fact that oncologists now have Dr. Hussain is Associate Director for Clinical Research and Co-Leader of the Prostate Cancer Program at University of Michigan Comprehensive Cancer Center, Ann Arbor.

many treatment options to offer their patients is a wonderful development.

However, the contexts in which these agents were tested creates clinical decision dilemmas as to what to pick first, how to sequence therapies, and how best to counsel patients on what to expect from individual treatments— since, in practice, patients’ prior therapy profiles are increasingly different from those of the patients included in the phase III trials.

It is within this context that the ASCO Clinical Practice Guidelines Committee and the Cancer Care On-

Important Decision Factors The guidelines recommend offering abiraterone/prednisone, enzalutamide, and radium-223, with docetaxel/prednisone also being offered with accompanying discussion of toxicity risk. Sipuleucel-T may be offered to ­asymptomatic/minimally symptomatic men, whereas cabazitaxel can be offered to patients experiencing disease progression on docetaxel. The recommendations do not provide guidance on sequencing of therapy for obvious reasons—lack of data—yet, this is one of the key clinical needs in recom-

We must raise the bar for future trials by requiring greater therapeutic efficacy, minimizing use of placebo, avoiding artificial disease contexts, developing multitargeted treatment strategies, and evaluating and maximizing cost-effectiveness.

—Maha Hussain, MD, FACP, FASCO

tario (CCO) program in evidencebased care have released a clinical practice guideline on systemic therapy in men with metastatic castrationresistant prostate cancer,1 published in the Journal of Clinical Oncology and reviewed in this issue of The ASCO Post. The evidentiary foundation of the guideline consists of 26 randomized controlled trials identified through a 2012 CCO systematic review and an updated literature search through June 2014.

With regard to the specific recommendations of the guideline, the data regarding the continued importance of androgen receptor signaling in prostate cancer progression are the foundation for the guidance to continue primary gonadal suppression in patients with metastatic castration-resistant prostate cancer. While luteinizing hormonereleasing hormone–based therapy has pretty much replaced bilateral orchiectomy, patients should be informed of the option for orchiectomy, which, in addition to convenience, will minimize the cost of care.

mending therapy to patients.

In the absence of definitive data on proper sequencing, clinical decisions should take into account patient performance status, comorbidities, presence or absence of symptoms, disease extent and location, nature of prior response to therapy, and cost. When all is equal and feasible, treating physician recommendation/judgment, patient preferences, and cost/logistics of therapy are very important decision factors. While tempting, it is important not to assume that combining treatments, because it’s possible, will have a better outcome than sequencing therapy.

The guideline does include mitoxantrone/prednisone, and this combination is certainly an option when all life-prolonging therapies have been exhausted and when the patient has no experimental options, is in need of pain palliation, and is fit enough to undergo chemotherapy. However, it is not clear that the recommendations for ketoconazole or antiandrogens (eg, bicalutamide, flutamide, and nilutamide [Nilandron]) are justified by today’s

standards, considering the lack of meaningful clinical benefits with these agents in this disease context.

The recent data from the CHAARTED intergroup trial comparing androgen-deprivation therapy vs androgendeprivation therapy plus docetaxel in patients with hormone-sensitive metastatic prostate cancer demonstrated an unprecedented survival advantage with the addition of docetaxel in this setting. Although the bulk of the benefit seems to be in patients with highvolume disease (visceral disease or at least four bone metastatic lesions with at least one involving the appendicular skeleton), the data are practice-changing and will likely have an impact on the role of docetaxel in the setting of metastatic castration-resistant prostate cancer—that is, it is unclear whether patients receiving docetaxel for hormone-sensitive disease will respond to it when their disease is castration resistant.

At this time, there are no data on subsequent sensitivity or resistance to docetaxel and other therapies. Hence, there is a need for at least broad outcomes-based data to help inform treatment decisions, since it is unlikely that a prospective trial will address this question in the United States.

Practical Implications The authors should be congratulated on their effort and a very balanced discussion. As a practicing oncologist, however, I am not clear that the content and the guidance change what we are currently doing in practice. It is also important that we streamline the different practice and consensus guidelines through collaboration between representative societies and groups (eg, ASCO, American Urological Association, National Comprehensive Cancer Network) to create one unified guideline in this disease setting that is practical to use.

Short of cure, patients wish to know in the short term if their cancer is responding (a potential surrogate for clinical benefit), and in the long term whether they are likely to live longer and (as much as possible) “live better.” Despite the tremendous progcontinued on page 52

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References: 1. Chen DS, Mellman I. Oncology meets immunology: the cancer-immunity cycle. Immunity. 2013;39:1-10. 2. Chen DS, Irving BA, Hodi FS. Molecular pathways: next-generation immunotherapyâ&#x20AC;&#x201C;â&#x20AC;&#x201C;inhibiting programmed death-ligand 1 and programmed death-1. Clin Cancer Res. 2012;18:6580-6587.

3. Topalian SL, Drake CG, Pardoll DM. Targeting the PD-1/B7-H1(PD-L1) pathway to activate anti-tumor immunity. Curr Opin Immunol. 2012;24:207-212.

The ASCO Post | DECEMBER 1, 2014

PAGE 52

News Gynecologic Oncology

With New Innovator Award, Biomedical Engineer to Study How Ovarian Cancer Spreads

W

ith approximately 22,000 diagnoses annually in the United States, ovarian cancer isn’t among the most commonly occurring cancers.

Yet, the mortality rate for women who have ovarian cancer hovers above 60%.

For Pamela Kreeger, PhD, a University of Wisconsin–Madison Assistant Professor of Biomedical Engineering, that number is needlessly high. Dr. Kreeger is among a group of forward-thinking researchers to receive a 2014 New Innovator Award from the National Institutes of Health. And with funding of nearly $2.3 million, she is studying what factors cause ovarian cancer cells to progress from their origin in a woman’s fallopian tube through the ovaries and on to metastatic sites— where they become resistant to chemotherapy drugs.

“When we look at most cancers, we focus on gene mutations and how they impact the cells’ behavior, and then that’s the drug target,” she said. “Cancer is somewhat clonal, so early mutations tend to replicate throughout the tumor.

But some cancers don’t show this clear pattern of mutated genes for clinicians to target.”

Role of TP53 That’s the case with ovarian cancer, according to a 2011 study of the disease

by The Cancer Genome Atlas (TCGA)

Maha Hussain, MD, FACP, FASCO continued from page 49

ress in metastatic castration-resistant prostate cancer, there are several glaring limitations to the current portfolio of agents. The impact on survival continues to be modest, we use a “one size fits all” approach despite the fact that a significant percentage of patients will not respond to or will have

Research Network. Nearly all ovarian cancers have a mutation in the gene TP53—a gene that encodes a tumorsuppressor protein that normally prevents cancer development, and is very difficult to target therapeutically.

However, ovarian cancer cells also tend to have increased or decreased copies of genes—rather than muta-

the genomic instability where we see changes in the levels of proteins,” she said. “I’m trying to figure out what we can target as a result of this variation.”

Three Areas of Expertise Dr. Kreeger’s research will draw on her background in three seemingly different areas: ovarian cancer biology,

The disease is nearly universally diagnosed too late — so understanding ovarian cancer’s early stages might lead to new screens for the disease, as well as potential treatments.

—Pamela Kreeger, PhD

tions in the genes themselves. “So, the proteins are all potentially there and may function in the normal way, but their relative levels are skewed,” said Dr. Kreeger. “Ovarian cancer patients have a common mutation and then a proteomic mess.”

As a result of this pattern, Dr. Kreeger’s hypothesis is that the genetic mutation is less of a factor in the cancer’s spread than is protein expression, which is the way that proteins are made, regulated and modified in cells.

“What the TP53 mutation sets up is

biomimetic culture development, and using systems biology models to analyze quantitative data. For this project, she is developing in vitro culture systems to mimic the spread of ovarian cancer cells through a woman’s body, and how they develop resistance to chemotherapy.

Using these models, she and her students will examine how cells with different protein expression patterns will behave, and then, drawing on Dr. Kreeger’s expertise in developing computer models, they will simulate how

a suboptimal response to therapy, and the cost of therapy is escalating.

That said, the past decade has demonstrated that investment in research will produce significant returns and progress in treating this deadly disease is possible. The need for greater therapeutic impact necessitates significantly more investment and commitment to high-quality research. Patients should be offered opportunities for clinical

trials. Finally, we must raise the bar for future trials by requiring greater therapeutic efficacy, minimizing use of placebo, avoiding artificial disease contexts, developing multitargeted treatment strategies aiming at a maximum cytotoxic impact, and evaluating and maximizing cost-effectiveness. n Disclosure: Dr. Hussain has received funding from the National Cancer Institute and the Prostate Cancer Foundation, research

multiple variables impact cell decisions and influence tumor progression.

“Progress in treating ovarian cancer over the past 30 years has been flat,” she says. “One reason is that the disease is nearly universally diagnosed too late—so understanding ovarian cancer’s early stages might lead to new screens for the disease, as well as potential treatments.”

Dr. Kreeger hopes researchers can use her tools and approach in their efforts to understand progression in other cancer types, because many tumors have both genetic mutations and quantitative protein variations in their cell networks.

Two Other Keys Dr. Kreeger says there are two other keys to her research: an engineering background, which helps her address a multifaceted biologic challenge, and UW-Madison’s culture of transdisciplinary collaboration. “Wisconsin is the kind of environment in which people can take on this high-risk, high-reward research because of the intellectual openness here,” she said. “People talk to each other, and they naturally want to collaborate. They want to see if there’s a way to do it better by working together. It’s just a part of our culture and what makes Wisconsin a fantastic place to do research.” n

support from Astellas/Medivation, Pfizer, Genentech, and Bayer, and is a consultant for Synthon and Johnson & Johnson.

Reference 1. Basch E, Loblaw DA, Oliver, TK, et al: Systemic therapy in men with metastatic castration-resistant prostate cancer: American Society of Clinical Oncology and Cancer Care Ontario Clinical Practice Guideline. J Clin Oncol 32:3436-3448, 2014.

Visit The ASCO Post website at ASCOPost.com

ASCOPost.com | DECEMBER 1, 2014

PAGE 53

News Technology

Focused Ultrasound, a Young Technology, Begins to Grow

By Caroline McNeil

I

n the United States, it’s been a good 2 years for focused ultrasound. The technology, which uses multiple, intersecting ultrasound beams to treat cancer and other diseases, completed its first successful U.S. phase III oncology trial—to alleviate the pain of bone metastases— and received approval from the U.S. Food and Drug Administration (FDA) in 2012.

Medicare began covering it in 2013, and in 2014, Health Care Service Corporation, a large Blue Cross/Blue Shield insurer, began providing coverage.

An FDA panel did not recommend approval of two other focused ultrasound devices for treating prostate cancer in 2014 but left the door open for future consideration.

Not surprisingly, next steps and future directions were a major theme at a recent meeting of the Focused Ultrasound Foundation in Washington, DC. Speakers described studies not only in

We are enthusiasts but are careful to use the word ‘potential.’ This technology is in an early stage.

—Neal F. Kassell, MD

pain palliation, but also for tumor ablation in several cancers. Recent successes with essential tremor and other neurologic diseases were also discussed.

Still, speakers were careful to point out that the field was young. “We are enthusiasts but are careful to use the word ‘potential,’ said Neal F. Kassell, MD, Professor of Neurosurgery at the University of Virginia, who chairs the Foundation. “This technology is in an early stage.”

Studies of focused ultrasound to treat cancer go back several decades.

In the 1990s, INSERM, the French national research institute, and a commercial firm, EDAP-TMS, developed the Ablatherm® system, which uses ultrasound imaging to guide high-intensity

beams. Ablatherm won approval in Europe 1999 as an alternative to radiation therapy in early prostate cancer.

In the meantime, the Israeli firm InSightec began studying magnetic

resonance-guided focused ultrasound to treat painful bone metastases, the system that won FDA approval in the United States.

The focused ultrasound systems

combine beams that heat and destroy targeted tissue with a real-time imaging component—either magnetic resonance or ultrasound—that enables continued on page 54

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The ASCO Post | DECEMBER 1, 2014

PAGE 54

News Focused Ultrasound continued from page 53

precise targeting and potentially a lower risk of collateral damage. In the ExAblate trial, the magnetic resonance–guided beam was used to destroy pain-causing nerves in the outer membrane of the bone overlying a painful metastasis.

Focused ultrasound has the advantage of being noninvasive compared with other thermal treatments, such as cryotherapy, and can be performed on an outpatient basis. Its risks include damage to healthy tissue and skin burns, among others.

Painful Bone Metastases Clinical Trial The trial that led to FDA approval enrolled 147 patients who still had pain after radiation therapy or other standard interventions for painful bone metastases or who were not eligible for or had refused radiation therapy. Participants were ran-

events included two pathologic fractures (one outside the treatment field), one skin burn, and one neuropathy. The study was published in the Journal of the National Cancer Institute in April 2014.1 New randomized trials of focused ultrasound for bone metastases are now on the horizon. In October 2013, the Focused Ultrasound Foundation convened a workshop in Rome, bringing together researchers and industry representatives to talk about future trials.

Many believe that the ideal study would be a three-arm trial comparing radiation therapy alone, focused ultrasound alone, and the combination of radiation therapy and focused ultrasound, Dr. Hurwitz said. Another, possibly more feasible, option would compare radiation alone with radiation therapy plus focused ultrasound. A consensus statement with recommendations from the workshop is in press.

Another approach to painful bone metastases is to ablate the entire tumor as well as the nerve endings. This might lead to even better results, said Dr. Hurwitz, since some of the pain may be due to mechanical factors, such as the tumor pressing on expansion within bones.

Beyond Palliation Mark Hurwitz, MD

domly assigned to receive either focused ultrasound or placebo treatment. Nearly two-thirds of those on the focused ultrasound arm had an improvement in selfreported pain score without an increase in pain medication, compared with about 20% on the placebo arm.

Pain scores improved by an average of 3.6 points on a 10-point scale (more than a 50% improvement in pain), indicating the treatment had a significant impact, said principal investigator Mark Hurwitz, MD, Director of Thermal Oncology at Jefferson University in Philadelphia. Patients on the focused ultrasound arm also reported less painrelated interference with functioning, often within a day of treatment. Adverse

In other cancers, tumor ablation is the goal. Localized prostate cancer remains a prime candidate for focused ultrasound treatment, with five actively recruiting phase I and II trials listed in ClinicalTrials.gov. Two companies have completed trials of ultrasound-guided focused ultrasound and submitted premarket approval applications to the FDA. One of these trials, a phase II/III study looking at EDAP-TMS’s A ­ blatherm system in localized prostate cancer, was designed to determine its “substantial equivalence” to cryotherapy. An FDA advisory panel recommended against its approval in July 2014, indicating that benefits did not appear to outweigh risks, but kept open the possibility of future consideration. In a statement, EDAP-TMS said that the FDA recommended it provide

more data on patients at higher risk, such as those with Gleason scores > 6.

Also this year, SonaCare Medical asked an FDA panel to approve its Sonablate system. The panel responded, as it did with Ablatherm, that it would be useful to have data in patients with Gleason scores > 6. According to a company statement by SonaCare Medical, “several panel members suggested that for this more specific indication for use, the efficacy, safety profile, and benefit-risk ratio for the device may provide the basis for a

Another potential use of this approach is for the localized delivery of chemotherapy, she said. A liposomal drug, for instance, could be injected in conjunction with focused ultrasound.

The liposome would be activated or disrupted to release its contents at the precise focus of the ultrasound.

In addition, focused ultrasound might be used to “jump start” an antitumor immune response. Thermal therapies including focused ultrasound can stimulate anti-immune responses in

I’m excited to see it work, to see patients [with bone metastases] with no other options [for managing their pain] to be able to pursue normal activities again.

—Pejman Ghanouni, MD, PhD

more favorable recommendation.”

Both firms said they were moving ahead on the recommendations.

Focused ultrasound is in early clinical studies in other cancers, including pancreatic and breast cancers, sarcoma, brain metastases, and glioblastomas, with 51 open trials listed in ClinicalTrials.gov. For example, a sarcoma study at Stanford University is evaluating safety in patients who receive focused ultrasound followed by surgery. It is also looking at efficacy, comparing the magnetic resonance imaging results with pathology findings. Pejman Ghanouni, MD, PhD, the principal investigator, along with Raffi Avedian, MD, said that results so far have been encouraging.

Researchers are also thinking in terms of applications beyond ablation, said Jessica Foley, PhD, the Focused Ultrasound Foundation’s Scientific Director. For instance, the concentrated ultrasound beams can loosen the network of endothelial cells joined by tight junctions within the blood-brain barrier, allowing drugs to get through.

part through heat shock protein–mediated pathways, said Dr. Hurwitz. “We are actively exploring how best to both stimulate and effectively target this response to the tumor,” he said.

For the present, focused ultrasound enthusiasts are glad to have another tool to manage metastatic bone pain.

Radiation therapy does not work in everyone, and as Dr. Ghanouni pointed out, patients are now living longer with bone metastases. “I’m excited to see it work,” he said, “to see patients with no other options [for managing their pain] to be able to pursue normal activities again.” n

Disclosure: Dr. Hurwitz has provided consulting services to Insightec. Dr. Ghanouni has participated in multicenter clinical trials that were funded by InSightec. Dr. Foley reported no potential conflicts of interest.

Reference 1. Hurwitz MD, Ghanouni P, Kanaev SV, et al: Magnetic resonance-guided focused ultrasound for patients with painful bone metastases: Phase III trial results. J Natl Cancer Inst 106(5):dju082, 2014.

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PAGE 55

Perspective John F. Smyth, MD continued from page 1

is, when to recognize that the best medical care should focus on palliation of symptoms and quality of life rather than pursuing tumor destruction.

Confusing Array of Choices After an exciting afternoon listen-

ing to updates on the plethora of new molecules available for the treatment of malignant melanoma, I was involved in a discussion with a group of young oncologists who were trying to digest the range of possibilities now open to those who manage this disease, which until only a few years ago was considered essentially refractory to all medicines.

GAZYVA® (obinutuzumab) Injection, for intravenous infusion Initial U.S. Approval: 2013 This is a brief summary of information about GAZYVA. Before prescribing, please see full Prescribing Information.

WARNING: HEPATITIS B VIRUS REACTIVATION AND PROGRESSIVE MULTIFOCAL LEUKOENCEPHALOPATHY • Hepatitis B Virus (HBV) reactivation, in some cases resulting in fulminant hepatitis, hepatic failure, and death, can occur in patients receiving CD20-directed cytolytic antibodies, including GAZYVA. Screen all patients for HBV infection before treatment initiation. Monitor HBV positive patients during and after treatment with GAZYVA. Discontinue GAZYVA and concomitant medications in the event of HBV reactivation [see Warnings and Precautions (5.1)].

• Progressive Multifocal Leukoencephalopathy (PML) including fatal PML, can occur in patients receiving GAZYVA [see Warnings and Precautions (5.2)].

1 INDICATIONS AND USAGE GAZYVA, in combination with chlorambucil, is indicated for the treatment of patients with previously untreated chronic lymphocytic leukemia (CLL) [see Clinical Studies (14.1)].

4 CONTRAINDICATIONS None.

5 WARNINGS AND PRECAUTIONS 5.1 Hepatitis B Virus Reactivation Hepatitis B virus (HBV) reactivation, in some cases resulting in fulminant hepatitis, hepatic failure and death, can occur in patients treated with anti-CD20 antibodies such as GAZYVA. HBV reactivation has been reported in patients who are hepatitis B surface antigen (HBsAg) positive and also in patients who are HBsAg negative but are hepatitis B core antibody (anti-HBc) positive. Reactivation has also occurred in patients who appear to have resolved hepatitis B infection (i.e., HBsAg negative, anti-HBc positive, and hepatitis B surface antibody [anti-HBs] positive).

HBV reactivation is defined as an abrupt increase in HBV replication manifesting as a rapid increase in serum HBV DNA level or detection of HBsAg in a person who was previously HBsAg negative and anti-HBc positive.

Reactivation of HBV replication is often followed by hepatitis, i.e., increase in transaminase levels and, in severe cases, increase in bilirubin levels, liver failure, and death.

Screen all patients for HBV infection by measuring HBsAg and anti-HBc before initiating treatment with GAZYVA. For patients who show evidence of hepatitis B infection (HBsAg positive [regardless of antibody status] or HBsAg negative but anti-HBc positive), consult physicians with expertise in managing hepatitis B regarding monitoring and consideration for HBV antiviral therapy.

Monitor patients with evidence of current or prior HBV infection for clinical and laboratory signs of hepatitis or HBV reactivation during and for several months following treatment with GAZYVA. HBV reactivation has been reported for other CD20-directed cytolytic antibodies following completion of therapy.

In patients who develop reactivation of HBV while receiving GAZYVA, immediately discontinue GAZYVA and any concomitant chemotherapy, and institute appropriate treatment. Resumption of GAZYVA in patients whose HBV reactivation resolves should be discussed with physicians with expertise in managing hepatitis B. Insufficient data exist regarding the safety of resuming GAZYVA in patients who develop HBV reactivation.

5.2 Progressive Multifocal Leukoencephalopathy JC virus infection resulting in progressive multifocal leukoencephalopathy (PML), which can be fatal, was observed in patients treated with GAZYVA. Consider the diagnosis of PML in any patient presenting with new onset or changes to pre-existing neurologic manifestations.

Evaluation of PML includes, but is not limited to, consultation with a neurologist, brain MRI, and lumbar puncture.

Discontinue GAZYVA therapy and consider discontinuation or reduction of any concomitant chemotherapy or immunosuppressive therapy in patients who develop PML. 5.3 Infusion Reactions GAZYVA can cause severe and life-threatening infusion reactions. Two-thirds of patients experienced a reaction to the first 1000 mg infused of GAZYVA. Infusion reactions can also occur with subsequent infusions. Symptoms may include hypotension, tachycardia, dyspnea, and respiratory symptoms (e.g., bronchospasm, larynx and throat irritation, wheezing, laryngeal edema). Other common symptoms include nausea, vomiting, diarrhea, hypertension, flushing, headache, pyrexia, and chills [see Adverse Reactions (6.1)].

The afternoon presentations detailed a range of new medicines prescribed singly or in combination, sequential exposure, and so forth.

Leaving aside any consideration of cost, I realized that these young oncologists were tempted to think that you could go on prescribing one medicine after another literally until the patient

Premedicate patients with acetaminophen, anti-histamine, and a glucocorticoid. Institute medical management (e.g., glucocorticoids, epinephrine, bronchodilators, and/or oxygen) for infusion reactions as needed. Closely monitor patients during the entire infusion. Infusion reactions within 24 hours of receiving GAZYVA have occurred [see Dosage and Administration (2)].

For patients with any Grade 4 infusion reactions, including but not limited to anaphylaxis, acute life-threatening respiratory symptoms, or other life-threatening infusion reaction: Stop the GAZYVA infusion. Permanently discontinue GAZYVA therapy.

For patients with Grade 1, 2, or 3 infusion reactions: Interrupt GAZYVA for Grade 3 reactions until resolution of symptoms. Interrupt or reduce the rate of the infusion for Grade 1 or 2 reactions and manage symptoms [see Dosage and Administration (2)].

For patients with pre-existing cardiac or pulmonary conditions, monitor more frequently throughout the infusion and the post-infusion period since they may be at greater risk of experiencing more severe reactions. Hypotension may occur as part of the GAZYVA infusion reaction.

Consider withholding antihypertensive treatments for 12 hours prior to, during each GAZYVA infusion, and for the first hour after administration until blood pressure is stable. For patients at increased risk of hypertensive crisis, consider the benefits versus the risks of withholding their hypertensive medication as is suggested here.

5.4 Tumor Lysis Syndrome Acute renal failure, hyperkalemia, hypocalcemia, hyperuricemia, and/or hyperphosphatemia from Tumor Lysis Syndrome (TLS) can occur within 12–24 hours after the first infusion.

Patients with high tumor burden and/or high circulating lymphocyte count (> 25 x 109/L) are at greater risk for TLS and should receive appropriate tumor lysis prophylaxis with anti-hyperuricemics (e.g., allopurinol) and hydration beginning 12–24 hours prior to the infusion of GAZYVA [see Dosage and Administration (2.2)]. For treatment of TLS, correct electrolyte abnormalities, monitor renal function, and fluid balance, and administer supportive care, including dialysis as indicated.

dropped—this is not good medical practice! Our conversation then developed into the challenges of explaining relapsed or resistant disease to patients and families and how to choose between recommending further treatment or a change of strategy to palliative care.

In earlier times, patients looked to continued on page 56

• Infusion reactions [see Warnings and Precautions (5.3)] • Tumor lysis syndrome [see Warnings and Precautions (5.4)] • Infections [see Warnings and Precautions (5.5)] • Neutropenia [see Warnings and Precautions (5.6)] • Thrombocytopenia [see Warnings and Precautions (5.7)] The most common adverse reactions (incidence ≥ 10%) were: infusion reactions, neutropenia, thrombocytopenia, anemia, pyrexia, cough, and musculoskeletal disorders.

6.1 Clinical Trial Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

The data described in Tables 3 and 4 below are based on a total of 356 previously untreated patients with CLL during treatment with GAZYVA in combination with chlorambucil or with chlorambucil alone. Patients received three 1000 mg doses of GAZYVA on the first cycle and a single dose of 1000 mg once every 28 days for 5 additional cycles in combination with chlorambucil (6 cycles of 28 days each in total). In the last 45 patients enrolled, the first dose of GAZYVA was split between day 1 (100 mg) and day 2 (900 mg) [see Dosage and Administration (2.1)]. In total, 81% of patients received all 6 cycles (of 28 days each) of GAZYVA based therapy.

Table 3 Summary of Adverse Reactions Reported with ≥ 5% Incidence and ≥ 2% Greater in the GAZYVA Treated Arm

Neutropenia can also be of late onset (occurring more than 28 days after completion of treatment) and/or prolonged (lasting longer than 28 days).

Patients with neutropenia are strongly recommended to receive antimicrobial prophylaxis throughout the treatment period. Antiviral and antifungal prophylaxis should be considered.

5.7 Thrombocytopenia GAZYVA in combination with chlorambucil caused Grade 3 or 4 thrombocytopenia in 11% of patients in the trial. In 5% of patients, GAZYVA caused acute thrombocytopenia occurring within 24 hours after the GAZYVA infusion.

Fatal hemorrhagic events during Cycle 1 have also been reported in patients treated with GAZYVA. Monitor all patients frequently for thrombocytopenia and hemorrhagic events, especially during the first cycle. In patients with Grade 3 or 4 thrombocytopenia, monitor platelet counts more frequently until resolution and consider subsequent dose delays of GAZYVA and chlorambucil or dose reductions of chlorambucil. Transfusion of blood products (i.e., platelet transfusion) may be necessary.

Consider withholding concomitant medications which may increase bleeding risk (platelet inhibitors, anticoagulants), especially during the first cycle.

5.8 Immunization The safety and efficacy of immunization with live or attenuated viral vaccines during or following GAZYVA therapy has not been studied. Immunization with live virus vaccines is not recommended during treatment and until B-cell recovery.

6 ADVERSE REACTIONS The following adverse reactions are discussed in greater detail in other sections of the label: • Hepatitis B reactivation [see Warnings and Precautions (5.1)] • Progressive multifocal leukoencephalopathy [see Warnings and Precautions (5.2)]

Chlorambucil n = 116

All Grades All Grades Grades % 3–4b % Grades % 3–4b % Injury, Poisoning and Procedural Complications Infusion related reactions

69

21

0

0

Blood and lymphatic system disordersc

5.5 Infections Serious bacterial, fungal, and new or reactivated viral infections can occur during and following GAZYVA therapy.

Do not administer GAZYVA to patients with an active infection. Patients with a history of recurring or chronic infections may be at increased risk of infection.

5.6 Neutropenia GAZYVA in combination with chlorambucil caused Grade 3 or 4 neutropenia in 34% of patients in the trial. Patients with Grade 3 to 4 neutropenia should be monitored frequently with regular laboratory tests until resolution. Anticipate, evaluate, and treat any symptoms or signs of developing infection.

GAZYVA + Chlorambucil n = 240

Adverse Reactions (MedDRAa) System Organ Class

Neutropenia

40

34

18

Thrombocytopenia

15

11

7

16 3

Anemia

12

4

10

5

Leukopenia

7

5

0

0

General disorders and administration site conditions Pyrexia

10

<1

7

0

Respiratory, thoracic and mediastinal disorders Cough

10

0

7

<1

a MedDRA coded adverse reactions as reported by investigators. b c

No Grade 5 adverse reactions have been observed with a difference of ≥ 2% between the treatment arms.

Adverse events reported under ‘Blood and lymphatic system disorders’ reflect those reported by investigator as clinically significant.

Table 4 Post-Baseline Laboratory Abnormalities

by CTCAE Grade with ≥ 5% Incidence and ≥ 2% Greater in the GAZYVA Treated Arm GAZYVA + Chlorambucil n = 240

Investigations

Chlorambucil n = 116

All Grades All Grades Grades % 3–4 % Grades % 3–4 % Hematology Neutropenia Lymphopenia Leukopenia Thrombocytopenia Chemistry Hypocalcemia Hyperkalemia Hyponatremia AST (SGOT increased) Creatinine increased ALT (SGPT increased) Hypoalbuminemia Alkaline Phosphatase increased Hypokalemia

77 80 84 47

46 40 36 14

53 9 12 50

27 2 <1 11

32

3

29

<1

31

5

17

2

29

8

11

2

28

<1

12

0

28

<1

18

<1

25

<1

14

0

22 16

<1 0

14 11

<1 0

13

1

4

<1

The ASCO Post | DECEMBER 1, 2014

PAGE 56

Perspective John F. Smyth, MD continued from page 55

their physicians for guidance, and some still do, but the modern tendency is to offer a menu of options and ask the patient to decide which choice to accept.

While patients and their families should always make such decisions, they must of course be informed by their doctor,

Infusion reactions: The incidence of infusion reactions was 69% with the first infusion of GAZYVA. The incidence of Grade 3 or 4 infusion reactions was 21% with 8% of patients discontinuing therapy. The incidence of reactions with subsequent infusions was 3% with the second 1000 mg and < 1% thereafter. No Grade 3 or 4 infusion reactions were reported beyond the first 1000 mg infused.

Of the first 53 patients receiving GAZYVA on the trial, 47 (89%) experienced an infusion reaction. After this experience, study protocol modifications were made to require pre-medication with a corticosteroid, anti-histamine, and acetaminophen. The first dose was also divided into two infusions (100 mg on day 1 and 900 mg on day 2). For the 45 patients for whom these mitigation measures were implemented, 21 patients (47%) experienced a reaction with the first 1000 mg and < 2% thereafter [see Dosage and Administration (2)].

Neutropenia: The incidence of neutropenia reported as an adverse reaction was 40% in the GAZYVA treated arm and 18% in the chlorambucil alone arm with the incidence of serious adverse events being 1% and 0%, respectively (Table 3). Cases of late onset neutropenia (occurring 28 days after completion of treatment or later) were 16% in the GAZYVA treated arm and 12% in the chlorambucil alone arm.

Infection: The incidence of infections was similar between arms. Thirty-eight percent of patients in the GAZYVA treated arm experienced an infection, 9% were Grade 3–4 and none were fatal.

Thrombocytopenia: The incidence of thrombocytopenia reported as an adverse reaction was 15% in the GAZYVA treated arm and 7% in the chlorambucil alone arm (Table 3). Five percent of patients in the GAZYVA treated arm experienced acute thrombocytopenia (occurring within 24 hours after the GAZYVA infusion). The number of fatal hemorrhagic events was similar between the treatment arms, with 4 in the GAZYVA treated arm. However, all fatal hemorrhagic events in patients treated with GAZYVA occurred in Cycle 1.

Tumor Lysis Syndrome: The incidence of Grade 3 or 4 tumor lysis syndrome was 2% in the GAZYVA treated arm versus 0% in the chlorambucil arm.

Musculoskeletal Disorders: Adverse events related to musculoskeletal disorders, including pain (System Organ Class) have been reported with GAZYVA with higher incidence than in the comparator arm (17% vs. 13%).

6.2 Immunogenicity Serum samples from patients with previously untreated CLL were tested during and after treatment for antibodies to GAZYVA. Approximately 13% (9/70) of GAZYVA treated patients tested positive for anti-GAZYVA antibodies at one or more time points during the 12 month follow-up period.

Neutralizing activity of anti-GAZYVA antibodies has not been assessed.

Immunogenicity data are highly dependent on the sensitivity and specificity of the test methods used.

Additionally, the observed incidence of a positive result in a test method may be influenced by several factors, including sample handling, timing of sample collection, drug interference, concomitant medication and the underlying disease. Therefore, comparison of the incidence of antibodies to GAZYVA with the incidence of antibodies to other products may be misleading. Clinical significance of anti-GAZYVA antibodies is not known.

6.3 Additional Clinical Trial Experience Progressive multifocal leukoencephalopathy: PML has been reported with GAZYVA [see Warnings and Precautions (5.2)].

Worsening of pre-existing cardiac conditions: Fatal cardiac events have been reported in patients treated with GAZYVA. Hepatitis B reactivation: Hepatitis B virus reactivation has been reported with GAZYVA [see Warnings and Precautions (5.1)].

7 DRUG INTERACTIONS No formal drug interaction studies have been conducted with GAZYVA. 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Pregnancy Category C Risk Summary There are no adequate and well-controlled studies of GAZYVA in pregnant women. Women of childbearing potential should use effective contraception while receiving GAZYVA and for 12 months following treatment. GAZYVA should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

and good doctors guide their patients to the most appropriate choice.

The new challenge is that there are an ever-increasing number of third-, fourth-, and fifth-line treatments for malignancies such as breast cancer, lymphoma, and even melanoma, and the patient and physician sometimes seem to have a confusing array of choic-

Animal Data In a pre- and post-natal development study, pregnant cynomolgus monkeys received weekly intravenous doses of 25 or 50 mg/kg obinutuzumab from day 20 of pregnancy until parturition. There were no teratogenic effects in animals. The high dose results in an exposure (AUC) that is 2.4 times the exposure in patients with CLL at the recommended label dose. When first measured on Day 28 postpartum, obinutuzumab was detected in offspring and B cells were completely depleted. The B-cell counts returned to normal levels, and immunologic function was restored within 6 months after birth.

8.3 Nursing Mothers It is not known whether obinutuzumab is excreted in human milk. However, obinutuzumab is excreted in the milk of lactating cynomolgus monkeys and human IgG is known to be excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from GAZYVA, a decision should be made whether to discontinue nursing, or discontinue drug, taking into account the importance of the drug to the mother.

8.4 Pediatric Use The safety and effectiveness of GAZYVA in pediatric patients has not been established.

8.5 Geriatric Use Of 240 previously untreated CLL patients who received GAZYVA in combination with chlorambucil, 196 patients (82%) were ≥ 65 years of age and 109 patients (45%) were ≥ 75 years of age. The median age was 74 years. Of the 109 patients ≥ 75 years of age, 49 (45%) experienced serious adverse events and 5 (5%) experienced adverse events leading to death. For 131 patients < 75 years of age, 39 (30%) experienced a serious adverse event and 3 (2%) an adverse event leading to death. Similar rates were observed in the comparator arm. No significant differences in efficacy were observed between patients ≥ 75 years of age and those < 75 years of age [see Clinical Studies (14.1)].

8.6 Renal Impairment Based on population pharmacokinetic analysis, a baseline creatinine clearance (CLcr) > 30 mL/min does not affect the pharmacokinetics of GAZYVA. GAZYVA has not been studied in patients with a baseline CLcr < 30 mL/min [see Clinical Pharmacology (12.3)].

8.7 Hepatic Impairment GAZYVA has not been studied in patients with hepatic impairment.

10 OVERDOSAGE There has been no experience with overdose in human clinical trials. Doses ranging from 50 mg up to and including 2000 mg per infusion have been administered in clinical trials. For patients who experience overdose, treatment should consist of immediate interruption or reduction of GAZYVA and supportive therapy.

17 PATIENT COUNSELING INFORMATION Advise patients to seek immediate medical attention for any of the following: • Signs and symptoms of infusion reactions including dizziness, nausea, chills, fever, vomiting, diarrhea, breathing problems, or chest pain [see Warnings and Precautions (5.3) and Adverse Reactions (6.1)].

• Symptoms of tumor lysis syndrome such as nausea, vomiting, diarrhea, and lethargy [see Warnings and Precautions (5.4) and Adverse Reactions (6.1)].

• Signs of infections including fever and cough [see Warnings and Precautions (5.5) and Adverse Reactions (6.1)].

• Symptoms of hepatitis including worsening fatigue or yellow discoloration of skin or eyes [see Warnings and Precautions (5.1)].

• New or changes in neurological symptoms such as confusion, dizziness or loss of balance, difficulty talking or walking, or vision problems [see Warnings and Precautions (5.2)].

Advise patients of the need for: • Periodic monitoring of blood counts [see Warnings and Precautions (5.6 and 5.7) and Adverse Reactions (6.1)].

• Avoid vaccinations with live viral vaccines [see Warnings and Precautions (5.8)].

• Patients with a history of hepatitis B infection (based on the blood test) should be monitored and sometimes treated for their hepatitis [see Warnings and Precautions (5.1)].

es. The reason I’m reporting this discussion with the young oncologists is to emphasize from my own experience the importance of knowing when to stop.

Difficult Discussion Sometimes the patient makes this choice for him/herself—“doctor, I have had enough”—but there may be inap-

GAZYVA® [obinutuzumab] Manufactured by: Genentech, Inc. A Member of the Roche Group South San Francisco, CA 94080-4990 U.S. License No: 1048

GAZYVA is a trademark of Genentech, Inc. 8/14 GAZ0002214501 © 2014 Genentech, Inc.

John F. Smyth, MD

propriate hope that the next treatment will work a miracle, or conflicting ambitions from close friends or family desperately keen that no option should be left untried, although the patient clearly wants to stop. From the doctor’s perspective (and, again, I am leaving aside the financial aspects of all of this), it is important to recognize when further active treatment is very unlikely to alter the course of the disease.

Death is not a medical failure—indeed, it is the only certainty that awaits us all—but, as physicians, we can influence the timing (sometimes) and the quality (always) of the weeks or months that precede a death from cancer. It is much easier to recommend that a further line of treatment be tried, however flimsy the evidence of likely benefit, than to begin the discussion that now is the time to change the emphasis and objectives of care to focus solely on symptoms and emotional support of a preterminal patient.

Nevertheless, some of the best conversations I have ever had have been with patients at this stage of their disease, and I have witnessed the gratitude that follows if you get this conversation right. However painful the emotional experience, helping patients to understand that death is not far off allows them to move beyond false hope, and to relate to family and friends in a different way from the situation at diagnosis or during active treatment, when optimism is usually prevalent.

Enabling Experience Having time to reflect, and allowing family to plan for later, is a wonderful and enabling experience for many patients, whatever their age. It is sad if we as doctors deny patients that opportunity by taking the easier route of prescribing more medicines, knowing that the likelihood of side effects is certain and the extension of useful life unlikely. That said, the advent of ever more choices can only confound this situation. I am not sure if my conversation in Madrid did anything to help the young oncologists involved, but at least we aired this important topic. n

Disclosure: Dr. Smyth reported no potential conflicts of interest.

ASCOPost.com | DECEMBER 1, 2014

PAGE 57

Direct From ASCO

ASCO Announces Top 5 Advances in Modern Oncology

T

o mark ASCO’s 50th anniversary, the Society called on the oncology community to select the five most pivotal advances in cancer research and patient care over the past 50 years.

Now, with more than 2,000 votes cast, ASCO has announced the results on CancerProgress.Net, its interactive website on the history of progress against cancer.

The results offer a range of clinical research advances, from cancer prevention to chemotherapy, molecularly targeted therapy to supportive care.

in medical research through the National Institutes of Health (NIH). Patients and advocates will also join in a call to Congress for greater funding for the NIH, which actually lost almost a quarter of its purchasing power in the past decade, adjusting for inflation.

“Progress builds on progress. Over the past 5 decades, NIH-funded research has transformed the outlook for people with cancer. These Top 5 in 50 highlight transformational discoveries that represent a shining sliver of what we have

1. MOPP chemotherapy cures advanced Hodgkin lymphoma In 1965, Vincent T. DeVita, Jr, MD, FASCO (ASCO Past President, 1977-1978) and his colleagues at the National Institutes of Health discovered that combination chemotherapy— mechlorethamine, vincristine, procar-

These Top 5 in 50 highlight transformational discoveries that represent a shining sliver of what we have learned from a sustained investment in federally funded research.

Spotlight on NIH-Funded Research Voters selected these milestones from a “ballot” of 32 advances drawn from CancerProgress.Net’s “Major Milestones” timeline, which was developed under the guidance of leading oncologists. The ballot also allowed voters to describe why they made their selection (see the sidebar, “Why They Voted”).

Importantly, federal research funding played a role in many of these advances, which were announced a day ahead of the second annual Rally for Medical Research Hill Day on September 18, in Washington, DC. The goal of this event is to call attention to the real and meaningful progress that has been made because of the federal investment

cut to patient enrollment in NIH-funded cancer clinical trials just since 2009.”

Here are the results of the vote on the “Top 5 Advances in Modern Oncology”:

—Peter Paul Yu, MD, FACP, FASCO

learned from a sustained investment in federally funded research,” said ASCO President Peter Paul Yu, MD, FACP, FASCO. “However, without greater federal investment going forward, the pace of progress against cancer and other diseases will be far slower. We’re already seeing more high-quality research grants being turned down and a projected 40%

Why They Voted: Comments From the Oncology Community 1965: MOPP chemotherapy cures Hodgkin lymphoma

“This was the clearest proof of concept that cancer was/is curable. It gave great impulse to therapeutic research that ultimately improved outcomes in breast, colon, kidney cancer, the leukemias, and most childhood malignancies.”

2006: HPV vaccine approved to prevent cervical cancer

bazine (Matulane), and prednisone (MOPP)—induced long-term remissions in over half of adults with Hodgkin lymphoma. The discovery sparked the first hope that advanced cancers could be cured with drug treatment and paved the way for 90% cure rates in patients with this disease today.

2. HPV vaccine approved to prevent cervical cancer The first human papillomavirus (HPV) vaccine—approved in 2006— brought 100% protection against the two strains of HPV known to cause most cervical cancers. Widespread vaccination, if fully implemented, could drive dramatic reductions in cervical and other HPVrelated cancers in the United States and worldwide.

“This advance—if broadly adopted—could lead to the total eradication of cervical cancer globally as well. …Millions could be saved.”

3. Imatinib transforms treatment of chronic myelogenous leukemia

2001: Imatinib transforms treatment for CML

The rapid U.S. Food and Drug Administration review and approval of imatinib (Gleevec) in 2001 transformed treatment for most patients with chronic myelogenous leukemia (CML). This easy-to-take pill turned a disease with no long-term survivors into one with 5-year survival rates of almost 90%. It also heralded a new era of research on molecularly targeted anticancer drugs. Today, over 60 of these medicines are available.

“[Imatinib] not only revolutionized CML, but cancer therapy in general.

A targeted agent directed at a cancer-causing gene—it represents the dawn of targeted therapy for cancer.”

1977: PVB cures men with testicular cancer

“Took the most lethal cancer for young men to the most curable.”

1991: Powerful antinausea drugs alleviate major side effect of cancer treatment

“[Antiemetics] permit millions of patients to receive full cancer regimens, delivered in a timely fashion . . . many even continue to work and lead high-functioning lives during treatment.”

4. PVB chemotherapy cures testicular cancer In 1977, Lawrence H. Einhorn,

MD, FASCO (ASCO Past President, 2000-2001) and colleagues showed that a new three-drug combination chemotherapy regimen—cisplatin, vinblastine, and bleomycin (PVB)—produced complete remissions for 70% of men with aggressive testicular cancer. Prior chemotherapy treatments worked in just 5% of men. This discovery, coupled with later multidisciplinary advances, made testicular cancer treatment one of oncology’s biggest success stories.

5. Powerful antinausea drugs dramatically improve many patients’ quality of life The introduction of ondansetron in 1991, together with other supportive care advances, dramatically changed the experience of cancer treatment for patients.

These drugs not only brought relief from intense, treatment-induced nausea and vomiting, but also made it possible for patients to avoid once-routine hospital stays, complete their full course of treatment, and live longer and better overall.

“All of these advances mark major turning points for cancer care and have improved and saved the lives of countless Americans,” said Dr. Yu. “Federally funded research answers questions that are critically important to patients, questions that would otherwise go unanswered— like comparing the effectiveness of two regimens, exploring new uses for generic drugs, finding new ways to improve patients’ quality of life, and testing truly novel approaches like many of those highlighted in the Top 5 in 50 announced today.”

These results not only demonstrate the remarkable progress achieved in cancer research since ASCO’s founding, but also the payoff of federal investment in clinical research: NIH research grants played a role in many of the discoveries that made the “Top 5.”

For more information on the “Top 5,” including historic photos and more comments from people who voted, go to www.CancerProgress.Net/Top5. n © 2014. American Society of Clinical Oncology. All rights reserved.

The ASCO Post | DECEMBER 1, 2014

PAGE 58

Direct From ASCO

Top 5 Features of ASCO’s Newly Redesigned Patient Education Website Highlighted

A

SCO recently launched a new and redesigned version of Cancer.Net, its patient-facing website that includes timely, comprehensive, and oncologist-approved information.

With support from the Conquer Cancer Foundation, Cancer.Net is able to bring the expertise and resources of ASCO to your patients and their families and caregivers. The redesign was based on extensive consumer testing

about the top 5 new or updated features of Cancer.Net’s redesign.

1. Cancer.Net Blog One of the first new features of the redesign to be pushed live is the Cancer.

Net Blog, which launched in December 2013. Unlike some of the more traditional content on the website, which is peer-reviewed and has a more formal tone, the new blog provides a much

The redesign has solidified Cancer.

Net’s position as the premier website of oncologist-approved information for cancer patients and their families.

may be of interest to patients and family members, but it also includes topical posts about cancer treatment, prevention, supportive care, or, in some cases, the personal stories and experiences of survivors.

2. Ease of Navigation, Redesigned Homepage The relaunched Cancer.Net has been thoroughly designed to be more streamlined and easy to navigate. One of the most prominent new features of the homepage includes the six navi-

gational tiles in its center, introducing the major navigational sections of the website: Types of Cancer, Navigating Cancer Care, Coping & Emotions, Research & Advocacy, Survivorship, and Support Our Work.

According to Dr. Miller, usability testing and focus groups helped to focus the content of the website, grouping the vast majority of Cancer.Net’s extensive content into these six categories. Website users can also find the main categories listed across the top of continued on page 59

—Robert S. Miller, MD, FACP, FASCO

and included several phases of implementation over the past year, all aimed at providing patients and caregivers with the best educational experience.

“The redesign has solidified Cancer.Net’s position as the premier website of oncologist-approved information for cancer patients and their families,” said Cancer.Net Editor-inChief ­Robert S. Miller, MD, FACP, FASCO. “We encourage all healthcare professionals to recommend the site for all of the patients and families that they serve.”

We recently talked with Dr. Miller

more flexible and conversational platform for communicating with patients and their caregivers.

“We are proud to have many different types of authors contributing content to the blog,” Dr. Miller said. “To date, blog posts have been authored by physician members of the website’s editorial board and ASCO staff, and a growing number of guest authors including health-care professionals, advocates, patients, and families.”

In addition, the blog posts frequently cover breaking scientific news from ASCO’s conferences and journals that

New ASCO Survivorship Care Plan Template Is Simpler, Faster for Health-Care Providers

A

SCO has issued a new template for health-care professionals to use when providing a survivorship care plan to patients who have completed curative cancer therapy. The survivorship care plan contains important information about treatment the patient received, the patient’s need for future checkups and cancer tests, the potential long-term late effects of treatment, and ideas for ways survivors can improve their health.

The new template, updating a previous version ASCO developed nearly a decade ago, was published in the Journal of Oncology Practice as part of an ASCO statement on the importance of—and minimum components for—survivorship care plans.

“This cleaner, simpler form will help health-care professionals get survivorship care plans into the hands of patients,” said Deborah K. Mayer, PhD, RN, Chair of the ASCO Survivorship Care Plan Working Group and Professor in the School of Nursing and Director of Cancer Survivorship at University of North Carolina Lineberger Comprehensive Cancer Center. “At the end of their treatment, patients should expect to receive a survivorship care plan, but if they don’t get one, they should ask their doctor or nurse for one.”

Streamlined Care Plan ASCO believes that all cancer survivors benefit from a survivorship

care plan to assist survivors and their primary care provider in coordination of care. Based on feedback from ASCO members, the survivorship care plan template has been revised and streamlined. The new version focuses more on critical information, is easier for physicians and patients to use, and requires less time to ­complete.

The Commission on Cancer of the American College of Surgeons has endorsed ASCO’s recommendations for the minimum elements included in the

new template. These elements were defined through a consensus process involving multidisciplinary stakeholders including oncology providers, social workers, survivors, and primary care providers. The template was proven through an IRB-approved pilot test in 11 practices to be a time-saving and useful instrument.

View the template at www.asco .org/survivorship. n © 2014. American Society of Clinical Oncology. All rights reserved.

ASCOPost.com | DECEMBER 1, 2014

PAGE 59

Direct From ASCO Cancer.Net Redesign continued from page 58

each page, so they are easily available as visitors navigate throughout the site.

If these categories do not point a user to what they are looking for quickly, they can turn to an enhanced and much more prominent search function.

“We always had a search function, but it was harder to find, and the behind-the-scenes functionality of the search system is much more robust now,” Dr. Miller said.

For example, if a user misspells what they are searching for, the search function will now offer suggestions based on corrected spellings, using the “did you mean?” functionality that is available on most major search engine websites.

3. ‘Find a Cancer Doctor’ Database Enhancements Find a Cancer Doctor is one of the most widely used features of Cancer.

Net. This database of oncology professionals is populated using self-identified information from ASCO members who opt to be included when filling out demographic information for his or her societal membership.

The enhanced database now allows users to filter their search results by specialty, and by tumor type as well. Users can also filter their results by distance, choosing to search all of the United States, internationally, or within a certain number of miles from their home.

Once their search results appear, users can sort the results using the same options, distance, city name, oncologist name, or view their results on a map.

4. Multimedia Integration Cancer.Net visitors may also notice that video content is now integrated into the content available throughout the website. Years ago, when the site first began to produce audio and video content for its patient audience it was all grouped together under a “multimedia” heading.

“The old method was not particularly logical,” Dr. Miller said. “When most people are looking for information they are interested in seeing all different channels. When searching for a specific cancer topic, they want to see articles, podcasts, and videos that are appropriate all in the same spot.”

Now, for example, if a user is trying to research information about teens with cancer, they will navigate to an article about the topic, with a video embedded on the page. And, different collaborations between ASCO and the LIVESTRONG Foundation have also

yielded a greater amount of video content for patients, which has been integrated within the website.

5. Spanish Language Content Spanish language users of Cancer.

Net are now able to enjoy a mirror of the site in their native language. The homepage features an “Español” button

in the top right hand corner that will toggle to a Spanish homepage, introducing the site and its sections in Spanish, just like the English version. This toggle appears on all pages that have a Spanish translation available.

“With the relaunch, it was important that the website looked the same but include Spanish content,” Dr. Miller

said. “People who require Spanish content are no longer sent to a subsection of the English site, but to a specialized, Spanish-language Cancer.Net.” To check out these new features and more, visit Cancer.Net. n © 2014. American Society of Clinical Oncology. All rights reserved.

WHAT DOES THE BLOOD-BRAIN BARRIER HAVE TO DO WITH ALK+ NSCLC? In up to 46% of ALK+ NSCLC patients, the CNS is the first site of progression while receiving an ALK-directed therapy1 • The blood-brain barrier, composed of numerous efflux transporters, forms a sanctuary for metastatic disease by actively preventing some therapeutic molecules from entering the CNS2 • Therapies with minimal exposure in the CNS may be unable to inhibit progression in the CNS1,2 • Patients with CNS metastases often experience poor outcomes and significant morbidity3

Discover more at ResearchALK.com

ALK=anaplastic lymphoma kinase; CNS=central nervous system; NSCLC=non-small cell lung cancer.

References: 1. Weickhardt AJ, Scheier B, Burke JM, et al. Local ablative therapy of oligoprogressive disease prolongs disease control by tyrosine kinase inhibitors in oncogene-addicted non–small-cell lung cancer. J Thorac Oncol. 2012;7:1807-1814. 2. Deeken JF, Löscher W. The blood-brain barrier and cancer: transporters, treatment, and Trojan horses. Clin Cancer Res. 2007;13:1663-1674. 3. Chi A, Komaki R. Treatment of brain metastasis from lung cancer. Cancers (Basel). 2010;2:2100-2137. © 2014 Genentech USA, Inc. All rights reserved. BIO/100814/0053 Printed in USA.

The ASCO Post | DECEMBER 1, 2014

PAGE 60

Direct From ASCO

Charting the Successes: CancerProgress.Net Chronicles More Than 50 Years of ASCO and Progress Against Cancer

O

n this historic year, as ASCO proudly commemorates its 50th anniversary and decades of evolutionary change and growth, it also celebrates the significant progress that has been made against cancer throughout history. ASCO’s anniversary website, CancerProgress.Net,

cancer, aggregated news and views on ASCO’s anniversary and progress, and social media features.

The interactive Cancer Progress Timeline, a key feature of the site developed under the guidance of an editorial board of 21 of the nation’s leading on-

It’s the integration of all of the human aspects into the personalized medical approaches that is really helping us move toward a far better era of delivering care.

—Lidia Schapira, MD, FASCO

chronicles these achievements and more.

In honor of the Society’s anniversary, the site features stories about ASCO’s evolution, a timeline of advances in

Now in Spanish on Cancer.Net: Managing Your Weight After a Cancer Diagnosis, and More!

cologists, explores advances in nearly 20 types of cancers. The story of progress is shared by the timeline editors in their video interviews.

Decades of Improvements in Quality of Life In her video interview, Quality of Life Specialty Editor Lidia Schapira, MD, FASCO, said, “We’ve come a long way in making our cancer treatments better, more precise, and also easier to bear. Years ago, getting cancer treatment—which usually just meant chemotherapy—was a pretty awful experience for many patients.

We had very few drugs to help them deal with side effects, and we had a culture that was far less open than it is now.

“I think that just as important as our advances in understanding the differences between cancers is our understanding that human beings are different. It’s the integration of all of the human aspects

Conquering

into the personalized medical approaches that is really helping us move toward a far better era of delivering care, where patients and their families will feel supported throughout their cancer journey and hopefully also will have far better outcomes.”

Tour ASCO’s anniversary website, CancerProgress.Net, to navigate the timeline advances and to hear from other editors about milestones in cancer research. Also, follow ASCO on ASCO Connection, Twitter, and Facebook to join in on the conversation about progress. n © 2014. American Society of Clinical Oncology. All rights reserved.

Cancer.

Together, anything is possible.

A

SCO’s booklet to help patients learn how to manage weight gain after a cancer diagnosis is now available in Spanish. In addition, new information in Spanish has been added to Cancer.

Net on obesity, weight, and cancer risk, as well as articles on nutrition and physical activity. Your patients can download a PDF of this booklet and find these articles at www.cancer.net/obesidad. n

The Conquer Cancer Foundation. Our name says a lot.

Our mission says even more: Conquering cancer worldwide by funding breakthrough research and sharing cutting-edge knowledge. We are the go-to organization in supportingthe world’s preeminent cancer specialists, so one day we can live in a world free from the fear of cancer. To get to know us better now and be a part of our ambitious future, visit ConquerCancerFoundation.org.

DonATe ToDAY! ConquerCancerFoundation.org

© 2014. American Society of Clinical Oncology. All rights reserved.

Save the Date

Gastrointestinal Cancers Symposium

Genitourinary Cancers Symposium

January 15-17, 2015

February 26-28, 2015

Moscone West Building

Rosen Shingle Creek

San Francisco, California

Orlando, Florida

ASCOPost.com | DECEMBER 1, 2014

PAGE 61

Expert’s Corner Quality of Care

Advancing ASCO’s Commitment to Quality to Ensure That Every Patient Receives the Highest Level of Cancer Care A Conversation With Robert S. Miller, MD, FACP, FASCO

By Jo Cavallo biggest obstacles to quality improvement in cancer care, and his decision to make a career change.

New Role

Robert S. Miller, MD, FACP, FASCO

O

n December 3, 2014, Robert S. Miller, MD, FACP, FASCO, will start his new position as Medical Director of ASCO’s Institute for Quality (iQ). Established in 2012 to oversee the development of clinical practice guidelines, the Quality Oncology Practice Initiative (QOPI), the QOPI Certification Program, Performance Measures and Practice Improvement, and CancerLinQ, iQ provides ASCO members with the resources necessary to ensure that every patient receives the highest level of oncology care.

Currently Assistant Professor of Oncology and Oncology Medical Information Officer at the Sidney Kimmel Comprehensive Cancer Center at the Johns Hopkins University School of Medicine in Baltimore, Dr. Miller is a pioneer in health-related information technology and an expert on social media for professional education and patient engagement. He has served on ASCO’s Board of Directors, the Quality of Care Committee, the Clinical Practice Committee, the Cancer Education Committee, the Integrated Media and Technology Committee, and the Health Information Technology Workgroup. He is also currently Editor-in-Chief of Cancer.Net and is on the editorial board of the Journal of Oncology Practice.

An ASCO member since 1992, Dr. Miller said he decided to join ASCO as Medical Director of the Institute for Quality because, “ASCO’s vision for the future of oncology has always been something that has resonated with me personally.”

The ASCO Post talked with Dr. Miller about his immediate goals for iQ, the

Please talk about your new position as Medical Director of ASCO’s Institute for Quality. What are some of your priorities?

My job will be to provide medical oversight and bring a clinician’s perspective to the Institute for Quality’s initiatives. One area of particular focus will be ASCO’s learning health system CancerLinQ, which is scheduled to launch next year.

Among the things I’ll bring to my position as Medical Director of iQ is an ability to provide more regular input as a physician into the Institute’s quality improvement efforts. I have practiced both in an academic medical center setting and in the community practice setting, so I’ve seen both sides in terms of some of the pressures oncologists face (and I think there are more similarities than differences in the two modes of practice).

Right now, ASCO’s quality initiatives are under the purview of the Qual-

Measuring and Improving Quality What role does quality measurement play in physician reimbursement, and how is quality improvement being incorporated into the American Board of Internal Medicine’s (ABIM’s) Maintenance of Certification program?

We are working to transition reimbursement from a quantity-based system tied only to face-to-face patient encounters to one that reimburses physicians for medical outcomes. This is a very complex area, and clearly we do not have one structure in place yet, but quality measurement will continue to rise in importance because oncologists will need feedback for practices to remain viable. Oncologists have to know how they are doing in meeting the various quality metrics and how they compare with their peers.

No one quite yet has the vision about how the nuts and bolts are going to work, but I think that there is no ambiguity about the importance of outcomes in patient care and the fact that this is the direction in which healthcare reimbursement is moving.

A secondary aspect of quality im-

I think that there is no ambiguity about the importance of outcomes in patient care and the fact that this is the direction in which health-care reimbursement is moving.

—Robert S. Miller, MD, FACP, FASCO

ity of Care Committee and a number of important CancerLinQ committees.

The fact that ASCO is a volunteer, mission-driven organization is not going to change, but I think the Society decided to create this new position because having someone on staff with my background who can provide consistent input in these areas will help strengthen ASCO’s effort to improve the quality of cancer care.

To some extent, I’m going to be discovering exactly how my insights will be useful in the first year I’m here, but I think the idea for hiring me was that ASCO needed specific medical oversight on the development and implementation of some of these programs.

provement is adherence to the ABIM’s Maintenance of Certification (MOC) program. ABIM recently changed its MOC program, which now requires physicians to have continuous engagement in MOC activities, and these changes will become integral to daily practice.

Major Obstacle What do you see as the biggest obstacle to quality improvement?

The biggest obstacle to quality improvement is probably access to quality measurement data. Despite the fact that the majority of oncology practices now use electronic health records, we still struggle with extracting meaningful, specialty-specific quality measure-

ment data from our systems to know how we are doing even in our own practices.

One of the advantages of the QOPI program is that it forces oncology practices to look at very specific quality measurement indicators. Although we’ve seen a marked increase in the adoption of electronic health records, as a specialty we are still struggling to identify what metrics we are meeting in our practices and what the outcomes and improvements might be. I think that will be key to the future of quality improvement efforts.

Career Move What made you decide to make this change in your oncology career?

ASCO’s vision for the future of oncology has always been something that has resonated with me personally. ASCO’s guiding principle is that all patients with cancer should have access to high-quality care and that information learned from every patient should accelerate the progress against cancer. These are the things that I really believe in as an oncologist.

In my current position, I’m a clinician and I’m involved in informatics, and in those roles I can have some influence over a single institution. But this position potentially allows me to benefit cancer patients everywhere. It is a great opportunity to become involved in a visionary organization like ASCO, where the staff is passionate about this mission. I’m hoping it allows me the opportunity to focus my energies and interests on more global areas and enable me to have a broader impact than I could at my single institution.

One thing I have clearly learned is that when you work in an institution, you have a responsibility to your patients, of course, and to the goals of the institution when it comes to administrative responsibilities. I realized that I would not be able to focus on these important, more global ASCO initiatives if I continued to be employed where I am now. It is a bit of a leap and a change for me professionally, but I am really excited about starting my new position. n Disclosure: Dr. Miller reported no potential conflicts of interest.

Take a bite out of G-CSF acquisition costs*

*Based on wholesale acquisition cost (WAC) of all short-acting G-CSF products as of November 11, 2013. WAC represents published catalogue or list prices and may not represent actual transactional prices. Please contact your supplier for actual prices.

Indication » GRANIXTM (tbo-filgrastim) Injection is a leukocyte growth factor indicated for reduction in the duration of severe neutropenia in patients with nonmyeloid malignancies receiving myelosuppressive anticancer drugs associated with a clinically significant incidence of febrile neutropenia.

Important Safety Information » Splenic rupture: Splenic rupture, including fatal cases, can occur following the administration of human granulocyte colony-stimulating factors (hG-CSFs). Discontinue GRANIX and evaluate for an enlarged spleen or splenic rupture in patients who report upper abdominal or shoulder pain after receiving GRANIX.

» Acute respiratory distress syndrome (ARDS): ARDS can occur in patients receiving hG-CSFs. Evaluate patients who develop fever and lung infiltrates or respiratory distress after receiving GRANIX, for ARDS. Discontinue GRANIX in patients with ARDS.

» Allergic reactions: Serious allergic reactions, including anaphylaxis, can occur in patients receiving hG-CSFs. Reactions can occur on initial exposure. Permanently discontinue GRANIX in patients with serious allergic reactions. Do not administer GRANIX to patients with a history of serious allergic reactions to filgrastim or pegfilgrastim.

GRANIX is another option in short-acting G-CSF therapy TM

» GRANIX demonstrated a 71% reduction in duration of severe neutropenia (DSN) vs placebo1 – GRANIX significantly reduced DSN when compared to placebo (1.1 days vs 3.8 days; p<0.001)1 – Efficacy was evaluated in a multinational, multicenter, randomized, controlled, Phase III study of chemotherapy-naïve patients with high-risk breast cancer receiving doxorubicin (60 mg/m2 IV bolus)/docetaxel (75 mg/m2)1

» Safety was evaluated in 3 Phase III clinical trials1

Important Safety Information (continued) » Use in patients with sickle cell disease: Severe and sometimes fatal sickle cell crises can occur in patients with sickle cell disease receiving hG-CSFs. Consider the potential risks and benefits prior to the administration of GRANIX in patients with sickle cell disease. Discontinue GRANIX in patients undergoing a sickle cell crisis.

» Potential for tumor growth stimulatory effects on malignant cells: The granulocyte colonystimulating factor (G-CSF) receptor, through which GRANIX acts, has been found on tumor cell lines.

The possibility that GRANIX acts as a growth factor for any tumor type, including myeloid malignancies and myelodysplasia, diseases for which GRANIX is not approved, cannot be excluded.

» Most common treatment-emergent adverse reaction: The most common treatment-emergent adverse reaction that occurred in patients treated with GRANIX at the recommended dose with an incidence of at least 1% or greater and two times more frequent than in the placebo group was bone pain.

Please see brief summary of Full Prescribing Information on adjacent page.

For more information, visit GRANIXhcp.com.

Reference: 1. GRANIX TM (tbo-filgrastim) Injection Prescribing Information. North Wales, PA: Teva Pharmaceuticals; 2013.

©2014 Cephalon, Inc., a wholly-owned subsidiary of Teva Pharmaceutical Industries Ltd. GRANIX is a trademark of Teva Pharmaceutical Industries Ltd. All rights reserved. GRX-40175 January 2014. Printed in USA.

The ASCO Post | DECEMBER 1, 2014

PAGE 64

Journal Spotlight Gynecologic Oncology

Cancer-Killing Virus Plus Chemotherapy Studied in Recurrent Ovarian Cancer

I

n 6 out of 10 cases, ovarian cancer is diagnosed when the disease is advanced and 5-year survival is only 27%. A new study suggests that a cancer-killing virus combined with a chemotherapy drug might safely and effectively treat advanced or recurrent forms of the disease.

Researchers at The Ohio State University Comprehensive Cancer Center–Arthur G. James Cancer Hospital and Richard J. Solove Research Institute (OSUCCC–James), led the cell and animal study. Reporting in the journal Clinical Cancer Research,1 the researchers

BRIEF SUMMARY OF PRESCRIBING INFORMATION FOR GRANIX™ (tbo-filgrastim) Injection, for subcutaneous use SEE PACKAGE INSERT FOR FULL PRESCRIBING INFORMATION 1 INDICATIONS AND USAGE GRANIX is indicated to reduce the duration of severe neutropenia in patients with non-myeloid malignancies receiving myelosuppressive anti-cancer drugs associated with a clinically significant incidence of febrile neutropenia.

4 CONTRAINDICATIONS None.

5 WARNINGS AND PRECAUTIONS 5.1 Splenic Rupture Splenic rupture, including fatal cases, can occur following administration of human granulocyte colony-stimulating factors. In patients who report upper abdominal or shoulder pain after receiving GRANIX, discontinue GRANIX and evaluate for an enlarged spleen or splenic rupture.

5.2 Acute Respiratory Distress Syndrome (ARDS) Acute respiratory distress syndrome (ARDS) can occur in patients receiving human granulocyte colony-stimulating factors. Evaluate patients who develop fever and lung infiltrates or respiratory distress after receiving GRANIX, for ARDS. Discontinue GRANIX in patients with ARDS. 5.3 Allergic Reactions Serious allergic reactions including anaphylaxis can occur in patients receiving human granulocyte colony-stimulating factors. Reactions can occur on initial exposure. The administration of antihistamines‚ steroids‚ bronchodilators‚ and/or epinephrine may reduce the severity of the reactions. Permanently discontinue GRANIX in patients with serious allergic reactions. Do not administer GRANIX to patients with a history of serious allergic reactions to filgrastim or pegfilgrastim.

5.4 Use in Patients with Sickle Cell Disease Severe and sometimes fatal sickle cell crises can occur in patients with sickle cell disease receiving human granulocyte colony-stimulating factors. Consider the potential risks and benefits prior to the administration of human granulocyte colony-stimulating factors in patients with sickle cell disease.

Discontinue GRANIX in patients undergoing a sickle cell crisis.

5.5 Potential for Tumor Growth Stimulatory Effects on Malignant Cells The granulocyte colony-stimulating factor (G-CSF) receptor through which GRANIX acts has been found on tumor cell lines. The possibility that GRANIX acts as a growth factor for any tumor type, including myeloid malignancies and myelodysplasia, diseases for which GRANIX is not approved, cannot be excluded.

6 ADVERSE REACTIONS The following potential serious adverse reactions are discussed in greater detail in other sections of the labeling: • Splenic Rupture [see Warnings and Precautions (5.1)] • Acute Respiratory Distress Syndrome [see Warnings and Precautions (5.2)] • Serious Allergic Reactions [see Warnings and Precautions (5.3)] • Use in Patients with Sickle Cell Disease [see Warnings and Precautions (5.4)] • Potential for Tumor Growth Stimulatory Effects on Malignant Cells [see Warnings and Precautions (5.5)] The most common treatment-emergent adverse reaction that occurred at an incidence of at least 1% or greater in patients treated with GRANIX at the recommended dose and was numerically two times more frequent than in the placebo group was bone pain.

6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.

GRANIX clinical trials safety data are based upon the results of three randomized clinical trials in patients receiving myeloablative chemotherapy for breast cancer (N=348), lung cancer (N=240) and non-Hodgkin’s lymphoma (N=92). In the breast cancer study, 99% of patients were female, the median age was 50 years, and 86% of patients were Caucasian. In the lung cancer study, 80% of patients were male, the median age was 58 years, and 95% of patients were Caucasian. In the non-Hodgkin’s lymphoma study, 52% of patients were male, the median age was 55 years, and 88% of patients were Caucasian. In all three studies a placebo (Cycle 1 of the breast cancer study only) or a non-US-approved filgrastim product were used as controls. Both GRANIX and the non-US-approved filgrastim product were administered at 5 mcg/kg subcutaneously once daily beginning one day after chemotherapy for at least five days and continued to a maximum of 14 days or until an ANC of ≥10,000 x 106/L after nadir was reached.

showed that the oncolytic virus called 34.5ENVE has significant antitumor activity against ovarian cancer on its own, and that its activity is even greater when combined with the chemotherapy drug doxorubicin in an animal model of disseminated peritoneal ovarian cancer.

Bone pain was the most frequent treatment-emergent adverse reaction that occurred in at least 1% or greater in patients treated with GRANIX at the recommended dose and was numerically two times more frequent than in the placebo group. The overall incidence of bone pain in Cycle 1 of treatment was 3.4% (3.4% GRANIX, 1.4% placebo, 7.5% non-US-approved filgrastim product).

Leukocytosis In clinical studies, leukocytosis (WBC counts > 100,000 x 106/L) was observed in less than 1% patients with non-myeloid malignancies receiving GRANIX. No complications attributable to leukocytosis were reported in clinical studies.

6.2 Immunogenicity As with all therapeutic proteins, there is a potential for immunogenicity. The incidence of antibody development in patients receiving GRANIX has not been adequately determined.

7 DRUG INTERACTIONS No formal drug interaction studies between GRANIX and other drugs have been performed.

Drugs which may potentiate the release of neutrophils‚ such as lithium‚ should be used with caution.

Increased hematopoietic activity of the bone marrow in response to growth factor therapy has been associated with transient positive bone imaging changes. This should be considered when interpreting bone-imaging results.

8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Pregnancy Category C There are no adequate and well-controlled studies of GRANIX in pregnant women. In an embryofetal developmental study, treatment of pregnant rabbits with tbo-filgrastim resulted in adverse embryofetal findings, including increased spontaneous abortion and fetal malformations at a maternally toxic dose. GRANIX should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

In the embryofetal developmental study, pregnant rabbits were administered subcutaneous doses of tbo-filgrastim during the period of organogenesis at 1, 10 and 100 mcg/kg/day. Increased abortions were evident in rabbits treated with tbo-filgrastim at 100 mcg/kg/day. This dose was maternally toxic as demonstrated by reduced body weight. Other embryofetal findings at this dose level consisted of post-implantation loss‚ decrease in mean live litter size and fetal weight, and fetal malformations such as malformed hindlimbs and cleft palate. The dose of 100 mcg/kg/day corresponds to a systemic exposure (AUC0-24) of approximately 50-90 times the exposures observed in patients treated with the clinical tbo-filgrastim dose of 5 mcg/kg/day.

8.3 Nursing Mothers It is not known whether tbo-filgrastim is secreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when GRANIX is administered to a nursing woman. Other recombinant G-CSF products are poorly secreted in breast milk and G-CSF is not orally absorbed by neonates.

8.4 Pediatric Use The safety and effectiveness of GRANIX in pediatric patients have not been established.

8.5 Geriatric Use Among 677 cancer patients enrolled in clinical trials of GRANIX, a total of 111 patients were 65 years of age and older. No overall differences in safety or effectiveness were observed between patients age 65 and older and younger patients.

8.6 Renal Impairment The safety and efficacy of GRANIX have not been studied in patients with moderate or severe renal impairment. No dose adjustment is recommended for patients with mild renal impairment.

8.7 Hepatic Impairment The safety and efficacy of GRANIX have not been studied in patients with hepatic impairment.

10 OVERDOSAGE No case of overdose has been reported. ©2013 Cephalon, Inc., a wholly owned subsidiary of Teva Pharmaceutical Industries Ltd. All rights reserved.

GRANIX is a trademark of Teva Pharmaceutical Industries Ltd. Manufactured by: Distributed by: Sicor Biotech UAB Teva Pharmaceuticals USA, Inc. Vilnius, Lithuania North Wales, PA 19454 U.S. License No. 1803 Product of Israel GRX-40188 January 2014 This brief summary is based on TBO-003 GRANIX full Prescribing Information.

Potential Therapy “Our findings suggest that this could be a promising therapy, and we believe it should be further developed for the treatment of recurrent or refractory ovarian cancer in humans,” said principal investigator Balveen Kaur, PhD, Professor of Neurological Surgery and an OSUCCC–James researcher.

Among women treated for ovarian cancer whose tumors regress, 70% experience recurrence. The recurrent tumors are thought to develop from reserves of cancer stem-like cells that are chemotherapy-resistant and survive therapy. Consequently, recurrent tumors also tend to be resistant to primary chemotherapy regimens, and lethal.

The oncolytic herpes simplex virus 34.5ENVE is engineered to target cancer cells that overexpress the protein nestin and to inhibit the growth of blood vessels to tumors. The researchers chose to combine the oncolytic virus with doxorubicin because the drug is often administered to patients with recurrent ovarian cancer.

“This study underscores the significance of combining the oncolytic virus with doxorubicin for patients who have developed resistance to primary chemotherapy,” Dr. Kaur said.

Key Findings The investigators assessed the anticancer activity of the oncolytic virus 34.5ENVE, which is a genetically engineered herpesvirus, using several ovarian cancer cell lines, human and mouse tumor cells, and an animal model. Key technical findings included: • The expression of nestin was 10 to 100 times greater in human ovarian tumor cells than in normal ovarian cells.

• In a model of disseminated peritoneal ovarian cancer, the combination of doxorubicin plus the oncolytic virus increased survival, with an average survival of 58 days for treated animals vs 32.5 days for controls.

• The combination of doxorubicin and the oncolytic virus showed a synergistic increase in apoptosis in ovarian cancer cells compared to each agent alone. n

Disclosure: Funding from the NIH/National Cancer Institute (grant CA150153) supported this research. For full disclosures of the study authors, visit clincancerres.aacrjournals.org.

Reference 1. Bolyard CM, Yoo JY, Wang PY, et al: Doxorubicin synergizes with 34.5ENVE to enhance antitumor efficacy against metastatic ovarian cancer. Clin Cancer Res. October 7, 2014 (early release online).

ASCOPost.com | DECEMBER 1, 2014

PAGE 65

Journal Spotlight Hematology

Adding Pan-Deacetylase Inhibitor Panobinostat to Bortezomib and Dexamethasone Improves Progression-Free Survival in Relapsed Myeloma

By Matthew Stenger

I

n the phase III PANORAMA 1 trial reported in The Lancet Oncology, Jesus F. San-Miguel, MD, of Clinica Universidad de Navarra-CIMA, Pamplona, Spain, and colleagues found that adding the pan-deacetylase inhibitor panobinostat to bortezomib (Velcade) and dexamethasone improved progression-free survival in patients with relapsed or relapsed and refractory multiple myeloma.1

Study Details In this double-blind trial, 768 patients from 215 centers in 34 countries who had relapsed or relapsed and refractory myeloma and who had received one to three previous treatments were randomly assigned between January 2010 and February 2012 to receive panobinostat, bortezomib, and dexamethasone (n = 387) or placebo, bortezomib, and dexamethasone (n = 381).

Regimens consisted of 21-day cycles of panobinostat at 20 mg on days 1, 3, 5, 8, 10, and 12, bortezomib at 1.3 mg/m² on days 1, 4, 8, and 11, and dexamethasone at 20 mg on days 1, 2, 4, 5, 8, 9, 11, and 12.

Randomization was stratified by the number of previous treatment lines and previous use of bortezomib. Patients with primary refractory or bortezomibrefractory myeloma were not eligible.

Crossover was not permitted. The primary endpoint was progression-free survival.

The panobinostat and placebo groups were well balanced for age (median, 63 years in both, 58% in both < 65 years), sex (52% and 54% male), ethnicity (64% and 66% white, 33% and 27% Asian, 1% and 4% black), Eastern Cooperative Oncology Group performance status (0 in 45% and 43%, 1 in 49% in both), creatinine clearance (60– 89 mL/min in 68% and 65%, ≥ 90 mL/ min in 31% and 34%).

Myeloma was relapsed in 64% and 62%, and relapsed/refractory in 35% and 37%. Patients had undergone previous autologous stem cell transplantation in 56% and 59%, and the number of previous treatment lines was one in 51% and 52%, two in 32% and 28%, and three in 17% and 20%.

Previous treatments included bortezomib in 44% and 42%, lenalidomide (Revlimid) in 19% and 22%, thalido-

mide (Thalomid) in 53% and 49%, oral melphalan (Alkeran) in 30% and 27%, cyclophosphamide in 47% and 44%, dexamethasone in 80% and 83%, bortezomib plus an immunomodulatory drug in 24% and 26%, and bortezomib plus dexamethasone in 38% of both groups.

Improved Progression-Free Survival Median follow-up was 6.47 months (interquartile range = 1.81–13.47 months) in the panobinostat group and 5.59 months (interquartile range = 2.14–11.30 months) in the placebo group. Median progression-free survival was 11.99 months (95% confidence interval [CI] = 10.33–12.94) in the panobinostat group vs 8.08 months (95% CI = 7.56–9.23) in the placebo group (hazard ratio [HR] = 0.63, P < .0001). The hazard ratio for progression-free survival was similar on multivariate analysis (HR = 0.58, P < .0001).

Impact of Panobinostat on Relapsed/Refractory Myeloma ■■ Adding panobinostat to bortezomib/dexamethasone significantly increased progression-free survival in patients with relapsed or relapsed and refractory disease.

■■ Follow-up for overall survival is ongoing.

complete response rates of 27.6% vs 15.7% (P = .00006). Median time to response was 1.51 vs 2.00 months.

Median duration of response (partial response or better) was 13.14 vs 10.87 months. Among patients with at least a near-complete response, median progression-free survival was 19.38 vs 15.21 months.

Toxicity The most common nonhematologic adverse events of any grade in the panobinostat group were diarrhea (68% vs 42% in the placebo group), peripheral neuropathy (61% vs 67%), and asthenia/fatigue (57% vs 41%). The most

Our results suggest that panobinostat could be a useful addition to the treatment armamentarium for patients with relapsed or relapsed and refractory multiple myeloma.

—Jesus F. San-Miguel, MD, and colleagues

Two-year progression-free survival was 20.6% vs 8.4%.

The progression-free survival benefit of panobinostat was observed across most prespecified subgroups, including patients with relapsed and refractory disease (HR = 0.54), those with stage II and III disease (HR = 0.61), those aged ≥ 65 years (HR = 0.72), and those with prior use of bortezomib (HR = 0.58).

Survival and Response Overall survival data were not mature at the time of reporting. Median overall survival was 33.64 months (95% CI = 31.34 months–not estimable) vs 30.39 months (95% CI = 26.87 months–not estimable; HR = 0.87, P = .26). Objective response was observed in 60.7% vs 54.6% of patients (P = .09), including complete or near-

common grade 3/4 events were diarrhea (25% vs 8%), asthenia/fatigue (24% vs 12%), peripheral neuropathy (18% vs 15%), and pneumonia (13% vs 11%). Grade 3/4 hematologic adverse events included thrombocytopenia in 67% vs 31%, lymphopenia in 53% vs 40%, neutropenia in 35% vs 11%, and anemia in 18% vs 19%.

Serious adverse events occurred in 60% vs 42% of patients in the placebo group. Dose modifications were required for panobinostat in 51% of patients, bortezomib in 61%, and dexamethasone in 24% of the panobinostat group and for placebo in 23%, bortezomib in 42%, and dexamethasone in 17% of the placebo group.

Discontinuation of treatment due to adverse events occurred in 36% vs 20%.

Grade 3/4 adverse events led to discon-

tinuation in 25% vs 13%, with the most common events being diarrhea (4%), peripheral neuropathy (4%), asthenia/ fatigue (6%), thrombocytopenia (2%), and pneumonia (1%) in the panobinostat group and fatigue (3%), pneumonia (2%), peripheral neuropathy (2%), and diarrhea (2%) in the placebo group.

There were few cases of QT prolongation in either group; 0 vs 2 patients had QTc > 500 ms and 3 vs 4 had a QTc increase > 60 ms from baseline. T-wave changes (40% vs 18%) and ST-T segment changes (22% vs 3%) were more common in the panobinostat group but appeared to be asymptomatic.

A total of 11 deaths were considered possibly related to study treatment in the panobinostat group, consisting of 7 due to infection, 2 to hemorrhage, 1 to myocardial infarction, and 1 to cerebrovascular accident. A total of 7 deaths in the placebo group were considered possibly related to treatment, consisting of 4 due to infection, 1 to hemorrhage, 1 to pulmonary embolism, and 1 to cardiac arrest.

The investigators concluded: “Our results suggest that panobinostat could be a useful addition to the treatment armamentarium for patients with relapsed or relapsed and refractory multiple myeloma. Longer follow-up will be necessary to determine whether there is any effect on overall survival.” n

Disclosure: The study was funded by Novartis Pharmaceuticals. For full disclosures of the study authors, visit www.thelancet.com/ oncology.

Reference 1. San-Miguel JF, Hungria VTM, Yoon S-S, et al: Panobinostat plus bortezomib and dexamethasone versus placebo plus bortezomib and dexamethasone in patients with relapsed or relapsed and refractory multiple myeloma: A multicentre, randomised, double-blind phase 3 trial. Lancet Oncol 15:1195-1206, 2014.

See commentary by Sagar Lonial, MD, on page 66.

The ASCO Post | DECEMBER 1, 2014

PAGE 66

Perspective

HDAC Inhibitors and Triple Therapy in Relapsed Myeloma

By Sagar Lonial, MD

T

he use of histone deacetylase (HDAC) inhibitors as human cancer therapy has focused on the impact of these agents on epigenetic regulation and gene transcription. However, the use of HDAC inhibitors in myeloma may be working through a different mechanism. Specifically, HDAC6 is known to regulate the aggresome/ autophagy pathway, a secondary pathway for protein catabolism. When the proteasome is inhibited, the aggresome pathway becomes an accessory pathway through which protein homeostasis is maintained intracellularly.1,2

with bortezomib/dexamethasone to 12 months with panobinostat plus bortezomib/dexamethasone.

Overall survival data were not mature at the time of reporting. The difference in progression-free survival was, interestingly, not associated with an improvement in overall response rate, though the quality of response was better among those who received panobinostat. While the combination clearly demonstrated benefit, a significant fraction of patients were not able to continue on study due to the development of adverse events.

Early Trials

Interpreting PANORAMA Findings

This concept of HDAC/proteasome inhibitor was first tested in earnest with the combination of vorinostat (Zolinza) and bortezomib (Velcade); the combination demonstrated efficacy,3 but at the doses and schedule used in the larger phase II and phase III clinical trials, the regimen was simply not tolerated well enough to support long-term use among a majority of patients. The studies did, however, provide proof of principle that the combination was able to overcome bortezomib resistance, and at certain doses, could be tolerated.

The use of panobinostat in a similar set of trials4,5 was based on early data again suggesting the potential to overcome bortezomib resistance.6 In the PANORAMA 2 trial,7 patients with known bortezomib-resistant myeloma were treated with the combination of panobinostat and bortezomib.

Overall, the trial demonstrated that 30% of patients responded to the novel combination.

This encouraging early data gave rise to the phase III PANORAMA 1 trial, reported by San-Miguel and colleagues and reviewed in this issue of The ASCO Post.8 This trial is evaluating the benefit of adding panobinostat to bortezomib/dexamethasone vs bortezomib/dexamethasone alone.

The primary endpoint of the study was met, with an improvement in progression-free survival from 8 months Dr. Lonial is Vice Chair of Clinical Affairs, Department of Hematology and Medical Oncology, Winship Cancer Institute, Emory University, Atlanta.

So what are the challenges with interpretation of this study, and how do we as clinicians use the information to provide better care for our patients?

The clinical benefit of the treatment is clear, with a significant improvement

of concomitant steroids or stimulants.

In terms of hematologic toxicity, there was a higher incidence of grade 4 thrombocytopenia seen with the combination, but given that thrombocytopenia is a common adverse event for both agents, this is not a surprise.

In an in vivo murine model of thrombocytopenia, it was demonstrated that while the nadir of platelets was lower when panobinostat was combined with bortezomib, the time to platelet recovery (back to baseline) was the same as when either agent was given alone.9 Thus, patients may need support for hematologic toxicity during the initial therapy, but such toxicity should not be a reason to limit delivery of therapy.

Patient Selection The question remains: Which patients are best suited for this treatment approach? From the outset, it is

HDAC inhibitors would be a welcome addition to our treatment armamentarium—one that may be very helpful for those challenging patients with more aggressive myeloma.

—Sagar Lonial, MD

in progression-free survival. But what about the adverse events that were encountered by patients that limited the duration of therapy?

First, it should be recalled that at the time of study initiation, the routine use of subcutaneous administration of bortezomib had not yet become the standard. Thus, toxicity of the regimen overall may in part be related to the use of intravenous rather than subcutaneous bortezomib.

Second, the most common adverse events that occurred on study were gastrointestinal events (nausea and diarrhea) as well as fatigue. Gastrointestinal toxicity is likely in part due to the overlap with intravenous bortezomib but also directly related to panobinostat itself. Management requires some experience with the drug and may include modification of dose and schedule and use of antiemetics. Fatigue can often be reversed through the use

clear from the data that patients with high-risk myeloma and those who appear to be less sensitive to bortezomib should likely receive the combination.

From the subset analyses, it was apparent that patients from these groups gained benefit vs those who received bortezomib/dexamethasone alone.

The larger question revolves around the patients with early relapse in general. Do we know that triplets are better than doublets in this setting? This has been nicely demonstrated among newly diagnosed myeloma patients, where there is near global consensus that a three-drug induction is superior to two-drug induction, and there are now hints that the same may apply to patients with early relapse (after one to three prior lines of therapy, the same population that was studied in the current study).

This concept began to take hold several years ago, when the MMVAR/

IFM 2005-04 trial showed a significant improvement in progression-free survival and a trend toward improved overall survival with bortezomib/ thalidomide (Thalomid)/dexamethasone vs thalidomide/dexamethasone.10 The ASPIRE trial comparing carfilzomib (Kyprolis)/lenalidomide (Revlimid)/dexamethasone vs lenalidomide/dexamethasone also suggests a similar benefit of triple-drug salvage, and now we have the PANORAMA 1 findings continuing the trend of three drugs being superior to two in the early relapse setting.

I suspect that in order to make the leap to three drugs being better than two in the relapsed disease setting, we will likely need to see an impact on overall survival. Nevertheless, the question is an interesting one, especially as we begin to delve into the importance of minimal residual disease and its impact on duration and durability of response.11-13 While attention to this issue has been focused on newly diagnosed myeloma, the issue is also likely to be relevant in the early relapse setting.

HDAC inhibitors would be a welcome addition to our treatment armamentarium—one that may be very helpful for those challenging patients with more aggressive myeloma. Careful attention to symptom management and supportive care will help to increase the duration of HDAC inhibitor–containing therapy, which will ultimately allow more patients to gain benefit from the new treatment. n

Disclosure: Dr. Lonial reported no potential conflicts of interest.

References 1. McConkey DJ, White M, Yan W: HDAC inhibitor modulation of proteotoxicity as a therapeutic approach in cancer. Adv Cancer Res 116:131-163, 2012.

2. Simms-Waldrip T, Rodriguez-Gonzalez A, Lin T, et al: The aggresome pathway as a target for therapy in hematologic malignancies. Mol Genet Metab 94:283286, 2008.

3. Dimopoulos M, Siegel DS, Lonial S, et al: Vorinostat or placebo in combination with bortezomib in patients with multiple myeloma (VANTAGE 088): A multicentre, randomised, double-blind study. Lancet Oncol 14:1129-1140, 2013. continued on page 67

ASCOPost.com | DECEMBER 1, 2014

PAGE 67

Journal Spotlight Guidelines

Study Finds Wide Variation in Quality, Content of Clinical Cancer Guidelines

W

hat’s the best way to treat rectal cancer? Consult any of five top clinical guidelines for rectal cancer and you will get a different answer, according to a new study by researchers at the University of Michigan Comprehen-

how they were developed. The tool used gives a percentage score based on six quality domains. Average scores for the rectal cancer guidelines ranged from 27% to 90%, suggesting wide variation in quality.

Randomized clinical trials are supposed to be the gold standard, but even then, we’re interpreting results differently. It suggests the data can actually be controversial.

—Sandra L. Wong, MD, MS

sive Cancer Center. Their findings were published online in the journal Cancer.1 They looked at clinical practice guidelines for rectal cancer from five highly regarded organizations in the United States, Europe, and Canada.

The guidelines, which were all published within the last 6 years, were assessed for overall quality based on

Sagar Lonial, MD continued from page 66

4. Wolf JL, Siegel D, Goldschmidt H, et al: Phase II trial of the pan-deacetylase inhibitor panobinostat as a single agent in advanced relapsed/refractory multiple myeloma. Leuk Lymphoma 53:1820-1823, 2012.

5. Hideshima T, Richardson PG, Anderson KC: Mechanism of action of proteasome inhibitors and deacetylase inhibitors and the biological basis of synergy in multiple myeloma. Mol Cancer Ther 10:2034-2042, 2011.

6. Neri P, Bahlis NJ, Lonial S: Panobinostat for the treatment of multiple myeloma. Expert Opin Investig Drugs 21:733-747, 2012.

21 Points of Care Compared A good amount of published data and randomized clinical trials exist to help guide best practices for rectal cancer treatment. The researchers took a deep dive into the guideline content itself, looking at 21 common points of care. They found that the five guidelines all agreed on only eight processes

7. Richardson PG, Schlossman RL, Alsina M, et al: PANORAMA 2: Panobinostat in combination with bortezomib and dexamethasone in patients with relapsed and bortezomib-refractory myeloma.

Blood 122:2331-2337, 2013.

8. San-Miguel JF, Hungria VT, Yoon SS, et al: Panobinostat plus bortezomib and dexamethasone versus placebo plus bortezomib and dexamethasone in patients with relapsed or relapsed and refractory multiple myeloma: A multicentre, randomised, double-blind phase 3 trial. Lancet Oncol 15:1195-1206, 2014.

9. Giver CR, Jaye DL, Waller EK, et al: Rapid recovery from panobinostat (LBH589)-induced thrombocytope-

“Guideline panels should be reviewing and assimilating data to help physicians understand what to do. Randomized clinical trials are supposed to be the gold standard, but even then, we’re interpreting results differently. It suggests the data can actually be controversial,” Dr. Wong said.

She urges physicians as well as patients to be aware of this variation in guidelines and not follow them blindly.

In addition, organizations that produce guidelines should make it clear when expert consensus or opinion enters into the recommendations. n

of care and that six recommendations were in direct conflict.

“In this day and age of practicing medicine, particularly with cancer, physicians rely on these guidelines heavily.

Our study suggests we need to be careful about that. The guidelines are of varying quality and they have varying recommendations. It’s not as easy as just viewing a guideline and following it,” said senior study author Sandra L. Wong, MD, MS, Associate Professor of Surgery at the University of Michigan Medical School.

Dr. Wong, a cancer surgeon, also serves on several guideline panels. She and her colleagues have previously published a study that found cancer guidelines do not fully meet Institute of Medicine standards for how they are developed.

Disclosure: The study was supported by Agency for Healthcare Research and Quality grants T32 HS000053-22 and 1K08 HS2093701, and National Cancer Institute grant 1K07 CA163665-22. The authors reported no potential conflicts of interest.

Same Data, Different Recommendations

Reference 1. Abdelsattar ZM, Reames BN, Regenbogen SE, et al: Critical evaluation of the scientific content in clinical practice guidelines. Cancer. November 6, 2014 (early release online).

In the current study, the researchers found instances where guidelines cited the same published research but offered different recommendations.

nia in mice involves a rebound effect of bone marrow megakaryocytes. Leukemia 25:362-365, 2011.

10. Garderet L, Iacobelli S, Moreau P, et al: Superiority of the triple combination of bortezomib-thalidomide-dexamethasone over the dual combination of thalidomide-dexamethasone in patients with multiple myeloma progressing or relapsing after autologous transplantation: The MMVAR/IFM 2005-04 randomized phase III trial from the Chronic Leukemia Working Party of the European Group for Blood and Marrow Transplantation. J Clin Oncol 30:24752482, 2012.

11. Galimberti S, Benedetti E, Morabito

F, et al: Prognostic role of minimal residual disease in multiple myeloma patients after non-myeloablative allogeneic transplantation. Leuk Res 29:961-966, 2005.

12. Martinez-Sanchez P, Montejano L, Sarasquete ME, et al: Evaluation of minimal residual disease in multiple myeloma patients by fluorescent-polymerase chain reaction: The prognostic impact of achieving molecular response. Br J Haematol 142:766-774, 2008.

13. Paiva B, Vidriales MB, Cervero J, et al: Multiparameter flow cytometric remission is the most relevant prognostic factor for multiple myeloma patients who undergo autologous stem cell transplantation. Blood 112:4017-4023, 2008.

The ASCO Post Like us on Facebook facebook.com/TheASCOPost

Does your ovarian cancer patient have a BRCA mutation?

Only testing will tell.

Screening based on family history or age misses a substantial number of ovarian cancer patients with a BRCA mutation.

Approximately 15% of women with ovarian cancer have a deleterious BRCA mutation.1 Testing for a BRCA mutation provides powerful information for patients with ovarian cancer, their families, and their physicians. Yet most patients with ovarian cancer are not tested, leaving their BRCA status unknown.

positive ovarian cancer patients are aged 50 or older, and about one-third are aged 60 or older.8,9 BRCAm Ovarian Cancer Patients by Age at Diagnosis8

National guidelines recommend that all patients with epithelial ovarian cancer be considered for BRCA testing, regardless of family history, age, or ethnicity. 2,3

39% 29

%

[A]ll women diagnosed with ovarian, fallopian tube or peritoneal carcinoma, regardless of age or family history, should receive genetic counseling and be offered genetic testing.”

- SGO Clinical Practice Statement, October 2014 4 In clinical practice, however, the decision to recommend genetic testing is too often based on certain patient and disease characteristics.5 Despite guidelines, every year less than a quarter of patients with ovarian cancer are tested for a BRCA1/2 mutation.6,7

Family history and age at diagnosis are poor predictors of BRCA status in ovarian cancer patients. 8,9 Nearly half of patients with ovarian cancer and a BRCA1/2 mutation have no significant family history of ovarian or breast cancer. In addition, more than two-thirds of BRCABRCAm Ovarian Cancer Patients by Family History Status8

53%

47% No relevant family history Relevant family history

32%

71%

of patients with ovarian cancer and a BRCA mutation are aged 50 or older at diagnosis.8 <50 50-59 >60

Moreover, the prevalence of a BRCA mutation has been shown to be remarkably similar regardless of ethnicity, yet BRCA testing is not as common in women of non-European descent.10 Even sophisticated predictive models, which attempt to use a number of factors (including family history and age) to determine who should be tested for a BRCA mutation, fail to identify a significant proportion of patients who carry a BRCA mutation.11,12

Ovarian cancer cells with a BRCA mutation have DNA repair deficiencies and therefore are particularly sensitive to DNA-damaging agents.13 Germline BRCA mutations are associated with improved survival and generally favorable response to platinum-based chemotherapy in ovarian cancer.9,13 Additionally, there is evidence to suggest that BRCA expression is predictive of a clinical benefit for the use of IP-administered chemotherapy compared with IV-administered chemotherapy.14

Testing ALL of your ovarian cancer patients for their BRCA status provides powerful information for you, your patient, and her family.

REFERENCES: 1. Pal T, Permuth-Wey J, Betts, et al. BRCA1 and BRCA2 mutations account for a large proportion of ovarian carcinoma cases. Cancer. 2005;104(12):2807-2816. 2. National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology: Genetic/Familial High-Risk Assessment: Breast and Ovarian. Version 1.2014. 3. Lu KH, Wood ME, Daniels M, et al; American Society of Clinical Oncology. American Society of Clinical Oncology Expert Statement: collection and use of a cancer family history for oncology providers. J Clin Oncol. 2014;32(8):833-840. 4. Society of Gynecologic Oncology. SGO clinical practice statement: genetic testing for ovarian cancer. October 2014. http://www.sgo.org/clinical-practice/ guidelines/genetic-testing-for-ovarian-cancer/. Accessed October 23, 2014. 5. Norquist BM, Pennington KP, Agnew KW, et al. Characteristics of women with ovarian carcinoma who have BRCA1 and BRCA2 mutations not identified by clinical testing. Gynecol Oncol. 2013;128(3):483-487. 6. Myriad Genetics. http://www.myriadpro.com. Accessed November 4, 2014. 7. Meyer LA, Anderson ME, Lacour RA, et al. Evaluating women with ovarian cancer for BRCA1 and BRCA2 mutations: missed opportunities. Obstet Gynecol. 2010;115(5):945-952. 8. Song H, Cicek MS, Dicks E, et al. The contribution of deleterious germline mutations in BRCA1, BRCA2 and the mismatch repair genes to ovarian cancer in the population. Hum Mol Gen. 2014;(April 30):1-7. 9. Alsop K, Fereday S, Meldrum C, et al. BRCA mutation frequency and patterns of treatment response in BRCA mutation–positive women with ovarian cancer: a report from the Australian Ovarian Cancer Study Group. J Clin Oncol. 2012;30(21):2654-2663. 10. Hall MJ, Reid JE, Burbidge LA, et al. BRCA1 and BRCA2 mutations in women of different ethnicities undergoing testing for hereditary breast-ovarian cancer. Cancer. 2009;115(10):2222-2233. 11. Vargas CA, Da Silva L, Lakhani SR. The contribution of breast cancer pathology to statistical models to predict mutation risk in BRCA carriers. Fam Cancer. 2010:9(4):545-553. 12. Daniels MS, Babb SA, King RH, et al. Underestimation of risk of a BRCA1 or BRCA2 mutation in women with high-grade serous ovarian cancer by BRCAPRO: a multi-institution study. J Clin Oncol. 2014;32(12):1249-1255. 13. Bouwman P, Jonkers J. The effects of deregulated DNA damage signalling on cancer chemotherapy response and resistance. Nat Rev Cancer. 2012;12(9):587-598. 14. Lesnock JL, Darcy KM, Tian C, et al. BRCA1 expression and improved survival in ovarian cancer patients treated with intraperitoneal cisplatin and paclitaxel: a Gynecologic Oncology Group Study. Br J Cancer. 2013;108(6):1231-1237. ©2014 AstraZeneca. All Rights Reserved. 3061900 Last Updated 11/14

The ASCO Post | DECEMBER 1, 2014

PAGE 70

State of the Art Neuro-oncology

Treating Brain Cancer in 2014 A Conversation With Tracy Batchelor, MD

By Ronald Pi­­­ana

W

hile primary malignant brain tumors account for only 2% of all adult cancers, these deadly neoplasms cause severe cancer-related disability; the 5-year survival rates for brain tumors rank third lowest among all cancers, with those for pancreas and lung cancers being first and second lowest, respectively. However, new developments in molecular biology have led to a better understanding and classification of central nervous system (CNS) tumors, offering the potential for the development of promising new treatments. Internationally regarded brain tumor expert Tracy Batchelor, MD, spoke with The ASCO Post about recent advances and future directions in the treatment of CNS tumors.

medical therapy have been the U.S. Food and Drug Administration approval of temozolomide in 2005 and bevacizumab (Avastin) in 2009, both indicated for glioblastoma—the deadliest of CNS tumors. It’s important to highlight diagnostic and pathologic advances as well.

Over the past several years, we’ve seen the expanded use of tumor profiling, which, for instance, has allowed us to divide glioblastoma into more relevant biologic categories. The next WHO classification of CNS tumors will incorporate molecular markers for the first time.

Most importantly, this new information will ultimately be the basis for the development of more personalized therapies and better-designed clinical trials.

Major Advances

Clinical Challenges

What have been the biggest advances in brain tumor treatment over the course of your career?

I would arrange the advances according to surgical, radiation, and medical therapies. Certainly in the surgical setting, the advent of intraoperative magnetic resonance imaging (MRI) has markedly increased our ability to perform complete and much safer resection of various types of CNS tumors.

In radiation, we’ve seen the development of far more precise and controlled conformal techniques, which limits the amount of neurotoxicity that was associated with older radiation delivery techniques. The newer conformal techniques also offer the possibility of limiting the long-term side cognitive and endocrine effects of brain irradiation.

By far, the two biggest advances in

Please discuss the different clinical challenges involved in managing brain metastases and primary tumors.

Brain metastases are more difficult to treat than most primary brain tumors, because by the time they develop in the brain

Dr. Batchelor is Executive Director, Stephen E. and Catherine Pappas Center for NeuroOncology, Director, Division of Neuro-Oncology, Department of Neurology, Massachusetts General Hospital, and Director, Division of Neuro-Oncology, Department of Neurology, Harvard Medical School, Boston.

quently, the treatment options in surgery and radiation for brain metastases haven’t really changed much over the past decade.

Naturally, we still have a lot of work to do in primary brain tumors, but since we’re usually not dealing with the burden of widespread disease in those cases, it becomes a more focused challenge. Recently completed randomized trials have identified new drug combinations (bevacizumab plus lomustine), immunotherapies (rindopepimut) and novel techniques (alternating electrical fields) that may prove to be useful for glioblastoma patients.

CNS Lymphoma CNS lymphoma has historically been associated with poor survival. Over the past decade, however, we’ve seen some improvement in survival. Please give the readers an update on this issue.

Outcomes for primary CNS diffuse large B-cell lymphoma (PCNSL), > 90% of all cases of primary CNS lymphoma, remain inferior to other extranodual forms of non-Hodgkin lymphoma. This may be

Glioblastoma is where we have the most work to do….

The most promising area is in molecular diagnostics that enable us to subdivide glioblastomas into specific subtypes, which at least gives us an opportunity to develop more personalized therapeutic approaches and clinical trials.

—Tracy Batchelor, MD

they are usually the result of advanced, refractory cancer that hasn’t responded to standard treatments. Another challenge is that it is very difficult to deliver some of the newer targeted drugs effective in lung cancer, melanoma and other malignancies to the brain, as these agents have difficulty crossing the blood-brain barrier.

This area is in desperate need of new therapies, but before we get there, we need to have a better scientific understanding of the metastatic process as a whole. Conse-

due to the fact that > 90% of PCNSL cases consist of the more aggressive activated Bcell–like form. The improvement we’ve seen in PCNSL is due largely to the development of customized chemotherapy regimens that can cross the blood brain barrier and effectively treat the lymphoma.

The drug combinations used to treat a nonHodgkin lymphoma of the body are very different from those used to treat PCNSL. As we’ve gotten better at devising ways that allow our patients to tolerate high-dose

therapy, we’re now seeing early evidence suggesting that combining high-dose chemotherapy and bone marrow transplant could be quite effective for this group of patients. Also, investigators are developing treatment regimens for PCNSL that include targeted agents with demonstrated activity against the activated B-cell subtype of diffuse large B-cell lymphoma.

Moreover, we’ve finally reached a point in this rare brain cancer where we are able to conduct cooperative group randomized clinical trials. It’s important to note that when I began in this field, there had only been one published randomized trial that was terminated early because it failed to get proper accrual numbers. Now we have three completed and five ongoing randomized trials. So, for the first time we are truly beginning to develop some evidence-based medical practice data around PCNSL.

Treatment Tolerance You mentioned that a major step forward in treatment and research came with patients’ ability to tolerate regimens such as high-dose chemotherapy with bone marrow transplantation. Please elaborate on that.

First of all, not every patient is a candidate for transplantation, because many of the older patients are not. But in those patients with adequate organ function who are candidates for bone marrow transplant, we now have much better supportive treatments that allow them to tolerate the toxicities associated with these rather aggressive therapies.

Detection and Diagnosis Please talk a bit about the challenges involved in detection and diagnosis of brain tumors.

A big challenge in detection is that neurologic symptoms due to a brain tumor have many similarities to other neurologic disorders such as stroke or multiple sclerosis. Given the dearth of symptoms unique to brain tumors, there is no way for early detection un-

ASCOPost.com | DECEMBER 1, 2014

PAGE 71

State of the Art

less you use imaging. Since these are relatively rare tumors, there is no rationale to use imaging as a screening tool. Plus, we currently have no curative therapies for the most common primary brain cancers like glioblastoma.

On the other hand, if certain symptoms could possibly be caused by a brain tumor, then we advise a contrast-enhanced brain MRI, which in most cases gives us enough information either to rule a tumor out or make an accurate diagnosis. Because surgical techniques and perioperative care have improved so much, resection or biopsy of a brain is much safer with far less chance of side effects.

Closing Thoughts Do you have any closing thoughts on this very difficult oncologic setting that you’ve devoted much of your career to?

In this varied group of CNS malignancies, glioblastoma is where we have the most work to do and the biggest clinical and scientific questions to answer. A promising area is in molecular diagnostics, which enable us to subdivide glioblastomas into specific subtypes, giving us an opportunity to develop more personalized therapeutic approaches and clinical trials. At the same time, by reclassifying an uncommon tumor like glioblastoma into mul-

tiple molecular groups, we are creating rare biological tumor subtypes, which makes it more difficult to execute clinical trials.

This highlights the need for those of us in the clinical and research communities to develop and standardize molecular profiling platforms so that we’re all on the same page with regard to the markers we are using to classify tumors. Once we cross that bridge, we need to initiate large cooperative group and intergroup studies so that we have the numbers to adequately investigate these targeted drugs in subtypes of glioblastoma.

Another area of promise in glioblastoma is immunotherapy. We’re anticipating the results of a randomized trial that should be wrapping up fairly soon.

There are also some interesting glioblastoma studies underway examining the role of vaccines and checkpoint inhibitors. And, as mentioned, we are still hopeful that combinations of certain antiangiogenic treatments will prove active in glioblastoma. We have a long way to go, but there is also great promise in several areas that didn’t exist a decade ago. n Disclosure: Dr. Batchelor reported no potential conflicts of interest.

Don’t Miss These Important Reports in This Issue of The ASCO Post Peter Paul Yu, MD, on building a data infrastructure see page 1

John F. Smyth, MD, on when to stop prescribing see page 1

Norman Wolmark, MD, on hormonal therapy for early breast cancer see page 4

D. Ross Camidge, MD, PhD, on treatment of advanced lung cancer see page 11

William Berry, MD, MPA, MPH, FACS, on tools that enhance quality see page 20

Lawrence N. Shulman, MD, on a national cancer database see page 22

Deborah Schrag, MD, MPH, on tumor board participation see page 24

Suzanne Tamang, PhD, on the nature of unplanned cancer care see page 25

Steven D. Mittelman, MD, PhD, on childhood obesity and leukemia see page 30

Visit The ASCO Post online at ASCOPost.com

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The ASCO Post | DECEMBER 1, 2014

PAGE 72

EORTC-NCI-AACR Symposium Gynecologic Oncology

Scientists Develop New Approach to Treating HPV-Related Cervical Cancer

C

idofovir, an antiviral drug that is well established as a treatment for infection of the retina in people with AIDS, has been shown to be effective in combination with chemoradiation in a phase I study of women with human papillomavirus (HPV)-

related cervical cancer. The study results were presented at the recent EORTC-NCI-AACR Symposium on Molecular Targets and Cancer Therapeutics in Barcelona.1 Fifteen women were enrolled in the study and received injections of

ADDRESSING THE TOUGHEST CHALLENGES IN ONCOLOGY TAKES ALL OF US. That’s why we collaborate each day with peers, academics, clinical experts and others.

Together, we aim to create solutions that work against the ability of cancer cells to survive.

At AbbVie, our solutions start with science and end with a vision of a better future for patients around the world.

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cidofovir at doses ranging from 1 to 6.5 mg per kilogram of body weight weekly for 2 weeks, and then every 2 weeks from the start of chemoradiation (45 Gy radiotherapy delivered to the pelvis and weekly intravenous carboplatin until the start of brachy-

therapy in the uterus and vagina).

The women received a total of six injections of cidofovir, and the median duration of therapy was 10 weeks.

The combination of cidofovir and chemoradiation resulted in tumor shrinkage in all patients and did not increase toxicity or the tumor’s resistance to radiation.

“The major finding from the trial is that cidofovir did not increase the toxicity or worsen the tolerability of chemoradiation,” said Eric Deutsch, MD, PhD, Professor of Radiation Oncology at the Institut Gustave Roussy, in Villejuif, France, and a coauthor of the study, in a press statement. “We also found that the combination resulted in tumor shrinkage in all the patients who could be evaluated in the trial, with a complete response, in which the tumors disappeared for a time, in 80% of these patients.”

A Safe Approach Although one of the major side effects from cidofovir can be kidney damage, none was seen in this trial, suggesting the dosage was safe.

“The results from this phase I trial show that the combination of cidofovir with chemoradiation is a new, targeted anticancer approach, which enables us to target cancer cells specifically with a limited impact on healthy tissues, thereby avoiding unacceptable adverse side effects,” said Dr. Deutsch.

The researchers hope to launch a phase II/III trial soon to investigate how the combination therapy impacts overall survival. n

Disclosure: The study authors reported no potential conflicts of interest.

Reference 1. Deutsch E, et al: Phase I trial evaluating the antiviral agent cidofovir in combination with chemoradiation in cervical cancer patients: A novel approach to treat HPV related malignancies? EORTC-NCI-AACR Symposium on Molecular Targets and Cancer Therapeutics. Abstract 219. Presented November 20, 2014.

Send Us Your NEWS Write to editor@ASCOPost.com.

All submissions will be considered for publication

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ASCOPost.com | DECEMBER 1, 2014

PAGE 73

Expert’s Corner AYA Oncology

Helping Adolescents and Young Adults Cope With Cancer A Conversation With Susan K. Parsons, MD, MRP, and Tully Saunders, BS

By Jo Cavallo

Susan K. Parsons, MD, MRP

Tully Saunders, BS

ach year, about 70,000 adolescents and young adults (AYAs) are diagnosed with cancer in the United States, almost six times the number of cases diagnosed in children up to 14 years of age. While overall cancer survival rates continue to rise—according to the American Cancer Society, there are currently 14.5 million cancer survivors in the United States—most of that improvement is among pediatric and older adult patients.

For adolescent and young adult patients with cancer, defined by the National Cancer Institute as those between the ages of 15 and 39, survival rates have remained stagnant since 1975. In certain cancer types, such as acute lymphoblastic leukemia, the 5-year survival rate has actually decreased—91% for children younger than 15 years compared with 78% for adolescents aged 15 to 19 years.

The possible reasons for this discrepancy in survival rates are many, including lack of health insurance or underinsurance, delayed diagnosis, lack of participation in clinical trials, inadequate treatment practices, the unique social needs of this age group, and a major emerging potential factor: underlying biologic differences.

To generate attention to the physical, cognitive, and emotional challenges that AYAs face, spur clinical trial development for this age group, and provide ongoing psychological and social support services to AYA survivors, in 2013, Tufts Medical Center in Boston opened the Reid R. Sacco Adolescent and Young Adult Program for Cancer and Hereditary Blood Diseases. So far, the clinic has accepted 60 AYAs who are either on active treatment or have completed treatment for cancer.

The ASCO Post talked with Susan K. Parsons, MD, MRP, Founding Di-

rector of the Reid R. Sacco Adolescent and Young Adult Program for Cancer and Hereditary Blood Diseases at Tufts Medical Center, and Tully Saunders, BS, the Program Coordinator, about the issues confronting AYAs during or after a cancer diagnosis and treatment and how programs like Reid R. Sacco’s are meeting the long-term needs of these survivors.

At age 27, Mr. Saunders brought his personal perspective of coping with

E

all patients, updating them with each subsequent visit.

We also help AYA survivors in ways that are a little bit nontraditional. For example, we focus on many of the liferelated issues they are dealing with as a function of their age and developmental stage. To help with this, we have incorporated trained peer navigators into the clinic. The peer navigators have all completed a 12-week course in patient navigation and receive in-depth clinical and administrative supervision. Each patient is assigned a peer navigator who works with the patient on a range of topics, including education, employment, personal and professional relationships, financial concerns, and housing.

The peer navigators and clinicians help the patients explore their cancer history within the context of their life stage and address their psychological, social, and financial needs. One issue that we have grappled with repeatedly is their health insurance status. Some AYAs are transitioning from their par-

Adolescents and young adults are a fascinating group to work with, and now that more attention is being paid to them and the potential barriers to their care and survivorship, I believe we are making progress in understanding the multiple factors contributing to their cancers and in improving their care and survival.

—Susan K. Parsons, MD, MRP

cancer to our conversation. Diagnosed with a rare form of lung cancer when he was just 3 years old, Mr. Saunders was treated by Dr. Parsons when she was a pediatric oncologist at Dana-Farber Cancer Institute.

Variety of Services Please talk about the services provided by the Reid R. Sacco Adolescent and Young Adult Program for Cancer and Hereditary Blood Diseases.

Dr. Parsons: Like other AYA programs, we provide holistic patient care.

We help our patients with disease and survivorship management, initial and late effects of therapy, and primary and secondary cancer prevention. We help them learn more about their health history and how to self-advocate within the health-care environment. We prepare survivorship care plans for survivors and construct active care plans for

ents’ health-care plans. Others don’t have stable employment or income.

But regardless of the situation, we help patients navigate through the maze of health insurance options to find an appropriate plan and ensure that they understand their plan’s costs and copays.

Another big area we touch on is educational and vocational counseling. Some patients are dealing with neurocognitive late effects from their treatment. When appropriate, we refer patients to formal neuropsychological testing and provide coaching and discussions about educational and professional goals.

We also help AYAs as they create and maintain social relationships. One of the advantages of this type of life-stage– based program is that our patients feel like they are now part of a group—a feeling they lost as a result of their can-

cer and treatment.

The program also offers services to help patients maintain health-care follow-up appointments.

Role of Social Media What role can social media play in helping AYA survivors stay healthy, and how can oncologists be better prepared in using social media to stay current with their patients’ needs?

Dr. Parsons: We recognize that our patients are much more connected to social media than we might be!

Mr. Saunders: True. Many AYAs are engaged in social media. It is heavily incorporated into their daily lives and is their main source of communicating with peers and receiving news.

At our clinic, we are very proactive in reaching out to AYAs through Facebook, our website, e-mail, and blog.

We were fortunate to receive a grant to build a secure website so we could have a dedicated patient forum where patients can interact and “meet” each other virtually. Patients receive a user name and can log into a secure portal to connect with other AYAs, privately contact our clinic team, and ask questions about their care. Having this virtual tool has helped us improve the level of care we provide AYAs.

Helpful Technology Do you use mobile device apps to keep these survivors engaged in their medical care?

Mr. Saunders: We leverage smart phone technology to e-mail patients if we have a question, want to schedule appointments, and as a reminder to take a daily medication. We ask patients early on about their preferred mode of communication: text, e-mail, or phone call, and we try to accommodate their communication style.

Dr. Parsons: We have found technology to be very powerful in helping patients remember their appointments, medications, and medication schedules. We worked with one patient, who could not remember his medications, to enter his medication list into his smart phone. Now, when he comes into the clinic he just pulls up the list on his phone. Another patient had a difficult time remembering to take her medication, so we helped her set alarms on her smart phone to remind her. continued on page 76

Cancer cell

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The ASCO Post | DECEMBER 1, 2014

PAGE 76

Expert’s Corner Adolescents and Young Adults With Cancer continued from page 73

Mr. Saunders: We’ve been pleased with the results of our peer navigator program. A peer navigator is present during every patient visit and represents our “boots on the ground” to help patients access resources, find clinical trial information, or program their smart phone or other mobile device to set appointment or medication reminders.

Survival Issues Why haven’t survival rates improved for AYAs as they have for younger and older patients with cancer?

Dr. Parsons: There are many, many factors contributing to the lack of survival progress among AYAs. This gap is a huge motivator for those of us involved in AYA care to determine how to improve those survival rates. Several reasons for this lack of progress have been proposed.

Prior to the Affordable Care Act, underinsurance or lack of insurance was a huge problem for this age group, but with provisions in the Affordable Care Act that allow some children to stay on their parent’s insurance plans until age 26 and with the elimination of preexisting conditions, more people in this age group have insurance, so that is one less health barrier to deal with.

The other issue is a function of age and a sense of invincibility. Some AYAs believe that cancer only happens to old people. Health-care providers, too, don’t have cancer in the front of their minds when they are examining people in this age group, so we often see delayed diagnosis as a result. Many of our survivors believe that cancer only strikes once, which is why it is challenging to sell some AYAs on secondarycancer prevention.

Some AYA experts have also argued that there may be underlying biologic differences in this age group. Furthermore, we may not be treating some of the diseases aggressively enough.

Emerging research suggests that treatment of some diseases may benefit from a pediatric approach, while others may best be treated with an adult approach.

The biologic differences are intriguing to us. Several interesting studies are underway, looking at whether there is something about when these cancers occur, how they present, and how they respond to treatment that may be different in this age group.

Several years ago, Wendy Stock, MD [Professor of Medicine, Section of Hematology/Oncology and Director of the Leukemia Program at the University of Chicago Comprehensive Cancer Center], did a study1 that examined the

survival differences of AYAs with acute lymphoblastic leukemia being treated on adult chemotherapy regimens vs pediatric chemotherapy regimens. While the individual chemotherapy drugs were similar, the doses and schedules were different. The study showed a 63% disease-free survival for individuals on pediatric trials vs 34% for those on adult trials.

Similar studies have been undertaken for patients with sarcoma and lymphoma to see which treatment approach would yield better outcomes for patients in this age group. There may not be a one-size-fits-all approach.

The good news is that there is now heightened awareness that much more research is needed in this area.

Improving Adherence How can oncologists encourage their patients to adhere to care recommendations?

Dr. Parsons: A lot of discussion is needed to convince AYAs to follow care guidelines. Some patients want to see the evidence behind the guidelines, while others don’t want to hear any of the details. Some are worried about copays or about missing time from work or school.

We provide each patient with a concrete care plan, including the specific follow-up tests, indication(s) for these tests, the date of the last test, and the

person responsible for getting the test done. That responsible party might be the AYA team, the primary care provider, or the patient him/herself.

We review the updated care plan at each visit and share a copy with the primary care provider. By clearly outlining and communicating care recommendations, we hope to empower patients to effectively manage their care.

Closing Thoughts Do you have any closing thoughts about working with AYAs? Adolescents and young adults are a fascinating group to work with. Now that more attention is being paid to them and the potential barriers to their care and survivorship, I believe we will make progress in understanding the multiple factors contributing to their cancers and in improving their care and survival.

Disclosure: Dr. Parsons and Mr. Saunders reported no potential conflicts of interest.

Reference 1. Stock W, La M, Sanford B, et al: What determines the outcomes for adolescents and young adults with acute lymphoblastic leukemia treated on cooperative group protocols? A comparison of Children’s Cancer Group and Cancer Leukemia Group B studies. Blood 112:16461654, 2008.

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PAGE 77

Journal Spotlight Proteomics

Proteome-Scale Map of the Human Interactome Network Created

R

esearchers have produced a new largest-scale map of human protein interactions that will better enable scientists to trace how genetic changes lead to diseases ranging from cancer to Huntington’s disease. The expanded map, published in the journal Cell,1 is about 30% larger than the combination of all small-scale studies published in scientific literature and suggests that scientists may have been too narrowly focused in tracking the mechanisms responsible for disease.

“The search for genetic connections to disease has been compared to an individual looking for his car keys beneath a streetlight at night,” said Thomas ­Rolland, PhD, a researcher at Dana-Farber Cancer Institute in Boston, and a co–lead author of the study.

“When a police officer asks why he’s looking there, he explains that that’s where the light is. By analogy, the new map casts a wider beam over the area to be searched, where the car keys would lie.”

ers found that instead of well-known proteins being densely interconnected, their interactions were evenly distributed across the proteome, suggesting that the human interactome is broader than previously thought.

“The map will be especially useful

in cancer research,” said Dr. Rolland.

“It revealed numerous connections between known and suspected cancer proteins, broadening the landscape for understanding the mechanics behind the disease. Combining our map with the results of small-scale studies, we

now know of about 30,000 interacting pairs of proteins in human cells.” n

Disclosure: For full disclosures of the study authors, visit www.cell.com.

Reference 1. Rolland T, et al: Cell. November 20, 2014 (early release online).

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New Protein-Protein Map In the study, scientists first searched the scientific literature to identify all the protein pairs that have been tested so far.

Of that group, they found 11,000 highquality interactions, representing less than 10% of all the protein-protein interactions thought to be in the human interactome.

The studies made it appear that less than half of human proteins are densely interconnected while the rest did not participate in any interaction, the researchers found. The pattern suggested to the researchers one of two possibilities: either those proteins interact only rarely with other proteins, or, because previous studies have focused on proteins known to be involved in disease, interactions involving other, less notorious proteins have been overlooked.

To determine which conclusion was correct, the researchers generated a new map by systematically looking for interactions among 13,000 proteins, covering almost half the space to be searched.

Unlike smaller-scale studies, which were built around known disease proteins, the new study tested proteins “across the board,” regardless of whether they had previously been implicated in disease.

The result was a high-quality map of almost 14,000 interactions among 4,300 distinct proteins. It is the largest experimentally determined binary proteinprotein interaction map yet produced, more than doubling the number of highquality interactions identified in the past 2 decades by small-scale studies.

Based on the new map, the research-

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The ASCO Post | DECEMBER 1, 2014

PAGE 78

Palliative Care in Oncology How the Earlier Introduction of Palliative Care Improves Quality of Life for Patients With Advanced Cancer A Conversation With Camilla Zimmermann, MD, PhD, FRCPC

By Jo Cavallo patients’ quality of life—and we found that it does,” she said.

The ASCO Post talked with Dr. Zimmermann, Head of the Palliative Care Program and Rose Family Chair in Supportive Care at the Princess Margaret Cancer Center and University Health Network, about the results of her study and how improving the quality of life of patients also improves the quality of life of their caregivers.

Camilla Zimmermann, MD, PhD, FRCPC

A

4-year study involving 461 patients with advanced stages of lung, gastrointestinal, genitourinary, breast, and gynecologic cancers has found that providing early outpatient palliative care vs standard oncology care alone improved quality of life and patient satisfaction. The study participants received care at 24 medical oncology clinics at Princess Margaret Cancer Center, University Health Network in Toronto, Canada, and had a clinical prognosis of between 6 and 24 months. The clinics were cluster randomized in a 1:1 ratio using a computer-generated sequence and stratified by clinic size and tumor site to consultation and follow-up by a palliative care team or to standard cancer care.

The aim of the study, said lead investigator Camilla Zimmermann, MD, PhD, FRCPC, was to determine whether the early involvement of a team of palliative care specialists made a difference in the quality of life of patients and their caregivers and improved patient satisfaction with the care they received. Despite recommendations by ASCO2 that palliative care services be integrated into standard oncology practice at the time a person is diagnosed with metastatic or advanced cancer to relieve pain and other physical, psychosocial, and spiritual issues, palliative care is most often introduced at the end of life, if at all, according to Dr. Zimmermann.

“Right now there is a difference between what we say we should be doing and what we actually do regarding palliative care in the advanced cancer setting. We wanted to see if there is any proof that doing what we say we should do has any positive impact on 1

Study Details What were the major results of your study?

Patients were assessed monthly for 4 months for quality of life using the Functional Assessment of Chronic Illness Therapy–Spiritual Well-Being (FACIT-Sp) scale and Quality of Life at the End of Life (QUAL-E) scale, symptom severity using the Edmonton Symptom Assessment System (ESAS), satisfaction with care using FAMCARE-P16, and problems with medical interactions using the Cancer Rehabilitation Evaluation

Relevance to Early Disease Can the results of your study also be used to show the benefit of palliative care for patients with early-stage disease, especially to remedy physical symptoms such as fatigue, pain, and sexual dysfunction, and mental health issues such as depression and anxiety?

I would be careful about extrapolating too much from this study, because it was focused on patients with advancedstage disease and their overall quality of life. There would have to be a specific study for patients with earlier-stage disease to see what benefits might be derived from early palliative care in that setting. However, I think that intervening in these sorts of symptoms in earlier disease makes a lot of sense and would improve patients’ quality of life.

Today, more and more, the whole focus of palliative care is from initial diagnosis and throughout survivorship.

During cancer treatment of any kind, patients and their families need support, both physical and psychological, throughout the illness and not just at

At 3 months, there was a trend toward a significant change in our primary outcome measure [FACIT-Sp], a significant change in the other quality-of-life measure, and a highly significant change in satisfaction with care, all favoring the intervention group.

—Camilla Zimmermann, MD, PhD, FRCPC

System Medical Interaction Subscale (CARES-MIS).

We defined the primary outcome in advance as the change in score on the FACIT-Sp measure from baseline to 3 months. Secondary endpoints included the change in FACIT-Sp score at 4 months and change for the other scales at 3 and 4 months.

We found that at 3 months, there was a trend toward a significant change in our primary outcome measure, a significant change in the other quality-of-life measure, and a highly significant change in satisfaction with care, all favoring the intervention group. At 4 months, almost all the outcomes were significantly positive. The only score that wasn’t positive was the one measuring problems with medical interactions.

the end of life. It doesn’t make sense to suddenly become very interested in patients’ symptoms only at the end of life.

Palliative care is relevant throughout the course of the illness and survivorship.

Acute Myeloid Leukemia You are currently investigating the palliative care needs of patients with acute myeloid leukemia. Do these patients have different needs than patients with other types of cancer?

They certainly do. Despite the fact that patients with acute myeloid leukemia have a very poor prognosis, especially those over age 65, traditionally the palliative care needs of these patients have not been adequately addressed.

Overall, the 5-year survival rate is between 20% and 30%, and in patients over age 65, the survival rate is about 15%, so

GUEST EDITOR

Jamie H. Von Roenn, MD

A

ddressing the evolving needs of cancer survivors at various stages of their illness and care, Palliative Care in Oncology is guest edited by Jamie H. Von Roenn, MD. Dr. Von Roenn is ASCO’s Senior Director of Education, Science and Professional Development Department.

there is a high death rate from this disease right from diagnosis. That said, in some cases the disease can be cured, so the focus is very much on cure and less on quality of life. But from initial diagnosis and throughout the disease trajectory, because the outcome is so variable, acute myeloid leukemia patients have high degrees of stress and anxiety, so they have significant psychosocial issues. They also have physical symptoms from both the leukemia and its treatment side effects.

For that reason, we are investigating whether the early integration of palliative care services at diagnosis can improve traumatic stress symptoms, which are prevalent in this population, as well as achieve physical symptom control. We have just launched a randomized phase II pilot study and will plan a phase III study based on the results of the pilot study.

Early palliative care is relevant in all sorts of cancers, but there probably needs to be slightly different treatment models, with a tailored approach for each disease.

Team Approach Please talk about what you have found in your research focusing on the effective delivery of palliative care.

The effective delivery of palliative care will vary depending on the healthcare system in which it is given and the collaboration among the existing professional caregivers in that field.

ASCOPost.com | DECEMBER 1, 2014

PAGE 79

Palliative Care in Oncology In our cancer center setting, which includes a large outpatient population with many physical and psychosocial concerns and care planning issues, we have a palliative care team comprising palliative care physicians and nurses, physical and occupational therapists, spiritual care professionals, and mental health and social work experts to provide support for the patient and family members. The core team in the outpatient palliative care clinic was a palliative care physician and nurse who brought in the other team members when required and also collaborated with the home-care team. We found that this type of multidisciplinary effort was very effective in improving patients’ quality of life and satisfaction with care.

Cost Considerations Does introducing palliative care earlier in a patient’s cancer diagnosis also

have a cost-saving benefit?

We are investigating cost, and that aspect of the study is ongoing. I don’t have the exact findings yet. But it makes sense that if palliative care specialists are involved in a patient’s care from the beginning, there will probably be more discussions about questions such as: Is this last line of chemotherapy really necessary?

Will it improve the patient’s quality of life, or is it being done to avoid confronting the reality of the situation (ie, that the patient is dying)?

Sometimes when we give palliative chemotherapy very late in the course of illness, it can result in a worse survival outcome. When that is the case, there is no cost-effectiveness benefit.

Providing palliation that allows the patient to remain at home and avoids admission to the hospital (and even travel to and from the cancer center

to treat symptoms) will also reduce medical costs.

Caregiver Benefit What did your study show regarding how palliative care support for the patient can also benefit the caregiver?

Although we didn’t recruit enough caregivers in our study to give it sufficient power to determine conclusive results, one thing we have seen is that the quality of life of caregivers is very closely associated with the quality of life of patients. So if you improve patient quality of life, you can likely also improve caregiver quality of life.

One reason for this might be that the caregivers’ ability to engage in activities outside of their caregiving duties—for example, continuing to work, going to exercise class, or meeting with friends—is directly affected by the pa-

tient’s quality of life. Also, there will be increased caregiver distress if the patient being cared for has uncontrolled pain or other symptoms. Therefore, it makes sense that if we improve the patient’s quality of life, we improve the caregiver’s quality of life as well. n

Disclosure: Dr. Zimmermann reported no potential conflicts of interest.

References 1. Zimmermann C, Swami N, Krzyzanowska M, et al: Early palliative care for patients with advanced cancer: A cluster-randomized controlled trial. Lancet 383:1721-1730, 2014.

2. Smith TJ, Temin S, Alesi ER, et al: American Society of Clinical Oncology Provisional Clinical Opinion: The Integration of Palliative Care Into Standard Oncology Care. J Clin Oncol 30:880-887, 2012.

Journal Spotlight Palliative Care

Use of Hospice Care by Medicare Patients Associated With Lower Rate of Hospitalization, ICU Admission, Invasive Procedures, and Costs

M

edicare patients with poor­ prognosis cancers who received hospice care had significantly lower rates of hospitalization, intensive care unit (ICU) admissions and invasive procedures at the end of life, along with significantly lower health care expenditures during the last year of life, according to a study in a recent issue of JAMA.1 Multiple studies have documented the high intensity of medical care at

the end of life, and there is increasing consensus that such care can produce poor outcomes and conflict with patient preferences. The Institute of Medicine report Dying in America has drawn attention to the difficulties of promoting palliative care, including Medicare’s hospice program, the largest palliative care intervention in the United States.

More patients with cancer use hospice currently than ever before, but there

EXPERT POINT OF VIEW

J

oan M. Teno, MD, MS, and Pedro L. Gozalo, PhD, of the Brown University School of Public Health, Providence, Rhode Island, commented on endof-life care in an editorial accompanying the JAMA study by Obermeyer et al.

“As financial incentives change in the U.S. health-care system, valid measures of care quality are increasingly important for ensuring transparency and accountability. Obermeyer and colleagues assessed hospitalization rates, intensive care admissions, and invasive procedures, but additional measures must have evidence of their ability to discriminate the quality of care and must be responsive to change, easy to understand, and actionable. This will involve investing public dollars in the ‘quality’ of quality measures and their dissemination. If quality of care is not front and center, the momentum to improve end-of-life care in the United States could face a serious setback.” n

Disclosure: Dr. Teno is the recipient of a Robert Wood Johnson Foundation Health Policy Investigators Award grant. She and Dr. Gozalo reported no potential conflicts of interest.

Reference 1. Teno JM, Gozalo PL: Quality and costs of end-of-life care: The need for transparency and accountability. JAMA 312:1868-1869, 2014.

Ziad Obermeyer, MD, MPhil

are indications that care intensity outside of hospice is increasing, and length of hospice stay decreasing. Uncertainties regarding how hospice affects healthcare utilization and costs have hampered efforts to promote it, according to background information in the article.

Study Details Using data from Medicare beneficiaries with poor-prognosis cancers (eg, brain, pancreatic, metastatic malignancies), Ziad Obermeyer, MD, MPhil, of Brigham and Women’s Hospital and Harvard Medical School, Boston, and colleagues matched those enrolled in hospice before death to those who died without hospice care and compared utilization and costs at the end of life. The study included a nationally representative 20% sample of Medicare feefor-service beneficiaries who died in 2011.

Among 86,851 patients with poorprognosis cancers, 51,924 (60%) entered hospice before death. Matching pa-

tients based on various criteria produced a hospice and nonhospice group, each with 18,165 patients. Median hospice duration was 11 days.

The researchers found that nonhospice beneficiaries had significantly greater health-care utilization, largely for acute conditions not directly related to cancer and higher overall costs. Rates of hospitalizations (65% vs 42%), ICU admissions (36% vs 15%), invasive procedures (51% vs 27%), and death in a hospital or nursing facility (74% vs 14%) were higher for nonhospice beneficiaries compared to hospice patients. Overall, costs during the last year of life were $62,819 for hospice beneficiaries and $71,517 for nonhospice beneficiaries.

“Our findings highlight the potential importance of frank discussions between physicians and patients about the realities of care at the end of life, an issue of particular importance as the Medicare administration weighs decisions around reimbursing physicians for advance care planning,” the authors wrote. n

Disclosure: This work was supported by grants from the National Institutes of Health, National Cancer Institute, and Agency for Healthcare Research and Quality. For full disclosures of the study authors, visit jama.jamanetwork.com.

Reference 1. Obermeyer Z, et al: JAMA 312:18881896, 2014.

Consider Iclusig (ponatinib) as an option for appropriate third-line CML and Ph+ ALL patients. ®

IMPORTANT SAFETY INFORMATION, INCLUDING THE BOXED WARNING WARNING: VASCULAR OCCLUSION, HEART FAILURE, and HEPATOTOXICITY See full Prescribing Information for complete boxed warning.

• Vascular Occlusion: Arterial and venous thrombosis and occlusions have occurred in at least 27% of Iclusig-treated patients, including fatal myocardial infarction, stroke, stenosis of large arterial vessels of the brain, severe peripheral vascular disease, and the need for urgent revascularization procedures. Patients with and without cardiovascular risk factors, including patients less than 50 years old, experienced these events. Monitor for evidence of thromboembolism and vascular occlusion.

Interrupt or stop Iclusig immediately for vascular occlusion. A benefit-risk consideration should guide a decision to restart Iclusig therapy.

• Heart Failure: Heart failure, including fatalities, occurred in 8% of Iclusig-treated patients. Monitor cardiac function. Interrupt or stop Iclusig for new or worsening heart failure.

• Hepatotoxicity: Hepatotoxicity, liver failure, and death have occurred in Iclusig-treated patients. Monitor hepatic function. Interrupt Iclusig if hepatotoxicity is suspected.

Vascular Occlusion: Arterial and venous thrombosis and occlusions, including fatal myocardial infarction, stroke, stenosis of large arterial vessels of the brain, severe peripheral vascular disease, and the need for urgent revascularization procedures have occurred in at least 27% of Iclusig-treated patients from the phase 1 and phase 2 trials. Iclusig can also cause recurrent or multi-site vascular occlusion. Overall, 20% of Iclusig-treated patients experienced an arterial occlusion and thrombosis event of any grade. Fatal and life-threatening vascular occlusion has occurred within 2 weeks of starting Iclusig treatment and in patients treated with average daily dose intensities as low as 15 mg per day. The median time to onset of the first vascular occlusion event was 5 months. Patients with and without cardiovascular risk factors have experienced vascular occlusion although these events were more frequent with increasing age and in patients with prior history of ischemia, hypertension, diabetes, or hyperlipidemia.

Interrupt or stop Iclusig immediately in patients who develop vascular occlusion events.

Heart Failure: Fatal and serious heart failure or left ventricular dysfunction occurred in 5% of Iclusig-treated patients (22/449). Eight percent of patients (35/449)

experienced any grade of heart failure or left ventricular dysfunction. Monitor patients for signs or symptoms consistent with heart failure and treat as clinically indicated, including interruption of Iclusig. Consider discontinuation of Iclusig in patients who develop serious heart failure.

Hepatotoxicity: Iclusig can cause hepatotoxicity, including liver failure and death.

Fulminant hepatic failure leading to death occurred in an Iclusig-treated patient within one week of starting Iclusig. Two additional fatal cases of acute liver failure also occurred. The fatal cases occurred in patients with blast phase CML (BP-CML) or Philadelphia chromosome positive acute lymphoblastic leukemia (Ph+ ALL).

Severe hepatotoxicity occurred in all disease cohorts. Iclusig treatment may result in elevation in ALT, AST, or both. Monitor liver function tests at baseline, then at least monthly or as clinically indicated. Interrupt, reduce, or discontinue Iclusig as clinically indicated.

Hypertension: Treatment-emergent hypertension (defined as systolic BP≥140 mm Hg or diastolic BP≥90 mm Hg on at least one occasion) occurred in 67% of patients (300/449). Eight patients treated with Iclusig (2%) experienced treatment-emergent symptomatic hypertension as a serious adverse reaction, including one patient (<1%) with hypertensive crisis. Patients may require urgent clinical intervention for hypertension associated with confusion, headache, chest pain, or shortness of breath. In 131 patients with Stage 1 hypertension at baseline, 61% (80/131) developed Stage 2 hypertension. Monitor and manage blood pressure elevations during Iclusig use and treat hypertension to normalize blood pressure.

Interrupt, dose reduce, or stop Iclusig if hypertension is not medically controlled.

Pancreatitis: Clinical pancreatitis occurred in 6% (28/449) of patients (5%, grade 3) treated with Iclusig. Pancreatitis resulted in discontinuation or treatment interruption in 6% of patients (25/449). The incidence of treatmentemergent lipase elevation was 41%. Check serum lipase every 2 weeks for the first 2 months and then monthly thereafter or as clinically indicated. Consider additional serum lipase monitoring in patients with a history of pancreatitis or alcohol abuse.

Dose interruption or reduction may be required. In cases where lipase elevations are accompanied by abdominal symptoms, interrupt treatment with Iclusig and evaluate patients for pancreatitis. Do not consider restarting Iclusig until patients have complete resolution of symptoms and lipase levels are less than 1.5 x ULN. Neuropathy: Peripheral and cranial neuropathy have occurred in Iclusig-treated patients. Overall, 13% (59/449) of Iclusig-treated patients experienced a peripheral neuropathy event of any grade (2%, grade 3/4). In clinical trials, the most common

INDICATIONS AND USAGE Iclusig® (ponatinib) is a kinase inhibitor indicated for the: • Treatment of adult patients with T315I-positive chronic myeloid leukemia (CML) (chronic phase, accelerated phase, or blast phase) or T315I-positive Philadelphia chromosome positive acute lymphoblastic leukemia (Ph+ ALL).

• Treatment of adult patients with chronic phase, accelerated phase, or blast phase chronic myeloid leukemia or Ph+ ALL for whom no other tyrosine kinase inhibitor (TKI) therapy is indicated.

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These indications are based upon response rate. There are no trials verifying an improvement in disease-related symptoms or increased survival with Iclusig.

More than half of CP-CML patients who experienced resistance or intolerance to prior TKI therapy achieved MCyR within a median of 12 weeks (range: 7-48 weeks).*

54% MCyR (144/267) 95% CI: 48-60

44% CCyR (118/267) 95% CI: 38-50

Most patients who achieved MCyR also achieved CCyR.*† Efficacy results described should be interpreted within the context of updated safety information. *

10-month median duration of follow-up.

†

peripheral neuropathies reported were peripheral neuropathy (4%, 18/449), paresthesia (4%, 17/449), hypoesthesia (2%, 11/449), and hyperesthesia (1%, 5/449). Cranial neuropathy developed in 1% (6/449) of Iclusig-treated patients (<1%, grade 3/4). Of the patients who developed neuropathy, 31% (20/65) developed neuropathy during the first month of treatment. Monitor patients for symptoms of neuropathy, such as hypoesthesia, hyperesthesia, paresthesia, discomfort, a burning sensation, neuropathic pain, or weakness. Consider interrupting Iclusig and evaluate if neuropathy is suspected.

Ocular Toxicity: Serious ocular toxicities leading to blindness or blurred vision have occurred in Iclusig-treated patients. Retinal toxicities including macular edema, retinal vein occlusion, and retinal hemorrhage occurred in 3% of Iclusig-treated patients. Conjunctival or corneal irritation, dry eye, or eye pain occurred in 13% of patients. Visual blurring occurred in 6% of the patients. Other ocular toxicities include cataracts, glaucoma, iritis, iridocyclitis, and ulcerative keratitis. Conduct comprehensive eye exams at baseline and periodically during treatment.

Hemorrhage: Serious bleeding events, including fatalities, occurred in 5% (22/449) of patients treated with Iclusig. Hemorrhagic events occurred in 24% of patients.

The incidence of serious bleeding events was higher in patients with accelerated phase CML (AP-CML), BP-CML, and Ph+ ALL. Most hemorrhagic events, but not all occurred in patients with grade 4 thrombocytopenia. Interrupt Iclusig for serious or severe hemorrhage and evaluate.

Fluid Retention: Serious fluid retention events occurred in 3% (13/449) of patients treated with Iclusig. One instance of brain edema was fatal. In total, fluid retention occurred in 23% of the patients. The most common fluid retention events were peripheral edema (16%), pleural effusion (7%), and pericardial effusion (3%).

Monitor patients for fluid retention and manage patients as clinically indicated.

Interrupt, reduce, or discontinue Iclusig as clinically indicated.

Cardiac Arrhythmias: Symptomatic bradyarrhythmias that led to a requirement for pacemaker implantation occurred in 1% (3/449) of Iclusig-treated patients.

Advise patients to report signs and symptoms suggestive of slow heart rate (fainting, dizziness, or chest pain). Supraventricular tachyarrhythmias occurred in 5% (25/449) of Iclusig-treated patients. Atrial fibrillation was the most common supraventricular tachyarrhythmia and occurred in 20 patients. For 13 patients, the event led to hospitalization. Advise patients to report signs and symptoms of rapid heart rate (palpitations, dizziness). Interrupt Iclusig and evaluate.

The primary efficacy endpoint of the PACE trial in CP-CML was MCyR.

Myelosuppression: Severe (grade 3 or 4) myelosuppression occurred in 48% (215/449) of patients treated with Iclusig. The incidence of these events was greater in patients with AP-CML, BP-CML and Ph+ ALL than in patients with CP-CML. Obtain complete blood counts every 2 weeks for the first 3 months and then monthly or as clinically indicated, and adjust the dose as recommended.

Tumor Lysis Syndrome: Two patients (<1%) with advanced disease (AP-CML, BP-CML, or Ph+ ALL) treated with Iclusig developed serious tumor lysis syndrome.

Hyperuricemia occurred in 7% (30/449) of patients overall; the majority had CP-CML (19 patients). Due to the potential for tumor lysis syndrome in patients with advanced disease, ensure adequate hydration and treat high uric acid levels prior to initiating therapy with Iclusig.

Compromised Wound Healing and Gastrointestinal Perforation: Since Iclusig may compromise wound healing, interrupt Iclusig for at least 1 week prior to major surgery.

Serious gastrointestinal perforation (fistula) occurred in one patient 38 days postcholecystectomy.

Embryo-Fetal Toxicity: Iclusig can cause fetal harm. If Iclusig is used during pregnancy, or if the patient becomes pregnant while taking Iclusig, the patient should be apprised of the potential hazard to the fetus. Advise women to avoid pregnancy while taking Iclusig.

Most common non-hematologic adverse reactions: (≥20%) were hypertension, rash, abdominal pain, fatigue, headache, dry skin, constipation, arthralgia, nausea, and pyrexia. Hematologic adverse reactions included thrombocytopenia, anemia, neutropenia, lymphopenia, and leukopenia.

Please see the Brief Summary of the full Prescribing Information on the following pages, including the Boxed Warning, for additional Important Safety Information.

Note: Unless otherwise indicated, data presented are from Iclusig [package insert].

Cambridge, MA: ARIAD Pharmaceuticals, Inc.; September 2014.

Iclusig is a registered trademark of ARIAD Pharmaceuticals, Inc. © 2014 ARIAD Pharmaceuticals, Inc. All rights reserved.

PB/1014/0156/USf

BRIEF SUMMARY Iclusig® (ponatinib) Rx only Please consult full Prescribing Information, including Boxed Warning, available at Iclusig.com.

WARNING: VASCULAR OCCLUSION, HEART FAILURE, and HEPATOTOXICITY See full prescribing information for complete boxed warning.

• Vascular Occlusion: Arterial and venous thrombosis and occlusions have occurred in at least 27% of Iclusig treated patients, including fatal myocardial infarction, stroke, stenosis of large arterial vessels of the brain, severe peripheral vascular disease, and the need for urgent revascularization procedures. Patients with and without cardiovascular risk factors, including patients less than 50 years old, experienced these events. Monitor for evidence of thromboembolism and vascular occlusion. Interrupt or stop Iclusig immediately for vascular occlusion. (5.1).

• Heart Failure, including fatalities, occurred in 8% of Iclusig-treated patients. Monitor cardiac function. Interrupt or stop Iclusig for new or worsening heart failure (5.2).

• Hepatotoxicity, liver failure and death have occurred in Iclusig-treated patients. Monitor hepatic function. Interrupt Iclusig if hepatotoxicity is suspected (2.3, 5.3).

1

4 5 5.1

INDICATIONS AND USAGE Iclusig is a kinase inhibitor indicated for the: • Treatment of adult patients with T315I-positive chronic myeloid leukemia (chronic phase, accelerated phase, or blast phase) or T315I-positive Philadelphia chromosome positive acute lymphoblastic leukemia (Ph+ ALL).

• Treatment of adult patients with chronic phase, accelerated phase, or blast phase chronic myeloid leukemia or Ph+ ALL for whom no other tyrosine kinase inhibitor (TKI) therapy is indicated. (1) These indications are based upon response rate. There are no trials verifying an improvement in disease-related symptoms or increased survival with Iclusig.

CONTRAINDICATIONS None WARNINGS AND PRECAUTIONS Vascular Occlusion Arterial and venous thrombosis and occlusions, including fatal myocardial infarction, stroke, stenosis of large arterial vessels of the brain, severe peripheral vascular disease, and the need for urgent revascularization procedures have occurred in at least 27% of Iclusig-treated patients from the phase 1 and phase 2 trials. Iclusig can cause fatal and life-threatening vascular occlusion within 2 weeks of starting treatment. Iclusig can also cause recurrent or multi-site vascular occlusion.

In the dose-escalation (phase 1) clinical trial, 48% (31/65) of patients with CML or Ph+ ALL developed vascular occlusive events. The median time to onset of the first vascular occlusion event was 5 months. Iclusig can cause fatal and life-threatening vascular occlusion in patients treated at dose levels as low as 15 mg per day.

Patients with and without cardiovascular risk factors, including patients age 50 years or younger, experienced these events. Vascular occlusion adverse events were more frequent with increasing age and in patients with prior history of ischemia, hypertension, diabetes, or hyperlipidemia (see Table 4).

5.2

5.3

5.4

5.5

5.6

Table 4: Vascular Occlusion Incidence in Iclusig-Treated Patients in Phase 2 Trial According to Risk Categories Prior history of ischemia, hypertension, diabetes, or hyperlipidemia

No history of ischemia, hypertension, diabetes, or hyperlipidemia

Age: 49 or younger

18% (6/33)

12% (13/112)

Age: 50 to 74 years

33% (50/152)

18% (20/114)

Age: 75 and older

56% (14/25)

46% (6/13)

All age groups

33% (70/210)

Total

16% (39/239)

5.7

24% (109/449)

Arterial Occlusion and Thrombosis Arterial occlusion and thrombosis occurred in at least 20% (91/449) of Iclusig-treated patients with some patients experiencing events of more than one type. Patients have required revascularization procedures (cerebrovascular, coronary, and peripheral arterial) due to vascular occlusion from Iclusig.

Cardiac vascular occlusion, including fatal and life-threatening myocardial infarction and coronary artery occlusion has occurred in 12% (55/449) of Iclusig-treated patients. Patients have developed heart failure concurrent or subsequent to the myocardial ischemic event.

Cerebrovascular occlusion, including fatal stroke, has occurred in 6% (27/449) of Iclusigtreated patients. Iclusig can cause stenosis over multiple segments in major arterial vessels that supply the brain (e.g., carotid, vertebral, middle cerebral artery).

Peripheral arterial occlusive events, including fatal mesenteric artery occlusion and lifethreatening peripheral arterial disease, have occurred in 8% (36/449) of Iclusig-treated patients. Patients have developed digital or distal extremity necrosis and have required amputations.

Clinicians should consider whether the benefits of Iclusig treatment are expected to exceed the risks of therapy. In patients suspected of developing arterial thrombotic events, interrupt or stop Iclusig. A benefit-risk consideration should guide a decision to restart Iclusig therapy. [see Dosage and Administration (2.3)].

Venous Thromboembolism Venous thromboembolic events occurred in 5% (23/449) of Iclusig-treated patients, including deep venous thrombosis (8 patients), pulmonary embolism (6 patients), superficial thrombophlebitis (3 patients), and retinal vein thrombosis (2 patients). Consider

5.8

5.9

dose modification or discontinuation of Iclusig in patients who develop serious venous thromboembolism [see Dosage and Administration (2.3)].

Heart Failure Fatal and serious heart failure or left ventricular dysfunction occurred in 5% of Iclusigtreated patients (N=22). Eight percent of patients (N=35) experienced any grade of heart failure or left ventricular dysfunction. Monitor patients for signs or symptoms consistent with heart failure and treat as clinically indicated, including interruption of Iclusig. Consider discontinuation of Iclusig in patients who develop serious heart failure [see Dosage and Administration (2.3)].

Hepatotoxicity Iclusig can cause hepatotoxicity, including liver failure and death. Fulminant hepatic failure leading to death occurred in an Iclusig-treated patient within one week of starting Iclusig. Two additional fatal cases of acute liver failure also occurred. The fatal cases occurred in patients with blast phase (BP) CML or Ph+ ALL. Severe hepatotoxicity occurred in all disease cohorts.

The incidence of aspartate aminotransferase (AST) or alanine aminotransferase (ALT) elevation was 56% (all grades) and 8% (grade 3 or 4). Iclusig treatment may result in elevation in ALT, AST, or both. ALT or AST elevation was not reversed by the date of last follow-up in 5% of patients.

Monitor liver function tests at baseline, then at least monthly or as clinically indicated.

Interrupt, reduce or discontinue Iclusig as clinically indicated [see Dosage and Administration (2.3)].

Hypertension Treatment-emergent hypertension occurred in 67% of patients (300/449). Eight patients (2%) treated with Iclusig in clinical trials experienced treatment-emergent symptomatic hypertension as a serious adverse reaction, including hypertensive crisis. Patients may require urgent clinical intervention for hypertension associated with confusion, headache, chest pain, or shortness of breath [see Adverse Reactions (6)]. In patients with baseline systolic BP<140 mm Hg and baseline diastolic BP<90 mm Hg, 78% (220/282) experienced treatment-emergent hypertension; 49% (139/282) developed Stage 1 hypertension (defined as systolic BP≥140 mm Hg or diastolic BP≥90 mm Hg) while 29% developed Stage 2 hypertension (defined as systolic BP≥160 mm Hg or diastolic BP≥100 mm Hg). In 131 patients with Stage 1 hypertension at baseline, 61% (80/131) developed Stage 2 hypertension. Monitor and manage blood pressure elevations during Iclusig use and treat hypertension to normalize blood pressure. Interrupt, dose reduce, or stop Iclusig if hypertension is not medically controlled.

Pancreatitis Clinical pancreatitis occurred in 6% (28/449) of patients (5% grade 3) treated with Iclusig.

Pancreatitis resulted in discontinuation or treatment interruption in 6% of patients (25/449).

Twenty-two of the 28 cases of pancreatitis resolved within 2 weeks with dose interruption or reduction. The incidence of treatment-emergent lipase elevation was 41%.

Check serum lipase every 2 weeks for the first 2 months and then monthly thereafter or as clinically indicated. Consider additional serum lipase monitoring in patients with a history of pancreatitis or alcohol abuse. Dose interruption or reduction may be required. In cases where lipase elevations are accompanied by abdominal symptoms, interrupt treatment with Iclusig and evaluate patients for pancreatitis [see Dosage and Administration (2.3)]. Do not consider restarting Iclusig until patients have complete resolution of symptoms and lipase levels are less than 1.5 x ULN. Neuropathy Peripheral and cranial neuropathy have occurred in Iclusig-treated patients. Overall, 13% (59/449) of Iclusig-treated patients experienced a peripheral neuropathy event of any grade (2%, grade 3/4). In clinical trials, the most common peripheral neuropathies reported were peripheral neuropathy (4%, 18/449), paresthesia (4%, 17/449), hypoesthesia (2%, 11/449), and hyperesthesia (1%, 5/449). Cranial neuropathy developed in 1% (6/449) of Iclusigtreated patients (<1% grade 3/4).

Of the patients who developed neuropathy, 31% (20/65) developed neuropathy during the first month of treatment. Monitor patients for symptoms of neuropathy, such as hypoesthesia, hyperesthesia, paresthesia, discomfort, a burning sensation, neuropathic pain or weakness. Consider interrupting Iclusig and evaluate if neuropathy is suspected.

Ocular Toxicity Serious ocular toxicities leading to blindness or blurred vision have occurred in Iclusigtreated patients. Retinal toxicities including macular edema, retinal vein occlusion, and retinal hemorrhage occurred in 3% of Iclusig-treated patients. Conjunctival or corneal irritation, dry eye, or eye pain occurred in 13% of patients. Visual blurring occurred in 6% of patients. Other ocular toxicities include cataracts, glaucoma, iritis, iridocyclitis, and ulcerative keratitis. Conduct comprehensive eye exams at baseline and periodically during treatment [see Adverse Reactions (6)].

Hemorrhage Serious bleeding events, including fatalities, occurred in 5% (22/449) of patients treated with Iclusig. Hemorrhage occurred in 24% of patients. The incidence of serious bleeding events was higher in patients with accelerated phase (AP) CML, BP-CML, and Ph+ ALL. Cerebral hemorrhage and gastrointestinal hemorrhage were the most commonly reported serious bleeding events. Most hemorrhagic events, but not all, occurred in patients with grade 4 thrombocytopenia [see Warnings and Precautions (5.11)]. Interrupt Iclusig for serious or severe hemorrhage and evaluate [see Dosage and Administration (2.3)].

Fluid Retention Fluid retention events judged as serious occurred in 3% (13/449) of patients treated with Iclusig. One instance of brain edema was fatal. Serious fluid retention events in more than 1 patient included: pericardial effusion (6/449, 1%), pleural effusion (5/449, 1%), and ascites (2/449, <1%).

In total, fluid retention occurred in 23% of the patients. The most common fluid retention events were peripheral edema (16%), pleural effusion (7%), and pericardial effusion (3%).

Monitor patients for fluid retention and manage patients as clinically indicated. Interrupt, reduce, or discontinue Iclusig as clinically indicated [see Dosage and Administration (2.3)].

5.10 Cardiac Arrhythmias Symptomatic bradyarrhythmias that led to a requirement for pacemaker implantation occurred in 1% (3/449) of Iclusig-treated patients. The cardiac rhythms (1 case each) identified were complete heart block, sick sinus syndrome, and atrial fibrillation with bradycardia and pauses. Advise patients to report signs and symptoms suggestive of slow heart rate (fainting, dizziness, or chest pain). Interrupt Iclusig and evaluate.

Supraventricular tachyarrhythmias occurred in 5% (25/449) of Iclusig-treated patients.

Atrial fibrillation was the most common supraventricular tachyarrhythmia and occurred in 20 patients. The other supraventricular tachyarrhythmias were atrial flutter (4 patients), supraventricular tachycardia (4 patients), and atrial tachycardia (1 patient). For 13 patients, the event led to hospitalization. Advise patients to report signs and symptoms of rapid heart rate (palpitations, dizziness). Interrupt Iclusig and evaluate.

5.11 Myelosuppression Severe (grade 3 or 4) myelosuppression occurred in 48% (215/449) of patients treated with Iclusig. The incidence of these events was greater in patients with AP-CML, BP-CML, and Ph+ ALL than in patients with CP-CML. Obtain complete blood counts every 2 weeks for the first 3 months and then monthly or as clinically indicated, and adjust the dose as recommended [see Dosage and Administration (2.2)].

5.12 Tumor Lysis Syndrome Two patients (<1%) treated with Iclusig developed serious tumor lysis syndrome. Both cases occurred in patients with advanced CML. Hyperuricemia occurred in 7% (30/449) of patients; the majority had CP-CML (19 patients). Due to the potential for tumor lysis syndrome in patients with advanced disease (AP-CML, BP-CML, or Ph+ ALL), ensure adequate hydration and treat high uric acid levels prior to initiating therapy with Iclusig.

5.13 Compromised Wound Healing and Gastrointestinal Perforation No formal studies of the effect of Iclusig on wound healing have been conducted. Based on the mechanism of action [see Clinical Pharmacology (12.1)], Iclusig could compromise wound healing. Serious gastrointestinal perforation (fistula) occurred in one patient 38 days post-cholecystectomy.

Interrupt Iclusig for at least 1 week prior to major surgery. The decision when to resume Iclusig after surgery should be based on clinical judgment of adequate wound healing.

5.14 Embryo-Fetal Toxicity Iclusig can cause fetal harm when administered to a pregnant woman based on its mechanism of action and findings in animals. Ponatinib caused embryo-fetal toxicity in rats at exposures lower than human exposures at the recommended human dose. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus. Advise women to avoid pregnancy while taking Iclusig [see Use in Specific Populations (8.1)].

6 ADVERSE REACTIONS Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared with rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.

The following adverse reactions are discussed in greater detail in other sections of the prescribing information: • Vascular Occlusion [see Warnings and Precautions (5.1)] • Heart Failure [see Dosage and Administration (2.3) and Warnings and Precautions (5.2)] • Hepatotoxicity [see Dosage and Administration (2.3) and Warnings and Precautions (5.3)] • Hypertension [see Warnings and Precautions (5.4)] • Pancreatitis [see Dosage and Administration (2.3) and Warnings and Precautions (5.5)] • Neuropathy [see Warnings and Precautions (5.6)] • Ocular Toxicity [see Warnings and Precautions (5.7)] • Hemorrhage [see Warnings and Precautions (5.8)] • Fluid Retention [see Warnings and Precautions (5.9)] • Cardiac Arrhythmias [see Warnings and Precautions (5.10)] • Myelosuppression [see Dosage and Administration (2.2) and Warnings and Precautions (5.11)] The adverse reactions described in this section were identified in a single-arm, openlabel, international, multicenter trial in 449 patients with CML or Ph+ ALL whose disease was considered to be resistant or intolerant to prior tyrosine kinase inhibitor (TKI) therapy including those with the BCR-ABL T315I mutation. All patients received a starting dose of 45 mg Iclusig once daily. At the time of analysis, the median duration of treatment with Iclusig was 337 days in patients with CP-CML, 362 days in patients with AP-CML, 89 days in patients with BP-CML, and 81 days in patients with Ph+ ALL. The median dose intensity was 37 mg or 83% of the expected 45 mg dose. The events of arterial ischemia, cardiac failure, and peripheral neuropathy reported in Tables 5 and 6 include data from an additional 13 months of follow-up (median duration of treatment CP-CML: 672 days, AP-CML: 590 days, BP-CML: 89 days, Ph+ ALL: 81 days).

Adverse reactions reported in more than 10% of all patients treated with Iclusig in this trial are presented in Table 5. Overall, the most common non-hematologic adverse reactions (≥ 20%) were hypertension, rash, abdominal pain, fatigue, headache, dry skin, constipation, arthralgia, nausea, and pyrexia.

The rates of treatment-emergent adverse events resulting in discontinuation were 13% in CP-CML, 11% in AP-CML, 15% in BP-CML, and 9% in Ph+ ALL. The most common adverse events that led to treatment discontinuation were thrombocytopenia (4%) and infections (1%).

Dose modifications (dose delays or dose reductions) due to adverse reactions occurred in 74% of the patients. The most common adverse reactions (≥5%) that led to dose modifications include thrombocytopenia (30%), neutropenia (13%), lipase increased (12%), rash (11%), abdominal vpain (11%), pancreatitis (6%), and ALT, AST, or GGT increased (6%).

Table 5: Adverse Reactions Occurring in >10% of Patients, Any Group

System Organ Class

CP-CML (N=270) CTCAE Any Grade Grade (%) 3/4 (%)

Cardiac or Vascular disorders Hypertension (a) 68 39 Arterial ischemia (b)* 20 11 Cardiac Failure (c)* 7 4 Gastrointestinal disorders Abdominal pain (d) 49 10 Constipation 37 2 Nausea 23 1 Diarrhea 16 1 Vomiting 13 2 Oral mucositis (e) 10 1 GI hemorrhage (f) 2 <1 Blood and lymphatic system disorders Febrile neutropenia 1 <1 Infections and infestations Sepsis 1 1 Pneumonia 3 2 Urinary tract infection 7 1 Upper respiratory tract infection 11 1 Nasopharyngitis 9 0 Cellulitis 2 1 Nervous system disorders Headache 39 3 Peripheral neuropathy (g)* 16 2 Dizziness 11 0 Respiratory, thoracic, and mediastinal disorders Pleural effusion 3 1 Cough 12 0 Dyspnea 11 2 Skin and subcutaneous tissue disorders Rash and related conditions 54 5 Dry skin 39 2 Musculoskeletal and connective tissue disorders Arthralgia 26 2 Myalgia 22 1 Pain in extremity 17 2 Back pain 15 1 Muscle spasms 12 0 Bone pain 12 <1 General disorders and administration site conditions Fatigue or asthenia 39 3 Pyrexia 23 1 Edema, peripheral 13 <1 Pain 8 <1 Chills 7 0 Metabolism and nutrition disorders Decreased appetite 8 <1 Investigations Weight decreased 6 <1 Psychiatric disorders

AP-CML (N=85) CTCAE Any Grade Grade (%) 3/4 (%)

BP-CML (N=62) CTCAE Any Grade Grade (%) 3/4 (%)

Ph+ ALL (N=32) CTCAE Any Grade Grade 3/4 (%) (%)

71 19 6

36 9 4

65 10 15

26 5 8

53 3 6

31 0 3

40 24 27 26 24 15 8

8 2 0 0 0 1 1

34 26 32 18 23 23 11

6 0 2 3 2 0 5

44 47 22 13 22 9 9

6 3 0 3 0 3 6

4

4

11

11

25

25

5 11 12 8 12 4

5 9 1 0 0 2

8 13 0 11 3 11

8 11 0 2 0 3

22 9 9 0 3 0

22 3 0 0 0 0

28 11 5

0 1 0

31 8 5

3 0 0

25 6 3

0 0 0

11 17 15

2 0 2

13 18 21

0 0 7

19 6 6

3 0 0

48 27

8 1

39 24

5 2

34 25

6 0

31 20 17 11 5 12

1 0 0 2 0 1

19 16 13 16 5 11

0 0 0 2 0 3

13 6 9 13 13 9

0 0 0 0 0 3

36 31 19 7 11

6 5 0 0 0

35 32 13 16 13

5 3 0 3 2

31 25 22 6 9

3 0 0 3 0

12

1

8

0

31

0

7

0

5

0

13

0

Adverse drug reactions, reported using MedDRA and graded using NCI-CTC-AE v 4.0 (NCI Common Terminology Criteria for Adverse Events) for assessment of toxicity.

Treatment-emergent, all causality events (a) derived from blood pressure (BP) measurement recorded monthly while on trial (b) includes cardiovascular, cerebrovascular, and peripheral vascular ischemia (c) includes cardiac failure, cardiac failure congestive, cardiogenic shock, cardiopulmonary failure, ejection fraction decreased, pulmonary edema, right ventricular failure (d) includes abdominal pain, abdominal pain upper, abdominal pain lower, abdominal discomfort (e) includes aphthous stomatitis, lip blister, mouth ulceration, oral mucosal eruption, oral pain, oropharyngeal pain, pharyngeal ulceration, stomatitis, tongue ulceration (f) includes gastric hemorrhage, gastric ulcer hemorrhage, hemorrhagic gastritis, gastrointestinal hemorrhage, hematemesis, hematochezia, hemorrhoidal hemorrhage, intra-abdominal hemorrhage, melena, rectal hemorrhage, and upper gastrointestinal hemorrhage (g) includes burning sensation, skin burning sensation, hyperesthesia, hypoesthesia, neuralgia, neuropathy peripheral, paresthesia, peripheral sensorimotor neuropathy, peripheral motor neuropathy, peripheral sensory neuropathy, polyneuropathy *represents an additional 13 months of follow-up Table 6: Serious Adverse Reactions (SAR)

Cardiovascular disorders Arterial ischemic event* Cardiovascular Cerebrovascular Peripheral vascular Hemorrhage CNS hemorrhage Cardiac failure* Effusions(a) Atrial fibrillation Venous thromboembolism Hypertension Gastrointestinal disorders Pancreatitis Abdominal pain Blood and lymphatic system disorders Febrile neutropenia Thrombocytopenia Anemia Infections Pneumonia Sepsis General (a) includes pericardial effusion, pleural effusion, and ascites * represents an additional 13 months of follow-up

N (%) 53 (11.8%) 28 (6.2%) 18 (4.0%) 16 (3.6%) 22 (4.9%) 10 (2.2%) 22 (4.9%) 13 (2.9%) 11 (2.4%) 10 (2.2%) 8 (1.8%) 23 (5.1%) 17 (3.8%) 13 (2.9%) 13 (2.9%) 12 (2.7%) 24 (5.3%) 11 (2.4%)

Laboratory Abnormalities Myelosuppression was commonly reported in all patient populations. The frequency of grade 3 or 4 thrombocytopenia, neutropenia, and anemia was higher in patients with AP-CML, BP-CML, and Ph+ ALL than in patients with CP-CML (see Table 7).

Table 7: Incidence of Clinically Relevant Grade 3/4* Hematologic Abnormalities Laboratory Test

Hematology Thrombocytopenia (platelet count decreased) Neutropenia (ANC decreased) Leukopenia (WBC decreased) Anemia (Hgb decreased)

CP-CML (N=270) (%)

AP-CML (N=85) (%)

BP-CML (N=62) (%)

Ph+ ALL (N=32) (%)

36

47

57

47

24 14 9

51 35 26

55 53 55

63 63 34

8.3

ANC=absolute neutrophil count, Hgb=hemoglobin, WBC=white blood cell count *Reported using NCI-CTC-AE v 4.0

Table 8: Incidence of Clinically Relevant Non-Hematologic Laboratory Abnormalities Laboratory Test

Liver function tests ALT increased AST increased Alkaline phosphatase increased Albumin decreased Bilirubin increased Pancreatic enzymes Lipase increased Amylase increased Chemistry Glucose increased Phosphorus decreased Calcium decreased Sodium decreased Glucose decreased Potassium decreased Potassium increased Sodium increased Bicarbonate decreased Creatinine increased Calcium increased

Safety Population N=449 Any Grade* (%)

CTCAE Grade 3/4 (%)

53 41 37 28 19

8 4 2 1 1

41 3

15 <1

58 57 52 29 24 16 15 10 11 7 5

6 8 1 5 0 2 2 <1 <1 <1 0

8.4

8.5

8.6

ALT=alanine aminotransferase, AST=aspartate aminotransferase. *Graded using NCI-CTC-AE v 4.0

7

7.1

7.2

7.3

7.4

8 8.1

DRUG INTERACTIONS Based on in vitro studies, ponatinib is a substrate of CYP3A and to a lesser extent CYP2C8 and CYP2D6. Ponatinib also inhibits the P-glycoprotein (P-gp), ATP-binding cassette G2 (ABCG2) [also known as BCRP], and bile salt export pump (BSEP) transporter systems in vitro [see Clinical Pharmacology (12.3)].

Drugs That Are Strong Inhibitors of CYP3A Enzymes In a drug interaction study in healthy volunteers, coadministration of Iclusig with ketoconazole increased plasma ponatinib AUC 0-inf and Cmax by 78% and 47%, respectively [see Clinical Pharmacology (12.3)]. When administering Iclusig with strong CYP3A inhibitors (e.g., boceprevir, clarithromycin, conivaptan, grapefruit juice, indinavir, itraconazole, ketoconazole, lopinavir/ritonavir, nefazodone, nelfinavir, posaconazole, ritonavir, saquinavir, telaprevir, telithromycin, voriconazole), the recommended starting dose should be reduced [see Dosage and Administration (2.4)]. Patients taking concomitant strong CYP3A inhibitors may be at increased risk for adverse reactions [see Clinical Pharmacology (12.3)].

Drugs That Are Strong Inducers of CYP3A Enzymes Coadministration of strong CYP3A inducers (e.g., carbamazepine, phenytoin, rifampin, and St. John’s Wort) with Iclusig should be avoided unless the benefit outweighs the risk of decreased ponatinib exposure. Monitor patients for reduced efficacy. Selection of concomitant medication with no or minimal CYP3A induction potential is recommended. In a drug interaction study in healthy volunteers, co-administration of Iclusig following multiple doses of rifampin resulted in decreased ponatinib AUC0-inf and Cmax values by 62% and 42%, respectively [see Clinical Pharmacology (12.3)].

Drugs That Elevate Gastric pH Iclusig may be co-administered with gastric pH-elevating medications. In a drug interaction study in healthy volunteers, co-administration of Iclusig following multiple doses of lansoprazole resulted in a minimal (6%) decrease in ponatinib exposure. [see Clinical Pharmacology (12.3)].

Drugs That Are Substrates of the P-gp or ABCG2 Transporter Systems In vitro studies demonstrate that Iclusig inhibits the P-gp and ABCG2 transporter systems.

The effect of coadministration of Iclusig with sensitive substrates of the P-gp (e.g., aliskiren, ambrisentan, colchicine, dabigatran etexilate, digoxin, everolimus, fexofenadine, imatinib, lapatinib, maraviroc, nilotinib, posaconazole, ranolazine, saxagliptin, sirolimus, sitagliptin, tolvaptan, topotecan) and ABCG2 (e.g., methotrexate, mitoxantrone, imatinib, irinotecan, lapatinib, rosuvastatin, sulfasalazine, topotecan) transporter systems on exposure of these substrates has not been evaluated in clinical studies.

USE IN SPECIFIC POPULATIONS Pregnancy Pregnancy Category D Risk Summary Based on its mechanism of action and findings in animals, Iclusig can cause fetal harm when administered to a pregnant woman. There are no adequate and well-controlled studies with Iclusig in pregnant women. Advise women to avoid becoming pregnant while

8.7

10

taking Iclusig. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to a fetus.

Animal Data Ponatinib was studied for effects on embryo-fetal development in pregnant rats given oral doses of 0.3, 1, and 3 mg/kg/day during organogenesis. At the maternally toxic dose of 3 mg/kg/day (equivalent to the AUC in patients receiving the recommended dose of 45 mg/day), ponatinib caused embryo-fetal toxicity as shown by increased resorptions, reduced body weight, external alterations, multiple soft tissue and skeletal alterations, and reduced ossification. Embryo-fetal toxicities also were observed at 1 mg/kg/day (approximately 24% the AUC in patients receiving the recommended dose) and involved multiple fetal soft tissue and skeletal alterations, including reduced ossification.

Nursing Mothers It is unknown whether ponatinib is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from ponatinib, a decision should be made whether to discontinue nursing or to discontinue Iclusig, taking into account the importance of the drug to the mother.

Pediatric Use The safety and efficacy of Iclusig in patients less than 18 years of age have not been established.

Geriatric Use One hundred and fifty-five of 449 patients (35%) in the clinical trial of Iclusig were 65 years of age and over. In patients with CP-CML, patients of age ≥ 65 years had a lower major cytogenetic response rate (38%) as compared with patients < 65 years of age (64%). In patients with AP-CML, BP-CML, and Ph+ ALL, patients of age ≥ 65 years had a higher major hematologic response rate (47%) as compared with patients < 65 years of age (40%). Forty-six percent of patients ≥ 65 years had vascular occlusion events. Patients of age ≥ 65 years are more likely to experience adverse reactions including vascular occlusion, decreased platelet count, peripheral edema, increased lipase, dyspnea, asthenia, muscle spasms, and decreased appetite. In general, dose selection for an elderly patient should be cautious, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.

Hepatic Impairment Administer Iclusig at a dose of 30 mg once daily in patients with hepatic impairment (ChildPugh A, B, or C). [see Dosage and Administration (2.5) and Clinical Pharmacology (12.3)].

In a single-dose (30 mg) pharmacokinetic (PK) study; compared to subjects with normal liver function, no major differences in ponatinib PK were observed in subjects with hepatic impairment (Child-Pugh A, B, or C). However, there was an increased overall incidence of adverse reactions (e.g., gastrointestinal disorders, including a case of severe pancreatitis) in the subjects with hepatic impairment following the single 30 mg dose compared to subjects with normal liver function. The safety of multiple ponatinib doses, or doses higher than 30 mg have not been studied in patients with hepatic impairment.

Renal Impairment Iclusig has not been studied in patients with renal impairment. Although renal excretion is not a major route of ponatinib elimination, the potential for moderate or severe renal impairment to affect hepatic elimination has not been determined [see Clinical Pharmacology (12.3)].

OVERDOSAGE Overdoses with Iclusig were reported in clinical trials. One patient was accidentally administered the entire contents of a bottle of study medication via nasogastric tube. The investigator estimated that the patient received 540 mg of Iclusig. Two hours after the overdose, the patient had an uncorrected QT interval of 520 ms. Subsequent ECGs showed normal sinus rhythm with uncorrected QT intervals of 480 and 400 ms. The patient died 9 days after the overdose from pneumonia and sepsis. Another patient accidentally selfadministered 165 mg on cycle 1 day 2. The patient experienced fatigue and non-cardiac chest pain on day 3. Multiple doses of 90 mg per day for 12 days in a patient resulted in pneumonia, systemic inflammatory response, atrial fibrillation, and a moderate pericardial effusion.

In the event of an overdose of Iclusig, stop Iclusig, observe the patient and provide appropriate supportive treatment.

Manufactured for: ARIAD Pharmaceuticals, Inc. 26 Landsdowne Street Cambridge, MA 02139-4234 For information contact: 1-855-55-ARIAD (1-855-552-7423) medinfo@ariad.com PB/0314/0074/US(1)

ASCOPost.com | DECEMBER 1, 2014

PAGE 85

Palliative Care in Oncology Symposium Supportive Care

Experts Stress the Need for Integrating Palliative Care Into Standard Oncology Care

By Jo Cavallo

T

he overriding consensus from the 2014 Palliative Care in Oncology Symposium: Patient-Centered Care Across the Cancer Continuum held in Boston was that achieving optimal high-quality cancer care requires both state-of-the-art cancer therapy and the integration of palliative care principles throughout the course of a patient’s care to monitor and reduce the physical and psychosocial effects of cancer or its treatment.

‘usual’ care by 2020. Thus, ASCO made plans to carve out a symposium that would put palliative oncology care at center stage,” he added.

Dr. Fisch opened the 2-day symposium with a review of ASCO’s 50-year history and the parallel advancement

It will take creativity, courage, and a lot of team science to find the best ways to integrate the principles and practices of palliative care throughout the trajectory of cancer care.

Part of the Puzzle “As we strive for optimal care for our patients throughout the trajectory of illness, we are actively exploring where palliative care in oncology fits as part of the puzzle,” said Michael J. Fisch, MD, MPH, Chair, Department of General Oncology, Division of Cancer Medicine at The University of Texas MD Anderson Cancer Center and Chair of the Palliative Care in Oncology Symposium.

“ASCO leadership had a vision in 2009 that concurrent palliative care and oncology care would become

posium of palliative care in oncology,” said Dr. Fisch. “There is no question that the intersection of several disciplines in this overlapping and crosscutting realm that we call palliative oncology is one of great interest and ­opportunity.”

—Michael J. Fisch, MD, MPH

of the concept of palliative care for the whole patient, first introduced

by Dame Cicely Saunders (founder of the modern hospice movement) in 1964.1 “The first ASCO meeting was in April 1965, with 70 people present. We have nearly 10-fold that many here in Boston for this inaugural sym-

Recipients of the 2014 Conquer Cancer Foundation of ASCO Merit Awards in Palliative Care Honored The following seven recipients of the 2014 Conquer Cancer Foundation of ASCO Merit Awards in Palliative Care were honored at the 2014 Palliative Care in Oncology Symposium for their work in improving the care of people living with cancer around the world.

• Erin Alexi, MD, Virginia Commonwealth University: Palliating oncologists: A pilot study on primary palliative care development in hematology-oncology trainee outpatient clinics (Abstract 21) • Kenneth Bishop, MD, PhD, Brown University Oncology Group: Perspectives on palliative care in a multisite oncology practice (Abstract 52) • David Einstein, MD, Tufts Medical Center: Dying for advice: Code-status discussions between resident physicians and patients with advanced cancer—A national survey (Abstract 83) • Neha Gupta, MD, State University of New York at Buffalo: Meta-analysis of trials comparing standard antiemetic treatment with aprepitant containing antiemetic regimens for prevention of chemotherapy-induced nausea and vomiting (Abstract 171) • Carolyn Lefkowits, MD, MPH, Magee-Womens Hospital of UPMC: Change in symptom burden within one day of palliative care consultation in a cohort of gynecologic oncology inpatients (Abstract 28) • Harminder Singh, MD, MBBS, Baba Farid University of Health Sciences, University in Faridkot, Punjab, India: Quality of life and adverse drug reaction measured in patients undergoing cancer chemotherapy (Abstract 214) • Alysson Wann, MBSS, Fellowship of the Royal Australian College of Physician, Sydney: Use of targeted therapy in cancer patients in the end-of-life period (Abstract 129)

Diversity of Talent and Ideas The symposium, which was cosponsored by ASCO, the American Academy of Hospice and Palliative Medicine, the American Society for Radiation Oncology, and the Multinational Association of Supportive Care in Cancer, attracted 700 attendees, 119 from outside the United States, and presented 272 abstracts.

The greatest number of abstracts dealt with the early integration of palliative care in cancer care (97), followed by end-of-life care (73); patient-reported outcomes, mechanisms of symptoms, and treatment toxicities (64); psycho-oncology (21); and survivorship (17).

The abstracts covered research in a range of areas, including the use of a “smart technology” telephonebased symptom management system to monitor and ease patient symptoms during the final weeks of life2; the financial burden of cancer3,4; the partnership between medical oncologists and palliative care specialists to improve patient care; and the prevalence of burnout among palliative care clinicians,5 among others.

The symposium’s program included sessions in five tracks: • Symptom Science: Mechanisms, Measurement, Management • Survivorship • Skills for Addressing End-of-Life Care • Early Integration of Palliative Care in Cancer Care • Psycho-oncology

“This meeting attracted people who are interested in achieving optimal ways to deliver cancer care that are individualized to the circumstances and preferences of each patient and family and resonate with the six major aims of health care, as outlined by the Institute of Medicine,”6 said Dr. Fisch.

“It will take creativity, courage, and a lot of team science to find the best ways to integrate the principles and practices of palliative care throughout the trajectory of cancer care. The attendees seem energized by this meeting and, hopefully, inspired with some new ideas as well as new contacts to enhance teamwork and sharing of best practices,” he added.

The diversity and high number of attendees, abstracts presented, and level of enthusiasm generated at the symposium made this inaugural palliative care meeting a “tremendous success” said Dr. Fisch. “I especially enjoyed the diversity of attendees, ranging from physicians in cancer specialties, including medical oncologists, surgeons, and radiation oncologists, to palliative care and hospice, to primary care physicians as well as physicians from other subspecialties, including geriatrics, cardiology, and others.” n [Editor’s note: For a complete listing of the study abstracts presented at the Palliative Care in Oncology Symposium and to view the presentations, visit pallonc.org.]

Disclosure: Drs. Fisch and Kamal reported no potential conflicts of interest.

References 1. Saunders C: The symptomatic treatment of incurable malignant disease. Prescribers J 4:68-73, 1964.

2. Mooney K, Berry P, Wong B, et al: Helping cancer-family caregivers with end-of-life home symptom management: Initial evaluation of an automated symptom monitoring and coaching system.

2014 Palliative Care in Oncology Symposium. Abstract 85. Presented ­October 24, 2014.

3. Whitney RL, Bell J, Reed S, et al: Work and financial disparities among adult cancer survivors in the United States. 2014 Palliative Care in Oncology Symposium. continued on page 86

The ASCO Post | DECEMBER 1, 2014

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Palliative Care in Oncology Symposium Integrating Palliative Care continued from page 85

Abstract 238. Presented October 24, 2014.

4. Nipp RD, Zullig LL, Samsa G, et al: Coping with cancer treatment-related financial burden. 2014 Palliative Care in Oncology Symposium. Abstract 161. Presented October 24, 2014.

5. Kamal A, Bull J, Wolf S, et al: Preva-

lence and predictors of burnout among specialty palliative care clinicians in the United States: Results of a national survey. 2014 Palliative Care in Oncology Symposium.

Abstract 87. Presented October 25, 2014.

6. Institute of Medicine: Crossing the Quality Chasm: A New Health System for the 21st Century. March 2001. www.iom. edu. Accessed November 18, 2014.

Save the Date 2015 Palliative Care in Oncology Symposium October 9–10, Boston

Don’t Miss These Important Reports in This Issue of The ASCO Post

Andrew Evens, DO, MSc, on CAR T-cell therapy see page 32

Felicia Knaul, PhD, on the Harvard Global Equity Initiative see page 41

Carolyn D. Runowicz, MD, on her personal perspective on being an oncologist see page 95

Visit ASCOPost.com

ASCOPost.com | DECEMBER 1, 2014

PAGE 87

Announcements

The American Society of Hematology Elects New Leadership

T

he American Society of Hematology (ASH) recently announced the election of four new members to its Executive Committee, the governing body of the organization, for terms beginning after the 2014 ASH Annual Meeting, which will be held December 6–9 in San Francisco.

Kenneth C. Anderson, MD, will serve a 1-year term as Vice President, followed by successive terms as President-Elect and President. Susan B. Shurin, MD, will serve a 4-year term as Treasurer. Mary C. Dinauer, MD, PhD, and Terry B. Gernsheimer, MD, will both serve 4-year terms as Councillors.

“The field of hematology is changing rapidly around us—from the way we educate trainees to the way we deliver care at the patient bedside. These changes present opportunities and challenges that must be met by visionary leadership,” said ASH President Linda J. Burns, MD, of the University of Minnesota. “Drs. Anderson, Shurin, Dinauer, and Gernsheimer bring vast knowledge and diverse experience to address these opportunities and challenges, and we look forward to working with them to help further the Society’s mission to conquer blood diseases worldwide.”

Kenneth C. Anderson, MD Dr. Anderson is Director of the Lebow Institute for Myeloma Therapeutics and the Jerome Lipper Myeloma Center at Dana-Farber Cancer Institute

in Boston. He also serves as Kraft Family Professor of Medicine and Vice Chair of the Joint Program in Transfusion Medicine at Harvard Medical School.

Dr. Anderson’s maSusan B. Shurin, MD Mary C. Dinauer, MD, PhD Terry B. Gernsheimer, MD jor fields of interest in- Kenneth C. Anderson, MD clude the biology and Her fields of interest include nonma- the journal of the American Society of treatment of plasma cell disorders and transfusion. Outside of the laboratory, he lignant hematologic diseases; pediatric Hematology, and she served as a Sciis interested in identifying new opportu- oncology; noncommunicable diseases; entific Program Co-Chair of the 2011 nities for mentorship and role models to and the biology and epidemiology of ASH Annual Meeting. attract the next generation into hematol- cardiovascular, pulmonary, and blood ogy as well as strengthening international diseases. Dr. Shurin has previously Terry B. Gernsheimer, MD Dr. Gernsheimer is Medical Dileadership to improve the care of patients served as a member of the ASH Committee on Government Relations and as rector of the Platelet Immunology with blood disorders across the world.

During his more than 15 years of faculty for the ASH Clinical Research Laboratory at Puget Sound Blood Center, Medical Director of Transfuinvolvement in ASH, Dr. Anderson Training Institute. sion at the Seattle Cancer Care Allihas served in a variety of Society volance, and Assistant Medical Director unteer roles. He currently serves as Mary C. Dinauer, MD, PhD Dr. Dinauer is the Fred M. Saigh of Clinical Transfusion Service at the Executive Editor of Hematology (the ASH Education Program) and served a Distinguished Chair in Pediatric Re- University of Washington Medical 4-year term as an ASH councillor from search and Professor of Pediatrics and Center. She also serves as Professor of of Pathology and Immunology at Wash- Medicine in the Division of Hematol2010 to 2013. ington University School of Medicine ogy and Adjunct Professor of LaboSusan B. Shurin, MD in St. Louis. She is also the Scientific ratory Medicine at the University of Dr. Shurin is Senior Adviser to the Director at the Children’s Discovery In- Washington.

Center for Global Health of the Na- stitute of Washington University and St. Dr. Gernsheimer’s major research tional Cancer Institute at the National Louis Children’s Hospital. interests include platelet immunology Institutes of Health (NIH) in BethesDr. Dinauer’s fields of interest in- and immune platelet disorders, platelet da, Maryland, working from San Di- clude molecular mechanisms of innate transfusion and hemostasis in hematoego. Her most recent NIH roles have immunity, inflammatory responses, logic malignancies, and hemostasis and included Deputy and Acting Direc- and the development and function of transfusion management of the perioptor of the National Heart, Lung, and white blood cells. Dr. Dinauer currently erative patient. She currently serves on Blood Institute. serves as an Associate Editor of Blood, the ASH Committee on Practice. n

News and Views from the World of Clinical Oncology and Hematology Visit The ASCO Post website at

www.ASCOPost.com

The ASCO Post | DECEMBER 1, 2014

PAGE 88

Announcements

ASH Awards New Bridge Grants to Help Alleviate Pain of Federal Funding Cuts

I

n November, the American Society of Hematology (ASH) announced the names of seven recipients of its Bridge Grant awards. These 1-year, $150,000 awards provide critical interim support for hematology research proposals that, despite earning high scores, could not be funded by the National Institutes of Health (NIH) amid severe funding reductions. The recently announced ASH Bridge Grant award recipients join 44 hematologists who have received funding since ASH committed $9 million in Society funds to create the program in July 2012.

Competititve Funding “Since 2003, congressional appropriations for NIH have stagnated and failed to keep pace with inflation. As a result, research dollars have become

The ASH Bridge Grant program is designed to help bridge talented hematology investigators to their next NIH research grant by funding their efforts to gather additional data to ultimately strengthen their next application.

—Linda J. Burns, MD

much more competitive, and researchers whose projects might have been funded 5 years ago might not be funded today,” said ASH President Linda J. Burns, MD, of the University of Minnesota. “The ASH Bridge Grant program is designed to help bridge talented hematology investigators to their next NIH research grant by funding their efforts to gather additional data to ultimately strengthen their next application.”

In addition to helping basic, clinical, and translational hematology investigators sustain their current research projects, another goal of the

ASH Bridge Grant program is to ensure that recipients remain committed to hematology despite NIH budget austerity. While the program provides short-term relief, continued investment in NIH is necessary to keep U.S. biomedical research moving forward.

“While ASH is fortunate to be able to provide researchers with the resources they desperately require, we hope that lawmakers understand the urgent need to directly invest in research so scientists will not have to worry about whether they can sustain

their projects and staff for another year,” said Dr. Burns.

Wide-Ranging Research Research projects supported by ASH’s fourth round of Bridge Grants span the breadth of hematology. Fund-

ASCOPost.com | DECEMBER 1, 2014

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Announcements

ed projects range from exploring the biologic significance of recurrent mutations in disease to the impact of exploring the role of natural killer cells in fighting myeloma to studying how stem cell dysfunction can affect chronic inflammation.

Lisa Borghesi, PhD, Associate Professor of Immunology at the Uni-

versity of Pittsburgh and one of seven Bridge Grant recipients announced in November, is studying the close relationship between blood cell production and inflammation. The goal of her research is to better understand the mechanisms regulating blood cell production after infection. While Dr. Borghesi received a major NIH grant sev-

eral years ago, her latest grant renewal application did not meet the NIH payline, despite earning high marks from reviewers.

“The ASH Bridge Grant enables my team to test new ideas and develop new concepts to the fullest potential,” said Dr. Borghesi. “This critical ASH support will not only benefit my research

We want to change the face of EGFR-targeted therapy Rash is caused by inhibition of wild-type epidermal growth factor receptor (EGFR) and can be debilitating1,2 In the treatment of EGFR mutation–positive non–small cell lung cancer (NSCLC), rash and other skin toxicities are wellestablished side effects of EGFR tyrosine kinase inhibitors.3,4

90% of patients treated with approved EGFR inhibitors experience rash3,4 In some studies, rash and paronychia were among the most frequent causes of dose modification, combining to cause dose reductions in as many as 33% of patients.3,4

Rash and its symptoms can negatively affect both patient quality of life and patient compliance, while its psychosocial impact contributes to the assessment of severity.5,6 Beyond the clinical symptom burden, rash visibility can cause significant patient distress even when it is not severe.5 At Clovis Oncology, we’re committed to exploring new approaches in EGFR therapy to advance the fight against NSCLC.

program, but it will also help advance the career trajectories of my trainees who represent the next generation of innovative scientists.”

Myeloma Investigator Among this next generation of investigators is Fotis Asimakopoulos, MD, PhD, Assistant Professor of Medicine at the University of Wisconsin and another recipient of the recently announced ASH Bridge Grants. Dr. Asimakopoulos’ current research focuses on evaluating experimental therapies for multiple myeloma.

“My situation is typical among many new investigators: I’m entering a zone of uncertainty between dwindling start-up funds and the need for additional investment,” said Dr. Asimakopoulos. “This is a critical time that will determine my ability to launch into a sustainable, productive, and independent career in science and I am grateful to ASH for helping to support me through this period.”

The awards announced in November constitute the last of two rounds of ASH Bridge Grants awarded in 2014. Beyond the Society’s financial commitment that will provide grants to be awarded annually through at least 2015, additional awards will be supplemented by support from corporate and individual contributors. Generous support from individual donors as well as Millenium: The Takeda Oncology Company, Novartis Pharmaceuticals, and Onyx Pharmaceuticals enabled the Society to award several additional Bridge Grants as part of this fourth round. n

The ASCO Post Follow us on

Clovis Oncology is leading the fight

@ASCOPost

REFERENCES: 1. Lynch TJ Jr et al. Epidermal growth factor receptor inhibitor–associated cutaneous toxicities: an evolving paradigm in clinical management.

Oncologist. 2007;12(5):610-621. 2. Pérez-Soler R et al. HER1/EGFR inhibitor-associated rash: future directions for management and investigation outcomes from the HER1/EGFR Inhibitor Rash Management Forum. Oncologist. 2005;10(5):345-356. 3. Tarceva [package insert]. Northbrook, IL: OSI Pharmaceuticals LLC; 2014.

4. Gilotrif [package insert]. Ridgefield, CT: Boehringer Ingelheim Pharmaceuticals Inc; 2014. 5. White KJ et al. Psychosocial impact of cutaneous toxicities associated with epidermal growth factor receptor–inhibitor treatment. Clin J Oncol Nurse. 2011;15(1):88-96. 6. National Cancer Institute. Common Terminology Criteria for Adverse Events (CTCAE), Version 4.0. http://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03_2010-06-14_QuickReference_8.5x11.pdf. Published May 28, 2009.

Updated June 14, 2010. Accessed August 26, 2014.

Copyright © 2014 Clovis Oncology. DARO-101 8/14

The ASCO Post | DECEMBER 1, 2014

PAGE 90

Best of ASCO® Survivorship

Major Strides Seen This Year in Survivorship Care

By Susan London

“T

his year was actually a boon for the patient and survivor care section,” Arif H. Kamal, MD, said at the Best of ASCO meeting in Seattle, where he reviewed the leading abstracts and gave some of his own perspective.

“What you see is a lot of the limitations of research in the palliative care and survivor care setting are now being met with [randomized] clinical trials…that are starting to match the evidence level that’s already apparent in all the other [oncology] disease groups. So the evidence base is building, and it’s building very quickly.”

gastroparesis, was given at 20 mg four times daily on days 2 to 4. “As long as your patient is not older and does not have a history of Parkinson-type symptoms, you can actually get away with doses like that,” commented Dr. Kamal, who is Director of Quality and Outcomes at the Duke Cancer Institute in Durham, North Carolina.

Results showed no significant differences between the metoclopramide and aprepitant groups in the rate of complete response (lack of any vomiting and rescue medication)—82.5% vs 80.3%—or in use of breakthrough

A lot of the limitations of research in the palliative care and survivor care setting are now being met with [randomized] clinical trials.…

[T]he evidence base is building, and it’s building very quickly.

—Arif H. Kamal, MD

Older, Less Costly Drug Controls Nausea and Vomiting An Italian randomized noninferiority trial compared the neurokinin inhibitor aprepitant with the antidopaminergic agent metoclopramide, each combined with dexamethasone, for prevention of delayed nausea and vomiting in patients receiving cisplatin-containing chemotherapy.1 Metoclopramide, often used in the United States at lower doses to treat diabetic

medication, quality of life, or adverse effects. Dr. Kamal estimated that a 30day prescription of metoclopramide costs roughly $4, whereas two tablets of aprepitant cost $144 to $340.

“The major limitation to this study was that they did not use fosaprepitant [Emend] and eliminate aprepitant on days 2 and 3, although fosaprepitant still has a higher cost than metoclopramide. Even if you use fosaprepitant, the antidopaminergic

Tapping Palliative Care’s Survival Benefit

A

trial reported in 2010 found that adding palliative care to standard care at the time of lung cancer diagnosis prolonged overall survival by an average of about 2.6 months,1 Arif H. Kamal, MD, told attendees at the Best of ASCO meeting in Seattle. Dr. Kamal is Director of Quality and Outcomes at the Duke Cancer Institute in Durham, North Carolina.

In the reported study, the amount of chemotherapy given did not differ between groups, but the timing did. “If patients got early palliative care, they got just as much, but they got less of it in the last 30 days of life. And that is thought to be why there may be a survival benefit,” he elaborated. Studies comparing palliative care alone with active therapy in lung cancer do show better survival with the latter, he acknowledged. “The models that are being studied are in addition to [standard care], and that’s a huge difference that needs to be understood: it’s in addition to, not instead of,” Dr. Kamal stressed. n Reference 1. Temel JS, Greer JA, Muzikansky A, et al: Early palliative care for patients with metastatic non-small-cell lung cancer. N Engl J Med 363:733-742, 2010.

Discussing Cessation of Medications Near the End of Life

D

iscussions with patients and families about stopping non–cancer-related medications near the end of life are thorny but necessary, according to Arif H. Kamal, MD, of Duke Cancer Institute, at the Best of ASCO meeting in Seattle.

“What’s happening now is that a lot of hospices are having a conversation with patients because of financial reasons. So there is a lot more scrutiny now because of accurately shifting medications to Medicare Part D, which is where a lot of these should be vs being covered by the hospices themselves.

Now, hospices have to go through every single medication and either put it on the Part A side, which is the hospital benefit, or the Part D side [the drug benefit], and at the same time indicate whether it is for quality of life or not, and whether it needs to be continued or not, whether it is essential or not,” he explained. “It’s a delicate conversation.”

For example, in patients who have had a pulmonary embolism and are now on heparin or a similar agent, oncologists may need to have a discussion about CHADS2 risk scores (congestive heart failure, hypertension, age, diabetes, and prior stroke, transient ischemic attack, or thromboembolism) and how they apply over various time periods. “I think ultimately if you talk to patients about what their goals are and what’s important to them, and ask them if, by stopping [warfarin], what they’re afraid of, and they say I’m afraid of having a stroke or that kind of thing, then you can address that,” Dr. Kamal said. n

medications—metoclopramide, olanzapine, and [haloperidol]—are very, very good as antiemetics and should be used commonly,” he maintained.

“Metoclopramide can be considered as a first-line antiemetic, and certainly, if a patient cannot afford a neurokinin inhibitor, should be considered.”

Less Frequent Zoledronic Acid Dosing Is Just as Efficacious The OPTIMIZE-2 randomized noninferiority trial compared the bisphosphonate zoledronic acid given every 4 weeks vs every 12 weeks to patients with bone metastases of breast cancer.2 “These are patients who had been living a long time with advanced disease and who had already received quite a bit of bisphosphonates up front,” Dr. Kamal commented.

The time to a first skeletal-related event was statistically indistinguishable between treatment groups, at a median of about 1 year. There was also no significant difference in the rate of skeletal morbidity.

As a result of the findings, “the issue of frequency of bisphosphonates or bone-modifying agents is certainly up for question,” Dr. Kamal commented.

The trial had methodologic issues, such as the need to drop a placebo arm because of the low accrual and the advent of RANKL inhibitors, he noted. In fact,

a similar denosumab (Xgeva)-based trial is now enrolling patients.3

DHEA With Moisturizer Relieves Vaginal Symptoms A trial from the Alliance group tested a combination of vaginal dehydroepiandrosterone (DHEA) and a bioadhesive moisturizer for relieving vaginal symptoms in postmenopausal women treated for breast or gynecologic cancers.4 Patients were randomly assigned to lower-dose DHEA (3.25 mg) plus moisturizer, higher-dose DHEA (6.5 mg) plus moisturizer, or moisturizer alone—each applied nightly for 12 weeks. “So this was not [as-needed] use, which is very different from other trials in how they’ve been designed and certainly differently than how it may be clinically given,” Dr. Kamal pointed out.

Results showed significant improvements in some sexual function outcomes with lower-dose DHEA and in nearly all of them with the higher dose, relative to moisturizer alone. The products studied are not yet on the market, but in the meantime, “bioadhesive moisturizers, which can be found over the counter— one example is Replens—should be used in patients with sexual dysfunction who are on antihormonal treatments for breast cancer specifically and should be continued on page 92

FO L NEW RM IQ — UL UID AT IO N

Single-agent TREANDA® (bendamustine HCl) Injection provided durable responses that lasted a median of 9 months Median DR

9.2 months

All responders (n=74)

(95% CI: 7.1, 10.8)

Patients who achieved a CR/CRu

10.4 months

1

(95% CI: 9.3, 13.6)

8.3 months

Patients who achieved a PR

1

(95% CI: 6.3, 10.8)

0

2

4

6

Months

8

10

12

The efficacy of TREANDA was evaluated in a single-arm study of 100 patients with indolent B-cell NHL that had progressed during or within six months of treatment with rituximab or a rituximab-containing regimen.

In 2 single-arm studies of patients with indolent B-cell NHL that had progressed (N=176), the most common non-hematologic adverse reactions (frequency ≥30%) were nausea (75%), fatigue (57%), vomiting (40%), diarrhea (37%), and pyrexia (34%). The most common hematologic abnormalities (frequency ≥15%) were lymphopenia (99%), leukopenia (94%), anemia (88%), neutropenia (86%), and thrombocytopenia (86%).

Preparing for IV administration is:

Fast

Precise

Convenient

Less preparation time

No reconstitution necessary

Fewer steps prior to admixing

Indication TREANDA is indicated for the treatment of patients with indolent B-cell non-Hodgkin lymphoma (NHL) that has progressed during or within six months of treatment with rituximab or a rituximab-containing regimen.

Important Safety Information Contraindication: TREANDA is contraindicated in patients with a known hypersensitivity (e.g., anaphylactic and anaphylactoid reactions) to bendamustine.

Myelosuppression: TREANDA caused severe myelosuppression (Grade 3-4) in 98% of patients in the two NHL studies. Three patients (2%) died from myelosuppression-related adverse reactions. If myelosuppression occurs, monitor leukocytes, platelets, hemoglobin (Hgb), and neutrophils frequently. Myelosuppression may require dose delays and/or subsequent dose reductions if recovery to the recommended values has not occurred by the first day of the next scheduled cycle.

Infections: Infection, including pneumonia, sepsis, septic shock, and death have occurred. Patients with myelosuppression following treatment with TREANDA are more susceptible to infections.

Anaphylaxis and Infusion Reactions: Infusion reactions to TREANDA have occurred commonly in clinical trials. Symptoms include fever, chills, pruritus, and rash. In rare instances severe anaphylactic and anaphylactoid reactions have occurred, particularly in the second and subsequent cycles of therapy. Monitor clinically and discontinue drug for severe (Grade 3-4) reactions.

Ask patients about symptoms suggestive of infusion reactions after their first cycle of therapy. Consider measures to prevent severe reactions, including antihistamines, antipyretics, and corticosteroids in subsequent cycles in patients who have experienced Grade 1 or 2 infusion reactions.

Tumor Lysis Syndrome: Tumor lysis syndrome associated with TREANDA treatment has occurred. The onset tends to be within the first treatment cycle of TREANDA and, without intervention, may lead to acute renal failure and death. Preventive measures include vigorous hydration and close monitoring of blood chemistry, particularly potassium and uric acid levels.

There may be an increased risk of severe skin toxicity when TREANDA and allopurinol are administered concomitantly.

Skin Reactions: Skin reactions have been reported with TREANDA treatment and include rash, toxic skin reactions, and bullous exanthema. In a study of TREANDA (90 mg/m2) in combination with rituximab, one case of toxic epidermal necrolysis (TEN) occurred. TEN has been reported for rituximab. Cases of Stevens-Johnson syndrome (SJS) and TEN, some fatal, have been reported when TREANDA was administered concomitantly with allopurinol and other medications known to cause these syndromes. Where skin reactions occur, they may be progressive and increase in severity with further treatment. Monitor patients with skin reactions closely. If skin reactions are severe or progressive, withhold or discontinue TREANDA. Other Malignancies: There are reports of pre-malignant and malignant diseases that have developed in patients who have been treated with TREANDA, including myelodysplastic syndrome, myeloproliferative disorders, acute myeloid leukemia, and bronchial carcinoma. The association with TREANDA therapy has not been determined.

Extravasation Injury: TREANDA extravasations have been reported in postmarketing resulting in hospitalizations from erythema, marked swelling, and pain. Ensure good venous access prior to starting TREANDA infusion and monitor the intravenous infusion site for redness, swelling, pain, infection, and necrosis during and after administration of TREANDA. Embryo-fetal Toxicity: TREANDA can cause fetal harm when administered to a pregnant woman. Women should be advised to avoid becoming pregnant while using TREANDA. Most Common Adverse Reactions: The most common non-hematologic adverse reactions for NHL (frequency ≥15%) are nausea, fatigue, vomiting, diarrhea, pyrexia, constipation, anorexia, cough, headache, weight decreased, dyspnea, rash, and stomatitis. The most common hematologic abnormalities (frequency ≥15%) are lymphopenia, leukopenia, anemia, neutropenia, and thrombocytopenia.

Please see accompanying brief summary of Full Prescribing Information on the following pages.

Learn more at TREANDAHCP.com Reference: 1. Data on file. Teva Pharmaceuticals.

©2014 Cephalon, Inc., a wholly-owned subsidiary of Teva Pharmaceutical Industries Ltd. All rights reserved. TRE-40428 November 2014

The ASCO Post | DECEMBER 1, 2014

PAGE 92

Best of ASCO® Survivorship Care continued from page 90

used daily or nightly, and for a long period of time,” Dr. Kamal recommended.

Cardiomyopathy Screening in Childhood Cancer Survivors A randomized trial among at-risk adult survivors of pediatric malignan-

cies from the Childhood Cancer Survivor Study assessed whether adding counseling by an advanced practice nurse to a printed survivorship care plan improved cardiomyopathy screening.5 The counseling consisted of two telephone motivational interviewing sessions plus two follow-up letters summarizing the content.

The patients studied had not had cardiomyopathy screening during the past 5 years. “So these are patients who are not getting very close follow-up support, for example, not participating in any other long-term follow-up program. So this was their major way of having contact with anything in survivorship,” Dr. Kamal noted.

At 12 months, 52% of intervention

™

Brief Summary of Prescribing Information for Indolent B-cell Non-Hodgkin Lymphoma That Has Progressed 1 INDICATIONS AND USAGE 1.2 Non-Hodgkin Lymphoma (NHL) TREANDA® is indicated for the treatment of patients with indolent B-cell non-Hodgkin lymphoma that has progressed during or within six months of treatment with rituximab or a rituximab-containing regimen.

2 DOSAGE AND ADMINISTRATION 2.2 Dosing Instructions for NHL Recommended Dosage: The recommended dose is 120 mg/m2 administered intravenously over 60 minutes on Days 1 and 2 of a 21-day cycle, up to 8 cycles.

Dose Delays, Dose Modifications and Reinitiation of Therapy for NHL: TREANDA administration should be delayed in the event of a Grade 4 hematologic toxicity or clinically significant ≥ Grade 2 non-hematologic toxicity.

Once non-hematologic toxicity has recovered to ≤ Grade 1 and/or the blood counts have improved [Absolute Neutrophil Count (ANC) ≥ 1 x 109/L, platelets ≥ 75 x 109/L], TREANDA can be reinitiated at the discretion of the treating physician. In addition, dose reduction may be warranted. [See Warnings and Precautions (5.1)] Dose modifications for hematologic toxicity: for Grade 4 toxicity, reduce the dose to 90 mg/m2 on Days 1 and 2 of each cycle; if Grade 4 toxicity recurs, reduce the dose to 60 mg/m2 on Days 1 and 2 of each cycle.

Dose modifications for non-hematologic toxicity: for Grade 3 or greater toxicity, reduce the dose to 90 mg/m2 on Days 1 and 2 of each cycle; if Grade 3 or greater toxicity recurs, reduce the dose to 60 mg/m2 on Days 1 and 2 of each cycle.

2.3 Preparation for Intravenous Administration Each vial of TREANDA Injection is intended for single use only. Aseptically withdraw the volume needed for the required dose from the 90 mg/mL solution.

Immediately transfer the solution to a 500 mL infusion bag of 0.9% Sodium Chloride Injection, USP (normal saline). As an alternative to 0.9% Sodium Chloride Injection, USP (normal saline), a 500 mL infusion bag of 2.5% Dextrose/0.45% Sodium Chloride Injection, USP, may be considered. The resulting final concentration of bendamustine HCl in the infusion bag should be within 0.2 - 0.7 mg/mL. The admixture should be a clear colorless to yellow solution.

Use either 0.9% Sodium Chloride Injection, USP, or 2.5% Dextrose/0.45% Sodium Chloride Injection, USP, for dilution, as outlined above. No other diluents have been shown to be compatible.

Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permit. Any unused solution should be discarded according to institutional procedures for antineoplastics.

2.4 Admixture Stability TREANDA Injection contains no antimicrobial preservative. The admixture should be prepared as close as possible to the time of patient administration.

Once diluted with either 0.9% Sodium Chloride Injection, USP, or 2.5% Dextrose/0.45% Sodium Chloride Injection, USP, the final admixture is stable for 24 hours when stored under refrigerated conditions at 2°-8°C (36°-46°F) or for 2 hours when stored at room temperature 15°-30°C (59°-86°F) and room light. Administration of TREANDA must be completed within this period.

3 DOSAGE FORMS AND STRENGTHS TREANDA for Injection is supplied in single-use vials containing either 45 mg/0.5 mL or 180 mg/2 mL of bendamustine HCl. 4 CONTRAINDICATIONS TREANDA is contraindicated in patients with a known hypersensitivity (e.g., anaphylactic and anaphylactoid reactions) to bendamustine. [See Warnings and Precautions (5.3)] 5 WARNINGS AND PRECAUTIONS 5.1 Myelosuppression TREANDA caused severe myelosuppression (Grade 3-4) in 98% of patients in the two NHL studies (see Table 2). Three patients (2%) died from myelosuppression-related adverse reactions; one each from neutropenic sepsis, diffuse alveolar hemorrhage with Grade 3 thrombocytopenia, and pneumonia from an opportunistic infection (CMV).

In the event of treatment-related myelosuppression, monitor leukocytes, platelets, hemoglobin (Hgb), and neutrophils frequently. In the clinical trials, blood counts were monitored every week initially. Hematologic nadirs were observed predominantly in the third week of therapy. Myelosuppression may require dose delays and/or subsequent dose reductions if recovery to the recommended values has not occurred by the first day of the next scheduled cycle. Prior to the initiation of the next cycle of therapy, the ANC should be ≥ 1 x 109/L and the platelet count should be ≥ 75 x 109/L. [See Dosage and Administration (2.2)] 5.2 Infections Infection, including pneumonia, sepsis, septic shock, and death have occurred in adult and pediatric patients in clinical trials and in postmarketing reports. Patients with myelosuppression following treatment with TREANDA

patients had undergone echocardiography compared with 22% of control patients (adjusted relative risk = 2.31).

“What’s not surprising is that the piece of paper on its own has limited value,” Dr. Kamal commented. “The highlight of this is that the value is still at 52%. So you essentially are putting a lot of resources into survivorship follow-up here for an

TREANDA® (bendamustine hydrochloride) Injection are more susceptible to infections. Advise patients with myelosuppression following TREANDA treatment to contact a physician if they have symptoms or signs of infection.

5.3 Anaphylaxis and Infusion Reactions Infusion reactions to TREANDA have occurred commonly in clinical trials.

Symptoms include fever, chills, pruritus and rash. In rare instances severe anaphylactic and anaphylactoid reactions have occurred, particularly in the second and subsequent cycles of therapy. Monitor clinically and discontinue drug for severe reactions. Ask patients about symptoms suggestive of infusion reactions after their first cycle of therapy. Patients who experience Grade 3 or worse allergic-type reactions should not be rechallenged. Consider measures to prevent severe reactions, including antihistamines, antipyretics and corticosteroids in subsequent cycles in patients who have experienced Grade 1 or 2 infusion reactions. Discontinue TREANDA for patients with Grade 4 infusion reactions. Consider discontinuation for Grade 3 infusions reactions as clinically appropriate considering individual benefits, risks, and supportive care.

5.4 Tumor Lysis Syndrome Tumor lysis syndrome associated with TREANDA treatment has occurred in patients in clinical trials and in postmarketing reports. The onset tends to be within the first treatment cycle of TREANDA and, without intervention, may lead to acute renal failure and death. Preventive measures include vigorous hydration and close monitoring of blood chemistry, particularly potassium and uric acid levels. Allopurinol has also been used during the beginning of TREANDA therapy. However, there may be an increased risk of severe skin toxicity when TREANDA and allopurinol are administered concomitantly [see Warnings and Precautions (5.5)].

5.5 Skin Reactions Skin reactions have been reported with TREANDA treatment in clinical trials and postmarketing safety reports, including rash, toxic skin reactions and bullous exanthema. Some events occurred when TREANDA was given in combination with other anticancer agents.

In a study of TREANDA (90 mg/m2) in combination with rituximab, one case of toxic epidermal necrolysis (TEN) occurred. TEN has been reported for rituximab (see rituximab package insert). Cases of Stevens-Johnson syndrome (SJS) and TEN, some fatal, have been reported when TREANDA was administered concomitantly with allopurinol and other medications known to cause these syndromes. The relationship to TREANDA cannot be determined.

Where skin reactions occur, they may be progressive and increase in severity with further treatment. Monitor patients with skin reactions closely. If skin reactions are severe or progressive, withhold or discontinue TREANDA. 5.6 Other Malignancies There are reports of pre-malignant and malignant diseases that have developed in patients who have been treated with TREANDA, including myelodysplastic syndrome, myeloproliferative disorders, acute myeloid leukemia and bronchial carcinoma. The association with TREANDA therapy has not been determined.

5.7 Extravasation Injury TREANDA extravasations have been reported in post marketing resulting in hospitalizations from erythema, marked swelling, and pain. Assure good venous access prior to starting TREANDA infusion and monitor the intravenous infusion site for redness, swelling, pain, infection, and necrosis during and after administration of TREANDA. 5.8 Embryo-fetal Toxicity TREANDA can cause fetal harm when administered to a pregnant woman.

Single intraperitoneal doses of bendamustine in mice and rats administered during organogenesis caused an increase in resorptions, skeletal and visceral malformations, and decreased fetal body weights.

6 ADVERSE REACTIONS The following serious adverse reactions have been associated with TREANDA in clinical trials and are discussed in greater detail in other sections [See Warnings and Precautions] of the label: Myelosuppression (5.1); Infections (5.2); Anaphylaxis and Infusion Reactions (5.3); Tumor Lysis Syndrome (5.4); Skin Reactions (5.5); Other Malignancies (5.6); Extravasation injury (5.7). The data described below reflect exposure to TREANDA in 176 patients who participated in two single-arm trials for the treatment of indolent B-cell NHL. Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

6.2 Clinical Trials Experience in NHL The data described below reflect exposure to TREANDA in 176 patients with indolent B-cell NHL treated in two single-arm studies. The population was 31-84 years of age, 60% male, and 40% female. The race distribution was 89% White, 7% Black, 3% Hispanic, 1% other, and <1% Asian. These patients received TREANDA at a dose of 120 mg/m2 intravenously on Days 1 and 2 for up to eight 21-day cycles.

The adverse reactions occurring in at least 5% of the NHL patients, regardless of severity, are shown in Table 1. The most common non-hematologic adverse reactions (≥ 30%) were nausea (75%), fatigue (57%), vomiting (40%), diarrhea (37%) and pyrexia (34%). The most common non-hematologic Grade 3 or 4 adverse reactions (≥ 5%) were fatigue (11%), febrile neutropenia (6%), and pneumonia, hypokalemia and dehydration, each reported in 5% of patients.

ASCOPost.com | DECEMBER 1, 2014

PAGE 93

Best of ASCO® echocardiogram and you’re still only getting to about 50%, which highlights the idea that probably the actual solution to this problem is going to be multimodality and potentially even multiprofessional.”

Palliative Care for Caregivers The randomized ENABLE III trial compared immediate vs delayed pal-

liative care for family caregivers of patients with advanced cancer.6 In the immediate group, patients had an in-person consult with an advanced practice nurse that the caregiver was welcome to attend; thereafter, nurses conducted telephone-based sessions and follow-up with both. Patients in the delayed group were wait-listed.

“This is actually the first time in the world ever that I am aware of that a family caregiver study using palliative care was actually performed and with this rigor of methodology,” Dr. Kamal noted.

Results showed that relative to wait-listed peers, caregivers in the early palliative care group had better

TREANDA® (bendamustine hydrochloride) Injection

TREANDA® (bendamustine hydrochloride) Injection

Table 1: Non-Hematologic Adverse Reactions Occurring in at Least 5% of NHL Patients Treated with TREANDA by System Organ Class and Preferred Term (N=176) Number (%) of patients* System organ class Preferred term All Grades Grade 3/4 Total number of patients with at least 1 adverse reaction 176 (100) 94 (53) Cardiac disorders 0 Tachycardia 13 (7) Gastrointestinal disorders 7 (4) Nausea 132 (75) 5 (3) Vomiting 71 (40) 6 (3) Diarrhea 65 (37) 1 (<1) Constipation 51 (29) 1 (<1) Stomatitis 27 (15) 2 (1) Abdominal pain 22 (13) 0 Dyspepsia 20 (11) 0 Gastroesophageal reflux disease 18 (10) 1 (<1) Dry mouth 15 (9) 0 Abdominal pain upper 8 (5) 0 Abdominal distension 8 (5) General disorders and administration site conditions 19 (11) Fatigue 101 (57) 3 (2) Pyrexia 59 (34) 0 Chills 24 (14) 1 (<1) Edema peripheral 23 (13) 4 (2) Asthenia 19 (11) 1 (<1) Chest pain 11 (6) 0 Infusion site pain 11 (6) 0 Pain 10 (6) 0 Catheter site pain 8 (5) Infections and infestations 5 (3) Herpes zoster 18 (10) 0 Upper respiratory tract infection 18 (10) 4 (2) Urinary tract infection 17 (10) 0 Sinusitis 15 (9) 9 (5) Pneumonia 14 (8) 11 (6) Febrile neutropenia 11 (6) 2 (1) Oral candidiasis 11 (6) 0 Nasopharyngitis 11 (6) Investigations 3 (2) Weight decreased 31 (18) Metabolism and nutrition disorders 3 (2) Anorexia 40 (23) 8 (5) Dehydration 24 (14) 1 (<1) Decreased appetite 22 (13) 9 (5) Hypokalemia 15 (9) Musculoskeletal and connective tissue disorders 5 (3) Back pain 25 (14) 0 Arthralgia 11 (6) 2 (1) Pain in extremity 8 (5) 0 Bone pain 8 (5) Nervous system disorders 0 Headache 36 (21) 0 Dizziness 25 (14) 0 Dysgeusia 13 (7) Psychiatric disorders 0 Insomnia 23 (13) 1 (<1) Anxiety 14 (8) 0 Depression 10 (6) Respiratory, thoracic and mediastinal disorders Cough 1 (<1) 38 (22) Dyspnea 3 (2) 28 (16) Pharyngolaryngeal pain 1 (<1) 14 (8) Wheezing 0 8 (5) Nasal congestion 0 8 (5) Skin and subcutaneous tissue disorders Rash 1 (<1) 28 (16) Pruritus 0 11 (6) Dry skin 0 9 (5) Night sweats 0 9 (5) Hyperhidrosis 0 8 (5) Vascular disorders Hypotension 2 (1) 10 (6) *Patients may have reported more than 1 adverse reaction.

NOTE: Patients counted only once in each preferred term category and once in each system organ class category.

Hematologic toxicities, based on laboratory values and CTC grade, in NHL patients treated in both single arm studies combined are described in Table 2.

Clinically important chemistry laboratory values that were new or worsened from baseline and occurred in >1% of patients at Grade 3 or 4, in NHL patients treated in both single arm studies combined were hyperglycemia (3%), elevated creatinine (2%), hyponatremia (2%), and hypocalcemia (2%).

Table 2: Incidence of Hematology Laboratory Abnormalities in Patients Who Received TREANDA in the NHL Studies Percent of patients Hematology variable All Grades Grades 3/4 Lymphocytes Decreased 99 94 Leukocytes Decreased 94 56 Hemoglobin Decreased 88 11 Neutrophils Decreased 86 60 Platelets Decreased 86 25 In both studies, serious adverse reactions, regardless of causality, were reported in 37% of patients receiving TREANDA. The most common serious adverse reactions occurring in ≥ 5% of patients were febrile neutropenia and pneumonia. Other important serious adverse reactions reported in clinical trials and/or postmarketing experience were acute renal failure, cardiac failure, hypersensitivity, skin reactions, pulmonary fibrosis, and myelodysplastic syndrome. Serious drug-related adverse reactions reported in clinical trials included myelosuppression, infection, pneumonia, tumor lysis syndrome and infusion reactions [see Warnings and Precautions (5)]. Adverse reactions occurring less frequently but possibly related to TREANDA treatment were hemolysis, dysgeusia/taste disorder, atypical pneumonia, sepsis, herpes zoster, erythema, dermatitis, and skin necrosis.

6.3 Postmarketing Experience The following adverse reactions have been identified during post-approval use of TREANDA. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure: anaphylaxis; and injection or infusion site reactions including phlebitis, pruritus, irritation, pain, and swelling; pneumocystis jiroveci pneumonia and pneumonitis.

Skin reactions including SJS and TEN have occurred when TREANDA was administered concomitantly with allopurinol and other medications known to cause these syndromes. [See Warnings and Precautions (5.5)] 10 OVERDOSAGE The intravenous LD50 of bendamustine HCl is 240 mg/m2 in the mouse and rat.

Toxicities included sedation, tremor, ataxia, convulsions and respiratory distress.

Across all clinical experience, the reported maximum single dose received was 280 mg/m2. Three of four patients treated at this dose showed ECG changes considered dose-limiting at 7 and 21 days post-dosing. These changes included QT prolongation (one patient), sinus tachycardia (one patient), ST and T wave deviations (two patients), and left anterior fascicular block (one patient).

Cardiac enzymes and ejection fractions remained normal in all patients.

No specific antidote for TREANDA overdose is known. Management of overdosage should include general supportive measures, including monitoring of hematologic parameters and ECGs. 15 REFERENCES 1. OSHA Hazardous Drugs. OSHA. [Accessed on June 19, 2013, from http://www.osha.gov/SLTC/hazardousdrugs/index.html] 16 HOW SUPPLIED/STORAGE AND HANDLING 16.1 Safe Handling and Disposal As with other potentially toxic anticancer agents, care should be exercised in the handling and preparation of solutions prepared from TREANDA Injection. The use of gloves and safety glasses is recommended to avoid exposure in case of breakage of the vial or other accidental spillage. If a solution of TREANDA contacts the skin, wash the skin immediately and thoroughly with soap and water. If TREANDA contacts the mucous membranes, flush thoroughly with water.

TREANDA is a cytotoxic drug. Follow special handling and disposal procedures1.

16.2 How Supplied TREANDA (bendamustine hydrochloride) Injection is supplied as a 90 mg/mL clear colorless to yellow solution as follows: NDC 63459-395-02: 45 mg/0.5 mL of solution in an amber single-use vial NDC 63459-396-02: 180 mg/2 mL of solution in an amber single-use vial Vials are supplied in individual cartons.

16.3 Storage TREANDA Injection must be stored refrigerated between 2°-8°C (36°-46°F).

Retain in original package until time of use to protect from light.

Distributed By: Teva Pharmaceuticals USA, Inc. North Wales, PA 19454 TREANDA is a trademark of Cephalon, Inc. or its affiliates. ©2008-2014 Cephalon, Inc., a wholly owned subsidiary of Teva Pharmaceutical Industries Ltd. or its affiliates. All rights reserved.

9/2013 (Label Code: 00016287.06) TRE-40361 This brief summary is based on TRE-009 TREANDA full Prescribing Information.

quality of life, less depression, and lower subjective burden. However, among families in which the patient died, early palliative care did not reduce depression or grief.

“This is the first trial that shows that [palliative care] does the same thing for families and caregivers as long as they are brought in at the same time as the patient,” Dr. Kamal noted. At his facility, “as a rule we don’t do a lot of palliative care consults—certainly first visits—without having somebody else in the room, such as other caregivers.” n Disclosure: Dr. Kamal reported no potential conflicts of interest.

References 1. Roila F, Ballatori E, Ruggeri B, et al: Aprepitant versus metoclopramide, both combined with dexamethasone, for preventing cisplatin-induced delayed emesis: A randomized, double-blind study.

2014 ASCO Annual Meeting. Abstract 9503.

2. Hortobagyi GN, Lipton A, Chew HK, et al: Efficacy and safety of continued zoledronic acid every 4 weeks versus every 12 weeks in women with bone metastases from breast cancer: Results of the OPTIMIZE-2 trial. 2014 ASCO Annual Meeting. Abstract LBA9500.

3. U.S. National Institutes of Health: Prevention of symptomatic skeletal events with denosumab administered every 4 weeks versus every 12 weeks.

Available at ClinicalTrials.gov/show/ NCT02051218. Accessed November 17, 2014.

4. Barton DL, Sloan JA, Shuster LT, et al: Impact of vaginal dehydroepiandosterone (DHEA) on vaginal symptoms in female cancer survivors: Trial N10C1 (Alliance). 2014 ASCO Annual Meeting.

Abstract 9507.

5. Hudson MM, Leisenring WM, Stratton K, et al: Increasing cardiovascular screening in at-risk adult survivors of pediatric malignancies: A randomized controlled trial. 2014 ASCO Annual Meeting. Abstract 9506.

6. Dionne-Odom JN, Azuero A, Lyons K, et al: Benefits of immediate versus delayed palliative care to informal family caregivers of persons with advanced cancer: Outcomes from the ENABLE III randomized clinical trial. 2014 ASCO Annual Meeting. Abstract LBA9513.

Send Us Your NEWS Write to editor@ASCOPost.com.

All submissions will be considered for publication

The ASCO Post | DECEMBER 1, 2014

PAGE 94

Journal Spotlight Melanoma

Memorial Sloan Kettering Team Discovery Advances Understanding of Immunotherapy’s Successes—and Its Failures

A

collaborative team of leaders in the field of cancer immunology from Memorial Sloan Kettering Cancer Center has made a key discovery that advances the understanding of why some patients respond to the CTLA-4 blocking antibody ipilimumab ­(Yervoy), an immunotherapy drug, while others do not.

A report published online first in The New England Journal of Medicine1 shows that in patients who respond to ipilimumab, their cancer cells carry a high number of gene mutations—some of which make tumors more visible to the immune system, and therefore easier to fight. The research was led by Vice Chair of Ra-

produced practice-changing results for many types of cancer. The drug works by blocking a protein called CTLA-4, boosting the body’s natural immune defense against tumors. Normally, CTLA4 keeps the tumor-fighting activity of the immune system’s T cells in check.

In the presence of the drug, T cells are unleashed and their inherent ability to recognize and destroy cancer cells is ­enhanced.

For some patients, the drug shrinks tumors and significantly prolongs lives.

Over the past decade, immunotherapy has signaled a scientific game changer.

“We’ve spent much time and effort studying how to target the tumor. And

We are learning that there are few treatments that don’t have some footprint in the cancer genome.

—Timothy Chan, MD, PhD

diation Oncology and cancer genomics researcher Timothy Chan, MD, PhD, oncology fellow Alexandra ­Snyder Charen, MD, and Chief of the Melanoma and Immunotherapeutics Service and the Lloyd J. Old Chair for Clinical Investigation Jedd Wolchok, MD, PhD. “We are learning that there are few treatments that don’t have some footprint in the cancer genome,” said Dr. Chan. “For the first time, it might be feasible to develop a reliable diagnostic test to help guide treatment decisions by predicting who will respond.”

Practice-Changing Data Clinical trials of ipilimumab have

we’ve only recently understood how to have the patient’s immune defenses mobilized to treat the tumor. Immunotherapy is by definition how that happens,” said Dr. Wolchok.

But the approach doesn’t help everyone. In fact, about 80% of people with melanoma get little or no benefit from ipilimumab. And thus far, doctors have had no way of predicting which patients are more likely to respond to the drug.

This new study brings the team one step closer to finding an answer. “There was a correlation between having an elevated number of mutations, or more DNA changes in a tumor, and benefit-

Jedd Wolchok, MD, PhD

ting from the treatment with ipilimumab, with benefit being long-term stability or resolution of metastatic disease,” explained Dr. Snyder Charen.

of mutation that makes cancer cells express new antigens. The collaborative team responsible for these key findings also includes patients.

“These advances would not have been made without the generosity of patients who consented to having their tumor tissue collected and analyzed,” Dr. Snyder Charen concluded. “Dr. Wolchok and his lab members have spent many years banking samples, and it’s an invaluable resource for research.”

Study Methodology The team collected tumor samples from 64 melanoma patients who had been treated with ipilimumab or tremelimumab, an experimental drug that works in a similar way. The tumors were analyzed by whole-exome sequencing, a method that deciphers DNA changes across all parts of the genome that code for protein. About half of the tumors analyzed came from patients for whom the treatment had been successful and the other half from people who derived little or no benefit from it.

“We found that tumors that had responded to the drug had a higher mutational burden, or overall number of DNA changes,” said Dr. Snyder Charen. “But the correlation isn’t perfect.

Not all patients with a high mutational burden in their tumors responded to the drug.”

“This made us ask, ‘What is the immune system seeing?’” said Dr. ­Wolchok.

“What is it about the mutational landscape of a tumor that helps the immune system recognize and attack it?”

Using sophisticated computational tools, the researchers were able to explore their data through the lens of immunology. They found that drugresponsive tumors share a certain type

Alexandra Snyder Charen, MD

Practical Implications Eventually, these findings could translate into a diagnostic test to detect the mutations in melanoma patients. Results could help doctors and patients make more-informed treatment choices. In addition, the Memorial Sloan Kettering team plans to investigate whether specific tumor mutations influence the effectiveness of other immunotherapy drugs. Dr. Chan says, “If we know a patient won’t respond to ipilimumab, we may be able to identify other drugs that are more likely to be effective against this person’s tumor.” n

Disclosure: For full disclosures of the study authors, visit www.nejm.org.

Reference 1. Snyder A, Makarov V, Merghoub T, et al: Genetic basis for clinical response to CTLA-4 blockade in melanoma. N Engl J Med. November 19, 2014 (early release online).

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ASCOPost.com | DECEMBER 1, 2014

PAGE 95

Reflections

When Life Couldn’t Be Better

By Carolyn D. Runowicz, MD

The following essay by Carolyn D. Runowicz, MD, is adapted from The Big Casino: America’s Best Cancer Doctors Share Their Most Powerful Stories, which was coedited by Stan Winokur, MD, and Vincent Coppola and published in May 2014. The book is available on Amazon.com and thebigcasino.org.

the office. I wanted to be just like them.

Later, as a resident at Mount Sinai Hospital in New York, I joined the Department of Obstetrics and Gynecology led by Dr. Saul Gusberg, a founding father of gynecologic oncology.

Larger than life, Saul was President of the American Cancer Society, a nationally and internationally renowned oncologist. Yet he was always available and never too busy [to talk with me].

We became lifelong colleagues. When he died, at the memorial service, his son stated that I was the daughter that Dr. Gusberg never had. I was so proud.

Progress in Cancer Treatment As a resident, I worked under researchers designing and participating in clinical trials using a new drug, cisplatin. It would prove incredibly effective

cology and a fellowship program. Training fellows and watching them become leaders in the field are enormously rewarding experiences.

Underserved Population In the Bronx, where Einstein is located, patients are very different from those in Manhattan. Generally speaking, they are underserved and consequently present with much more advanced disease. I recall a 35-year-old patient with advanced cervical cancer that had spread to her lungs. I’d never encountered such advanced gynecologic cancer in a newly diagnosed patient.

Such extensive disease is uncommon in the United States. Working in the Bronx was like being in a Third World country.

I reviewed her medical records and realized that she had been told of an “ab-

My hope is that one day, we will think of cancer like we do polio—a historical footnote in medicine.

J

ust imagine a world without cancer!

I encountered my first patient with advanced ovarian cancer during the summer before my second year of medical school. It was the early 1970s. I remember her sitting in a chair, her legs swollen and her abdomen distended with fluid; she was unable to eat. She died a few days later. I was astounded that a disease could be so virulent.

This woman never knew the profound impact her disease had on me. She influenced my career choice and commitment to care for women with gynecologic cancers.

As a first-year medical student, I’d been awarded an American Cancer Society student fellowship to shadow an oncologist. That’s how I met Dr. George C. Lewis, Jr, and Dr. Jim Lee, my first mentors. They radiated an excitement and enthusiasm for their specialty— gynecologic oncology—that was infectious and inspirational. They loved being physicians and were never too busy to teach and have me tag along on hospital rounds, the operating room, or Dr. Runowicz is Professor, Obstetrics and Gynecology, and Executive Associate Dean for Academic Affairs at the Herbert Wertheim College of Medicine at Florida International University in Miami.

—Carolyn D. Runowicz, MD

in the treatment of ovarian cancer, but it was also terribly toxic. One of my responsibilities was to persuade (at times, cajole) patients to be admitted for treatment. At the time, we did not have the arsenal of antinausea agents and other supportive therapies that we have today. I recall some patients stating they would rather die than be treated with these toxic drugs.

Vividly remembering that patient from my first summer in medical school, I was sure that cisplatin toxicity was better than the torment she suffered before she died. Eventually, all the patients agreed to be admitted. I had a growing appreciation and admiration for these strong women. I still shudder when I think of what they went through. The chemotherapy now available for ovarian cancer patients and the antinausea and supportive therapies have eradicated this horrible experience.

After my fellowship, I continued on at Mount Sinai for a couple of years as a faculty member, and then I was recruited to Albert Einstein College of Medicine and Montefiore Medical Center to develop a division of gynecologic on-

normal” Pap smear at the birth of her youngest child 7 years earlier. I asked her why she had not accessed the Einstein/Montefiore health-care system, which was right in her backyard. She said her priority was taking care of her seven children—providing food, clothing, and shelter. How many times had she visited the pediatrician and emergency room for her children? Yet, she didn’t have time for herself.

At her deathbed, she was surrounded by her children. The oldest was 17 years old and pregnant. I realized that these children would not likely escape the same vicious cycle of poverty. I envisioned this teenager in 10 years with seven children, neglecting her own health care, just as her mother had done. Ironically, she told me she was having a girl and would name the baby after her mother.

Surviving Breast Cancer At Einstein/Montefiore, we were able to establish a successful clinical program and fellowship. Just when I thought my life couldn’t be better, I was diagnosed with breast cancer. I was 41.

I was not only an oncologist but also a cancer patient. Because the disease had spread to my lymph nodes, I was treated with chemotherapy, radiation, and tamoxifen. My treatments went from July until the following Memorial Day, a grueling 11 months.

Antinausea therapy and supportive treatments were not yet available. I lost weight and truly looked like a concentration camp victim. (My family and friends consistently told me how good I looked.) I thought I was an empathetic and caring physician before I was diagnosed with cancer, but now I had lived through it all. I developed even more respect for my patients and truly understood that those of us who survive feel like survivors. We have won a personal battle against cancer.

Cancer as a Chronic Disease With my cancer behind me, my next big career challenge was moving to the University of Connecticut School of Medicine to rebuild its cancer program into a multidisciplinary, comprehensive cancer center. During this time, there were many advances in ovarian cancer. Patients began living with the “chronic” disease of ovarian cancer—living for years on chemotherapy. I remember one patient who was diagnosed with ovarian cancer at the time of her cesarean section. This patient is still alive with the disease, intermittently on chemotherapy—and her “baby” is now getting ready for college.

Over my career, I have seen progress in ovarian cancer but few long-term cures. The cure is elusive, but we work on understanding the disease and developing more effective therapies. My first patient with ovarian cancer would most likely have lived a very different life if she had been diagnosed today.

My journey as a patient was not yet over. One weekend night, I found myself short of breath, wheezing, and coughing. I was sure I had very bad bronchitis and just needed antibiotics. I went to the emergency room and again entered the world of the patient. A nurse took my pulse and vital signs and immediately moved me to a monitored bed. Everyone around me looked much too serious—not at all what I had anticipated for bronchitis.

Finally, the radiologist, a friend of mine, came to my bed and said my chest x-ray looked bad. My first thoughts were that my cancer had recurred and that I had continued on page 100

XOFIGO® IS INDICATED for the treatment of patients with castration-resistant prostate cancer (CRPC), symptomatic bone metastases and no known visceral metastatic disease.1

Give your patient’s standard EARLIEST ONSET OF SYMPTOMSa

30%

BEST STANDARD OF CARE

• In ALSYMPCA, best standard of care was defined as local EBRT, treatment with glucocorticoids, ketoconazole, or antihormonal agents2 • Xofigo is not recommended in combination with chemotherapy1

REDUCED RISK OF DEATH vs PLACEBO PLUS BEST STANDARD OF CARE1

START NOW

WITH 6 INJECTIONS OF

EBRT=external beam radiation therapy; OTC=over-the-counter.

Not an actual doctor. Model used for illustrative purposes only. a

In the ALSYMPCA trial, symptomatic was defined as regular analgesic use, including OTC, or use of EBRT to treat bone pain.

Important Safety Information • Contraindications: Xofigo is contraindicated in women who are or may become pregnant. Xofigo can cause fetal harm when administered to a pregnant woman

neutropenia, pancytopenia, and leukopenia—has been reported in patients treated with Xofigo.

Monitor patients with evidence of compromised bone • Bone Marrow Suppression: In the randomized trial, marrow reserve closely and provide supportive care 2% of patients in the Xofigo arm experienced bone measures when clinically indicated. Discontinue Xofigo marrow failure or ongoing pancytopenia, compared to in patients who experience life-threatening complications no patients treated with placebo. There were two deaths despite supportive care for bone marrow failure due to bone marrow failure. For 7 of 13 patients treated • Hematological Evaluation: Monitor blood counts at with Xofigo bone marrow failure was ongoing at the time baseline and prior to every dose of Xofigo. Prior to first of death. Among the 13 patients who experienced bone administering Xofigo, the absolute neutrophil count (ANC) marrow failure, 54% required blood transfusions. Four should be ≥1.5 × 109/L, the platelet count ≥100 × 109/L, percent (4%) of patients in the Xofigo arm and 2% in and hemoglobin ≥10 g/dL. Prior to subsequent the placebo arm permanently discontinued therapy due administrations, the ANC should be ≥1 × 109/L and to bone marrow suppression. In the randomized trial, the platelet count ≥50 × 109/L. Discontinue Xofigo if deaths related to vascular hemorrhage in association hematologic values do not recover within 6 to 8 weeks with myelosuppression were observed in 1% of Xofigoafter the last administration despite receiving treated patients compared to 0.3% of patients treated with supportive care placebo. The incidence of infection-related deaths (2%), • Concomitant Use With Chemotherapy: Safety and efficacy serious infections (10%), and febrile neutropenia (<1%) of concomitant chemotherapy with Xofigo have not been was similar for patients treated with Xofigo and placebo. established. Outside of a clinical trial, concomitant use Myelosuppression—notably thrombocytopenia,

© 2014 Bayer HealthCare Pharmaceuticals Inc. BAYER, the Bayer Cross, and Xofigo are registered trademarks of Bayer.

PP-600-US-0474

09/14

Printed in USA

of care a survival boost

1

Median Overall Survival (OS) Was Extended1b 100

Xofigoc (n=614) Placeboc (n=307)

Probability of survival (%)

90

HR=0.695 (95% CI: 0.581-0.832)

80

Xofigo median OS: 14.9 months (95% CI: 13.9-16.1)

70 60

THE XOFIGO BOOST

3.6 month increase in

50 40

median overall survival1

Placebo median OS: 11.3 months (95% CI: 10.4-12.8)

30 20 10 0

0

Xofigo 614 Placebo 307

3

6

9

12

15

18

21

24

27

30

33

36

39

578 288

504 228

369 157

277 104

178 67

105 39

60 24

41 14

18 7

7 4

1 2

0 1

0 0

Time (months)

An exploratory updated overall survival analysis was performed before patient crossover, incorporating an additional 214 events, resulting in findings consistent with the interim analysis.1 c Plus best standard of care.1

• In a prespecified interim analysis, median overall survival was 14.0 months for Xofigo (95% CI: 12.1-15.8) vs 11.2 months for placebo (95% CI: 9.0-13.2)1 — P=0.00185; 95% CI: 0.552-0.875; HR=0.6951

b

of Xofigo in patients on chemotherapy is not recommended due to the potential for additive myelosuppression. If chemotherapy, other systemic radioisotopes, or hemibody external radiotherapy are administered during the treatment period, Xofigo should be discontinued • Administration and Radiation Protection: Xofigo should be received, used, and administered only by authorized persons in designated clinical settings. The administration of Xofigo is associated with potential risks to other persons from radiation or contamination from spills of bodily fluids such as urine, feces, or vomit. Therefore, radiation protection precautions must be taken in accordance with national and local regulations • Adverse Reactions: The most common adverse reactions (≥10%) in the Xofigo arm vs the placebo arm, respectively, were nausea (36% vs 35%), diarrhea (25% vs 15%), vomiting (19% vs 14%), and peripheral edema (13% vs 10%).

Grade 3 and 4 adverse events were reported in 57% of Xofigo-treated patients and 63% of placebo-treated

patients. The most common hematologic laboratory abnormalities in the Xofigo arm (≥10%) vs the placebo arm, respectively, were anemia (93% vs 88%), lymphocytopenia (72% vs 53%), leukopenia (35% vs 10%), thrombocytopenia (31% vs 22%), and neutropenia (18% vs 5%) References: 1. Xofigo® (radium Ra 223 dichloride) injection [prescribing information]. Wayne, NJ: Bayer HealthCare Pharmaceuticals Inc.; May 2013. 2. Parker C, Nilsson S, Heinrich D, et al. Alpha emitter radium-223 and survival in metastatic prostate cancer. N Engl J Med. 2013;369(3):213-223.

Please see following pages for brief summary of full Prescribing Information.

To learn more, visit www.xofigo-us.com

Xofigo (radium Ra 223 dichloride) Injection, for intravenous use Initial U.S. Approval: 2013 BRIEF SUMMARY OF PRESCRIBING INFORMATION CONSULT PACKAGE INSERT FOR FULL PRESCRIBING INFORMATION

6 ADVERSE REACTIONS The following serious adverse reactions are discussed in greater detail in another section of the label: s¬¬"ONE¬-ARROW¬3UPPRESSION¬[see Warnings and Precautions (5.1)]

6.1 Clinical Trials Experience 1 INDICATIONS AND USAGE Because clinical trials are conducted under widely varying conditions, adverse reaction rates Xofigo™ is indicated for the treatment of patients with castration-resistant prostate cancer, observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of symptomatic bone metastases and no known visceral metastatic disease. another drug and may not reflect the rates observed in practice.

In the randomized clinical trial in patients with metastatic castration-resistant prostate cancer with 2 DOSAGE AND ADMINISTRATION bone metastases, 600 patients received intravenous injections of 50 kBq/kg (1.35 microcurie/kg) 2.3 Instructions for Use/Handling of Xofigo and best standard of care and 301 patients received placebo and best standard of care General warning once every 4 weeks for up to 6 injections. Prior to randomization, 58% and 57% of patients had Xofigo (an alpha particle-emitting pharmaceutical) should be received, used and administered received docetaxel in the Xofigo and placebo arms, respectively. The median duration of treatment only by authorized persons in designated clinical settings. The receipt, storage, use, transfer and was 20 weeks (6 cycles) for Xofigo and 18 weeks (5 cycles) for placebo. disposal Xofigo are subject to the regulations and/or appropriate licenses of the competent official The most common adverse reactions (≥ 10%) in patients receiving Xofigo were nausea, diarrhea, organization. vomiting, and peripheral edema (Table 3). Grade 3 and 4 adverse events were reported among 57% Xofigo should be handled by the user in a manner which satisfies both radiation safety and of Xofigo-treated patients and 63% of placebo-treated patients. The most common hematologic pharmaceutical quality requirements. Appropriate aseptic precautions should be taken. laboratory abnormalities in Xofigo-treated patients (≥ 10%) were anemia, lymphocytopenia, leukopenia, thrombocytopenia, and neutropenia (Table 4).

Radiation protection The administration of Xofigo is associated with potential risks to other persons (e.g., medical staff, Treatment discontinuations due to adverse events occurred in 17% of patients who received caregivers and patient’s household members) from radiation or contamination from spills of bodily Xofigo and 21% of patients who received placebo. The most common hematologic laboratory fluids such as urine, feces, or vomit. Therefore, radiation protection precautions must be taken in abnormalities leading to discontinuation for Xofigo were anemia (2%) and thrombocytopenia (2%). accordance with national and local regulations.

Table 3 shows adverse reactions occurring in ≥ 2% of patients and for which the incidence for For drug handling Follow the normal working procedures for the handling of radiopharmaceuticals and use universal Xofigo exceeds the incidence for placebo. precautions for handling and administration such as gloves and barrier gowns when handling Table 3: Adverse Reactions in the Randomized Trial blood and bodily fluids to avoid contamination. In case of contact with skin or eyes, the affected System/Organ Class Xofigo (n=600) Placebo (n=301) area should be flushed immediately with water. In the event of spillage of Xofigo, the local radiation Preferred Term Grades 1-4 Grades 3-4 Grades 1-4 Grades 3-4 safety officer should be contacted immediately to initiate the necessary measurements and required % % % % procedures to decontaminate the area. A complexing agent such as 0.01 M ethylene-diamineBlood and lymphatic system disorders tetraacetic acid (EDTA) solution is recommended to remove contamination.

Pancytopenia 2 1 0 0 For patient care Whenever possible, patients should use a toilet and the toilet should be flushed several times Gastrointestinal disorders after each use. When handling bodily fluids, simply wearing gloves and hand washing will protect Nausea 36 2 35 2 caregivers. Clothing soiled with Xofigo or patient fecal matter or urine should be washed promptly Diarrhea 25 2 15 2 and separately from other clothing.

19 2 14 2 Radium-223 is primarily an alpha emitter, with a 95.3% fraction of energy emitted as alpha-particles. Vomiting The fraction emitted as beta-particles is 3.6%, and the fraction emitted as gamma-radiation is 1.1%. General disorders and administration site conditions The external radiation exposure associated with handling of patient doses is expected to be low, Peripheral edema 13 2 10 1 because the typical treatment activity will be below 8,000 kBq (216 microcurie). In keeping with the As Low As Reasonably Achievable (ALARA) principle for minimization of radiation exposure, it is Renal and urinary disorders recommended to minimize the time spent in radiation areas, to maximize the distance to radiation Renal failure and impairment 3 1 1 1 sources, and to use adequate shielding. Any unused product or materials used in connection with Laboratory Abnormalities the preparation or administration are to be treated as radioactive waste and should be disposed of Table 4 shows hematologic laboratory abnormalities occurring in > 10% of patients and for which in accordance with local regulations. the incidence for Xofigo exceeds the incidence for placebo.

The gamma radiation associated with the decay of radium-223 and its daughters allows for the radioactivity measurement of Xofigo and the detection of contamination with standard instruments. Table 4: Hematologic Laboratory Abnormalities 4 CONTRAINDICATIONS Xofigo is contraindicated in pregnancy.

Xofigo can cause fetal harm when administered to a pregnant woman based on its mechanism of action. Xofigo is not indicated for use in women. Xofigo is contraindicated in women who are or may become pregnant. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, apprise the patient of the potential hazard to the fetus [see Use in Specific Populations (8.1)].

5 WARNINGS AND PRECAUTIONS 5.1 Bone Marrow Suppression In the randomized trial, 2% of patients on the Xofigo arm experienced bone marrow failure or ongoing pancytopenia compared to no patients treated with placebo. There were two deaths due to bone marrow failure and for 7 of 13 patients treated with Xofigo, bone marrow failure was ongoing at the time of death. Among the 13 patients who experienced bone marrow failure, 54% required blood transfusions. Four percent (4%) of patients on the Xofigo arm and 2% on the placebo arm permanently discontinued therapy due to bone marrow suppression.

In the randomized trial, deaths related to vascular hemorrhage in association with myelosuppression were observed in 1% of Xofigo-treated patients compared to 0.3% of patients treated with placebo.

The incidence of infection-related deaths (2%), serious infections (10%), and febrile neutropenia (<1%) were similar for patients treated with Xofigo and placebo. Myelosuppression; notably thrombocytopenia, neutropenia, pancytopenia, and leukopenia; has been reported in patients treated with Xofigo. In the randomized trial, complete blood counts (CBCs) were obtained every 4 weeks prior to each dose and the nadir CBCs and times of recovery were not well characterized.

In a separate single-dose phase 1 study of Xofigo, neutrophil and platelet count nadirs occurred 2 to 3 weeks after Xofigo administration at doses that were up to 1 to 5 times the recommended dose, and most patients recovered approximately 6 to 8 weeks after administration [see Adverse Reactions (6)].

Hematologic evaluation of patients must be performed at baseline and prior to every dose of Xofigo. Before the first administration of Xofigo, the absolute neutrophil count (ANC) should be ≥ 1.5 x 109/L, the platelet count ≥ 100 x 109/L and hemoglobin ≥ 10 g/dL. Before subsequent administrations of Xofigo, the ANC should be ≥ 1 x 109/L and the platelet count ≥ 50 x 109/L. If there is no recovery to these values within 6 to 8 weeks after the last administration of Xofigo, despite receiving supportive care, further treatment with Xofigo should be discontinued. Patients with evidence of compromised bone marrow reserve should be monitored closely and provided with supportive care measures when clinically indicated. Discontinue Xofigo in patients who experience life-threatening complications despite supportive care for bone marrow failure.

The safety and efficacy of concomitant chemotherapy with Xofigo have not been established. Outside of a clinical trial, concomitant use with chemotherapy is not recommended due to the potential for additive myelosuppression. If chemotherapy, other systemic radioisotopes or hemibody external radiotherapy are administered during the treatment period, Xofigo should be discontinued.

Hematologic Laboratory Abnormalities

Xofigo (n=600) Placebo (n=301) Grades 1-4 Grades 3-4 Grades 1-4 Grades 3-4 % % % % Anemia 93 6 88 6 Lymphocytopenia 72 20 53 7 Leukopenia 35 3 10 <1 Thrombocytopenia 31 3 22 <1 Neutropenia 18 2 5 <1 Laboratory values were obtained at baseline and prior to each 4-week cycle.

As an adverse reaction, grade 3-4 thrombocytopenia was reported in 6% of patients on Xofigo and in 2% of patients on placebo. Among patients who received Xofigo, the laboratory abnormality grade 3-4 thrombocytopenia occurred in 1% of docetaxel naïve patients and in 4% of patients who had received prior docetaxel. Grade 3-4 neutropenia occurred in 1% of docetaxel naïve patients and in 3% of patients who have received prior docetaxel.

Fluid Status Dehydration occurred in 3% of patients on Xofigo and 1% of patients on placebo. Xofigo increases adverse reactions such as diarrhea, nausea, and vomiting which may result in dehydration. Monitor patients’ oral intake and fluid status carefully and promptly treat patients who display signs or symptoms of dehydration or hypovolemia.

Injection Site Reactions Erythema, pain, and edema at the injection site were reported in 1% of patients on Xofigo.

Secondary Malignant Neoplasms Xofigo contributes to a patient’s overall long-term cumulative radiation exposure. Long-term cumulative radiation exposure may be associated with an increased risk of cancer and hereditary defects. Due to its mechanism of action and neoplastic changes, including osteosarcomas, in rats following administration of radium-223 dichloride, Xofigo may increase the risk of osteosarcoma or other secondary malignant neoplasms [see Nonclinical Toxicology (13.1)].

However, the overall incidence of new malignancies in the randomized trial was lower on the Xofigo arm compared to placebo (<1% vs. 2%; respectively), but the expected latency period for the development of secondary malignancies exceeds the duration of follow up for patients on the trial.

Subsequent Treatment with Cytotoxic Chemotherapy In the randomized clinical trial, 16% patients in the Xofigo group and 18% patients in the placebo group received cytotoxic chemotherapy after completion of study treatments. Adequate safety monitoring and laboratory testing was not performed to assess how patients treated with Xofigo will tolerate subsequent cytotoxic chemotherapy.

7 DRUG INTERACTIONS No formal clinical drug interaction studies have been performed.

3UBGROUPÂŹ ANALYSESÂŹ INDICATEDÂŹ THATÂŹ THEÂŹ CONCURRENTÂŹ USEÂŹ OFÂŹ BISPHOSPHONATESÂŹ ORÂŹ CALCIUMÂŹ CHANNELÂŹ blockers did not affect the safety and efďŹ cacy of XoďŹ go in the randomized clinical trial.

8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Category X [see Contraindications (4)] XoďŹ go can cause fetal harm when administered to a pregnant woman based on its mechanism of action. While there are no human or animal data on the use of XoďŹ go in pregnancy and XoďŹ go is not indicated for use in women, maternal use of a radioactive therapeutic agent could affect development of a fetus. XoďŹ go is contraindicated in women who are or may become pregnant while receiving the drug. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, apprise the patient of the potential hazard to the fetus and the potential risk for pregnancy loss. Advise females of reproductive potential to avoid becoming pregnant during treatment with XoďŹ go.

8.3 Nursing Mothers XoďŹ go is not indicated for use in women. It is not known whether radium-223 dichloride is excreted in human milk. Because many drugs are excreted in human milk, and because of potential for serious adverse reactions in nursing infants from XoďŹ go, a decision should be made whether to discontinue nursing, or discontinue the drug taking into account the importance of the drug to the mother.

8.4 Pediatric Use The safety and efďŹ cacy of XoďŹ go in pediatric patients have not been established.

In single- and repeat-dose toxicity studies in rats, ďŹ ndings in the bones (depletion of osteocytes, osteoblasts, osteoclasts, ďŹ bro-osseous lesions, disruption/disorganization of the physis/growth line) and teeth (missing, irregular growth, ďŹ bro-osseous lesions in bone socket) correlated with a reduction of osteogenesis that occurred at clinically relevant doses beginning in the range of 20 â&#x20AC;&#x201C; 80 kBq (0.541 - 2.16 microcurie) per kg body weight.

8.5 Geriatric Use Of the 600 patients treated with XoďŹ go in the randomized trial, 75% were 65 years of age and over and while 33% were 75 years of age and over. No dosage adjustment is considered necessary in elderly patients. No overall differences in safety or effectiveness were observed between these subjects and younger subjects, and other reported clinical experience has not identiďŹ ed differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out.

8.6 Patients with Hepatic Impairment .OÂŹ DEDICATEDÂŹ HEPATICÂŹ IMPAIRMENTÂŹ TRIALÂŹ FORÂŹ 8OlGOÂŹ HASÂŹ BEENÂŹ CONDUCTED ÂŹ 3INCEÂŹ RADIUM ÂŹ ISÂŹ neither metabolized by the liver nor eliminated via the bile, hepatic impairment is unlikely to affect the pharmacokinetics of radium-223 dichloride [see Clinical Pharmacology (12.3)]. Based on subgroup analyses in the randomized clinical trial, dose adjustment is not needed in patients with mild hepatic impairment. No dose adjustments can be recommended for patients with moderate or severe hepatic impairment due to lack of clinical data.

8.7 Patients with Renal Impairment No dedicated renal impairment trial for XoďŹ go has been conducted. Based on subgroup analyses in the randomized clinical trial, dose adjustment is not needed in patients with existing mild (creatinine clearance [CrCl] 60 to 89 mL/min) or moderate (CrCl 30 to 59 mL/min) renal impairment. No dose adjustment can be recommended for patients with severe renal impairment (CrCl less than 30 mL/ min) due to limited data available (n = 2) [see Clinical Pharmacology (12.3)].

8.8 Males of Reproductive Potential Contraception Because of potential effects on spermatogenesis associated with radiation, advise men who are sexually active to use condoms and their female partners of reproductive potential to use a highly effective contraceptive method during and for 6 months after completing treatment with XoďŹ go.

Infertility There are no data on the effects of XoďŹ go on human fertility. There is a potential risk that radiation

by XoďŹ go could impair human fertility [see Nonclinical Toxicology (13.1)].

10 OVERDOSAGE There have been no reports of inadvertent overdosing of XoďŹ go during clinical studies.

There is no speciďŹ c antidote. In the event of an inadvertent overdose of XoďŹ go, utilize general supportive measures, including monitoring for potential hematological and gastrointestinal toxicity, and consider using medical countermeasures such as aluminum hydroxide, barium sulfate, calcium carbonate, calcium gluconate, calcium phosphate, or sodium alginate.1 3INGLEÂŹ8OlGOÂŹDOSESÂŹUPÂŹTOÂŹ ÂŹK"QÂŹ ÂŹMICROCURIE ÂŹPERÂŹKGÂŹBODYÂŹWEIGHTÂŹWEREÂŹEVALUATEDÂŹINÂŹAÂŹPHASEÂŹ 1 clinical trial and no dose-limiting toxicities were observed.

13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Animal studies have not been conducted to evaluate the carcinogenic potential of radium-223 dichloride. However, in repeat-dose toxicity studies in rats, osteosarcomas, a known effect of bone-seeking radionuclides, were observed at clinically relevant doses 7 to 12 months after the start of treatment. The presence of other neoplastic changes, including lymphoma and mammary gland carcinoma, was also reported in 12- to 15-month repeat-dose toxicity studies in rats.

Genetic toxicology studies have not been conducted with radium-223 dichloride. However, the mechanism of action of radium-223 dichloride involves induction of double-strand DNA breaks, which is a known effect of radiation.

Animal studies have not been conducted to evaluate the effects of radium-223 dichloride on male or female fertility or reproductive function. XoďŹ go may impair fertility and reproductive function in humans based on its mechanism of action.

17 PATIENT COUNSELING INFORMATION Advise patients: sÂŹ ÂŹ4OÂŹBEÂŹCOMPLIANTÂŹWITHÂŹBLOODÂŹCELLÂŹCOUNTÂŹMONITORINGÂŹAPPOINTMENTSÂŹWHILEÂŹRECEIVINGÂŹ8OlGO ÂŹ%XPLAINÂŹ the importance of routine blood cell counts. Instruct patients to report signs of bleeding or infections. sÂŹ ÂŹ4OÂŹSTAYÂŹWELLÂŹHYDRATEDÂŹANDÂŹTOÂŹMONITORÂŹORALÂŹINTAKE ÂŹmUIDÂŹSTATUS ÂŹANDÂŹURINEÂŹOUTPUTÂŹWHILEÂŹBEINGÂŹ treated with XoďŹ go. Instruct patients to report signs of dehydration, hypovolemia, urinary retention, or renal failure / insufďŹ ciency. sÂŹ ÂŹ4HEREÂŹ AREÂŹ NOÂŹ RESTRICTIONSÂŹ REGARDINGÂŹ CONTACTÂŹ WITHÂŹ OTHERÂŹ PEOPLEÂŹ AFTERÂŹ RECEIVINGÂŹ 8OlGO ÂŹ &OLLOWÂŹ good hygiene practices while receiving XoďŹ go and for at least 1 week after the last injection in order to minimize radiation exposure from bodily ďŹ&#x201A;uids to household members and caregivers.

Whenever possible, patients should use a toilet and the toilet should be ďŹ&#x201A;ushed several times after each use. Clothing soiled with patient fecal matter or urine should be washed promptly and separately from other clothing. Caregivers should use universal precautions for patient care such as gloves and barrier gowns when handling bodily ďŹ&#x201A;uids to avoid contamination.

When handling bodily ďŹ&#x201A;uids, wearing gloves and hand washing will protect caregivers. sÂŹ ÂŹ7HOÂŹAREÂŹSEXUALLYÂŹACTIVEÂŹTOÂŹUSEÂŹCONDOMSÂŹANDÂŹTHEIRÂŹFEMALEÂŹPARTNERSÂŹOFÂŹREPRODUCTIVEÂŹPOTENTIALÂŹ to use a highly effective method of birth control during treatment and for 6 months following completion of XoďŹ go treatment.

Manufactured for:

Bayer HealthCare Pharmaceuticals Inc. Wayne, NJ 07470 Manufactured in Norway XoďŹ go is a trademark of Bayer Aktiengesellschaft. Š 2013, Bayer HealthCare Pharmaceuticals Inc. All rights reserved.

Revised: 05/2013 "3

The ASCO Post | DECEMBER 1, 2014

PAGE 100

Book Review

A Good Life, All the Way to the Very End

By Ronald Piana

M

ortality is the invisible observer in the oncology exam room.

When people hear the three words, “You have cancer,” they see their world as they knew it swiftly passing as they enter the other world of the sick. This human experience was strikingly described in the opening lines of Susan Sontag’s modern classic, Illness as a Metaphor: Illness is the night-side of life, a more onerous citizenship. Everyone who is born holds dual citizenship, in the kingdom of the sick. Although we all prefer to use only the good passport, sooner or later each of us is obliged, at least for a spell, to identify ourselves as citizens of that other place.

From Euripides to Sontag, authors have tried to come to understand and demystify illnesses, aging, and mortality.

Now, in his deeply affecting new book, Being Mortal, internationally regarded author Atul Gawande, MD, MPH, examines the limitations and missteps in our health-care culture within the inescapable realities of aging and death. During this intense medical literary journey, the reader is introduced to people who know how to have the hard conversations about being mortal, which is one of many reasons this is a valuable book for readers of The ASCO Post.

aging or frailty or dying. How the process unfolds, how people experience the end of their lives, and how it affects those around them seemed beside the point.”

Further on, Dr. Gawande makes another important observation, one that he will explore throughout the narrative.

“Modern scientific capability has profoundly altered the course of human life … but scientific advances have turned the process of aging and dying into medical experiences, matters to be managed by health-care professionals. And in the medical world, we have proved alarmingly unprepared for it.”

That is a serious charge, one that he qualifies within a few pages. “This is a book about mortality—about what it’s like to be creatures who age and die.…

I find that neither I nor my patients find our current medical state tolerable. But I have also found it unclear what the answers should be, or even whether any adequate ones are possible.”

Over the past couple of decades, the oncology community has been addressing the

Carolyn D. Runowicz, MD continued from page 95

lung metastases. He said, “No, it’s worse.”

What is worse than recurrent breast cancer? Then I learned that I had a cardiomyopathy and was in congestive heart failure. The medical team admitted me to the cardiac unit and began treatment that night. I spent the next 2 weeks in that unit.

I went home; it was the middle of a cold and snowy winter. I was not able to

Title: Being Mortal Author: Atul Gawande, MD Publisher: Metropolitan Books Publication date: October 7, 2014 Price: $26.00; hardcover, 304 pages

state of end-of-life care that Dr. Gawande finds intolerable. For one, the integration of palliative care into best practices along with state-of-the-art psychosocial services has greatly enhanced the quality of care for our patients with advanced cancer. Leaders in the oncology community acknowledge that there is much work ahead in this difficult clinical setting, but the growing quality-of-life data are proof of the advances that have been made.

to examine various scenarios surrounding mortality. Readers looking for health-care policy discussions about cost-effective end-of-life care won’t find them here. But they won’t be disappointed, either.

Dr. Gawande briefly delves into the debate about “rationing” medical care and the costs of end-of-life care in today’s cost-constrained environ-

ment, but those details are lost within his larger musings on our society that he feels—and rightly so—is decidedly ageist and unwilling to confront the realities of mortality.

Dr. Gawande contrasts and compares the way we age and die in different societies, using the experiences of his grandfather, who emigrated from India, and his college girlfriend’s aged grandmother, Alice. He makes some interesting points about cultural differences and how we look at the elderly. He writes, “My father’s father had the kind of traditional old age that, from a Western perspective, seems idyllic.… [W]hen we ate, we served him first. When young people came into his home, they bowed and touched his feet in supplication.…

[I]n America, he would almost certainly have been placed in a nursing home.”

Dr. Gawande’s criticism of our rush to institutionalize our elderly has some merit, but his grandfather was a robust man until he died, falling off a bus at the age of 100, and he didn’t fit the stereotype Dr. Gawande was looking to make his point. He married his

return to work for nearly 4 months while the medications worked on restoring my cardiac function. I was lucky: it came back to almost normal. I take my eight pills a day. I’m back to working and taking care of patients. Taking care of my patients was very important for me to feel that I was truly recovered.

sociate dean in a new medical school.

My doctors gave me the medical clearance, and I was off to warmer climes and new challenges.

Although my new position is mostly administrative, it is important for me to see patients at least part-time. I enjoy taking care of them as they embark on their cancer journey. I hope to lighten their burdens.

Training the next generation of physicians is exciting and rewarding.

They are excited about the future that awaits them. Once again, I think back to my summer in medical school and the ovarian cancer patient I met. What lies ahead for these students is likely to be far more exciting, with technologic advances beyond our imagination. My hope is that one day, we will think of cancer like we do polio—a historical footnote in medicine.

Just imagine a world without cancer! n

Being Mortal is as much about the broader cultural issue regarding aging and death as it is about how our medical system deals with mortality. The book consists of eight chapters that use anecdotes from Dr. Gawande’s personal and professional life

This is a book about mortality—about what it’s like to be creatures who age and die.… I find that neither I nor my patients find our current medical state tolerable. But I have also found it unclear what the answers should be, or even whether any adequate ones are possible.

—Atul Gawande, MD, MPH

Key Narrative Thread The first few lines of Being Mortal’s introduction speak to one of the disappointments in current medical school curricula, an issue that parallels ongoing discussions in the oncology community over best practices in end-of-life care. Dr. Gawande writes, “I learned a lot of things in medical school, but mortality wasn’t one of them. Although I was given a dry, leathery corpse to dissect my first term, that was solely a way to learn about human anatomy. Our textbooks had almost nothing on

Bookmark

Looking Toward a Bright Future About this same time, I was offered a new and challenging position as an as-

Cultural Observations

ASCOPost.com | DECEMBER 1, 2014

PAGE 101

Book Review

college girlfriend, and we follow her grandmother, Alice, who by her mid80s had dementia and multiple comorbidities, leaving her helplessly frail and vulnerable. She was indeed put into a less-than-optimum nursing home.

We live in an aging society, and many cash-strapped American working families are simply not equipped to handle the difficult care issues of elderly parents and grandparents who are very sick. Writing about Alice’s nursing home experience, Dr. Gawande comments, “All privacy was gone. She was put into hospital clothes most of the time. She woke when they told her. She lived with whomever they said she had to.… [S]he felt incarcerated, like she was in prison for being old.”

Dr. Gawande then cites the sociologist Erving Goffman, who noted the likeness between prisons and nursing

homes a half a century ago in his book Asylums. Some of this is difficult reading because we know the vast disparities of medical care that exist between the haves and have-nots in our society, and some nursing homes are indeed depressing and lonely “prisons.”

But placing a loved one in a nursing home is a heartbreaking experience, and Dr. Gawande is at times a bit hard in his judgments. That said, once he gets rolling into more inspiring territory, the book sails along as he follows a hospice nurse on her rounds, a geriatrician in his clinic, and reformers who want to radically change the nursing home model.

Provocative Vignettes This book was never intended to be a blueprint for policymakers who want to fix broken parts of our health-care system. The power of Being Mortal lies

in the writing and story-telling gifts of Dr. Gawande, as he offers provocative vignettes that drill to the marrow of the human mortality experience.

His candor is also refreshing, as he recounts some of his own misguided prejudices about the healthcare system. “Like many people, I had believed that hospice care hastens death, because patients forgo hospital treatments and are allowed high-dose narcotics to combat pain.

But multiple studies show otherwise.” The oncology community has long known that earlier initiation of hospice creates better patient and family outcomes.

Being Mortal’s sections on the cancer death journey, exacting and well drawn, will be valuable for the readers of The ASCO Post. “My father was in his early seventies when I was forced to realize that he might not be immortal,” writes

Dr. Gawande, as he introduces some of the book’s most instructive and moving scenes.

His beloved father, a well-known urologist of uncanny vigor, is diagnosed with a spinal cord tumor. After several years of heroic struggling that included surgery and chemotherapy, father and son had the difficult conversation about his prognosis. In the end, after a shared decision-making discussion with his son, Dr. Gawande’s father chose not to have more treatments with their debilitating side effects. He was ready to face his mortality.

“We went to his bedside. My mother took his hand. And we listened, each of us silent.… [N]o more breaths came.” So ends this powerful and endearing book about human mortality, something we all share. Being Mortal is a must-read, especially for medical students. n

O Physician, MY Physician

By Parvez Dara, MD FACP Where Art thou O Physician With comforting smiles Soft touching hands Your words that soothe And eyes that sympathize What happened O Physician With transforming skills A frown is affixed The hands barely touch Your words are hurried And eyes barely size Like a peach O Physician Once with intricate fuzz And heavenly sweetness Now the texture all gone The surface all bland You seem empty inside Dr. Dara is an oncologist practicing in Toms River, New Jersey.

The student O Physician With wide opened eyes Filled with human tenderness Now dons the cap Marketing his promotions All emotions aside

It is time O Physician To gather your love For all you hold dear Before your vessel hardens The change gains permanence And you lose all pride

Where once O Physician Sleep turned to winks And concern filled the space Now emptiness games The hardened shelled domain And yawns the great divide

You are remembered O Physician For the Hands you hold For the touch to console For the joy you share Think hard, the journey And don’t let your pride slide

From thought O Physician Where purpose once dwelt And concern crafted desire Now time is the enemy And productivity reigns With anemic emotions implied

O Physician My Physician Let me see within you The love you hold To nurture and care The desire to heal Before both our souls are buried in cries

Visit The ASCO Post website at ASCOPost.com

The ASCO Post | DECEMBER 1, 2014

PAGE 102

Announcements

ASTRO Commends Medicare’s Proposed Decision to Cover Annual Low-Dose CT Screening for High-Risk Lung Cancer Patients Aged 55–74

T

he American Society for Radiation Oncology (ASTRO) praised the November 11, 2014, decision proposal by the Centers for Medicare and Medicaid Services (CMS) to provide coverage for annual lung cancer screening via low-dose computed tomography (CT) screening for those at highest-risk for lung cancer.

According to ASTRO, the Proposed Decision Memo for Screening for Lung Cancer with Low Dose Computed Tomography confirms that there is sufficient evidence to warrant annual lung cancer screening for patients most at-risk for developing lung cancer. The Memo details the patient

for both men and women in the United States, causing the death of more than 160,000 people each year, surpassing the number of deaths from breast, colon and prostate cancers combined. Data

also indicate that nearly 60% of all new lung cancer diagnoses are among those who have never smoked or who have already quit smoking. With this highly effective, annual screening in place, we

will be able to diagnose patients earlier when treatment can be most successful, which will save thousands of lives.”

CMS’s decision follows the United States Preventive Task Force’s Decem-

ASTRO is pleased that CMS has weighed the evidence and decided in favor of annual screening for patients at highest risk for lung cancer, potentially reducing their lung cancer mortality by nearly 20%.

—Bruce G. Haffty, MD

criteria for eligibility as follows: aged 55 to 74, asymptomatic, a smoking history of at least 30 pack-years, a current smoker or someone who has quit smoking within the last 15 years. CMS is accepting comments on the rule until December 10, 2014, and an effective date is expected in the final coverage decision.

Could Save Thousands of Lives “ASTRO is pleased that CMS has weighed the evidence and decided in favor of annual screening for patients at highest risk for lung cancer, potentially reducing their lung cancer mortality by nearly 20%,” said ASTRO Chair Bruce G. Haffty, MD, FASTRO. “Lung cancer is the leading cause of cancer death

© 2014 Genentech USA, Inc. All rights reserved. COB/092414/0002 Printed in USA.

ASCOPost.com | DECEMBER 1, 2014

PAGE 103

Announcements

ber 2013 recommendation that lowdose CT is a Grade B screening, and which reviewed the results of four randomized clinical trials, including the National Cancer Institute’s National Lung Screening Trial. That study included more than 50,000 asymptomatic adults aged 55 to 75 who had at least a 30 pack-year history and found a 16%

reduction in lung cancer mortality for those who received annual screening and thus, earlier treatment.

ASTRO’s membership includes nearly 11,000 physicians, nurses, biologists, physicists, radiation therapists, dosimetrists and other health-care professionals who specialize in treating patients with radiation therapies. n

The ASCO Post Wants to Hear From You

We encourage readers to share their opinions and thoughts on issues of interest to the oncology community.

Write to The ASCO Post at editor@ASCOPost.com

Contact

The ASCO Post

IN METASTATIC MELANOMA, HAVE WE

MAXIMIZED THE POTENTIAL OF TARGETING THE MAPK PATHWAY?

Editorial Correspondence James O. Armitage, MD Editor-in-Chief e-mail: Editor@ASCOPost.com Cara H. Glynn Director of Editorial e-mail: Cara@harborsidepress.com Phone: 631.935.7654 Andrew Nash Assoc. Director of Editorial e-mail: Andrew@harborsidepress.com Phone: 631.935.7657

Rights & Permissions e-mail: Permissions@harborsidepress.com

Research has found that abnormal MAPK signaling may lead to increased or uncontrolled cell proliferation and resistance to apoptosis.1 Overactivation of MAPK signaling has been implicated as a key driver of metastatic melanoma.2 Based on these findings, Genentech is investigating further ways to target the MAPK pathway.

Learn more at TargetMAPK.com.

Advertising

Rates, reprints, or supplements Leslie Dubin e-mail: Leslie@harborsidepress.com Phone: 631.935.7660

Editorial Office Harborside Press 37 Main Street Cold Spring Harbor, NY 11724 Phone: 631.692.0800 Fax: 631.692.0805 ASCOPost.com HarborsidePress.com

REFERENCES: 1. Santarpia L, Lippman SM, El-Naggar AK. Targeting the MAPK-RAS-RAF signaling pathway in cancer therapy. Expert Opin Ther Targets. 2012;16:103-119. 2. Wang AX, Qi XY. Targeting RAS/RAF/MEK/ERK signaling in metastatic melanoma. IUBMB Life. 2013;65:748-758.

The ASCO Post | DECEMBER 1, 2014

PAGE 104

2014-2015 Oncology Meetings

2014-2015

December

January 2015

February

Society of Urologic Oncology 15th Annual Meeting December 3-5 • Bethesda, Maryland For more information: http://suonet. org/meetings/2014/default.aspx

Melanoma 2015: 25th Annual Cutaneous Malignancy Update January 10-11 • San Diego, California For more information: www.scripps.org/events/melanomaannual-cutaneous-malignancyupdate-january-10-2015

26th International Congress on Anti-Cancer Treatment February 3-5 • Paris, France For more information: http://www.icact.fr

UICC World Cancer Congress December 3-6 • Melbourne, Australia For more information: www.worldcancercongress.org 1st Rome International Meeting on Geriatric Oncology December 4-5 • Rome, Italy For more information: www.rimog.com Advances in Cancer Immunotherapy™ December 5 • Tampa, Florida For more information: www.sitcancer.org/sitc-meetings/ aci2014/fl 24th World Congress of the International Association of Surgeons, Gastroenterologists and Oncologists December 5-7 • Vienna, Austria For more information: iasgo2014.org ASH Annual Meeting and Exposition December 6-9 • San Francisco, California For more information: hematology.org

7th Breast Gynecological International Cancer Conference January 15-16 • Cairo, Egypt For more information: www.bgicc.eg.net/Home.aspx Gastrointestinal Cancers Symposium January 15-17 • San Francisco, California For more information: www.gicasym.org 13th Oncology Update: Advances and Controversies January 16-19 • Steamboat Springs, Colorado For more information: www.mdanderson.org 11th Annual Clinical Breakthroughs and Challenges in Hematologic Malignancies January 17 • Lake Buena Vista, Florida For more information: http://moffitt.org/for-physicianshealthcare-professionals/ conferences/conferences The Society of Thoracic Surgeons 51st Annual Meeting January 24-28 • San Diego, California For more information: www.sts.org/education-meetings/ educational-meetings-activities/ future-meetings

37th Annual San Antonio Breast Cancer Symposium December 9-13 • San Antonio, Texas For more information: www.sabcs.org Inaugural Venous Thromboembolism Symposium: Advances in the Treatment of VTE December 13 • Miami, Florida For more information: http://cme.baptisthealth.net/vte/ pages/index.aspx

7th Annual T-cell Lymphoma Forum January 29-31 • San Francisco, California For more information: www.tcellforum.com

Translation of the Cancer Genome February 7-9 • San Francisco, California For more information: www.aacr.org AACR-SNMMI Joint Conference: State-of-the-Art Molecular Imaging in Cancer Biology and Therapy February 11-14 • San Diego, California For more information: www.aacr.org 2015 BMT Tandem Meeting American Society for Blood and Marrow Transplantation February 11-15 • San Diego, California For more information: www.asbmt.org 5th International Conference on Innovative Approaches in Head & Neck Oncology February 12-14 • Nice, France For more information: www.estro.org/congressesmeetings/items/5th-ichno 15th Annual Targeted Therapies of The Treatment of Lung Cancer February 18-21 • Santa Monica, California For more information: www.iaslc.org/events/15th-annualtargeted-therapies-treatment-lungcancer The 17th Annual Symposium on Anti-Angiogenesis and Immune Therapies for Cancer: Recent Advances and Future Directions in Basic and Clinical Cancer Research February 19-21 • San Diego, California For more information: www.imedex.com/antiangiogenesis-and-immunetherapies/ Genitourinary Cancers Symposium February 26-28 • Orlando, Florida For more information: www.gucasym.org

6th Current Concepts in the Management of Thyroid and Parathyroid Neoplasms February 26-28 • Houston, Texas For more information: www.mdanderson.org 32nd Annual Miami Breast Cancer Conference® February 26-March 1 • Miami Beach, Florida For more information: www.gotoper.com/conferences/ mbcc/meetings/32nd-AnnualMiami-Breast-Cancer-Conference Society of Interventional Radiology February 28-March 5 • Atlanta, Georgia For more information: www.sirmeeting.org

March

13th International Congress on Targeted Anticancer Therapies March 2-4 • Paris, France For more information: www.tatcongress.org Tumor Angiogenesis and Vascular Normalization: Bench to Bedside to Biomarkers March 5-8 • Orlando, Florida For more information: www.aacr.org 16th European Congress: Perspectives in Lung Cancer March 6-7 • Torino, Italy For more information: www.imedex.com Advances in the Management of Multiple Myeloma March 6-7 • Saint Petersburg, Florida For more information: http://moffitt .org/for-physicians-healthcareprofessionals/conferences/ conferences

continued on page 112

indications

ignited we stand with

ABRAXANE is indicated for the treatment of breast cancer after failure of combination chemotherapy for metastatic disease or relapse within 6 months of adjuvant chemotherapy.

Prior therapy should have included an anthracycline unless clinically contraindicated.

ABRAXANE is indicated for the first-line treatment of locally advanced or metastatic non–small cell lung cancer (NSCLC), in combination with carboplatin, in patients who are not candidates for curative surgery or radiation therapy.

ABRAXANE is indicated for the first-line treatment of patients with metastatic adenocarcinoma of the pancreas (MPAC), in combination with gemcitabine.

Important Safety Information CONTRAINDICATIONS WARNING - NEUTROPENIA • Do not administer ABRAXANE therapy to patients who have baseline neutrophil counts of less than 1500 cells/mm3. In order to monitor the occurrence of bone marrow suppression, primarily neutropenia, which may be severe and result in infection, it is recommended that frequent peripheral blood cell counts be performed on all patients receiving ABRAXANE • Note: An albumin form of paclitaxel may substantially affect a drug’s functional properties relative to those of drug in solution. DO NOT SUBSTITUTE FOR OR WITH OTHER PACLITAXEL FORMULATIONS

Neutrophil Counts • ABRAXANE should not be used in patients who have baseline neutrophil counts of <1500 cells/mm3 Hypersensitivity • Patients who experience a severe hypersensitivity reaction to ABRAXANE should not be rechallenged with the drug WARNINGS AND PRECAUTIONS Hematologic Effects • Bone marrow suppression (primarily neutropenia) is dose-dependent and a dose-limiting toxicity of ABRAXANE. In clinical studies, Grade 3-4 neutropenia occurred in 34% of patients with metastatic breast cancer (MBC), 47% of patients with non–small cell lung cancer (NSCLC), and 38% of patients with pancreatic cancer

Please see additional Important Safety Information and Brief Summary for ABRAXANE, including Boxed WARNING, on following pages.

Important Safety Information WARNINGS AND PRECAUTIONS (cont’d) • Monitor for myelotoxicity by performing complete blood cell counts frequently, including prior to dosing on Day 1 (for MBC) and Days 1, 8, and 15 (for NSCLC and for pancreatic cancer) • Do not administer ABRAXANE to patients with baseline absolute neutrophil counts (ANC) of less than 1500 cells/mm3 • In the case of severe neutropenia (<500 cells/mm3 for 7 days or more) during a course of ABRAXANE therapy, reduce the dose of ABRAXANE in subsequent courses in patients with either MBC or NSCLC • In patients with MBC, resume treatment with every-3-week cycles of ABRAXANE after ANC recovers to a level >1500 cells/mm3 and platelets recover to a level >100,000 cells/mm3 • In patients with NSCLC, resume treatment if recommended at permanently reduced doses for both weekly ABRAXANE and every-3-week carboplatin after ANC recovers to at least 1500 cells/mm3 and platelet count of at least 100,000 cells/mm3 on Day 1 or to an ANC of at least 500 cells/mm3 and platelet count of at least 50,000 cells/mm3 on Days 8 or 15 of the cycle • In patients with adenocarcinoma of the pancreas, withhold ABRAXANE and gemcitabine if the ANC is less than 500 cells/mm3 or platelets are less than 50,000 cells/mm3 and delay initiation of the next cycle if the ANC is less than 1500 cells/mm3 or platelet count is less than 100,000 cells/mm3 on Day 1 of the cycle. Resume treatment with appropriate dose reduction if recommended Nervous System • Sensory neuropathy is dose- and schedule-dependent • The occurrence of Grade 1 or 2 sensory neuropathy does not generally require dose modification • If ≥ Grade 3 sensory neuropathy develops, withhold ABRAXANE treatment until resolution to Grade 1 or 2 for MBC or until resolution to ≤ Grade 1 for NSCLC and pancreatic cancer followed by a dose reduction for all subsequent courses of ABRAXANE Sepsis • Sepsis occurred in 5% of patients with or without neutropenia who received ABRAXANE in combination with gemcitabine • Biliary obstruction or presence of biliary stent were risk factors for severe or fatal sepsis • If a patient becomes febrile (regardless of ANC), initiate treatment with broad-spectrum antibiotics • For febrile neutropenia, interrupt ABRAXANE and gemcitabine until fever resolves and ANC ≥1500 cells/mm3, then resume treatment at reduced dose levels Pneumonitis • Pneumonitis, including some cases that were fatal, occurred in 4% of patients receiving ABRAXANE in combination with gemcitabine • Monitor patients for signs and symptoms and interrupt ABRAXANE and gemcitabine during evaluation of suspected pneumonitis • Permanently discontinue treatment with ABRAXANE and gemcitabine upon making a diagnosis of pneumonitis Hypersensitivity • Severe and sometimes fatal hypersensitivity reactions, including anaphylactic reactions, have been reported • Patients who experience a severe hypersensitivity reaction to ABRAXANE should not be rechallenged with this drug Hepatic Impairment • Because the exposure and toxicity of paclitaxel can be increased with hepatic impairment, administration of ABRAXANE in patients with hepatic impairment should be performed with caution • For MBC and NSCLC, the starting dose should be reduced for patients with moderate or severe hepatic impairment • For pancreatic adenocarcinoma, ABRAXANE is not recommended for patients with moderate or severe hepatic impairment Albumin (Human) • ABRAXANE contains albumin (human), a derivative of human blood Use in Pregnancy: Pregnancy Category D • ABRAXANE can cause fetal harm when administered to a pregnant woman • If this drug is used during pregnancy, or if the patient becomes pregnant while receiving this drug, the patient should be apprised of the potential hazard to the fetus

(cont’d)

• Women of childbearing potential should be advised to avoid becoming pregnant while receiving ABRAXANE Use in Men • Men should be advised not to father a child while receiving ABRAXANE ADVERSE REACTIONS Randomized Metastatic Breast Cancer (MBC) Study • The most common adverse reactions (≥20%) with singleagent use of ABRAXANE vs paclitaxel injection in the MBC study are alopecia (90%, 94%), neutropenia (all cases 80%, 82%; severe 9%, 22%), sensory neuropathy (any symptoms 71%, 56%; severe 10%, 2%), abnormal ECG (all patients 60%, 52%; patients with normal baseline 35%, 30%), fatigue/ asthenia (any 47%, 39%; severe 8%, 3%), myalgia/arthralgia (any 44%, 49%; severe 8%, 4%), AST elevation (any 39%, 32%), alkaline phosphatase elevation (any 36%, 31%), anemia (any 33%, 25%; severe 1%, <1%), nausea (any 30%, 22%; severe 3%, <1%), diarrhea (any 27%, 15%; severe <1%, 1%) and infections (24%, 20%), respectively • Sensory neuropathy was the cause of ABRAXANE discontinuation in 7/229 (3%) patients • Other adverse reactions of note with the use of ABRAXANE vs paclitaxel injection included vomiting (any 18%, 10%; severe 4%, 1%), fluid retention (any 10%, 8%; severe 0%, <1%), mucositis (any 7%, 6%; severe <1%, 0%), hepatic dysfunction (elevations in bilirubin 7%, 7%), hypersensitivity reactions (any 4%, 12%; severe 0%, 2%), thrombocytopenia (any 2%, 3%; severe <1%, <1%), neutropenic sepsis (<1%, <1%), and injection site reactions (<1%, 1%), respectively.

Dehydration and pyrexia were also reported • Renal dysfunction (any 11%, severe 1%) was reported in patients treated with ABRAXANE (n=229) • In all ABRAXANE-treated patients (n=366), ocular/visual disturbances were reported (any 13%; severe 1%) • Severe cardiovascular events possibly related to single-agent ABRAXANE occurred in approximately 3% of patients and included cardiac ischemia/infarction, chest pain, cardiac arrest, supraventricular tachycardia, edema, thrombosis, pulmonary thromboembolism, pulmonary emboli, and hypertension • Cases of cerebrovascular attacks (strokes) and transient ischemic attacks have been reported Please see next page for adverse events in the NSCLC study.

Pancreatic Adenocarcinoma Study • Among the most common (≥20%) adverse reactions in the phase III study, those with a ≥5% higher incidence in the ABRAXANE/gemcitabine group compared with the gemcitabine group are neutropenia (73%, 58%), fatigue (59%, 46%), peripheral neuropathy (54%, 13%), nausea (54%, 48%), alopecia (50%, 5%), peripheral edema (46%, 30%), diarrhea (44%, 24%), pyrexia (41%, 28%), vomiting (36%, 28%), decreased appetite (36%, 26%), rash (30%, 11%), and dehydration (21%, 11%) • Of these most common adverse reactions, those with a ≥2% higher incidence of Grade 3-4 toxicity in the ABRAXANE/ gemcitabine group compared with the gemcitabine group, respectively, are neutropenia (38%, 27%), fatigue (18%, 9%), peripheral neuropathy (17%, 1%), nausea (6%, 3%), diarrhea (6%, 1%), pyrexia (3%, 1%), vomiting (6%, 4%), decreased appetite (5%, 2%), and dehydration (7%, 2%) • Thrombocytopenia (all grades) was reported in 74% of patients in the ABRAXANE/gemcitabine group vs 70% of patients in the gemcitabine group • The most common serious adverse reactions of ABRAXANE (with a ≥1% higher incidence) are pyrexia (6%), dehydration (5%), pneumonia (4%), and vomiting (4%) • The most common adverse reactions resulting in permanent discontinuation of ABRAXANE were peripheral neuropathy (8%), fatigue (4%), and thrombocytopenia (2%) • The most common adverse reactions resulting in dose reduction of ABRAXANE are neutropenia (10%) and peripheral neuropathy (6%) • The most common adverse reactions leading to withholding or delay in ABRAXANE dosing are neutropenia (16%), thrombocytopenia (12%), fatigue (8%), peripheral neuropathy (15%), anemia (5%), and diarrhea (5%) • Other selected adverse reactions with a ≥5% higher incidence for all-grade toxicity in the ABRAXANE/ gemcitabine group compared to the gemcitabine group, respectively, are asthenia (19%, 13%), mucositis (10%, 4%), dysgeusia (16%, 8%), headache (14%, 9%), hypokalemia (12%, 7%), cough (17%, 7%), epistaxis (15%, 3%), urinary tract infection (11%, 5%), pain in extremity (11%, 6%),

ABRAXANE® is a registered trademark of Celgene Corporation. © 2014 Celgene Corporation 06/14 US-ABR140034

arthralgia (11%, 3%), myalgia (10%, 4%), and depression (12%, 6%) • Other selected adverse reactions with a ≥2% higher incidence for Grade 3-4 toxicity in the ABRAXANE/ gemcitabine group compared to the gemcitabine group are thrombocytopenia (13%, 9%), asthenia (7%, 4%), and hypokalemia (4%, 1%) Postmarketing Experience With ABRAXANE and Other Paclitaxel Formulations • Severe and sometimes fatal hypersensitivity reactions have been reported with ABRAXANE. The use of ABRAXANE in patients previously exhibiting hypersensitivity to paclitaxel injection or human albumin has not been studied • There have been reports of congestive heart failure, left ventricular dysfunction and atrioventricular block with ABRAXANE, primarily among individuals with underlying cardiac history or prior exposure to cardiotoxic drugs • There have been reports of extravasation of ABRAXANE. Given the possibility of extravasation, it is advisable to monitor closely the ABRAXANE infusion site for possible infiltration during drug administration DRUG INTERACTIONS • Caution should be exercised when administering ABRAXANE concomitantly with medicines known to inhibit or induce either CYP2C8 or CYP3A4 USE IN SPECIFIC POPULATIONS Nursing Mothers • It is not known whether paclitaxel is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants, a decision should be made to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother Pediatric • The safety and effectiveness of ABRAXANE in pediatric patients have not been evaluated Geriatric • No toxicities occurred notably more frequently among patients ≥65 years of age who received ABRAXANE for MBC • Myelosuppression, peripheral neuropathy, and arthralgia were more frequent in patients ≥65 years of age treated with ABRAXANE and carboplatin in NSCLC • Diarrhea, decreased appetite, dehydration, and epistaxis were more frequent in patients 65 years or older compared with patients younger than 65 years old who received ABRAXANE and gemcitabine in adenocarcinoma of the pancreas Renal Impairment • The use of ABRAXANE has not been studied in patients with renal impairment DOSAGE AND ADMINISTRATION • For MBC and NSCLC, dose adjustment is recommended for patients with moderate and severe hepatic impairment.

Withhold ABRAXANE if AST >10 x ULN or if bilirubin >5 x ULN • For adenocarcinoma of the pancreas, withhold ABRAXANE if bilirubin ≥1.26 x ULN or if AST >10 x ULN • Dose reductions or discontinuation may be needed based on severe hematologic, neurologic, cutaneous, or gastrointestinal toxicity • Monitor patients closely References: 1. Referenced with permission from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Non-Small Cell Lung Cancer V.3.2014. © National Comprehensive Cancer Network, Inc 2014. All rights reserved. Accessed April 16, 2014. To view the most recent and complete version of the guideline, go online to NCCN.org. NATIONAL COMPREHENSIVE CANCER NETWORK®, NCCN®, NCCN GUIDELINES®, and all other NCCN Content are trademarks owned by the National Comprehensive Cancer Network, Inc. 2. Referenced with permission from the NCCN Drugs and Biologics Compendium (NCCN Compendium®): Non-Small Cell Lung Cancer V.3.2014. © National Comprehensive Cancer Network, Inc 2014.

All rights reserved. Accessed April 16, 2014. To view the most recent and complete version of the guideline, go online to NCCN.org. NATIONAL COMPREHENSIVE CANCER NETWORK®, NCCN®, NCCN GUIDELINES®, and all other NCCN Content are trademarks owned by the National Comprehensive Cancer Network, Inc.

For more information, please visit www.abraxane.com.

ABRAXANE® is indicated for the first-line treatment of locally advanced or metastatic non–small cell lung cancer (NSCLC), in combination with carboplatin, in patients who are not candidates for curative surgery or radiation therapy.

significantly superior ORR in first-line ITT population with advanced NSCLC Primary end point: First-line ABRAXANE + carboplatin significantly improved ORR in the phase 3 NSCLC trial (ITT population)

CATEGORY 1 ABRAXANE + carboplatin %

33

n=521

(170/521) 95% CI: 28.6%-36.7%

Paclitaxel injection + carboplatin %

25

n=531

0

A National Comprehensive Cancer Network ® (NCCN ®) Category 1 recommendation1,2,b,c

5

10

15

20

25

(132/531) 95% CI: 21.2%-28.5% 30

35

40

45

First-line albumin-bound paclitaxel (ABRAXANE) + carboplatin is recommended for PS 0-1 patients with advanced NSCLC of negative or unknown EGFR mutation and ALK status.

c

Category 1: Based upon high-level evidence, there is uniform NCCN consensus that the intervention is appropriate.

50

ORR (%)

ITT=intent-to-treat; ORR=overall response rate. a P value based on chi-square test.

b

P=0.005a

ALK=anaplastic lymphoma kinase; EGFR=epidermal growth factor receptor; PS=performance status.

There was no statistically significant difference in overall survival between the 2 study arms.

41% ORR in squamous patients ORR by histology in the phase 3 NSCLC trial 50 45 40

ABRAXANE + carboplatin

41%

ORR (%)

35 30

24%

25

26% 27

%

Paclitaxel injection + carboplatin

33% 24% 15%

15%

20 15 10 5 0

94/229

54/221

Squamous cell carcinoma

66/254

71/264

3/9

Carcinoma/adenocarcinoma

2/13

Large cell carcinoma

7/29

5/33

STUDY DESIGN • Multicenter 1:1 randomized, phase 3 study comparing ABRAXANE (100 mg/m2 IV; Days 1, 8, and 15 of each 21-day cycle) + carboplatin (AUC=6 mg•min/mL IV, Day 1 of each 21-day cycle) with paclitaxel injection (200 mg/m2 IV, Day 1 of each 21-day cycle) + carboplatin (AUC=6 mg•min/mL IV, Day 1 of each 21-day cycle) in 1052 chemonaïve patients with advanced NSCLC

Other

Adverse events in the NSCLC study • The most common adverse reactions (≥20%) of ABRAXANE in combination with carboplatin are anemia, neutropenia, thrombocytopenia, alopecia, peripheral neuropathy, nausea, and fatigue • The most common serious adverse reactions of ABRAXANE in combination with carboplatin for NSCLC are anemia (4%) and pneumonia (3%) • The most common adverse reactions resulting in permanent discontinuation of ABRAXANE are neutropenia (3%), thrombocytopenia (3%), and peripheral neuropathy (1%) • The most common adverse reactions resulting in dose reduction of ABRAXANE are neutropenia (24%), thrombocytopenia (13%), and anemia (6%)

• The most common adverse reactions leading to withholding or delay in ABRAXANE dosing are neutropenia (41%), thrombocytopenia (30%), and anemia (16%) • The following common (≥10% incidence) adverse reactions were observed at a similar incidence in ABRAXANE plus carboplatin–treated and paclitaxel injection plus carboplatin– treated patients: alopecia (56%), nausea (27%), fatigue (25%), decreased appetite (17%), asthenia (16%), constipation (16%), diarrhea (15%), vomiting (12%), dyspnea (12%), and rash (10%); incidence rates are for the ABRAXANE plus carboplatin treatment group

• Adverse reactions with a difference of ≥5%, Grades 1-4, with combination use of ABRAXANE and carboplatin vs combination use of paclitaxel injection and carboplatin in NSCLC are anemia (98%, 91%), thrombocytopenia (68%, 55%), peripheral neuropathy (48%, 64%), edema peripheral (10%, 4%), epistaxis (7%, 2%), arthralgia (13%, 25%), and myalgia (10%, 19%), respectively • Neutropenia (all grades) was reported in 85% of patients who received ABRAXANE and carboplatin vs 83% of patients who received paclitaxel injection and carboplatin

• Adverse reactions with a difference of ≥2%, Grade 3 or higher, with combination use of ABRAXANE and carboplatin vs combination use of paclitaxel injection and carboplatin in NSCLC are anemia (28%, 7%), neutropenia (47%, 58%), thrombocytopenia (18%, 9%), and peripheral neuropathy (3%, 12%), respectively

Please see Brief Summary for ABRAXANE, including Boxed WARNING, on following pages.

ABRAXANE® for Injectable Suspension (paclitaxel protein-bound particles for injectable suspension) (albumin-bound) The following is a Brief Summary; refer to full Prescribing Information for complete product information.

WARNING: NEUTROPENIA • Do not administer ABRAXANE therapy to patients who have baseline neutrophil counts of less than 1,500 cells/mm3. In order to monitor the occurrence of bone marrow suppression, primarily neutropenia, which may be severe and result in infection, it is recommended that frequent peripheral blood cell counts be performed on all patients receiving ABRAXANE [see Contraindications (4), Warnings and Precautions (5.1) and Adverse Reactions (6.1, 6.2, 6.3)].

• Note: An albumin form of paclitaxel may substantially affect a drug’s functional properties relative to those of drug in solution. DO NOT SUBSTITUTE FOR OR WITH OTHER PACLITAXEL FORMULATIONS. 1 INDICATIONS AND USAGE 1.1 Metastatic Breast Cancer ABRAXANE is indicated for the treatment of breast cancer after failure of combination chemotherapy for metastatic disease or relapse within 6 months of adjuvant chemotherapy. Prior therapy should have included an anthracycline unless clinically contraindicated.

1.2 Non-Small Cell Lung Cancer ABRAXANE is indicated for the first-line treatment of locally advanced or metastatic non-small cell lung cancer, in combination with carboplatin, in patients who are not candidates for curative surgery or radiation therapy.

1.3 Adenocarcinoma of the Pancreas ABRAXANE is indicated for the first-line treatment of patients with metastatic adenocarcinoma of the pancreas, in combination with gemcitabine.

2 DOSAGE AND ADMINISTRATION 2.1 Metastatic Breast Cancer After failure of combination chemotherapy for metastatic breast cancer or relapse within 6 months of adjuvant chemotherapy, the recommended regimen for ABRAXANE is 260 mg/m2 administered intravenously over 30 minutes every 3 weeks.

2.2 Non-Small Cell Lung Cancer The recommended dose of ABRAXANE is 100 mg/m2 administered as an intravenous infusion over 30 minutes on Days 1, 8, and 15 of each 21-day cycle. Administer carboplatin on Day 1 of each 21 day cycle immediately after ABRAXANE [see Clinical Studies (14.2)].

2.3 Adenocarcinoma of the Pancreas The recommended dose of ABRAXANE is 125 mg/m2 administered as an intravenous infusion over 30-40 minutes on Days 1, 8 and 15 of each 28-day cycle. Administer gemcitabine immediately after ABRAXANE on Days 1, 8 and 15 of each 28-day cycle [see Clinical Studies (14.3)].

2.4 Dosage in Patients with Hepatic Impairment No dose adjustment is necessary for patients with mild hepatic impairment. Patients with moderate and severe hepatic impairment treated with ABRAXANE may be at increased risk of toxicities known to paclitaxel. Withhold ABRAXANE if AST >10 x ULN or bilirubin > 5 x ULN. Recommendations for dosage adjustment for the first course of therapy are shown in Table 1.

For metastatic breast cancer, the dose of ABRAXANE can be increased from 130 mg/m2 up to 200 mg/m2 in patients with severe hepatic impairment in subsequent cycles based on individual tolerance.

For non-small cell lung cancer, reduce the dose of ABRAXANE to 50 mg/m2 in patients with severe hepatic impairment. In subsequent cycles, the dose of ABRAXANE may be increased to 75 mg/m2 as tolerated.

Monitor patients closely [see Warnings and Precautions (5.6), Use in Specific Populations (8.6) and Clinical Pharmacology (12.3)].

Table 1: Recommendations for Starting Dose in Patients with Hepatic Impairment SGOT (AST) Bilirubin ABRAXANE Dosea Levels Levels Pancreaticc MBC NSCLCc Adenocarcinoma Mild < 10 x ULN AND > ULN to 260 mg/m2 100 mg/m2 125 mg/m2 ≤ 1.25 x ULN Moderate < 10 x ULN AND 1.26 to 200 mg/m2 75 mg/m2 not 2 x ULN recommended 50 mg/m2 not Severe < 10 x ULN AND 2.01 to 130 mg/m2 b 5 x ULN recommended > 10 x ULN OR > 5 x ULN not not not recommended recommended recommended MBC = Metastatic Breast Cancer; NSCLC = Non-Small Cell Lung Cancer. a Dosage recommendations are for the first course of therapy. The need for further dose adjustments in subsequent courses should be based on individual tolerance. b A dose increase to 200 mg/m2 in subsequent courses should be considered based on individual tolerance. c Patients with bilirubin levels above the upper limit of normal were excluded from clinical trials for pancreatic or lung cancer.

2.5 Dose Reduction/Discontinuation Recommendations Metastatic Breast Cancer Patients who experience severe neutropenia (neutrophil <500 cells/mm3 for a week or longer) or severe sensory neuropathy during ABRAXANE therapy should have dosage reduced to 220 mg/m2 for subsequent courses of ABRAXANE. For recurrence of severe neutropenia or severe sensory neuropathy, additional dose reduction should be made to 180 mg/m2. For Grade 3 sensory neuropathy hold treatment until resolution to Grade 1 or 2, followed by a dose reduction for all subsequent courses of ABRAXANE [see Contraindications (4), Warnings and Precautions (5.1, 5.2) and Adverse Reactions (6.1)].

Non-Small Cell Lung Cancer • Do not administer ABRAXANE on Day 1 of a cycle until absolute neutrophil count (ANC) is at least 1500 cells/mm3 and platelet count is at least 100,000 cells/mm3 [see Contraindications (4), Warnings and Precautions (5.1) and Adverse Reactions (6.2)].

• In patients who develop severe neutropenia or thrombocytopenia withhold treatment until counts recover to an absolute neutrophil count of at least 1500 cells/mm3 and platelet count of at least 100,000 cells/mm3 on Day 1 or to an absolute neutrophil count of at least 500 cells/mm3 and platelet count of at least 50,000 cells/mm3 on Days 8 or 15 of the cycle. Upon resumption of dosing, permanently reduce ABRAXANE and carboplatin doses as outlined in Table 2.

• Withhold ABRAXANE for Grade 3-4 peripheral neuropathy. Resume ABRAXANE and carboplatin at reduced doses (see Table 2) when peripheral neuropathy improves to Grade 1 or completely resolves [see Warnings and Precautions (5.2) and Adverse Reactions (6.2)].

Table 2: Permanent Dose Reductions for Hematologic and Neurologic Adverse Drug Reactions in NSCLC Weekly Every 3-Week Adverse Drug Reaction Occurrence ABRAXANE Dose Carboplatin Dose (mg/m2) (AUC mg•min/mL) Neutropenic Fever (ANC less than First 75 4.5 500/mm3 with fever >38°C) OR Delay of next cycle by more than 7 days for ANC less than 1500/mm3 OR ANC less than 500/mm3 for more than 7 days Platelet count less than 50,000/mm3 Severe sensory Neuropathy – Grade 3 or 4

Second

Third First Second First Second Third

50

3

Discontinue Treatment 75 4.5 Discontinue Treatment 75 4.5 50 3 Discontinue Treatment

Adenocarcinoma of the Pancreas Dose level reductions for patients with adenocarcinoma of the pancreas, as referenced in Tables 4 and 5, are provided in Table 3.

Table 3: Dose Level Reductions for Patients with Adenocarcinoma of the Pancreas Dose Level ABRAXANE (mg/m2) Gemcitabine (mg/m2) Full dose 125 1000 1st dose reduction 100 800 2nd dose reduction 75 600 If additional dose reduction required Discontinue Discontinue Recommended dose modifications for neutropenia and thrombocytopenia for patients with adenocarcinoma of the pancreas are provided in Table 4.

Table 4: Dose Recommendation and Modifications for Neutropenia and/or Thrombocytopenia at the Start of a Cycle or within a Cycle for Patients with Adenocarcinoma of the Pancreas Cycle Day ANC (cells/mm3) Platelet count (cells/mm3) ABRAXANE / Gemcitabine Day 1 < 1500 OR < 100,000 Delay doses until recovery Day 8 500 to < 1000 OR 50,000 to < 75,000 Reduce 1 dose level < 500 OR < 50,000 Withhold doses Day 15: IF Day 8 doses were reduced or given without modification: 500 to < 1000 OR 50,000 to < 75,000 Reduce 1 dose level from Day 8 < 500 OR < 50,000 Withhold doses Day 15: IF Day 8 doses were withheld: ≥ 1000 OR ≥ 75,000 Reduce 1 dose level from Day 1 500 to < 1000 OR 50,000 to < 75,000 Reduce 2 dose levels from Day 1 < 500 OR < 50,000 Withhold doses Abbreviations: ANC = Absolute Neutrophil Count.

Recommended dose modifications for other adverse drug reactions in patients with adenocarcinoma of the pancreas are provided in Table 5.

Table 5: Dose Modifications for Other Adverse Drug Reactions in Patients with Adenocarcinoma of the Pancreas Adverse Drug Reaction ABRAXANE Gemcitabine Withhold until fever resolves and ANC ≥ 1500; resume at Febrile Neutropenia: Grade 3 or 4 next lower dose level Peripheral Neuropathy: Withhold until improves to Grade 3 or 4 ≤ Grade 1; resume at next No dose reduction lower dose level Cutaneous Toxicity: Reduce to next lower dose level; discontinue treatment Grade 2 or 3 if toxicity persists Gastrointestinal Toxicity: Withhold until improves to ≤ Grade 1; resume at Grade 3 mucositis or diarrhea next lower dose level 4 CONTRAINDICATIONS • ABRAXANE should not be used in patients who have baseline neutrophil counts of < 1,500 cells/mm3.

• Patients who experience a severe hypersensitivity reaction to ABRAXANE should not be rechallenged with the drug.

5 WARNINGS AND PRECAUTIONS 5.1 Hematologic Effects Bone marrow suppression (primarily neutropenia) is dose-dependent and a dose-limiting toxicity of ABRAXANE. In clinical studies, Grade 3-4 neutropenia occurred in 34% of patients with metastatic breast cancer (MBC), 47% of patients with non-small cell lung cancer (NSCLC), and 38% of patients with pancreatic cancer.

Monitor for myelotoxicity by performing complete blood cell counts frequently, including prior to dosing on Day 1 (for MBC) and Days 1, 8, and 15 (for NSCLC and for pancreatic cancer). Do not administer ABRAXANE to patients with baseline absolute neutrophil counts (ANC) of less than 1,500 cells/mm3. In the case of severe neutropenia (<500 cells/mm3 for seven days or more) during a course of ABRAXANE therapy, reduce the dose of ABRAXANE in subsequent courses in patients with either MBC or NSCLC. In patients with MBC, resume treatment with every-3-week cycles of ABRAXANE after ANC recovers to a level >1,500 cells/mm3 and platelets recover to a level >100,000 cells/mm3.

In patients with NSCLC, resume treatment if recommended (see Dosage and Administration, Table 2) at permanently reduced doses for both weekly ABRAXANE and every-3-week carboplatin after ANC recovers to at least 1500 cells/mm3 and platelet count of at least 100,000 cells/mm3 on Day 1 or to an ANC of at least 500 cells/mm3 and platelet count of at least 50,000 cells/mm3 on Days 8 or 15 of the cycle [see Dosage and Administration (2.5)].

In patients with adenocarcinoma of the pancreas, withhold ABRAXANE and gemcitabine if the ANC is less than 500 cells/mm3 or platelets are less than 50,000 cells/mm3 and delay initiation of the next cycle if the ANC is less than 1500 cells/mm3 or platelet count is less than 100,000 cells/mm3 on Day 1 of the cycle. Resume treatment with appropriate dose reduction if recommended [see Dosage and Administration (2.5)].

ABRAXANE® for Injectable Suspension (paclitaxel protein-bound particles for injectable suspension) (albumin-bound) 5.2 Nervous System Sensory neuropathy is dose- and schedule-dependent [see Adverse Reactions (6.1, 6.2, 6.3)]. The occurrence of Grade 1 or 2 sensory neuropathy does not generally require dose modification. If ≥ Grade 3 sensory neuropathy develops, withhold ABRAXANE treatment until resolution to Grade 1 or 2 for metastatic breast cancer or until resolution to ≤ Grade 1 for NSCLC and pancreatic cancer followed by a dose reduction for all subsequent courses of ABRAXANE [see Dosage and Administration (2.5)].

5.3 Sepsis Sepsis occurred in 5% of patients with or without neutropenia who received ABRAXANE in combination with gemcitabine. Biliary obstruction or presence of biliary stent were risk factors for severe or fatal sepsis. If a patient becomes febrile (regardless of ANC) initiate treatment with broad spectrum antibiotics. For febrile neutropenia, interrupt ABRAXANE and gemcitabine until fever resolves and ANC ≥ 1500, then resume treatment at reduced dose levels [see Dosage and Administration (2.5)].

5.4 Pneumonitis Pneumonitis, including some cases that were fatal, occurred in 4% of patients receiving ABRAXANE in combination with gemcitabine. Monitor patients for signs and symptoms of pneumonitis and interrupt ABRAXANE and gemcitabine during evaluation of suspected pneumonitis. After ruling out infectious etiology and upon making a diagnosis of pneumonitis, permanently discontinue treatment with ABRAXANE and gemcitabine.

5.5 Hypersensitivity Severe and sometimes fatal hypersensitivity reactions, including anaphylactic reactions, have been reported. Patients who experience a severe hypersensitivity reaction to ABRAXANE should not be re-challenged with this drug.

5. 6 Hepatic Impairment Because the exposure and toxicity of paclitaxel can be increased with hepatic impairment, administration of ABRAXANE in patients with hepatic impairment should be performed with caution.

The starting dose should be reduced for patients with moderate or severe hepatic impairment [see Dosage and Administration (2.4), Use in Specific Populations (8.6) and Clinical Pharmacology (12.3)].

5.7 Albumin (Human) ABRAXANE contains albumin (human), a derivative of human blood. Based on effective donor screening and product manufacturing processes, it carries a remote risk for transmission of viral diseases. A theoretical risk for transmission of Creutzfeldt-Jakob Disease (CJD) also is considered extremely remote. No cases of transmission of viral diseases or CJD have ever been identified for albumin.

5.8 Use in Pregnancy ABRAXANE can cause fetal harm when administered to a pregnant woman. Administration of paclitaxel protein-bound particles to rats during pregnancy at doses lower than the maximum recommended human dose, based on body surface area, caused embryofetal toxicities, including intrauterine mortality, increased resorptions, reduced numbers of live fetuses, and malformations.

There are no adequate and well-controlled studies in pregnant women receiving ABRAXANE. If this drug is used during pregnancy, or if the patient becomes pregnant while receiving this drug, the patient should be apprised of the potential hazard to the fetus. Women of childbearing potential should be advised to avoid becoming pregnant while receiving ABRAXANE [see Use in Specific Populations (8.1)].

5.9 Use in Men Men should be advised not to father a child while receiving ABRAXANE [see Nonclinical Toxicology (13.1)].

6 ADVERSE REACTIONS Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

The most common adverse reactions (≥ 20%) with single-agent use of ABRAXANE in metastatic breast cancer are alopecia, neutropenia, sensory neuropathy, abnormal ECG, fatigue/asthenia, myalgia/arthralgia, AST elevation, alkaline phosphatase elevation, anemia, nausea, infections, and diarrhea [see Adverse Reactions (6.1)].

The most common adverse reactions (≥ 20%) of ABRAXANE in combination with carboplatin for non-small cell lung cancer are anemia, neutropenia, thrombocytopenia, alopecia, peripheral neuropathy, nausea, and fatigue [see Adverse Reactions (6.2)]. The most common serious adverse reactions of ABRAXANE in combination with carboplatin for non-small cell lung cancer are anemia (4%) and pneumonia (3%). The most common adverse reactions resulting in permanent discontinuation of ABRAXANE are neutropenia (3%), thrombocytopenia (3%), and peripheral neuropathy (1%). The most common adverse reactions resulting in dose reduction of ABRAXANE are neutropenia (24%), thrombocytopenia (13%), and anemia (6%). The most common adverse reactions leading to withholding or delay in ABRAXANE dosing are neutropenia (41%), thrombocytopenia (30%), and anemia (16%).

In a randomized open-label trial of ABRAXANE in combination with gemcitabine for pancreatic adenocarcinoma [see Clinical Studies (14.3)], the most common (≥ 20%) selected (with a ≥ 5% higher incidence) adverse reactions of ABRAXANE are neutropenia, fatigue, peripheral neuropathy, nausea, alopecia, peripheral edema, diarrhea, pyrexia, vomiting, decreased appetite, rash, and dehydration. The most common serious adverse reactions of ABRAXANE (with a ≥ 1% higher incidence) are pyrexia (6%), dehydration (5%), pneumonia (4%) and vomiting (4%). The most common adverse reactions resulting in permanent discontinuation of ABRAXANE are peripheral neuropathy (8%), fatigue (4%) and thrombocytopenia (2%). The most common adverse reactions resulting in dose reduction of ABRAXANE are neutropenia (10%) and peripheral neuropathy (6%).

The most common adverse reactions leading to withholding or delay in ABRAXANE dosing are neutropenia (16%), thrombocytopenia (12%), fatigue (8%), peripheral neuropathy (15%), anemia (5%) and diarrhea (5%).

6.1 Clinical Trials Experience in Metastatic Breast Cancer Table 6 shows the frequency of important adverse events in the randomized comparative trial for the patients who received either single-agent ABRAXANE or paclitaxel injection for the treatment of metastatic breast cancer.

Table 6: Frequencya of Important Treatment Emergent Adverse Events in the Randomized Metastatic Breast Cancer Study on an Every-3-Weeks Schedule Percent of Patients ABRAXANE Paclitaxel Injection 175 mg/m2 over 3 hb 260 mg/m2 over 30 min (n=229) (n=225) Bone Marrow Neutropenia < 2.0 x 109/L 80 82 < 0.5 x 109/L 9 22 Thrombocytopenia < 100 x 109/L 2 3 < 50 x 109/L <1 <1 Anemia < 11 g/dL 33 25 < 8 g/dL 1 <1 Infections 24 20 Febrile Neutropenia 2 1 Neutropenic Sepsis <1 <1 Bleeding 2 2 Hypersensitivity Reactionc All 4 12 Severed 0 2 Cardiovascular Vital Sign Changes During Administration Bradycardia <1 <1 Hypotension 5 5 Severe Cardiovascular Eventsd 3 4 Abnormal ECG All Patients 60 52 Patients with Normal Baseline 35 30 Respiratory Cough 7 6 Dyspnea 12 9 Sensory Neuropathy Any Symptoms 71 56 Severe Symptomsd 10 2 Myalgia / Arthralgia Any Symptoms 44 49 Severe Symptomsd 8 4 Asthenia Any Symptoms 47 39 Severe Symptomsd 8 3 Fluid Retention/Edema Any Symptoms 10 8 Severe Symptomsd 0 <1 Gastrointestinal Nausea Any Symptoms 30 22 Severe Symptomsd 3 <1 Vomiting Any Symptoms 18 10 Severe Symptomsd 4 1 Diarrhea Any Symptoms 27 15 Severe Symptomsd <1 1 Mucositis Any Symptoms 7 6 Severe Symptomsd <1 0 Alopecia 90 94 Hepatic (Patients with Normal Baseline) Bilirubin Elevations 7 7 Alkaline Phosphatase Elevations 36 31 AST (SGOT) Elevations 39 32 Injection Site Reaction <1 1 a Based on worst grade by NCI Common Terminology Criteria for Adverse Events (CTCAE) version 2. b Paclitaxel injection patients received premedication. c Includes treatment-related events related to hypersensitivity (e.g., flushing, dyspnea, chest pain, hypotension) that began on a day of dosing. d Severe events are defined as at least grade 3 toxicity.

Adverse Event Experiences by Body System Hematologic Disorders Neutropenia was dose dependent and reversible. Among patients with metastatic breast cancer in the randomized trial, neutrophil counts declined below 500 cells/mm3 (Grade 4) in 9% of the patients treated with a dose of 260 mg/m2 compared to 22% in patients receiving paclitaxel injection at a dose of 175 mg/m2. Pancytopenia has been observed in clinical trials.

Infections Infectious episodes were reported in 24% of the patients treated with ABRAXANE. Oral candidiasis, respiratory tract infections and pneumonia were the most frequently reported infectious complications.

ABRAXANE® for Injectable Suspension (paclitaxel protein-bound particles for injectable suspension) (albumin-bound)

Hypersensitivity Reactions (HSRs) Grade 1 or 2 HSRs occurred on the day of ABRAXANE administration and consisted of dyspnea (1%) and flushing, hypotension, chest pain, and arrhythmia (all <1%). The use of ABRAXANE in patients previously exhibiting hypersensitivity to paclitaxel injection or human albumin has not been studied.

Cardiovascular Hypotension, during the 30-minute infusion, occurred in 5% of patients. Bradycardia, during the 30-minute infusion, occurred in <1% of patients. These vital sign changes most often caused no symptoms and required neither specific therapy nor treatment discontinuation.

Severe cardiovascular events possibly related to single-agent ABRAXANE occurred in approximately 3% of patients. These events included cardiac ischemia/infarction, chest pain, cardiac arrest, supraventricular tachycardia, edema, thrombosis, pulmonary thromboembolism, pulmonary emboli, and hypertension. Cases of cerebrovascular attacks (strokes) and transient ischemic attacks have been reported.

Electrocardiogram (ECG) abnormalities were common among patients at baseline. ECG abnormalities on study did not usually result in symptoms, were not dose-limiting, and required no intervention.

ECG abnormalities were noted in 60% of patients. Among patients with a normal ECG prior to study entry, 35% of all patients developed an abnormal tracing while on study. The most frequently reported ECG modifications were non-specific repolarization abnormalities, sinus bradycardia, and sinus tachycardia.

Respiratory Dyspnea (12%), cough (7%), and pneumothorax (<1%) were reported after treatment with ABRAXANE. Neurologic The frequency and severity of sensory neuropathy increased with cumulative dose. Sensory neuropathy was the cause of ABRAXANE discontinuation in 7/229 (3%) patients. Twenty-four patients (10%) treated with ABRAXANE developed Grade 3 peripheral neuropathy; of these patients, 14 had documented improvement after a median of 22 days; 10 patients resumed treatment at a reduced dose of ABRAXANE and 2 discontinued due to peripheral neuropathy. Of the 10 patients without documented improvement, 4 discontinued the study due to peripheral neuropathy.

No Grade 4 sensory neuropathies were reported. Only one incident of motor neuropathy (Grade 2) was observed in either arm of the controlled trial.

Vision Disorders Ocular/visual disturbances occurred in 13% of all patients (n=366) treated with ABRAXANE and 1% were severe. The severe cases (keratitis and blurred vision) were reported in patients who received higher doses than those recommended (300 or 375 mg/m2). These effects generally have been reversible.

Arthralgia/Myalgia The symptoms were usually transient, occurred two or three days after ABRAXANE administration, and resolved within a few days.

Hepatic Grade 3 or 4 elevations in GGT were reported for 14% of patients treated with ABRAXANE and 10% of patients treated with paclitaxel injection in the randomized trial.

Renal Overall 11% of patients experienced creatinine elevation, 1% severe. No discontinuations, dose reductions, or dose delays were caused by renal toxicities.

Other Clinical Events Nail changes (changes in pigmentation or discoloration of nail bed) have been reported. Edema occurred in 10% of patients; no patients had severe edema. Dehydration and pyrexia were also reported.

6.2 Clinical Trials Experience in Non-Small Cell Lung Cancer Adverse reactions were assessed in 514 ABRAXANE/carboplatin-treated patients and 524 paclitaxel injection/carboplatin-treated patients receiving first-line systemic treatment for locally advanced (stage IIIB) or metastatic (IV) non-small cell lung cancer (NSCLC) in a multicenter, randomized, open-label trial. ABRAXANE was administered as an intravenous infusion over 30 minutes at a dose of 100 mg/m2 on Days 1, 8, and 15 of each 21-day cycle. Paclitaxel injection was administered as an intravenous infusion over 3 hours at a dose of 200 mg/m2, following premedication. In both treatment arms carboplatin at a dose of AUC = 6 mg•min/mL was administered intravenously on Day 1 of each 21-day cycle after completion of ABRAXANE/paclitaxel infusion.

The differences in paclitaxel dose and schedule between the two arms limit direct comparison of doseand schedule-dependent adverse reactions. Among patients evaluable for adverse reactions, the median age was 60 years, 75% were men, 81% were White, 49% had adenocarcinoma, 43% had squamous cell lung cancer, 76% were ECOG PS 1. Patients in both treatment arms received a median of 6 cycles of treatment.

The following common (≥ 10% incidence) adverse reactions were observed at a similar incidence in ABRAXANE plus carboplatin-treated and paclitaxel injection plus carboplatin-treated patients: alopecia 56%, nausea 27%, fatigue 25%, decreased appetite 17%, asthenia 16%, constipation 16%, diarrhea 15%, vomiting 12%, dyspnea 12%, and rash 10% (incidence rates are for the ABRAXANE plus carboplatin treatment group).

Table 7 provides the frequency and severity laboratory-detected abnormalities which occurred with a difference of ≥ 5% for all grades (1-4) or ≥ 2% for Grade 3-4 toxicity between ABRAXANE plus carboplatin-treated patients or paclitaxel injection plus carboplatin-treated patients.

Table 7: Selected Hematologic Laboratory-Detected Abnormalities With a Difference of ≥ 5% for grades (1-4) or ≥ 2% for Grade 3-4 Toxicity Between Treatment Groups ABRAXANE Paclitaxel Injection (200 mg/m2 every 3 weeks) (100 mg/m2 weekly) plus carboplatin plus carboplatin Grades 1-4 Grade 3-4 Grades 1-4 Grade 3-4 (%) (%) (%) (%) Anemia1,2 98 28 91 7 Neutropenia 1,3 85 47 83 58 Thrombocytopenia1,3 68 18 55 9 1 508 patients assessed in ABRAXANE/carboplatin-treated group 2 514 patients assessed in paclitaxel injection/carboplatin-treated group 3 513 patients assessed in paclitaxel injection/carboplatin-treated group Table 8 provides the frequency and severity of adverse reactions, which occurred with a difference of ≥ 5% for all grades (1-4) or ≥ 2% for Grade 3-4 between either treatment group for the 514 ABRAXANE plus carboplatin-treated patients compared with the 524 patients who received paclitaxel injection plus carboplatin.

Table 8: Selected Adverse Reactions with a Difference of ≥5% for All Grade Toxicity or ≥2% for Grade 3-4 Toxicity Between Treatment Groups ABRAXANE Paclitaxel Injection (100 mg/m2 weekly) (200 mg/m2 every 3 weeks) + carboplatin (N=514) + carboplatin (N=524) Grade 1-4 Grade 3-4 Grades 1-4 Grade 3-4 MedDRA v 12.1 Toxicity Toxicity Toxicity Toxicity System Organ Class Preferred Term (%) (%) (%) (%) Nervous system Peripheral 48 3 64 12 disorders neuropathya General disorders Edema peripheral 10 0 4 <1 and administration site conditions Respiratory thoracic Epistaxis 7 0 2 0 and mediastinal disorders Musculoskeletal Arthralgia 13 <1 25 2 and connective Myalgia 10 <1 19 2 tissue disorders a Peripheral neuropathy is defined by the MedDRA Version 14.0 SMQ neuropathy (broad scope).

For the ABRAXANE plus carboplatin treated group, 17/514 (3%) patients developed Grade 3 peripheral neuropathy and no patients developed Grade 4 peripheral neuropathy. Grade 3 neuropathy improved to Grade 1 or resolved in 10/17 patients (59%) following interruption or discontinuation of ABRAXANE. 6.3 Clinical Trials Experience in Adenocarcinoma of the Pancreas Adverse reactions were assessed in 421 patients who received ABRAXANE plus gemcitabine and 402 patients who received gemcitabine for the first-line systemic treatment of metastatic adenocarcinoma of the pancreas in a multicenter, multinational, randomized, controlled, open-label trial. Patients received a median treatment duration of 3.9 months in the ABRAXANE/gemcitabine group and 2.8 months in the gemcitabine group. For the treated population, the median relative dose intensity for gemcitabine was 75% in the ABRAXANE/gemcitabine group and 85% in the gemcitabine group. The median relative dose intensity of ABRAXANE was 81%.

Table 9 provides the frequency and severity of laboratory-detected abnormalities which occurred at a higher incidence for Grades 1-4 (≥ 5%) or for Grade 3-4 (≥ 2%) toxicity in ABRAXANE plus gemcitabine-treated patients.

Table 9: Selected Hematologic Laboratory-Detected Abnormalities with a Higher Incidence (≥ 5% for Grades 1-4 or ≥ 2% for Grades 3-4 Events) in the ABRAXANE/Gemcitabine Arm ABRAXANE(125 mg/m2)/ Gemcitabine Gemcitabined Grades 1-4 Grade 3-4 Grades 1-4 Grade 3-4 (%) (%) (%) (%) Neutropeniaa,b 73 38 58 27 Thrombocytopeniab,c 74 13 70 9 a 405 patients assessed in ABRAXANE/gemcitabine-treated group b 388 patients assessed in gemcitabine-treated group c 404 patients assessed in ABRAXANE/gemcitabine-treated group d Neutrophil growth factors were administered to 26% of patients in the ABRAXANE/gemcitabine group.

Table 10 provides the frequency and severity of adverse reactions which occurred with a difference of ≥ 5% for all grades or ≥ 2% for Grade 3 or higher in the ABRAXANE plus gemcitabine-treated group compared to the gemcitabine group.

Table 10: Selected Adverse Reactions with a Higher Incidence (≥5% for All Grade Toxicity or ≥2% for Grade 3 or Higher Toxicity) in the ABRAXANE/Gemcitabine Arm ABRAXANE Gemcitabine (N=402) (125 mg/m2) and gemcitabine (N=421) Adverse Grade 3 Grade 3 System Organ Class Reaction All Grades or Higher All Grades or Higher Fatigue 248 (59%) 77 (18%) 183 (46%) 37 (9%) General disorders and administration site Peripheral conditions edema 194 (46%) 13 (3%) 122 (30%) 12 (3%) Pyrexia 171 (41%) 12 (3%) 114 (28%) 4 (1%) Asthenia 79 (19%) 29 (7%) 54 (13%) 17 (4%) Mucositis 42 (10%) 6 (1%) 16 (4%) 1 (<1%) 228 (54%) 27 (6%) 192 (48%) 14 (3%) Gastrointestinal disorders Nausea Diarrhea 184 (44%) 26 (6%) 95 (24%) 6 (1%) Vomiting 151 (36%) 25 (6%) 113 (28%) 15 (4%) Alopecia 212 (50%) 6 (1%) 21 (5%) 0 Skin and subcutaneous tissue disorders Rash 128 (30%) 8 (2%) 45 (11%) 2 (<1%) Nervous system disorders Peripheral neuropathya 227 (54%) 70 (17%) 51 (13%) 3 (1%) Dysgeusia 68 (16%) 0 33 (8%) 0 Headache 60 (14%) 1 (<1%) 38 (9%) 1 (<1%) Metabolism and nutrition Decreased appetite 152 (36%) 23 (5%) 104 (26%) 8 (2%) disorders Dehydration 87 (21%) 31 (7%) 45 (11%) 10 (2%) Hypokalemia 52 (12%) 18 (4%) 28 (7%) 6 (1%) Respiratory, thoracic and Cough 72 (17%) 0 30 (7%) 0 mediastinal disorders Epistaxis 64 (15%) 1 (<1%) 14 (3%) 1 (<1%) Infections and infestations Urinary tract infectionsb 47 (11%) 10 (2%) 20 (5%) 1 (<1%) Musculoskeletal and Pain in connective tissue extremity 48 (11%) 3 (1%) 24 (6%) 3 (1%) disorders Arthralgia 47 (11%) 3 (1%) 13 (3%) 1 (<1%) Myalgia 44 (10%) 4 (1%) 15 (4%) 0 Psychiatric disorders Depression 51 (12%) 1 (<1%) 24 (6%) 0 a Peripheral neuropathy is defined by the MedDRA Version 15.0 Standard MedDRA Query neuropathy (broad scope). b Urinary tract infections includes the preferred terms of: urinary tract infection, cystitis, urosepsis, urinary tract infection bacterial, and urinary tract infection enterococccal.

ABRAXANE® for Injectable Suspension (paclitaxel protein-bound particles for injectable suspension) (albumin-bound) Additional clinically relevant adverse reactions that were reported in < 10% of the patients with adenocarcinoma of the pancreas who received ABRAXANE/gemcitabine included: Infections & infestations: oral candidiasis, pneumonia Vascular disorders: hypertension Cardiac disorders: tachycardia, congestive cardiac failure Eye disorders: cystoid macular edema Peripheral Neuropathy Grade 3 peripheral neuropathy occurred in 17% of patients who received ABRAXANE/gemcitibine compared to 1% of patients who received gemcitabine only; no patients developed grade 4 peripheral neuropathy. The median time to first occurrence of Grade 3 peripheral neuropathy in the ABRAXANE arm was 140 days. Upon suspension of ABRAXANE dosing, the median time to improvement from Grade 3 peripheral neuropathy to ≤ Grade 1 was 29 days. Of ABRAXANE-treated patients with Grade 3 peripheral neuropathy, 44% resumed ABRAXANE at a reduced dose.

Sepsis Sepsis occurred in 5% of patients who received ABRAXANE/gemcitabine compared to 2% of patients who received gemcitabine alone. Sepsis occurred both in patients with and without neutropenia. Risk factors for sepsis included biliary obstruction or presence of biliary stent.

Pneumonitis Pneumonitis occurred in 4% of patients who received ABRAXANE/gemcitabine compared to 1% of patients who received gemcitabine alone. Two of 17 patients in the ABRAXANE arm with pneumonitis died.

6.4 Post-Marketing Experience with ABRAXANE and other Paclitaxel Formulations Unless otherwise noted, the following discussion refers to the adverse reactions that have been identified during post-approval use of ABRAXANE. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. In some instances, severe events observed with paclitaxel injection may be expected to occur with ABRAXANE. Hypersensitivity Reactions Severe and sometimes fatal hypersensitivity reactions have been reported with ABRAXANE. The use of ABRAXANE in patients previously exhibiting hypersensitivity to paclitaxel injection or human albumin has not been studied.

Cardiovascular There have been reports of congestive heart failure, left ventricular dysfunction, and atrioventricular block with ABRAXANE. Most of the individuals were previously exposed to cardiotoxic drugs, such as anthracyclines, or had underlying cardiac history.

Respiratory There have been reports of pneumonitis, interstitial pneumonia and pulmonary embolism in patients receiving ABRAXANE and reports of radiation pneumonitis in patients receiving concurrent radiotherapy.

Reports of lung fibrosis have been received as part of the continuing surveillance of paclitaxel injection safety and may also be observed with ABRAXANE. Neurologic Cranial nerve palsies and vocal cord paresis have been reported, as well as autonomic neuropathy resulting in paralytic ileus.

Vision Disorders Reports in the literature of abnormal visual evoked potentials in patients treated with paclitaxel injection suggest persistent optic nerve damage. These may also be observed with ABRAXANE. Reduced visual acuity due to cystoid macular edema (CME) has been reported during treatment with ABRAXANE as well as with other taxanes. After cessation of treatment, CME improves and visual acuity may return to baseline.

Hepatic Reports of hepatic necrosis and hepatic encephalopathy leading to death have been received as part of the continuing surveillance of paclitaxel injection safety and may occur following ABRAXANE treatment.

Gastrointestinal (GI) There have been reports of intestinal obstruction, intestinal perforation, pancreatitis, and ischemic colitis following ABRAXANE treatment. There have been reports of neutropenic enterocolitis (typhlitis), despite the coadministration of G-CSF, occurring in patients treated with paclitaxel injection alone and in combination with other chemotherapeutic agents.

Injection Site Reaction There have been reports of extravasation of ABRAXANE. Given the possibility of extravasation, it is advisable to monitor closely the ABRAXANE infusion site for possible infiltration during drug administration.

Severe events such as phlebitis, cellulitis, induration, necrosis, and fibrosis have been reported as part of the continuing surveillance of paclitaxel injection safety. In some cases the onset of the injection site reaction in paclitaxel injection patients either occurred during a prolonged infusion or was delayed by a week to ten days. Recurrence of skin reactions at a site of previous extravasation following administration of paclitaxel injection at a different site, i.e., “recall”, has been reported.

Other Clinical Events Skin reactions including generalized or maculopapular rash, erythema, and pruritus have been observed with ABRAXANE. There have been case reports of photosensitivity reactions, radiation recall phenomenon, and in some patients previously exposed to capecitabine, reports of palmar-plantar erythrodysesthesia. Stevens-Johnson syndrome and toxic epidermal necrolysis have been reported.

There have been reports of conjunctivitis, cellulitis, and increased lacrimation with paclitaxel injection.

6.5 Accidental Exposure No reports of accidental exposure to ABRAXANE have been received. However, upon inhalation of paclitaxel, dyspnea, chest pain, burning eyes, sore throat, and nausea have been reported. Following topical exposure, events have included tingling, burning, and redness.

7 DRUG INTERACTIONS The metabolism of paclitaxel is catalyzed by CYP2C8 and CYP3A4. In the absence of formal clinical drug interaction studies, caution should be exercised when administering ABRAXANE concomitantly with medicines known to inhibit (e.g., ketoconazole and other imidazole antifungals, erythromycin, fluoxetine, gemfibrozil, cimetidine, ritonavir, saquinavir, indinavir, and nelfinavir) or induce (e.g., rifampicin, carbamazepine, phenytoin, efavirenz, and nevirapine) either CYP2C8 or CYP3A4.

8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Pregnancy Category D [see Warnings and Precautions (5.9)].

There are no adequate and well-controlled studies in pregnant women using ABRAXANE. Based on its mechanism of action and findings in animals, ABRAXANE can cause fetal harm when administered to a pregnant woman. If this drug is used during pregnancy, or if the patient becomes pregnant while receiving this drug, the patient should be apprised of the potential hazard to the fetus. Women of childbearing potential should be advised to avoid becoming pregnant while receiving ABRAXANE. Administration of paclitaxel protein-bound particles to rats during pregnancy, on gestation days 7 to 17 at doses of 6 mg/m2 (approximately 2% of the daily maximum recommended human dose on a mg/m2 basis) caused embryofetal toxicities, as indicated by intrauterine mortality, increased resorptions (up to 5-fold), reduced numbers of litters and live fetuses, reduction in fetal body weight and increase in fetal anomalies. Fetal anomalies included soft tissue and skeletal malformations, such as eye bulge,

folded retina, microphthalmia, and dilation of brain ventricles. A lower incidence of soft tissue and skeletal malformations were also exhibited at 3 mg/m2 (approximately 1% of the daily maximum recommended human dose on a mg/m2 basis).

8.3 Nursing Mothers It is not known whether paclitaxel is excreted in human milk. Paclitaxel and/or its metabolites were excreted into the milk of lactating rats. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants, a decision should be made to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.

8.4 Pediatric Use The safety and effectiveness of ABRAXANE in pediatric patients have not been evaluated.

8.5 Geriatric Use Of the 229 patients in the randomized study who received ABRAXANE for the treatment of metastatic breast cancer, 13% were at least 65 years of age and < 2% were 75 years or older. No toxicities occurred notably more frequently among patients who received ABRAXANE. Of the 514 patients in the randomized study who received ABRAXANE and carboplatin for the first-line treatment of non-small cell lung cancer, 31% were 65 years or older and 3.5% were 75 years or older.

Myelosuppression, peripheral neuropathy, and arthralgia were more frequent in patients 65 years or older compared to patients younger than 65 years old. No overall difference in effectiveness, as measured by response rates, was observed between patients 65 years or older compared to patients younger than 65 years old.

Of the 431 patients in the randomized study who received ABRAXANE and gemcitabine for the first-line treatment of pancreatic adenocarcinoma, 41% were 65 years or older and 10% were 75 years or older.

No overall differences in effectiveness were observed between patients who were 65 years of age or older and younger patients. Diarrhea, decreased appetite, dehydration and epistaxis were more frequent in patients 65 years or older compared with patients younger than 65 years old. Clinical studies of ABRAXANE did not include sufficient number of patients with pancreatic cancer who were 75 years and older to determine whether they respond differently from younger patients.

8.6 Patients with Hepatic Impairment Because the exposure and toxicity of paclitaxel can be increased in patients with hepatic impairment, the administration of ABRAXANE should be performed with caution in patients with hepatic impairment [see Dosage and Administration (2.4), Warnings and Precautions (5.6) and Clinical Pharmacology (12.3)]. Abraxane has not been studied in combination with gemcitabine for the treatment of pancreatic cancer in patients with a bilirubin greater than the upper limit of normal.

8.7 Patients with Renal Impairment The use of ABRAXANE has not been studied in patients with renal impairment.

10 OVERDOSAGE There is no known antidote for ABRAXANE overdosage. The primary anticipated complications of overdosage would consist of bone marrow suppression, sensory neurotoxicity, and mucositis.

16 HOW SUPPLIED/STORAGE AND HANDLING 16.1 How Supplied Product No.: 103450 NDC No.: 68817-134-50 100 mg of paclitaxel in a single-use vial, individually packaged in a carton.

16.2 Storage Store the vials in original cartons at 20°C to 25°C (68° F to 77°F). Retain in the original package to protect from bright light.

16.3 Handling and Disposal Procedures for proper handling and disposal of anticancer drugs should be considered. Several guidelines on this subject have been published [see References (15)]. There is no general agreement that all of the procedures recommended in the guidelines are necessary or appropriate.

17 PATIENT COUNSELING INFORMATION See FDA-approved patient labeling • ABRAXANE injection may cause fetal harm. Advise patients to avoid becoming pregnant while receiving this drug. Women of childbearing potential should use effective contraceptives while receiving ABRAXANE [see Warnings and Precautions (5.8) and Use in Specific Populations (8.1)].

• Advise men not to father a child while receiving ABRAXANE [see Warnings and Precautions (5.9)].

• Patients must be informed of the risk of low blood cell counts and severe and life-threatening infections and instructed to contact their physician immediately for fever or evidence of infection. [see Warnings and Precautions (5.1), (5.3)].

• Patients should be instructed to contact their physician for persistent vomiting, diarrhea, or signs of dehydration.

• Patients must be informed that sensory neuropathy occurs frequently with ABRAXANE and patients should advise their physicians of numbness, tingling, pain or weakness involving the extremities [see Warnings and Precautions (5.2)].

• Explain to patients that alopecia, fatigue/asthenia, and myalgia/arthralgia occur frequently with ABRAXANE • Instruct patients to contact their physician for signs of an allergic reaction, which could be severe and sometimes fatal [see Warnings and Precautions (5.5)].

• Instruct patients to contact their physician immediately for sudden onset of dry persistent cough, or shortness of breath [see Warnings and Precautions (5.4)].

Manufactured for:

Celgene Corporation Summit, NJ 07901

ABRAXANE® is a registered trademark of Abraxis BioScience, LLC. ©2005-2013 Abraxis BioScience, LLC. All Rights Reserved.

Abraxis BioScience, LLC is a wholly owned subsidiary of Celgene Corporation.

U.S. Patent Numbers: See www.celgene.com.

ABR_ALL_HCP_BSv007 10_2013

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2014-2015 Oncology Meetings

2014-2015 American Association for Cancer Research Annual Meeting April 18-22 • Philadelphia, Pennsylvania For more information: www.aacr.org

continued from page 104

Hematology and Medical Oncology Board Review: Contemporary Practice from Memorial Sloan-Kettering Cancer Center March 6-9 • New York, New York For more information: www.mskcc.org/ hemoncreviewcourse Advanced Prostate Cancer Consensus Conference March 12-14 • St. Gallen, Switzerland For more information: www.prostatecancerconsensus.org

8th Annual Interdisciplinary Prostate Cancer Congress™ March 14 • New York, New York For more information: http://www.gotoper.com/ conferences/ipcc/meetings/8thAnnual-Interdisciplinary-ProstateCancer-Congress 25th Annual Interdisciplinary Breast Center Conference March 14-18 • Las Vegas, Nevada For more information: www2.breastcare.org American Society of Preventive Oncology (ASPO) Annual Meeting March 15-17 • Birmingham, Alabama For more information: http://aspo.org/annual-meeting

NCCN Annual Conference: Advancing the Standard of Cancer Care March 12-15 • Hollywood, Florida For more information: www.nccn.org/professionals/ meetings/annual_conference.asp

Save the Date

13th International Conference on Malignant Lymphoma (ICML) June 17–20, 2015 Lugano, Switzerland The 13-ICML will bring 3,000 physicians to Lugano from all over the world: hematologists, clinical oncologists, radiation oncologists, pediatricians, pathologists, and leading researchers involved in the study and treatment of lymphoid neoplasms.

For more information, visit www.lymphcon.ch/imcl/index.php2

ACCC 41st Annual National Meeting March 16-18 • Arlington, Virginia For more information: www.accc-cancer.org/meetings/ calendar.asp

14th St. Gallen International Breast Cancer Conference March 18-21 • Vienna, Austria For more information: www.oncoconferences.ch State-of-the-Art Neuro-Oncology Conference: 3rd Annual Meeting March 19-20 • Clearwater Beach, Florida For more information: http://moffitt.org/for-physicianshealthcare-professionals/ conferences/conferences 21st Annual Blood-Brain Barrier and Neuro-Oncology Meeting March 19-21 • Stevenson, Washington For more information: www.ohsu.edu/bbb Society of Surgical Oncology Annual Meeting March 25-28 • Houston, Texas For more information: www.surgonc.org/ EORTC-EANO-ESMO 2015 March 27-28 • Istanbul, Turkey For more information: www.ecco-org.eu/Events/EORTC_ EANO_ESMO-2015

46th Annual Meeting on Women’s Cancer March 28-31 • Chicago, Illinois For more information: www.sgo.org

April American Brachytherapy Society Annual Meeting April 9-11 • Orlando, Florida For more information: http://www.americanbrachytherapy .org/meetings/annual2015/index.cfm Hematologic Malignancies: New Therapies and the Evolving Role of Transplant April 10-11 • Chicago, Illinois For more information: www.mayo.edu/cme/hematologyand-oncology-2015r919 7th Asian Oncology Summit and the 11th Annual Conference of the Organisation for Oncology and Translational Research April 10-12 • Shanghai, China For more information: www.asianoncologysummit.com HPV-induced Head and Neck Cancer: Screening, Detection and Less Invasive Therapies April 11 • Miami, Florida For more information: http://cme.baptisthealth.net/ headneckcancer/pages/index.aspx ESMO European Lung Cancer Conference April 15-18 • Geneva, Switzerland For more information: www.esmo.org/Conferences/ELCC2015-Lung-Cancer Multidisciplinary Spine Oncology Symposium April 17-18 • New York, New York For more information: www.mskcc.org/events/cme/ multidisciplinary-spine-oncologysymposium/form

ONS 40th Annual Congress April 23–26 • Orlando, Florida For more information: www.ons.org/conferences/ congress-2015 3rd ESTRO Forum April 23-28 • Barcelona, Spain For more information: http://www.estro.org/congressesmeetings/items/3rd-estro-forum

May The 28th Annual Meeting of the American Society of Pediatric Hematology/Oncology May 6-9 • Phoenix, Arizona For more information: www.aspho.org/education/content/ annualmeeting.html American Association for Cancer Research: Advances in Brain Cancer Research May 27-30 • Washington, DC For more information: www.aacr.org ASCO Annual Meeting May 29-June 2 • Chicago, Illinois For more information: http://am.asco.org/

June International Cancer Screening Network (ICSN) Triennial Meeting June 2-4 • Rotterdam, The Netherlands For more information: www.scgcorp.com/ICSN2015/ 2015 Clinical Update: 21st Century Prevention of HPV-Associated Cancer June 5-7 • Baltimore, Maryland For more information: www.asccp .org/Education/2015-21st-CenturyPrevention-of-HPV-AssociatedCancer

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2014-2015 Oncology Meetings Society of Nuclear Medicine and Molecular Imaging Annual Meeting June 6-10 • Baltimore, Maryland For more information: www.snm.org

13th International Conference on Malignant Lymphoma (ICML) June 17-20 • Lugano, Switzerland For more information: www.lymphcon.ch/imcl/index.php2 Anticancer Drug Action and Resistance: from Cancer Biology to the Clinic June 20-23 • Florence, Italy For more information: www.ecco-org.eu/Events/EAS2015 International Society on Thrombosis and Haemostasis Annual Meeting June 20-25 • Toronto, Canada For more information: www.isth.org/page/2015Microsite/ MASCC/ISOO Annual Meeting on Supportive Care in Cancer June 25-27 • Copenhagen, Denmark For more information: http://www.kenes.com/mascc2015/

July 7th World Congress on Gastrointestinal Cancer July 1-4 • Barcelona, Spain For more information: http://worldgicancer.com/WCGI/ WGIC2015/index.asp NRG Oncology Meeting July 10-13 • Chicago. Illinois For more information: www.gog.org/meetinginformation .html 14th Annual International Congress on the Future of Breast Cancer® July 16-18 • Huntington Beach, California For more information: www.gotoper.com/conferences/ibc/ meetings/14th-Annual-InternationalCongress-on-the-Future-of-BreastCancer

2014-2015

16th World Conference on Lung Cancer September 6-9 • Denver, Colorado For more information: http://wclc2015.iaslc.org

APOS 12th Annual Conference and IPOS 17th World Congress of Psycho-Oncology July 28–August 1 • Washington, DC For more information: http://www.apos-society.org/ professionals/meetings-ed/ annualconference.aspx 16th Annual International Lung Cancer Congress® July 30-August 1 • Huntington Beach, California For more information: www.gotoper.com/conferences/ilc/ meetings/16th-International-LungCancer-Congress

25th World Congress of Lymphology September 7-11 • San Francisco, California For more information: www.lymphology2015.com/ American Society of Head & Neck Radiology Annual Meeting September 9-13 • Naples, Florida For more information: http://ashnr.org/meetings/ashnrannual-meeting/ ASCO Breast Cancer Symposium September 25-27 • San Francisco, California For more information: breastcasym.org

Best of ASCO® Boston July 31-August 1 • Boston, Massachusetts For more information: http://boa.asco.org/

The European Cancer Congress September 25-29 • Vienna, Austria For more information: www.esmo.org/Conferences/ European-Cancer-Congress-2015

August

October

Best of ASCO - San Francisco August 7-8 • San Francisco, California For more information: http://boa.asco.org/

American College of Surgeons Clinical Congress October 4-8 • Chicago, Illinois For more information: www.facs.org/education/clinicalcongress/future-clinical-congresses

Best of ASCO - Chicago August 28-29 • Chicago, Illinois For more information: http://boa.asco.org/ European Society for Medical Oncology Academy 2015 August 28-30 • Oxford, United Kingdom For more information: www.esmo.org/Conferences/ ESMO-Academy-2015

September 9th Annual Conference of the International Liver Cancer Association September 4-6 • Paris, France For more information: www.ilca2015.org

6th InterAmerican Oncology Conference: Current Status and Future of Anti-Cancer Targeted Therapies October 8-9 • Buenos Aires, Argentina For more information: www.oncologyconferences.com.ar Palliative Care in Oncology Symposium October 9-10 • Boston, Massachusetts For more information: www.pallonc.org ASTRO’s 57th Annual Meeting October 18-21 • San Antonio, Texas For more information: www.astro.org

ACCC 32nd National Oncology Conference October 21-24 • Portland, Oregon For more information: www.accc-cancer.org/meetings/ calendar.asp

November

Chemotherapy Foundation Symposium November 3-7 • New York, New York For more information: www

.chemotherapyfoundationsymposium .org Advanced Breast Cancer Third International Consensus Conference November 5-7 • Lisbon, Portugal For more information: www.abc-lisbon.org Fascia, Acupuncture and Cancer November 14 • Boston, Massachusetts For more information: www.fasciacongress.org 12th International Conference of the Society for Integrative Oncology November 15-16 • Boston, Massachusetts For more information: www.integrativeonc.org/index.php/ events

December Markers in Cancer 2015 December 1-2 • Brussels, Belgium For more information: http://markersincancer.org 38th Annual San Antonio Breast Cancer Symposium December 8-12 • San Antonio, Texas For more information: www.sabcs.org ESMO Asia 2015 Congress December 18-21 • Singapore For more information: www.esmo.org/Conferences/ ESMO-Asia-2015-Congress

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In the Clinic

Bevacizumab Plus Chemotherapy in Platinum-Resistant Recurrent Epithelial Ovarian, Fallopian Tube, or Primary Peritoneal Cancer In the Clinic provides overviews of novel oncology agents, addressing indications, mechanisms, administration recommendations, safety profiles, and other essential information needed for the appropriate clinical use of these drugs.

O

n November 14, 2014, bevacizumab (Avastin) in combination with paclitaxel, pegylated liposomal doxorubicin, or topotecan was approved for treatment of patients with platinum-resistant recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer who have received no more than two prior chemotherapy regimens.1,2

Supporting Trial Approval was based on the finding of prolonged progression-free survival in the international open-label phase III AURELIA trial, in which 361 patients with platinum-resistant disease were randomly assigned to receive bevacizumab plus chemotherapy (n =179) or chemotherapy alone (n = 182).2,3 Chemotherapy consisted of paclitaxel (80 mg/m2 on days 1, 8, 15, and 22 every 4 weeks), pegylated liposomal doxorubicin (40 mg/m2 on day 1 every 4 weeks), or topotecan (4 mg/m2 on days 1, 8, and 15 every 4 weeks or 1.25 mg/m2 on days 1 to 5 every 3 weeks). Bevacizumab was given at 10 mg/kg every 2 weeks or at 15 mg/kg every 3 weeks in patients receiving topotecan in the 3-week schedule.

Investigator-assessed progression-free survival was the primary endpoint.

Patients had received no more than two prior chemotherapy regimens and had experienced a recurrence at no more than 6 months from the most recent platinumbased therapy. Patients with evidence of rectosigmoid involvement by pelvic examination, bowel involvement on computed tomography scan, or clinical symptoms of bowel obstruction were excluded.

Overall, patients had a median age of 61 years (range = 25–84 years; 37% ≥ 65 years), 79% had measurable disease; 87% had CA-125 level at least 2 × upper limit of normal; 31% had ascites; platinum-free interval was 3 to 6 months in 73% and < 3 months in 27%; and Eastern Cooperative Oncology Group performance status was 0 in 59%, 1 in 34%, and 2 in 7%.

Among all patients, median progression-free survival was 6.8 months with bevacizumab/chemotherapy vs 3.4 months with chemotherapy (hazard ratio [HR]

= 0.38, P < .0001, stratified log-rank test).

Median overall survival did not significantly differ between groups (16.3 vs 13.3 months, HR = 0.89, 95% confidence interval [CI] = 0.69–1.14). Objective response rate was 28% vs 13%, and median duration of response was 9.4 vs 5.4 months.

Exploratory analyses by chemotherapy regimen showed that the best outcomes were for the bevacizumab/paclitaxel vs paclitaxel comparison (n = 60 vs 55), with median progression-free survival of 9.6 vs 3.9 months (HR = 0.47, 95% CI = 0.31–0.72), median overall survival of 22.4 vs 13.2 months (HR = 0.64, 95% CI = 0.41–1.01), and response rate of 53% vs 30%. This analysis suggests that patients with prior paclitaxel treatment may benefit from bevacizumab plus weekly paclitaxel.

For the bevacizumab/pegylated liposomal doxorubicin vs doxorubicin com-

bination with paclitaxel, pegylated liposomal doxorubicin, or weekly topotecan regimens. Bevacizumab at 15 mg/kg every 3 weeks may be combined with topotecan regimen given every 3 weeks. The chemotherapy regimens are paclitaxel at 80 mg/m2 on days 1, 8, 15, and 22 every 4 weeks; pegylated liposomal doxorubicin at 40 mg/m2 on day 1 every 4 weeks; or topotecan at 4 mg/m2 on days 1, 8, and 15 every 4 weeks or at 1.25 m/m2 on days 1 to 5 every 3 weeks.

There are no recommended dose reductions for bevacizumab. Treatment should be permanently discontinued for gastrointestinal (GI) perforations (GI perforations, fistula formation in the GI tract, intra-abdominal abscess) or fistula formation involving an internal organ; wound dehiscence and wound healing complications requiring medical intervention; seri-

Combination Drug for Chemotherapy-Related Nausea/Vomiting ■■ Bevacizumab (Avastin) combined with paclitaxel, pegylated liposomal doxorubicin, or topotecan was approved to treat patients with platinumresistant recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer who have received no more than two prior chemotherapy regimens.

■■ The recommended bevacizumab dosage is 10 mg/kg every 2 weeks in combination with paclitaxel, pegylated liposomal doxorubicin, or weekly topotecan regimens.

parison (n = 62 vs 64), median progression-free survival was 5.1 vs 3.5 months (HR = 0.47, 95% CI = 0.32–0.71), median overall survival was 13.7 vs 14.1 months (HR = 0.94, 95% CI = 0.63–1.42), and objective response rate was 16% vs 8%.

For the bevacizumab/topotecan vs topotecan comparison (n = 57 vs 63), median progression-free survival was 6.2 vs 2.1 months (HR = 0.24, 95% CI = 0.15–0.38), median overall survival was 13.8 vs 13.3 months (HR = 1.12, 95% CI = 0.73–1.73), and response rate was 17% vs 2%.

How It Works Bevacizumab is recombinant humanized monoclonal IgG1 antibody that binds vascular endothelial growth factor (VEGF) and prevents interaction of VEGF with its receptors on the surface of endothelial cells. Inhibition of this interaction results in inhibition of endothelial cell proliferation and new blood vessel formation in in vitro models of angiogenesis.

How It Is Given The recommended bevacizumab dosage is 10 mg/kg every 2 weeks in com-

ous hemorrhage; severe arterial thromboembolic events; life-threatening (grade 4) venous thromboembolic events, including pulmonary embolism; hypertensive crisis or hypertensive encephalopathy; posterior reversible encephalopathy syndrome; or nephrotic syndrome.

Bevacizumab should be temporarily suspended at least 4 weeks prior to elective surgery and for severe hypertension not controlled with medical management, moderate to severe proteinuria, and severe infusion reactions. Bevacizumab should not be given to patients with serious hemorrhage or recent hemoptysis.

Safety Profile In the phase III trial, grade 2 to 4 adverse events occurring at an incidence ≥ 5% higher in the bevacizumab/chemotherapy group included neutropenia (30.7% vs 25.4%), hypertension (19.0% vs 5.5%), peripheral sensory neuropathy (17.9% vs 7.2%), mucosal inflammation (12.8% vs 5.5%), and proteinuria (12.3% vs 0.6%).

Grade 3 or 4 adverse events occurring at an incidence ≥ 2% higher consisted of hypertension (6.7% vs 1.1%) and palmar-plantar

OF NOTE Bevacizumab carries boxed warnings for gastrointestinal perforation, surgery and wound healing complications, and hemorrhage.

erythrodysesthesia syndrome (4.5% vs 1.7%). GI perforation occurred in 1.7% of bevacizumab-treated patients.

The exclusion of patients with evidence of rectosigmoid involvement, bowel involvement, or bowel obstruction from this trial may have contributed to the relatively low rate of perforation observed. Fistulae occurred in 2% of bevacizumab-treated patients and in no patients receiving chemotherapy alone.

Bevacizumab carries boxed warnings for GI perforation, surgery and wound healing complications, and hemorrhage (including severe or fatal hemorrhage, hemoptysis, gastrointestinal bleeding, central nervous system [CNS] hemorrhage, and vaginal bleeding). The appropriate interval between termination of bevacizumab and subsequent elective surgery to reduce the risk of impaired wound healing/wound dehiscence has not been determined; in addition to discontinuing bevacizumab ≥ 28 days prior to elective surgery, it should not be restarted for ≥ 28 days after surgery and until the surgical wound is fully healed.

Severe or fatal hemorrhage, including hemoptysis, GI bleeding, CNS hemorrhage, epistaxis, and vaginal bleeding, occur up to fivefold more frequently in patients receiving bevacizumab.

Bevacizumab also carries warnings/ precautions for perforation or fistula, arterial thromboembolic events, venous thromboembolic events, hypertension, posterior reversible encephalopathy syndrome, proteinuria, infusion reactions, and ovarian failure. Patients must undergo routine monitoring of blood pressure and urine protein. Women of reproductive potential must be informed of the risk of ovarian failure. n References 1. U.S. Food and Drug Administration: Bevacizumab solution. Available at www. fda.gov.

2. AVASTIN® (bevacizumab) solution for intravenous infusion prescribing information, Genentech, Inc, November 2014. Available at www.accessdata.fda.gov.

3. Pujade-Lauraine E, Hilpert F, Weber B, et al: Bevacizumab combined with chemotherapy for platinum-resistant recurrent ovarian cancer. J Clin Oncol 32:1302-1308, 2014.

How Well Can Risk of Relapse Be Predicted in

Adult B-ALL?

Complete Remission May Not Ensure Survival in Adults with B-ALL (B-cell Acute Lymphoblastic Leukemia) Of the adult patients with B-ALL who achieve a hematologic complete remission,1,2 44% will eventually relapse,1-3 with only 10% still alive 5 years after their first relapse.4 Several risk factors such as a patient’s age, cytogenetics, and the speed and depth at which a minimal residual disease (MRD) response is achieved can predict risk of relapse.1,3,5-9 Testing at the molecular level for MRD can allow a patient’s risk of relapse to be accurately gauged and treatment to be tailored accordingly.3

Is your treatment approach getting to the molecular level?

Take a Closer Look at ALL

Visit www.UnderstandingALL.com References: 1. Jain N, Gurbuxani S, Rhee C, Stock W. In: Hoffman R, Benz EJ Jr, Silberstein LE, Heslop H, Weitz J, Anastasi J, eds.

Hematology: Basic Principles and Practice. 6th ed. Philadelphia, PA: Saunders-Elsevier; 2013:960-980. 2. Hoelzer D. Am Soc Clin Oncol Educ Book. 2013:290-293. doi:10.1200/EdBook_AM.2013.33.290. 3. Hoelzer D, Gökbuget N, Ottmann O, et al. Hematology Am Soc Hematol Educ Program. 2002;162-192. 4. Forman SJ, Rowe JM. Blood. 2013;121:1077-1082. 5. Referenced with permission from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Acute Lymphoblastic Leukemia V.1.2014. © National Comprehensive Cancer Network, Inc 2014. All rights reserved. Accessed July 8, 2014. To view the most recent and complete version of the guideline, go online to NCCN.org. NATIONAL COMPREHENSIVE CANCER NETWORK®, NCCN®, NCCN GUIDELINES®, and all other NCCN Content are trademarks owned by the National Comprehensive Cancer Network, Inc. 6. Leukemia and Lymphoma Society. Acute Lymphoblastic Leukemia. Published February 2014. http://www.lls.org/content/nationalcontent/resourcecenter/ freeeducationmaterials/leukemia/pdf/all.pdf. Accessed July 8, 2014. 7. Rowe JM. Br J Haematol. 2009;144:468-483.

8. Moorman AV, Harrison CJ, Buck GA, et al. Blood. 2007;109:3189-3197. 9. Bassan R, Hoelzer D. J Clin Onc. 2011;29:532-543.

© 2014 Amgen Inc. All rights reserved. USA-103-100324

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Through the Lens of Oncology History

A Century of Progress The text and photographs on these pages represent the establishment of oncology as a viable medical specialty during the mid-1800s to the mid-1900s and showcase the early medical advances and treatments in cancer.

The images and captions are excerpted from a four-volume series of books titled Oncology Tumors & Treatment: A Photographic History by Stanley B. Burns, MD, FACS. To view additional photos from this series of books, visit burnsarchive.com.

The Anesthesia Era 1845-1875 Preoperative Rodent Cancer Patient of Charles Moore, MD, Albumen Print, London, 1864

“A

disease more repulsive and distressing can hardly be conceived than a Rodent Cancer of the face. Commencing in some trifling manner in the skin, and then sometimes producing so little irritation as scarcely to attract notice, it spreads abroad in all directions with a slow but unswerving advance. It grows and ulcerates. It ulcerates but never heals. The skin suffers most widely from its ravages, but no structure arrests its progress. It removes whole organs, but restores nothing. In its front all is healthy: behind it is vacancy and frightful disfigurement. Whilst eroding integument, cartilage, or bone, the disease is not, or is little, painful; but when eyelids disappear, when the eye or the inner ear is invaded, when branches of the fifth nerve are exposed, or are ulcerating, pain and sometimes severe pain, is added to the deformity.”

With these opening lines, cancer specialist Charles Hewitt Moore, MD (1821-1870), of London’s Middlesex Hospital, presented the first medical text devoted to the treatment of cancer and illustrated the text with a photograph. In his 1867 textbook Rodent Cancer: With Photographic and other Illustrations of Its Nature and Treatment, he presented the classic description of basal cell carcinoma, or rodent cancer as it was then best known. Massive destructive lesions of the face were called lupus or rodent in emulation of the effect a wolf or rodent bite would have to the face.

In 1867, Dr. Moore also published in the Medico-Chirgical Transaction, Volume 50, “On the influence of inadequate operations on the theory of cancer.” Because of these publications Dr. Moore has been credited with laying down the modern principles for the surgical treatment of cancer. His surgical accomplishments were already well known and respected. In 1864 he and

Charles Murchison, MD (1830-1879), had devised a fairly successful treatment for aneurysms. They introduced

the method whereby a wire was passed into an ‘incurable’ aneurysmal sac, resulting in the formation of a fibrin clot in the mass, which helped decrease the growth rate and danger of rupture.

Since the Middle Ages, facial skin cancer was known as ‘noli-me-tangere’ (touchme-not), as physicians assumed the lesions incurable.

Neither surgery nor the use of caustics seemed to stop the disease. In 1755, Jacques Daviel, MD (1696-1762),

first claimed that certain types of these cancers could be cured by wide surgical excision; he is best remembered for his 1753 introduction of the modern method of cataract lens extraction. Several noted physicians studied the facially destructive lesions and separated rodent cancer from syphilitic and tubercular forms, as well as ‘epithelioma’ and other cancers, all of which were rapidly growing and metastasized.

Dr. Moore’s exhaustive treatise reviewed the prior knowledge of the condition, further distinguished the disease, and de-

scribed effective treatment.

Dr. Moore advised wide surgical excision to be followed by caustic agents and, when possible, transplanted skin flaps to cover as much of the defect as possible. In most cases of advanced disease, a vulcanite mask was necessary to allow the patient to be seen in public.

He concluded this cancer “is eminently a local disease: it is also eminently a curable disease.” Dr. Moore’s favorite caustic was chloride of zinc, which he noted if “applied to the cranium or the dura matter, an epileptiform fit” ensues, in one or more days after the application.

Dr. Moore advised surgeons to attempt treating aggressively all but the most advanced cases. As a result of his successes, the most serious cases in England were referred to him.

The patient shown in this photograph arrived at the hospital on May 24, 1864, and was case number two in his text with four photographs to document the study. This 54-year-old man “was living as an incurable patient in the Infirmary of the Uxbridge Union.

The disease in him being of 13 years duration… at the first sight of the fellow’s face it seemed hardly possible that any operation could afford him relief….”

Some notion of the formidable character of the disease may be obtained from an inspection of the photographic drawings, but these representations fall short of the reality, as they exhibit only the rugged orifice in the face, “the vast cavern amongst the bones behind it not being lighted up and visible….” n Excerpted from Oncology: Tumors & Treatment: A Photographic History, The Anesthesia Era 1845-1875 by Stanley B. Burns, MD, FACS. Photograph courtesy of Stanley B. Burns, MD, and The Burns Archive.

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Through the Lens of Oncology History The X-Ray Era 1901-1915 Fluoroscopy for Lung Disease, Boston, 1903

W

hen Thomas Alva Edison, the Wizard of Menlo Park, heard of Roentgen’s discovery of the x-ray, he directed his research staff to create x-ray tubes and better screens on which to view the images. Edison owned America’s first industrial research laboratory and could easily supply the know-how, money, and the most modern technology to devise new uses and improvements to almost any device. Edison’s scientists used a thinner glass bulb and aluminum disks as electrodes to create a more efficient x-ray tube. They also tested over 8,000 chemicals in their search to improve the resolution on the fluorescent x-ray screen. They found calcium tungstate provided the best results. Edison named his devise the ‘fluoroscope.’ It was an easy-to-use, hand-held machine as seen here.

By the end of 1896, radiology’s

prime tools had been improved and their use spread worldwide. During its development, however, Edison had noticed that the skin around his eyes was reddening and he had developed rashes.

By 1902, Edison had given up all x-ray work, but it was too late for his assistant Clarence Daly, the one who had tested the tubes. He had burns on his face and hands, which were soon followed by the extreme loss of head and facial hair. The burns turned into ulcers, then painful malignancies that started at his fingers and slowly ate their way up his arms.

Trying to stop its advance, he gradually lost both his arms from multiple amputations. Finally succumbing in 1904, “Daly had died by inches.” All over the world pioneer radiologists were losing their lives and limbs to the new machine.

Edison’s fluoroscope was used to

tract internal disease, and derangements of internal organs could be seen in real time. In this image, a radiologist is drawing the disease areas directly onto the patient’s chest.

This was a common method of analyzing a patient’s lung disease in this era. Modifications of Edison’s fluoroscope were used in shoe stores until the 1950s. n Excerpted from Oncology: Tumors & Treatment: A Photographic History, The X-Ray Era 1901-1915 by Stanley B. Burns, MD, FACS. Photograph courtesy of Stanley B. Burns, MD, and The Burns Archive.

The Radium Era 1916-1945 Chevalier Jackson, MD, Performing Bronchoscopy, Philadelphia, Circa 1920

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he bronchoscope was first used for extracting foreign bodies and the evaluation of infectious processes, especially abscesses. By the end of the twentieth century, the bronchoscope had been determined the single most useful tool for accurate diagnosis of lung cancer. It allowed for the collection of biopsy specimens or cells for histological and cytological analysis and, in some cases, direct observation of a lesion.

Chevalier Jackson, MD (18651958), is considered by many to be the father of modern broncho-esophagoscopy. In 1890, he constructed an oesophagoscope and continually refined his instruments over the next decade-and-a-half using them in a wide variety of clinical cases. Dr. Jackson’s improvements included the major step of removing the lighting system from the distal end, placing it at the proximal end, and making the illuminating tube itself an auxiliary tube. This freed the main lumen for instrumentation.

In 1905, he designed a bronchoscope with a suction tube, a light carrier, and a right-angled handle that made the instrument easy to manipulate. He created his own instrument shop for implementing the constant improvements. In 1907, he published the first book on endoscopy, Tracheo-bronchos-

copy, Esophagoscopy and Gastroscopy.

By the second decade of the twentieth century, his improved instruments and expertise in laryngoscopy and other endoscopic procedures were drawing a worldwide audience of physicians to his postgraduate courses held in Philadelphia as well as Paris. Because of the constant demand, he continued these courses after his retirement until a few years before his death at age 93 in 1958.

Few physicians have exerted as great an influence or remained ‘the world authority’ for as long a period of time.

In Surgical Diagnosis and Treatment by American Authors by Albert J. Ochsner, MD, published in 1920, Dr. Jackson describes his use of the bronchoscope and outlines its place in the treatment of disease and foreign bodies: “Lung Abscesses can be entered directly and drained… Abscesses caused by foreign bodies can be relieved by removal of the foreign body along with the abscess contents… Endobronchial lavage and instillation of local medication (is important)… Removal of secretions are difficult because they are too viscous and a special ‘sponge-pump’ system must be used… Foreign body removal is the bronchoscope’s biggest blessing… if no harm is done, the bronchoscopy can be repeated any number of times. Therefore it is

absolutely unjustifiable to take the risk of pulling out a foreign body not free to move… Only too often in the early days of the work death promptly followed the ruthless tearing out of an entangled foreign body.”

(He does not mention its use in identification, biopsy, or the testing of secretions for lung tumors. His only reference to “growths” accompanies this photograph.) The heavy laryngoscope has been removed leaving the light bronchoscope in position. The operator (Dr. Jackson) is inserting forceps. Note how the operator holds the

tube lightly between the thumb and first two fingers of the left hand, while the last two fingers are hooked over the upper teeth of the patient, ‘anchoring’ the tube to prevent it from moving in or out or otherwise changing the relation of the distal tube-mouth to a foreign body or growth while the forceps are being used. n Excerpted from Oncology: Tumors & Treatment: A Photographic History, The Radium Era 1916-1945 by Stanley B. Burns, MD, FACS. Photograph courtesy of Stanley B. Burns, MD, and The Burns Archive.

The ASCO Post | DECEMBER 1, 2014

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Patient’s Corner

Beating the Odds

Diagnosed with non–small cell lung cancer 10 years ago, the disease altered the course of my life but not my sense of purpose.

By Richard Heimler, as told to Jo Cavallo

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years, I’ve managed to increase my lung capacity somewhat. Although I can no longer work full time, I am able to lead a fairly normal lifestyle.

Coping With Cancer Recurrence

PharmaGraphics PG QC TC AD CD

cade, I’ve had eight recurrences: three in my brain and several in my chest and remaining lung, with the latest lung tumor diagnosed in June 2014. Having a recurrence in my remaining lung was my worst fear, but my oncologist was able to keep me ahead of the disease with chemotherapy. Although the prior tumors never completely disappeared, they remained stable for several years.

Then in 2010, I got lucky when my oncologist sent a tissue sample of my

SIGNOFF

returning from a business trip to London. Although just 44 at the time, I was worried that I was having a heart attack or stroke and saw a cardiologist immediately.

A battery of tests found my heart was healthy, but I had a 3-cm spot on my right lung. A biopsy confirmed that it was stage IA NSCLC. After surgery, my remaining lung was only at 30% breathing capacity, due to scoliosis that was diagnosed when I was younger. Over the

Mech

—Richard Heimler

DATE

I have dedicated my life to raising awareness of lung cancer and helping other survivors find information and support. When I was first diagnosed with the disease, I didn’t know where to turn for guidance, and I want to spare other people that sense of helplessness and fear.

GNH_HER_Q40680_JA_D01.indd

After the surgery, I was bombarded with a series of standard chemotherapies, including cisplatin, carboplatin, paclitaxel, and vinorelbine. Despite the extensive treatment, over the past de-

primary tumor for molecular diagnos- give people hope that although lung tic testing and found that my cancer cancer is not curable, it is treatable and was ALK-positive. I was enrolled in a manageable, and it is possible to live a clinical trial investigating crizotinib full and meaningful life.

(Xalkori), and for 4 years, the drug worked wonders for me, either shrink- Cancer Is Imbedded ing my tumors completely or keeping in My Life’s Blueprint Although I’ve been beating the odds them from progressing. for more than 10 years, I want more When the cancer recurred in my S&H lung this past June, the tissue was time. Like most parents, I’d like to screened for new mutations, and I was see my children get married and have prescribed ceritinib (Zykadia), a new- children, but, ultimately, I know that er ALK inhibitor, and it is working. whatever the future holds is out of my What’s more, ceritinib appears to pro- control. For some reason, cancer is now hibit brain metastases, so I’m hoping it imbedded in my life’s blueprint, and the will prevent new tumors from develop- rest of my life will unfold the way it is meant to. In the meantime, I’m going to ing in my brain. enjoy every minute of it.

Living a Purposeful Life If my disease does become unconI know that if these two drugs hadn’t trollable at some point, I won’t have any been discovered, I probably would not regrets, because I know my oncologist be alive today, and since my diagnosis, has done everything possible to keep I don’t take any days for granted. I’ve al- me alive. He has been with me every ways been a person who tries to get the step of the way, and when I’m having a most out of every day and sees the glass bad day, he encourages me to see him half full, but there is no question that or calls me on the phone and reassures over the past decade, I’ve become even me. I’ve put my life in his hands. What a more conscious of living a more fully wonderful gift it is to find a doctor you engaged life. I make it a point of seeing can trust with your life. my children, parents, and friends more Despite the challenges over the past frequently and telling them how much 10 years, I have a wonderful life. Rather I love them. than a story filled with sadness and deI have also dedicated my life to spair, my story is one of hope. That is raising awareness of lung cancer and the message I give to my family, friends, helping other survivors find informa- and other survivors. n tion and support. When I was first diagnosed with the disease, I didn’t Richard Heimler lives in Stamford, Conknow where to turn for guidance, and necticut. This past June, the LUNGevity I want to spare other people that sense Foundation honored Mr. Heimler with its of helplessness and fear. I also want to Hero award for his advocacy in lung cancer.

JOB#: 40680 CLIENT: Genentech DESC: Journal Ad 3-pg FILE NAME: GNH_HER_Q40680_JA_D01.indd PG: ParedesA/GolaG AD: R Vetrano-Pyke PM: B Fu x4416 AE: K McGinty TRIM: 15.5” x 10.5” BLEED: 17.5” x 11.5” SAFETY: 14.75” x 9.875” PROD: M Haight FONTS: Myriad Pro (Bold, Regular, Light), Helvetica Neue LT Std (45 Light) IMAGES: 40680_JA_1_fn.tif (CMYK; 300 ppi; 100%), 40680_glow_fn.psd (CMYK; 300 ppi; 100%), Perjeta_US_MBC_NEO_4C.eps (69.5%) INKS: Cyan, Magenta, Yellow, Black DOC PATH: Macintosh HD:Users:paredesa:De..._JA_D01:GNH_HER_Q40680_JA_D01.indd NOTES: None

know it sounds odd, but the past 10 years spent living with non–small cell lung cancer (NSCLC) have been very productive, wonderful years. It is not the life I had before my diagnosis, but it is the life I remember most clearly, and knowing how deadly this cancer is, I’m grateful for every day of those years.

I never expected a diagnosis of lung cancer. A nonsmoker, I’ve always lived a healthy lifestyle and was surprised when I began having chest pains after

DATE: 11-3-2014 11:13 AM CW: L Gibbons INK Spec: 4C

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Patient Guides Available Through ASCO University Bookstore

PROD

Galley: 1

Copies of these booklets can be purchased through the ASCO University Bookstore at www.cancer.net/estore. All booklets ship for free, and ASCO members receive a 20% discount. n

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PRINT SCALE: 82.94%

ROUND: 1 Last Saved: 11-3-2014 11:13 AM

• ASCO Answers: Survivorship helps patients transition into life after active treatment has finished. In addition to information on the challenges survivors may face and the importance of follow-up care, it includes a blank treatment summary and survivorship care form that patients can fill out with the help of their health-care team. Learn more at www.cancer.net/survivorship.

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• ASCO Answers: Managing the Cost of Cancer Care explains the various costs associated with cancer treatment, including health-care coverage through the Affordable Care Act. It also provides a list of financial resources available to help offset expenses related to care and tips for organizing financial paperwork. Learn more at www.cancer.net/managingcostofcare.

The ASCO Post Wants to Hear From You

We encourage readers to share their opinions and thoughts on issues of interest to the oncology community.

Write to The ASCO Post at editor@ASCOPost.com

ASCOPost.com | DECEMBER 1, 2014

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FDA Update

FDA Approves Extended-Release, Single-Entity Hydrocodone Product With Abuse-Deterrent Properties

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he U.S. Food and Drug Administration (FDA) today approved hydrocodone bitartrate (Hysingla ER), an extended-release opioid analgesic to treat pain severe enough to require daily, around-the-clock, longterm opioid treatment and for which

tive treatment options are ineffective, not tolerated, or would be otherwise inadequate to provide sufficient pain management. As a single-entity opioid, The new drug does not carry the seri-

ous liver toxicity risks associated with hydrocodone combination products B:8.75” containing acetaminophen.

The FDA T:7.75” professionals to encourages health-care S:6.875” review and consider all available infor-

mation as part of their decision-making when prescribing opioid analgesics.

Strengths of the new product contain 20, 30, 40, 60, 80, 100 and 120 mg of hycontinued on page 120

alternative treatment options are inadequate. The product has approved labeling describing the product’s abuse-deterrent properties consistent with the FDA’s 2013 draft guidance for industry, Abuse-Deterrent Opioids – Evaluation and Labeling.

Abuse-Deterrence Properties The new product has properties that are expected to reduce, but not totally prevent, abuse of the drug when chewed and then taken orally, or crushed and snorted or injected. The tablet is difficult to crush, break or dissolve. It also forms a viscous hydrogel and cannot be easily prepared for injection. The FDA has determined that the physical and chemical properties of the new product are expected to make abuse by these routes difficult. However, abuse of the drug by these routes is still possible, and overdosing may result in death.

“While the science of abuse deterrence is still evolving, the development of opioids that are harder to abuse is helpful in addressing the public health crisis of prescription drug abuse in the United States,” said Janet Woodcock, MD, Director of the FDA’s Center for Drug Evaluation and Research. “Preventing prescription opioid abuse is a top public health priority for the FDA, and encouraging the development of opioids with abuse-deterrent properties is just one component of a broader approach to reducing abuse and misuse, and will better enable the agency to balance addressing this problem with ensuring that patients have access to appropriate treatments for pain.”

About Hydrocodone Bitartrate Extended-release hydrocodone bitartrate is not approved for, and should not be used for, as-needed pain relief.

Given the drug’s risks for abuse, misuse, and addiction, it should only be prescribed to people for whom alterna-

STRENGTHEN HER DEFENSE

Treatment guidelines have been updated to recommend PERJETA-based therapy as the preferred first-line option • NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) recommend pertuzumab (PERJETA) + trastuzumab (Herceptin) + docetaxel as a (category 1) preferred option for the first-line treatment of patients with HER2+ MBC1 NCCN®=National Comprehensive Cancer Network®; HER2=human epidermal growth factor receptor 2.

Indication

PERJETA® (pertuzumab) is a HER2/neu receptor antagonist indicated in combination with Herceptin® (trastuzumab) and docetaxel for the treatment of patients with HER2-positive metastatic breast cancer who have not received prior anti-HER2 therapy or chemotherapy for metastatic disease.

Boxed WARNINGS: Cardiomyopathy and Embryo-Fetal Toxicity

PERJETA administration can result in subclinical and clinical cardiac failure. Evaluate left ventricular function in all patients prior to and during treatment with PERJETA. Discontinue PERJETA treatment for a confirmed clinically significant decrease in left ventricular function.

Exposure to PERJETA can result in embryo-fetal death and birth defects. Studies in animals have resulted in oligohydramnios, delayed renal development, and death.

Advise patients of these risks and the need for effective contraception.

Please see Brief Summary of PERJETA full Prescribing Information including Boxed WARNINGS for additional Important Safety Information on the following pages.

The ASCO Post | DECEMBER 1, 2014

PAGE 120

FDA Update Hydrocodone Bitartrate continued from page 119

drocodone to be taken every 24 hours.

Doses of 80 mg/d and higher should not be prescribed to people who have not previously taken an opioid medication. While the product contains larger amounts of hydrocodone compared to immediate-release hydrocodone com-

bination products, the range of tablet strengths of the drug is comparable to existing approved extended-release opioids.

The safety and effectiveness of the product were evaluated in a clinical trial of 905 people with chronic low back pain. Additional data from studies conducted in laboratories and in people demonstrated the abuse-deterrent fea-

tures of the drug for certain types of abuse (oral, snorting, and injection).

The most common side effects are constipation, nausea, fatigue, upper respiratory tract infection, dizziness, headache, and drowsiness.

The FDA is requiring postmarketing studies to assess the effects of the abuseS:6.875” deterrent features on the risk for abuse

and the consequences of that abuse in the community. In addition, the new drug is part of the ER/LA Opioid Analgesics Risk Evaluation and Mitigation Strategy (REMS), which requires companies to make available to health-care professionals educational programs on how to safely prescribe extended-release/long-acting opioid analgesics. n

PERJETA + Herceptin (trastuzumab) + docetaxel

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Significantly extend progression-free survival (PFS) in first-line HER2+ metastatic breast cancer Combining PERJETA with Herceptin + docetaxel added 6 months median PFS2

6.1-month improvement in median PFS by independent review (primary endpoint)2

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Placebo + Herceptin + docetaxel

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PERJETA + Herceptin + docetaxel

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• At the first interim analysis, PFS events occurred in 191 (47.5%) patients treated with PERJETA + Herceptin + docetaxel and 242 (59.6%) patients treated with Herceptin + docetaxel2

Select Important Safety Information: Discontinue/Interrupt/Withhold

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Withhold PERJETA and Herceptin and repeat left ventricular ejection fraction assessment within 3 weeks in patients with significant decrease in LVEF. Discontinue PERJETA and Herceptin if LVEF has not improved or has declined further. If a significant infusion reaction occurs, slow or interrupt the infusion and administer appropriate medical therapies.

Consider permanent discontinuation in patients with severe infusion reactions. PERJETA treatment should be withheld or discontinued if Herceptin treatment is withheld or discontinued. Advise nursing mothers receiving PERJETA to discontinue treatment, taking into account the importance of the drug to the mother.

HR=hazard ratio; CI=confidence interval.

Median PFS was reached at the first interim analysis.2 Results of the phase III, randomized, double-blind, placebo-controlled CLEOPATRA trial in patients (N=808) with HER2+ locally recurrent, unresectable, or metastatic breast cancer previously untreated with a biologic or chemotherapy for metastatic disease. Patients received PERJETA + Herceptin + docetaxel or placebo + Herceptin + docetaxel every 3 weeks until progression or unacceptable toxicity. Primary endpoint: PFS, assessed by independent review.2

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Important Safety Information

Boxed WARNINGS: Cardiomyopathy and Embryo-Fetal Toxicity

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• PERJETA administration can result in subclinical and clinical cardiac failure. Evaluate left ventricular function in all patients prior to and during treatment with PERJETA. Discontinue PERJETA treatment for a confirmed clinically significant decrease in left ventricular function • Exposure to PERJETA can result in embryo-fetal death and birth defects.

Studies in animals have resulted in oligohydramnios, delayed renal development, and death. Advise patients of these risks and the need for effective contraception —Verify pregnancy status prior to the initiation of PERJETA. Advise patients of the risks of embryo-fetal death and birth defects and the need for contraception during and after treatment. Advise patients to contact their healthcare provider immediately if they suspect they may be pregnant —If PERJETA is used during pregnancy or if a patient becomes pregnant while being treated with PERJETA, immediately report exposure to the Genentech Adverse Event Line at 1-888-835-2555. Encourage women who may be exposed during pregnancy to enroll in the MotHER Pregnancy Registry by contacting 1-800-690-6720 —Monitor patients who become pregnant during PERJETA therapy for oligohydramnios. If oligohydramnios occurs, perform fetal testing that is appropriate for gestational age and consistent with community standards of care. The efficacy of intravenous hydration in the management of oligohydramnios due to PERJETA exposure is not known

Additional Important Safety Information

PERJETA is contraindicated in patients with known hypersensitivity to pertuzumab or to any of its excipients.

Left Ventricular Dysfunction (LVD)

• In Study 1, for patients with MBC, PERJETA in combination with Herceptin and docetaxel was not associated with increases in the incidence of symptomatic left ventricular systolic dysfunction (LVSD) or decreases in left ventricular ejection fraction (LVEF) compared with placebo in combination with Herceptin and docetaxel • Left ventricular dysfunction occurred in 4.4% of patients in the PERJETA-treated group and in 8.3% of patients in the placebo-treated group • Symptomatic LVSD (congestive heart failure) occurred in 1.0% of patients in the PERJETA-treated group and in 1.8% of patients in the placebo-treated group • Patients who have received prior anthracyclines or prior radiotherapy to the chest area may be at higher risk of decreased LVEF • Assess LVEF prior to initiation of PERJETA and at regular intervals (eg, every 3 months in the metastatic setting) during treatment to ensure that LVEF is within your institution’s normal limits • If LVEF is <45%, or is 45% to 49% with a 10% or greater absolute decrease below the pretreatment value, withhold PERJETA and Herceptin and repeat LVEF assessment within approximately 3 weeks. Discontinue PERJETA and Herceptin if LVEF has not improved or has declined further, unless benefits for the individual patient outweigh the risks

Infusion-Associated Reactions

• PERJETA has been associated with infusion reactions • In Study 1, for patients with MBC, on the first day, when only PERJETA was administered, the overall frequency of infusion reactions was 13.0% in the PERJETAtreated group and 9.8% in the placebo-treated group, with the majority being mild to moderate. The most common infusion reactions (≥1.0%) were pyrexia, chills, fatigue, headache, asthenia, hypersensitivity, and vomiting • During the second cycle, when all drugs were administered on the same day, the most common infusion reactions in the PERJETA-treated group (≥1.0%) were fatigue, dysgeusia, hypersensitivity, myalgia, and vomiting

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Announcements

Rolf-Detlef Treede, MD, PhD, Elected IASP President

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embers of the International Association for the Study of Pain (IASP) have elected Rolf-Detlef Treede, MD, PhD, as the organization’s new president. Dr. Treede is Chair of Neurophysiology and Managing Director of the Center for Biomedicine

S:6.875” Rolf-Detlef Treede, MD, PhD

and Medical Te c h n o l o g y Mannheim at Heidelberg University in Germany.

Dr.Treede

assumed presidency in October at IASP’s 15th World Congress on Pain and will remain President until October 2016. He succeeds Fernando ­Cervero, MD, PhD, DSc, Director of the Alan Edwards Centre for Research on Pain and Professor of Anesthesiology at

­McGill University in Montreal.

Dr. Treede has been a member of IASP for more than 30 years, and he is committed to expanding IASP’s scope to reach out to neighboring disciplines such as rheumatology, pediatrics, oncology, and neurology. n

Overall survival (OS) data PERJETA demonstrated an OS improvement when combined with Herceptin + docetaxel at the final analysis3 • In the second interim analysis, there was a statistically significant improvement in OS (secondary endpoint)2 — Median not yet reached in the PERJETA-containing arm vs 37.6 months with Herceptin + docetaxel (HR=0.66; 95% CI: 0.52-0.84; P=0.0008)

15.7-month improvement in median OS in the final analysis (secondary endpoint)3 Placebo + Herceptin + docetaxel

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• At the final analysis, the OS benefit was maintained (HR=0.68, 95% CI: 0.56-0.84; P=0.0002) and the median was reached in the PERJETA + Herceptin + docetaxel arm (56.5 months vs 40.8 months in the Herceptin + docetaxel arm)3 • The most common adverse reactions (>30%) seen with the PERJETA-based regimen were diarrhea, alopecia, neutropenia, nausea, fatigue, rash, and peripheral neuropathy 2

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At the second interim analysis (30 months median follow-up, 1 year after the first interim analysis), the HR and P value for OS crossed the predefined efficacy stopping boundary (HR ≤0.739, P≤0.0138). OS improvement with PERJETA + trastuzumab + docetaxel was statistically significant at the second interim analysis (HR=0.66, P=0.0008).2 The final analysis was performed when 221 patient deaths occurred in the placebo-treated group and 168 in the PERJETA-treated group. The statistically significant OS benefit in favor of the PERJETA-treated group was maintained (HR=0.68, P=0.0002).3

• In Study 1, the overall frequency of hypersensitivity/anaphylaxis reactions was 10.8% in the PERJETA-treated group and 9.1% in the placebo-treated group. The incidence of Grades 3-4 hypersensitivity/anaphylaxis reactions was 2.0% in the PERJETA-treated group and 2.5% in the placebo-treated group according to NCICTCAE (version 3). Overall, 4 patients in PERJETA-treated group and 2 patients in the placebo-treated group experienced anaphylaxis • Patients should be observed closely for hypersensitivity reactions. Severe hypersensitivity, including anaphylaxis, has been observed in clinical trials with treatment of PERJETA. Medications to treat such reactions, as well as emergency equipment, should be available for immediate use. PERJETA is contraindicated in patients with known hypersensitivity to pertuzumab or to any of its excipients

HER2 Testing

• Detection of HER2 protein overexpression is necessary for selection of patients appropriate for PERJETA therapy because these are the only patients studied and for whom benefit has been shown • Patients were required to have evidence of HER2 overexpression, defined as 3+ IHC or FISH amplification ratio ≥2.0 in the clinical studies. Only limited data were available for patients whose breast cancer was positive by FISH but did not demonstrate protein overexpression by IHC

© 2014 Genentech USA, Inc.

All rights reserved.

PER/103014/0028

Printed in USA.

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Most Common Adverse Reactions

• In MBC, the most common adverse reactions (>30%) seen with PERJETA in combination with Herceptin and docetaxel were diarrhea, alopecia, neutropenia, nausea, fatigue, rash, and peripheral neuropathy. The most common NCI-CTCAE (version 3) Grade 3-4 adverse reactions (>2%) were neutropenia, febrile neutropenia, leukopenia, diarrhea, peripheral neuropathy, anemia, asthenia, and fatigue You may report side effects to the FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

You may also report side effects to Genentech at 1-888-835-2555.

For more information about PERJETA, contact your local representative or visit www.PERJETA.com/hcp.

Please see Brief Summary of PERJETA full Prescribing Information including Boxed WARNINGS for additional Important Safety Information on the following pages.

References: 1. Referenced with permission from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Breast Cancer V.3.2014. © National Comprehensive Cancer Network, Inc. 2014. All rights reserved. Accessed May 12, 2014. To view the most recent and complete version of the guideline, go online to NCCN.org. NATIONAL COMPREHENSIVE CANCER NETWORK®, NCCN®, NCCN GUIDELINES®, and all other NCCN Content are trademarks owned by the National Comprehensive Cancer Network, Inc. 2. PERJETA Prescribing Information. Genentech, Inc. September 2013. 3. Data on file. Genentech, Inc. 4. Swain SM, Kim S-B, Cortes J, et al. Pertuzumab, trastuzumab, and docetaxel for HER2-positive metastatic breast cancer (CLEOPATRA study): overall survival results from a randomized, double-blind, placebo-controlled, phase 3 study. Lancet Oncol. 2013;14:461-471. 5. Baselga J, Cortés J, Kim S-B, et al; CLEOPATRA Study Group. Pertuzumab plus trastuzumab plus docetaxel for metastatic breast cancer.

N Engl J Med. 2012;366:109-119.

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Hypersensitivity Reactions/Anaphylaxis

• Assessment of HER2 status should be performed by laboratories with demonstrated proficiency in the specific technology being utilized

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• Observe patients closely for 60 minutes after the first infusion and for 30 minutes after subsequent infusions of PERJETA. If a significant infusion reaction occurs, slow or interrupt the infusion and administer appropriate medical therapies. Monitor patients carefully until complete resolution of signs and symptoms. Consider permanent discontinuation in patients with severe infusion reactions

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• In the second interim analysis, PERJETA improved both PFS and OS when combined with Herceptin + docetaxel in patients, including the visceral metastasis subgroup4,5 —There was an inability to show an OS benefit with PERJETA in patients with nonvisceral metastases (n=178; HR=1.42 [95% CI: 0.71-2.84])2

The ASCO Post | DECEMBER 1, 2014

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Announcements

ACCC Honors Nicholas J. Petrelli, MD, With 2014 Clinical Research Award

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icholas J. Petrelli, MD, FACS, the Bank of America endowed Medical Director of Christiana Care’s Helen F. Graham Cancer Center & Research Institute, Newark, Delaware, received the 2014 Clinical Research Award from the Association of Community Cancer

Centers (ACCC) in recognition of his leadership initiatives promoting and advocating for oncology clinical research.

The ACCC presented Dr. Petrelli with the award at the 31st National Oncology Conference held recently in San Diego.

A recognized expert on colorectal

PERJETA® (pertuzumab) INJECTION, FOR INTRAVENOUS USE INITIAL U.S. APPROVAL: 2012 WARNING: CARDIOMYOPATHY and EMBRYO-FETAL TOXICITY Cardiomyopathy PERJETA administration can result in subclinical and clinical cardiac failure. Evaluate left ventricular function in all patients prior to and during treatment with PERJETA. Discontinue PERJETA treatment for a confirmed clinically significant decrease in left ventricular function. (2.2, 5.2, 6.1) Embryo-Fetal Toxicity Exposure to PERJETA can result in embryo-fetal death and birth defects. Studies in animals have resulted in oligohydramnios, delayed renal development, and death.

Advise patients of these risks and the need for effective contraception. (5.1, 8.1, 8.6)

1 INDICATIONS AND USAGE 1.1 Metastatic Breast Cancer (MBC) PERJETA is indicated for use in combination with trastuzumab and docetaxel for the treatment of patients with HER2-positive metastatic breast cancer who have not received prior anti-HER2 therapy or chemotherapy for metastatic disease.

1.2 Neoadjuvant Treatment of Breast Cancer PERJETA is indicated for use in combination with trastuzumab and docetaxel for the neoadjuvant treatment of patients with HER2-positive, locally advanced, inflammatory, or early stage breast cancer (either greater than 2 cm in diameter or node positive) as part of a complete treatment regimen for early breast cancer. This indication is based on demonstration of an improvement in pathological complete response rate. No data are available demonstrating improvement in event-free survival or overall survival [see Clinical Studies (14.2) and Dosage and Administration (2.1)].

Limitations of Use: • The safety of PERJETA as part of a doxorubicin-containing regimen has not been established.

• The safety of PERJETA administered for greater than 6 cycles for early breast cancer has not been established.

4 CONTRAINDICATIONS PERJETA is contraindicated in patients with known hypersensitivity to pertuzumab or to any of its excipients.

5 WARNINGS AND PRECAUTIONS 5.1 Embryo-Fetal Toxicity PERJETA can cause fetal harm when administered to a pregnant woman. Treatment of pregnant cynomolgus monkeys with pertuzumab resulted in oligohydramnios, delayed fetal kidney development, and embryo-fetal death. If PERJETA is administered during pregnancy, or if the patient becomes pregnant while receiving this drug, the patient should be apprised of the potential hazard to a fetus [see Use in Specific Populations (8.1)].

Verify pregnancy status prior to the initiation of PERJETA. Advise patients of the risks of embryo-fetal death and birth defects and the need for contraception during and after treatment. Advise patients to contact their healthcare provider immediately if they suspect they may be pregnant.

If PERJETA is administered during pregnancy or if a patient becomes pregnant while receiving PERJETA, immediately report exposure to the Genentech Adverse Event Line at 1-888-835-2555. Encourage women who may be exposed during pregnancy to enroll in the MotHER Pregnancy Registry by contacting 1-800-690-6720 [see Patient Counseling Information (17)].

Monitor patients who become pregnant during PERJETA therapy for oligohydramnios. If oligohydramnios occurs, perform fetal testing that is appropriate for gestational age and consistent with community standards of care. The efficacy of intravenous hydration in the management of oligohydramnios due to PERJETA exposure is not known.

5.2 Left Ventricular Dysfunction Decreases in LVEF have been reported with drugs that block HER2 activity, including PERJETA. In Study 1, for patients with MBC, PERJETA in combination with trastuzumab and docetaxel was not associated with increases in the incidence of symptomatic left ventricular systolic dysfunction (LVSD) or decreases in LVEF compared with placebo in combination with trastuzumab and docetaxel [see Clinical Studies (14.1)]. Left ventricular dysfunction occurred in 4.4% of patients in the PERJETA-treated group and 8.3% of patients in the placebo-treated group. Symptomatic left ventricular systolic dysfunction (congestive heart failure) occurred in 1.0% of patients in the PERJETA-treated group and 1.8% of patients in the placebo-treated group [see Adverse Reactions (6.1)]. Patients who have received prior anthracyclines or prior radiotherapy to the chest area may be at higher risk of decreased LVEF.

cancer, Dr. Petrelli has led the development of a state-of-the-art clinical oncology care program at the Graham Cancer Center. The center has served as a National Cancer Institute (NCI) Community Cancer Center Program site and has achieved an accrual rate of

In patients receiving neoadjuvant treatment in Study 2, the incidence of LVSD was higher in the PERJETA-treated groups compared to the trastuzumab- and docetaxeltreated group. An increased incidence of LVEF declines was observed in patients treated with PERJETA in combination with trastuzumab and docetaxel. In the overall treatment period, LVEF decline > 10% and a drop to less than 50% occurred in 1.9% of patients treated with neoadjuvant trastuzumab and docetaxel as compared to 8.4% of patients treated with neoadjuvant PERJETA in combination with trastuzumab and docetaxel. Symptomatic LVSD occurred in 0.9% of patients treated with neoadjuvant PERJETA in combination with trastuzumab and no patients in the other 3 arms. LVEF recovered to ≥ 50% in all patients.

In patients receiving neoadjuvant PERJETA in Study 3, in the overall treatment period, LVEF decline > 10% and a drop to less than 50% occurred in 6.9% of patients treated with PERJETA plus trastuzumab and FEC followed by PERJETA plus trastuzumab and docetaxel, 16.0% of patients treated with PERJETA plus trastuzumab and docetaxel following FEC, and 10.5% of patients treated with PERJETA in combination with TCH. Symptomatic LVSD occurred in 4.0% of patients treated with PERJETA plus trastuzumab and docetaxel following FEC, 1.3% of patients treated with PERJETA in combination with TCH, and none of the patients treated with PERJETA plus trastuzumab and FEC followed by PERJETA plus trastuzumab and docetaxel. LVEF recovered to ≥ 50% in all but one patient.

PERJETA has not been studied in patients with a pretreatment LVEF value of ≤ 50%, a prior history of CHF, decreases in LVEF to < 50% during prior trastuzumab therapy, or conditions that could impair left ventricular function such as uncontrolled hypertension, recent myocardial infarction, serious cardiac arrhythmia requiring treatment or a cumulative prior anthracycline exposure to > 360 mg/m2 of doxorubicin or its equivalent.

Assess LVEF prior to initiation of PERJETA and at regular intervals (e.g., every three months in the metastatic setting and every six weeks in the neoadjuvant setting) during treatment to ensure that LVEF is within the institution’s normal limits. If LVEF is < 45%, or is 45% to 49% with a 10% or greater absolute decrease below the pretreatment value, withhold PERJETA and trastuzumab and repeat LVEF assessment within approximately 3 weeks. Discontinue PERJETA and trastuzumab if the LVEF has not improved or has declined further, unless the benefits for the individual patient outweigh the risks [see Dosage and Administration (2.2)].

5.3 Infusion-Related Reactions PERJETA has been associated with infusion reactions [see Adverse Reactions (6.1)]. An infusion reaction was defined in Study 1 as any event described as hypersensitivity, anaphylactic reaction, acute infusion reaction, or cytokine release syndrome occurring during an infusion or on the same day as the infusion. The initial dose of PERJETA was given the day before trastuzumab and docetaxel to allow for the examination of PERJETA-associated reactions. On the first day, when only PERJETA was administered, the overall frequency of infusion reactions was 13.0% in the PERJETAtreated group and 9.8% in the placebo-treated group. Less than 1% were Grade 3 or 4. The most common infusion reactions (≥ 1.0%) were pyrexia, chills, fatigue, headache, asthenia, hypersensitivity, and vomiting.

During the second cycle when all drugs were administered on the same day, the most common infusion reactions in the PERJETA-treated group (≥ 1.0%) were fatigue, dysgeusia, hypersensitivity, myalgia, and vomiting.

In Study 2 and Study 3, PERJETA was administered on the same day as the other study treatment drugs. Infusion reactions were consistent with those observed in Study 1, with a majority of reactions being National Cancer Institute - Common Terminology Criteria for Adverse Events (NCI CTCAE v3.0) Grade 1 – 2.

Observe patients closely for 60 minutes after the first infusion and for 30 minutes after subsequent infusions of PERJETA. If a significant infusion-related reaction occurs, slow or interrupt the infusion, and administer appropriate medical therapies. Monitor patients carefully until complete resolution of signs and symptoms. Consider permanent discontinuation in patients with severe infusion reactions [see Dosage and Administration (2.2)].

5.4 Hypersensitivity Reactions/Anaphylaxis In Study 1, the overall frequency of hypersensitivity/ anaphylaxis reactions was 10.8% in the PERJETA-treated group and 9.1% in the placebo-treated group. The incidence of Grade 3 – 4 hypersensitivity/anaphylaxis reactions was 2.0% in the PERJETA-treated group and 2.5% in the placebotreated group according to NCI - CTCAE v3.0. Overall, 4 patients in PERJETA-treated group and 2 patients in the placebo-treated group experienced anaphylaxis.

24% in NCI-sponsored clinical trials, well above the national rate of 5%.

In August 2014 the Graham Cancer Center earned a 5-year, $8.2 million grant from NCI’s Community Oncology Research Program to bring leading-edge cancer screenings, prevention, control,

In Study 2 and Study 3, hypersensitivity/anaphylaxis events were consistent with those observed in Study 1. In Study 2, two patients in the PERJETA- and docetaxel-treated group experienced anaphylaxis. In Study 3, the overall frequency of hypersensitivity/anaphylaxis was highest in the PERJETA plus TCH treated group (13.2%), of which 2.6% were NCICTCAE (version 3) Grade 3 – 4.

Patients should be observed closely for hypersensitivity reactions. Severe hypersensitivity, including anaphylaxis, has been observed in clinical trials with treatment of PERJETA [see Clinical Trials Experience (6.1)]. Medications to treat such reactions, as well as emergency equipment, should be available for immediate use. PERJETA is contraindicated in patients with known hypersensitivity to pertuzumab or to any of its excipients [see Contraindications (4)].

5.5 HER2 Testing Detection of HER2 protein overexpression is necessary for selection of patients appropriate for PERJETA therapy because these are the only patients studied and for whom benefit has been shown [see Indications and Usage (1) and Clinical Studies (14)]. Patients with breast cancer were required to have evidence of HER2 overexpression defined as 3+ IHC or FISH amplification ratio ≥ 2.0 in the clinical studies. Only limited data were available for patients whose breast cancer was positive by FISH, but did not demonstrate protein overexpression by IHC. Assessment of HER2 status should be performed by laboratories using FDA-approved tests with demonstrated proficiency in the specific technology being utilized.

Improper assay performance, including use of sub-optimally fixed tissue, failure to utilize specified reagents, deviation from specific assay instructions, and failure to include appropriate controls for assay validation, can lead to unreliable results.

6 ADVERSE REACTIONS The following adverse reactions are discussed in greater detail in other sections of the label: • Embryo-Fetal Toxicity [see Warnings and Precautions (5.1)] • Left Ventricular Dysfunction [see Warnings and Precautions (5.2)] • Infusion-Related Reactions [see Warnings and Precautions (5.3)] • Hypersensitivity Reactions/Anaphylaxis [see Warnings and Precautions (5.4)] 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.

Metastatic Breast Cancer (MBC) The adverse reactions described in Table 1 were identified in 804 patients with HER2-positive metastatic breast cancer treated in Study 1. Patients were randomized to receive either PERJETA in combination with trastuzumab and docetaxel or placebo in combination with trastuzumab and docetaxel. The median duration of study treatment was 18.1 months for patients in the PERJETA-treated group and 11.8 months for patients in the placebo-treated group. No dose adjustment was permitted for PERJETA or trastuzumab. The rates of adverse events resulting in permanent discontinuation of all study therapy were 6.1% for patients in the PERJETA-treated group and 5.3% for patients in the placebo-treated group. Adverse events led to discontinuation of docetaxel alone in 23.6% of patients in the PERJETA-treated group and 23.2% of patients in the placebo-treated group. Table 1 reports the adverse reactions that occurred in at least 10% of patients in the PERJETA-treated group. The safety profile of PERJETA remained unchanged with an additional year of follow-up (median total follow-up of 30 months) in Study 1.

The most common adverse reactions (> 30%) seen with PERJETA in combination with trastuzumab and docetaxel were diarrhea, alopecia, neutropenia, nausea, fatigue, rash, and peripheral neuropathy. The most common NCI - CTCAE v3.0 Grade 3 – 4 adverse reactions (> 2%) were neutropenia, febrile neutropenia, leukopenia, diarrhea, peripheral neuropathy, anemia, asthenia, and fatigue. An increased incidence of febrile neutropenia was observed for Asian patients in both treatment arms compared with patients of other races and from other geographic regions. Among Asian patients, the incidence of febrile neutropenia was higher in the pertuzumab-treated group (26%) compared with the placebo-treated group (12%).

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treatment, and imaging research trials to more people in the places closest to where they live.

In addition, Dr. Petrelli spearheaded the development of a Tissue Procurement Center with more than 5,000 specimens, cataloged through the NCI’s Cancer Bioinformatics Grid (caBIG/ caTissue), which led to $4.6 million

Table 1 Summary of Adverse Reactions Occurring in ≥ 10% of Patients on the PERJETA Treatment Arm in Study 1 PERJETA Placebo + trastuzumab + trastuzumab + docetaxel + docetaxel n=407 n=397 Body System/ Adverse Reactions Frequency rate, % Frequency rate, % All Grades All Grades Grades, % 3–4, % Grades, % 3–4, %

General disorders and administration site conditions Fatigue 37.6 2.2 36.8 3.3 Asthenia 26.0 2.5 30.2 1.5 Edema peripheral 23.1 0.5 30.0 0.8 Mucosal inflammation 27.8 1.5 19.9 1.0 Pyrexia 18.7 1.2 17.9 0.5 Skin and subcutaneous tissue disorders Alopecia 60.9 0.0 60.5 0.3 Rash 33.7 0.7 24.2 0.8 Nail disorder 22.9 1.2 22.9 0.3 Pruritus 14.0 0.0 10.1 0.0 Dry skin 10.6 0.0 4.3 0.0 Gastrointestinal disorders Diarrhea 66.8 7.9 46.3 5.0 Nausea 42.3 1.2 41.6 0.5 Vomiting 24.1 1.5 23.9 1.5 Constipation 15.0 0.0 24.9 1.0 Stomatitis 18.9 0.5 15.4 0.3 Blood and lymphatic system disorders Neutropenia 52.8 48.9 49.6 45.8 Anemia 23.1 2.5 18.9 3.5 Leukopenia 18.2 12.3 20.4 14.6 Febrile neutropenia* 13.8 13.0 7.6 7.3 Nervous system disorders Neuropathy peripheral 32.4 3.2 33.8 2.0 Headache 20.9 1.2 16.9 0.5 Dysgeusia 18.4 0.0 15.6 0.0 Dizziness 12.5 0.5 12.1 0.0 Musculoskeletal and connective tissue disorders Myalgia 22.9 1.0 23.9 0.8 Arthralgia 15.5 0.2 16.1 0.8 Infections and infestations Upper respiratory tract 16.7 0.7 13.4 0.0 infection Nasopharyngitis 11.8 0.0 12.8 0.3 Respiratory, thoracic, and mediastinal disorders Dyspnea 14.0 1.0 15.6 2.0 Metabolism and nutrition disorders Decreased appetite 29.2 1.7 26.4 1.5 Eye disorders Lacrimation increased 14.0 0.0 13.9 0.0 Psychiatric disorders Insomnia 13.3 0.0 13.4 0.0 *In this table this denotes an adverse reaction that has been reported in association with a fatal outcome The following clinically relevant adverse reactions were reported in < 10% of patients in the PERJETA-treated group in Study 1: Skin and subcutaneous tissue disorders: Paronychia (7.1% in the PERJETA-treated group vs. 3.5% in the placebotreated group) Respiratory, thoracic and mediastinal disorders: Pleural effusion (5.2% in the PERJETA-treated group vs. 5.8% in the placebo-treated group) Cardiac disorders: Left ventricular dysfunction (4.4% in the PERJETA-treated group vs. 8.3% in the placebo-treated group) including symptomatic left ventricular systolic dysfunction (CHF) (1.0% in the PERJETA-treated group vs.

1.8% in the placebo-treated group) Immune system disorders: Hypersensitivity (10.1% in the PERJETA-treated group vs. 8.6% in placebo-treated group) Adverse Reactions Reported in Patients Receiving PERJETA and Trastuzumab after Discontinuation of Docetaxel In Study 1, adverse reactions were reported less frequently after discontinuation of docetaxel treatment. All adverse reactions in the PERJETA and trastuzumab treatment group occurred in < 10% of patients with the exception of diarrhea (19.1%), upper respiratory tract infection (12.8%), rash (11.7%), headache (11.4%), and fatigue (11.1%).

Neoadjuvant Treatment of Breast Cancer (Study 2) In Study 2, the most common adverse reactions seen with PERJETA in combination with trastuzumab and docetaxel administered for 4 cycles were similar to those seen in the PERJETA-treated group in Study 1. The most common adverse reactions (> 30%) were alopecia, neutropenia, diarrhea, and nausea. The most common NCI – CTCAE v3.0 Grade 3 – 4 adverse reactions (> 2%) were neutropenia, febrile neutropenia, leukopenia, and diarrhea. In this group, one patient permanently discontinued neoadjuvant treatment due to an adverse event. Table 2 reports the adverse reactions that occurred in patients who received neoadjuvant treatment with PERJETA for breast cancer in Study 2.

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Announcements

Nicholas J. Petrelli, MD

Table 2 Summary of Adverse Reactions Occurring in ≥ 10% in the Neoadjuvant Setting for Patients Receiving PERJETA in Study 2

Body System/ Adverse Reactions

PERJETA PERJETA PERJETA Trastuzumab + trastuzumab + docetaxel + trastuzumab + docetaxel + docetaxel n=108 n=108 n=107 n=107 Frequency rate Frequency rate Frequency rate Frequency rate % % % % All Grades All Grades All Grades All Grades Grades 3–4 Grades 3–4 Grades 3–4 Grades 3–4 % % % % % % % %

General disorders and administration site conditions Fatigue 27.1 0.0 26.2 0.9 12.0 0.0 25.5 1.1 Asthenia 17.8 0.0 20.6 1.9 2.8 0.0 16.0 2.1 Edema 10.3 0.0 2.8 0.0 0.9 0.0 5.3 0.0 peripheral Mucosal 21.5 0.0 26.2 1.9 2.8 0.0 25.5 0.0 inflammation Pyrexia 10.3 0.0 16.8 0.0 8.3 0.0 8.5 0.0 Skin and subcutaneous tissue disorders Alopecia 66.4 0.0 65.4 0.0 2.8 0.0 67.0 0.0 Rash 21.5 1.9 26.2 0.9 11.1 0.0 28.7 1.1 Gastrointestinal disorders Diarrhea 33.6 3.7 45.8 5.6 27.8 0.0 54.3 4.3 Nausea 36.4 0.0 39.3 0.0 13.9 0.0 36.2 1.1 Vomiting 12.1 0.0 13.1 0.0 4.6 0.0 16.0 2.1 Stomatitis 7.5 0.0 17.8 0.0 4.6 0.0 9.6 0.0 Blood and lymphatic system disorders Neutropenia 63.6 58.9 50.5 44.9 0.9 0.9 64.9 57.4 Leukopenia 21.5 11.2 9.3 4.7 0.0 0.0 13.8 8.5 Nervous system disorders Headache 11.2 0.0 11.2 0.0 13.9 0.0 12.8 0.0 Dysgeusia 10.3 0.0 15.0 0.0 4.6 0.0 7.4 0.0 Peripheral 12.1 0.9 8.4 0.9 1.9 0.0 10.6 0.0 Sensory Neuropathy Musculoskeletal and connective tissue disorders Myalgia 22.4 0.0 22.4 0.0 9.3 0.0 21.3 0.0 Arthralgia 8.4 0.0 10.3 0.0 4.6 0.0 9.6 0.0 Metabolism and nutrition disorders Decreased 6.5 0.0 14.0 0.0 1.9 0.0 14.9 0.0 appetite Psychiatric disorders Insomnia 11.2 0.0 8.4 0.0 3.7 0.0 8.5 0.0 The following adverse reactions were reported in < 10% of patients receiving neoadjuvant treatment and occurred more frequently in PERJETA-treated groups in Study 2: (Ptz=pertuzumab; T=trastuzumab; D=docetaxel) Blood and lymphatic system disorders: Anemia (6.5% in the T+D arm, 2.8% in the Ptz+T+D arm, 4.6% in the Ptz+T arm and 8.5% in the Ptz+D arm), Febrile neutropenia (6.5% in the T+D arm, 8.4% in the Ptz+T+D arm, 0.0% in the Ptz+T arm and 7.4% in the Ptz+D arm) Immune system disorders: Hypersensitivity (1.9% in the T+D arm, 5.6% in the Ptz+T+D arm, 5.6% in the Ptz+T arm and 5.3% in the Ptz+D arm) Nervous system disorders: Dizziness (3.7% in the T+D arm, 2.8% in the Ptz+T+D arm, 5.6% in the Ptz+T arm and 3.2% in the Ptz+D arm) Infections and infestations: Upper respiratory tract infection (2.8% in the T+D arm, 4.7% in the Ptz+T+D arm, 1.9% in the Ptz+T arm and 7.4% in the Ptz+D arm) Respiratory, thoracic and mediastinal disorders: Dyspnea (3.7% in the T+D arm, 4.7% in the Ptz+T+D arm, 2.8% in the Ptz+T arm and 2.1% in the Ptz+D arm) Cardiac disorders: Left ventricular dysfunction (0.9% in the T+D arm, 2.8% in the Ptz+T+D arm, 0.0% in the Ptz+T arm, and 1.1% in the Ptz+D arm) including symptomatic left ventricular dysfunction (CHF) (0.9% in the Ptz+T arm and 0.0% in the T+D arm, Ptz+T+D arm, and Ptz+D arm) Eye disorders: Lacrimation increased (1.9% in the T+D arm, 3.7% in the Ptz+T+D arm, 0.9% in the Ptz+T arm, and 4.3% in the Ptz+D arm) Neoadjuvant Treatment of Breast Cancer (Study 3) In Study 3, when PERJETA was administered in combination with trastuzumab and docetaxel for 3 cycles following 3 cycles of FEC, the most common adverse reactions (> 30%) were diarrhea, nausea, alopecia, neutropenia, vomiting, and fatigue. The most common NCI-CTCAE (version 3) Grade 3 – 4 adverse reactions (> 2%) were neutropenia, leukopenia, febrile neutropenia, diarrhea, left ventricular dysfunction, anemia, dyspnea, nausea, and vomiting.

Similarly, when PERJETA was administered in combination with docetaxel, carboplatin, and trastuzumab (TCH) for 6 cycles, the most common adverse reactions (> 30%) were diarrhea, alopecia, neutropenia, nausea, fatigue, vomiting, anemia, and thrombocytopenia. The most common NCICTCAE (version 3) Grade 3 – 4 adverse reactions (> 2%) were neutropenia, febrile neutropenia, anemia, leukopenia, diarrhea, thrombocytopenia, vomiting, fatigue, ALT increased, hypokalemia, and hypersensitivity.

The rates of adverse events resulting in permanent discontinuation of any component of neoadjuvant treatment were 6.7% for patients receiving PERJETA in combination with trastuzumab and docetaxel following FEC and 7.9% for

funding for participation in the Cancer Genome Atlas Project. Dr. Petrelli also developed the first Delaware statewide High Risk Family Cancer Registry, consisting of 5,640 families with more than 200,000 individuals.

Dr. Petrelli joined Helen F. Graham Cancer Center & Research Institute in August 2001. Previously, he was Chair

patients receiving PERJETA in combination with TCH. Table 3 reports the adverse reactions that occurred in patients who received neoadjuvant treatment with PERJETA for breast cancer in Study 3.

Table 3 Summary of Adverse Reactions Occurring in ≥ 10% of Patients Receiving Neoadjuvant Treatment with PERJETA in Study 3

Body System/ Adverse Reactions

PERJETA + trastuzumab PERJETA + FEC followed + trastuzumab

by PERJETA + docetaxel + trastuzumab following FEC PERJETA + TCH + docetaxel n=75 n=76 n=72 Frequency rate, % Frequency rate, % Frequency rate, % All Grades Grades 3 – 4 % %

All Grades All Grades Grades 3 – 4 Grades 3 – 4 % % % %

General disorders and administration site conditions Fatigue 36.1 0.0 36.0 0.0 42.1 3.9 Asthenia 9.7 0.0 14.7 1.3 13.2 1.3 Edema peripheral 11.1 0.0 4.0 0.0 9.2 0.0 Mucosal 23.6 0.0 20.0 0.0 17.1 1.3 inflammation Pyrexia 16.7 0.0 9.3 0.0 15.8 0.0 Skin and subcutaneous tissue disorders Alopecia 48.6 0.0 52.0 0.0 55.3 0.0 Rash 19.4 0.0 10.7 0.0 21.1 1.3 Dry skin 5.6 0.0 9.3 0.0 10.5 0.0 Palmar-Plantar Erythrodysaesthesia 6.9 0.0 10.7 0.0 7.9 0.0 Syndrome Gastrointestinal disorders Diarrhea 61.1 4.2 61.3 5.3 72.4 11.8 Dyspepsia 25.0 1.4 8 0.0 22.4 0.0 Nausea 52.8 0.0 53.3 2.7 44.7 0.0 Vomiting 40.3 0.0 36.0 2.7 39.5 5.3 Constipation 18.1 0.0 22.7 0.0 15.8 0.0 Stomatitis 13.9 0.0 17.3 0.0 11.8 0.0 Blood and lymphatic system disorders Neutropenia 51.4 47.2 46.7 42.7 48.7 46.1 Anemia 19.4 1.4 9.3 4.0 38.2 17.1 Leukopenia 22.2 19.4 16.0 12.0 17.1 11.8 Febrile 18.1 18.1 9.3 9.3 17.1 17.1 neutropenia Thrombocytopenia 6.9 0.0 1.3 0.0 30.3 11.8 Immune system disorders Hypersensitivity 9.7 2.8 1.3 0.0 11.8 2.6 Nervous system disorders Neuropathy 5.6 0.0 1.3 0.0 10.5 0.0 peripheral Headache 22.2 0.0 14.7 0.0 17.1 0.0 Dysgeusia 11.1 0.0 13.3 0.0 21.1 0.0 Dizziness 8.3 0.0 8.0 1.3 15.8 0.0 Musculoskeletal and connective tissue disorders Myalgia 16.7 0.0 10.7 1.3 10.5 0.0 Arthralgia 11.1 0.0 12.0 0.0 6.6 0.0 Respiratory, thoracic, and mediastinal disorders Cough 9.7 0.0 5.3 0.0 11.8 0.0 Dyspnea 12.5 0.0 8.0 2.7 10.5 1.3 Epistaxis 11.1 0.0 10.7 0.0 15.8 1.3 Oropharyngeal 8.3 0.0 6.7 0.0 11.8 0.0 pain Metabolism and nutrition disorders Decreased 20.8 0.0 10.7 0.0 21.1 0.0 appetite Eye disorders Lacrimation 12.5 0.0 5.3 0.0 7.9 0.0 increased Psychiatric disorders Insomnia 11.1 0.0 13.3 0.0 21.1 0.0 Investigations ALT increased 6.9 0.0 2.7 0.0 10.5 3.9 FEC=5-fluorouracil, epirubicin, cyclophosphamide, TCH=docetaxel, carboplatin, trastuzumab The following selected adverse reactions were reported in < 10% of patients receiving neoadjuvant treatment in Study 3: (Ptz=pertuzumab; T=trastuzumab; D=docetaxel; FEC=fluorouracil, epirubicin, and cyclophosphamide; TCH=docetaxel, carboplatin, and trastuzumab) Skin and subcutaneous tissue disorders: Nail disorder (9.7% in the Ptz+T+FEC/Ptz+T+D arm, 6.7% in the FEC/ Ptz+T+D arm, and 9.2% in the Ptz+TCH arm), Paronychia (0% in the Ptz+T+FEC/Ptz+T+D and 1.3% in both the FEC/Ptz+T+D and Ptz+TCH arms), Pruritis (2.8% in the Ptz+T+FEC/Ptz+T+D arm, 4.0% in the FEC/Ptz+T+D arm, and 3.9% in the Ptz+TCH arm) Infections and infestations: Upper respiratory tract infection (8.3% in the Ptz+T+FEC/Ptz+T+D arm, 4.0% in the FEC/Ptz+T+D arm, and 2.6% in the Ptz+TCH arm), Nasopharyngitis (6.9% in the Ptz+T+FEC/Ptz+T+D arm, 6.7% in the FEC/Ptz+T+D arm, and 7.9% in the Ptz+TCH arm)

of the Department of Surgical Oncology and Director of the Surgical Oncology fellowship training program at Roswell Park Cancer Institute. He received his medical degree from Tulane Medical School in New Orleans, Louisiana. Following a general surgery residency in San Francisco, he completed a surgical oncology fellowship at Roswell Park Cancer Institute. n

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Announcements

Yale Cancer Center’s Dr. Susan Mayne Appointed to FDA Position

S

usan T. Mayne, PhD, C-EA, Winslow Professor of Epidemiology; Associate Director for Population Sciences at Yale Cancer Center; and Chair of the Department of Chronic Disease Epidemiology at Yale School of Public Health, has been appointed to the position of

Center Director of the Center for Food Safety and Applied Nutrition (CFSAN) at the U.S. Food and Drug Administration (FDA).

Dr. Mayne joined Yale University in 1987 as a post-doctoral fellow, and directed Yale Cancer Center’s Cancer Pre-

vention and Control Research Program from 1993-2010. She also served as Associate Director for Population Sciences from 1995. Dr. Mayne played a key role in Cancer Center leadership and contributed significantly to the Center’s ongoing status as a National Cancer Institute Susan T. Mayne, PhD, C-EA

PERJETA® (pertuzumab) INJECTION, FOR INTRAVENOUS USE INITIAL U.S. APPROVAL: 2012 WARNING: CARDIOMYOPATHY and EMBRYO-FETAL TOXICITY Cardiomyopathy PERJETA administration can result in subclinical and clinical cardiac failure. Evaluate left ventricular function in all patients prior to and during treatment with PERJETA. Discontinue PERJETA treatment for a confirmed clinically significant decrease in left ventricular function. (2.2, 5.2, 6.1) Embryo-Fetal Toxicity Exposure to PERJETA can result in embryo-fetal death and birth defects. Studies in animals have resulted in oligohydramnios, delayed renal development, and death.

Advise patients of these risks and the need for effective contraception. (5.1, 8.1, 8.6)

1 INDICATIONS AND USAGE 1.1 Metastatic Breast Cancer (MBC) PERJETA is indicated for use in combination with trastuzumab and docetaxel for the treatment of patients with HER2-positive metastatic breast cancer who have not received prior anti-HER2 therapy or chemotherapy for metastatic disease.

1.2 Neoadjuvant Treatment of Breast Cancer PERJETA is indicated for use in combination with trastuzumab and docetaxel for the neoadjuvant treatment of patients with HER2-positive, locally advanced, inflammatory, or early stage breast cancer (either greater than 2 cm in diameter or node positive) as part of a complete treatment regimen for early breast cancer. This indication is based on demonstration of an improvement in pathological complete response rate. No data are available demonstrating improvement in event-free survival or overall survival [see Clinical Studies (14.2) and Dosage and Administration (2.1)].

Limitations of Use: • The safety of PERJETA as part of a doxorubicin-containing regimen has not been established.

• The safety of PERJETA administered for greater than 6 cycles for early breast cancer has not been established.

4 CONTRAINDICATIONS PERJETA is contraindicated in patients with known hypersensitivity to pertuzumab or to any of its excipients.

5 WARNINGS AND PRECAUTIONS 5.1 Embryo-Fetal Toxicity PERJETA can cause fetal harm when administered to a pregnant woman. Treatment of pregnant cynomolgus monkeys with pertuzumab resulted in oligohydramnios, delayed fetal kidney development, and embryo-fetal death. If PERJETA is administered during pregnancy, or if the patient becomes pregnant while receiving this drug, the patient should be apprised of the potential hazard to a fetus [see Use in Specific Populations (8.1)].

Verify pregnancy status prior to the initiation of PERJETA. Advise patients of the risks of embryo-fetal death and birth defects and the need for contraception during and after treatment. Advise patients to contact their healthcare provider immediately if they suspect they may be pregnant.

If PERJETA is administered during pregnancy or if a patient becomes pregnant while receiving PERJETA, immediately report exposure to the Genentech Adverse Event Line at 1-888-835-2555. Encourage women who may be exposed during pregnancy to enroll in the MotHER Pregnancy Registry by contacting 1-800-690-6720 [see Patient Counseling Information (17)].

Monitor patients who become pregnant during PERJETA therapy for oligohydramnios. If oligohydramnios occurs, perform fetal testing that is appropriate for gestational age and consistent with community standards of care. The efficacy of intravenous hydration in the management of oligohydramnios due to PERJETA exposure is not known.

5.2 Left Ventricular Dysfunction Decreases in LVEF have been reported with drugs that block HER2 activity, including PERJETA. In Study 1, for patients with MBC, PERJETA in combination with trastuzumab and docetaxel was not associated with increases in the incidence of symptomatic left ventricular systolic dysfunction (LVSD) or decreases in LVEF compared with placebo in combination with trastuzumab and docetaxel [see Clinical Studies (14.1)]. Left ventricular dysfunction occurred in 4.4% of patients in the PERJETA-treated group and 8.3% of patients in the placebo-treated group. Symptomatic left ventricular systolic dysfunction (congestive heart failure) occurred in 1.0% of patients in the PERJETA-treated group and 1.8% of patients in the placebo-treated group [see Adverse Reactions (6.1)]. Patients who have received prior anthracyclines or prior radiotherapy to the chest area may be at higher risk of decreased LVEF.

In patients receiving neoadjuvant treatment in Study 2, the incidence of LVSD was higher in the PERJETA-treated groups compared to the trastuzumab- and docetaxeltreated group. An increased incidence of LVEF declines was observed in patients treated with PERJETA in combination with trastuzumab and docetaxel. In the overall treatment period, LVEF decline > 10% and a drop to less than 50% occurred in 1.9% of patients treated with neoadjuvant trastuzumab and docetaxel as compared to 8.4% of patients treated with neoadjuvant PERJETA in combination with trastuzumab and docetaxel. Symptomatic LVSD occurred in 0.9% of patients treated with neoadjuvant PERJETA in combination with trastuzumab and no patients in the other 3 arms. LVEF recovered to ≥ 50% in all patients.

In patients receiving neoadjuvant PERJETA in Study 3, in the overall treatment period, LVEF decline > 10% and a drop to less than 50% occurred in 6.9% of patients treated with PERJETA plus trastuzumab and FEC followed by PERJETA plus trastuzumab and docetaxel, 16.0% of patients treated with PERJETA plus trastuzumab and docetaxel following FEC, and 10.5% of patients treated with PERJETA in combination with TCH. Symptomatic LVSD occurred in 4.0% of patients treated with PERJETA plus trastuzumab and docetaxel following FEC, 1.3% of patients treated with PERJETA in combination with TCH, and none of the patients treated with PERJETA plus trastuzumab and FEC followed by PERJETA plus trastuzumab and docetaxel. LVEF recovered to ≥ 50% in all but one patient.

PERJETA has not been studied in patients with a pretreatment LVEF value of ≤ 50%, a prior history of CHF, decreases in LVEF to < 50% during prior trastuzumab therapy, or conditions that could impair left ventricular function such as uncontrolled hypertension, recent myocardial infarction, serious cardiac arrhythmia requiring treatment or a cumulative prior anthracycline exposure to > 360 mg/m2 of doxorubicin or its equivalent.

Assess LVEF prior to initiation of PERJETA and at regular intervals (e.g., every three months in the metastatic setting and every six weeks in the neoadjuvant setting) during treatment to ensure that LVEF is within the institution’s normal limits. If LVEF is < 45%, or is 45% to 49% with a 10% or greater absolute decrease below the pretreatment value, withhold PERJETA and trastuzumab and repeat LVEF assessment within approximately 3 weeks. Discontinue PERJETA and trastuzumab if the LVEF has not improved or has declined further, unless the benefits for the individual patient outweigh the risks [see Dosage and Administration (2.2)].

5.3 Infusion-Related Reactions PERJETA has been associated with infusion reactions [see Adverse Reactions (6.1)]. An infusion reaction was defined in Study 1 as any event described as hypersensitivity, anaphylactic reaction, acute infusion reaction, or cytokine release syndrome occurring during an infusion or on the same day as the infusion. The initial dose of PERJETA was given the day before trastuzumab and docetaxel to allow for the examination of PERJETA-associated reactions. On the first day, when only PERJETA was administered, the overall frequency of infusion reactions was 13.0% in the PERJETAtreated group and 9.8% in the placebo-treated group. Less than 1% were Grade 3 or 4. The most common infusion reactions (≥ 1.0%) were pyrexia, chills, fatigue, headache, asthenia, hypersensitivity, and vomiting.

During the second cycle when all drugs were administered on the same day, the most common infusion reactions in the PERJETA-treated group (≥ 1.0%) were fatigue, dysgeusia, hypersensitivity, myalgia, and vomiting.

In Study 2 and Study 3, PERJETA was administered on the same day as the other study treatment drugs. Infusion reactions were consistent with those observed in Study 1, with a majority of reactions being National Cancer Institute - Common Terminology Criteria for Adverse Events (NCI CTCAE v3.0) Grade 1 – 2.

Observe patients closely for 60 minutes after the first infusion and for 30 minutes after subsequent infusions of PERJETA. If a significant infusion-related reaction occurs, slow or interrupt the infusion, and administer appropriate medical therapies. Monitor patients carefully until complete resolution of signs and symptoms. Consider permanent discontinuation in patients with severe infusion reactions [see Dosage and Administration (2.2)].

5.4 Hypersensitivity Reactions/Anaphylaxis In Study 1, the overall frequency of hypersensitivity/ anaphylaxis reactions was 10.8% in the PERJETA-treated group and 9.1% in the placebo-treated group. The incidence of Grade 3 – 4 hypersensitivity/anaphylaxis reactions was 2.0% in the PERJETA-treated group and 2.5% in the placebotreated group according to NCI - CTCAE v3.0. Overall, 4 patients in PERJETA-treated group and 2 patients in the placebo-treated group experienced anaphylaxis.

In Study 2 and Study 3, hypersensitivity/anaphylaxis events were consistent with those observed in Study 1. In Study 2, two patients in the PERJETA- and docetaxel-treated group experienced anaphylaxis. In Study 3, the overall frequency of hypersensitivity/anaphylaxis was highest in the PERJETA plus TCH treated group (13.2%), of which 2.6% were NCICTCAE (version 3) Grade 3 – 4.

Patients should be observed closely for hypersensitivity reactions. Severe hypersensitivity, including anaphylaxis, has been observed in clinical trials with treatment of PERJETA [see Clinical Trials Experience (6.1)]. Medications to treat such reactions, as well as emergency equipment, should be available for immediate use. PERJETA is contraindicated in patients with known hypersensitivity to pertuzumab or to any of its excipients [see Contraindications (4)].

5.5 HER2 Testing Detection of HER2 protein overexpression is necessary for selection of patients appropriate for PERJETA therapy because these are the only patients studied and for whom benefit has been shown [see Indications and Usage (1) and Clinical Studies (14)]. Patients with breast cancer were required to have evidence of HER2 overexpression defined as 3+ IHC or FISH amplification ratio ≥ 2.0 in the clinical studies. Only limited data were available for patients whose breast cancer was positive by FISH, but did not demonstrate protein overexpression by IHC. Assessment of HER2 status should be performed by laboratories using FDA-approved tests with demonstrated proficiency in the specific technology being utilized.

Improper assay performance, including use of sub-optimally fixed tissue, failure to utilize specified reagents, deviation from specific assay instructions, and failure to include appropriate controls for assay validation, can lead to unreliable results.

6 ADVERSE REACTIONS The following adverse reactions are discussed in greater detail in other sections of the label: • Embryo-Fetal Toxicity [see Warnings and Precautions (5.1)] • Left Ventricular Dysfunction [see Warnings and Precautions (5.2)] • Infusion-Related Reactions [see Warnings and Precautions (5.3)] • Hypersensitivity Reactions/Anaphylaxis [see Warnings and Precautions (5.4)] 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.

Metastatic Breast Cancer (MBC) The adverse reactions described in Table 1 were identified in 804 patients with HER2-positive metastatic breast cancer treated in Study 1. Patients were randomized to receive either PERJETA in combination with trastuzumab and docetaxel or placebo in combination with trastuzumab and docetaxel. The median duration of study treatment was 18.1 months for patients in the PERJETA-treated group and 11.8 months for patients in the placebo-treated group. No dose adjustment was permitted for PERJETA or trastuzumab. The rates of adverse events resulting in permanent discontinuation of all study therapy were 6.1% for patients in the PERJETA-treated group and 5.3% for patients in the placebo-treated group. Adverse events led to discontinuation of docetaxel alone in 23.6% of patients in the PERJETA-treated group and 23.2% of patients in the placebo-treated group. Table 1 reports the adverse reactions that occurred in at least 10% of patients in the PERJETA-treated group. The safety profile of PERJETA remained unchanged with an additional year of follow-up (median total follow-up of 30 months) in Study 1.

The most common adverse reactions (> 30%) seen with PERJETA in combination with trastuzumab and docetaxel were diarrhea, alopecia, neutropenia, nausea, fatigue, rash, and peripheral neuropathy. The most common NCI - CTCAE v3.0 Grade 3 – 4 adverse reactions (> 2%) were neutropenia, febrile neutropenia, leukopenia, diarrhea, peripheral neuropathy, anemia, asthenia, and fatigue. An increased incidence of febrile neutropenia was observed for Asian patients in both treatment arms compared with patients of other races and from other geographic regions. Among Asian patients, the incidence of febrile neutropenia was higher in the pertuzumab-treated group (26%) compared with the placebo-treated group (12%).

(NCI) Comprehensive Cancer Center.

“Dr. Mayne’s leadership has been invaluable in the growth and evolution of Yale Cancer Center,” said Thomas J. Lynch, MD, Director of the Yale Cancer Center. “It is a testament to her research excellence and exceptional leadership that she has been given this new opportunity to apply her expertise to significant public health issues at the national level.”

Supporting Public Health Dr. Mayne and her trainees have received national recognition for their outstanding research, and Dr. Mayne is the recipient of several national awards in mentoring/training and for her service to many organizations, including the National Academy of Sciences. She is well known in the cancer community, having served on the Board of Scientific Counselors for the NCI. Dr. Mayne has also led a competitively funded cooperative training program in cancer epidemiology and genetics with the NCI since 2003.

The FDA center she will lead is responsible for promoting the public’s health by ensuring that the nation’s food supply is safe, sanitary, wholesome, and honestly labeled, and that cosmetic products are safe and properly labeled. The center regulates $417 billion worth of domestic food, $49 billion worth of imported foods, and over $60 billion worth of cosmetics sold across state lines, and is supported by a staff of over 800 employees, with a budget of nearly $300 million, over one-third of which supports research.

The CFSAN is the scientific, regulatory, and educational cornerstone of the U.S. food and nutrition system, working to reduce chronic diseases like cancer and obesity. In today’s global marketplace, it has an important international role as well, routinely engaging foreign governments. Drawing on her scientific background in nutrition, toxicology, epidemiology, and public health, Dr. Mayne will provide strong leadership and continue to elevate the Center’s work across many diverse areas ranging from the detection of foodborne pathogens to food labeling/health claims on foods. n

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Clinical Trials Resource Guide

Clinical Trials Actively Recruiting Patients With Hodgkin Lymphoma and Non-Hodgkin Lymphoma Compiled by Jo Cavallo

T

he information contained in this Clinical Trials Resource Guide includes clinical studies actively recruiting people with Hodgkin lymphoma, non-Hodgkin lymphoma (NHL), including AIDS-related NHL, as well as studies that are also recruiting patients with multiple myeloma and mantle cell lymphoma. The studies include pilot, phase I, II, and interventional trials evaluating gene therapy; therapies in the relapsed/refractory setting; single-agent and combination chemotherapies; and a geriatric assessment to predict chemotherapy or chemoimmunotherapy toxicity in older patients with NHL. All of the studies are listed on the National Institutes of Health website at ClinicalTrials.gov.

PILOT Study Type: Pilot/interventional/ single-group assignment Study Title: Safety and Feasibility of Gene Transfer After Frontline Chemotherapy for Non-Hodgkin Lymphoma in AIDS Patients Using Peripheral Blood Stem/Progenitor Cells Treated With a Lentivirus Vector-Encoding Multiple Anti-HIV RNAs Study Sponsor and Collaborators: City of Hope Medical Center; National Cancer Institute Purpose: To study gene therapy after front-line chemotherapy in treating patients with AIDS-related nonHodgkin lymphoma. Placing genes for anti–human immunodeficiency virus (HIV) RNA into stem/progenitor cells may make the body build an immune response to AIDS. Giving the chemotherapy drug busulfan (Busulfex) before gene therapy can help gene-modified cells engraft and work better.

Ages Eligible for Study: 18 to 65 years Genders Eligible for Study: Both Accepts Health Volunteers: No Primary Outcome Measures: Procedure related toxicity as determined by adverse events grading scale using the NCI Common Terminology Criteria for Adverse Events version 4.0 (time frame: up to 15 years) Principal Investigator: Amrita Y.

Krishnan, MD, City of Hope; 626-2564673, akrishnan@coh.org.

For More Information: Visit ClinicalTrials.gov and refer to this study by its identifier: NCT01961063 Study Type: Pilot/interventional/ single-group assignment Study Title: A Pilot Study of SingleAgent Ibrutinib in Relapsed or Refractory Transformed Indolent B-Cell NonHodgkin Lymphoma Study Sponsor and Collaborators: University of Washington; National Cancer Institute Purpose: To study ibrutinib (Imbruvica) in the treatment of patients with relapsed or refractory indolent Bcell non-Hodgkin lymphoma Ages Eligible for Study: 18 years and older Genders Eligible for Study: Both Accepts Health Volunteers: No Primary Outcome Measures: Overall response rate, combined complete response, plus partial response (time frame: up to 5 years) Principal Investigator: Ajay K. Gopal, MD, Fred Hutchinson Cancer Research Center/University of Washington Cancer Consortium; 206-288-2037 For More Information: Visit ClinicalTrials.gov and refer to this study by its identifier: NCT02207062

PHASE I Study Type: Phase I/interventional/single-group assignment Study Title: Phase I Study of the Aurora Kinase Inhibitor MLN8237 in Combination With the Histone Deacetylase Inhibitor Vorinostat in Lymphoid Malignancies Study Sponsor and Collaborators: National Cancer Institute Purpose: To study the side effects and the best dose of alisertib (MLN8237) when given together with vorinostat (Zolinza) in treating patients with relapsed or recurrent Hodgkin lymphoma, B-cell non-Hodgkin lymphoma, or peripheral T-cell lymphoma Ages Eligible for Study: 18 years and older Genders Eligible for Study: Both Accepts Health Volunteers: No Primary Outcome Measures: Maximum-tolerated dose of alisertib defined as the highest dose tested in

which less than 33% of patients experienced dose-limiting toxicity graded according to the NCI Common Terminology Criteria for Adverse Events version 4.0 (time frame: 21 days) Principal Investigator: Tanya Siddiqi, MD, Beckman Research Institute; 626-256-4673, tanyasiddiqi@coh.org For More Information: Visit ClinicalTrials.gov and refer to this study by its identifier: NCT01567709 Study Type: Phase I/interventional/single-group assignment Study Title: A Phase I Study of MLN8237 in Combination With Bortezomib and Rituximab in Relapsed and Refractory Mantle Cell and Low Grade Non-Hodgkin Lymphoma Study Sponsor and Collaborators: National Cancer Institute Purpose: To study the side effects and best dose of alisertib (MLN8237) and bortezomib (Velcade) when given together with rituximab (Rituxan) in treating patients with mantle cell lymphoma or B-cell low-grade non-Hodgkin lymphoma that has relapsed or is refractory Ages Eligible for Study: 18 years and older Genders Eligible for Study: Both Accepts Health Volunteers: No Primary Outcome Measures: Recommended phase II dose of alisertib when combined with bortezomib and rituximab, defined as the highest dose level at which < 33% of the dose cohort experience a dose-limiting toxicity (time frame: 21 days) Principal Investigator: Catherine S. Diefenbach, MD, Montefiore Medical Center; 212-731-5670, catherine. diefenbach@nyumc.org For More Information: Visit ClinicalTrials.gov and refer to this study by its identifier: NCT01695941 Study Type: Phase I/interventional/single-group assignment Study Title: Phase I Study of the Administration of EBV CTLs Expressing CD30 Chimeric Receptors for Relapsed CD30+ Hodgkin’s Lymphoma and CD30+ Non-Hodgkin’s Lymphoma (CAR CD 30) Study Sponsor and Collaborators: Baylor College of Medicine; Center for Cell and Gene Therapy, Baylor College of Medicine; Texas Children’s Hospital;

The Methodist Hospital System Purpose: Researchers have found that they can put a new gene into T cells that will make them recognize cancer cells and kill them. This study will investigate whether researchers can attach a new gene to T cells that will help them do a better job at recognizing and killing lymphoma cells.

Ages Eligible for Study: 18 years and older Genders Eligible for Study: Both Accepts Health Volunteers: No Primary Outcome Measures: To evaluate the safety of escalating doses of autologous EBV-specific cytotoxic T lymphocytes (time frame: 6 weeks) Principal Investigator: Helen E. Heslop, MD, Baylor College of Medicine/Center for Cell and Gene Therapy; 832-824-4662, heheslop@txch.org For More Information: Visit ClinicalTrials.gov and refer to this study by its identifier: NCT01192464 Study Type: Phase I/interventional/single-group assignment Study Title: Phase I Dose-Escalation Study of CPI-613, in Combination With Bendamustine, in Patients With Relapsed or Refractory T-Cell NonHodgkin Lymphoma or Classic Hodgkin Lymphoma Study Sponsor and Collaborators: Comprehensive Cancer Center of Wake Forest University; National Cancer Institute Purpose: To test the side effects and best dose of CPI-613 when given together with bendamustine hydrochloride (Treanda) in patients with relapsed or refractory T-cell non-Hodgkin lymphoma or Hodgkin lymphoma Ages Eligible for Study: 18 years and older Genders Eligible for Study: Both Accepts Health Volunteers: No Primary Outcome Measures: Maximum tolerated dose of 6,8-bis (benzylthio) octanoic acid when used in combination with bendamustine hydrochloride, defined as the dose level immediately below the dose level that induced a dose-limiting toxicity in patients (time frame: up to 28 days) Principal Investigator: Zanetta S. Lamar, MD, Comprehensive Cancer Center of Wake Forest University; 336716-7448, ziamar@wakehealth.edu continued on page 126

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Clinical Trials Resource Guide Hodgkin and Non-Hodgkin Lymphoma continued from page 125

For More Information: Visit ClinicalTrials.gov and refer to this study by its identifier: NCT02168140 Study Type: Phase I/interventional/single-group assignment Study Title: Phase I Study of Cellular Immunotherapy Using Central Memory-Enriched T Cells Lentivirally Transduced to Express a CD19Specific, Hinge-Optimized, CD28-Costimulatory Chimeric Receptor and a Truncated EGFR Following Peripheral Blood Stem Cell Transplantation for Patients With High-Risk Intermediate Grade B-Lineage Non-Hodgkin ­Lymphoma Study Sponsor and Collaborators: City of Hope Medical Center; National Cancer Institute Purpose: To investigate the highest possible dose of central memory enriched T cells that can be given following standard stem cell transplant before unmanageable side effects are seen in patients with B-cell non-Hodgkin lymphoma that has returned after previous treatment Ages Eligible for Study: 18 years and older Genders Eligible for Study: Both Accepts Health Volunteers: No Primary Outcome Measures: Incidence of dose-limiting toxicities defined as any grade 3 or higher toxicity requiring the use of steroids, any grade 3 or greater autoimmune toxicity, or failure for a research participant with documented T-cell persistence to engraft by day 21 post–hematopoietic stem cell transplant (time frame: up to 28 days) Principal Investigator: Leslie L. Popplewell, MD, City of Hope Medical Center; 800-826-4673 For More Information: Visit ClinicalTrials.gov and refer to this study by its identifier: NCT02051257 Study Type: Phase I/interventional/single-group assignment Study Title: Phase I and Pharmacokinetic Study of Ibrutinib in HIVInfected Patients With Relapsed or Refractory B-Cell Non-Hodgkin Lymphoma or Multiple Myeloma Study Sponsor and Collaborators: National Cancer Institute Purpose: To study the side effects and best dose of ibrutinib (Imbruvica) in the treatment of B-cell non-Hodgkin lymphoma that has recurred or does

not respond to treatment in patients with human immunodeficiency virus (HIV) infection Ages Eligible for Study: 18 years and older Genders Eligible for Study: Both Accepts Health Volunteers: No Primary Outcome Measures: Incidence of toxicities assessed using NCI Common Terminology Criteria for Adverse Events version 4.0 (time frame: 28 days) Principal Investigator: Yvette L. Kasamon, MD, AIDS Associated Malignancies Clinical Trials Consortium; 410-955-8839, ykasamon@jhmi.edu For More Information: Visit ClinicalTrials.gov and refer to this study by its identifier: NCT02109224

PHASE II Study Type: Phase II/Interventional/Single Group Assignment Study Title: A Phase 2 Multicenter Study of High Dose Chemotherapy With Autologous Stem Cell Transplant Followed by Maintenance Therapy With Romidepsin for the Treatment of T-Cell Non-Hodgkin Lymphoma Study Sponsor and Collaborators: Memorial Sloan Kettering Cancer Center; University of Washington; Weill Medical College of Cornell University Purpose: To test the benefit of romidepsin (Istodax) in patients with Tcell non-Hodgkin lymphoma who have undergone autologous transplantation Ages Eligible for Study: 16 years and older Genders Eligible for Study: Both Accepts Health Volunteers: No Primary Outcome Measures: Progression-free survival for patients with high-risk histologies (time frame: 2 years) Principal Investigator: Steven Horowitz, MD, Memorial Sloan Kettering Cancer Center; 212-639-3045 For More Information: Visit ClinicalTrials.gov and refer to this study by its identifier: NCT01908777 Study Type: Phase II/interventional/single-group assignment Study Title: A Phase II Trial of Prostaglandin E2 Inhibition, Using Meloxicam, Plus Filgrastim for Mobilization of Autologous Peripheral Blood Stem Cells in Patients With Multiple Myeloma and Non-Hodgkin’s Lymphoma Study Sponsor and Collaborators: Indiana University; National Cancer Institute Purpose: This trial is an open-label

Simon optimal two-stage phase II trial of fixed doses of oral meloxicam and subcutaneous filgrastim (Neupogen) to assess the safety and efficacy in mobilizing autologous peripheral blood stem cells from patients with multiple myeloma and non-Hodgkin lymphoma who are planning to undergo high-dose chemotherapy with stem cell support.

Clinical data regarding the cellular composition and function of the graft mobilized by this combination will be obtained.

Ages Eligible for Study: 18 years and older Genders Eligible for Study: Both Accepts Health Volunteers: No Primary Outcome Measures: Number of patients who mobilize and collect at least half of the total target CD34-positive cell dose in the first apheresis (time frame: 4 years) Principal Investigator: Sherif Farag, MBBS, PhD, Indiana University; 317-944-1781, ssfarag@iupui.edu For More Information: Visit ClinicalTrials.gov and refer to this study by its identifier: NCT02078102 Study Type: Phase II/interventional/single-group assignment Study Title: Once Daily Intravenous Busulfex as Part of Reduced-toxicity Conditioning for Patients With Relapsed/Refractory Hodgkin’s and Non-Hodgkin’s Lymphomas Undergoing Allogeneic Hematopoietic Progenitor Cell Transplantation—A Multicenter Phase II Study Study Sponsor and Collaborators: West Virginia University Purpose: To investigate reduced toxicity conditioning with once daily intravenous busulfan (Busulfex) and fludarabine in patients with relapsed/ refractory Hodgkin and non-Hodgkin lymphoma undergoing allogeneic hematopoietic cell transplantation Ages Eligible for Study: 18 to 70 years Genders Eligible for Study: Both Accepts Health Volunteers: No Primary Outcome Measures: To assess 1 year progression-free survival in patients with chemotherapy-refractory Hodgkin and non-Hodgkin lymphoma undergoing reduced-toxicity conditioning with once daily intravenous busulfan and fludarabine (time frame: 1 year) Principal Investigator: Abraham Kanate, MD, West Virginia University.

Contact: Crystal Stevens, MT; 304-5984512, stevensc@wvuhealthcare.com For More Information: Visit Clini-

calTrials.gov and refer to this study by its identifier: NCT01203020

INTERVENTIONAL Study Type: Interventional/singlegroup assignment Study Title: Personalized Monitoring of Intravenous Busulfan Dosing for Patients With Lymphoma Undergoing Autologous Stem Cell Transplantation Study Sponsor and Collaborators: Case Comprehensive Cancer Center; National Cancer Institute Purpose: To investigate personalized dose monitoring of busulfan (Busulfex) and combination chemotherapy in treating patients with Hodgkin or non-Hodgkin lymphoma undergoing stem cell transplant Ages Eligible for Study: 2 years and older Genders Eligible for Study: Both Accepts Health Volunteers: No Primary Outcome Measures: Feasibility of performing real-time therapeutic dose monitoring, determined by the proportion of enrolled patients who are able to have an area under the curve for busulfan calculated (time frame: up to day 6) Principal Investigator: Brian T. Hill, MD, Case Comprehensive Cancer Center; 216-445-9451, hillb2@ccf.org For More Information: Visit ClinicalTrials.gov and refer to this study by its identifier: NCT01959477 Study Type: Interventional/nonrandomized/parallel assignment Study Title: Comprehensive Geriatric Assessment to Predict Toxic Events in Older Patients With Non-Hodgkin Lymphoma With Imbedded Pilot Study of Pre-Phase Therapy Study Sponsor and Collaborators: Memorial Sloan Kettering Cancer Center Purpose: To evaluate the ability of a largely self-administered geriatric assessment to predict toxicity in patients 60 years and older with non-Hodgkin lymphoma receiving chemotherapy or chemoimmunotherapy Ages Eligible for Study: 60 years and older Genders Eligible for Study: Both Accepts Health Volunteers: No Primary Outcome Measures: Toxicity assessment (time frame: 3 years) Principal Investigator: Paul Hamlin, MD, Memorial Sloan Kettering Cancer Center; 212-639-6143 For More Information: Visit ClinicalTrials.gov and refer to this study by its identifier: NCT01829958 n

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Announcements

Fred Hutchinson Cancer Research Center Recruits D. Gary Gilliland, MD, PhD as New President and Director

F

red Hutchinson Cancer Research Center announced that it has named D. Gary Gilliland, MD, PhD, an expert in cancer genetics and precision medicine as its new President and Director. He will take the helm as the Center’s new leader on January 2.

comes up with ideas and a hypothesis before anyone else does, and has tech know-how,” he said.

Gilliland has received many honors and awards for his academic research,

including the William Dameshek Prize from the American Society of Hematology, the Emil J. Freireich Award from the MD Anderson Cancer Center and the Stanley J. Korsmeyer

Award from the American Society for Clinical Investigation, of which he is an elected member. He is also an elected member of the American Association of Physicians. n

NOW ENROLLING: 2L T790M+ MUTANT EGFR NSCLC

D. Gary Gilliland, MD, PhD

Dr. Gilliland comes to Fred Hutchinson from the University of Pennsylvania’s Perelman School of Medicine, where he was the Vice President of Precision Medicine. Prior to that he was an executive at Merck Research Laboratories and also spent more than 20 years at Harvard Medical School, where he was a Professor of Medicine and a Howard Hughes Medical Institute investigator.

Seminal Discoveries Dr. Gilliland has made seminal discoveries that have shed light on the genetic basis of leukemias and other blood cancers. His work has led to the development of new investigational cancer treatments, including precise, molecularly targeted therapies tailored to the unique characteristics of each patient’s tumor.

He is deeply familiar with Fred Hutch’s innovative research in the areas of immunotherapy, personalized medicine, bone marrow transplantation and more, so when he was tapped for the position, he said he couldn’t resist.

“It feels like coming home,” he said.

“It feels like I’ve been preparing my entire life for this job. This is the perfect time and perfect place and opportunity to truly target cures for cancer.

Everything I’ve done in my career has pointed here.”

‘Deep Thinker’ Fred Appelbaum, MD, Deputy Director of Fred Hutchinson, who has known Gilliland for more than 25 years, said he couldn’t be happier about the new President and Director.

“Gary is a really wonderful scientist who thinks deeply about problems,

Evaluating the safety and efficacy of rociletinib (CO-1686) in patients with non–small cell lung cancer (NSCLC) with the T790M EGFR mutation Key inclusion criteria • Metastatic or unresectable locally advanced NSCLC • T790M mutation-positive tumor • Progression after only one prior EGFR-targeted therapy • Previous treatment with ≤1 prior chemotherapy • No intervening treatment between prior EGFR-targeted therapy and rociletinib

Rociletinib (CO-1686)

Primary endpoint • Objective response rate

For more details about the TIGER-2 trial or to refer a patient Call:

Visit:

E-mail:

• 1-855-262-3040 (inside the United States) • +1-303-625-5160 (outside the United States)

• TIGERtrials.com • clinicaltrials.gov (NCT02147990)

• ClovisTrials@emergingmed.com

Learn more about all ongoing TIGER clinical trials at TIGERtrials.com.

Rociletinib (CO-1686) is an investigational product and is not approved in any country.

Copyright © 2014 Clovis Oncology. ROCI-201 10/14

The ASCO Post | DECEMBER 1, 2014

PAGE 128

In the News Thyroid Cancer

South Korean Study Sparks Warnings About the Hazards of Overscreening

By Charlotte Bath

A

n “epidemic of diagnosis” of thyroid cancer is occurring in South Korea and “absolutely could happen here,” according to H. Gilbert Welch, MD, MPH, Professor of Medicine at the Dartmouth Institute for Health Policy and Clinical Practice, Hanover, New Hampshire. Dr. Welch is coauthor of an article in The New England Journal of Medicine1 reporting that widespread and inexpensive thyroid cancer screening in South Korea led to a 15-fold increase in the rate of thyroid cancer diagnoses there over the past 2 decades. The authors suggest that if the United States and other countries “want to prevent their own ‘epidemic,’ they will need to discourage early thyroid-cancer detection.”

In an interview with The ASCO Post, Dr. Welch said, “As a profession, this is a place where we need to actively discourage early detection, because so many people have thyroid nodules, and such a high proportion of them could be said to be cancer.” Virtually all of the tumors found in the South Korean screening program were papillary thyroid tumors,

“the vast majority of which will not produce symptoms during a person’s lifetime,” according to the journal article.

Problem Is Not Just Screening “The problem is not just screening, as in people coming in for an ultrasound,” Dr. Welch stated. Problems also arise when patients are encouraged to do neck exams. “We shouldn’t have the public starting to worry and systematically try to feel bumps in their thyroid.

That would be the wrong thing to do,” Dr. Welch said.

“We’ve got another issue,” he added, “which is that we have enough imaging going on near the thyroid that physicians stumble on to thyroid nodules” while performing carotid duplex or other scans. And “once they’re stumbled on,” it sets in motion the sequence of diagnosis and treatment.

“It would be very useful for us also to discourage that kind of action,” Dr. Welch noted.

“The first thing is to mitigate as much unnecessary testing as possible.

I think we need more balance in the messaging, because for years, the only message that the general public has been hearing is that you should be looking for early forms of every disease, the earlier the better. We need more nuance than that.

—H. Gilbert Welch, MD, MPH

We’ve got people going into scanners too frequently anyway. But when thyroid abnormalities are identified, patients shouldn’t be scared about them, and for most small thyroid nodules that are incidentally detected, we shouldn’t be pursuing them,” he said. “So it has to be broader than just saying, don’t screen for thyroid cancer using ultrasound.”

Dr. Welch applauds the recently released guidelines from the American College of Radiology recommending that incidentally detected thyroid nodules less than 1.5 cm in size (< 1 cm in

patients younger than age 35) recieve no further evaluation.2

Consequences of Treatment “The majority of patients given diagnoses of thyroid cancer have their thyroid removed,” Dr. Welch wrote in an op-ed piece for The New York Times.3 According to the data for South Korea, virtually all are treated and roughly twothirds of the patients had radical thyroidectomy and require lifelong thyroid replacement therapy. “An analysis of continued on page 130

Expect Questions From Patients

S

creening for thyroid cancer should be discouraged to prevent an “epidemic of diagnosis”—like the one occurring in South Korea—from happening in the United States and other countries, according to the authors of an analysis of the South Korean screening program. That study was published in The New England Journal of Medicine.1 In an op-ed piece in The New York Times,2 one of the study’s authors, H. Gilbert Welch, MD, MPH, further explained the implications of the study.

Dr. Welch, Professor of Medicine at the Dartmouth Institute for Health Policy and Clinical Practice, Hanover, New Hampshire, cautioned readers, “Having doctors not look too hard for early cancer is in your interest.”

That message might seem jarring to patients used to hearing that early detection is their best defense against cancer. What they need to understand, Dr. Welch said in an interview with The ASCO Post, is that the vast majority of cancers discovered by thyroid cancer screening are papillary thyroid cancers, many of which will never become evident during a per-

son’s lifetime except through screening or as incidental findings from imaging tests near the thyroid.

Once found, these cancers are usually treated with radical thyroidectomy,

the potential benefit in the future— and who are willing to accept the chance of harm from unneeded treatment now—may also decide that the screening makes sense for them,” Dr.

It is not that all early detection is bad. The question is: how early? If we always go in the same direction, looking for smaller and smaller lesions, it is a recipe for finding something wrong with all of us.

—H. Gilbert Welch, MD, MPH

requiring lifelong thyroid replacement.

Hypoparathyroidism and vocal-cord paralysis has occurred as a surgical complication in a small percentage of patients.

Makes Sense in Some Cases “Of course, screening makes sense in some situations: in particular for people who are at a genuinely high risk for the cancer—those with multiple cancer deaths in their family history. People at average risk who expect to live long enough to experience

Welch wrote in The New York Times.2 “It is not that all early detection is bad,” he told The ASCO Post. “The question is: how early? If we always go in the same direction, looking for smaller and smaller lesions, it is a recipe for finding something wrong with all of us. So we have to understand that this question of how early is going to become more important as we are increasingly able to identify tiny perturbations in immune function or biochemical information, or genetic marker or imaging structural abnormalities.”

Understanding the Balances “When we are talking about screening, we are talking about trying to get ahead of symptoms. And whenever you try to get ahead of symptoms, you are going to be treating some people for something that is never going to bother them. That treatment may lead to anxiety. It may cost them a lot of money, and can even lead to death,” Dr. Welch said.

“There are balances, and it is a matter of having people understand those balances, and also having the system understand those balances—so we are not always going to the most extreme, looking for the smallest abnormality, trying to find the most abnormalities, and turning the most people into patients.” n

Disclosure: Dr. Welch reported no potential conflicts of interest.

References 1. Ahn HS, Kim HJ, Welch HG: Korea’s thyroid-cancer “epidemic”—screening and overdiagnosis. N Engl J Med 371:17651767, 2014.

2. Welch HG: An epidemic of thyroid cancer? New York Times, November 5, 2014.

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PAGE 130

In the News Hazards of Overscreening continued from page 128

insurance claims for more than 15,000 Koreans who underwent surgery showed that 11% had hypoparathyroidism and 2% had vocal-cord paralysis,” according to The New England Journal article.

Dr. Welch noted that it “is a very useful step to move from” radical thyroidectomy to lobectomy (a less extensive surgery removing only half the thyroid) because “there is a good chance you will not need thyroid replacement, and your chance of hypoparathyroidism goes to almost 0.”

In this country, too, most people diagnosed with thyroid cancer “do get thyroid-directed surgery,” Dr. Welch said. From the Surveillance, Epidemiology, and End Results (SEER) data, “it looks like most are coded as radical thyroidectomy,” he added.

Some Opt for Observation “Some doctors are willing to manage these small cancers with observation.

And, of course, that makes more sense,” Dr. Welch stated.

A news article about the thyroid

cancer screening study reported in The New York Times: “A few places, like Memorial Sloan Kettering Cancer Center in Manhattan, offer patients with small tumors the option of simply waiting and having regular scans to see if the tumor grows. But few patients have joined the program.”4 “I understand that,” Dr. Welch said.

“It is always hard once you say someone has cancer; in some sense, the horse is out of the barn. But it does make it clear that more and more doctors are getting sensitized to this problem—not just in thyroid cancer, but in early cancer detection in general. And that’s good.”

How Do We Know It’s Overdiagnosis?

Although the rate of diagnosis of thyroid cancer in South Korea has increased 15-fold since 1993, the mortality rate has remained stable. “If the screening were saving lives,” Dr. Welch noted, “the death rate would decline or increase more slowly as the epidemic spread—but not stay perfectly flat.”

The mass screenings for thyroid cancer in South Korea were not begun

as a result of any particular perceived high risk, Dr. Welch stated. As The New England Journal article pointed out, the screenings were an add-on to a 1999 national cancer-screening program. “Although thyroid-cancer screening was not included in the program, providers frequently chose to offer screening with ultrasonography as an inexpensive add-on for $30 to $50,” according to the journal article.

“Remember, this is a single-payer system, but it has an active private sector that is delivering it—fee-for-service doctors and hospitals—and this was an easy extra service for them to sell. They already had the ultrasound machines. They were very common, and there was all this messaging about early cancer detection. They could add on a thyroid ultrasound, and patients would pay for it out of pocket,” Dr. Welch said. “It just sort of worked well with the general promotion of screening…. Then you generate a fair amount of money afterward, because you find a lot of nodules and get a lot of biopsies,” he continued.

“I think understanding this example could help people understand how far

wrong you can go with an early-detection strategy,” Dr. Welch said. “You can end up treating a whole lot more people for something that was never going to bother them.”

He added, “I think we need more balance in the messaging, because for years, the only message that the general public has been hearing is that you should be looking for early forms of every disease, the earlier the better. We need more nuance than that.” n

Disclosure: Dr. Welch reported no potential conflicts of interest.

References 1. Ahn HS, Kim HJ, Welch HG: Korea’s thyroid-cancer “epidemic”—screening and overdiagnosis. N Engl J Med 371:17651767, 2014.

2. Hoang JK, Langer, JE, Middleton WD, et al: Managing incidental thyroid nodules detected on imaging: White paper of the ACR Incidental Thyroid Findings Committee. J Am Coll Radiol 2014 (in press).

3. Welch HG: An epidemic of thyroid cancer? New York Times, November 5, 2014.

4. Kolata G: Study points to overdiagnosis of thyroid cancer, New York Times, November 5, 2014.

Contact The ASCO Post Advertising

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PAGE 131

Announcements Guidelines

NCCN Publishes 20th Annual Guidelines in NSCLC, Reflecting Advances in Screening, Diagnosis, Radiology, and Systemic Therapies cess in which the expert panels integrate comprehensive clinical and scientific data with the judgment of the multidisciplinary panel members and other experts drawn from NCCN Member In-

stitutions. Access to the complete library of NCCN Guidelines is available free-ofcharge at NCCN.org.

“Today, lung cancer is the second most common cancer in both men and

After progression following initial antiestrogen therapy in postmenopausal women with hormone receptor-positive (HR+) metastatic breast cancer (mBC)...

David S. Ettinger, MD, FACP, FCCP

de

xU

p d ate d D

Primary Endpoint: Progression-Free Survival (PFS)1,*

A Secondary Endpoint: Overall Survival (OS)1

Median 6.5 months with FASLODEX 500 mg vs 5.4 months with 250 mg in CONFIRM2,†

Median 26.4 months with FASLODEX 500 mg vs 22.3 months with 250 mg in CONFIRM2

At minimum 18-month follow-up, HR=0.80 (95% CI: 0.68-0.94) (P=0.006) 2

m .c o

Final O Analy S sis From CONFI RM*

le

“Today, clinicians understand the importance of histology—adenocarcinoma vs squamous cell carcinoma—as well as the use of molecular diagnostic studies,” said Dr. Ettinger. “Systemic therapy has come a long way with innovations in adjuvant and maintenance therapies, as well as the use of bevacizumab [Avastin] and targeted therapies. In the future, we will likely look to further innovation in immunotherapy, as well.”

NCCN currently develops and publishes a library of 60 NCCN Guidelines, covering 97% of malignant cancers. The NCCN Guidelines are developed and updated through an evidence-based pro-

Now Availa b

o

Other Key Advances

Go with FASLODEX. w w w.F asl

David S. Ettinger, MD, FACP, FCCP, Alex Grass Professor of Oncology, The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, and NCCN Guidelines Panel Chair for NSCLC. Dr. Ettinger, who has chaired the NCCN Guidelines Panel for NSCLC since 1996, notes major accomplishments in the diagnosis and treatment of NSCLC, including the use of low-dose computed tomography (CT) scan in screening for NSCLC, as well as positronemission tomography (PET)/CT scan in diagnosis. According to Dr. E ­ ttinger, notable radiotherapy advances include stereotactic body radiotherapy and intensity-modulated radiotherapy. In surgery, he said, the use of video-assisted thoracic surgery or minimally invasive surgery has been an important advance.

women, and NCCN is proud to have played a pivotal role in promoting the optimal care for these patients for 20 years,” said Robert W. Carlson, MD, Chief Executive Officer, NCCN. n

ta

T

he National Comprehensive Cancer Network (NCCN) has published the 20th annual edition of the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Non-Small Cell Lung Cancer (NSCLC), one of the eight original NCCN Guidelines published in November 1996.

“Since the first NCCN Guidelines for NSCLC were published 20 years ago, there have indeed been many advances in the diagnosis, screening, and treatment of non–small cell lung cancer,” said

a

• Not statistically signifcant as no adjustments were made for multiplicity2

At minimum 50-month follow-up, HR=0.81 (95% CI: 0.69-0.96) 2

Important Safety Information About FASLODEX • FASLODEX is contraindicated in patients with known hypersensitivity to the drug or to any of its components. Hypersensitivity reactions, including urticaria and angioedema have been reported in association with FASLODEX • Because FASLODEX is administered intramuscularly, it should be used with caution in patients with bleeding diatheses, thrombocytopenia, or in patients on anticoagulants • FASLODEX is metabolized primarily in the liver. A 250-mg dose is recommended in patients with moderate hepatic impairment. FASLODEX has not been evaluated in patients with severe hepatic impairment (Child-Pugh Class C) Please see additional Important Safety Information on reverse and brief summary of full Prescribing Information for FASLODEX on following pages. * PFS is defned as the time between randomization and the

earliest evidence of progression or death from any cause. 2 † COmparisoN of FASLODEX In Recurrent or Metastatic Breast Cancer.1

Go with Confdence Learn more at www.FaslodexUpdatedData.com

The ASCO Post | DECEMBER 1, 2014

PAGE 132

Announcements

Huntsman Cancer Institute Investigator Receives Leadership Award from the National Cancer Institute

N

eeraj Agarwal, MD, a Huntsman Cancer Institute investigator and Associate Professor of Medicine at the University of Utah, has received the 2014 Cancer Clinical Investigator Team

Leadership Award from the National Cancer Institute (NCI). This highly competitive award recognizes exceptional cancer investigators for contributions to advancing clinical research

through collaborative team science.

Only 12 physicians nationwide received the $100,000 awards to support their clinical research leadership efforts over a 2-year period. Dr. Agarwal’s re-

search focuses on clinical trials in advanced prostate cancer and other urologic cancers.

As Associate Director of Huntsman Cancer Institute’s Clinical Trials Office, Dr.

FASLODEX is indicated for the treatment of hormone receptor-positive (HR+) metastatic breast cancer (mBC) in postmenopausal women with disease progression following antiestrogen therapy.

See more a t

FASLODEX 500 mg vs 250 mg in the Updated OS Analysis in CONFIRM2,§ • Median 26.4 months with FASLODEX 500 mg vs 22.3 months with 250 mg at minimum 50-month follow-up, HR=0.81 (95% CI: 0.69-0.96)2 • Not statistically signifcant as no adjustments were made for multiplicity.2 • In the initial OS analysis after a minimum duration of 18 months, there was no statistically signifcant difference in OS between the 2 treatment groups2 * The CONFIRM trial was a randomized, double-blind, controlled phase III

study of 736 postmenopausal women with advanced breast cancer who had disease recurrence on or after adjuvant endocrine therapy or progression following endocrine therapy for advanced disease.1 † PFS was the primary endpoint.1 ‡ ORR is defned as the number of patients with complete response or partial response.2 § OS was a secondary endpoint.1

em FASLODEX 500 mg Showed 4 b er 01 9-1 3, 2 a Comparable Safety Profle to FASLODEX 250 mg in CONFIRM1 c

• Median 6.5 months with FASLODEX 500 mg vs 5.4 months with 250 mg at minimum 18-month follow-up, HR=0.80 (95% CI: 0.68-0.94) (P=0.006)2 • Objective response rates (ORRs)‡ were not signifcantly different between FASLODEX 500 mg (13.8%) and 250 mg (14.6%) (OR=0.94; 95% CI: 0.57-1.55) (P=0.795)1,2 — Only patients with measurable disease at baseline were analyzed (FASLODEX 500 mg: n=240; FASLODEX 250 mg: n=261)2 — ORRs in the full patient population were 9.1% and 10.2% for the FASLODEX 500 mg and 250 mg arms, respectively1

De

Prolonged PFS With FASLODEX 500 mg vs 250 mg in CONFIRM2,*,†

SABC BoothS #465

Additional Important Safety Information About FASLODEX

• Fetal harm can occur when administered to a pregnant woman. Women should be advised of the potential hazard to the fetus and to avoid becoming pregnant while receiving FASLODEX • The most common, clinically signifcant adverse reactions occurring in ≥5% of patients receiving FASLODEX were: injection site pain, nausea, bone pain, arthralgia, headache, back pain, fatigue, pain in extremity, hot fash, vomiting, anorexia, asthenia, musculoskeletal pain, cough, dyspnea, and constipation • Increased hepatic enzymes (ALT, AST, ALP) occurred in >15% of FASLODEX users and were non dose-dependent Indication For FASLODEX • FASLODEX is indicated for the treatment of hormone receptor-positive metastatic breast cancer in postmenopausal women with disease progression following antiestrogen therapy

Please read brief summary of full Prescribing Information for FASLODEX on following pages.

References: 1. Di Leo A, Jerusalem G, Petruzelka L, et al. Results of the CONFIRM phase III trial comparing fulvestrant 250 mg with fulvestrant 500 mg in postmenopausal women with estrogen receptor–positive advanced breast cancer. J Clin Oncol. 2010;28(30):4594-4600. 2. Full Prescribing Information for FASLODEX. AstraZeneca Pharmaceuticals LP, Wilmington, DE.

Go with Confdence FASLODEX is a registered trademark of the AstraZeneca group of companies.

©2014 MedImmune, Specialty Care Division of AstraZeneca.

All rights reserved.

3017912

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ASCOPost.com | DECEMBER 1, 2014

PAGE 133

Announcements

Neeraj Agarwal, MD

Agarwal facilitates development of innovative clinical trial protocols. The award will allow him to dedicate more time to mentoring junior faculty, fellows, and residents in both research and career development, as well as providing clinical trial education for faculty and community clinicians.

Dr. Agarwal will continue active participation in SWOG, one of the four

FASLODEX® (fulvestrant) Injection

national adult cancer research groups in the NCI-funded National Clinical Trial Network, and in his own investigatorinitiated clinical trials.

Early Career Agarwal received his medical degree from All India Institute of Medical Sciences in New Delhi, India, and com-

Table 1: Summary of Most Commonly Reported Adverse Reactions in Study 1 (≥5% in either treatment group): Safety Population Body System Number (%) of Patients Fulvestrant 500 mg N=361

Fulvestrant 250 mg N=374

Injection Site Pain

42 (11.6)

34 (9.1)

Headache

28 (7.8)

25 (6.7)

DOSAGE AND ADMINISTRATION

Back Pain

27 (7.5)

40 (10.7)

Recommended Dose

Fatigue

27 (7.5)

24 (6.4)

Pain in Extremity

25 (6.9)

26 (7.0)

Asthenia

21 (5.8)

23 (6.1)

24 (6.6)

22 (5.9)

Nausea

35 (9.7)

51 (13.6)

Vomiting

22 (6.1)

21 (5.6)

Anorexia

22 (6.1)

14 (3.7)

Constipation

18 (5.0)

13 (3.5)

Bone Pain

34 (9.4)

28 (7.5)

Arthralgia

29 (8.0)

29 (7.8)

Musculoskeletal Pain

20 (5.5)

12 (3.2)

Cough

19 (5.3)

20 (5.3)

Dyspnea

16 (4.4)

19 (5.1)

BRIEF SUMMARY For full Prescribing Information, see package insert.

INDICATIONS AND USAGE FASLODEX is indicated for the treatment of hormone receptor positive metastatic breast cancer in postmenopausal women with disease progression following antiestrogen therapy.

The recommended dose is 500 mg to be administered intramuscularly into the buttocks slowly (1 - 2 minutes per injection) as two 5 mL injections, one in each buttock, on days 1, 15, 29 and once monthly thereafter [see Clinical Studies (14) in full Prescribing Information].

Dose Modification Hepatic Impairment: A dose of 250 mg is recommended for patients with moderate hepatic impairment (Child-Pugh class B) to be administered intramuscularly into the buttock slowly (1 - 2 minutes) as one 5 mL injection on days 1, 15, 29 and once monthly thereafter.

FASLODEX has not been evaluated in patients with severe hepatic impairment (Child-Pugh class C) [see Warnings and Precautions and Use in Specific Populations].

Administration Technique

The proper method of administration of FASLODEX for intramuscular use is described in the instructions that follow: 1. Remove glass syringe barrel from tray and check that it is not damaged.

2. Remove perforated patient record label from syringe.

3. Peel open the safety needle (SafetyGlide™) outer packaging. For complete SafetyGlide™ instructions refer below to the “Directions for Use of SafetyGlide™.”

4. Break the seal of the white plastic cover on the syringe luer connector to remove the cover with the attached rubber tip cap.

5. Twist to lock the needle to the luer connector.

6. Remove needle sheath.

7. Remove excess gas from the syringe (a small gas bubble may remain).

8. Administer intramuscularly slowly in the buttock.

9. Immediately activate needle protection device upon withdrawal from patient by pushing lever arm completely forward until needle tip is fully covered.

10. Visually confirm that the lever arm has fully advanced and the needle tip is covered. If unable to activate, discard immediately into an approved sharps collector.

11. Repeat steps 1 through 10 for second syringe.

For additional directions for use, see Administration Technique (2.3) in full Prescribing Information.

CONTRAINDICATIONS FASLODEX is contraindicated in patients with a known hypersensitivity to the drug or to any of its components. Hypersensitivity reactions, including urticaria and angioedema, have been reported in association with FASLODEX.

WARNINGS AND PRECAUTIONS Blood Disorders Because FASLODEX is administered intramuscularly, it should be used with caution in patients with bleeding diatheses, thrombocytopenia, or anticoagulant use.

Hepatic Impairment The safety and pharmacokinetics of FASLODEX were evaluated in a study in seven subjects with moderate hepatic impairment (Child-Pugh class B) and seven subjects with normal hepatic function.

Exposure was increased in patients with moderate hepatic impairment, therefore a dose of 250 mg is recommended [see Dosage and Administration].

FASLODEX has not been studied in patients with severe hepatic impairment (Child-Pugh class C) [see Use in Specific Populations].

Use in Pregnancy Based on its mechanism of action and findings in animals, FASLODEX can cause fetal harm when administered to a pregnant woman. Fulvestrant caused fetal loss or abnormalities in animals when administered during the period of organogenesis at doses significantly smaller than the maximum recommended human dose based on the body surface area. There are no adequate and wellcontrolled studies in pregnant women using FASLODEX. Women of childbearing potential should be advised not to become pregnant while receiving FASLODEX. If FASLODEX is used during pregnancy, or if the patient becomes pregnant while receiving this drug, the patient should be apprised of the potential hazard to the fetus [see Use in Specific Populations].

ADVERSE REACTIONS Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, the adverse reaction rates observed cannot be directly compared to rates in other trials and may not reflect the rates observed in clinical practice.

Comparison of FASLODEX 500 mg and FASLODEX 250 mg The following frequency categories for adverse reactions (ARs) were calculated based on the safety analysis of Study 1 that compared FASLODEX 500 mg with FASLODEX 250 mg. The most frequently reported adverse reactions in the fulvestrant 500 mg group were injection site pain (11.6% of patients), nausea (9.7% of patients) and bone pain (9.4% of patients); the most frequently reported adverse reactions in the fulvestrant 250 mg group were nausea (13.6% of patients), back pain (10.7% of patients) and injection site pain (9.1% of patients).

Table 1 lists adverse reactions reported with an incidence of 5% or greater, regardless of assessed causality, from the controlled clinical trial Study 1 comparing the administration of FASLODEX 500 mg intramuscularly once a month with FASLODEX 250 mg intramuscularly once a month.

and Adverse Reaction Body as a Whole

Vascular System

Hot Flash Digestive System

Musculoskeletal System

Respiratory System

In the pooled safety population (N=1127) from clinical trials comparing FASLODEX 500 mg to FASLODEX 250 mg, post-baseline increases of ≥1 CTC grade in either AST, ALT, or alkaline phosphatase were observed in >15% of patients receiving FASLODEX. Grade 3-4 increases were observed in 1-2% of patients. The incidence and severity of increased hepatic enzymes (ALT, AST, ALP) did not differ between the 250 mg and the 500 mg FASLODEX arms.

Comparison of FASLODEX 250 mg and Anastrozole 1 mg in Combined Trials (Studies 2 and 3) The most commonly reported adverse reactions in the FASLODEX and anastrozole treatment groups, regardless of the investigator’s assessment of causality, were gastrointestinal symptoms (including nausea, vomiting, constipation, diarrhea and abdominal pain), headache, back pain, vasodilatation (hot flashes), and pharyngitis.

Injection site reactions with mild transient pain and inflammation were seen with FASLODEX and occurred in 7% of patients (1% of treatments) given the single 5 mL injection (predominantly European Trial Study 3) and in 27% of patients (4.6% of treatments) given the 2 x 2.5 mL injections (North American Trial Study 2).

Table 2 lists adverse reactions reported with an incidence of 5% or greater, regardless of assessed causality, from the two controlled clinical trials comparing the administration of FASLODEX 250 mg intramuscularly once a month with anastrozole 1 mg orally once a day.

Table 2: Combined Data from Studies 2 and 3, Adverse Reactions ≥ 5% Body System FASLODEX 250 mg Anastrozole 1 mg N=423 N=423 and Adverse Reactiona (%) (%) Body as a Whole Asthenia Pain Headache Back Pain Abdominal Pain Injection Site Painb Pelvic Pain Chest Pain Flu Syndrome Fever Accidental Injury Cardiovascular System Vasodilatation Digestive System Nausea Vomiting Constipation Diarrhea Anorexia Hemic and Lymphatic Systems Anemia

68.3 22.7 18.9 15.4 14.4 11.8 10.9 9.9 7.1 7.1 6.4 4.5 30.3 17.7 51.5 26.0 13.0 12.5 12.3 9.0 13.7 4.5

67.6 27.0 20.3 16.8 13.2 11.6 6.6 9.0 5.0 6.4 6.4 5.7 27.9 17.3 48.0 25.3 11.8 10.6 12.8 10.9 13.5 5.0

—continued

pleted a residency in internal medicine at the University of Iowa. He then completed a hematology-oncology fellowship at Huntsman Cancer Institute.

Currently, he directs Huntsman Cancer Institute’s genitourinary medical oncology program and coleads the urologic oncology multidisciplinary program. n

The ASCO Post | DECEMBER 1, 2014

PAGE 134

Lab Notes

Ongoing Molecular Research in the Science of Oncology NOVEL STRATEGIES Antitumor Effect of Intratumoral Injection of Clostridium Spores Species of Clostridium bacteria

have been shown to kill tumor cells growing under hypoxic conditions.

In a study reported in Science Translational Medicine, Roberts and colleagues showed that intratumoral injection of an attenuated strain

of Clostridium novyi (C novyi-NT) produced a microscopically precise tumor-localized response in a rat orthotopic brain tumor model.

In a study in naturally occurring canine solid tumors, intratumoral in-

FASLODEX® (fulvestrant) Injection Body System and Adverse Reactiona

FASLODEX 250 mg N=423 (%) Metabolic and Nutritional Disorders 18.2 Peripheral Edema 9.0 Musculoskeletal System 25.5 Bone Pain 15.8 Arthritis 2.8 Nervous System 34.3 Dizziness 6.9 Insomnia 6.9 Paresthesia 6.4 Depression 5.7 Anxiety 5.0 Respiratory System 38.5 Pharyngitis 16.1 Dyspnea 14.9 Cough Increased 10.4 Skin and Appendages 22.2 Rash 7.3 Sweating 5.0 Urogenital System 18.2 Urinary Tract Infection 6.1

Anastrozole 1 mg N=423 (%) 17.7 10.2 27.9 13.7 6.1 33.8 6.6 8.5 7.6 6.9 3.8 33.6 11.6 12.3 10.4 23.4 8.0 5.2 14.9 3.5

a A patient may have more than one adverse reaction. b All patients on FASLODEX received injections, but only those anastrozole patients who were in the North American Study 2 received placebo injections.

Post-Marketing Experience For FASLODEX 250 mg, other adverse reactions reported as drug-related and seen infrequently (<1%) include thromboembolic phenomena, myalgia, vertigo, leukopenia, and hypersensitivity reactions including angioedema and urticaria.

Vaginal bleeding has been reported infrequently (<1%), mainly in patients during the first 6 weeks after changing from existing hormonal therapy to treatment with FASLODEX. If bleeding persists, further evaluation should be considered.

Elevation of bilirubin, elevation of gamma GT, hepatitis, and liver failure have been reported infrequently (<1%).

DRUG INTERACTIONS There are no known drug-drug interactions. Although, fulvestrant is metabolized by CYP 3A4 in vitro, drug interactions studies with ketoconazole or rifampin did not alter fulvestrant pharmacokinetics.

Dose adjustment is not needed in patients co-prescribed CYP3A4 inhibitors or inducers [see Clinical Pharmacology (12.3) in full Prescribing Information].

USE IN SPECIFIC POPULATIONS Pregnancy Pregnancy Category D [see Warnings and Precautions] FASLODEX can cause fetal harm when administered to a pregnant woman. Fulvestrant caused fetal loss or abnormalities in animals when administered during the period of organogenesis at doses significantly smaller than the maximum recommended human dose based on the body surface area (BSA). Women of childbearing potential should be advised not to become pregnant while receiving FASLODEX. If FASLODEX is used during pregnancy, or if the patient becomes pregnant while receiving this drug, the patient should be apprised of the potential hazard to the fetus.

In studies in female rats at intramuscular doses ≥0.01 mg/kg/day (0.6% of the human recommended dose based on BSA), fulvestrant caused a reversible reduction in female fertility, as well as effects on embryo-fetal development consistent with its antiestrogenic activity. Fulvestrant caused an increased incidence of fetal abnormalities in rats (tarsal flexure of the hind paw at 2 mg/kg/day; equivalent to the human dose based on BSA) and non-ossification of the odontoid and ventral tubercle of the first cervical vertebra at doses ≥0.1 mg/kg/day (6% the human dose based on BSA) when administered during the period of organogenesis. Rabbits failed to maintain pregnancy when dosed intramuscularly with 1 mg/kg/day fulvestrant (equivalent to the human dose based on BSA) during the period of organogenesis. Further, in rabbits dosed at 0.25 mg/kg/day (30% the human dose based on BSA), increases in placental weight and post-implantation loss were observed.

Fulvestrant was associated with an increased incidence of fetal variations in rabbits (backwards displacement of the pelvic girdle, and 27 pre-sacral vertebrae at 0.25 mg/kg/day; 30% the human dose based on BSA) when administered during the period of organogenesis. Because pregnancy could not be maintained in the rabbit following doses of fulvestrant of 1 mg/kg/day and above, this study was inadequate to fully define the possible adverse effects on fetal development at clinically relevant exposures.

Baseline measurements for vaginal bleeding days, bone age, growth velocity, and Tanner staging for at least 6 months prior to study entry were provided retrospectively by the parent, guardian or local consultant. All measurements during the study period were collected prospectively. Patients’ baseline characteristics included the following: a mean ± SD chronological age of 5.9 ± 1.8 years; a mean rate of bone age advancement (change in bone age in years divided by change in chronological age in years) of 2.0 ± 1.03; and a mean growth velocity z-score of 2.4 ± 3.26.

Twenty-nine of 30 patients completed the 12-month study period. The following results were observed: 35% (95% CI: 16%, 57%) of the 23 patients with baseline vaginal bleeding experienced a complete cessation of vaginal bleeding on-treatment (month 0 to 12); a reduction in the rate of bone age advancement during the 12-month study period compared to baseline (mean change = -0.9 [95% CI = -1.4, -0.4]); and a reduction in mean growth velocity Z-score on-treatment compared to baseline (mean change = -1.1 [95% CI = -2.7, 0.4]). There were no clinically meaningful changes in median Tanner stage (breast or pubic), mean uterine volume, or mean ovarian volume, or predicted adult height (PAH) on-treatment compared to baseline. The effect of FASLODEX on bone mineral density in children has not been studied and is not known.

Eight patients (27%) experienced adverse reactions that were considered possibly related to FASLODEX. These included injection site reactions (inflammation, pain, hematoma, pruritis, rash), abdominal pain, contusion, tachycardia, hot flush, extremity pain, and vomiting. Nine (30.0%) patients reported an SAE, none of which were considered related to FASLODEX. No patients discontinued study treatment due to an AE and no patients died.

Pharmacokinetics The pharmacokinetics of fulvestrant was characterized using a population pharmacokinetic analysis with sparse samples per patient obtained from 30 female pediatric patients aged 1 to 8 years with PPP associated with MAS. Pharmacokinetic data from 294 postmenopausal women with breast cancer who received 125 or 250 mg monthly dosing regimen were also included in the analysis.

In these pediatric patients receiving 4 mg/kg monthly intramuscular dose of fulvestrant, the geometric mean (SD) CL/F was 444 (165) mL/min which was 32% lower than adults. The geometric mean (SD) steady state trough concentration (Cmin,ss) and AUCss was 4.19 (0. 87) ng/mL and 3680 (1020) ng*hr/mL, respectively.

Geriatric Use For FASLODEX 250 mg, when tumor response was considered by age, objective responses were seen in 22% and 24% of patients under 65 years of age and in 11% and 16% of patients 65 years of age and older, who were treated with FASLODEX in Study 2 and Study 3, respectively.

Hepatic Impairment FASLODEX is metabolized primarily in the liver.

The pharmacokinetics of fulvestrant were evaluated after a single dose of 100 mg in subjects with mild and moderate hepatic impairment and normal hepatic function (n = 7 subjects/group), using a shorter-acting intramuscular injection formulation. Subjects with mild hepatic impairment (ChildPugh class A) had comparable mean AUC and clearance values to those with normal hepatic function. In subjects with moderate hepatic impairment (Child-Pugh class B) the average AUC of fulvestrant increased by 70% compared to patients with normal hepatic function. AUC was positively correlated with total bilirubin concentration (p = 0.012). FASLODEX has not been studied in patients with severe hepatic impairment (Child-Pugh class C).

A dose of FASLODEX 250 mg is recommended in patients with moderate hepatic impairment (ChildPugh class B) [see Dosage and Administration and Warnings and Precautions].

Renal Impairment Negligible amounts of fulvestrant are eliminated in urine; therefore, a study in patients with renal impairment was not conducted. In the advanced breast cancer trials, fulvestrant concentrations in women with estimated creatinine clearance as low as 30 mL/min were similar to women with normal creatinine.

OVERDOSAGE Animal studies have shown no effects other than those related directly or indirectly to antiestrogen activity with intramuscular doses of fulvestrant higher than the recommended human dose. There is no clinical experience with overdosage in humans. No adverse reactions were seen in healthy male and female volunteers who received intravenous fulvestrant, which resulted in peak plasma concentrations at the end of the infusion, that were approximately 10 to 15 times those seen after intramuscular injection.

Nursing Mothers It is not known if fulvestrant is excreted in human milk. Fulvestrant is found in rat milk at levels significantly higher (approximately 12-fold) than plasma after administration of 2 mg/kg. Drug exposure in rodent pups from fulvestrant-treated lactating dams was estimated as 10% of the administered dose. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from FASLODEX, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.

Pediatric Use A multi-center, single-arm, open-label, study of fulvestrant was conducted in 30 girls with McCuneAlbright Syndrome (MAS) associated with progressive precocious puberty (PPP). The median age at informed consent was 6 years old (range: 1 to 8).

The first 10 patients initially received fulvestrant 2 mg/kg. Based on PK data from the first 6 patients, all 10 patients receiving 2 mg/kg were escalated to a dose of 4 mg/kg and all other patients received 4 mg/kg from study entry.

2

SafetyGlide™ is a trademark of Becton Dickinson and Company.

FASLODEX is a trademark of the AstraZeneca group of companies. © AstraZeneca 2013 Distributed by: AstraZeneca Pharmaceuticals LP, Wilmington, DE 19850 Manufactured for: AstraZeneca UK Limited, Macclesfield, Cheshire, England By: Vetter Pharma-Fertigung GMBH & Co. KG, Ravensburg, Germany Rev. 11/12 2355400 2/13

jection of the spores was well tolerated, with the most common toxicities being symptoms associated with bacterial infection. Objective response occurred in 6 (37.5%) of 16 dogs, including three complete responses.

Intratumoral injection of C novyiNT spores in a patient with advanced leiomyosarcoma resulted in tumor shrinkage within and surrounding the bone.

The investigators concluded: “Together, these results show that C novyi-NT can precisely eradicate neoplastic tissues and suggest that further clinical trials of this agent in selected patients are warranted.”

Roberts NJ, et al: Sci Transl Med 6:249ra111, 2014.

Mitochondrial Respiration as Target in KRAS-Mutant Pancreatic Cancer Targeting of oncogenes can produce tumor shrinkage, but the frequency of relapse indicates that a population of tumor cells survives oncogene inhibition. In a study in a KRAS-mutant pancreatic ductal adenocarcinoma mouse model reported in Nature, Viale and colleagues found that a subpopulation of dormant tumor cells that survived oncogene ablation and were responsible for tumor relapse had features of cancer stem cells and relied on oxidative phosphorylation for survival.

Transcriptomic and metabolic analyses of these surviving cells showed pronounced expression of genes regulating mitochondrial function, autophagy, and lysosome activity, with increased reliance on mitochondrial respiration and reduced dependence on glycolysis in cellular energy use being observed. The surviving cells were sensitive to oxidative phosphorylation inhibitors, which were found to inhibit tumor recurrence.

The investigators concluded: “Our integrated analyses illuminate a therapeutic strategy of combined targeting of the KRAS pathway and mitochondrial respiration to manage pancreatic cancer.”

Viale A, et al: Nature 514:628-632, 2014.

Selective Generation of Reactive Oxygen Species in Tumor Cells In a study reported in Clinical Cancer Research, Shin and colleagues

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Lab Notes

synthesized a novel polyphenol conjugate (DPP-23) that exerted antitumor effects by targeting the unfolded protein response in the endoplasmic reticulum via production of reactive oxygen species in cancer cells but not in normal cells. The polyphenol conjugate was synthesized on the basis of quantitative structure-activity relationships, and its molecular targets were investigated using genome-wide expression profiling by DNA microarray and real-time polymerase chain reaction array.

DPP-23 was found to inhibit the growth of various tumor cells in vitro and in vivo in Balb/c nude mice xenografts. The selective generation of reactive oxygen species resulted in tumor cell death via caspase-dependent apoptosis.

The investigators concluded: “The selective generation of [reactive oxygen species] in cancer cells could be an attractive strategy for the selective killing of cancer cells, while maintaining negligible cytotoxicity to normal cells. DPP-23 represents a promising novel therapeutic agent for the selective production of [reactive oxygen species] in cancer cells.”

Shin SY, et al: Clin Cancer Res 20:4302-4313, 2014.

PRC2 Loss Amplifies RASDriven Transcription and Results in Sensitivity to Bromodomain Inhibition PRC2 (polycomb repressive complex 2) has been shown to promote oncogenesis in many tumor types; however, loss of function mutations in PRC2 components has also been shown to occur in some hematopoietic malignancies, raising questions about the precise role of the complex in cancer.

In a study reported in Nature, De Raedt and colleagues showed that the polycomb group gene SUZ12 functions as a tumor suppressor in peripheral nervous system tumors, high-grade glioma, and melanoma by cooperating with mutations in NF1.

Loss of NF1, which encodes a RAS GTPase-activating protein, drives tumorigenesis by activating RAS. Loss of SUZ12 was shown to potentiate the effects of NF1 mutations by amplifying RAS-driven transcription through effects on chromatin. However, inactivation of SUZ12 was also associated with an epigenetic switch that resulted in sensitivity of these cancers to bromodomain inhibitors.

The investigators concluded:

“Collectively, these studies not only reveal an unexpected connection between the PRC2 complex, NF1 and RAS, but also identify a promising epigenetic-based therapeutic strategy that may be exploited for a variety of cancers.”

De Raedt T, et al: Nature 514:247251, 2014.

TREATMENT RESISTANCE Hyperthermia Reduces Gemcitabine Resistance Removal of incorporated gemcitabine by DNA repair mechanisms may contribute to resistance to the agent in solid tumors. In a study reported in Journal of the National Cancer Institute, Raoof and colleagues found that radiofrequency-induced hyperthermia blocked repair of gemcitabine-stalled replication forks and thus improved gemcitabine antitumor activity.

The study showed that Mre11-mediated homologous recombination repair of gemcitabine-stalled replication forks was crucial to hepatocellular carcinoma cell survival. Mre11 was inhibited by an exonuclease inhibitor and by radiofrequency field-induced hyperthermia. In orthotopic mouse models of chemoresistant hepatocellular carcinoma, Hep3B tumor mass was significantly smaller with radiofrequency-induced hyperthermia plus gemcitabine vs gemcitabine alone (mean = 180 vs 661 mg, P = .0063).

The investigators concluded: “This study provides mechanistic understanding of homologous recombination inhibiting-strategies, such as noninvasive radiofrequency field-induced hyperthermia, to overcome resistance to gemcitabine in refractory human solid tumors.”

Raoof M, et al: J Natl Cancer Inst 106(8):dju183 2014.

rearrangements occurred early in tumor evolution and remained highly stable as clonal expansion, reflecting gradual evolution of point mutations, occurred within tumor masses.

Use of targeted single-molecule sequencing showed that many of the point mutations occurred at low frequencies (< 10%) in tumor masses.

Mathematical modeling showed that the triple-negative tumor cells had a 13-fold increased mutation rate, whereas the increased mutation rate was not observed in estrogen receptor–positive tumor cells.

The investigators concluded: “These findings have important implications for the diagnosis, therapeutic treatment and evolution of chemoresistance in breast cancer.”

Wang Y, et al: Nature 512:155-160, 2014.

TARGETED THERAPY mTOR Cotargeting Active in Cetuximab-Resistant Head/ Neck Cancers With PIK3CA and RAS Mutations In a study reported in Journal of the National Cancer Institute, Wang and colleagues found that adding an mTOR inhibitor to cetuximab (Erbitux) resulted in marked improvement in antitumor activity in squamous cell carcinomas of the head and neck expressing PIK3CA and RAS oncogenes.

Cetuximab treatment of PIK3CA-

and RAS-expressing squamous cell head and neck carcinoma mouse xenografts resulted in initial tumor response followed by relapse within a few weeks. It was found that cetuximab did not reduce the activity of mTOR (a downstream signaling target of EGFR, PIK3CA, and RAS) in these tumors. The addition of an mTOR inhibitor to cetuximab produced markedly greater antitumor activity, particularly in the head and neck cancer cells resistant to cetuximab as a single agent; combined treatment produced prompt tumor collapse of both PIK3CA- and RASexpressing head and neck carcinoma xenografts (P < .001), together with significant reductions in proliferation (P < .001) and lymphangiogenesis (P < .001).

The investigators concluded: “The presence of PIK3CA and RAS mutations and other alterations affecting the mTOR pathway activity in [squamous cell carcinomas of the head and neck] could be exploited to predict potential resistance to cetuximab and to select the patients who may benefit the most from the concomitant administration of cetuximab and PI3K and/or mTOR inhibitors as a precision molecular therapeutic option for [patients with squamous cell carcinoma of the head and neck].” n Wang Z, et al: J Natl Cancer Inst 106(9):dju215, 2014.

Lab Notes is compiled and written for The ASCO Post by Matthew Stenger.

Single-Nucleus Genome Sequencing Shows Early Aneuploid Rearrangement and Gradual Clonal Evolution in Breast Cancer In a study reported in Nature, Wang and colleagues developed a whole-genome and exome singlecell sequencing approach (nuc-seq) using G2/M nuclei and used the method to sequence single normal and tumor nuclei from an estrogen receptor–positive breast cancer and a triple-negative ductal carcinoma. The investigators found that aneuploid

©Leo Cullum/The New Yorker Collection/www.cartoonbank.com

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In the Literature

Emerging Clinical Data on Cancer Management SMOKING Over 14 Million Major Medical Conditions in U.S. Adults Linked to Cigarette Smoking At least 14 million major medical

conditions among U.S. adults aged 35 years and older were attributed to cigarette smoking by a study estimating the disease burden of cigarette smoking, which, according to the study’s authors, “remains immense.” Among current and

former smokers, prevalence ratios were “particularly high for lung cancer,” reported Brian L. Roston, MD, MPH, and colleagues from the Center for Tobacco Products, U.S. Food and Drug Administration, Silver Spring, Mary-

2015 Gastrointestinal Cancers Symposium BRIDGING CANCER BIOLOGY TO CLINICAL GI ONCOLOGY January 15-17, 2015 • Moscone West Building • San Francisco, California

Meeting Highlights • Three keynote lectures - Immune Checkpoints for Upper GI Cancers - Genetic Landscape of Pancreatic Cancer - Molecular Characterization of Colorectal Cancer • Robust scientific program - All-day poster sessions, featuring Trials in Progress posters (new this year!)

- Disease-specific oral abstract sessions • Tumor Board: Management of Challenging Cases of Upper GI Cancers (ARS) • Translational Research Sessions: - Tumor Microenvironment - Understanding Molecular Testing • Interactive Meet the Professor ticketed sessions • New this year: Opportunity for ABIM diplomates to earn up to 10 Maintenance of Certification (MOC) points • Networking luncheon for fellows, residents, and junior faculty

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gicasym.org This live activity has been approved for AMA PRA Category 1 Credit™.

TARG E T I NG

C A NC E R

C A RE

land, and the Centers for Disease Control and Prevention (CDC), Atlanta.

The study, published online in JAMA Internal Medicine, used U.S. Census Bureau population estimates from 2009, National Health Interview Survey data on smoking and smoking-related disease prevalence from 2006 through 2012, and National Health and Nutrition Examination Survey spirometry data obtained from medical examinations of surveyed adults from 2007 through 2010. The researchers centered “the estimates around 2009 to allow for sufficient data to make accurate estimates,” they explained.

“Estimated prevalence ratios were higher for current and former smokers for most conditions,” the researchers reported. Prevalence ratios for lung cancer ranged from 4.45 to 9.35. Prevalence rates for other types of cancer among current or former smokers ranged from 1.54 to 3.01 for bladder cancer, 1.94 to 3.65 for cervical cancer, 1.36 to 1.60 for colorectal cancer, 1.15 to 2.00 for kidney cancer, 2.02 to 3.40 for oral cancers, and 0.44 to 1.51 for stomach cancer.

Other medical conditions with high prevalence ratios for current or former smokers were chronic obstructive pulmonary disease (2.02–4.00), diabetes mellitus (1.17–1.30), heart attack (1.54–3.03), and stroke (1.17–2.43).

“Heart attack, stroke, chronic bronchitis, emphysema, and cancers of the bladder, cervix, esophagus, kidney, larynx, mouth and/or pharynx, and pancreas have been previously identified as smoking-related conditions and were included in the previous CDC analysis of smoking-attributable morbidity. Stomach cancer was identified as a smoking-attributable condition in the 2004 Report of the Surgeon General, and colorectal and liver cancer and diabetes were identified as smoking attributable conditions in the 2014 Report of the Surgeon General,” the authors noted.

“Cigarette smoking remains a leading cause of preventable disease in the United States, underscoring the need for continuing and vigorous smokingprevention efforts,” the investigators concluded.

Additional Perspectives Although the prevalence of smoking is declining, “that decline is excruciatingly slow, and there are still more than 40 million smokers in the United States,” Steven A. Schroeder, MD, of the University of California, San Fran-

ASCOPost.com | DECEMBER 1, 2014

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In the Literature

Funds that should be dedicated to prevention and cessation are casualties of state budget crises, and there is no citizen advocacy movement such as those that exist with conditions like breast cancer and human immunodeficiency virus and AIDS. Physician involvement has been inconsistent, even among the subspecialties that most encounter smokers with disease: cardiologists, oncologists, and pulmonologists. The data from Rostron et al should serve to keep tobacco control and its 2-fold aims of preventing initiation and helping smokers quit as the most important clinical and public health priorities for the foreseeable future.

Lung Cancer Screening JAMA Internal Medicine online for October 13 also includes an editor’s note and two special communications about whether lung cancer screening with low-dose computed tomography should be covered under Medicare. “At issue is not only whether low-dose CT will be covered but, if it is covered, the specifics, such as the number and frequency of scans, the beneficiaries who would be eligible, and the procedures to assure that scans are of high quality and that false-positive results are minimized,” Robert Steinbrook, MD, wrote in the editor’s note.

Steven H. Woolf, MD, MPH, of Virginia Commonwealth University and colleagues argued that “implementation of national screening may be premature. The magnitude of benefit from routine screening is uncertain,” and “potential harms— which could affect a large population— include false-positive results, anxiety, radiation exposure, diagnostic workups, and the resulting complications.”

It is unclear whether routine screening would result in net benefit or net harm. Woolf et al also expressed concern that low-dose CT screening could “draw attention or resources away from the priority of tobacco control.

Douglas E. Wood, MD, of the University of Washington, Seattle, argued that “a “decision to add lung cancer screening with low-dose CT as a covered benefit for Medicare beneficiaries should be inevitable given the high level of evidence that screening can lead to early diagnosis and cure for thousands of patients each year in the United States. Professional societies,” he stated, “have great expertise and experience in screening and can help [the Centers for Medicare & Medicaid Services] responsibly implement a program that is patient-centered and minimizes unin-

tended harms and costs.”

Rostron BL, et al: JAMA Intern Med. October 13, 2014 (early release online).

Schroeder SA: JAMA Intern Med. October 13, 2014 (early release online).

Wood DE: JAMA Intern Med. October 13, 2014 (early release online).

Woolf SH, et al: JAMA Intern Med. October 13, 2014 (early release online).

ESOPHAGEAL CANCER Customizing Surveillance BLEED:8.375” Strategy in Patients With TRIM:7.875” Esophageal Adenocarcinoma SAFETY:7” for patients A surveillance strategy with esophageal adenocarcinoma treated with chemoradiation and sur-

gery (trimodality therapy) can potentially be customized based on surgical pathology stage, according to an analysis of 518 patients with esophageal adenocarcinoma who underwent trimodality therapy at The University of Texas MD Anderson Cancer Center in Houston and were frequently surcontinued on page 138

Now enrolling for alectinib

NCT 02075840 BO28984

A Randomized, Phase III Study Comparing Alectinib With Crizotinib in Treatment-Naïve Anaplastic Lymphoma Kinase (ALK)-Positive Advanced Non-Small Cell Lung Cancer (NSCLC) Patients

Randomize 1:1

cisco, pointed out in an accompanying editorial. He continued:

Patients (N=286) • Advanced, recurrent, or metastatic ALK-positive NSCLC

Primary Endpoint:

Alectinib1

Crizotinib

Secondary Endpoints:

• Progression-free survival (PFS), investigator-assessed,

• Objective response rate, investigator-assessed,

by RECIST 1.1

using RECIST 1.1 • Time to CNS progression, IRC-assessed, using

RECIST 1.1 • PFS, IRC-assessed, using RECIST 1.1 • Duration of response • Overall survival • Safety: incidence of adverse events • AUC of alectinib • Patient-reported outcomes

Key Inclusion Criteria2:

Key Exclusion Criteria2:

• Advanced, recurrent, or metastatic ALK-positive NSCLC

• Prior malignancy in past 3 years

• Life expectancy ≥12 weeks

• Any ≥ grade 3 toxicity (NCI CTCAE 4.0) from

• ECOG performance status of 0-2 • No prior systemic therapy for advanced, recurrent, or

metastatic disease • Measurable disease by RECIST 1.1

a prior therapy

• Baseline QTc >470 ms or symptomatic

bradycardia <45 beats per minute • Concomitant strong cytochrome P4503A

inhibitors/inducers or QT-prolonging medications

For more information, please call the Genentech Trial Information Support Line at 1-888-662-6728 (US only), visit clinicaltrials.gov, or e-mail global.rochegenentechtrials@roche.com.

1. Product under investigation has not been approved for use outside of the clinical trial setting. This information is presented only for the purpose of providing an overview of the clinical trial and should not be construed as a recommendation for the use of any product for unapproved purposes.

2. For more information on trial inclusion and exclusion criteria, visit clinicaltrials.gov.

© 2014 Genentech USA, Inc. All rights reserved. BIO0002445101 Printed in USA.

The ASCO Post | DECEMBER 1, 2014

PAGE 138

In the Literature Emerging Clinical Data continued from page 137

veyed. “The compelling data show an excellent association between surgical pathology stage and frequency/type/ timing of relapses after trimodality therapy in patients with esophageal adenocarcinoma, Takashi Taketa, MD, and colleagues at MD Anderson wrote in the Journal of the National Comprehensive Cancer Network.

All patients in the study had preoperative chemoradiation with intravenous or oral fluoropyrimidine with either a platinum compound or a taxane and a median total radiation dose of 50.4 Gy (range, 39.6–64.8 Gy) in daily fractions of 1.8 Gy. The median age of patients was 61 years (range 23–79 years) and most had clinical stage II (39%) or III (51.7%) cancer. The median follow-up time after esophageal surgery was 55.4 months, and disease relapse occurred in 215 patients (41.5%).

“The higher the [surgical pathology stage], reflecting the resistance of the primary tumor to chemoradiation, the higher the metastatic potential of esophageal adenocarcinoma. The present data show that distant metastases are much more frequent than locoregional-only relapses and that a higher [surgical pathology stage] leads to higher rates of relapses,” the investigators reported.

“In addition, patients with a higher [surgical pathology stage] tend to develop metastases not only more frequently but also sooner than those with a lower [surgical pathology stage].” In the first 12 months after surgery, the fraction of all relapses in various surgical pathology stage categories were as follows: stage 0 = 41%, I = 42%, II = 61%, and III = 68%.

The authors proposed that “the frequency of relapses based on timing could be exploited in formulating future surveillance strategies.” For example, since almost all relapses among patients with surgical pathology stages 0 and I occurred within 36 months of surgery, surveillance might be terminated in these patients after 3 years.

“The quandary is whether it is reasonable to recommend any surveillance (and what the frequency should be and what tests should be performed) for [surgical pathology stage] II or III. Based on the present data,” the authors stated, “one could question the benefit of surveillance in patients with [surgical pathology stage] III, because approximately 60% of patients are likely to experience relapse and 86% of these relapses are anticipated to be metastatic.

Considerable discussion would be necessary to establish guidance for patients

with [surgical pathology stage] II.” The authors called for “a serious national dialogue … to restructure the overall surveillance strategy for [esophageal adenocarcinoma] (and this can be extended to a few other solid tumors).

Such a dialogue may lead to the launch of a prospective trial to establish a firm evidence-based strategy.”

Taketa T, et al: J Natl Compr Canc Netw 12:1139-1144, 2014.

LYMPHOMA Second-Line Gemcitabine the Preferred Option for Relapsed or Refractory Lymphoma For patients with relapsed or refractory aggressive lymphoma in a National Cancer Institute of Canada clinical trial, second-line treatment with GDP (gemcitabine, dexamethasone, and cisplatin) was as effective as DHAP (dexamethasone, cytarabine, and cisplatin).

Treatment with GDP “can be considered the preferred treatment option for these patients,” Michael Crump, MD, of Princess Margaret Cancer Center in Toronto and colleagues concluded in the Journal of Clinical Oncology.

The trial “tested the hypothesis that comparable efficacy could be achieved with GDP and that this treatment, administered on an outpatient basis, would be associated with fewer adverse events and less frequent hospitalization compared with DHAP,” the authors wrote. “Our trial is the largest randomized comparison of secondline chemotherapy regimens administered before autologous stem-cell transplantation, to our knowledge, and the results confirmed our hypothesis.”

Most of the patients in the study had stage III or IV and high intermediate-risk or high-risk disease at random assignment to GDP or DHAP. Moreover, most patients “had either not achieved a remission with initial therapy or had recurrence of lymphoma within 1 year of completing treatment,” the authors noted.

Among the 619 intention-to-treat patients, 71% had diffuse large B-cell lymphoma, 15% had lymphoma that had transformed from an indolent B-cell histology, and 8% had T-cell or anaplastic large cell lymphoma.

Among 554 B-cell lymphoma patients, 411 had previously been given rituximab (Rituxan). Patients with B-cell lymphoma also received rituximab along with GDP or DHAP. Patients who responded proceeded to stem cell collection and autologous stem cell transplantation.

The two primary endpoints of the study were response rate after two treatment cycles, with the noninferiority margin for the response rate to GDP relative to DHAP set at 10%, and transplantation rate. Among the intentionto-treat population, “the response rate with GDP was 45.2%; with DHAP the response rate was 44.0% (95% CI for difference, −9.0% to 6.7%), meeting protocol-defined criteria for noninferiority of GDP (P = .005),” the investigators reported. “The transplantation rates were 52.1% with GDP and 49.3% with DHAP (P = .44). At a median followup of 53 months, no differences were detected in event-free survival (hazard ratio [HR] = 0.99; stratified log-rank P = .95) or overall survival (HR, 1.03; P = .78) between GDP and DHAP.” Grade 3 or 4 adverse events during the first two cycles of chemotherapy occurred in 47% of patients receiving GDP vs 61% receiving DHAP (P < .001). Patients receiving GDP had fewer episodes of febrile neutropenia, reduced need for platelet transfusion support, less frequent hospitalizations related to toxicity, and less deterioration of quality of life from baseline.

“Eight patients died as a result of protocol treatment–related complications: two during treatment with GDP and six after receiving DHAP,” the researchers noted.

Crump M, et al: J Clin Oncol. October 6, 2014 (early release online)

Risk of Premature Menopause Raised by Some but Not All Hodgkin Lymphoma Therapies An analysis of nonsurgical menopause risk among 2,127 women treated for Hodgkin lymphoma found that “risk of premature menopause increased more than 20-fold” after ovarian radiotherapy, alkylating chemotherapy other than dacarbazine, or BEAM (carmustine [BiCNU], etoposide, cytarabine, melphalan) chemotherapy for stem cell transplantation but was not statistically significantly raised after ABVD (doxorubicin, bleomycin, vinblastine, dacarbazine). Results were reported in the Journal of the National Cancer Institute by Anthony J. Swerdlow, DSc, of the Institute of Cancer Research, Surrey, United Kingdom, and colleagues in the England and Wales Hodgkin Lymphoma Follow-up Group.

The authors concluded that patients treated for Hodgkin lymphoma “need to plan intended pregnancies using personalized information on their risk of menopause by different future time

points” and provided tables to give individualized information to women based on the type of treatment, dose, and age at treatment.

The women were first treated from 1960 through 2004, mainly in the 1980s and 1990s, and were followed to 2003 through 2012. All the women were younger than 36 years when treated, with 5.5% younger than 15 and 50% aged 15 to 24 years. With increasing age at treatment, there was a moderate but statistically significant increased risk of premature menopause.

“During follow-up, 605 patients underwent nonsurgical menopause before age 40 years,” the investigators reported. Menopause generally occurred sooner after ovarian radiotherapy (with 62.5% of women experiencing menopause within 5 years of ≥ 5 Gy treatment), and after BEAM (with 50.9% of women experiencing menopause within 5 years), than after alkylating chemotherapy (with 24.2% of women experiencing menopause within 5 years of at least six cycles).

“Compared with women who had received neither alkylating chemotherapy nor pelvic radiotherapy, risk of premature nonsurgical menopause was increased about 20-fold in women who had received pelvic radiotherapy or classic alkylating chemotherapy, 36fold in women who had received both, and over 50-fold in those who had received a stem cell transplant (more again if they had also received pelvic radiotherapy),” the investigators reported.

“Risk was greatly raised after treatment with each common classic alkylating regimen,” the researchers added.

The risk was greatest with mechlorethamine, vinblastine, procarbazine, prednisone (hazard ratio [HR] = 37.1, 95% CI = 21.2–65.0, P < .001) and least for chlorambucil, vincristine, procarbazine, prednisone (HR = 17.9, 95% CI = 10.8–29.9, P < .001).

“Risk was greater again after BEAM, the most common regimen for stem cell transplantation; almost all BEAM-treated patients had also received other classic alkylating treatments. Risk was also statistically significantly raised in patients treated with etoposide who had not received classic alkylating chemotherapy or pelvic radiotherapy (HR = 6.1, 95% CI = 1.7–21.4, P < .001).” n Swerdlow AJ, et al: J Natl Cancer Inst 106(9):dju207, 2014.

In the Literature is compiled and written for The ASCO Post by Charlotte Bath.

ASCOPost.com | DECEMBER 1, 2014

PAGE 139

Letters to the Editor

Unique Barriers to Pain Control

I

read with great interest your interview with Virginia LeBaron, PhD, APRN, about barriers to adequate pain control (“Despite Growing Awareness, the Global Crisis of Untreated Cancer Pain Persists,” The ASCO Post, October 15, 2014).

Having served as the medical director of a hospice, I am passionate about palliative care and end-of-life issues. I worked in Saudi Arabia between 2001 and 2007 at the King Faisal Specialist Hospital as a medical oncologist, and I am recently retired. I would like to share a few additional unique barriers that I encountered and how they were overcome in Saudi Arabia.

the desert. To accommodate him, the hospital converted a large room into a desert abode. The bed and other furniture were removed from the room.

Sand was brought in and laid on the floor. The man was asked to bring in his personal sheets and blankets to

spread on the sand and create his own bedding. He died in his own little desert tent some time later.

I admire Dr. LeBaron for pursuing a career in palliative care and her recent travels to India (I am originally from Pakistan) in pursuit of learning how

King Faisal Specialist Hospital and Research Center had a 30-bed palliative care unit along with a 100-bed hematology/oncology inpatient unit at that time. Since Saudi Arabia is a conservative Muslim country, morphine was officially labeled as a narcotic and was not allowed to be imported, not even in medicinal form.

The palliative care team, with support of the hospital leadership, reached their way up to the King and

I admire Dr. LeBaron for … [her] pursuit of learning how best to overcome the barriers to achieving optimal pain control.

—Khalid L. Rehman, MD, FACP, MPA

2015

Annual Conference

ADVANCING THE STANDARD OF CANCER CARE TM

March 12 – 14, 2015 The Diplomat • Hollywood, Florida

Track Session Topics*:

• Breast Cancer Early Stage | HER2-Positive and Triple Negative Cancer | New Therapies for Hormone-Sensitive Advanced Disease

• Gastrointestinal (GI) Cancers Esophageal | Metastatic Colorectal Cancer | Pancreatic Cancer

through him to the top religious authorities. They convinced the great mufti to issue a fatwa, or edict, that taking morphine for pain control was acceptable from the religious ­perspective.

The country’s import policy had to be rewritten so that medicinal morphine could be imported. Each patient was given a copy of the official edict to convince him that it was not a sin to take morphine for pain control.

On another cultural note, I remember that one elderly man with advanced cancer and his family agreed to be admitted to the palliative care service but did not like to be in the palliative inpatient unit. He was from

Disclaimer: This letter represents the views of the author and may not necessarily represent the views of ASCO.

REGISTER NOW!

th

Cultural Impediments

best to overcome the barriers to achieving optimal pain control. I salute her. n —Khalid L. Rehman, MD, FACP, MPA New York, New York

• Genitourinary (GU) Cancers

Castration-Recurrent Prostate Cancer | Bladder Cancer | Kidney Cancer

• Hematologic Cancers Chronic Myelogenous Leukemia | Chronic

Save the Date!

Thursday, March 12, 2015

20 Years of Improving Cancer Care Together An NCCN Roundtable Discussion

Lymphocytic Leukemia | Multiple Myeloma | B-cell Lymphomas

• Lung Cancers Non-Small Cell Lung Cancer: Minimally Invasive Techniques | Adjuvant Therapy and Treatment of Metastatic Disease | Small Cell Lung Cancer: Role of Radiation Therapy

• Skin Cancers Localized and Advanced Melanoma and Toxicities Associated with Targeted Therapies • Supportive Care Fertility | Smoking Cessation | Anthracycline-Induced Cardiac Toxicity * Subject to change.

Visit NCCN.org/AC2015 to register

or to view more information for this educational program.

JNCCN-N-0200-1114

The ASCO Post | DECEMBER 1, 2014

PAGE 140

Letters to the Editor

Raising Consciousness About Drug Costs: A Call to Action

A

s medical oncologists working in chemotherapy utilization management (Oncology Analytics, Inc), my colleagues and I find ourselves daily in the center of the drug-cost maelstrom.

what might be done—while medical oncologists are short on creating and implementing actionable strategies to address drug costs. Indeed, the descriptor “unsustainable” has been around for

By not being tuned in to the economics of our profession, and not knowing the downstream financial consequences of every prescription we write, we physicians are complicit in the ultimate undoing of our society’s ability to continue providing the medical marvels now at hand.

—William S. Shimp, MD

While it is encouraging to see that more attention is being paid in the popular and medical press to this “unsustainable” escalation of drug costs, it seems most of the articles (including recently in The ASCO Post) are long on bemoaning the problem and on theorizing

so long that it has become a hackneyed term that by now has lost most of its shock value.

U.S. Food and Drug Administration (FDA) evaluations, National Comprehensive Cancer Network (NCCN) and ASCO guidelines, and

enthusiastic reports in The ASCO Post are, for the most part, devoid of cost information about the drugs or regimens referenced. True, ASCO’s “Choosing Wisely” initiative, and the NCCN Journal’s advice to select the most cost-effective approach if all else is equal, represent welcome attempts to focus oncologists’ attention on the cost of care. But where are the numbers, and where are the cost comparisons that deserve to be front-andcenter in the minds of patients, physicians, policymakers, and insurers?

I would propose that the The ASCO Post take the lead in calling out the elephant in the room. Though sometimes cost data are not immediately known upon FDA approval of new drugs, in most cases the sticker prices quickly become available and can be added easily in parentheses ($10,000/month is usually fairly accurate!) to the clinical data presented. With The ASCO Post as

a trendsetter, how informative it would be if NCCN and ASCO Guidelines, and the Journal of Clinical Oncology, would follow TAP’s lead by similarly and consistently documenting the cost of chemotherapy care.

By not being tuned in to the economics of our profession, and not knowing the downstream financial consequences of every prescription we write, we physicians are complicit in the ultimate undoing of our society’s ability to continue providing the medical marvels now at hand. With the stroke of a pen or the click of a mouse, The ASCO Post’s editorial policy could become a transformative force in finally launching us on a course we should have been on long ago. n —William S. Shimp, MD Plantation, Florida Disclaimer: This letter represents the views of the author and may not necessarily reflect the views of ASCO.

The 10th anniversary of the Lilly Oncology On Canvas Art Competition was celebrated with the presentation of awards and display of winning entries in New York’s Grand Central Terminal on October 23, 2014. First-, second-, and third-place winners were published in the November 15 issue of The ASCO Post. Here we present additional winning artwork from the competition.

Dawn a New Day,

by Cindy Wemette: Best Oil by a Person Diagnosed With Cancer

Monday, by Julie Miller: Best Oil by a Family Member of a Person With Cancer

Inspiration, by Amy Brewer: Best Mixed Media from a Family Member of a Person Diagnosed With Cancer

BRIEF SUMMARY TAFINLAR® (dabrafenib) capsules, for oral use MEKINIST® (trametinib) tablets, for oral use The following is a brief summary only; see Full Prescribing Information for each product to view the complete product information 1 INDICATIONS AND USAGE TAFINLAR, in combination with MEKINIST, is indicated for the treatment of patients with unresectable or metastatic melanoma with BRAF V600E or V600K mutations, as detected by an FDA-approved test. This indication is based on the demonstration of durable response rate.

Improvement in disease-related symptoms or overall survival has not been demonstrated for TAFINLAR in combination with MEKINIST. Limitation of use: TAFINLAR is not indicated for treatment of patients with wild-type BRAF melanoma.

5 WARNINGS AND PRECAUTIONS 5.1 New Primary Malignancies New primary malignancies, cutaneous and non-cutaneous, can occur when TAFINLAR is administered as a single agent or when used in combination with MEKINIST. Cutaneous Malignancies: In Trial 2, the incidence of basal cell carcinoma was increased in patients receiving TAFINLAR in combination with MEKINIST: 9% (5/55) of patients receiving TAFINLAR in combination with MEKINIST compared with 2% (1/53) of patients receiving TAFINLAR as a single agent.

The range of time to diagnosis of basal cell carcinoma was 28 to 249 days in patients receiving TAFINLAR in combination with MEKINIST and was 197 days for the patient receiving TAFINLAR as a single agent.

Cutaneous squamous cell carcinoma (SCC), including keratoacanthoma, occurred in 7% of patients receiving TAFINLAR in combination with MEKINIST and 19% of patients receiving TAFINLAR as a single agent. The range of time to diagnosis of cuSCC was 136 to 197 days in the combination arm and was 9 to 197 days in the arm receiving TAFINLAR as a single agent.

New primary melanoma occurred in 2% (1/53) of patients receiving TAFINLAR as a single agent and in none of the 55 patients receiving TAFINLAR in combination with MEKINIST. Perform dermatologic evaluations prior to initiation of TAFINLAR as a single agent or in combination with MEKINIST, every 2 months while on therapy, and for up to 6 months following discontinuation of TAFINLAR. No dose modifications of TAFINLAR or MEKINIST are required in patients who develop new primary cutaneous malignancies.

Non-cutaneous Malignancies: Based on its mechanism of action, TAFINLAR may promote the growth and development of malignancies with activation of RAS through mutation or other mechanisms [see Warnings and Precautions (5.2)]. In patients receiving TAFINLAR in combination with MEKINIST four cases of non-cutaneous malignancies were identified: KRAS mutation-positive pancreatic adenocarcinoma (n = 1), recurrent NRAS mutation-positive colorectal carcinoma (n = 1), head and neck carcinoma (n = 1), and glioblastoma (n = 1). Monitor patients receiving the combination closely for signs or symptoms of non-cutaneous malignancies. Permanently discontinue TAFINLAR for RAS mutation-positive non-cutaneous malignancies. If used in combination with MEKINIST, no dose modification of MEKINIST is required for patients who develop non-cutaneous malignancies.

5.2 Tumor Promotion in BRAF Wild-Type Melanoma In vitro experiments have demonstrated paradoxical activation of MAP-kinase signaling and increased cell proliferation in BRAF wild-type cells which are exposed to BRAF inhibitors. Confirm evidence of BRAF V600E or V600K mutation status prior to initiation of TAFINLAR [see Indications and Usage (1)].

5.3 Hemorrhage Hemorrhages, including major hemorrhages defined as symptomatic bleeding in a critical area or organ, can occur when TAFINLAR is used in combination with MEKINIST. In Trial 2, treatment with TAFINLAR in combination with MEKINIST resulted in an increased incidence and severity of any hemorrhagic event: 16% (9/55) of patients treated with TAFINLAR in combination with MEKINIST compared with 2% (1/53) of patients treated with TAFINLAR as a single agent. The major hemorrhagic events of intracranial or gastric hemorrhage occurred in 5% (3/55) of patients treated with TAFINLAR in combination with MEKINIST compared with none of the 53 patients treated with TAFINLAR as a single agent. Intracranial hemorrhage was fatal in 4% (2/55) of patients receiving TAFINLAR in combination with MEKINIST. Permanently discontinue TAFINLAR and MEKINIST for all Grade 4 hemorrhagic events and for any Grade 3 hemorrhagic events that do not improve. Withhold TAFINLAR for Grade 3 hemorrhagic events; if improved resume at a lower dose level. Withhold MEKINIST for up to 3 weeks for Grade 3 hemorrhagic events; if improved, resume at a lower dose level.

5.4 Venous Thromboembolism Venous thromboembolism can occur when TAFINLAR is used in combination with MEKINIST. In Trial 2, treatment with TAFINLAR in combination with MEKINIST resulted in an increased incidence of deep venous thrombosis (DVT) and pulmonary embolism (PE): 7% (4/55) of patients treated with TAFINLAR in combination with MEKINIST compared with none of the 53 patients treated with TAFINLAR as a single agent. Pulmonary embolism was fatal in 2% (1/55) of patients receiving TAFINLAR in combination with MEKINIST. Advise patients to immediately seek medical care if they develop symptoms of DVT or PE, such as shortness of breath, chest pain, or arm or leg swelling. Permanently discontinue TAFINLAR and MEKINIST for life-threatening PE. Withhold MEKINIST and continue TAFINLAR at the same dose for uncomplicated DVT or PE; if improved within 3 weeks, MEKINIST may be resumed at a lower dose level.

5.5 Cardiomyopathy Cardiomyopathy can occur when TAFINLAR is used in combination with MEKINIST and with

MEKINIST as a single agent [refer to Full Prescribing Information for MEKINIST].

In Trial 2, cardiomyopathy occurred in 9% (5/55) of patients treated with TAFINLAR in combination with MEKINIST and in none of patients treated with TAFINLAR as a single agent. The median time to onset of cardiomyopathy in patients treated with TAFINLAR in combination with MEKINIST was 86 days (range: 27 to 253 days). Cardiomyopathy was identified within the first month of treatment with TAFINLAR in combination with MEKINIST in two of five patients. Development of cardiomyopathy resolved in all five patients following dose reduction (4/55) and/or dose interruption (1/55).

Across clinical trials of TAFINLAR administered in combination with MEKINIST (N = 202), 8% of patients developed evidence of cardiomyopathy (decrease in LVEF below institutional lower limits of normal with an absolute decrease in LVEF ≥10% below baseline). Two percent demonstrated a decrease in LVEF below institutional lower limits of normal with an absolute decrease in LVEF of ≥20% below baseline.

Assess LVEF by echocardiogram or multigated acquisition (MUGA) scan before initiation of TAFINLAR in combination with MEKINIST, one month after initiation, and then at 2- to 3-month intervals while on treatment with the combination. Withhold treatment with MEKINIST and continue TAFINLAR at the same dose if absolute LVEF value decreases by 10% from pretreatment values and is less than the lower limit of normal. For symptomatic cardiomyopathy or persistent, asymptomatic LV dysfunction that does not resolve within 4 weeks, permanently discontinue MEKINIST and withhold TAFINLAR. Resume TAFINLAR at the same dose level upon recovery of cardiac function.

5.6 Ocular Toxicities Retinal Vein Occlusion (RVO): Across all clinical trials of MEKINIST, the incidence of RVO was 0.2% (4/1,749).

RVO may lead to macular edema, decreased visual function, neovascularization, and glaucoma.

Urgently (within 24 hours) perform ophthalmological evaluation for patient-reported loss of vision or other visual disturbances. Permanently discontinue MEKINIST in patients with documented RVO. If MEKINIST is used in combination with TAFINLAR, do not modify TAFINLAR dose.

Retinal Pigment Epithelial Detachment (RPED): Retinal pigment epithelial detachments (RPED) can occur when TAFINLAR is used in combination with MEKINIST and with MEKINIST as a single agent [refer to Full Prescribing Information for MEKINIST]. Retinal detachments resulting from MEKINIST are often bilateral and multifocal, occurring in the macular region of the retina.

In Trial 2, ophthalmologic examinations including retinal evaluation were performed pretreatment and at regular intervals during treatment. RPED occurred in 2% (1/55) of patients receiving TAFINLAR in combination with MEKINIST. Across clinical trials of TAFINLAR administered in combination with MEKINIST (N = 202), the incidence of RPED was 1% (2/202).

Perform ophthalmological evaluation at any time a patient reports visual disturbances and compare with baseline, if available. If TAFINLAR is used in combination with MEKINIST, do not modify the dose of TAFINLAR. Withhold MEKINIST if RPED is diagnosed. If resolution of the RPED is documented on repeat ophthalmological evaluation within 3 weeks, resume MEKINIST at a lower dose level. Discontinue MEKINIST if no improvement after 3 weeks.

Uveitis and Iritis: Uveitis and iritis can occur when TAFINLAR is administered as a single agent or when used in combination with MEKINIST. Uveitis (including iritis) occurred in 1% (6/586) of patients treated with TAFINLAR as a single agent and uveitis occurred in 1% (2/202) of patients treated with TAFINLAR in combination with MEKINIST. Symptomatic treatment employed in clinical trials included steroid and mydriatic ophthalmic drops.

Monitor patients for visual signs and symptoms of uveitis (e.g., change in vision, photophobia, eye pain). If diagnosed, withhold TAFINLAR for up to 6 weeks until uveitis/iritis resolves to Grade 0-1. If TAFINLAR is used in combination with MEKINIST, do not modify the dose of MEKINIST. 5.6 Interstitial Lung Disease In clinical trials of MEKINIST (N = 329) as a single agent, ILD or pneumonitis occurred in 2% of patients. In Trial 1, 2% (5/211) of patients treated with MEKINIST developed ILD or pneumonitis; all five patients required hospitalization. The median time to first presentation of ILD or pneumonitis was 160 days (range: 60 to 172 days).

Withhold MEKINIST in patients presenting with new or progressive pulmonary symptoms and findings including cough, dyspnea, hypoxia, pleural effusion, or infiltrates, pending clinical investigations.

Permanently discontinue MEKINIST for patients diagnosed with treatment-related ILD or pneumonitis.

If MEKINIST is used in combination with TAFINLAR, do not modify the dose of TAFINLAR. 5.7 Serious Febrile Reactions The incidence and severity of pyrexia are increased when TAFINLAR is used in combination with MEKINIST compared with TAFINLAR as a single agent [see Adverse Reactions (6.1)].

In Trial 2, the incidence of fever (serious and non-serious) was 71% (39/55) in patients treated with TAFINLAR in combination with MEKINIST and 26% (14/53) in patients treated with TAFINLAR as a single agent. Serious febrile reactions and fever of any severity complicated by hypotension, rigors or chills occurred in 25% (14/55) of patients treated with TAFINLAR in combination with MEKINIST compared with 2% (1/53) of patients treated with TAFINLAR as a single agent. Fever was complicated with chills/rigors in 51% (28/55), dehydration in 9% (5/55), renal failure in 4% (2/55), and syncope in 4% (2/55) of patients in Trial 2.

In patients treated with TAFINLAR in combination with MEKINIST, the median time to initial onset of fever was 30 days compared with 19 days in patients treated with TAFINLAR as a single agent; the median duration of fever was 6 days with the combination compared with 4 days with TAFINLAR as a single agent.

Across clinical trials of TAFINLAR administered in combination with MEKINIST (N = 202), the incidence of pyrexia was 57% (116/202).

Withhold TAFINLAR for fever of 101.3°F or higher. Withhold MEKINIST for any fever higher than 104°F.

Withhold TAFINLAR, and MEKINIST if used in combination, for any serious febrile reaction or fever complicated by hypotension, rigors or chills, dehydration, or renal failure and evaluate for signs and symptoms of infection. Refer to Table 2 for recommended dose modifications for adverse reactions. Prophylaxis with antipyretics may be required when resuming TAFINLAR or MEKINIST. 5.8 Serious Skin Toxicity Serious skin toxicity can occur when TAFINLAR is used in combination with MEKINIST and with MEKINIST as a single agent [refer to Full Prescribing Information for MEKINIST].

In Trial 2, the incidence of any skin toxicity was similar for patients receiving TAFINLAR in combination with MEKINIST (65% [36/55]) compared with patients receiving TAFINLAR as a single agent (68% [36/53]). The median time to onset of skin toxicity in patients treated with TAFINLAR in combination with MEKINIST was 37 days (range: 1 to 225 days) and median time to resolution of skin toxicity was 33 days (range: 3 to 421 days). No patient required dose reduction or permanent discontinuation of TAFINLAR or MEKINIST for skin toxicity.

Across clinical trials of TAFINLAR in combination with MEKINIST (N = 202), severe skin toxicity and secondary infections of the skin requiring hospitalization occurred in 2.5% (5/202) of patients treated with TAFINLAR in combination with MEKINIST. Withhold TAFINLAR, and MEKINIST if used in combination, for intolerable or severe skin toxicity.

TAFINLAR and MEKINIST may be resumed at lower dose levels in patients with improvement or recovery from skin toxicity within 3 weeks.

5.9 Hyperglycemia Hyperglycemia can occur when TAFINLAR is administered as a single agent or when used in combination with MEKINIST. In Trial 2, the incidence of Grade 3 hyperglycemia based on laboratory values was 5% (3/55) in patients treated with TAFINLAR in combination with MEKINIST compared with 2% (1/53) in patients treated with TAFINLAR as a single agent.

Monitor serum glucose levels as clinically appropriate when TAFINLAR is administered as a single agent or when used in combination with MEKINIST in patients with pre-existing diabetes or hyperglycemia. Advise patients to report symptoms of severe hyperglycemia such as excessive thirst or any increase in the volume or frequency of urination.

5.10 Glucose-6-Phosphate Dehydrogenase Deficiency TAFINLAR, which contains a sulfonamide moiety, confers a potential risk of hemolytic anemia in patients with glucose-6-phosphate dehydrogenase (G6PD) deficiency. Closely observe patients with G6PD deficiency for signs of hemolytic anemia.

5.11 Embryofetal Toxicity TAFINLAR and MEKINIST both can cause fetal harm when administered to a pregnant woman.

Advise female patients of reproductive potential to use a highly effective non-hormonal contraception during treatment with TAFINLAR and MEKINIST in combination and for 4 months after treatment, since TAFINLAR can render hormonal contraceptives ineffective. Advise patients to contact their healthcare provider if they become pregnant, or if pregnancy is suspected, while taking TAFINLAR or MEKINIST. 6 ADVERSE REACTIONS The following adverse reactions are discussed in greater detail in another section of the label: • New Primary Malignancies [see Warnings and Precautions (5.1)] • Tumor Promotion in BRAF Wild-Type Melanoma [see Warnings and Precautions (5.2)] • Hemorrhage [see Warnings and Precautions (5.3)] • Venous Thromboembolism [see Warnings and Precautions (5.4)] • Cardiomyopathy [see Warnings and Precautions (5.5)] • Ocular Toxicities [see Warnings and Precautions (5.6)] • Interstitial Lung Disease [see Warnings and Precautions (5.6)] • Serious Febrile Reactions [see Warnings and Precautions (5.7)] • Serious Skin Toxicity [see Warnings and Precautions (5.8)] • Hyperglycemia [see Warnings and Precautions (5.9)] • Glucose-6-Phosphate Dehydrogenase Deficiency [see Warnings and Precautions (5.10)] 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

The data described in the Warnings and Precautions section and below reflect exposure to TAFINLAR as a single agent and in combination with MEKINIST. BRAF V600E or V600K Unresectable or Metastatic Melanoma: The safety of TAFINLAR in combination with MEKINIST was evaluated in Trial 2 and other trials consisting of a total of 202 patients with BRAF V600 mutation-positive unresectable or metastatic melanoma who received TAFINLAR 150 mg orally twice daily in combination with MEKINIST 2 mg orally once daily until disease progression or unacceptable toxicity. Among these 202 patients, 66 (33%) were exposed to TAFINLAR and 68 (34%) were exposed to MEKINIST for greater than 6 to 12 months while 40 (20%) were exposed to TAFINLAR and 36 (18%) were exposed to MEKINIST for greater than one year. The median age was 54 years, 57% were male, and >99% were white.

Table 5 presents adverse reactions from Trial 2, a multicenter, open-label, randomized trial of 162 patients with BRAF V600E or V600K mutation-positive melanoma receiving TAFINLAR 150 mg

twice daily in combination with MEKINIST 2 mg orally once daily (n = 55), TAFINLAR 150 mg orally twice daily in combination with MEKINIST 1 mg once daily (n = 54), and TAFINLAR as a single agent 150 mg orally twice daily (n = 53) [see Clinical Studies (14.2)]. Patients with abnormal LVEF, history of acute coronary syndrome within 6 months, current evidence of Class II or greater congestive heart failure (New York Heart Association), history RVO or RPED, QTc interval ≥480 msec, treatment refractory hypertension, uncontrolled arrhythmias, history of pneumonitis or interstitial lung disease, or a known history of G6PD deficiency were excluded. The median duration of treatment was 10.9 months for both TAFINLAR and MEKINIST (2-mg orally once-daily treatment group) when used in combination, 10.6 months for both TAFINLAR and MEKINIST (1-mg orally once-daily treatment group) when used in combination, and 6.1 months for TAFINLAR as a single agent.

In Trial 2, 13% of patients receiving TAFINLAR in combination with MEKINIST experienced adverse reactions resulting in permanent discontinuation of trial medication(s). The most common adverse reaction resulting in permanent discontinuation was pyrexia (4%). Adverse reactions led to dose reductions in 49% and dose interruptions in 67% of patients treated with TAFINLAR in combination with MEKINIST. Pyrexia, chills, and nausea were the most common reasons cited for dose reductions and pyrexia, chills, and decreased ejection fraction were the most common reasons cited for dose interruptions of TAFINLAR and MEKINIST when used in combination.

Table 5. Common Adverse Drug Reactions Occurring in ≥10% at (All Grades) or ≥5% (Grades 3 or 4) of Patients Treated With TAFINLAR in Combination With MEKINIST in Trial 2 TAFINLAR plus TAFINLAR plus MEKINIST 2 mg MEKINIST 1 mg TAFINLAR N = 55 N = 54 N = 53 All All Grades Adverse Reactions Gradesa 3 and 4 Gradesa General disorders and administrative site conditions Pyrexia 71 5 69 Chills 58 2 50 Fatigue 53 4 57 b 31 0 28 Edema peripheral Skin and subcutaneous tissue disorders 45 0 43 Rashc Night Sweats 24 0 15 Dry skin 18 0 9 Dermatitis acneiform 16 0 11 Actinic keratosis 15 0 7 Erythema 15 0 6 Pruritus 11 0 11 Gastrointestinal disorders Nausea 44 2 46 Vomiting 40 2 43 Diarrhea 36 2 26 33 2 24 Abdominal paind Constipation 22 0 17 Dry mouth 11 0 11 Nervous system disorders Headache 29 0 37 Dizziness 16 0 13 Respiratory, thoracic, and mediastinal disorders Cough 29 0 11 Oropharyngeal pain 13 0 7 Musculoskeletal, connective tissue, and bone disorders Arthralgia 27 0 44 Myalgia 22 2 24 Back pain 18 5 11 Muscle spasms 16 0 2 Pain in extremity 16 0 11 Metabolism and nutritional disorders Decreased appetite 22 0 30 Dehydration 11 0 6 Psychiatric Disorders Insomnia 18 0 11 Vascular disorders 16 5 11 Hemorrhagee Infections and infestations Urinary tract infection 13 2 6 Renal and urinary disorders 7 7 2 Renal failuref

Grades 3 and 4

All Gradesa

Grades 3 and 4

9 2 2 0

26 17 40 17

0 0 6 0

2 0 0 0 0 0 0

53 6 6 4 9 2 13

0 0 0 0 0 0 0

6 4 0 2 2 0

21 15 28 21 11 6

0 0 0 2 0 0

2 0

28 9

0 0

0 0

21 0

0 0

0 0 0 0 2

34 23 11 4 19

0 2 2 0 0

0 2

19 2

0 0

0

8

2

0

2

0

0

9

2

0

0

0

National Cancer Institute Common Terminology Criteria for Adverse Events, version 4.

Includes the following terms: peripheral edema, edema, and lymphedema. c Includes the following terms: rash, rash generalized, rash pruritic, rash erythematous, rash papular, rash vesicular, rash macular, and rash maculo-papular. d Includes the following terms: abdominal pain, abdominal pain upper, abdominal pain lower, and abdominal discomfort. e Includes the following terms: brain stem hemorrhage, cerebral hemorrhage, gastric hemorrhage, epistaxis, gingival hemorrhage, hematuria, vaginal hemorrhage, hemorrhage intracranial, eye hemorrhage, and vitreous hemorrhage. f Includes the following terms: renal failure and renal failure acute.

Other clinically important adverse reactions (N = 202) observed in <10% of patients treated with TAFINLAR in combination with MEKINIST were: Eye Disorders: Vision blurred, transient blindness.

Gastrointestinal Disorders: Stomatitis, pancreatitis.

General Disorders and Administration Site Conditions: Asthenia.

Infections and Infestations: Cellulitis, folliculitis, paronychia, rash pustular.

Neoplasms Benign, Malignant, and Unspecified (including cysts and polyps): Skin papilloma.

Skin and Subcutaneous Tissue Disorders: Palmar-plantar erythrodysesthesia syndrome, hyperkeratosis, hyperhidrosis.

Vascular Disorders: Hypertension.

Table 6. Treatment-Emergent Laboratory Abnormalities Occurring at ≥10% (All Grades) or ≥2% (Grades 3 or 4)] of Patients Treated With TAFINLAR in Combination With MEKINIST in Trial 2 TAFINLAR plus TAFINLAR plus MEKINIST 2 mg MEKINIST 1 mg TAFINLAR N = 55 N = 54 N = 53 a

b

All All All Grades Grades Grades Grades 3 and 4 Grades 3 and 4 Grades 3 and 4a Tests Hematology Leukopenia 62 5 46 4 21 0 Lymphopenia 55 22 59 19 40 6 Neutropenia 55 13 37 2 9 2 Anemia 55 4 46 7 28 0 Thrombocytopenia 31 4 31 2 8 0 Liver Function Tests Increased AST 60 5 54 0 15 0 Increased alkaline 60 2 67 6 26 2 phosphatase Increased ALT 42 4 35 4 11 0 Hyperbilirubinemia 15 0 7 4 0 0 Chemistry Hyperglycemia 58 5 67 6 49 2 Increased GGT 56 11 54 17 38 2 Hyponatremia 55 11 48 15 36 2 Hypoalbuminemia 53 0 43 2 23 0 Hypophosphatemia 47 5 41 11 40 0 Hypokalemia 29 2 15 2 23 6 Increased creatinine 24 5 20 2 9 0 Hypomagnesemia 18 2 2 0 6 0 Hyperkalemia 18 0 22 0 15 4 Hypercalcemia 15 0 19 2 4 0 Hypocalcemia 13 0 20 0 9 0 a No Grade 4 events were reported in patients receiving TAFINLAR as a single agent.

ALT = Alanine aminotransferase; AST = Aspartate aminotransferase; GGT = Gamma glutamyltransferase.

QT Prolongation: In Trial 2, QTcF prolongation to >500 msec occurred in 4% (2/55) of patients treated with TAFINLAR in combination with MEKINIST and in 2% (1/53) of patients treated with TAFINLAR as a single agent. The QTcF was increased more than 60 msec from baseline in 13% (7/55) of patients treated with TAFINLAR in combination with MEKINIST and 2% (1/53) of patients treated with TAFINLAR as a single agent.

7 DRUG INTERACTIONS 7.1 Effects of Other Drugs on Dabrafenib Dabrafenib is primarily metabolized by CYP2C8 and CYP3A4. Strong inhibitors of CYP3A4 or CYP2C8 may increase concentrations of dabrafenib and strong inducers of CYP3A4 or CYP2C8 may decrease concentrations of dabrafenib [see Clinical Pharmacology (12.3)]. Substitution of strong inhibitors or strong inducers of CYP3A4 or CYP2C8 is recommended during treatment with TAFINLAR. If concomitant use of strong inhibitors (e.g., ketoconazole, nefazodone, clarithromycin, gemfibrozil) or strong inducers (e.g., rifampin, phenytoin, carbamazepine, phenobarbital, St John’s wort) of CYP3A4 or CYP2C8 is unavoidable, monitor patients closely for adverse reactions when taking strong inhibitors or loss of efficacy when taking strong inducers.

7.2 Effects of Dabrafenib on Other Drugs Dabrafenib induces CYP3A4 and CYP2C9. Dabrafenib decreased the systemic exposures of midazolam (a CYP3A4 substrate), S-warfarin (a CYP2C9 substrate), and R-warfarin (a CYP3A4/CYP1A2 substrate) [see Clinical Pharmacology (12.3)]. Monitor international normalized ratio (INR) levels more frequently in patients receiving warfarin during initiation or discontinuation of dabrafenib. Coadministration of TAFINLAR with other substrates of these enzymes, including dexamethasone or hormonal contraceptives, can result in decreased concentrations and loss of efficacy [see Use in Specific Populations (8.1, 8.6)]. Substitute for these medications or monitor patients for loss of efficacy if use of these medications is unavoidable.

7.3 Trametinib Coadministration of TAFINLAR 150 mg twice daily and trametinib 2 mg once daily resulted in no clinically relevant pharmacokinetic drug interactions [see Clinical Pharmacology (12.3)].

8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy TAFINLAR Pregnancy Category D Risk Summary: Based on its mechanism of action, TAFINLAR can cause fetal harm when administered to a pregnant woman. Dabrafenib was teratogenic and embryotoxic in rats at doses three times greater than the human exposure at the recommended clinical dose of 150 mg twice daily based on AUC. If this drug is used during pregnancy or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to a fetus [see Warnings and Precautions (5.11)].

Animal Data: In a combined female fertility and embryofetal development study in rats, developmental toxicity consisted of embryo-lethality, ventricular septal defects, and variation in thymic shape at a dabrafenib dose of 300 mg/kg/day (approximately three times the human exposure at the recommended dose based on AUC). At doses of 20 mg/kg/day or greater (equivalent to the human exposure at the recommended dose based on AUC), rats demonstrated delays in skeletal development and reduced fetal body weight.

MEKINIST Pregnancy Category D Risk Summary: MEKINIST can cause fetal harm when administered to a pregnant woman. Trametinib was embryotoxic and abortifacient in rabbits at doses greater than or equal to those resulting in exposures approximately 0.3 times the human exposure at the recommended clinical dose. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus [see Warnings and Precautions (5.10)].

Animal Data: In reproductive toxicity studies, administration of trametinib to rats during the period of organogenesis resulted in decreased fetal weights at doses greater than or equal to 0.031 mg/kg/day (approximately 0.3 times the human exposure based on AUC at the recommended dose). In rats, at a dose resulting in exposures 1.8-fold higher than the human exposure at the recommended dose, there was maternal toxicity and an increase in post-implantation loss.

In pregnant rabbits, administration of trametinib during the period of organogenesis resulted in decreased fetal body weight and increased incidence of variations in ossification at doses greater than or equal to 0.039 mg/kg/day (approximately 0.08 times the human exposure at the recommended dose based on AUC). In rabbits administered trametinib at 0.15 mg/kg/day (approximately 0.3 times the human exposure at the recommended dose based on AUC) there was an increase in postimplantation loss, including total loss of pregnancy, compared with control animals.

8.3 Nursing Mothers It is not known whether this drug is present in human milk. Because many drugs are present in human milk and because of the potential for serious adverse reactions from TAFINLAR and MEKINIST in nursing infants, a decision should be made whether to discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother.

8.4 Pediatric Use The safety and effectiveness of TAFINLAR and MEKINIST have not been established in pediatric patients. In a repeat-dose toxicity study of dabrafenib in juvenile rats, an increased incidence of kidney cysts and tubular deposits were noted at doses as low as 0.2 times the human exposure at the recommended adult dose based on AUC. Additionally, forestomach hyperplasia, decreased bone length, and early vaginal opening were noted at doses as low as 0.8 times the human exposure at the recommended adult dose based on AUC. 8.5 Geriatric Use One hundred and twenty-six (22%) of 586 patients in clinical trials of TAFINLAR administered as a single agent and 40 (21%) of the 187 patients receiving TAFINLAR in Trial 1 were ≥65 years of age. No overall differences in the effectiveness or safety of TAFINLAR were observed in the elderly in Trial 1.

Across all clinical trials of TAFINLAR administered in combination with MEKINIST, there was an insufficient number of patients aged 65 years and over to determine whether they respond differently from younger patients. In Trial 2, 11 patients (20%) were 65 years of age and older, and 2 patients (4%) were 75 years of age and older.

8.6 Females and Males of Reproductive Potential TAFINLAR Contraception: Females: Advise female patients of reproductive potential to use highly effective contraception during treatment and for at least 2 weeks after the last dose of TAFINLAR or at least 4 months after the last dose of TAFINLAR taken in combination with MEKINIST. Counsel patients to use a non-hormonal method of contraception since TAFINLAR can render hormonal contraceptives

ineffective. Advise patients to contact their healthcare provider if they become pregnant, or if pregnancy is suspected, while taking TAFINLAR [see Warnings and Precautions (5.11), Drug Interactions (7.1), Use in Specific Populations (8.1)].

Infertility: Females: Increased follicular cysts and decreased corpora lutea were observed in female rats treated with trametinib. Advise female patients of reproductive potential that TAFINLAR taken in combination with MEKINIST may impair fertility in female patients.

Males: Effects on spermatogenesis have been observed in animals. Advise male patients of the potential risk for impaired spermatogenesis, and to seek counseling on fertility and family planning options prior to starting treatment with TAFINLAR [see Nonclinical Toxicology (13.1)].

MEKINIST Contraception: Females: MEKINIST can cause fetal harm when administered during pregnancy. Advise female patients of reproductive potential to use highly effective contraception during treatment and for 4 months after the last dose of MEKINIST. When MEKINIST is used in combination with TAFINLAR, counsel patients to use a non-hormonal method of contraception since dabrafenib can render hormonal contraceptives ineffective. Advise patients to contact their healthcare provider if they become pregnant, or if pregnancy is suspected, while taking MEKINIST [see Use in Specific Populations (8.1)].

Infertility: Females: MEKINIST may impair fertility in female patients [see Nonclinical Toxicology (13.1)].

Males: Effects on spermatogenesis have been observed in animals treated with dabrafenib. Advise male patients of the potential risk for impaired spermatogenesis, and to seek counseling on fertility and family planning options prior to starting treatment with MEKINIST in combination with TAFINLAR. 8.7 Hepatic Impairment TAFINLAR No formal pharmacokinetic trial in patients with hepatic impairment has been conducted. Dose adjustment is not recommended for patients with mild hepatic impairment based on the results of the population pharmacokinetic analysis. As hepatic metabolism and biliary secretion are the primary routes of elimination of dabrafenib and its metabolites, patients with moderate to severe hepatic impairment may have increased exposure. An appropriate dose has not been established for patients with moderate to severe hepatic impairment [see Clinical Pharmacology (12.3)].

MEKINIST No formal clinical trial has been conducted to evaluate the effect of hepatic impairment on the pharmacokinetics of trametinib. No dose adjustment is recommended in patients with mild hepatic impairment based on a population pharmacokinetic analysis [see Clinical Pharmacology (12.3)].

The appropriate dose of MEKINIST has not been established in patients with moderate or severe hepatic impairment.

8.8 Renal Impairment No formal pharmacokinetic trial for TAFINLAR or MEKINIST has been conducted in patients with renal impairment. Dose adjustment is not recommended for patients with mild or moderate renal impairment based on the results of the population pharmacokinetic analysis. An appropriate dose has not been established for patients with severe renal impairment [see Clinical Pharmacology (12.3)].

10 OVERDOSAGE There is no information on overdosage of TAFINLAR. Since dabrafenib is highly bound to plasma proteins, hemodialysis is likely to be ineffective in the treatment of overdose with TAFINLAR. There were no reported cases of overdosage with MEKINIST. The highest doses of MEKINIST evaluated in clinical trials were 4 mg orally once daily and 10 mg administered orally once daily on 2 consecutive days followed by 3 mg once daily. In seven patients treated on one of these two schedules, there were two cases of retinal pigment epithelial detachments for an incidence of 28%. Since trametinib is highly bound to plasma proteins, hemodialysis is likely to be ineffective in the treatment of overdose with MEKINIST. 17 PATIENT COUNSELING INFORMATION See FDA-approved patient labeling (Medication Guide) for TAFINLAR. See FDA-approved patient labeling (Patient Information) for MEKINIST. Inform patients of the following: • Evidence of BRAF V600E mutation in the tumor specimen is necessary to identify patients for whom treatment with TAFINLAR as a single agent is indicated and evidence of BRAF V600E or V600K mutation in tumor specimens is necessary to identify patients for whom treatment with TAFINLAR in combination with MEKINIST is indicated.

• TAFINLAR administered in combination with MEKINIST can result in the development of new primary cutaneous and non-cutaneous malignancies. Advise patients to contact their doctor immediately for any new lesions, changes to existing lesions on their skin, or other signs and symptoms of malignancies [see Warnings and Precautions (5.1)].

• TAFINLAR administered in combination with MEKINIST increases the risk of intracranial and gastrointestinal hemorrhage. Advise patients to contact their healthcare provider to seek immediate medical attention for signs or symptoms of unusual bleeding or hemorrhage [see Warnings and Precautions (5.3)].

• TAFINLAR administered in combination with MEKINIST increases the risks of pulmonary embolism and deep venous thrombosis. Advise patients to seek immediate medical attention for sudden onset of difficulty breathing, leg pain, or swelling [see Warnings and Precautions (5.4)].

• TAFINLAR administered in combination with MEKINIST can cause cardiomyopathy. Advise patients to immediately report any signs or symptoms of heart failure to their healthcare provider [see Warnings and Precautions (5.5)].

• TAFINLAR and MEKINIST can cause visual disturbances that can lead to blindness. Advise patients to

contact their healthcare provider if they experience any changes in their vision [see Warnings and Precautions (5.6)].

• MEKINIST can cause interstitial lung disease (or pneumonitis). Advise patients to contact their healthcare provider as soon as possible if they experience signs such as cough or dyspnea [see Warnings and Precautions (5.6)].

• TAFINLAR administered as a single agent and in combination with MEKINIST can cause pyrexia including serious febrile reactions. Inform patients that the incidence and severity of pyrexia are increased when TAFINLAR is given in combination with MEKINIST. Instruct patients to contact their doctor if they develop fever while taking TAFINLAR [see Warnings and Precautions (5.7)].

• TAFINLAR in combination with MEKINIST can cause serious skin toxicities which may require hospitalization. Advise patients to contact their healthcare provider for progressive or intolerable rash [see Warnings and Precautions (5.8)].

• TAFINLAR can impair glucose control in diabetic patients resulting in the need for more intensive hypoglycemic treatment. Advise patients to contact their doctor to report symptoms of severe hyperglycemia [see Warnings and Precautions (5.9)].

• TAFINLAR may cause hemolytic anemia in patients with glucose-6-phosphate dehydrogenase (G6PD) deficiency. Advise patients with known G6PD deficiency to contact their doctor to report signs or symptoms of anemia or hemolysis [see Warnings and Precautions (5.10)].

• MEKINIST causes hypertension. Advise patients that they need to undergo blood pressure monitoring and to contact their healthcare provider if they develop symptoms of hypertension such as severe headache, blurry vision, or dizziness.

• MEKINIST often causes diarrhea which may be severe in some cases. Inform patients of the need to contact their healthcare provider if severe diarrhea occurs during treatment.

• TAFINLAR and MEKINIST can cause fetal harm if taken during pregnancy. Instruct female patients to use non-hormonal, highly effective contraception during treatment and for 4 months after discontinuation of treatment with TAFINLAR in combination with MEKINIST. Advise patients to contact their doctor if they become pregnant, or if pregnancy is suspected, while taking TAFINLAR and MEKINIST [see Warnings and Precautions (5.11), Use in Specific Populations (8.1)].

• Nursing infants may experience serious adverse reactions if the mother is taking TAFINLAR or MEKINIST during breastfeeding. Advise breastfeeding mothers to discontinue nursing while taking TAFINLAR or MEKINIST [see Use in Specific Populations (8.3)].

• Male patients are at an increased risk for impaired spermatogenesis [see Use in Specific Populations (8.6)].

• TAFINLAR and MEKINIST should be taken either at least 1 hour before or at least 2 hours after a meal.

TAFINLAR is a registered trademark of GlaxoSmithKline.

MEKINIST is a registered trademark of GlaxoSmithKline.

GlaxoSmithKline Research Triangle Park, NC 27709

© 2014, GlaxoSmithKline group of companies. All rights reserved.

Revised: 01/2014 TFR:4BRS © 2014 GSK group of companies.

All rights reserved. Printed in USA. MEL156R0 July 2014

Important Safety Information for TAFINLAR and MEKINIST when used in combination (cont'd) Across clinical trials of TAFINLAR in combination with MEKINIST (N=202), the incidence of pyrexia was 57% (116/202).

Withhold TAFINLAR for fever of 101.3ºF or higher. Withhold MEKINIST for any fever higher than 104ºF. Withhold TAFINLAR, and MEKINIST if used in combination, for any serious febrile reaction or fever complicated by hypotension, rigors or chills, dehydration, or renal failure, and evaluate for signs and symptoms of infection. Refer to Table 2 of the Prescribing Information for TAFINLAR for recommended dose modifications.

Prophylaxis with antipyretics may be required when resuming TAFINLAR or MEKINIST. Serious Skin Toxicity. In Trial 2, the incidence of any skin toxicity was similar for patients receiving TAFINLAR in combination with MEKINIST (65% [36/55]) compared with patients receiving TAFINLAR as a single agent (68% [36/53]). The median time to onset of skin toxicity in patients treated with TAFINLAR in combination with MEKINIST was 37 days (range: 1 to 225 days) and median time to resolution of skin toxicity was 33 days (range: 3 to 421 days). No patient required dose reduction or permanent discontinuation of TAFINLAR or MEKINIST for skin toxicity.

Across clinical trials of TAFINLAR in combination with MEKINIST (N=202), severe skin toxicity and secondary infections of the skin requiring hospitalization occurred in 2.5% (5/202) of patients treated with TAFINLAR in combination with MEKINIST. Withhold TAFINLAR, and MEKINIST if used in combination, for intolerable or severe skin toxicity. TAFINLAR and MEKINIST may be resumed at lower dose levels in patients with improvement or recovery from skin toxicity within 3 weeks.

Hyperglycemia. In Trial 2, the incidence of Grade 3 hyperglycemia based on laboratory values was 5% (3/55) in patients treated with TAFINLAR in combination with MEKINIST compared with 2% (1/53) in patients treated with TAFINLAR as a single agent.

Monitor serum glucose levels as clinically appropriate when TAFINLAR is used in combination with MEKINIST in patients with pre-existing diabetes or hyperglycemia. Advise patients to report symptoms of severe hyperglycemia, such as excessive thirst or any increase in the volume or frequency of urination.

Glucose-6-Phosphate Dehydrogenase Deficiency. TAFINLAR, which contains a sulfonamide moiety, confers a potential risk of hemolytic anemia in patients with glucose-6-phosphate dehydrogenase (G6PD) deficiency. Closely observe patients with G6PD deficiency for signs of hemolytic anemia.

Embryofetal Toxicity. TAFINLAR and MEKINIST both can cause fetal harm when administered to a pregnant woman. Advise female patients of reproductive potential to use highly effective non-hormonal contraception during treatment with TAFINLAR and MEKINIST in combination and for 4 months after treatment, since TAFINLAR can render hormonal contraceptives ineffective.

Advise patients to contact their healthcare provider if they become pregnant, or if pregnancy is suspected, while taking TAFINLAR and MEKINIST. Most Common Adverse Reactions. The most common (≥20%) adverse reactions in Trial 2 (all grades) for TAFINLAR 150 mg twice daily and MEKINIST 2 mg once daily, TAFINLAR 150 mg

twice daily and MEKINIST 1 mg once daily, and TAFINLAR as a single agent, respectively, included: pyrexia (fever) (71%, 69%, 26%), chills (58%, 50%, 17%), fatigue (53%, 57%, 40%), rash (45%, 43%, 53%), nausea (44%, 46%, 21%), vomiting (40%, 43%, 15%), diarrhea (36%, 26%, 28%), abdominal pain (33%, 24%, 21%), peripheral edema (31%, 28%, 17%), cough (29%, 11%, 21%), headache (29%, 37%, 28%), arthralgia (27%, 44%, 34%), night sweats (24%, 15%, 6%), decreased appetite (22%, 30%, 19%), constipation (22%, 17%, 11%) and myalgia (22%, 24%, 23%).

The most common (≥5%) serious adverse reactions in Trial 2 (grades 3 or 4) for TAFINLAR 150 mg twice daily and MEKINIST 2 mg once daily, TAFINLAR 150 mg twice daily and MEKINIST 1 mg once daily, and TAFINLAR as a single agent, respectively, included: renal failure (7%, 0%, 0%), pyrexia (5%, 9%, 0%), back pain (5%, 0%, 2%), and hemorrhage (5%, 0%, 0%).

Drug Interactions Effects of Other Drugs on Dabrafenib. Dabrafenib is primarily metabolized by CYP2C8 and CYP3A4. Strong inhibitors of CYP3A4 or CYP2C8 may increase concentrations of dabrafenib and strong inducers of CYP3A4 or CYP2C8 may decrease concentrations of dabrafenib. Substitution of strong inhibitors or strong inducers of CYP3A4 or CYP2C8 is recommended during treatment with TAFINLAR. If concomitant use of strong inhibitors (eg, ketoconazole, nefazodone, clarithromycin, gemfibrozil) or strong inducers (eg, rifampin, phenytoin, carbamazepine, phenobarbital, St John’s wort) of CYP3A4 or CYP2C8 is unavoidable, monitor patients closely for adverse reactions when taking strong inhibitors or loss of efficacy when taking strong inducers.

Effects of Dabrafenib on Other Drugs. Dabrafenib induces CYP3A4 and CYP2C9. Dabrafenib decreased the systemic exposures of midazolam (a CYP3A4 substrate), S-warfarin (a CYP2C9 substrate), and R-warfarin (a CYP3A4/CYP1A2 substrate). Monitor international normalized ratio (INR) levels more frequently in patients receiving warfarin during initiation or discontinuation of dabrafenib. Coadministration of TAFINLAR with other substrates of these enzymes, including dexamethasone or hormonal contraceptives, can result in decreased concentrations and loss of efficacy. Substitute for these medications or monitor patients for loss of efficacy if use of these medications is unavoidable.

Effects of the Combination of Dabrafenib with Trametinib.

Coadministration of TAFINLAR 150 mg twice daily and MEKINIST 2 mg once daily resulted in no clinically relevant pharmacokinetic drug interactions.

To learn more, visit TAFINLARMEKINISTHCP.com Please see Brief Summary of Prescribing Information for TAFINLAR and MEKINIST on the following pages.

Please see full Prescribing Information and Medication Guide for TAFINLAR and full Prescribing Information and Patient Information Leaflet for MEKINIST.

References: 1. TAFINLAR [package insert]. Research Triangle Park, NC: GlaxoSmithKline; 2014. 2. Flaherty KT, Infante JR, Daud A, et al.

N Engl J Med. 2012;367:1694-1703.

TAFINLARMEKINISTHCP.com TAFINLAR and MEKINIST are registered trademarks of the GSK group of companies. ©2014 GSK group of companies. All rights reserved.

Printed in USA. MEL156R0 July 2014

®

(dabrafenib) 50 mg, 75 mg capsules

®

(trametinib) 0.5 mg, 1 mg, 2 mg tablets

TAFINLAR + MEKINIST demonstrated a 76% overall response rate1 Major efficacy outcome: Investigator-assessed response rate1 Overall Response

54%

(95% CI: 40, 67)

Overall Response

76%

(95% CI: 62, 87)

67%

80 70

50%

60

Response Rates

Study Design: Trial 2 was a multicenter, open-label, randomized (1:1:1) dose-ranging trial designed to evaluate the clinical activity and safety of TAFINLAR in combination with MEKINIST (at 2 different doses) and to compare the safety with TAFINLAR as a single agent in 162 patients with BRAF V600E or V600K mutationpositive, unresectable or metastatic melanoma. Patients were permitted to have had one prior chemotherapy regimen and prior aldesleukin; patients with prior exposure to BRAF or MEK inhibitors were ineligible.

Patients were randomized to receive TAFINLAR 150 mg orally twice daily with MEKINIST 2 mg orally once daily (N=54), TAFINLAR 150 mg orally twice daily with MEKINIST 1 mg orally once daily (N=54), or TAFINLAR 150 mg orally twice daily (N=54). Treatment continued until disease progression or unacceptable toxicity.1

50 40 30 20 10 0

9%

4

%

Complete Response

Partial Response

TAFINLAR as a single agent (N=54)

Complete Response

TAFINLAR

150 mg twice daily

+

Partial Response

MEKINIST

2 mg once daily

(N=54)

Important Safety Information for TAFINLAR and MEKINIST when used in combination (cont'd) Hemorrhage. Hemorrhages, including major hemorrhages defined as symptomatic bleeding in a critical area or organ, can occur when TAFINLAR is used in combination with MEKINIST. In Trial 2, treatment with TAFINLAR in combination with MEKINIST resulted in an increased incidence and severity of any hemorrhagic event: 16% (9/55) of patients treated with TAFINLAR in combination with MEKINIST compared with 2% (1/53) of patients treated with TAFINLAR as a single agent. The major hemorrhagic events of intracranial or gastric hemorrhage occurred in 5% (3/55) of patients treated with TAFINLAR in combination with MEKINIST compared with none of the 53 patients treated with TAFINLAR as a single agent. Intracranial hemorrhage was fatal in 4% (2/55) of patients receiving TAFINLAR in combination with MEKINIST. Permanently discontinue TAFINLAR and MEKINIST for all Grade 4 hemorrhagic events and for any Grade 3 hemorrhagic events that do not improve. Withhold TAFINLAR for Grade 3 hemorrhagic events; if improved resume at a lower dose level. Withhold MEKINIST for up to 3 weeks for Grade 3 hemorrhagic events; if improved, resume at a lower dose level.

Venous Thromboembolism. In Trial 2, treatment with TAFINLAR in combination with MEKINIST resulted in an increased incidence of deep venous thrombosis (DVT) and pulmonary embolism (PE): 7% (4/55) of patients treated with TAFINLAR in combination with MEKINIST compared with none of the 53 patients treated with TAFINLAR as a single agent. Pulmonary embolism was fatal in 2% (1/55) of patients receiving TAFINLAR in combination with MEKINIST. Advise patients to immediately seek medical care if they develop symptoms of DVT or PE, such as shortness of breath, chest pain, or arm or leg swelling. Permanently discontinue TAFINLAR and MEKINIST for life-threatening PE. Withhold MEKINIST and continue TAFINLAR at the same dose for uncomplicated DVT or PE; if improved within 3 weeks, MEKINIST may be resumed at a lower dose level.

Cardiomyopathy. In Trial 2, cardiomyopathy occurred in 9% (5/55) of patients treated with TAFINLAR in combination with MEKINIST

and in none of the patients treated with TAFINLAR as a single agent.

The median time to onset of cardiomyopathy in patients treated with TAFINLAR in combination with MEKINIST was 86 days (range: 27 to 253 days). Cardiomyopathy was identified within the first month of treatment with TAFINLAR in combination with MEKINIST in 2 of 5 patients. Development of cardiomyopathy resolved in all 5 patients following dose reduction (4/55) and/or dose interruption (1/55).

Across clinical trials of TAFINLAR in combination with MEKINIST (N=202), 2% demonstrated a decrease in LVEF below institutional lower limits of normal with an absolute decrease in LVEF of â&#x2030;Ľ20% below baseline.

Assess LVEF by echocardiogram or multigated acquisition (MUGA) scan before initiation of TAFINLAR in combination with MEKINIST, one month after initiation, and then at 2- to 3-month intervals while on treatment with the combination. Withhold treatment with MEKINIST and continue TAFINLAR at the same dose if absolute LVEF value decreases by 10% from pretreatment values and is less than the lower limit of normal. For symptomatic cardiomyopathy or persistent, asymptomatic LV dysfunction that does not resolve within 4 weeks, permanently discontinue MEKINIST and withhold TAFINLAR. Resume TAFINLAR at the same dose level upon recovery of cardiac function.

Ocular Toxicities. Retinal Vein Occlusion (RVO): Across all clinical trials of MEKINIST, the incidence of RVO was 0.2% (4/1,749).

RVO may lead to macular edema, decreased visual function, neovascularization, and glaucoma.

Urgently (within 24 hours) perform ophthalmological evaluation for patient-reported loss of vision or other visual disturbances.

Permanently discontinue MEKINIST in patients with documented RVO. If MEKINIST is used in combination with TAFINLAR, do not modify dose of TAFINLAR. Retinal Pigment Epithelial Detachment (RPED): Retinal pigment epithelial detachments (RPED) can occur when TAFINLAR is used in combination with MEKINIST and with MEKINIST as a single agent. Retinal detachments resulting from MEKINIST are often

TAFINLAR + MEKINIST achieved a median duration of response of 10.5 months1 Efficacy outcome: Investigator-assessed median duration of response1

TAFINLAR

+ MEKINIST

150 mg twice daily 2 mg once daily (N=54)

10.5

months

(95% CI: 7, 15)

Months Months TAFINLAR as a single agent (N=54)

5.6

months

(95% CI: 5, 7)

Independent Radiology Review Committee (IRRC) analyses were supportive of investigator-assessed results1 • 57% overall response rate (ORR) (95% CI: 43, 71) with TAFINLAR 150 mg twice daily + MEKINIST 2 mg once daily; 46% ORR (95% CI: 33, 60) with TAFINLAR as a single agent1 – Complete response (CR) with TAFINLAR 150 mg twice daily + MEKINIST 2 mg once daily: 9%; CR with TAFINLAR as a single agent: 7% – Partial response (PR) with TAFINLAR 150 mg twice daily + MEKINIST 2 mg once daily: 48%; PR with TAFINLAR as a single agent: 39% • Median duration of response of 7.6 months (95% CI: 7, not reported) with TAFINLAR 150 mg twice daily + MEKINIST 2 mg once daily; median duration of response of 7.6 months (95% CI: 6, not reported) with TAFINLAR as a single agent1

Important Safety Information for TAFINLAR and MEKINIST when used in combination (cont'd) bilateral and multifocal, occurring in the macular region of the retina. In Trial 2, ophthalmologic examinations including retinal evaluation were performed pretreatment and at regular intervals during treatment. RPED occurred in 2% (1/55) of patients receiving TAFINLAR in combination with MEKINIST. Perform ophthalmological evaluation at any time a patient reports visual disturbances and compare with baseline, if available. If TAFINLAR is used in combination with MEKINIST, do not modify the dose of TAFINLAR. Withhold MEKINIST if RPED is diagnosed. If resolution of the RPED is documented on repeat ophthalmological evaluation within 3 weeks, resume MEKINIST at a lower dose level. Discontinue MEKINIST if no improvement after 3 weeks.

Uveitis and Iritis: Uveitis (including iritis) occurred in 1% (6/586) of patients treated with TAFINLAR as a single agent and in 1% (2/202) of patients treated with TAFINLAR in combination with MEKINIST. Symptomatic treatment employed in clinical trials included steroid and mydriatic ophthalmic drops. Monitor patients for visual signs and symptoms of uveitis (eg, change in vision, photophobia, eye pain). If diagnosed, withhold TAFINLAR for up to 6 weeks until uveitis/iritis resolves to Grade 0-1.

If TAFINLAR is used in combination with MEKINIST, do not modify the dose of MEKINIST. Interstitial Lung Disease. In clinical trials of MEKINIST (N=329) as a single agent, ILD or pneumonitis occurred in 2% of patients.

Withhold MEKINIST in patients presenting with new or progressive pulmonary symptoms and findings including cough, dyspnea, hypoxia, pleural effusion, or infiltrates, pending clinical investigations. Permanently discontinue MEKINIST for patients diagnosed with treatment-related ILD or pneumonitis.

If MEKINIST is used in combination with TAFINLAR, do not modify the dose of TAFINLAR. Serious Febrile Drug Reactions. The incidence and severity of pyrexia are increased when TAFINLAR is used in combination

with MEKINIST compared with TAFINLAR as a single agent.

In Trial 2, the incidence of fever (serious and non-serious) was 71% (39/55) in patients treated with TAFINLAR in combination with MEKINIST and 26% (14/53) in patients treated with TAFINLAR as a single agent. Serious febrile reactions and fever of any severity complicated by hypotension, rigors, or chills occurred in 25% (14/55) of patients treated with TAFINLAR in combination with MEKINIST compared with 2% (1/53) of patients treated with TAFINLAR as a single agent. Fever was complicated with chills/rigors in 51% (28/55), dehydration in 9% (5/55), renal failure in 4% (2/55), and syncope in 4% (2/55) of patients in Trial 2.

In patients treated with TAFINLAR in combination with MEKINIST, the median time to initial onset of fever was 30 days compared with 19 days in patients treated with TAFINLAR as a single agent; the median duration of fever was 6 days with the combination compared with 4 days with TAFINLAR as a single agent.

To learn more, visit TAFINLARMEKINISTHCP.com Please see additional Important Safety Information for TAFINLAR and MEKINIST when used in combination on the following pages.

Please see Brief Summary of Prescribing Information for TAFINLAR and MEKINIST on the following pages.

®

(dabrafenib) 50 mg, 75 mg capsules

®

(trametinib) 0.5 mg, 1 mg, 2 mg tablets

The first and only FDA-approved combination therapy Indicated for the treatment of patients with unresectable or metastatic melanoma with BRAF V600E or V600K mutations, as detected by an FDA-approved test. This indication is based on the demonstration of durable response rate. Improvement in disease-related symptoms or overall survival has not been demonstrated for TAFINLAR in combination with MEKINIST. Limitation of use: TAFINLAR is not indicated for treatment of patients with wild-type BRAF melanoma.

2 AGENTS. 1 THERAPY.

DEMONSTRATED DURABLE RESPONSE RATE IN A PHASE II STUDY 1,2

Investigator-assessed analysis

TAFINLAR + MEKINIST

150 mg twice daily

2 mg once daily

in combination TAFINLAR

as a single agent

overall response rate1 overall response rate1

76 54%

% (95% CI: 62, 87)

median duration of response1

(95% CI: 40, 67)

median duration of response1

10.5 5.6

months

(95% CI: 7, 15)

months

(95% CI: 5, 7)

Important Safety Information for TAFINLAR and MEKINIST when used in combination New Primary Malignancies. New primary malignancies, cutaneous and non-cutaneous, can occur when TAFINLAR is used in combination with MEKINIST. Cutaneous Malignancies: In Trial 2, the incidence of basal cell carcinoma was increased in patients receiving TAFINLAR in combination with MEKINIST: 9% (5/55) of patients receiving TAFINLAR in combination with MEKINIST compared with 2% (1/53) of patients receiving TAFINLAR as a single agent. The range of time to diagnosis of basal cell carcinoma was 28 to 249 days in patients receiving TAFINLAR in combination with MEKINIST and was 197 days for the patient receiving TAFINLAR as a single agent.

Cutaneous squamous cell carcinoma, including keratoacanthoma, (cuSCC) occurred in 7% of patients receiving TAFINLAR in combination with MEKINIST and 19% of patients receiving TAFINLAR as a single agent. The range of time to diagnosis of cuSCC was 136 to 197 days in the combination arm and was 9 to 197 days in the arm receiving TAFINLAR as a single agent.

New primary melanoma occurred in 2% (1/53) of patients receiving TAFINLAR as a single agent and in none of the 55 patients receiving TAFINLAR in combination with MEKINIST. Perform dermatologic evaluations prior to initiation of TAFINLAR in combination with MEKINIST, every 2 months while on therapy, and for up to 6 months following discontinuation of TAFINLAR. No dose modifications of

TAFINLAR or MEKINIST are required in patients who develop new primary cutaneous malignancies.

Non-cutaneous Malignancies: In patients receiving TAFINLAR in combination with MEKINIST four cases of non-cutaneous malignancies were identified: KRAS mutation-positive pancreatic adenocarcinoma (n=1), recurrent NRAS mutation-positive colorectal carcinoma (n=1), head and neck carcinoma (n=1), and glioblastoma (n=1). Monitor patients receiving the combination closely for signs or symptoms of non-cutaneous malignancies.

Permanently discontinue TAFINLAR for RAS mutation-positive non-cutaneous malignancies. If used in combination with MEKINIST, no dose modification of MEKINIST is required for patients who develop non-cutaneous malignancies.

Tumor Promotion in BRAF Wild-Type Melanoma. In vitro experiments have demonstrated paradoxical activation of MAP-kinase signaling and increased cell proliferation in BRAF wild-type cells that are exposed to BRAF inhibitors. Confirm evidence of BRAF V600E or V600K mutation status prior to initiation of TAFINLAR in combination with MEKINIST. To learn more, visit TAFINLARMEKINISTHCP.com Please see additional Important Safety Information for TAFINLAR and MEKINIST when used in combination on the following pages.

Please see Brief Summary of Prescribing Information for TAFINLAR and MEKINIST on the following pages.