TAP Vol 5 Issue 12

Immunotherapy for Melanoma

9

| Thyroid Cancer

23, 56

| Doxorubicin Dermatologic Toxicities

VOLUME 5, ISSUE 12

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JULY 25, 2014

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

ASCO Annual Meeting

Considerable Extension of Survival Achieved With Conventional Treatment in Grade 2 Glioma

By Caroline Helwick

A Conversation With Clifford A. Hudis, MD, FACP

L

ong-term results from the Radiation Therapy Oncology Group (RTOG) 9802 study in high-risk grade 2 gliomas were presented at the 2014 ASCO Annual Meeting. The study’s mature analysis showed a 41% reduction in mortality at 5 years with combination radiation therapy followed by six cycles of PCV chemotherapy (procarbazine [Matulane], lomustine [CeeNU], and vincristine).

While grade 2 gliomas are relatively indolent, nearly all patients eventually develop progressive neurologic symptoms and die from their disease. This is the first prospective study to show a treatment-related survival benefit.

“For patients with grade 2 glioma, with less than gross total tumor resection or who are more than 40 years of age, radiotherapy plus PCV prolongs both progression-free and overall survival, compared to radiotherapy alone,” reported Jan C. Buckner, MD, of the Mayo Clinic, Rochester, Minnesota.

Study Details In the RTOG 9802 trial, 251 patients with diffuse grade 2 gliomas were randomly assigned to radiation therapy alone (54 Gy in 30 fractions) or to radiation therapy followed by six cycles of PCV. At a median follow-up of Jan C. Buckner, MD almost 12 years, median progression-free survival was 10.4 years with the combination vs 4.0 years with radiotherapy alone, a 50% reduction in risk (P < .001 by log-rank test).

Median overall survival was 13.3 years with the combination vs 7.8 years with radiotherapy alone (P = .002 by log-rank test). The 5-year overall survival rate was also better with the combination (72.3% vs continued on page 16

Issues in Oncology

Stakeholders Are Uniting Around Value in Cancer Care udging from its visibility at the 2014 ASCO Annual Meeting, the concept of “value” in cancer care has reached critical mass.

“ASCO is leading this difficult discussion on value in cancer care. This had to happen,” said ­Clifford A. Hudis, MD, FACP, Immediate Past President of ASCO and Chief of the Breast Medicine Service at Memorial Sloan Kettering Cancer Center, New York.

T

he ASCO Post recently spoke with ASCO Immediate Past President Clifford A. Hudis, MD, FACP, about his term as ASCO President. Dr. Hudis discussed his thoughts on ASCO today and shared his perspective on a number of important issues in oncology, including value in cancer care, big data, and more.

Role of ASCO Having served as ASCO President for 2013– 2014, you have a unique view of the Society. Would you share with us your insight into this view?

The way I view ASCO today is completely continued on page 105

Dr. Hudis is Chief of the Breast Cancer Medicine Service, Memorial Sloan Kettering Cancer Center, and Professor of Medicine, Weill Cornell Medical College, New York.

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

MORE IN THIS ISSUE

By Caroline Helwick

J

Take-Home Messages From ASCO’s Immediate Past President

Unsustainable Trend

At the ASCO session, “Can We Find Common Ground? Stakeholder Perspectives on Value in Cancer Care,” representatives from the oncology clinical community, health-care payers, industry, and patient advocacy groups offered insights from around the value equation, but the bottom line was unanimous: With 30% of the average $50,000 (approximate median) household income now spent on health care, the trend is unsustainable and a solution is urgently needed.

Ezekiel J. Emanuel, Oncologists have an obligation to MD, PhD, Diane v.S. Levy and Robert M. Levy Uniavoid unneccessary testing and to versity Professor, Profesprescribe the lower-cost option if it is sor of Health Care Management, and Professor of equivalent to a more expensive drug.

Medical Ethics and Health —Ezekiel J. Emanuel, MD, PhD Policy in the Perelman

Oncology Meetings Coverage ASCO 50th Annual Meeting � 1–27, 35, 36 ASPHO Annual Meeting ��������������������������38 ESMO World Congress on GI Cancers ����43 Direct From ASCO �������������������������� 50–53 Maria E. Cabanillas, MD, FACE, on Differentiated Thyroid Cancer ��������������57 Carol H. Lee, MD, FACR, on Swiss Medical Board Mammography Recommendations ��������������������������������������62 Clinical Trials ��������������������������������������������70 Lung-MAP Trial ���������������������������������������� 74 Oncology Worldwide ������������������������������� 80 In Memoriam: John M. Fitzpatrick, MCh, FRCSI ������� 102

continued on page 48

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The ASCO Post | JULY 25, 2014

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ASCO Annual Meeting Hematology

Multiple Myeloma Studies Explore Roles of Panobinostat in Relapsed/Refractory Disease and Thalidomide Compared to Lenalidomide as Part of Initial Therapy

By Caroline Helwick

A

t the 2014 ASCO Annual Meeting, one phase III trial confirmed the promise of a novel agent in advanced multiple myeloma, while another cooperative group trial returned some rather surprising results in newly diagnosed myeloma patients.

Panobinostat Doubles Response, Prolongs Remission The phase III PANORAMA 1 trial demonstrated clear benefit for adding the investigational agent panobinostat to bortezomib (Velcade) in previously treated advanced multiple myeloma.

The results were reported by Paul G. Richardson, MD, Clinical Disease Program Leader and Director of Clinical Research, Jerome Lipper Multiple Myeloma Center, Dana-Farber Cancer Institute, Boston.1 “The primary endpoint was met (P < .0001), with a clinically relevant increase in median progression-free survival of approximately 4 months,” Dr. Richardson announced.

Panobinostat is an oral pan–histone deacetylase (HDAC) inhibitor whose actions ultimately result in cell-cycle arrest and apoptosis. One of the drug’s key targets is HDAC6, an enzyme that is an important target in myeloma, as well as others in the HDAC family. In preclinical studies, the combination of panobinostat plus bortezomib shows synergy, as panobinostat inhibits the aggresome pathway of protein degradation that is upregulated when the proteasome pathway is inhibited by ­bortezomib.

PANORAMA 1 was an international randomized, double-blind, placebocontrolled phase III trial that enrolled 768 patients who had received one to three prior lines of treatment but were not bortezomib-refractory. More than half the patients had received a prior autologous stem cell transplant.

Patients were randomly assigned to panobinostat or placebo, each in combination with intravenous bortezomib (as subcutaneous bortezomib was not yet approved at the time of the trial’s initiation) and dexamethasone. Responders after eight cycles went on to receive less frequent dosing of bortezomib/ dexamethasone.

After a median follow-up of 28 months, the combination significantly

improved progression-free survival, from 8.1 months with placebo to 12.0 months, a 37% highly significant reduction in risk (P < .0001), which Dr. Richardson called a “clinically relevant benefit.”

While the overall response rate was similar between the arms—60.7% with panobinostat and 54.6% with placebo (P = .087)—the combination con-

with panobinostat and 31.4% with placebo, but was both generally manageable and reversible. Other grade 3/4 adverse events occurring more frequently with the HDAC inhibitor included lymphopenia, neutropenia, diarrhea, and asthenia/fatigue; however, these led to discontinuation of the drug in fewer than 5% of patients. Deaths deemed possibly

These results [PANORAMA] confirm the efficacy of panobinostat, bortezomib, and dexamethasone previously observed in the PANORAMA 2 trial with patients who were heavily pretreated and bortezomib-refractory.

—Paul G. Richardson, MD

The findings were [from E1A06] statistically inconclusive. The study did not prove inferiority or noninferiority of MPR-R compared to MPT-T. —A. Keith Stewart, MBChB

veyed a near-doubling in complete and near-complete responses—27.6% vs 15.7%, respectively (P = .00006). The panobinostat arm also improved the median duration of response (13.1 vs 10.9 months), median time to response (1.5 vs 2.0 months), and median time to progression (12.7 vs 8.5 months).

Median overall survival, however, was not significantly different between the arms: 33.6 months in the panobinostat arm and 30.4 months in the placebo arm (P = .87), although the analysis remained early and the data immature for this key endpoint.

“These results confirm the promising efficacy of panobinostat, bortezomib, and dexamethasone previously observed in the PANORAMA 2 trial with patients who were both heavily pretreated and also bortezomib-refractory,” Dr. Richardson said.

The most common adverse event with the combination arm was thrombocytopenia, which was grade 3/4 in 67.4%

treatment-related by the investigator numbered 11 (2.9%) in the panobinostat arm and 7 (1.9%) in the control arm.

“The adverse events were predictable and generally manageable with supportive measures and dose reduction,” he said.

Other panobinostat-containing combinations and additional HDAC inhibi-

tors are currently in clinical trials, with promising results to date, Dr. Richardson noted. Moreover, the use of subcutaneous bortezomib may further improve the therapeutic index of the combination, and trials are either underway or planned to confirm this, he added.

Lenalidomide No Better Than Thalidomide Results of the E1A06 trial, presented

by A. Keith Stewart, MBChB, Professor of Medicine at the Mayo Clinic, Scottsdale, Arizona, were met with some surprise, as thalidomide (Thalomid) performed as well as lenalidomide (Revlimid) in combination with melphalan/prednisone in newly diagnosed patients ineligible for high-dose therapy.2 The study enrolled 306 patients (median age, 76), randomly assigning them to melphalan/prednisone plus either 12 cycles of thalidomide (100 mg), with thalidomide as maintenance (MPT-T), or lenalidomide (10 mg), with lenalidomide as maintenance (MPR-R). The study had a noninferiority design with a superiority alternative. The median follow-up was 40.7 months.

“The findings were statistically inconclusive,” Dr. Stewart said. “The study did not prove inferiority or noninferiority of MPR-R compared to MPT-T.” The response rates, depth of response, time on therapy, progressionfree survival rates and overall survival rates for the two regimens were similar, Dr. Stewart reported (see Table 1).

For MPT-T and MRP-R, respectively, response rates were 75% and 70%, very good or complete response rates continued on page 4

Table 1: Clinical Outcomes with MPT-T vs MPR-R Outcome

MPT-T

MPR-R

Objective response rate

75%

70%

Very good or complete response rate

25%

32%

Median progression-free survival

21 months

18.7 months

2-year progression-free survival

45%

37%

Median overall survival

52.6 months

47.7 months

2-year overall survival

78%

72%

MPR-R = melphalan, prednisone, lenalidomide, with lenalidomide maintenance; MPT-T = melphalan, prednisone, thalidomide, with thalidomide maintenance.

Courtesy of Stewart AK, et al: ASCO Annual Meeting. Abstract 8511. Presented June 1, 2014.

The ASCO Post | JULY 25, 2014

PAGE 4

ASCO Annual Meeting EXPERT POINT OF VIEW

M

elphalan, prednisone, and thalidomide (Thalomid), or MPT, was a widely accepted regimen in newly diagnosed multiple myeloma when the E1A06 trial was launched, noted Philip McCarthy, MD, Director of the Blood and Marrow Transplant Program at the Roswell Park Cancer Institute, Buffalo, New York. E1A06 compared MPT with melphalan, prednisone, plus lenalidomide (Revlimid), or MPR, in non–transplant-eligible, elderly patients (median age: 75.7 years).1 Both inductions were continued for 12 28-day cycles, with daily thalidomide (MPT-T) or lenalidomide (MPR-R) maintenance, respectively, continued until progression or relapse.

There was no difference in progression-free or overall survival between the two arms, but there was improved quality of life for the MPR-R arm.

Nearly half the patients were off therapy at the end of induction and 9% remain on therapy at a median follow-up of 41 months. The second primary malignancy rate was 9.5% for MPT-T and 5.3% for MPR-R, he noted.

“What can we learn from this study?

The progression-free survival and overall survival were inferior to that seen in MM 015, which examined MPR-R vs MPR vs melphalan/prednisone alone.2 This likely was due to the lower MPR-R melphalan dose and the older age population in E1A06,” Dr. McCarthy indicated.

The incidence of secondary primary malignancies in this study confirms the risk of the combined use of lower-dose melphalan with immunomodulatory drugs, which was reported in a recent meta-analysis.3 Another recent study, MM 020, demonstrated a superior progression-free survival and a trend toward overall survival benefit with continuous lenalidomide and low-dose dexamethasone until disease progres-

Multiple Myeloma Studies continued from page 3

were 25% and 32%, median progression-free survival was 21 months and 18.7 months, and 2-year progressionfree survival was 45% and 37%.

The finding that thalidomide performed as well as lenalidomide was apparently not explained by differences in drug exposure. Median time on therapy was 12 months, with no differences between the arms. Both groups received approximately 80% of the planned dose and 46% started maintenance. Patients receiving maintenance treatment had a

sion vs 18 months of lenalidomide/ dexamethasone vs MPT.4 “Thus, the E1A06 study confirms the need for improved regimens with sustained tolerability for long-term disease control in multiple myeloma,” Dr. McCarthy concluded. “We are seeing the end of MPT and MPR as standard induction therapies for the non–transplant-eligible myeloma patient. Newer, better tolerated and more effective regimens incorporating [immunomodulatory drugs], proteasome inhibitors and

double blind phase III study of panobinostat or placebo plus bortezomib (Velcade) and dexamethasone in relapsed and refractory multiple myeloma patients. The study demonstrated that the panobinostat combination was superior.5 The progression-free survival for the panobinostat, bortezomib, dexamethasone arm was 12 months vs 8.1 months for bortezomib/dexamethasone plus placebo (P < .0001). There is no difference in overall survival at this time, Dr. McCarthy noted.

PANORAMA 1 is an important step in the development of HDAC inhibition as part of combination therapy for the long-term control of multiple myeloma.

—Philip McCarthy, MD

Histone deacetylases (HDACs) modify chromatin, leading to geneexpression changes, which can result in aberrant cell-proliferation changes, in particular, multiple myeloma. HDAC inhibition results in epigenetic and chromatin changes, leading to diminished cell proliferation. Panobinostat inhibits various HDAC enzymes, with low-concentration activity against class I, II, and IV HDAC enzymes, which are involved in histone and transcription factor function, protein chaperoning, and tubulin formation.

PANORAMA 1 was a randomized,

“What have we learned from this study? The study generated a 4-month gain in progression-free survival, which is greater than the 1-month difference in the VANTAGE 088 trial that compared vorinostat [Zolinza], bortezomib, dexamethasone with bortezomib/dexamethasone in relapsed/refractory patients.6 The combined complete response plus near complete response rate was higher in the study arm,” he pointed out.

“Bortezomib-refractory patients were not eligible for this study, so we do not know if panobinostat plus bortezomib/dexamethasone would have reversed this resistance,” he indicated.

“The bortezomib was given intravenously, whereas subcutaneous administration is now standard,” he added.

Dr. McCarthy further pointed out that there were approximately twice

median time on therapy of 23 months, which was also not different between groups.

“But overall toxicity was less with MPR-R,” Dr. Stewart noted. Grade ≥ 3 overall toxicity was 73% with MPTT vs 58% with MPR-R (P = .007), and nonhematologic toxicity was 40% vs 59%, respectively (P = .001).

“Patient-reported quality of life was also better with MPR-R at the end of induction.”

Dr. Stewart pointed out that the survival outcome for the thalidomide arm is similar to those seen in previ-

ous studies of this regimen. However, the results for the lenalidomide arm were less impressive than those previously reported: In the MM 05 trial, for example, median progression-free survival was 31 months for MPTR, and median overall survival was 56 months.

Dr. Stewart also put the results into the context of current treatment. “In the United States, melphalan-based regimens are now seldom utilized due to the availability of lenalidomide and bortezomib in newly diagnosed patients,” he noted. n

potentially other novel agents such as antibodies will be studied as investigators attempt to control multiple myeloma long-term, with the goal of cure.”

PANORAMA 1

the adverse events on the experimental arm, whereas there were twice as many cases of disease progression on the control arm. The adverse events were thrombocytopenia, fatigue, and gastrointestinal toxicity as well as a small increase in hemorrhagic events.

Questions remain, he said. “For example, could the schedule be modified to decrease these adverse events? Can this combination be utilized upfront to enhance efficacy?” While further research may provide answers, he called the PANORAMA 1 trial “an important step in the development of HDAC inhibition as part of combination therapy for the longterm control of multiple myeloma.” n

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

References 1. Richardson PG, Hungria VT, Yoon S, et al: Panorama 1. ASCO Annual Meeting.

Abstract 8510. Presented June 2, 2014.

2. Palumbo A, Hajek R, Delforge M, et al: Continuous lenalidomide treatment for newly diagnosed multiple myeloma. N Engl J Med 366:1759-1769, 2012.

3. Palumbo A, Bringhen S, Kumar SK, et al: Second primary malignancies with lenalidomide therapy for newly diagnosed myeloma. Lancet Oncol 15:333-342, 2014.

4. Facon T, Dimopoulos MA, Dispenzieri A, et al: Initial phase 3 results of the first (frontline investigation of lenalidomide + dexamethasone versus standard thalidomide) trial (MM-020/IFM 07 01) in newly diagnosed multiple myeloma patients ineligible for stem cell transplantation. 2013 American Society of Hematology Annual Meeting.

Abstract 2. Presented December 8, 2013.

5. Stewart AK, Jacobus SJ, Fonseca R, et al: E1A06. ASCO Annual Meeting. Abstract 8511. Presented June 1, 2014.

6. Dimopoulos M, Siegel DS, Lonial S, et al: Vorinostat or placebo in combination with bortezomib in patients with multiple myeloma (VANTAGE 088). Lancet Oncol 14:1129-1140, 2013.

Disclosure: Dr. Richardson is a consultant/ advisor for Celgene, Johnson & Johnson, Millennium, and Novartis. Dr. Stewart is a consultant/advisor for Celgene. For full disclosures of all study authors, visit meetinglibrary.asco.org.

References 1. Richardson PG, Hungria VT, Yoon S, et al: Panorama 1. ASCO Annual Meeting. Abstract 8510. Presented June 2, 2014.

2. Stewart AK, Jacobus SJ, Fonseca R, et al: E1A06. ASCO Annual Meeting. Abstract 8511. Presented June 1, 2014.

ASCOPost.com | JULY 25, 2014

PAGE 5

ASCO Annual Meeting Gynecologic Oncology

Neoadjuvant Chemotherapy Less Invasive Option for Advanced Ovarian Cancer, but Jury Still Out

By Alice Goodman

N

eoadjuvant chemotherapy followed by interval debulking surgery may be a better strategy for the initial treatment of advanced ovarian cancer than the current standard of care, suggest results of a phase III trial.

Neoadjuvant chemotherapy followed by interval debulking surgery led to fewer complications and was less invasive compared with upfront debulking surgery followed by chemotherapy.

“Treatment starting with neoadjuvant chemotherapy is less invasive than standard treatment for advanced ovarian cancer. If noninferiority of survival compared with the standard treatment is confirmed

If noninferiority of survival is confirmed when the survival analysis is conducted in 2017, neoadjuvant chemotherapy will be the new standard of care for advanced ovarian cancer.

—Takashi Onda, MD, PhD

when the survival analysis is conducted in 2017, neoadjuvant chemotherapy will be the new standard of care for advanced ovarian cancer,” stated lead author

EXPERT POINT OF VIEW

F

ormal discussant of the JCOG 0602 trial at the ASCO Annual Meeting, Dennis S. Chi, MD, Deputy Chief of the Gynecology Service at Memorial Sloan Kettering Cancer Center, New York, reviewed the strengths and weakness of the study.

“This is the third study to evaluate primary debulking surgery vs neoadjuvant chemotherapy and interval debulking surgery. The bottom line is that the other two studies showed no difference in progression-free survival or overall survival.

So far, the idea that you can improve optimal resection and that will translate to improved survival hasn’t panned out.”

Study weaknesses included low rates of optimal debulking (37%) and complete gross resection (12%).

Neoadjuvant chemotherapy may lead to decreased rates of complications and less surgical invasiveness than primary debulking surgery, but progression-free survival and overall survival are the key endpoints we need to have.

—Dennis S. Chi, MD

“Progression-free survival and overall survival are immature. The conclusion that if noninferiority is confirmed in 2017, neoadjuvant chemotherapy will become the new standard of care is an overstatement in my view,” Dr. Chi said.

Prospective planned trials comparing these approaches will shed more light on this issue, he continued. Two upcoming studies on primary debulking surgery vs neoadjuvant chemotherapy are an international trial and the U.S. TRUST study, with planned accrual of 800 patients for each investigation. A requirement of both studies is to achieve a complete gross resection rate of 50%, he added.

“In conclusion, neoadjuvant chemotherapy may lead to decreased rates of complications and less surgical invasiveness than primary debulking surgery, but progression-free survival and overall survival are the key endpoints we need to have,” he said. n Disclosure: Dr. Chi reported no potential conflicts of interest.

Takashi Onda, MD, PhD, Kitasato University School of Medicine, Japan. Dr. Onda presented results of the Japan Clinical Oncology Group (JCOG) 0602 trial at the 2014 ASCO Annual Meeting.1

Study Design The study was designed to compare the efficacy and invasiveness of neoadjuvant chemotherapy followed by interval debulking surgery vs the standard of care, which is primary debulking surgery followed by intravenous chemotherapy with paclitaxel/carboplatin.

Two previous studies showed noninferior survival for neoadjuvant chemotherapy followed by interval debulking surgery compared with standard treatment.

Unfortunately, invasiveness of treatment starting with neoadjuvant chemotherapy followed by interval debulking surgery has not yet been fully analyzed. The present study was designed to compare the two strategies regarding invasiveness of the treatments in addition to survival.

JCOG 0602 took almost 5 years to complete accrual. A total of 301 patients with stage III/IV ovarian, tubal, and peritoneal cancers were enrolled and randomly assigned to either standard therapy (surgery followed by eight cycles of chemotherapy) or four cycles of neoadjuvant chemotherapy followed by interval de­ bulking surgery followed by an additional four cycles of chemotherapy. Interval de­ bulking surgery was optional for patients in the standard therapy arm whose surgi-

cal results were suboptimal and mandatory for patients whose surgeries left any of the uterus, adnexa, and omentum with primary debulking surgery.

Approximately 30% of patients in both arms had stage IV disease. Patients in both arms were exposed to a similar number of cycles of chemotherapy.

Key Data Optimal surgery (defined as maximum residual tumor < 1 cm in diameter) was possible in 62% of patients in the standard arm vs 72% in the neoadjuvant chemotherapy arm. Patients treated with standard therapy underwent more surgeries and had longer operation times compared with neoadjuvant chemotherapy.

Of the 149 patients assigned to standard therapy, 147 underwent primary debulking surgery and 48 required subsequent interval debulking surgery; in the neoadjuvant chemotherapy arm, 131 of 152 patients underwent interval debulking surgery. Total operating time was longer in the standard arm (P < .001).

Pelvic and para-aortic lymphadenectomy was required more frequently in the neoadjuvant chemotherapy arm, but these patients needed bowel or organ resection less often (P = .012).

Amounts of blood loss and ascitic fluid loss were higher in the standard therapy arm. The frequency of intraoperative injury was low in both arms, but fewer postoperative adverse events were reported in the neoadjuvant chemotherapy arm. n

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

Reference 1. Onda T, Yoshikawa H, Shibata T, et al: Comparison of treatment invasiveness between upfront debulking surgery versus interval debulking surgery following neoadjuvant chemotherapy for stage III/IV ovarian, tubal, and peritoneal cancers in phase III randomized trial: JCOG0602. ASCO Annual Meeting. Abstract 5508. Presented May 31, 2014.

Role of Neoadjuvant Chemotherapy in Ovarian Cancer ■■ Preliminary results of a phase III trial show that neoadjuvant chemotherapy followed by interval debulking surgery is less invasive with fewer complications than standard primary debulking surgery.

■■ The authors state that if survival turns out to be noninferior in 2017, then neoadjuvant chemotherapy will replace the current standard of care.

■■ Expert opinion was more reserved and urged waiting for results of two other more definitive trials before changing standard of care.

Brief Summary: Consult package insert for complete Prescribing Information INDICATIONS AND USAGE: Bone Metastasis from Solid Tumors. Xgeva is indicated for the prevention of skeletal-related events in patients with bone metastases from solid tumors.

Important Limitation of Use. Xgeva is not indicated for the prevention of skeletal-related events in patients with multiple myeloma (see Clinical Trials in full Prescribing Information).

DOSAGE AND ADMINISTRATION: Recommended Dosage. The recommended dose of Xgeva is 120 mg administered as a subcutaneous injection every 4 weeks in the upper arm, upper thigh, or abdomen. Administer calcium and vitamin D as necessary to treat or prevent hypocalcemia (see Warnings and Precautions).

Preparation and Administration. Visually inspect Xgeva for particulate matter and discoloration prior to administration. Xgeva is a clear, colorless to pale yellow solution that may contain trace amounts of translucent to white proteinaceous particles. Do not use if the solution is discolored or cloudy or if the solution contains many particles or foreign particulate matter. Prior to administration, Xgeva may be removed from the refrigerator and brought to room temperature (up to 25°C/77°F) by standing in the original container.

This generally takes 15 to 30 minutes. Do not warm Xgeva in any other way (see How Supplied/Storage and Handling). Use a 27-gauge needle to withdraw and inject the entire contents of the vial. Do not re-enter the vial. Discard vial after single-use or entry.

CONTRAINDICATIONS: Hypocalcemia. Pre-existing hypocalcemia must be corrected prior to initiating therapy with Xgeva (see Warnings and Precautions).

Hypersensitivity. Xgeva is contraindicated in patients with known clinically significant hypersensitivity to Xgeva (see Warnings and Precautions and Adverse Reactions).

WARNINGS AND PRECAUTIONS: Drug Products with Same Active Ingredient.

Xgeva includes the same active ingredient (denosumab) found in Prolia.

Patients receiving Xgeva should not take Prolia.

Hypersensitivity. Clinically significant hypersensitivity including anaphylaxis has been reported with use of Xgeva. Reactions may include hypotension, dyspnea, upper airway edema, lip swelling, rash, pruritus, and urticaria. If an anaphylactic or other clinically significant allergic reaction occurs, initiate appropriate therapy and discontinue Xgeva therapy permanently (see Contraindications and Adverse Reactions).

Hypocalcemia. Xgeva can cause severe symptomatic hypocalcemia, and fatal cases have been reported. Correct pre-existing hypocalcemia prior to Xgeva treatment. Monitor calcium levels and administer calcium, magnesium, and vitamin D as necessary. Monitor levels more frequently when Xgeva is administered with other drugs that can also lower calcium levels. In the postmarketing setting, severe symptomatic hypocalcemia has been reported (see Adverse Reactions).

Advise patients to contact a healthcare professional for symptoms of hypocalcemia (see Contraindications, Adverse Reactions, and Patient Counseling Information in full Prescribing Information). Based on clinical trials using a lower dose of denosumab, patients with a creatinine clearance less than 30 mL/min or receiving dialysis are at greater risk of severe hypocalcemia compared to patients with normal renal function. In a trial of 55 patients, without cancer and with varying degrees of renal impairment, who received a single dose of 60 mg denosumab, 8 of 17 patients with a creatinine clearance less than 30 mL/min or receiving dialysis experienced corrected serum calcium levels less than 8.0 mg/dL as compared to 0 of 12 patients with normal renal function. The risk of hypocalcemia at the recommended dosing schedule of 120 mg every 4 weeks has not been evaluated in patients with a creatinine clearance less than 30 mL/min or receiving dialysis.

Osteonecrosis of the Jaw (ONJ). Osteonecrosis of the jaw (ONJ) can occur in patients receiving Xgeva, manifesting as jaw pain, osteomyelitis, osteitis, bone erosion, tooth or periodontal infection, toothache, gingival ulceration, or gingival erosion. Persistent pain or slow healing of the mouth or jaw after dental surgery may also be manifestations of ONJ. In clinical trials, in patients with osseous metastasis, the incidence of ONJ was higher with longer duration of exposure (see Adverse Reactions). Seventy-nine percent of patients with ONJ had a history of tooth extraction, poor oral hygiene, or use of a dental appliance as a predisposing factor. Perform an oral examination and appropriate preventive dentistry prior to the initiation of Xgeva and periodically during Xgeva therapy. Advise patients regarding oral hygiene practices. Avoid invasive dental procedures during treatment with Xgeva. Patients who are suspected of having or who develop ONJ while on Xgeva should receive care by a dentist or an oral surgeon. In these patients, extensive dental surgery to treat ONJ may exacerbate the condition.

Atypical Subtrochanteric and Diaphyseal Femoral Fracture. Atypical femoral fracture has been reported with Xgeva (see Adverse Reactions). These fractures can occur anywhere in the femoral shaft from just below the lesser trochanter to above the supracondylar flare and are transverse or short oblique in orientation without evidence of comminution. Atypical femoral fractures most commonly occur with minimal or no trauma to the affected area. They may be bilateral and many patients report prodromal pain in the affected area, usually presenting as dull, aching thigh pain, weeks to months before a complete fracture occurs. A number of reports note that patients were also receiving treatment with glucocorticoids (e.g. prednisone) at the time of fracture. During Xgeva treatment, patients should be advised to report new or unusual thigh, hip, or groin pain. Any patient who presents with thigh or groin pain should be suspected of having an atypical fracture and should be evaluated to rule out an incomplete femur fracture. Patient presenting with an atypical femur fracture should also be assessed for symptoms and signs of fracture in the contralateral limb. Interruption of Xgeva therapy should be considered, pending a risk/benefit assessment, on an individual basis.

EMBRyO-FETAL TOxICITy: Xgeva can cause fetal harm when administered to a pregnant woman. Based on findings in animals, Xgeva is expected to result in adverse reproductive effects. In utero denosumab exposure in cynomolgus monkeys resulted in increased fetal loss, stillbirths, and postnatal mortality, along with evidence of absent peripheral lymph nodes, abnormal bone growth, and decreased neonatal growth (see Use in Specific Populations). Advise females of reproductive potential to use highly effective contraception during therapy, and for at least 5 months after with the last dose of Xgeva. Apprise the patient of the potential hazard to a fetus if Xgeva is used during pregnancy or if the patient becomes pregnant while patients are exposed to Xgeva. Advise patients to contact their healthcare provider if they become pregnant or a pregnancy is suspected during this time (see Use in Specific Populations).

ADVERSE REACTIONS: The following adverse reactions are discussed below and elsewhere in the labeling: • Hypocalcemia (see Warnings and Precautions) • Osteonecrosis of the Jaw (see Warnings and Precautions) The most common adverse reactions in patients receiving Xgeva (per-patient incidence greater than or equal to 25%) were fatigue/asthenia, hypophosphatemia, and nausea (see Table 1). The most common serious adverse reaction in patients receiving Xgeva was dyspnea. The most common adverse reactions resulting in discontinuation of Xgeva were osteonecrosis and hypocalcemia.

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 other clinical trials and may not reflect the rates observed in practice. The safety of Xgeva was evaluated in three randomized, double-blind, double-dummy trials (see Clinical Trials in full Prescribing Information) in which a total of 2841 patients with bone metastasis from prostate cancer, breast cancer, or other solid tumors, or lytic bony lesions from multiple myeloma received at least one dose of Xgeva. In Trials 1, 2, and 3, patients were randomized to receive either 120 mg of Xgeva every 4 weeks as a subcutaneous injection or 4 mg (dose adjusted for reduced renal function) of zoledronic acid every 4 weeks by intravenous (IV) infusion. Entry criteria included serum calcium (corrected) from 8 to 11.5 mg/dL (2 to 2.9 mmol/L) and creatinine clearance 30 mL/min or greater.

Patients who had received IV bisphosphonates were excluded, as were patients with prior history of ONJ or osteomyelitis of the jaw, an active dental or jaw condition requiring oral surgery, non-healed dental/oral surgery, or any planned invasive dental procedure. During the study, serum chemistries including calcium and phosphorus were monitored every 4 weeks. Calcium and vitamin D supplementation was recommended but not required. The median duration of exposure to Xgeva was 12 months (range: 0.1 – 41) and median duration on-study was 13 months (range: 0.1 – 41). Of patients who received Xgeva, 46% were female. Eighty-five percent were White, 5% Hispanic/Latino, 6% Asian, and 3% Black. The median age was 63 years (range: 18 – 93). Seventy-five percent of patients who received Xgeva received concomitant chemotherapy.

Table 1. Per-patient Incidence of Selecteda Adverse Reactions of Any Severity (Trials 1, 2, and 3)

xgeva n = 2841 %

Zoledronic Acid n = 2836 %

GASTROINTESTINAL Nausea Diarrhea

31 20

32 19

GENERAL Fatigue/ Asthenia

45

46

INVESTIGATIONS Hypocalcemiab Hypophosphatemiab

18 32

9 20

NEUROLOGICAL Headache

13

14

RESPIRATORy Dyspnea Cough

21 15

18 15

Body System

Adverse reactions reported in at least 10% of patients receiving Xgeva in Trials 1, 2, and 3, and meeting one of the following criteria: • At least 1% greater incidence in Xgeva-treated patients, or • Between-group difference (either direction) of less than 1% and more than 5% greater incidence in patients treated with zoledronic acid compared to placebo (US Prescribing Information for zoledronic acid) b Laboratory-derived and below the central laboratory lower limit of normal [8.3 – 8.5 mg/dL (2.075 – 2.125 mmol/L) for calcium and 2.2 – 2.8 mg/dL (0.71 – 0.9 mmol/L) for phosphorus] Severe Mineral/Electrolyte Abnormalities • Severe hypocalcemia (corrected serum calcium less than 7 mg/dL or less than 1.75 mmol/L) occurred in 3.1% of patients treated with Xgeva and 1.3% of patients treated with zoledronic acid. Of patients who experienced severe hypocalcemia, 33% experienced 2 or more episodes of severe hypocalcemia and 16% experienced 3 or more episodes (see Warnings and Precautions and Use in Specific Populations).

• Severe hypophosphatemia (serum phosphorus less than 2 mg/dL or less than 0.6 mmol/L) occurred in 15.4% of patients treated with Xgeva and 7.4% of patients treated with zoledronic acid.

Osteonecrosis of the Jaw In the primary treatment phases of Trials 1, 2, and 3, ONJ was confirmed in 1.8% of patients in the Xgeva group (median exposure of 12.0 months; range 0.1 – 40.5) and 1.3% of patients in the zoledronic acid group. The trials in patients with breast (Trial 1) or prostate (Trial 3) cancer included an Xgeva open label extension treatment phase where patients were offered Xgeva 120 mg once every 4 weeks (median overall exposure of 14.9 months; range 0.1 – 67.2). The patient-year adjusted incidence of confirmed ONJ was 1.1% during the first year of treatment and 4.1% thereafter. The median time to ONJ was 20.6 months (range: 4 – 53) (See Warnings and Precautions).

Atypical Subtrochanteric and Diaphyseal Fracture Atypical femoral fracture has been reported with Xgeva (see Warnings and Precautions).

Postmarketing Experience. Because postmarketing 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.

The following adverse reactions have been identified during post approval use of Xgeva: • Hypocalcemia: Severe symptomatic hypocalcemia, including fatal cases.

• Hypersensitivity, including anaphylactic reactions.

Immunogenicity. As with all therapeutic proteins, there is potential for immunogenicity. Using an electrochemiluminescent bridging immunoassay, less than 1% (7/2758) of patients with osseous metastases treated with denosumab doses ranging from 30 – 180 mg every 4 weeks or every 12 weeks for up to 3 years tested positive for binding antibodies. No patient with positive binding antibodies tested positive for neutralizing antibodies as assessed using a chemiluminescent cell-based in vitro biological assay. There was no evidence of altered pharmacokinetic profile, toxicity profile, or clinical response associated with binding antibody development. The incidence of antibody formation is highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of a positive antibody (including neutralizing antibody) test result may be influenced by several factors, including assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of antibodies to denosumab with the incidence of antibodies to other products may be misleading.

DRUG INTERACTIONS: No formal drug-drug interaction trials have been conducted with Xgeva. In clinical trials in patients with breast cancer metastatic to bone, Xgeva was administered in combination with standard anticancer treatment. Serum denosumab concentrations at 1 and 3 months and reductions in the bone turnover marker uNTx/Cr (urinary N-terminal telopeptide corrected for creatinine) at 3 months were similar in patients with and without prior intravenous bisphosphonate therapy.

There was no evidence that various anticancer treatments affected denosumab systemic exposure and pharmacodynamic effect. Serum denosumab concentrations at 1 and 3 months were not altered by concomitant chemotherapy and/or hormone therapy. The median reduction in uNTx/Cr from baseline to month 3 was similar between patients receiving concomitant chemotherapy and/or hormone therapy (see Clinical Pharmacology in full Prescribing Information).

USE IN SPECIFIC POPULATIONS: Pregnancy: Category D [see Warnings and Precautions]. Risk Summary: Xgeva can cause fetal harm when administered to a pregnant woman based on findings in animals. In utero denosumab exposure in cynomolgus monkeys resulted in increased fetal loss, stillbirths, and postnatal mortality, along with evidence of absent lymph nodes, abnormal bone growth and decreased neonatal growth. There are no adequate and well-controlled studies with Xgeva in pregnant women. Women should be advised not to become pregnant when taking Xgeva. 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. Women who become pregnant during Xgeva treatment are encouraged to enroll in Amgen’s Pregnancy Surveillance Program. Patients or their physicians should call 1-800-77-AMGEN (1-800-772-6436) to enroll.

Clinical Considerations: The effects of Xgeva are likely to be greater during the second and third trimesters of pregnancy. Monoclonal antibodies are transported across the placenta in a linear fashion as pregnancy progresses, with the largest amount transferred during the third trimester. If the patient becomes pregnant during Xgeva therapy, consider the risks and benefits in continuing or discontinuing treatment with Xgeva. a

Animal Data: The effects of denosumab on prenatal development have been studied in both cynomolgus monkeys and genetically engineered mice in which RANK ligand (RANKL) expression was turned off by gene removal (a “knockout mouse”).

In cynomolgus monkeys dosed subcutaneously with denosumab throughout pregnancy at a pharmacologically active dose, there was increased fetal loss during gestation, stillbirths, and postnatal mortality. Other findings in offspring included absence of axillary, inguinal, mandibular, and mesenteric lymph nodes; abnormal bone growth, reduced bone strength, reduced hematopoiesis, dental dysplasia and tooth malalignment; and decreased neonatal growth. At birth out to one month of age, infants had measurable blood levels of denosumab (22-621% of maternal levels). Following a recovery period from birth out to 6 months of age, the effects on bone quality and strength returned to normal; there were no adverse effects on tooth eruption, though dental dysplasia was still apparent; axillary and inguinal lymph nodes remained absent, while mandibular and mesenteric lymph nodes were present, though small; and minimal to moderate mineralization in multiple tissues was seen in one recovery animal. There was no evidence of maternal harm prior to labor; adverse maternal effects occurred infrequently during labor. Maternal mammary gland development was normal. There was no fetal NOAEL (no observable adverse effect level) established for this study because only one dose of 50 mg/kg was evaluated.

In RANKL knockout mice, absence of RANKL (the target of denosumab) also caused fetal lymph node agenesis and led to postnatal impairment of dentition and bone growth. Pregnant RANKL knockout mice showed altered maturation of the maternal mammary gland, leading to impaired lactation (see Use in Nursing Mothers and Nonclinical Toxicology in full Prescribing Information).

Nursing Mothers. It is not known whether Xgeva is excreted into human milk.

Measurable concentrations of denosumab were present in the maternal milk of cynomolgus monkeys up to 1 month after the last dose of denosumab (≤ 0.5% milk:serum ratio). Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from Xgeva, a decision should be made whether to discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother. Maternal exposure to Xgeva during pregnancy may impair mammary gland development and lactation based on animal studies in pregnant mice lacking the RANK/RANKL signaling pathway that have shown altered maturation of the maternal mammary gland, leading to impaired lactation postpartum. However, in cynomolgus monkeys treated with denosumab throughout pregnancy, maternal mammary gland development was normal, with no impaired lactation. Mammary gland histopathology at 6 months of age was normal in female offspring exposed to denosumab in utero; however, development and lactation have not been fully evaluated (see Nonclinical Toxicology in full Prescribing Information).

Pediatric Use. Xgeva is not recommended in pediatric patients. The safety and effectiveness of Xgeva in pediatric patients have not been established. Treatment with Xgeva may impair bone growth in children with open growth plates and may inhibit eruption of dentition. In neonatal rats, inhibition of RANKL (the target of Xgeva therapy) with a construct of osteoprotegerin bound to Fc (OPG-Fc) at doses ≤ 10 mg/kg was associated with inhibition of bone growth and tooth eruption. Adolescent primates treated with denosumab at doses 5 and 25 times (10 and 50 mg/kg dose) higher than the recommended human dose of 120 mg administered once every 4 weeks, based on body weight (mg/kg), had abnormal growth plates, considered to be consistent with the pharmacological activity of denosumab. Cynomolgus monkeys exposed in utero to denosumab exhibited bone abnormalities, reduced hematopoiesis, tooth malalignment, decreased neonatal growth, and an absence of axillary, inguinal, mandibular, and mesenteric lymph nodes. Some bone abnormalities recovered once exposure was ceased following birth; however, axillary and inguinal lymph nodes remained absent 6 months post-birth (see Use in Specific Populations).

Geriatric Use. Of patients who received Xgeva in Trials 1, 2, and 3, 1260 (44%) were 65 years of age or older. No overall differences in safety or efficacy were observed between these patients and younger patients.

Renal Impairment. In a trial of 55 patients without cancer and with varying degrees of renal function who received a single dose of 60 mg denosumab, patients with a creatinine clearance of less than 30 mL/min or receiving dialysis were at greater risk of severe hypocalcemia with denosumab compared to patients with normal renal function. The risk of hypocalcemia at the recommended dosing schedule of 120 mg every 4 weeks has not been evaluated in patients with a creatinine clearance of less than 30 mL/min or receiving dialysis (see Warnings and Precautions, Adverse Reactions, and Clinical Pharmacology in full Prescribing Information).

Females and Males of Reproductive Potential. Contraception Females: Counsel patients on pregnancy planning and prevention. Advise females of reproductive potential to use highly effective contraception during therapy, and for at least 5 months after the last dose of Xgeva. Advise patients to contact their healthcare provider if they become pregnant, or a pregnancy is suspected, during treatment or within 5 months after the last dose of Xgeva [see Use in Specific Populations and Patient Counseling Information]. Males: The extent to which denosumab is present in seminal fluid is unknown. There is potential for fetal exposure to denosumab when a male treated with Xgeva has unprotected sexual intercourse with a pregnant partner.

Advise males of this potential risk.

OVERDOSAGE: There is no experience with overdosage of Xgeva.

HOW SUPPLIED/STORAGE AND HANDLING: Xgeva is supplied in a single-use vial. Store Xgeva in a refrigerator at 2°C to 8°C (36°F to 46°F) in the original carton. Do not freeze. Once removed from the refrigerator, Xgeva must not be exposed to temperatures above 25°C/77°F or direct light and must be used within 14 days. Discard Xgeva if not used within the 14 days. Do not use Xgeva after the expiry date printed on the label. Protect Xgeva from direct light and heat.

Avoid vigorous shaking of Xgeva.

PATIENT COUNSELING INFORMATION: Advise patients to contact a healthcare professional for any of the following: • Symptoms of a hypersensitivity reaction, including rash, urticaria, pruritus, lip swelling, shortness of breath, hypotension and respiratory tract edema (see Contraindications, Warnings and Precautions, and Adverse Reactions) • Symptoms of hypocalcemia, including paresthesias or muscle stiffness, twitching, spasms, or cramps (see Contraindications, Warnings and Precautions, and Adverse Reactions) • Symptoms of ONJ, including pain, numbness, swelling of or drainage from the jaw, mouth, or teeth (see Warnings and Precautions and Adverse Reactions) • Persistent pain or slow healing of the mouth or jaw after dental surgery (see Warnings and Precautions) • Symptoms of atypical femoral fracture, including new or unusual thigh, hip, or groin pain (see Warnings and Precautions) • Pregnancy or nursing (see Warnings and Precautions and Use in Specific Populations) Advise patients of the need for: • Avoiding therapy with Xgeva if a serious allergic reaction occurred with prior Xgeva or Prolia therapy (see Contraindications and Warnings and Precautions) • Proper oral hygiene and routine dental care • Informing their dentist that they are receiving Xgeva • Avoiding invasive dental procedures during treatment with Xgeva • The use of highly effective contraception during and for at least 5 months after treatment with Xgeva for females of reproductive potential Advise patients that denosumab is also marketed as Prolia®. Patients should inform their healthcare provider if they are taking Prolia.

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PAGE 9

ASCO Annual Meeting Dermatologic Oncology

Intralesional Injections Trigger Immune Responses in Melanoma

By Caroline Helwick

T

he emerging approach to treating metastatic melanoma is a fullthrottle effort to stimulate an immune response. One of the components of this strategy could be intralesional injections, according to studies presented at the 2014 ASCO Annual Meeting.

T-VEC Oncolytic Immunotherapy Talimogene laherparepvec (T-VEC) is a herpes simplex virus type 1–derived investigational oncolytic immunotherapy. It is designed to induce local and systemic immune responses in several ways: by selectively replicating in cancer cells while producing granulocytemacrophage colony-stimulating factor (GM-CSF) at the site of injection; by lysing cancer cells, resulting in the release of tumor-derived antigens; and by creating a microenvironment that promotes systemic immune responses against tumor-derived antigens.

The phase III OPTiM study of T-VEC in stage IIIB/IV melanoma included 295 patients treated with TVEC and 141 treated with recombinant GM-CSF (Leukine) as the control arm.

OPTiM met its primary endpoint of durable response, which was observed in 16.3% of the T-VEC arm and 2.1% of the control arm, creating an unadjusted odds ratio of 8.9 (P < .0001).1 The overall response rate was 26.4% and 5.7%, respectively.

At the ASCO Annual Meeting, Howard L. Kaufman, MD, FACS, Resident Member at Rutgers Cancer Institute of New Jersey, New Brunswick,

Howard L. Kaufman, MD, FACS

presented the primary analysis of overall survival, a secondary endpoint.2 “An improvement that closely approached statistical significance was seen in the intent-to-treat population,” he said.

Median survival was 23.3 months with T-VEC and 18.9 months with GM-CSF

Intralesional Injections in Advanced Melanoma ■■ At least three intralesional approaches are being investigated for unresectable advanced melanoma: T-VEC oncolytic viral immunotherapy, intralesional PV-10 (rose bengal), and intratumoral electroporation of plasmid interleukin-12.

■■ The most data come from T-VEC, which improved overall survival in two subsets of patients in the phase III OPTiM trial, though only trended toward a survival benefit in the entire population.

■■ With each of these approaches, injections lead to tumor regression, not only in the injected lesions but in “bystander” lesions as well, suggesting the strategy is successfully augmenting an immune response.

(hazard ratio [HR] = 0.79, P = .051), a 4.4-month improvement.

“In exploratory subset analyses, both durable response rate and overall survival effects appeared to be more pronounced among patients with stage IIIB/IV M1a disease and also among patients who were treated with T-VEC as first-line therapy,” he said.

Stage IIIB/C and IV M1a patients had a median overall survival of 41.1 months with T-VEC vs 21.5 months with GM-CSF (HR = .57, P < .001), whereas regardless of treatment, stage IV M1b/c patients had similar median

overall survival times—13.4 months and 15.9 months, respectively. T-VEC given as first-line treatment yielded a median survival of 33.1 months, vs 17.0 for GM-CSF (HR = 0.50, P < .001), but had no effect in the second line, Dr. Kaufman reported.

Merrick I. Ross, MD, Professor in the Department of Surgical Oncology at The University of Texas MD Anderson Cancer Center, Houston, described the patterns of durable response.3 “Approximately two-thirds of T-VEC responses have lasted at least 1 year,” he

EXPERT POINT OF VIEW

A

xel Hauschild, MD, Professor of Dermatology at the University Hospital Schleswig-Holstein, Campus Kiel, in Germany, discussed the evolving utility of intralesional approaches to melanoma in the ASCO Poster Highlights session.

ficult, and they are evaluating a highly selected subset of stage IIIB/IV patients (those with injectable lesions and no visceral metastasis), whose outcomes will be better.

Nevertheless, the durability of response and evidence of systemic im-

The future lies in combinational approaches with drugs from the new melanoma landscape.

—Axel Hauschild, MD

In general, he maintained that the overall and complete response rates are impressive, especially the regression of untreated lesions, ie, the bystander effect, as is the lack of toxicity associated with intralesional injections. However, the current studies use unconventional response criteria, which makes interpretation dif-

mune augmentation is encouraging, is hypothesis-building, and “gives a hint to future combinatorial trials with other immunodulators, such as anti– PD-1 antibodies,” he said.

Major Questions “The major questions are: How strong is the systemic response from

an intralesional treatment? And what is the size and localization of responding metastases, ie, skin vs visceral organs?” he asked. “I have only seen a tiny 1-cm nodule in the lung respond; I have not seen major responses in visceral organs. The vast majority of stage IV melanoma patients have M1c disease.”

Dr. Hauschild also emphasized that with the growing numbers of drugs for unresectable advanced melanoma, intralesional therapy has some competition. “The most interesting of these studies is the one combining TVEC with ipilimumab, which showed some benefit in M1c patients. Maybe this is a good compromise, and the setting where we need to move ahead…. The future lies in combinational approaches with drugs from the new melanoma landscape.” n Disclosure: Dr. Hauschild is either a member of the advisory board/consultant or received speaker’s honoraria or fees for clinical trials from Amgen, Bristol-Myers Squibb, Celgene, Eisai, GlaxoSmithKline, MedImmune, Melasciences, Merck/MSD, Merck Serono, Novartis, Oncosec, Roche, and SciBase.

Merrick I. Ross, MD

reported. “The majority of responders were still in response at the end of the evaluation period.”

The estimated probability of being in response at 12 months was 65% for patients who responded to T-VEC. Of 48 T-VEC–treated patients who achieved a durable response, 83% had responses ongoing at a median follow-up of 18.4 months.

As seen with other immunotherapies, disease progression prior to response did not negatively impact the frequency or duration of durable response, he said, suggesting that “T-VEC treatment through initial disease progression can be effective.”

T-VEC Plus Ipilimumab The best way to use T-VEC, however, may be in combination with other immune therapies, melanoma experts continued on page 13

To learn more, visit us at

www.IMBRUVICA.com CHRONIC LYMPHOCYTIC LEUKEMIA (CLL) IMBRUVICATM is indicated for the treatment of patients with CLL who have received at least one prior therapy. This indication is based on overall response rate. An improvement in survival or disease-related symptoms has not been established.

MANTLE CELL LYMPHOMA (MCL) IMBRUVICATM is indicated for the treatment of patients with MCL who have received at least one prior therapy. This indication is based on overall response rate. An improvement in survival or disease-related symptoms has not been established.

IMPORTANT SAFETY INFORMATION WARNINGS AND PRECAUTIONS Hemorrhage – Five percent of patients with MCL and 6% of patients with CLL had Grade 3 or higher bleeding events (subdural hematoma, ecchymoses, gastrointestinal bleeding, and hematuria).

Overall, bleeding events including bruising of any grade occurred in 48% of patients with MCL treated with 560 mg daily and 63% of patients with CLL treated at 420 mg daily.

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.

Infections - Fatal and non-fatal infections have occurred with IMBRUVICA™ therapy.

At least 25% of patients with MCL and 35% 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.

Myelosuppression - Treatment-emergent Grade 3 or 4 cytopenias were reported in 41% of patients with MCL and 35% of patients with CLL. These included neutropenia (29%), thrombocytopenia (17%) and anemia (9%) in patients with MCL and neutropenia (27%) and thrombocytopenia (10%) in patients with CLL. Monitor complete blood counts monthly.

Renal Toxicity - Fatal and serious cases of renal failure have occurred with IMBRUVICA™ therapy. Treatment-emergent increases in creatinine levels up to 1.5 times the upper limit of normal occurred in 67% of patients with MCL and 23% of patients with CLL. Increases in creatinine 1.5 to 3 times the upper limit of normal occurred in 9% of patients with MCL and 4% of patients with CLL. Periodically monitor creatinine levels. Maintain hydration.

Second Primary Malignancies - Other malignancies have occurred in 5% of patients with MCL and 10% of patients with CLL who have been treated with IMBRUVICA™. Four percent of patients with MCL, had skin cancers, and 1% had other carcinomas. Eight percent of patients with CLL had skin cancers and 2% had other carcinomas.

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 – MCL: The most commonly occurring adverse reactions (≥20%) in the clinical trial were thrombocytopenia*, diarrhea (51%), neutropenia*, anemia*, fatigue (41%), musculoskeletal pain (37%), peripheral edema (35%), upper respiratory tract infection (34%), nausea (31%), bruising (30%), dyspnea (27%), constipation (25%), rash (25%), abdominal pain (24%), vomiting (23%), and decreased appetite (21%). *Treatment-emergent decreases (all grades) of platelets (57%), neutrophils (47%) and hemoglobin (41%) were based on laboratory measurements and adverse reactions.

IMBRUVICATM: the first-in-class covalent BTK inhibitor

DISCOVERING HOW FAR THERAPY CAN GO Encouraging response rates in previously treated CLL and MCL1 Durable responses1:

Most common adverse reactions (ARs) (≥20%)1:

• Median duration of response (DOR) not reached in CLL —Range: 5.6 to 24.2+ months • 17.5 months median duration of response (95% CI: 15.8, NR) in MCL Phase 2 MCL Trial:

open-label, multi-center, single-arm 1

100

100

80

80

60 40

ORR 58.3%

PR 58.3%

20 0

Response (%)

Response (%)

CLL Trial: open-label, multi-center 1

ORR 65.8%

60 40

PR 48.6%

20

CLL (N=48)

0

CR 17.1% MCL (N=111)

None of the patients achieved a complete response.

CLL: 95% CI (43.2, 72.4) MCL: 95% CI (56.2, 74.5) CR=complete response; ORR=overall response rate; PR=partial response.

ORR and DOR were assessed using a modified version of the International Workshop on CLL (iwCLL) criteria by an Independent Review Committee.

ORR was investigator-assessed according to the revised International Working Group (IWG) non-Hodgkin lymphoma (NHL) criteria.

The most common Grade 3 or 4 nonhematological adverse reactions (≥5%) were pneumonia (7%), abdominal pain (5%), atrial fibrillation (5.4%), diarrhea (5%), fatigue (5%), and skin infections (5%).

Treatment-emergent Grade 3 or 4 cytopenias were reported in 41% of patients. 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.

CLL: The most commonly occurring adverse reactions (≥ 20%) in the clinical trial were thrombocytopenia*, diarrhea (63%), bruising (54%), neutropenia*, anemia*, upper respiratory tract infection (48%), fatigue (31%), musculoskeletal pain (27%), rash (27%), pyrexia (25%), constipation (23%), peripheral edema (23%), arthralgia (23%), nausea (21%), stomatitis (21%), sinusitis (21%), and dizziness (21%).

© Pharmacyclics, Inc. 2014 © Janssen Biotech, Inc. 2014 05/14 PRC-00300

• CLL: thrombocytopenia*, diarrhea (63%), bruising (54%), neutropenia*, anemia*, upper respiratory tract infection (48%), fatigue (31%), musculoskeletal pain (27%), rash (27%), pyrexia (25%), constipation (23%), peripheral edema (23%), arthralgia (23%), nausea (21%), stomatitis (21%), sinusitis (21%), and dizziness (21%) • MCL: thrombocytopenia†, diarrhea (51%), neutropenia†, anemia†, fatigue (41%), musculoskeletal pain (37%), peripheral edema (35%), upper respiratory tract infection (34%), nausea (31%), bruising (30%), dyspnea (27%), constipation (25%), rash (25%), abdominal pain (24%), vomiting (23%), and decreased appetite (21%)

*Treatment-emergent decreases (all grades) of platelets (71%), neutrophils (54%) and hemoglobin (44%) were based on laboratory measurements per IWCLL criteria and adverse reactions. † Treatment-emergent decreases (all grades) of platelets (57%), neutrophils (47%) and hemoglobin (41%) were based on laboratory measurements and adverse reactions.

The most common Grade 3 or 4 non-hematological ARs (≥5%) were1:

• CLL: pneumonia (8%), hypertension (8%), atrial fibrillation (6.3%), sinusitis (6%), skin infection (6%), dehydration (6.4%), and musculoskeletal pain (6%). Five patients (10%) discontinued treatment due to adverse reactions in the trial (N=48).

These included 3 patients (6%) with infections and 2 patients (4%) with subdural hematomas. Adverse reactions leading to dose reduction occurred in 13% of patients. Treatment-emergent Grade 3 or 4 cytopenias were reported in 35% of patients • MCL: pneumonia (7%), abdominal pain (5%), atrial fibrillation (5.4%), diarrhea (5%), fatigue (5%), and skin infections (5%).

Treatment-emergent Grade 3 or 4 cytopenias were reported in 41% of patients. Ten patients (9%) discontinued treatment due to adverse reactions in the trial (N=111)

*Treatment-emergent decreases (all grades) of platelets (71%), neutrophils (54%) and hemoglobin (44%) were based on laboratory measurements per IWCLL criteria and adverse reactions.

The most common Grade 3 or 4 nonhematological adverse reactions (≥ 5%) were pneumonia (8%), hypertension (8%), atrial fibrillation (6.3%), sinusitis (6%), skin infection (6%), dehydration (6.4%), and musculoskeletal pain (6%). Treatment-emergent Grade 3 or 4 cytopenias were reported in 35% of patients.

Five patients (10%) discontinued treatment due to adverse reactions in the trial (N=48).

These included 3 patients (6%) with infections and 2 patients (4%) with subdural hematomas.

Adverse reactions leading to dose reduction occurred in 13% 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.

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

Reference: 1. IMBRUVICATM (ibrutinib) Prescribing Information. Pharmacyclics, Inc. 2014.

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

Brief Summary of Prescribing Information for IMBRUVICATM (ibrutinib) IMBRUVICATM (ibrutinib) capsules Brief Summary of Prescribing Information for IMBRUVICATM (ibrutinib) IMBRUVICATM (ibrutinib) capsules TM (ibrutinib) capsules, for oral use IMBRUVICA TM IMBRUVICA (ibrutinib) capsules, for oral use See package insert for Full Prescribing Information Table 2: Treatment-Emergent* Decrease of Hemoglobin, Platelets, See package insert for Full Prescribing Information Table 2: Treatment-Emergent* Decrease of Hemoglobin, Platelets, or Neutrophils in Patients with MCL (N=111) INDICATIONS AND USAGE or Neutrophils in Patients with MCL (N=111) INDICATIONS AND USAGE IMBRUVICA is indicated for the treatment of patients with mantle cell lymphoma (MCL) who have Percent of Patients (N=111) IMBRUVICA is indicated for the treatment of patients with mantle cell lymphoma (MCL) who have Percent of Patients (N=111) received at least one prior therapy. This indication is based on overall response rate. An improvement received at least one prior therapy. This indication is based on overall response rate. An improvement All Grades (%) Grade 3 or 4 (%) in survival or disease-related symptoms has not been established [see Clinical Studies (14.1) in full All Grades (%) Grade 3 or 4 (%) in survival or disease-related symptoms has not been established [see Clinical Studies (14.1) in full Prescribing Information].

Platelets Decreased 57 17 Prescribing Information].

Platelets Decreased 57 17 CONTRAINDICATIONS Neutrophils Decreased 47 29 CONTRAINDICATIONS Neutrophils Decreased 47 29 None None Hemoglobin Decreased 41 9 Hemoglobin Decreased 41 9 WARNINGS AND PRECAUTIONS WARNINGS AND PRECAUTIONS * Based on laboratory measurements and adverse reactions Hemorrhage: Five percent of patients with MCL and 6% of patients with CLL had Grade 3 or higher * Based on laboratory measurements and adverse reactions Hemorrhage: Five percent of patients with MCL and 6% of patients with CLL had Grade 3 or higher bleeding events (subdural hematoma, ecchymoses, gastrointestinal bleeding, and hematuria). Overall, Ten patients (9%) discontinued treatment due to adverse reactions in the trial (N=111). The most bleeding events (subdural hematoma, ecchymoses, gastrointestinal bleeding, and hematuria). Overall, patients (9%) discontinued treatment due to adverse reactions in the trial (N=111). The most bleeding events including bruising of any grade occurred in 48% of patients with MCL treatedTen with frequent adverse reaction leading to treatment discontinuation was subdural hematoma (1.8%). bleeding events including bruising of any grade occurred in 48% of patients with MCL treated with frequent adverse reaction leading to treatment discontinuation was subdural hematoma (1.8%).

560 mg daily and 63% of patients with CLL treated at 420 mg daily.

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

560 mg daily and 63% of patients with CLL treated at 420 mg daily.

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

The mechanism for the bleeding events is not well understood.

Patients with MCL who develop lymphocytosis greater than 400,000/mcL have developed intracranial The mechanism for the bleeding events is not well understood.

Patients with MCL who develop lymphocytosis greater than 400,000/mcL have developed intracranial IMBRUVICA may increase the risk of hemorrhage in patients receiving antiplatelet or anticoagulant hemorrhage, lethargy, gait instability, and headache. However, some of these cases were in the IMBRUVICA may increase the risk of hemorrhage in patients receiving antiplatelet or anticoagulant hemorrhage, lethargy, gait instability, and headache. However, some of these cases were in the therapies. setting of disease progression. therapies. setting of disease progression.

Consider the benefit-risk of withholding IMBRUVICA for at least 3 to 7 days pre and post-surgery Forty percent of patients had elevated uric acid levels on study including 13% with values above Consider the benefit-risk of the withholding least to 7 days[see pre and post-surgery of patients had elevated uric acid levels on study including 13% with values above depending upon type of IMBRUVICA surgery and for theatrisk of 3bleeding Clinical Studies (14) Forty in fullpercent 10 mg/dL. Adverse reaction of hyperuricemia was reported for 15% of patients. dependingPrescribing upon the type of surgery and the risk of bleeding [see Clinical Studies (14) in full 10 mg/dL. Adverse reaction of hyperuricemia was reported for 15% of patients.

Information].

Prescribing Information].

Chronic Lymphocytic Leukemia: The data described below reflect exposure to IMBRUVICA in a Infections: Fatal and non-fatal infections have occurred with IMBRUVICA therapy. At least 25% of Lymphocytic Chronic Leukemia: The data described below reflect exposure to IMBRUVICA in a Infections:patients Fatal andwith non-fatal infections occurred withhad IMBRUVICA 25%NCI of Common clinical trial that included 48 patients with previously treated CLL treated with 420 mg daily with a MCL and 35% of have patients with CLL infectionstherapy.

Grade 3Atorleast greater clinical trial that included 48 patients with previously treated CLL treated with 420 mg daily with a patients with MCL and 35% of patients with CLL had infections Grade 3 or greater NCI Common median treatment of 15.6 months.

Terminology Criteria for Adverse Events (CTCAE) [See Adverse Reactions]. Monitor patients for treatment duration ofduration median 15.6 months.

Terminology Criteria for Adverse (CTCAE) [See Adverse Reactions]. Monitor patients for The most commonly occurring adverse reactions (≥ 20%) were thrombocytopenia, diarrhea, bruising, fever and infections andEvents evaluate promptly.

The most commonly occurring adverse reactions (≥ 20%) were thrombocytopenia, diarrhea, bruising, fever and infections and evaluate promptly. neutropenia, anemia, upper respiratory tract infection, fatigue, musculoskeletal pain, rash, pyrexia, Myelosuppression: Treatment-emergent Grade 3 or 4 cytopenias were reported in 41% of patients neutropenia, anemia, upper respiratory tract infection, fatigue, musculoskeletal pain, rash, pyrexia, Myelosuppression: Treatment-emergent Grade 3 or 4 cytopenias were reported in 41% of patients constipation, peripheral edema, arthralgia, nausea, stomatitis, sinusitis, and dizziness (See Tables 3 with MCL and 35% of patients with CLL. These included neutropenia (29%), thrombocytopenia constipation, peripheral edema, arthralgia, nausea, stomatitis, sinusitis, and dizziness (See Tables 3 with MCL (17%) and 35% patients CLL. These thrombocytopenia and 4). and of anemia (9%)with in patients with included MCL andneutropenia neutropenia (29%), (27%) and thrombocytopenia and (10%) 4).

(17%) and in anemia (9%) in patients with MCL and neutropenia (27%) and thrombocytopenia (10%) patients with CLL. The most common Grade 3 or 4 non-hematological adverse reactions (≥ 5%) were pneumonia, in patients with CLL. The most common Grade 3 or 4 non-hematological adverse reactions (≥ 5%) were pneumonia, hypertension, atrial fibrillation, sinusitis, skin infection, dehydration, and musculoskeletal pain.

Monitor complete blood counts monthly. hypertension, atrial fibrillation, sinusitis, skin infection, dehydration, and musculoskeletal pain.

Monitor complete blood counts monthly.

Adverse reactions from the CLL trial (N=48) using single agent IMBRUVICA 420 mg daily occurring at Renal Toxicity: Fatal and serious cases of renal failure have occurred with IMBRUVICA therapy.

Adverse reactions from the CLL trial (N=48) using single agent IMBRUVICA 420 mg daily occurring at Renal Toxicity: Fatal and serious cases ofin renal failure haveupoccurred withtheIMBRUVICA therapy. a rate of ≥ 10% are presented in Table 3.

Treatment-emergent increases creatinine levels to 1.5 times upper limit of normal occurred a rate of ≥ 10% are presented in Table 3.

Treatment-emergent increases in creatinine levels up to 1.5 times the upper limit of normal occurred in 67% of patients with MCL and 23% of patients with CLL. Increases in creatinine 1.5 to 3 times the in 67% of patients withofMCL andoccurred 23% of patients CLL. Increases in creatinine 1.5 to with 3 times the Table 3: Non-Hematologic Adverse Reactions in ≥ 10% of Patients with upper limit normal in 9% ofwith patients with MCL and 4% of patients CLL. Periodically Table 3: Non-Hematologic Adverse Reactions in ≥ 10% of Patients with upper limitmonitor of normal occurredlevels. in 9%Maintain of patients with MCL and 4% of patients with CLL. Periodically Chronic Lymphocytic Leukemia (N=48) creatinine hydration.

Chronic Lymphocytic Leukemia (N=48) monitor creatinine levels. Maintain hydration.

All Grades Grade 3 or 4 Second Primary Malignancies: Other malignancies have occurred in 5% of patients with MCL and Grade 3 or 4 System Organ Class Preferred Term All Grades Second Primary malignancies occurred in 5% of patients MCLofand Preferred Term (%) (%) 10% ofMalignancies: patients with Other CLL who have beenhave treated with IMBRUVICA. Four with percent patientsSystem with Organ Class (%) (%) 10% of patients with CLL who have been treated with IMBRUVICA. Four percent of patients with MCL, had skin cancers and 1% had other carcinomas. Eight percent of patients with CLL had skin 4 63 Gastrointestinal disorders Diarrhea MCL, had skin cancers and 1% had other carcinomas.

Eight percent of patients with CLL had skin 4 63 Gastrointestinal disorders Diarrhea cancers and 2% had other carcinomas.

2 23 Constipation cancers and 2% had other carcinomas.

2 23 Constipation 2 21 Nausea Embryo-Fetal Toxicity: Based on findings in animals, IMBRUVICA can cause fetal harm when 2 21 Nausea Embryo-Fetal Toxicity: Based on findings in animals, IMBRUVICA can cause fetal harm when 0 21 Stomatitis administered to a pregnant woman. Ibrutinib caused malformations in rats at exposures 14 times 0 21 Stomatitis 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 2 19 Vomiting those reported in patients with MCL and 20 times those reported in patients with CLL, receiving 2 19 Vomiting the ibrutinib dose of 560 mg per day and 420 mg per day, respectively. Reduced fetal weights were 0 15 Abdominal pain the ibrutinib dose of 560 mg per day and 420 mg per day, respectively.

Reduced fetal weights were 0 15 Abdominal pain observed at lower exposures. Advise women to avoid becoming pregnant while taking IMBRUVICA. 0 13 Dyspepsia observed atIf lower exposures.

Advise women to avoid becoming pregnant while taking IMBRUVICA. 0 13 Dyspepsia this drug is used during pregnancy or if the patient becomes pregnant while taking this drug, the Infections and infestations Upper respiratory If this drugpatient is usedshould duringbe pregnancy or if the patient becomes pregnant while taking this drug, the Upper respiratory apprised of the potential hazard to a fetus [see Use in Specific Populations]. Infections and infestations 2 48 patient should be apprised of the potential hazard to a fetus [see Use in Specific Populations]. tract infection 2 48 tract infection ADVERSE REACTIONS 6 21 Sinusitis ADVERSE REACTIONS 6 21 Sinusitis The following adverse reactions are discussed in more detail in other sections of the labeling: 6 17 Skin infection The following adverse reactions are discussed in more detail in other sections of the labeling: 6 17 Skin infection 8 10 Pneumonia • Hemorrhage [see Warnings and Precautions] 8 10 Pneumonia • Hemorrhage [see Warnings and Precautions] 0 10 Urinary tract infection • Infections [see Warnings and Precautions] 0 10 Urinary tract infection • Infections [see Warnings and Precautions] • Myelosuppression [see Warnings and Precautions] 4 31 General disorders and administrative Fatigue • Myelosuppression [see Warnings and Precautions] 4 31 General disorders and administrative Fatigue • Renal Toxicity [see Warnings and Precautions] 2 25 site conditions Pyrexia • Renal Toxicity [see Warnings and Precautions] 2 25 site conditions Pyrexia 0 23 Peripheral edema • Second Primary Malignancies [see Warnings and Precautions] 0 23 Peripheral edema • Second Primary Malignancies [see Warnings and Precautions] 4 13 Asthenia Because clinical trials are conducted under widely variable conditions, adverse event rates 4 13 Asthenia Because clinical trials are conducted widely variable conditions, event rates trials of 0 13 Chills observed in clinical trials of aunder drug cannot be directly comparedadverse with rates of clinical 0 13 Chills observed in clinical trials a drug cannotthe berates directly compared with rates of clinical trials of 2 54 Skin and subcutaneous tissue disorders Bruising another drug andofmay not reflect observed in practice.

2 54 Skin and subcutaneous tissue disorders Bruising another drug and may not reflect the rates observed in practice.

0 27 Rash Mantle Cell Lymphoma: The data described below reflect exposure to IMBRUVICA in a clinical trial 0 27 Rash Mantle Cell Lymphoma: described below reflect exposure IMBRUVICA in mg a clinical trial a median 0 17 Petechiae that included The 111 data patients with previously treated MCL to treated with 560 daily with 0 17 Petechiae that included 111 patients with previously treatment duration of 8.3 months. treated MCL treated with 560 mg daily with a median 0 19 Respiratory, thoracic and mediastinal Cough treatment duration of 8.3 months.

0 19 Respiratory, thoracic and mediastinal Cough The most commonly occurring adverse reactions (≥ 20%) were thrombocytopenia, diarrhea, 0 15 disorders Oropharyngeal pain The most neutropenia, commonly occurring adverse reactions (≥ 20%) were thrombo cytopenia, diarrhea, 0 15 disorders Oropharyngeal pain anemia, fatigue, musculoskeletal pain, peripheral edema, upper respiratory tract 0 10 Dyspnea neutropenia, anemia, fatigue, musculo skeletal pain, peripheral edema, upper respiratory tract 0 10 Dyspnea infection, nausea, bruising, dyspnea, constipation, rash, abdominal pain, vomiting and decreased 6 27 Musculoskeletal and connective tissue Musculoskeletal pain infection, nausea, bruising, dyspnea, constipation, rash, abdominal pain, vomiting and decreased 6 27 Musculoskeletal and connective tissue Musculoskeletal pain appetite (See Tables 1 and 2).

0 appetite (See Tables 1 and 2).

23 disorders Arthralgia 0 23 disorders Arthralgia The most common Grade 3 or 4 non-hematological adverse reactions (≥ 5%) were pneumonia, 2 19 Muscle spasms The most abdominal common Grade 3 or 4 non-hematological adverse reactions (≥ 5%) were pneumonia, 2 19 Muscle spasms pain, atrial fibrillation, diarrhea, fatigue, and skin infections. abdominal pain, atrial fibrillation, diarrhea, fatigue, and skin infections.

0 21 Nervous system disorders Dizziness 0 21 Nervous system disorders Dizziness Adverse reactions from the MCL trial (N=111) using single agent IMBRUVICA 560 mg daily occurring 2 19 Adverse reactions the MCL trial (N=111) agent IMBRUVICA 560 mg daily occurring Headache at a ratefrom of ≥ 10% are presented in using Table single 1.

2 19 Headache at a rate of ≥ 10% are presented in Table 1.

0 10 Peripheral 0 10 Peripheral neuropathy Table 1: Non-Hematologic Adverse Reactions in ≥ 10% of Patients with neuropathy Table 1: Non-Hematologic Adverse Reactions in ≥ 10% of Patients with Mantle Cell Lymphoma (N=111) Metabolism and nutrition disorders Decreased appetite 17 2 Mantle Cell Lymphoma (N=111) Metabolism and nutrition disorders Decreased appetite 17 2 All Grades Grade 3 or 4 Neoplasms benign, malignant, Second 10* 0 Grade 3 or 4 System Organ Class Preferred Term All Grades Neoplasms benign, malignant, Second 10* 0 System Organ Class Preferred Term (%) (%) unspecified malignancies* (%) (%) unspecified malignancies* 5 51 Gastrointestinal disorders Diarrhea Injury, poisoning and procedural Laceration 10 2 5 51 Gastrointestinal disorders Diarrhea Injury, poisoning and procedural Laceration 10 2 0 31 Nausea complications 0 31 Nausea complications 0 25 Constipation Psychiatric disorders Anxiety 10 0 0 25 Constipation Anxiety 10 0 5 Psychiatric disorders 24 Abdominal pain Insomnia 10 0 5 24 Abdominal pain Insomnia 10 0 0 23 Vomiting Vascular disorders Hypertension 17 8 0 23 Vomiting Hypertension 17 8 1 Vascular disorders 17 Stomatitis 1 17 Stomatitis *One patient death due to histiocytic sarcoma.

0 *One patient death due to histiocytic sarcoma.

11 Dyspepsia 0 11 Dyspepsia Infections and infestations Upper respiratory Infections and infestations Upper respiratory Table 4: Treatment-Emergent* Decrease of Hemoglobin, 0 34 tract infection Table 4: Treatment-Emergent* Decrease of Hemoglobin, 0 34 tract infection Platelets, or Neutrophils in Patients with CLL (N=48) 3 14 Urinary tract infection Platelets, or Neutrophils in Patients with CLL (N=48) 3 14 Urinary tract infection Percent of Patients (N=48) 7 14 Pneumonia Percent of Patients (N=48) 7 14 Pneumonia 5 14 Skin infections All Grades (%) Grade 3 or 4 (%) 5 14 Skin infections All Grades (%) Grade 3 or 4 (%) 1 13 Sinusitis 1 13 Sinusitis Platelets Decreased 71 10 71 10 5 Platelets Decreased 41 General disorders and administrative Fatigue 5 41 General disorders and administrative Fatigue 3 35 site conditions Peripheral edema Neutrophils Decreased 54 27 3 35 site conditions Peripheral edema Neutrophils Decreased 54 27 1 18 Pyrexia 1 18 Pyrexia Hemoglobin Decreased 44 0 3 Hemoglobin Decreased 14 Asthenia 44 0 3 14 Asthenia * Based on laboratory measurements per IWCLL criteria and adverse reactions 0 * Based on laboratory measurements per IWCLL criteria and adverse reactions 30 Skin and subcutaneous tissue disorders Bruising 0 30 Skin and subcutaneous tissue disorders Bruising 3 25 Rash Five patients (10%) discontinued treatment due to adverse reactions in the trial (N=48). These 3 25 Rash (10%) discontinued treatment due to adverse reactions in the trial (N=48). These 0 Five patients 11 Petechiae included 3 patients (6%) with infections and 2 patients (4%) with subdural hematomas. Adverse 0 11 Petechiae included 3 patients (6%) with infections and 2 patients (4%) with subdural hematomas. Adverse 1 37 Musculoskeletal and connective tissue Musculoskeletal pain reactions leading to dose reduction occurred in 13% of patients.

1 37 Musculoskeletal and connective tissue Musculoskeletal pain reactions leading to dose reduction occurred in 13% of patients.

0 14 disorders Muscle spasms Thirty-eight percent of patients had shifts from normal to elevated uric acid levels on study including 0 14 disorders Muscle spasms percent of patients had shifts from normal to elevated uric acid levels on study including 0 Thirty-eight4% 11 Arthralgia with values above 10 mg/dL. 0 11 Arthralgia 4% with values above 10 mg/dL. 4 27 Respiratory, thoracic and mediastinal Dyspnea 4 27 Respiratory, thoracic and mediastinal Dyspnea DRUG INTERACTIONS 0 DRUG INTERACTIONS 19 disorders Cough 0 19 disorders Cough is primarily metabolized by cytochrome P450 enzyme 3A. 0 Ibrutinib isIbrutinib 11 Epistaxis primarily metabolized by cytochrome P450 enzyme 3A. 0 11 Epistaxis CYP3A Inhibitors: In healthy volunteers, co-administration of ketoconazole, a strong CYP3A Metabolism and nutrition disorders Decreased appetite 21 2 CYP3A Inhibitors: In healthy volunteers, co-administration of ketoconazole, a strong CYP3A Metabolism and nutrition disorders Decreased appetite 21 2 inhibitor, increased Cmax and AUC of ibrutinib by 29- and 24-fold, respectively. The highest ibrutinib Dehydration 12 4 inhibitor, increased Cmax and AUC of ibrutinib by 29- and 24-fold, respectively. The highest ibrutinib Dehydration 12 4 dose evaluated in clinical trials was 12.5 mg/kg (actual doses of 840 – 1400 mg) given for 28 days in clinical trials was 12.5 mg/kg (actual doses of 840 – 1400 mg) given for 28 days Nervous system disorders Dizziness 14 0 dose evaluated with single dose AUC values of 1445 ± 869 ng • hr/mL which is approximately 50% greater than steady Nervous system disorders Dizziness 14 0 with single dose AUC values of 1445 ± 869 ng • hr/mL which is approximately 50% greater than steady Headache 13 0 state exposures seen at the highest indicated dose (560 mg).

Headache 13 0 state exposures seen at the highest indicated dose (560 mg).

IMBRUVICATM (ibrutinib) capsules IMBRUVICATM (ibrutinib) capsules Avoid concomitant administration of IMBRUVICA with strong or moderate inhibitors of CYP3A. For 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., 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 ketoconazole, itraconazole, voriconazole, posaconazole, clarithromycin, telithromycin) consider interrupting IMBRUVICA therapy during the duration of inhibitor use. Avoid strong CYP3A inhibitors 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. 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 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]. 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 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 inhibitors of CYP3A [see Dosage and Administration (2.4), and Clinical Pharmacology (12.3) in full Prescribing Information].

Prescribing Information].

CYP3A Inducers: Administration of IMBRUVICA with strong inducers of CYP3A decrease ibrutinib CYP3A Inducers: Administration of IMBRUVICA with strong inducers of CYP3A decrease ibrutinib plasma concentrations by approximately 10-fold. plasma concentrations by approximately 10-fold.

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

(12.3) in full Prescribing Information].

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

Pregnancy: Pregnancy Category D [see Warnings and Precautions].

Risk Summary: Based on findings in animals, IMBRUVICA can cause fetal harm when administered to 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 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. 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 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 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 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 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, 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 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 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. 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 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 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 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. 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 Pediatric Use: The safety and effectiveness of IMBRUVICA in pediatric patients has not been established. established.

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

Of the 48 patients treated for CLL, 52% were 65 years of age or older. No overall differences in Of the 48 patients treated for CLL, 52% were 65 years of age or older. No overall differences in effectiveness were observed between these patients and younger patients. A greater number of effectiveness were observed between these patients and younger patients. A greater number of adverse events were reported in those 65 years of age and older. Grade 3 or higher adverse events adverse events were reported in those 65 years of age and older. Grade 3 or higher adverse events occurred more frequently among elderly patients (80% of patients 65 and older versus 61% of occurred more frequently among elderly patients (80% of patients 65 and older versus 61% of younger patients). younger patients).

Renal Impairment: Less than 1% of ibrutinib is excreted renally. Ibrutinib exposure is not altered in 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 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 renal impairment (CLcr < 25 mL/min) or patients on dialysis [see Clinical Pharmacology (12.3) in full Prescribing Information].

Prescribing Information].

Hepatic Impairment: Ibrutinib is metabolized in the liver and significant increases in exposure of 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 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 (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 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]. 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 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]. taking IMBRUVICA because IMBRUVICA can cause fetal harm [see Use in Specific Populations].

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

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

• Renal toxicity: • Renal toxicity: Inform patients of the possibility of renal toxicity. Advise patients to maintain adequate hydration Inform patients of the possibility of renal toxicity. Advise patients to maintain adequate hydration [see Warnings and Precautions]. [see Warnings and Precautions].

• Second primary malignancies: • Second primary malignancies: Inform patients that other malignancies have occurred in patients who have been treated with 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].

IMBRUVICA, including skin cancers and other carcinomas [see Warnings and Precautions].

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

• Inform patients to take IMBRUVICA orally once daily according to their physician’s instructions and • 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, 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 or chewed at approximately the same time each day [see Dosage and Administration (2.1) in full Prescribing Information].

Prescribing Information].

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

Prescribing Information].

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

• 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. 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 • 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 prescription medicines, over-the-counter drugs, vitamins, and herbal products [see Drug Interactions].

Interactions].

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

Active ingredient made in China.

Active ingredient made in China.

Distributed and Marketed by: Distributed and Marketed by: Pharmacyclics, Inc. Pharmacyclics, Inc. Sunnyvale, CA USA 94085 Sunnyvale, CA USA 94085 and and Marketed by: Marketed by: Janssen Biotech, Inc. Janssen Biotech, Inc. Horsham, PA USA 19044 Horsham, PA USA 19044 Patent http://www.imbruvica.com Patent http://www.imbruvica.com IMBRUVICA™ is a trademark owned by Pharmacyclics, Inc. IMBRUVICA™ is a trademark owned by Pharmacyclics, Inc. ©Pharmacyclics, Inc. 2014 ©Pharmacyclics, Inc. 2014 PRC-00339 PRC-00339

Issued: February 2014 Issued: February 2014

ASCOPost.com | JULY 25, 2014

PAGE 13

ASCO Annual Meeting Immunotherapy in Melanoma continued from page 9

have suggested. In a phase Ib trial that combined T-VEC with ipilimumab (Yervoy), high response rates were observed, including complete responses in one-third of patients, reported Igor Puzanov, MD, Associate Professor of Medicine at Vanderbilt University in Nashville.4 “Combining T-VEC, which promotes the release of tumor-derived antigens, with an immune checkpoint in-

Sanjiv S. Agarwala, MD

of antigens targeted. The translational studies of individual T-cell receptors are underway,” Dr. Puzanov told The ASCO Post.

There were no unexpected toxicities from the combination. The phase II part of the study is currently enrolling (70 previously untreated patients per arm), with the primary endpoint of overall survival.

Intralesional PV-10 Igor Puzanov, MD

hibitor that improves T-cell responses, could potentially enhance the efficacy compared to either therapy alone,” Dr. Puzanov said.

The study enrolled 19 previously untreated patients whose tumors were injected with up to 4 mL of T-VEC, dosed periodically until all injectable tumors

Other promising results were achieved with intralesional PV-10, which contains a proprietary injectable formulation of rose bengal disodium, a water-soluble xanthene dye used in a topical opthalmic diagnostic.

Sanjiv S. Agarwala, MD, Chief of Medical Oncology and Hematology at St. Luke’s Cancer Center, Bethlehem, Pennsylvania, presented a subgroup

After PV-10 injection, we saw a significant increase in circulating T cells, including CD3-positive and cytotoxic CD8-positive cells. This suggests an immunologic-mediated antitumor response is engendered by PV-10.

—Amod Sarnaik, MD

disappeared or until progressive disease or intolerance. All responders received four doses of ipilimumab at 3 mg/kg every 3 weeks for 4 weeks, starting at week 6. Durable responses were observed in 10 of 18 (56%) evaluable patients, 33% being complete responses; the disease control rate was 72%.

“These data, although preliminary, suggest higher overall and complete response rates than with either agent alone,” Dr. Puzanov commented.

Total and activated CD8 T cells increased after treatment with T-VEC and increased further with T-VEC plus ipilimumab. Ongoing investigation with additional T-cell markers is planned.

“The two treatments may be activating complementary clones of T cells, broadening the potential repertoire

analysis of an international phase II study of 80 patients. In the current analysis of 54 evaluable patients with cutaneous lesions, 28 underwent intralesional PV-10 injections in target and bystander lesions, while 26 had no bystander treatment.5 The overall response rate was 71% for the all-lesion group, with 50% complete responses; of those with injections in only the target lesions, 54% responded, and 23% had complete responses.

In addition, Amod Sarnaik, MD, Assistant Member at H. Lee Moffitt Cancer Center, Tampa, reported interim results of a pilot study of 13 patients treated with intralesional PV-10 designed to investigate the local and immunologic effects of tumor ablation.6 “[Intralesional] PV-10 can induce continued on page 14

The ASCO Post | JULY 25, 2014

PAGE 14

ASCO Annual Meeting Gastrointestinal Oncology

Benefit Confirmed for Adjuvant Oxaliplatin in Rectal Cancer

By Caroline Helwick

P

atients with curatively resected rectal cancer are more likely to be disease-free at 3 years after treatment with an oxaliplatin-containing regimen than with fluorouracil (5-FU)/

5-FU/leucovorin in patients with pathologic stage II or III rectal cancer after fluoropyrimidine-based preoperative chemoradiotherapy,” said Tae Won Kim, MD, of Asan Medical Cen-

The ADORE study demonstrated that adjuvant FOLFOX improves 3-year disease-free survival compared with 5-FU/leucovorin in patients with pathologic stage II or III rectal cancer after fluoropyrimidine-based preoperative chemoradiotherapy.

—Tae Won Kim, MD

leucovorin, Korean investigators of the phase II multicenter ADORE trial reported at the ASCO Annual Meeting.1

Study Details “The ADORE study demonstrated that adjuvant FOLFOX [5-FU/leucovorin/oxaliplatin] improves 3-year disease-free survival compared with

Immunotherapy in Melanoma continued from page 9

regression of injected and uninjected metastatic melanoma, enhance tumorspecific reactivity in circulating T cells, and lead to responses in treatment-refractory tumors,” Dr. Sarnaik said.

In a comparison of lesions before and after treatment, intralesional PV-10 led to pathologic complete responses in both PV-10-injected and uninjected study lesions in four of eight evaluable patients, and all eight exhibited at least partial regression of the injected lesions. These outcomes were observed even in patients with metastatic disease refractory to previous ipilimumab, anti–PD-1 antibodies and/or vemurafenib (Zelboraf).

“After PV-10 injection, we saw a significant increase in circulating T cells, including CD3-positive and cytotoxic CD8-positive cells. This suggests an immunologic-mediated antitumor response is engendered by PV-10. We are hoping to undertake combination trials that combine PV-10 with promising systemic immunotherapies,” Dr. Sarnaik said.

Intratumoral Electroporation of Plasmid IL-12 Intratumoral delivery of interleukin (IL)-12 via electroporation (which

ter at the University of Ulsan College of Medicine, South Korea.

The study included 321 patients who underwent preoperative chemoradiotherapy and total mesorectal excision with curative intent. Only those with postoperative stage II or III were selected for this study. The study aimed to evaluate the benefit of adding saturates drug into the tumor) may avoid systemic toxicity while promoting systemic antitumor immunity. In a phase II study presented by Adil Daud, MD, Clinical Professor of Medicine and Director of Melanoma Clinical

Adil Daud, MD

Research at the University of California, San Francisco, Helen Diller Family Comprehensive Cancer Center, treated and nontreated tumors regressed with this approach and natural killer cells were increased.7 The 29 patients received at least one treatment cycle, which consisted of injections on days 1, 5, and 8 for a maximum of four cycles at 12-week intervals. Responses, which were assessed by a modification of RECIST criteria, were observed in 32.2%, of which 10.7% were complete responses. Among 22 evaluable patients, 13

EXPERT POINT OF VIEW

C

armen J. Allegra, MD, Professor of Medicine and Chief of Hematology/Oncology at the University of Florida, Gainesville, who discussed the findings at the ASCO Annual Meeting, said the study upholds what has become the practice of many oncologists—to use adjuvant FOLFOX (fluorouracil/leucovorin/oxaliplatin) after potentially curative rectal surgery.

The finding that oxaliplatin adds benefit to Carmen J. Allegra, MD fluoropyrimidine-based adjuvant therapy for rectal cancer, at least in select patients, “is supported by extrapolation from the colon adjuvant data, which in turn is supported by the genetic similarities reported by The Cancer Genome Atlas,” he noted.

“This abstract is the first direct evidence for benefit associated with the use of oxaliplatin in the rectal adjuvant setting,” Dr. Allegra said, and further supports this clinical practice. n Disclosure: Dr. Allegra reported no potential conflicts of interest.

oxaliplatin to fluoropyrimidine-based adjuvant therapy after this standard approach.

The phase II study randomly assigned 321 patients to adjuvant ­FOLFOX every 2 weeks for eight cy-

cles or 5-FU/leucovorin every 4 weeks for four cycles. Patients received conventional preoperative radiotherapy (median dose, 50 Gy; median duration, 5 weeks) and concurrent che-

(59.1%) had regression of untreated distant lesions. n

I, et al: Patterns of durable response with intralesional talimogene laherparepvec (TVEC): Results from a phase III trial in patients with stage IIIb-IV melanoma. ASCO Annual Meeting. Abstract 9026. Presented June 2, 2014.

4. Puzanov I, Milhem MM, Andtbacka RI, et al: Primary analysis of a phase 1b multicenter trial to evaluate safety and efficacy of talimogene laherparepvec (T-VEC) and iplimumab in previously untreated, unresected stage IIIB-IV melanoma. ASCO Annual Meeting. Abstract 9029. Presented June 2, 2014.

5. Agarwala SS, Thompson JF, Smithers BM, et al: Efficacy of intralesional rose Bengal in patients receiving injection of an existing melanoma in phase II study PV-10MM-02. ASCO Annual Meeting. Abstract 9027. Presented June 2, 2014.

6. Sarnaik A, Crago G, Liu H, et al: Assessment of immune and clinical efficacy after intralesional PV-10 in injected and uninjected metastatic melanoma. ASCO Annual Meeting. Abstract 9028. Presented June 2, 2014.

7. Daud A, Algazi P, Ashworth MT, et al: Systemic antitumor effect and clinical response in a phase 2 trial of intratumoral electroporation of plasmid interleukin-12 in patients with advanced melanoma. ASCO Annual Meeting.

Abstract 9025. Presented June 2, 2014.

Disclosure: Dr. Kaufman and Dr. Puzanov are consultants/advisors for Amgen. Dr. Ross is a consultant/advisor for and has received research funding from Amgen, and has received honoraria from Paradigm Medical Communications. Dr. Agarwala and Dr. Sarnaik have received research funding from Provectus Pharmaceuticals. Dr. Daud is a consultant/ advisor for and has received research funding from OncoSec. For full disclosures of all study authors, visit meetinglibrary.asco.org.

References 1. Andtbacka RI, Collichio FA, Amatruda T, et al: OPTiM: A randomized phase III trial of talimogene laherparepvec (T-VEC) versus subcutaneous granulocyte-macrophage colony-stimulating factor (GM-CSF) for the treatment of unresected stage IIIB/C and IV melanoma. ASCO Annual Meeting. Abstract LBA9008. Presented June 1, 2013.

2. Kaufman HL, Andtbacka RI, Collichio FA, et al: Primary overall survival from OPTiM, a randomized phase III trial of talimogene laherparepvec (T-VEC) versus subcutaneous granulocyte-macrophage colony-stimulating factor for the treatment of unresected stage IIIB/C and IV melanoma. ASCO Annual Meeting. Abstract 9008a. Presented June 2, 2014.

3. Ross MI, Andtbacka RI, Puzanov

continued on page 15

ASCOPost.com | JULY 25, 2014

PAGE 15

ASCO Annual Meeting Oxaliplatin in Rectal Cancer continued from page 14

motherapy with 5-FU or capecitabine.

The median follow-up was 38 months.

Improved Disease-Free Survival Disease-free survival events occurred in 39 patients receiving adjuvant FOLFOX and 53 receiving 5-FU/ leucovorin, amounting to 3-year disease-free survival rates of 71.6% and 62.9%, respectively (stratified hazard ratio [HR] = 0.630, P = .032).

The difference was seen only in patients with postneoadjuvant pathologic (yp) stage III disease , and not in patients with yp stage II disease, he added. Among patients with yp stage II rectal cancer, disease-free sur-

vival was 81.6% with FOLFOX and 71.3% with 5-FU/leucovorin (HR = 0.744, P = .469).

“Adjuvant FOLFOX remained as a significant factor affecting 3-year disease-free survival after stratified Cox regression analysis,” Dr. Kim reported.

FOLFOX was associated with more neutropenia and thrombocytopenia of

all grades and more fatigue and nausea, but there were no differences in grade 3/4 nonhematologic or hematologic adverse events. n

Disclosure: The authors reported no potential conflicts of interest.

Reference 1. Hong YS, Nam B, Kim K, et al: Adju-

vant chemotherapy with oxaliplatin/5-fluorouracil/leucovorin (FOLFOX) versus 5-fluorouracil/leucovorin for rectal cancer patients whose postoperative yp stage 2 or 3 after preoperative chemotherapy: Updated results of 3-year disease-free survival from a randomized phase II study (The ADORE). ASCO Annual Meeting. Abstract 3502. Presented June 2, 2014.

Adjuvant Oxaliplatin in Rectal Cancer ■■ The 321-patient ADORE trial examined the benefit of adjuvant FOLFOX vs 5-FU/ leucovorin, in patients with resected pathologic stage II or III rectal cancer.

■■ All patients also received neoadjuvant chemoradiotherapy.

■■ Disease-free survival at 3 years was 71.6% in the FOLFOX arm and 62.9% in the control arm (P = .032).

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PAGE 16

ASCO Annual Meeting Neuro-oncology

Grade 2 Glioma continued from page 1

63.1%), as was the 10-year overall survival rate (60.1% vs 40.1%).

earlier analyses of a progression-free survival benefit, and add statistical significance to the survival improvement.

In the earlier analysis, deaths were re-

For patients with grade 2 glioma, with less than gross total tumor resection or who are more than 40 years of age, radiotherapy plus PCV prolongs both progression-free and overall survival, compared to radiotherapy alone.

—Jan C. Buckner, MD

“Median survival was increased by 5.5 years, and 5-year and 10-year survival was increased by 9% and 20%, respectively,” he said.

“With further follow-up and more events [55% of patients had died], the difference in overall survival is now statistically significant,” Dr. Buckner reported. The mature findings confirm

duced by 28%, but this was not statistically significant.

The study also identified treatment with PCV, oligodendroglioma histology, and female gender as favorable prognostic variables.

Hematologic toxicity was greater with the combination, but only a few patients required red cell or platelet transfusion.

Radiotherapy Plus PCV in Low-Grade Glioma ■■ Long-term follow-up of RTOG 9802 found that radiation therapy followed by six cycles of chemotherapy improved progression-free survival and overall survival in patients with high-risk grade 2 glioma.

■■ Median overall survival was 13.3 years with the combination vs 7.8 years with radiotherapy alone; 10-year overall survival was 60.1% vs 40.1%.

■■ This is the third trial to show a survival benefit with PCV after radiotherapy.

“Toxicity was greater with PCV but is acceptable and similar to that seen with many combination chemotherapy regimens commonly in use,” Dr. Buckner noted. “Severe cognitive impairment at 5 years, measured by the MiniMental State Exam, was infrequent and, compared with baseline, improvement was somewhat more likely than decline.”

Longer-term or less-severe cognitive decline could not be assessed, he added.

Future analyses will assess treatment effect by histologic type, by molecular

markers, and by germline polymorphisms. n

Disclosure: Dr. Buckner reported no potential conflicts of interest. For full disclosures of all study authors visit meetinglibrary.asco.org.

Reference 1. Buckner JC, Pugh SL, Shaw EG, et al: Phase III study of radiation therapy with or without procarbazine, CCNU, and vincristine in low-grade glioma: RTOG 9802 with Alliance, ECOG, and SWOG. ASCO Annual Meeting. Abstract 2000. Presented June 2, 2014.

EXPERT POINT OF VIEW

S

ession moderator Howard A. Fine, MD, the Anne Murnick Cogan and David H. Cogan Professor of Oncology and Director of the Brain Tumor Center at New York University Cancer Institute, shared his enthusiasm over the findings of the RTOG 9802 study. “I don’t know of any other tumor type where the addition of chemotherapy has had such a profound extension of survival in a disease we usually think of as chemotherapy-resistant,” he said.

“That is remarkable.”

Management Questions Martin J. van den Bent, MD, Professor of Neuro-oncology at Erasmus Cancer Center in the Netherlands, was the study’s formal discussant at the ASCO Annual Meeting. He said that a number of management questions remain for low-grade gliomas.

vival, he said. “Today, this study helps answer some of these questions…. We can safely conclude that adjuvant PCV after radiotherapy improves overall survival in patients with low-grade, high-risk (age > 40, subtotal resection) gliHoward A. Fine, MD Martin J. van den Bent, MD omas,” he said. “There are not many studies in which What is the role of “watch and wait” such a magnificent increase in surand when should radiotherapy and vival has been reported.” chemotherapy be initiated? Since While this study demonstrated starting radiotherapy prematurely benefits in “all comers,” of interest can lead to more harm than good, will be the analysis by histology and many specialists tend to postpone molecular status, he said. radiotherapy when possible, sometimes using chemotherapy first, but Question of Relevance Dr. van den Bent further noted acknowledging that only a minor rethat the restuls of RTOG 9802 are sponse is expected, he said.

According to RTOG 9802, the in line with two other adjuvant PCV trade-off may be a reduction in sur- trials that initially reported a nega-

tive overall survival endpoint (despite increases in progression-free survival), but with long-term followup achieved at least a 40% reduction in deaths. “This was due to a striking similarity in the late separation of the curves 4 to 6 years after randomization,” he pointed out.

But in spite of three positive PCV trials, the question of relevance must be raised, Dr. van den Bent said.

“Most of us have moved on to temozolomide. Is it equivalent to PCV? We assume so, and we agree it is less toxic and better tolerated, but we don’t have the data.”

To help answer this, the CODEL study is comparing PCV to temozolomide in anaplastic oligodendrogliomas with codeletions of 1p/19q. n Disclosure: Dr. Fine reported no potential conflicts of interest. Dr. van den Bent is on the speakers bureau of MSD.

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In postmenopausal women with advanced HR+, HER2-negative breast cancer,

After letrozole or anastrozole fails,

Discover a treatment worth a DOUBLE take Abbreviation: HR+, hormone receptor-positive.

DOUBLE INHIBITION In advanced disease, targeting one pathway may not be enough AFINITOR® (everolimus) Tablets plus exemestane is the only regimen to deliver dual inhibition of the ER and PI3K/Akt/mTOR signaling pathways, providing synergistic inhibition of tumor survival signaling.1-3 Aromatase inhibition

Typical ER Pathway Blockade

Estrogen

In HR+ breast cancer, NSAI treatments (eg, letrozole or anastrozole) inhibit the production of estrogen, thereby reducing ER signaling, a key driver of tumor growth and survival in breast cancer.4,5

ER

Nucleus Cell Proliferation and Survival Aromatase inhibition

Key Mechanism of Progression

Estrogen

P ER

In the advanced setting, multiple signaling pathways and hyperactivation of the PI3K/Akt/mTOR pathway can give tumor cells alternate pathways for progression.4,6-8

mTOR

P ER

Nucleus Cell Proliferation and Survival

Cell Proliferation and Survival

AFINITOR + exemestane

Double Inhibition

Estrogen

AFINITOR

ER

mTOR

Cell Proliferation and Survival

Cell Proliferation and Survival

Nucleus

In patients who have progressed on an NSAI, AFINITOR, in combination with exemestane, offers a unique treatment strategy to address disease progression through dual inhibition of the ER and PI3K/Akt/mTOR signaling pathways.4,5

Only AFINITOR plus exemestane offers dual inhibition of the ER and mTOR pathways1 AFINITOR is indicated for the treatment of postmenopausal women with advanced hormone receptor-positive, HER2-negative breast cancer (advanced HR+ BC) in combination with exemestane after failure of treatment with letrozole or anastrozole.

Important Safety Information Noninfectious Pneumonitis: • Noninfectious pneumonitis was reported in up to 19% of patients treated with AFINITOR. The incidence of Common Terminology Criteria (CTC) grade 3 and 4 noninfectious pneumonitis was up to 4.0% and up to 0.2%, respectively. Fatal outcomes have been observed • If symptoms are moderate, consider interrupting therapy until symptoms improve. The use of corticosteroids may be indicated

• For grade 3 cases, interrupt AFINITOR until resolution to grade ≤1. AFINITOR may be reintroduced at a daily dose approximately 50% lower than the dose previously administered, depending on the individual clinical circumstances.

If toxicity recurs at grade 3, consider discontinuation of AFINITOR • For grade 4 cases, discontinue AFINITOR. Corticosteroids may be indicated until symptoms resolve • The development of pneumonitis has been reported even at a reduced dose Abbreviations: BOLERO-2, Breast Cancer Trials of Oral Everolimus-2; ER, estrogen receptor; HR+, hormone receptor-positive; mTOR, mammalian target of rapamycin; NSAI, nonsteroidal aromatase inhibitor; P, phosphorylation; PFS, progression-free survival.

DOUBLE MEDIAN PFS AFINITOR plus exemestane more than doubled median PFS over exemestane alone1

55%

Combination Therapy Gives You More: Median PFS in BOLERO-2 (Investigator Radiological Review)1 100

reduction in risk of progression or death1

HR=0.45 [95% CI, 0.38-0.54] Log-rank P value: <0.0001

PFS curves began to diverge at

6 weeks

(the first tumor assessment)1,3

PFS Probability (%)

80

Median PFS

7.8 months

60

40

[95% CI, 6.9-8.5] Median PFS

3.2 months

[95% CI, 2.8-4.1]

20

0 0

2

4

6

8

10

12

14

16

18

20

22

24

26

28

Time (months) AFINITOR plus exemestane (n/N=310/485)

Exemestane plus placebo (n/N=200/239)

Exemestane plus placebo (n/N=200/239)

62% reduction in risk of progression or death1

Independent central assessment confirmed benefit1 Median PFS was 11.0 months with AFINITOR plus exemestane [95% CI, 9.7-15.0] vs 4.1 months with placebo plus exemestane [95% CI, 2.9-5.6] (HR=0.38 [95% CI, 0.3-0.5]; P<0.0001)1

Overall survival (OS) results were not mature at the time of the interim analysis, and no statistically significant treatment-related difference in OS was noted (HR=0.77 [95% CI, 0.57-1.04]).1 Important Safety Information (cont) Infections: • AFINITOR has immunosuppressive properties and may predispose patients to bacterial, fungal, viral, or protozoal infections (including those with opportunistic pathogens) • Localized and systemic infections, including pneumonia, mycobacterial infections, other bacterial infections, invasive fungal infections such as aspergillosis or candidiasis, and viral infections, including reactivation of hepatitis B virus, have occurred. Some of these infections have been severe (eg, leading to sepsis, respiratory failure, or hepatic failure) or fatal • Physicians and patients should be aware of the increased risk of infection with AFINITOR. Treatment of preexisting invasive fungal infections should be completed prior to starting treatment with AFINITOR

• Be vigilant for signs and symptoms of infection and institute appropriate

treatment promptly; interruption or discontinuation of AFINITOR should be considered • Discontinue AFINITOR if invasive systemic fungal infection is diagnosed and institute appropriate antifungal treatment

Please see additional Important Safety Information and Brief Summary of Prescribing Information on adjacent pages.

Important Safety Information .

AFINITOR® (everolimus) Tablets is contraindicated in patients with hypersensitivity to everolimus, to other rapamycin derivatives, or to any of the excipients.

Noninfectious Pneumonitis: • Noninfectious pneumonitis was reported in up to 19% of patients treated with AFINITOR. The incidence of Common Terminology Criteria (CTC) grade 3 and 4 noninfectious pneumonitis was up to 4.0% and up to 0.2%, respectively. Fatal outcomes have been observed • If symptoms are moderate, consider interrupting therapy until symptoms improve. The use of corticosteroids may be indicated • For grade 3 cases, interrupt AFINITOR until resolution to grade ≤1. AFINITOR may be reintroduced at a daily dose approximately 50% lower than the dose previously administered, depending on the individual clinical circumstances. If toxicity recurs at grade 3, consider discontinuation of AFINITOR • For grade 4 cases, discontinue AFINITOR. Corticosteroids may be indicated until symptoms resolve • The development of pneumonitis has been reported even at a reduced dose Infections: • AFINITOR has immunosuppressive properties and may predispose patients to bacterial, fungal, viral, or protozoal infections (including those with opportunistic pathogens) • Localized and systemic infections, including pneumonia, mycobacterial infections, other bacterial infections, invasive fungal infections such as aspergillosis or candidiasis, and viral infections, including reactivation of hepatitis B virus, have occurred. Some of these infections have been severe (eg, leading to sepsis, respiratory failure, or hepatic failure) or fatal • Physicians and patients should be aware of the increased risk of infection with AFINITOR. Treatment of preexisting invasive fungal infections should be completed prior to starting treatment with AFINITOR • Be vigilant for signs and symptoms of infection and institute appropriate treatment promptly; interruption or discontinuation of AFINITOR should be considered • Discontinue AFINITOR if invasive systemic fungal infection is diagnosed and institute appropriate antifungal treatment Oral Ulceration: • Mouth ulcers, stomatitis, and oral mucositis have occurred in patients treated with AFINITOR at an incidence ranging from 44% to 78% across the clinical trial experience. Grade 3/4 stomatitis was reported in 4% to 9% of patients • In such cases, topical treatments are recommended, but alcohol-, hydrogen peroxide-, iodine-, or thyme-containing mouthwashes should be avoided • Antifungal agents should not be used unless fungal infection has been diagnosed

Novartis Pharmaceuticals Corporation East Hanover, New Jersey 07936-1080

Renal Failure: • Cases of renal failure (including acute renal failure), some with a fatal outcome, have been observed in patients treated with AFINITOR Impaired Wound Healing: • Everolimus delays wound healing and increases the occurrence of wound-related complications like wound dehiscence, wound infection, incisional hernia, lymphocele, and seroma • These wound-related complications may require surgical intervention. Exercise caution with the use of AFINITOR in the perisurgical period Geriatric Patients: • In the randomized advanced hormone receptor-positive, HER2-negative breast cancer study, the incidence of deaths due to any cause within 28 days of the last AFINITOR dose was 6% in patients ≥65 years of age compared with 2% in patients <65 years of age • Adverse reactions leading to permanent discontinuation occurred in 33% of patients ≥65 years of age compared with 17% in patients <65 years of age • Careful monitoring and appropriate dose adjustments for adverse reactions are recommended Laboratory Tests and Monitoring: • Elevations of serum creatinine and proteinuria have been reported. Renal function (including measurement of blood urea nitrogen, urinary protein, or serum creatinine) should be evaluated prior to treatment and periodically thereafter, particularly in patients who have additional risk factors that may further impair renal function • Hyperglycemia, hyperlipidemia, and hypertriglyceridemia have been reported. Blood glucose and lipids should be evaluated prior to treatment and periodically thereafter. More frequent monitoring is recommended when AFINITOR is coadministered with other drugs that may induce hyperglycemia. Management with appropriate medical therapy is recommended. When possible, optimal glucose and lipid control should be achieved before starting a patient on AFINITOR • Reductions in hemoglobin, lymphocytes, neutrophils, and platelets have been reported.

Monitoring of complete blood count is recommended prior to treatment and periodically thereafter Drug-Drug Interactions: • Avoid coadministration with strong CYP3A4/PgP inhibitors (eg, ketoconazole, itraconazole, clarithromycin, atazanavir, nefazodone, saquinavir, telithromycin, ritonavir, indinavir, nelfinavir, voriconazole) • Use caution and reduce the AFINITOR dose to 2.5 mg daily if coadministration with a moderate CYP3A4/PgP inhibitor is required (eg, amprenavir, fosamprenavir, aprepitant, erythromycin, fluconazole, verapamil, diltiazem) • Avoid coadministration with strong CYP3A4/PgP inducers (eg, phenytoin, carbamazepine, rifampin, rifabutin, rifapentine, phenobarbital); however, if coadministration is required, consider doubling the daily dose of AFINITOR using increments of 5 mg or less

© 2014 Novartis

Hepatic Impairment: • Exposure to everolimus was increased in patients with hepatic impairment • For patients with severe hepatic impairment (Child-Pugh class C), AFINITOR may be used at a reduced dose if the desired benefit outweighs the risk. For patients with mild (Child-Pugh class A) or moderate (Child-Pugh class B) hepatic impairment, a dose reduction is recommended Vaccinations: • The use of live vaccines and close contact with those who have received live vaccines should be avoided during treatment with AFINITOR Embryo-Fetal Toxicity: • Fetal harm can occur if AFINITOR is administered to a pregnant woman. Advise female patients of reproductive potential to use highly effective contraception while using AFINITOR and for up to 8 weeks after ending treatment Adverse Reactions: • The most common adverse reactions (incidence ≥30%) were stomatitis (67%), infections (50%), rash (39%), fatigue (36%), diarrhea (33%), and decreased appetite (30%) • The most common grade 3/4 adverse reactions (incidence ≥2%) were stomatitis (8%), infections (5%), hyperglycemia (5%), fatigue (4%), dyspnea (4%), pneumonitis (4%), and diarrhea (2%) Laboratory Abnormalities: • The most common laboratory abnormalities (incidence ≥50%) were hypercholesterolemia (70%), hyperglycemia (69%), increased aspartate transaminase (AST, 69%), anemia (68%), leukopenia (58%), thrombocytopenia (54%), lymphopenia (54%), increased alanine transaminase (ALT, 51%), and hypertriglyceridemia (50%) • The most common grade 3/4 laboratory abnormalities (incidence ≥3%) were lymphopenia (12%), hyperglycemia (9%), anemia (7%), decreased potassium (4%), increased AST (4%), increased ALT (4%), and thrombocytopenia (3%) Please see Brief Summary of Prescribing Information on adjacent pages.

To learn more, please visit www.AFINITOR.com.

References: 1. AFINITOR [prescribing information]. East Hanover, NJ: Novartis Pharmaceuticals Corp; 2014. 2. Fedele P, Calvani N, Marino A, et al. Targeted agents to reverse resistance to endocrine therapy in metastatic breast cancer: where are we now and where are we going?

Crit Rev Oncol Hematol. 2012;84:243-251. 3. Data on file. AFINITOR CRAD001Y2301 Clinical Study Report. Novartis Pharmaceuticals Corp; March 2012. 4. Johnston SRD. Enhancing the efficacy of hormonal agents with selected targeted agents. Clin Breast Cancer. 2009;9(suppl 1):S28-S36. 5. Miller TW, Hennessy BI, González-Angulo AM, et al.

Hyperactivation of phosphatidylinositol-3 kinase promotes escape from hormone dependence in estrogen receptor-positive human breast cancer. J Clin Invest. 2010;120(7):2406-2413. 6. Di Cosimo S, Baselga J. Management of breast cancer with targeted agents: importance of heterogeneity. Nat Rev Clin Oncol. 2010;7(3):139-147. 7. Shou J, Massarweh S, Osborne CK, et al. Mechanisms of tamoxifen resistance: increased estrogen receptor-HER2/neu cross-talk in ER/HER2-positive breast cancer. J Natl Cancer Inst. 2004;96(12):926-935. 8. De Laurentiis M, Arpino G, Massarelli G, et al. A meta-analysis on the interaction between HER-2 expression and response to endocrine treatment in advanced breast cancer. Clin Cancer Res. 2005;11(13):4741-4748.

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AFB-1086973

AFINITOR® (everolimus) tablets for oral administration Initial U.S. Approval: 2009 Brief Summary of Prescribing Information. See full prescribing information for complete product information.

1 INDICATIONS AND USAGE AFINITOR® is indicated for the treatment of postmenopausal women with advanced hormone receptor-positive, HER2-negative breast cancer (advanced HR+ BC) in combination with exemestane, after failure of treatment with letrozole or anastrozole.

4 CONTRAINDICATIONS AFINITOR is contraindicated in patients with hypersensitivity to the active substance, to other rapamycin derivatives, or to any of the excipients. Hypersensitivity reactions manifested by symptoms including, but not limited to, anaphylaxis, dyspnea, flushing, chest pain, or angioedema (e.g., swelling of the airways or tongue, with or without respiratory impairment) have been observed with everolimus and other rapamycin derivatives.

5 WARNINGS AND PRECAUTIONS Non-infectious Pneumonitis Non-infectious pneumonitis is a class effect of rapamycin derivatives, including AFINITOR. Non-infectious pneumonitis was reported in up to 19% of patients treated with AFINITOR in clinical trials. The incidence of Common Terminology Criteria (CTC) Grade 3 and 4 non-infectious pneumonitis was up to 4.0% and up to 0.2%, respectively [see Adverse Reactions (6.1, 6.2, 6.3, 6.4, 6.5) in the full prescribing information]. Fatal outcomes have been observed.

Consider a diagnosis of non-infectious pneumonitis in patients presenting with non-specific respiratory signs and symptoms such as hypoxia, pleural effusion, cough, or dyspnea, and in whom infectious, neoplastic, and other causes have been excluded by means of appropriate investigations. Advise patients to report promptly any new or worsening respiratory symptoms.

Patients who develop radiological changes suggestive of non-infectious pneumonitis and have few or no symptoms may continue AFINITOR therapy without dose alteration. Imaging appears to overestimate the incidence of clinical pneumonitis.

If symptoms are moderate, consider interrupting therapy until symptoms improve. The use of corticosteroids may be indicated. AFINITOR may be reintroduced at a daily dose approximately 50% lower than the dose previously administered [see Table 1 in Dosage and Administration (2.2) in the full prescribing information] .

For cases of Grade 3 non-infectious pneumonitis interrupt AFINITOR until resolution to less than or equal to Grade 1. AFINITOR may be re-introduced at a daily dose approximately 50% lower than the dose previously administered depending on the individual clinical circumstances [see Dosage and Administration (2.2) in the full prescribing information]. If toxicity recurs at Grade 3, consider discontinuation of AFINITOR. For cases of Grade 4 non-infectious pneumonitis, discontinue AFINITOR. Corticosteroids may be indicated until clinical symptoms resolve. The development of pneumonitis has been reported even at a reduced dose.

Infections AFINITOR has immunosuppressive properties and may predispose patients to bacterial, fungal, viral, or protozoal infections, including infections with opportunistic pathogens [see Adverse Reactions (6.1, 6.2, 6.3, 6.4, 6.5) in the full prescribing information]. Localized and systemic infections, including pneumonia, mycobacterial infections, other bacterial infections, invasive fungal infections, such as aspergillosis or candidiasis, and viral infections including reactivation of hepatitis B virus have occurred in patients taking AFINITOR. Some of these infections have been severe (e.g., leading to sepsis, respiratory or hepatic failure) or fatal. Physicians and patients should be aware of the increased risk of infection with AFINITOR. Complete treatment of pre-existing invasive fungal infections prior to starting treatment with AFINITOR. While taking AFINITOR, be vigilant for signs and symptoms of infection; if a diagnosis of an infection is made, institute appropriate treatment promptly and consider interruption or discontinuation of AFINITOR. If a diagnosis of invasive systemic fungal infection is made, discontinue AFINITOR and treat with appropriate antifungal therapy.

Oral Ulceration Mouth ulcers, stomatitis, and oral mucositis have occurred in patients treated with AFINITOR at an incidence ranging from 44%-78% across the clinical trial experience. Grade 3 or 4 stomatitis was reported in 4%-9% of patients [see Adverse Reactions (6.1, 6.2, 6.3, 6.4, 6.5) in the full prescribing information]. In such cases, topical treatments are recommended, but alcohol-, hydrogen peroxide-, iodine-, or thyme-containing mouthwashes should be avoided as they may exacerbate the condition. Antifungal agents should not be used unless fungal infection has been diagnosed [see Drug Interactions].

Renal Failure Cases of renal failure (including acute renal failure), some with a fatal outcome, have been observed in patients treated with AFINITOR [see Laboratory Tests and Monitoring].

Impaired Wound Healing Everolimus delays wound healing and increases the occurrence of wound-related complications like wound dehiscence, wound infection, incisional hernia, lymphocele, and seroma. These wound-related complications may require surgical intervention. Exercise caution with the use of AFINITOR in the peri-surgical period.

Geriatric Patients In the randomized advanced hormone receptor-positive, HER2-negative breast cancer study, the incidence of deaths due to any cause within 28 days of the last AFINITOR dose was 6% in patients ≥ 65 years of age compared to 2% in patients < 65 years of age. Adverse reactions leading to permanent treatment discontinuation occurred in 33% of patients ≥ 65 years of age compared to 17% in patients < 65 years of age. Careful monitoring and appropriate dose adjustments for adverse reactions are recommended [see Dosage and Administration (2.2) in the full prescribing information and Use in Specific Populations].

Laboratory Tests and Monitoring Renal Function Elevations of serum creatinine and proteinuria have been reported in patients taking AFINITOR [see Adverse Reactions (6.1, 6.2, 6.3, 6.4, 6.5) in the full prescribing information]. Monitoring of renal function, including measurement of blood urea nitrogen (BUN), urinary protein, or serum creatinine, is recommended prior to the start of AFINITOR therapy and periodically thereafter. Renal function of patients should be monitored particularly where patients have additional risk factors that may further impair renal function.

Blood Glucose and Lipids Hyperglycemia, hyperlipidemia, and hypertriglyceridemia have been reported in patients taking AFINITOR [see Adverse Reactions (6.1, 6.2, 6.3, 6.4, 6.5) in the full prescribing information]. Monitoring of fasting serum glucose and lipid profile is recommended prior to the start of AFINITOR therapy and periodically thereafter as well as management with appropriate medical therapy. More frequent monitoring is recommended when AFINITOR is co-administered with other drugs that may induce hyperglycemia. When possible, optimal glucose and lipid control should be achieved before starting a patient on AFINITOR. Hematologic Parameters Decreased hemoglobin, lymphocytes, neutrophils, and platelets have been reported in patients taking AFINITOR [see Adverse Reactions (6.1, 6.2, 6.3, 6.4, 6.5) in the full prescribing information]. Monitoring of complete blood count is recommended prior to the start of AFINITOR therapy and periodically thereafter.

Drug-drug Interactions Due to significant increases in exposure of everolimus, co-administration with strong CYP3A4/PgP inhibitors should be avoided [see Dosage and Administration (2.2, 2.5) in the full prescribing information and Drug Interactions].

A reduction of the AFINITOR dose is recommended when co-administered with a moderate CYP3A4/PgP inhibitor [see Dosage and Administration (2.2, 2.5) in the full prescribing information and Drug Interactions] .

An increase in the AFINITOR dose is recommended when co-administered with a strong CYP3A4/PgP inducer [see Dosage and Administration (2.2, 2.5) in the full prescribing information and Drug Interactions] .

Hepatic Impairment Exposure to everolimus was increased in patients with hepatic impairment [see Clinical Pharmacology (12.3) in the full prescribing information].

For advanced HR+ BC, advanced PNET, advanced RCC, and renal angiomyolipoma with TSC patients with severe hepatic impairment (Child-Pugh class C), AFINITOR may be used at a reduced dose if the desired benefit outweighs the risk. For patients with mild (Child-Pugh class A) or moderate (Child-Pugh class B) hepatic impairment, a dose reduction is recommended [see Dosage and Administration (2.2) and Clinical Pharmacology (12.3) in the full prescribing information].

For patients with SEGA and mild or moderate hepatic impairment, adjust the dose of AFINITOR Tablets or AFINITOR DISPERZ based on therapeutic drug monitoring. For patients with SEGA and severe hepatic impairment, reduce the starting dose of AFINITOR Tablets or AFINITOR DISPERZ by approximately 50% and adjust subsequent doses based on therapeutic drug monitoring [see Dosage and Administration (2.4, 2.5) in the full prescribing information].

Vaccinations During AFINITOR treatment, avoid the use of live vaccines and avoid close contact with individuals who have received live vaccines (e.g., intranasal influenza, measles, mumps, rubella, oral polio, BCG, yellow fever, varicella, and TY21a typhoid vaccines).

Embryo-fetal Toxicity Based on the mechanism of action, AFINITOR can cause fetal harm. Everolimus caused embryo-fetal toxicities in animals at maternal exposures that were lower than human exposures. 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].

Advise female patients of reproductive potential to avoid becoming pregnant and to use highly effective contraception while using AFINITOR and for up to 8 weeks after ending treatment [see Use in Specific Populations].

6 ADVERSE REACTIONS The efficacy and safety of AFINITOR (10 mg/day) plus exemestane (25 mg/day) (n=485) versus placebo plus exemestane (25 mg/day) (n=239) was evaluated in a randomized, controlled trial in patients with advanced or metastatic hormone receptor-positive, HER2-negative breast cancer. The median age of patients was 61 years (range 28-93 years), and 75% were Caucasian. Safety results are based on a median follow-up of approximately 13 months.

The most common adverse reactions (incidence ≥ 30%) were stomatitis, infections, rash, fatigue, diarrhea, and decreased appetite. The most common Grade 3/4 adverse reactions (incidence ≥ 2%) were stomatitis, infections, hyperglycemia, fatigue, dyspnea, pneumonitis, and diarrhea. The most common laboratory abnormalities (incidence ≥ 50%) were hypercholesterolemia, hyperglycemia, increased aspartate transaminase (AST), anemia, leukopenia, thrombocytopenia, lymphopenia, increased alanine transaminase (ALT), and hypertriglyceridemia.

The most common Grade 3/4 laboratory abnormalities (incidence ≥ 3%) were lymphopenia, hyperglycemia, anemia, decreased potassium, increased AST, increased ALT, and thrombocytopenia.

Fatal adverse reactions occurred more frequently in patients who received AFINITOR plus exemestane (2%) compared to patients on the placebo plus exemestane arm (0.4%). The rates of treatment-emergent adverse events resulting in permanent discontinuation were 24% and 5% for the AFINITOR plus exemestane and placebo plus exemestane treatment groups, respectively. Dose adjustments (interruptions or reductions) were more frequent among patients in the AFINITOR plus exemestane arm than in the placebo plus exemestane arm (63% versus 14%).

Table 2 compares the incidence of treatment-emergent adverse reactions reported with an incidence of ≥10% for patients receiving AFINITOR 10 mg daily versus placebo.

Table 2: Adverse Reactions Reported ≥ 10% of Patients with Advanced HR+ BC* AFINITOR (10 mg/day) + exemestanea N=482 All grades Grade 3 Grade 4 % % % Any adverse reaction 100 41 Gastrointestinal disorders 67 8 Stomatitisb Diarrhea 33 2 Nausea 29 0.2 Vomiting 17 0.8 Constipation 14 0.4 Dry mouth 11 0 General disorders and administration site conditions Fatigue 36 4 Edema peripheral 19 1 Pyrexia 15 0.2 Asthenia 13 2 Infections and infestations 50 4 Infectionsc Investigations Weight decreased 25 1 Metabolism and nutrition disorders Decreased appetite 30 1 Hyperglycemia 14 5 Musculoskeletal and connective tissue disorders Arthralgia 20 0.8 Back pain 14 0.2 Pain in extremity 9 0.4 Nervous system disorders Dysgeusia 22 0.2 Headache 21 0.4 Psychiatric disorders Insomnia 13 0.2 Respiratory, thoracic and mediastinal disorders Cough 24 0.6 Dyspnea 21 4 Epistaxis 17 0 Pneumonitisd 19 4 Skin and subcutaneous tissue disorders Rash 39 1 Pruritus 13 0.2 Alopecia 10 0 Vascular disorders Hot flush 6 0 Median duration of treatmente

Placebo + exemestanea N=238 All grades Grade 3 Grade 4 % % %

9

90

22

5

0 0.2 0.2 0.2 0 0

11 18 28 12 13 7

0.8 0.8 1 0.8 0.4 0

0 0 0 0 0 0

0.4 0 0 0.2

27 6 7 4

1 0.4 0.4 0

0 0 0 0

1

25

2

0

0

6

0

0

0 0.4

12 2

0.4 0.4

0 0

0 0 0

17 10 11

0 0.8 2

0 0 0

0 0

6 14

0 0

0 0

0

8

0

0

0 0.2 0 0.2

12 11 1 0.4

0 0.8 0 0

0 0.4 0 0

0 0 0

6 5 5

0 0 0

0 0 0

0

14

0

0

23.9 weeks

13.4 weeks

Grading according to CTCAE Version 3.0 *160 patients (33.2%) were exposed to AFINITOR therapy for a period of ≥ 32 weeks) a Exemestane (25 mg/day) b Includes stomatitis, mouth ulceration, aphthous stomatitis, glossodynia, gingival pain, glossitis and lip ulceration c Includes all preferred terms within the ‘infections and infestations’ system organ class, the most common being nasopharyngitis (10%), urinary tract infection (10%), upper respiratory tract infection (5%), pneumonia (4%), bronchitis (4%), cystitis (3%), sinusitis (3%), and also including candidiasis (<1%), and sepsis (<1%), and hepatitis C (<1%). d Includes pneumonitis, interstitial lung disease, lung infiltration, and pulmonary fibrosis e Exposure to AFINITOR or placebo Key observed laboratory abnormalities are presented in Table 3.

Table 3: Key Laboratory Abnormalities Reported in ≥ 10% of Patients with Advanced HR+ BC Laboratory parameter

Hematologyb Hemoglobin decreased WBC decreased Platelets decreased Lymphocytes decreased Neutrophils decreased Clinical chemistry Glucose increased Cholesterol increased Aspartate transaminase (AST) increased Alanine transaminase (ALT) increased Triglycerides increased Albumin decreased Potassium decreased Creatinine increased

AFINITOR (10 mg/day) Placebo + exemestanea + exemestanea N=482 N=238 All grades Grade 3 Grade 4 All grades Grade 3 Grade 4 % % % % % % 68 58 54 54 31

6 1 3 11 2

0.6 0 0.2 0.6 0

40 28 5 37 11

0.8 5 0 5 0.8

0.4 0.8 0.4 0.8 0.8

69 70 69 51 50 33 29 24

9 0.6 4 4 0.8 0.8 4 2

0.4 0.2 0.2 0.2 0 0 0.2 0.2

44 38 45 29 26 16 7 13

0.8 0.8 3 5 0 0.8 1 0

0.4 0.8 0.4 0 0 0 0 0

Grading according to CTCAE Version 3.0 a Exemestane (25 mg/day) b Reflects corresponding adverse drug reaction reports of anemia, leukopenia, lymphopenia, neutropenia, and thrombocytopenia (collectively as pancytopenia), which occurred at lower frequency.

7 DRUG INTERACTIONS Everolimus is a substrate of CYP3A4, and also a substrate and moderate inhibitor of the multidrug efflux pump PgP. In vitro, everolimus is a competitive inhibitor of CYP3A4 and a mixed inhibitor of CYP2D6.

Agents That May Increase Everolimus Blood Concentrations CYP3A4 Inhibitors and PgP Inhibitors In healthy subjects, compared to AFINITOR treatment alone there were significant increases in everolimus exposure when AFINITOR was coadministered with: • ketoconazole (a strong CYP3A4 inhibitor and a PgP inhibitor) - Cmax and AUC increased by 3.9- and 15.0-fold, respectively.

• erythromycin (a moderate CYP3A4 inhibitor and a PgP inhibitor) - Cmax and AUC increased by 2.0- and 4.4-fold, respectively.

• verapamil (a moderate CYP3A4 inhibitor and a PgP inhibitor) - Cmax and AUC increased by 2.3- and 3.5-fold, respectively.

Concomitant strong inhibitors of CYP3A4/PgP should not be used [see Dosage and Administration (2.2, 2.5) in the full prescribing information and Warnings and Precautions].

Use caution when AFINITOR is used in combination with moderate CYP3A4/PgP inhibitors. If alternative treatment cannot be administered reduce the AFINITOR dose [see Dosage and Administration (2.2, 2.5) in the full prescribing information and Warnings and Precautions].

Agents That May Decrease Everolimus Blood Concentrations CYP3A4/PgP Inducers In healthy subjects, co-administration of AFINITOR with rifampin, a strong inducer of CYP3A4 and an inducer of PgP, decreased everolimus AUC and Cmax by 63% and 58% respectively, compared to everolimus treatment alone.

Consider a dose increase of AFINITOR when co-administered with strong CYP3A4/PgP inducers if alternative treatment cannot be administered. St. John’s Wort may decrease everolimus exposure unpredictably and should be avoided [see Dosage and Administration (2.2, 2.5) in the full prescribing information].

Drugs That May Have Their Plasma Concentrations Altered by Everolimus Studies in healthy subjects indicate that there are no clinically significant pharmacokinetic interactions between AFINITOR and the HMG-CoA reductase inhibitors atorvastatin (a CYP3A4 substrate) and pravastatin (a nonCYP3A4 substrate) and population pharmacokinetic analyses also detected no influence of simvastatin (a CYP3A4 substrate) on the clearance of AFINITOR. A study in healthy subjects demonstrated that co-administration of an oral dose of midazolam (sensitive CYP3A4 substrate) with everolimus resulted in a 25% increase in midazolam Cmax and a 30% increase in midazolam AUC(0-inf).

Coadministration of everolimus and exemestane increased exemestane Cmin by 45% and C2h by 64%. However, the corresponding estradiol levels at steady state (4 weeks) were not different between the 2 treatment arms. No increase in adverse events related to exemestane was observed in patients with hormone receptor-positive, HER2-negative advanced breast cancer receiving the combination.

Coadministration of everolimus and depot octreotide increased octreotide Cmin by approximately 50%.

8 USE IN SPECIFIC POPULATIONS Pregnancy Pregnancy Category D Risk Summary Based on the mechanism of action, AFINITOR can cause fetal harm when administered to a pregnant woman.

Everolimus caused embryo-fetal toxicities in animals at maternal exposures that were lower than human exposures. If this drug is used during pregnancy or if the patient becomes pregnant while taking the drug, apprise the patient of the potential hazard to the fetus [see Warnings and Precautions].

Animal Data In animal reproductive studies, oral administration of everolimus to female rats before mating and through organogenesis induced embryo-fetal toxicities, including increased resorption, pre-implantation and post-implantation loss, decreased numbers of live fetuses, malformation (e.g., sternal cleft), and retarded skeletal development.

These effects occurred in the absence of maternal toxicities. Embryo-fetal toxicities in rats occurred at doses ≥ 0.1 mg/kg (0.6 mg/m2) with resulting exposures of approximately 4% of the exposure (AUC0-24h) achieved in patients receiving the 10 mg daily dose of everolimus. In rabbits, embryotoxicity evident as an increase in resorptions occurred at an oral dose of 0.8 mg/kg (9.6 mg/m2), approximately 1.6 times either the 10 mg daily dose or the median dose administered to SEGA patients on a body surface area basis. The effect in rabbits occurred in the presence of maternal toxicities.

In a pre- and post-natal development study in rats, animals were dosed from implantation through lactation. At the dose of 0.1 mg/kg (0.6 mg/m2), there were no adverse effects on delivery and lactation or signs of maternal toxicity; however, there were reductions in body weight (up to 9% reduction from the control) and in survival of offspring (~5% died or missing). There were no drug-related effects on the developmental parameters (morphological development, motor activity, learning, or fertility assessment) in the offspring.

Nursing Mothers It is not known whether everolimus is excreted in human milk. Everolimus and/or its metabolites passed into the milk of lactating rats at a concentration 3.5 times higher than in maternal serum. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from everolimus, 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 Pediatric use of AFINITOR Tablets and AFINITOR DISPERZ is recommended for patients 1 year of age and older with TSC for the treatment of SEGA that requires therapeutic intervention but cannot be curatively resected. The safety and effectiveness of AFINITOR Tablets and AFINITOR DISPERZ have not been established in pediatric patients with renal angiomyolipoma with TSC in the absence of SEGA.

The effectiveness of AFINITOR in pediatric patients with SEGA was demonstrated in two clinical trials based on demonstration of durable objective response, as evidenced by reduction in SEGA tumor volume [see Clinical Studies (14.5) in the full prescribing information]. Improvement in disease-related symptoms and overall survival in pediatric patients with SEGA has not been demonstrated. The long term effects of AFINITOR on growth and pubertal development are unknown.

Study 1 was a randomized, double-blind, multicenter trial comparing AFINITOR (n=78) to placebo (n=39) in pediatric and adult patients. The median age was 9.5 years (range 0.8 to 26 years). At the time of randomization, a total of 20 patients were < 3 years of age, 54 patients were 3 to < 12 years of age, 27 patients were 12 to < 18 years of age, and 16 patients were ≥ 18 years of age. The overall nature, type, and frequency of adverse reactions across the age groups evaluated were similar, with the exception of a higher per patient incidence of infectious serious adverse events in patients < 3 years of age. A total of 6 of 13 patients (46%) < 3 years of age had at least 1 serious adverse event due to infection, compared to 2 of 7 patients (29%) treated with placebo. No patient in any age group discontinued AFINITOR due to infection [see Adverse Reactions (6.5) in the full prescribing information].

Subgroup analyses showed reduction in SEGA volume with AFINITOR treatment in all pediatric age subgroups.

Study 2 was an open-label, single-arm, single-center trial of AFINITOR (N=28) in patients aged ≥ 3 years; median age was 11 years (range 3 to 34 years). A total of 16 patients were 3 to < 12 years, 6 patients were 12 to < 18 years, and 6 patients were ≥ 18 years. The frequency of adverse reactions across the age groups was generally similar [see Adverse Reactions (6.5) in the full prescribing information]. Subgroup analyses showed reductions in SEGA volume with AFINITOR treatment in all pediatric age subgroups.

Everolimus clearance normalized to body surface area was higher in pediatric patients than in adults with SEGA [see Clinical Pharmacology (12.3) in the full prescribing information]. The recommended starting dose and subsequent requirement for therapeutic drug monitoring to achieve and maintain trough concentrations of 5 to 15 ng/mL are the same for adult and pediatric patients with SEGA [see Dosage and Administration (2.3, 2.4) in the full prescribing information].

Geriatric Use In the randomized advanced hormone receptor positive, HER2-negative breast cancer study, 40% of AFINITORtreated patients were ≥ 65 years of age, while 15% were 75 years and over. No overall differences in effectiveness were observed between elderly and younger patients. The incidence of deaths due to any cause within 28 days of the last AFINITOR dose was 6% in patients ≥ 65 years of age compared to 2% in patients < 65 years of age.

Adverse reactions leading to permanent treatment discontinuation occurred in 33% of patients ≥ 65 years of age compared to 17% in patients < 65 years of age [see Warnings and Precautions].

In two other randomized trials (advanced renal cell carcinoma and advanced neuroendocrine tumors of pancreatic origin), no overall differences in safety or effectiveness were observed between elderly and younger patients. In the randomized advanced RCC study, 41% of AFINITOR treated patients were ≥ 65 years of age, while 7% were 75 years and over. In the randomized advanced PNET study, 30% of AFINITOR-treated patients were ≥ 65 years of age, while 7% were 75 years and over.

Other reported clinical experience has not identified differences in response between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out [see Clinical Pharmacology (12.3) in the full prescribing information].

No dosage adjustment in initial dosing is required in elderly patients, but close monitoring and appropriate dose adjustments for adverse reactions is recommended [see Dosage and Administration (2.2), Clinical Pharmacology (12.3) in the full prescribing information].

Females and Males of Reproductive Potential Contraception Females AFINITOR can cause fetal harm when administered to a pregnant woman. Advise female patients of reproductive potential to use highly effective contraception while receiving AFINITOR and for up to 8 weeks after ending treatment [see Use in Specific Populations].

Infertility Females Menstrual irregularities, secondary amenorrhea, and increases in luteinizing hormone (LH) and follicle stimulating hormone (FSH) occurred in female patients taking AFINITOR. Based on these clinical findings and findings in animals, female fertility may be compromised by treatment with AFINITOR [see Adverse Reactions (6.2, 6.4, 6.5) and Nonclinical Toxicology in the full prescribing information].

Males AFINITOR treatment may impair fertility in male patients based on animal findings [see Nonclinical Toxicology in the full prescribing information].

Renal Impairment No clinical studies were conducted with AFINITOR in patients with decreased renal function. Renal impairment is not expected to influence drug exposure and no dosage adjustment of everolimus is recommended in patients with renal impairment [see Clinical Pharmacology (12.3) in the full prescribing information].

Hepatic Impairment The safety, tolerability and pharmacokinetics of AFINITOR were evaluated in a 34 subject single oral dose study of everolimus in subjects with impaired hepatic function relative to subjects with normal hepatic function. Exposure was increased in patients with mild (Child-Pugh class A), moderate (Child-Pugh class B), and severe (Child-Pugh class C) hepatic impairment [see Clinical Pharmacology (12.3) in the full prescribing information].

For advanced HR+ BC, advanced PNET, advanced RCC, and renal angiomyolipoma with TSC patients with severe hepatic impairment, AFINITOR may be used at a reduced dose if the desired benefit outweighs the risk. For patients with mild (Child-Pugh class A) or moderate (Child-Pugh class B) hepatic impairment, a dose reduction is recommended [see Dosage and Administration (2.2) in the full prescribing information].

For patients with SEGA who have severe hepatic impairment (Child-Pugh class C), reduce the starting dose of AFINITOR Tablets or AFINITOR DISPERZ by approximately 50%. For patients with SEGA who have mild (ChildPugh class A) or moderate (Child-Pugh class B) hepatic impairment, adjustment to the starting dose may not be needed. Subsequent dosing should be based on therapeutic drug monitoring [see Dosage and Administration (2.4, 2.5) in the full prescribing information].

10 OVERDOSAGE In animal studies, everolimus showed a low acute toxic potential. No lethality or severe toxicity was observed in either mice or rats given single oral doses of 2000 mg/kg (limit test).

Reported experience with overdose in humans is very limited. Single doses of up to 70 mg have been administered. The acute toxicity profile observed with the 70 mg dose was consistent with that for the 10 mg dose.

Manufactured by: Novartis Pharma Stein AG Stein, Switzerland Distributed by: Novartis Pharmaceuticals Corporation East Hanover, New Jersey 07936 Revised Feb 2014 © Novartis T2014-16/T2014-17 February 2014/February 2014

ASCOPost.com | JULY 25, 2014

PAGE 23

ASCO Annual Meeting Thyroid Cancer

Impressive Delay in Thyroid Cancer Progression Achieved With Lenvatinib

By Caroline Helwick

T

he investigational tyrosine kinase inhibitor lenvatinib reduced disease progression by 79%, as compared to placebo, in patients with metastatic differentiated thyroid cancer that is refractory to radioactive iodine in the phase III SELECT trial. These findings were presented at the 2014 ASCO Annual Meeting by Martin Schlumberger, MD, Professor of Oncology at the University of Paris Sud in France.1

Limited Treatment Options “Based on our findings, we are confident that lenvatinib will eventually become a standard treatment for [radioiodine-refractory differentiated thyroid cancer],” Dr. Schlumberger said at a media briefing during the meeting.

“Patients with progressive radioiodine-refractory differentiated thyroid cancer typically have a 10-year survival rate of only 10% from the time

Primary Endpoint Robustly Met SELECT (Study of E7080 Lenvatinib in Differentiated Cancer of the Thyroid) included 392 patients with advanced radioiodine-refractory differentiated thyroid cancer, threefourths of whom had received prior treatment with a VEGF-targeted agent.

Patients were randomly assigned to receive lenvatinib (24 mg/d on a 28-day cycle) or placebo, with crossover allowed upon progression.

Median progression-free survival, the primary endpoint, was 18.3 months with lenvatinib vs 3.6 months with placebo—approximately a 14-month absolute benefit and a 79% reduction in risk that was highly significant (P < .0001) and is “an extraordinary improvement,” Dr. Schlumberger reported.

Progression at 2 years was observed in only 41% of the lenvatinib arm, vs 86% of the placebo arm. Receipt of prior anti-

T:14”

B:14.25”

S:13”

Based on our findings, we are confident that lenvatinib will eventually become a standard treatment for [radioiodine-refractory differentiated thyroid cancer].

—Martin Schlumberger, MD

of metastatic disease. Until recently, treatment options for these patients have been limited,” he noted.

In November 2013, sorafenib (Nexavar) was approved by the U.S. Food and Drug Administration for radioiodine-refractory differentiated thyroid cancer. Vandetinib (Caprelsa) and cabozantinib (Cometriq) are now approved for metastatic medullary thyroid cancer.

Vascular endothelial growth factor (VEGF)-signaling networks have been implicated in tumor angiogenesis and are associated with the aggressiveness and metastasis of thyroid tumors. Lenvatinib is an oral tyrosine kinase inhibitor that binds not only to VEGFR1-3, but to multiple other sites involved in angiogenesis and proliferation. This may be important, since other molecular drivers of tumor growth and maintenance beyond VEGF-driven angiogenesis contribute to the pathogenesis of thyroid cancer, Dr. Schlumberger added.

VEGF therapy did not adversely affect outcomes; previously treated patients had the same magnitude of risk reduction, and all other subgroups similarly benefited.

Similarly, response rates were 65% with lenvatinib, including four complete responses (2%), vs an overall 2% response rate with placebo (P < .0001).

terpret, the researchers noted.

In an interview with The ASCO Post, U.S. co-investigator Lori J. Wirth, MD, Assistant Professor of Medicine at Harvard Medical School, Boston, commented on the robust responses and prolonged remission time. “We don’t see numbers that high in oncology very often,” she said.

Gregory A. Masters, MD, FASCO

Lori J. Wirth, MD

The median progression-free survival with sorafenib in the DECISION trial was 10.8 months, vs 5.8 months with placebo.2

Major Adverse Events Treatment-emergent adverse events “reported as treatment-related” were observed in virtually all patients treated with lenvatinib (97%), compared with 60% of those receiving placebo. The most frequent events with lenvatinib were hypertension, diarrhea, fatigue, weight loss, and decreased appetite. These were grade ≥ 3 in 42%, 8%, 9%, 10%, and 5% of lenvatinib recipients, respectively. Proteinuria grade ≥ 3 was reported in 10%.

Dose reductions were necessary for 68%, and dose interruptions, for 82%; 14% of lenvatinib-treated patients discontinued the drug due to toxicity.

A total of 20 patients (8%) in the lenvatinib group died, compared to 6 (5%) in the placebo group. Of these 20 deaths, 6 (2%) were considered by the investigators to be treatment-related,

Lenvatinib in Thyroid Cancer ■■ For the treatment of metastatic differentiated radioiodine-refractory thyroid cancer, treatment with the multityrosine kinase inhibitor lenvatinib reduced disease progression by 79%, vs placebo.

■■ Median progression-free survival was improved by 14.7 months.

■■ Toxicity could be challenging, and there were six treatment-related deaths.

Time to response was prompt—about 2 months. Median duration of response has not been reached. Median tumor shrinkage for responders was 52%.

Median overall survival has not been reached in either arm, and due to expected crossover upon progression, this endpoint may be hard to in-

Dr. Schlumberger said. One patient died due to a pulmonary embolism, one died due to hemorrhagic stroke, and four others died as a result of general health deterioration, he explained. “Of course this is significant,” Dr. Schlumberger said, in response to questions from the media.

While treatment-related deaths are higher than seen in studies of the other agents used in differentiated thyroid cancer, general toxicity is not worse, he indicated, suggesting the risk/benefit ratio is positive.

ASCO press briefing moderator Gregory A. Masters, MD, FASCO, Attending Physician at the Helen F. Graham Cancer Center & Research Institute, Newark, Delaware, agreed, noting that the absolute improvement in progression-free survival shown with sorafenib vs placebo was less than 6 months, compared to almost 15 months with lenvatinib. “While it can be dangerous to compare two different trials, the numbers from this trial certainly show higher response rates and longer prolongation of progression-free survival,” he said.

Toxicities in Perspective “There’s always a trade-off,” Dr. Masters acknowledged. “We are still trying to understand the toxicities of these new therapies. We must use new therapies with caution, and in deciding which patients to treat, we must balance the risks that go along with any cancer therapy….

But it is really rewarding to see another active drug in this disease, where a year ago we really had no active therapies.”

Dr. Wirth added, “We have to think about the toxicities of these drugs in perspective. Many patients with [radioiodine-refractory differentiated thyroid cancer] have a low burden of disease that is growing slowly, and watchful waiting can be appropriate for them. Patients in the SELECT study had a median progression-free survival of only 3.6 months on placebo. These are patients with rapidly progressive disease, and they need effective treatment.”

In her experience, lenvatinib has not been much harder to tolerate than the other tyrosine kinase inhibitors. “I have patients who have remained on lenvatinib for up to 2 years, but we are very active in managing them,” she said. continued on page 24

The ASCO Post | JULY 25, 2014

PAGE 24

ASCO Annual Meeting Cancer Genetics

Women With BRCA Mutations Report Significant Side Effects Following Risk-Reducing Salpingo-Oophorectomy

T

he majority of women with BRCA1 and BRCA2 mutations experience sexual dysfunction, menopausal symptoms, cognitive and stress issues, and poor sleep following riskreducing salpingo-oophorectomy, according to results of a study from the

Abramson Cancer Center and the Perelman School of Medicine at the University of Pennsylvania. The team’s findings, which reaffirm the need for a better understanding of how to manage

long-term effects of the risk-reducing procedure, were presented at the 2014 ASCO Annual Meeting.1 “These results reinforce the need for care providers to better under-

stand and communicate with patients about the possible long-term effects of bilateral risk-reducing salpingooophorectomy,” said lead author Susan Domchek, MD, Director of the

Activated T Cell

Our work highlights the need for novel strategies to prevent breast and ovarian cancer. Despite the efficacy of oophorectomy, given the negative impact [on quality of life], we need to continue to strive towards other options for prevention.

Inactivated T Cell

PD-L1

PD-1 Receptor PD-L2

PD-1 Receptor PD-L1

—Susan Domchek, MD

Lenvatinib in Thyroid Cancer continued from page 23

“With active symptom management, supportive care, dose holds, and dose reductions, these drugs are very useful, and the risk/benefit ratio is favorable.” n

Disclosure: The study was funded by Eisai.

Dr. Schlumberger has consulted or received research support from Eisai, AstraZeneca, Bayer, and Genzyme/Sanofi, and honoraria from these companies and from Sobi. Drs. Wirth and Masters reported no potential conflicts of interest. For full disclosures of all study authors, visit meetinglibrary.asco.org.

References 1. Schlumberger M, Tahara M, Wirth LJ, et al: A phase 3, multicenter, randomized, double-blind, placebo-controlled trial of lenvatinib (E7080) in patients with 131Irefractory differentiated thyroid cancer (SELECT). ASCO Annual Meeting. Abstract LBA6008. Presented June 2, 2014.

2. Brose MS, Nutting C, Jarzab B, et al: Sorafenib in locally advanced or metastatic patients with radioactive iodine-refractory differentiated thyroid cancer: The phase III DECISION trial. ASCO Annual Meeting.

Abstract 4. Presented June 2, 2013.

Artist’s interpretation based on scanning electron microscopy.

ASCOPost.com | JULY 25, 2014

PAGE 25

ASCO Annual Meeting Salpingo-Oophorectomy and Quality of Life ■■ The majority of patients who had risk-reducing salpingo-oophorectomy reported suboptimal scores in sexual function, sleep, menopausal symptoms, and stress.

■■ The findings reaffirm the need for interventions to mitigate the negative quality-of-life impact of risk-reducing salpingo-oophorectomy.

Basser Research Center for BRCA at Abramson Cancer Center. “Removal of the fallopian tubes and ovaries is associated with a decreased risk of death from breast and ovarian cancer for BRCA carriers, and is one of the most important interventions we have at the current time. However, this procedure comes with a price, so it’s extremely

important that clinicians work with women to help alleviate symptoms.”

Study Details The study surveyed 637 women with BRCA1 or BRCA2 mutations who had undergone the risk-reducing surgical procedure to have both ovaries and fallopian tubes removed. Dr. Domchek and colleagues assessed participant qualityof-life through a series of questionnaires.

The median age of participants was 47 years, and the median age of risk-reducing salpingo-oophorectomy was 45. Fortythree percent of patients had a prior cancer history; of the 87% with breast cancer, 60% had undergone chemotherapy.

Most Patients Report Reduced Quality of Life

Discover PD-1: An immune checkpoint pathway1 Some tumor cells can evade the body’s immune response, which may result in disease progression2,3 • One function of the body’s immune response is to detect and destroy tumor cells through activated T cells and other mechanisms; tumor cells express multiple antigens that are not expressed in normal tissue.1—3 • However, some tumor cells may evade the body’s immune response by exploiting the PD-1 checkpoint pathway through expression of the dual PD-1 ligands PD-L1 and PD-L2.1,2,4—7 • PD-L1 and PD-L2 engage the PD-1 receptor on T cells in order to inactivate T cells, which may allow tumor cells to evade the immune response.1,2,8 Merck is committed to furthering the understanding of immunology in cancer, including the role of the PD-1 pathway.

TO DISCOVER MORE ABOUT THE PD-1 CHECKPOINT PATHWAY IN CANCER AND TO REGISTER FOR UPDATES, VISIT WWW.DISCOVERPD1PATHWAY.COM.

PD-1=programmed cell death protein 1; PD-L1=programmed cell death ligand 1; PD-L2=programmed cell death ligand 2.

References: 1. Pardoll DM. The blockade of immune checkpoints in cancer immunotherapy. Nat Rev Cancer. 2012;12(4):252–264.

2. Keir ME, Butte MJ, Freeman GJ, et al. PD-1 and its ligands in tolerance and immunity. Annu Rev Immunol. 2008;26:677–704.

3. Hanahan D, Weinberg RA. Hallmarks of cancer: the next generation. Cell. 2011;144(5):646–674. 4. Quezada SA, Peggs KS. Exploiting CTLA-4, PD-1 and PD-L1 to reactivate the host immune response against cancer. Br J Cancer. 2013;108(8):1560–1565.

5. Zou W, Chen L. Inhibitory B7-family molecules in the tumour microenvironment. Nat Rev Immunol. 2008;8(6):467–477.

6. Rosenwald A, Wright G, Leroy K, et al. Molecular diagnosis of primary mediastinal B cell lymphoma identifies a clinically favorable subgroup of diffuse large B cell lymphoma related to Hodgkin lymphoma. J Exp Med. 2003;198(6):851–862. 7. Nomi T, Sho M, Akahori T, et al. Clinical significance and therapeutic potential of the programmed death-1 ligand/programmed death-1 pathway in human pancreatic cancer. Clin Cancer Res. 2007;13(7):2151–2157. 8. Latchman Y, Wood CR, Chernova T, et al. PD-L2 is a second ligand for PD-1 and inhibits T cell activation. Nat Immunol. 2001;2(3):261–268.

Copyright © 2014 Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc. All rights reserved. ONCO-1105870-0000 02/14 merck.com

Results showed that suboptimal scores were present in the majority of patients for the majority of measures.

Specifically, 73% of patients reported sexual dysfunction, such as the absence of satisfaction and presence of pain; 61% had problems sleeping; 57% had symptoms of menopause such as hot flashes and vaginal dryness; and 56% had elevated levels of stress. Hormone replacement therapy did help mitigate symptoms, particularly in women with no cancer history who underwent oophorectomy prior to age 50.

Currently, it is recommended that BRCA1/2 mutation carriers undergo oophorectomy between ages 35 and 40 given the substantial benefits in decreasing breast and ovarian cancer risk and improving overall survival. “Our work highlights the need for novel strategies to prevent breast and ovarian cancer. Despite the efficacy of oophorectomy, given the negative impact [on quality of life], we need to continue to strive towards other options for prevention,” Dr. Domchek said. n

Disclosure: Dr. Domchek and all study authors reported no potential conflicts of interest. The study was supported by the Komen Foundation for the Cure and the Basser Research Center for BRCA.

Reference 1. Domchek SM, Li J, Digiovanni L, et al: Quality of life in BRCA1 and BRCA2 mutation carriers following risk-reducing salpingooophorectomy. Abstract 1508. Presented at the 2014 ASCO Annual Meeting, May 31, 2014.

Send Us Your NEWS Write to editor@ASCOPost.com.

All submissions will be considered for publication

The ASCO Post | JULY 25, 2014

PAGE 26

ASCO Annual Meeting Breast Cancer

Breast Cancer–Related Benefits of Weight Loss

By Alice Goodman

O

besity and physical inactivity are associated with an increased risk of developing and dying of breast cancer via several proposed mechanisms.

Two studies presented at the 2014 ASCO Annual Meeting explored the relationships among exercise, weight loss,

(n = 98), or a control group with the goal of maintaining stable weight (n = 48).

The study period was 16 weeks.

The diet intervention entailed caloric reduction of 500 kcal per day. The exercise intervention consisted of 4 hours of vigorous resistance and endurance

Compared with diet-induced weight loss, equivalent weight loss by exercise had, in addition to positive effects on breast cancer–related sex hormones, more beneficial effects on body composition, including more body fat loss and more lean mass preservation as well as better physical fitness.

—Anne May, PhD

similar demographic characteristics, with a mean age of 60 years and mean body mass index of 29 kg/m2. Both interventions met the primary endpoint for weight loss compared to controls (P < .001), while weight remained stable in the control arm.

Both interventions also achieved significant reductions in serum estradiol, free estradiol, and serum testosterone, and an increase in sex hormone–binding globulin compared with controls (P < .025).

But when findings were adjusted for the percentage change in body fat, the effects were attenuated or eliminated.

Patients who exercised showed significantly greater changes compared with the diet-alone group for body weight, body fat, lean mass preservation, and physical fitness as measured by peak VO2 levels (all P < .001).

Senior author and principal investigator of the LEAN study, Melinda Irwin, PhD, MPH, Associate Professor of Epidemiology at Yale School of Public Health, New Haven, Connecticut, observed that motivation to lose weight appears to be an important factor for success. “All the women who entered the study were motivated, and women in the intervention group and those in the usual-care group both lost weight,” she said.

Melinda Irwin, PhD, MPH

LEAN Study and breast cancer risk. One study was conducted in healthy postmenopausal women (SHAPE2),1 and the other, in breast cancer survivors (LEAN).2

SHAPE-2 Study SHAPE-2 was designed to compare the effects of a calorie-restricted diet vs exercise on parameters beyond weight loss. A current review of 19 cohort and 29 case-control studies showed strong evidence for an inverse association between physical activity and postmenopausal breast cancer, with risk reductions ranging from 20% to 40%.

Both exercise and diet achieved similar weight loss, and breast cancer-related sex hormones were positively affected, but exercise appears to exert more beneficial effects on body composition and fitness.

“Compared with diet-induced weight loss, equivalent weight loss by exercise had more beneficial effects on body composition, including more body fat loss and more lean mass preservation as well as better physical fitness,” said lead investigator Anne May, PhD, Assistant Professor at the Julius Center for Health Sciences and Primary Care, University Medical Center, Utrecht, the Netherlands.

SHAPE-2 enrolled 243 inactive, overweight, nonsmoking postmenopausal women from the Netherlands.

After a 4- to 6-week run-in period during which participants followed a standardized diet, participants were randomly assigned to a diet group (n = 97), an exercise-plus–small caloric restriction group

exercise per week plus caloric intake reduced by 250 kcal per day. The goal of both interventions was a weight loss of 5 to 6 kg. Control participants were instructed to maintain their body weight.

The primary outcome measure was change in serum levels of sex hormones at 16 weeks. Both intervention groups had

The Lifestyle, Exercise, and Nutrition (LEAN) study explored the effects of weight loss on inflammatory and metabolic biomarkers in breast cancer survivors. Interestingly, LEAN showed that patients assigned to counseling as well as those just given a brochure lost some weight, although weight loss was more substantial in the counseling groups.

LEAN enrolled 100 overweight or obese breast cancer patients; 33 were assigned to usual care and were presented with American Institute for Cancer Research nutrition and activity brochures as well as one 30-minute counseling session at 6 months. The other 67 women were assigned to 11 30-minute weight loss counseling sessions over 6 months (33 women

EXPERT POINT OF VIEW

W

endy Demark-Wahnefried, PhD, RD, Professor and Webb Endowed Chair of Nutrition Sciences at the University of Alabama at Birmingham, formal discussant for

tion are all necessary. But it is easy and simplistic to say exercise will make you lose weight. It takes a lot of exercise to burn off a few calories. For example, it takes 6 minutes of chopping wood

These results should encourage you to address weight loss with breast cancer survivors.

—Wendy Demark-Wahnefried, PhD, RD

the SHAPE-2 and LEAN trials at the ASCO Annual Meeting, emphasized the importance of weight loss, but noted that it can be challenging for patients.

“There is a consensus that women with increased body mass index are at increased risk. Guidelines suggest that diet, exercise, and behavior modifica-

to work off six jelly beans. Achieving exercise goals is somewhat easier than cutting calories, but eating less is key to weight loss.”

Implications for Survivors Dr. Demark-Wahnefried highlighted the importance of addressing

weight loss with breast cancer survivors, as reflected by results of the LEAN study.

“I want to pay attention to results in the control group who lost 2% of body weight in this study. We would expect people with no intervention to gain weight. This is a victory for a pamphlet,” she said.

“It is interesting that in-person and telephone counseling appear to have equivocal effects on weight loss.

These results should encourage you to address weight loss with breast cancer survivors. Tell them, ‘I’m counting on you to improve your well-being. Here is your body mass index and it could affect your outcome. You should exercise and think about what you eat,’” she said.

One of ASCO’s current public health initiatives is targeting weight loss, she continued, and a tool kit for this purpose has been developed. n Disclosure: Dr. Demark-Wahnefried reported no potential conflicts of interest.

ASCOPost.com | JULY 25, 2014

PAGE 27

ASCO Annual Meeting in person and 33 women by telephone).

The goal of the intervention was 10% weight loss, 150 minutes of physical activity per week, and 10,000 steps per day.

Fifty-two women (78%) completed the interventions, compared with 29 women (88%) in the usual-care group.

Mean age was 59 years, and all participants were overweight, physically inactive, highly educated, postmenopausal, and had a mean time since diagnosis of 2.8 years. Most women were non-Hispanic white, had stage I to II breast cancer, and were taking hormone therapy.

Weight loss was achieved in both groups. Women in the intervention group (whether counseled by phone or in person) lost significantly more

weight than those in the usual-care group (6% weight loss vs 2% weight loss, respectively).

Because similar results were seen for both in-person and telephone counseling, both groups were pooled for analysis of effects of weight loss on biomarkers.

The diet groups achieved a 30% decrease in C-reactive protein (a marker of inflammation), compared with 1% in the usual-care group. Women in the dietary intervention groups also had greater decreases in insulin, glucose, leptin, tumor necrosis factor–alpha, and increases in adiponectin, interleukin-6, and insulinlike growth factor–1 compared with usual care. Women who lost more than 5% of body weight had more beneficial changes in these factors than women

Weight Loss and Cancer Risk ■■ Weight loss reduces breast cancer risk.

■■ Weight loss due to exercise plus calorie restriction appears to exert more beneficial effects than weight loss due to dietary restriction alone.

■■ In-person and telephone counseling about weight loss are equally effective.

■■ Even giving patients a brochure about weight loss appears to have a positive effect.

who lost less than 5% of body weight. n Disclosure: Drs. May and Irwin reported no potential conflicts of interest.

References 1. May AM, van Gemert W, Peeters P, et al: Effects of equivalent weight loss, with or without exercise, on sex hormones related to breast cancer risk in postmenopausal wom-

en: The SHAPE-2 trial. ASCO Annual Meeting. Abstract 1504. Presented May 31, 2014.

2. Loftfield E, Harrigan M, Li F, et al: Effect of weight loss intervention on inflammatory and metabolic markers in breast cancer survivors: The lifestyle, exercise, and nutrition (LEAN) study. ASCO Annual Meeting. Abstract 1505. Presented May 31, 2014.

Don’t Miss These Important Reports in This Issue of The ASCO Post Takashi Onda, MD, PhD, and Dennis S. Chi, MD, on neoadjuvant therapy for advanced ovarian cancer see page 5 Paul G. Richardson, MD, A. Keith Stewart, MBChB, and Philip McCarthy, MD, on multiple myeloma studies presented at ASCO see pages 3 and 4

Carmen J. Allegra, MD, and Tae Won Kim, MD, on oxaliplatin in rectal cancer see page 14

Axel Hauschild, MD, on immune responses in melanoma see page 9

Visit The ASCO Post online at ASCOPost.com

Supplement • Volume 5, Issue 12 • July 15, 2014

Interventional Oncology and Its Role in the Management of Unresectable Hepatocellular Carcinoma Reports From the Society of Interventional Radiology (SIR) 2014 Annual Scientific Meeting, San Diego

Look for this important supplement to The ASCO Post, mailed with this issue:

Interventional Oncology and Its Role in the Management of Unresectable Hepatocellular Carcinoma Reports From the Society of Interventional Radiology (SIR) 2014 Annual Scientific Meeting, San Diego

The illustrations are copyrighted to the Society of Interventional Radiology.

Plus a Discussion on Interventional Oncology:

The Fourth Pillar of Oncology Editor-in-Chief, James O. Armitage, MD

Making a world of difference in cancer care

|

ASCOPost.com

A Harborside Press® Publication

For more information, visit ASCOPost.com

Continue treatment.* 1-4 Extend survival.

For patients with advanced nonsquamous† NSCLC Median Overall Survival: 13.9 months with ALIMTA® (pemetrexed for injection) 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, 50% of patients with advanced NSCLC off active treatment will experience rapid disease progression (<3 months)2,5-8 You may have patients* with advanced nonsquamous† NSCLC who are eligible for continuation maintenance with single-agent ALIMTA® (pemetrexed for injection) 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

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

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

NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for NSCLC

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; 22% reduction in the risk of death‡

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

‡ ALIMTA/cisplatin followed by continuation maintenance with ALIMTA + BSC met its primary endpoint of investigator-assessed PFS as compared to ALIMTA/cisplatin followed by placebo + BSC. § 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.3.2014. © National Comprehensive Cancer Network, Inc 2014. All rights reserved. Accessed April 3, 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® (pemetrexed for injection) 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.

PM90249

04/2014 PRINTED IN USA © Lilly USA, LLC 2014. ALL RIGHTS RESERVED. ALIMTA® is a registered trademark of Eli Lilly and Company.

ASCOPost.com | JULY 25, 2014

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FDA Update

FDA Grants Breakthrough Therapy Designation to Investigational Chimeric Antigen Receptor Therapy for Relapsed/Refractory ALL

T

he U.S. Food and Drug Administration (FDA) has granted Breakthrough Therapy status to CTL019, an investigational chimeric antigen receptor (CAR) therapy for the treatment of pe-

diatric and adult patients with relapsed/ refractory acute lymphoblastic leukemia (ALL). The Breakthrough Therapy filing was submitted by the University of Pennsylvania’s Perelman School of Medicine

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)

019517_elalns_PM90249_oncTIMES_ja_fa3.indd 4

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which has an exclusive global agreement with Novartis to research, develop, and commercialize personalized CAR T-cell therapies for the treatment of cancers.

Breakthrough Therapy designation

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)

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is intended to expedite the development and review of new medicines that treat serious or life-threatening conditions if the therapy has demonstrated continued on page 32

The ASCO Post | JULY 25, 2014

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FDA Update Breakthrough Therapy continued from page 31

substantial improvement over an available therapy on at least one clinically significant endpoint.

About CTL019 CTL019 uses CAR technology to reprogram a patient’s own T cells to tar-

get CD19-expressing cancer cells. After they have been reprogrammed, the T cells (now called CTL019) are reintroduced into the patient’s blood where they proliferate and bind to the targeted CD19-positive cancer cells and destroy them. Because CTL019 is an investigational therapy, the safety and efficacy profile has not yet been established.

“This is a major milestone as we are now one step closer in helping address the high unmet needs of this patient population,” said Carl H. June, MD, Richard W. Vague Professor in Immunotherapy in the Department of Pathology and Laboratory Medicine in the Perelman School of Medicine and Director of Translational Research in the

Abramson Cancer Center of the University of Pennsylvania. “We are excited about the strength of the positive early data seen in pediatric and adult patients with relapsed/refractory acute lymphoblastic leukemia and look forward to building upon these findings as we continue advancing the CTL019 clinical program in phase II trials.” n

3 count is ≥100,000 cells/mm , and [see creatinine clearance is ≥45 mL/min [seetoDosage Incidence 1% to 5% platelet count is ≥100,000 cells/mm3platelet , and creatinine clearance is ≥45 mL/min Dosage Incidence 1% 5% Sp Bodyinfection, as a Whole — febrile neutropenia, infection, pyrexia and Administration (2.4)].

Body as a Whole — febrile neutropenia, pyrexia and Administration (2.4)]. lacrimation General Disorders — dehydration 5.6 Pregnancy Category D General Disorders — dehydration Incid 5.6 Pregnancy Category D Metabolism and Nutrition Based on mechanism of action, ALIMTA can cause fetal harm when administered Metabolism and Nutrition — increased AST, increased ALT — increased AST, increased ALT Ca Based on its mechanism of action, ALIMTA canitscause fetal harm when administered Renal — creatinine clearance decrease, renal failure to aadministered pregnant woman.

Pemetrexedto administered during Renalto—mice creatinine clearance decrease, renal failure D to a pregnant woman. Pemetrexed intraperitoneally mice during intraperitoneally Special Senses — conjunctivitis organogenesis was embryotoxic, and 1/833rd teratogenic in mice atSpecial greaterSenses than 1/833rd — conjunctivitis G organogenesis was embryotoxic, fetotoxic and teratogenic in mice at fetotoxic greater than Incidence Less than 1% recommended humanpregnancy, dose. If ALIMTA used during pregnancy, or ifLess the than patient Incidence 1% N the recommended human dose. If the ALIMTA is used during or if theis patient Cardiovascular — arrhythmia while taking this drug, thepotential patient should be apprised of the potential Cardiovascular — arrhythmia Re becomes pregnant while taking thisbecomes drug, thepregnant patient should be apprised of the General Disorders — chest pain hazard topotential the fetus.

Women of childbearing to avoid becoming General Disorders — chest pain Cont hazard to the fetus. Women of childbearing should be advised to avoidpotential becomingshould be advised Metabolism and Nutrition — increased GGT Women should be advised to usetoeffective measures toand prevent Nutrition — increased GGT Indu pregnant. Women should be advisedpregnant. to use effective contraceptive measures prevent contraceptive Metabolism pregnancy during treatment with ALIMTA [see Use in Specific Populations (8.1)].— motor neuropathy Neurology — motor neuropathy Neurology Tabl pregnancy during treatment with ALIMTA [see Use in Specific Populations (8.1)].

Non-Small Cell Lung Cancer (NSCLC) – Maintenance Non-Small Cell Lung Cancer (NSCLC) – Maintenance of the 500 6 ADVERSE REACTIONS ALIMTA Maintenance Following Non-ALIMTA Containing, Platinum-Based 6 ADVERSE REACTIONS ALIMTA Maintenance Following Non-ALIMTA Containing, Platinum-Based Induction maintenanc Therapy Therapy 6.1 Clinical Trials Experience 6.1 Clinical Trials Experience The Table 5 provides the frequency and severity of adverse reactions reported Because clinical trials are conducted under widely varying conditions, adverse Table 5 provides the frequency and severity of adverse reactions reported in >5% of Because clinical trials are conducted under widely varying conditions, adverse doses of m the 438 patients with NSCLC who received ALIMTA maintenance and the 218 pa reactions rates cannot be directly compared to rates in other clinical trials and may not the 438 patients with NSCLC who received ALIMTA maintenance and the 218 patients with reactions rates cannot be directly compared to rates in other clinical trials and may not reductions NSCLC who received placebo the rates observed in clinical practice.

NSCLC who received placebo following a platinum-based inductionfollowing therapy.a platinum-based induction therapy. reflect the rates observed in clinical reflect practice. the of placebo All patients following received study therapy immediately following 4 cycles platin In clinical trials, the most common adverse reactions (incidence ≥20%) during All patients received study therapy immediately 4 cycles of platinum-based In clinical trials, the most common adverse reactions (incidence ≥20%) during arm and 16 treatment for locally advanced or metastatic NSCLC. Patients in both study arms therapy with ALIMTA as a single-agent were fatigue, nausea, and anorexia.

Additional treatment for locally advanced or metastatic NSCLC. Patients in both study arms were fully therapy with ALIMTA as a single-agent were fatigue, nausea, and anorexia. Additional acid and vit supplemented with folic acid and vitamin B .

12 common adverse reactions (incidence ≥20%) during therapy with ALIMTA when used in supplemented with folic acid and vitamin B12. common adverse reactions (incidence ≥20%) during therapy with ALIMTA when used in Table with cisplatin includedanemia, vomiting,stomatitis/ neutropenia, leukopenia, anemia, stomatitis/ TableReceiving 5: AdverseALIMTA Reactions in Patients Plac6 combination with cisplatin included combination vomiting, neutropenia, leukopenia, Table 5: Adverse Reactions in Patients versus PlaceboReceiving ALIMTA versus a ALIMTA in pharyngitis, thrombocytopenia, and constipation. in NSCLC Following Platinum-Based Induction Therapy a pharyngitis, thrombocytopenia, and constipation.

NSCLC Following Platinum-Based Induction Therapy Lung Cancerwith (NSCLC) – ALIMTA in Combination with in Cisplatin Non-Small Cell Lung Cancer (NSCLC)Non-Small – ALIMTA Cell in Combination Cisplatin ALIMTA Placebo ALIMTA Placebo Table 4 provides the frequency and severity of adverse reactions that have been Adverse Table 4 provides the frequency and severity of adverse reactions that have been (N=438) (N=218) R Reactionb b (N=438) (N=218) Reaction reported in >5% of 839 patients with NSCLC who were randomized to study and received System reported in >5% of 839 patients with NSCLC who were randomized to study and received All GradesGradeGrade ALIMTA cisplatin patients with NSCLC 3-4 3-4 All Grades Gr ALIMTA plus cisplatin and 830 patients withplus NSCLC who and were830 randomized to study andwho were randomized to study andAll Grades Grade 3-4 All Grades Toxicity (%) Toxicity (%) Toxicity (%) Tox received gemcitabine plus cisplatin.

All patients received study therapy as initial treatment Toxicity (%) Toxicity (%) Toxicity (%) Toxicity (%) received gemcitabine plus cisplatin. All patients received study therapy as initial treatment All Advers for locally advanced or metastatic NSCLC and patients in both treatment groups were fully All Adverse Reactions 66 16 37 for locally advanced or metastatic NSCLC and patients in both treatment groups were fully All Adverse Reactions 66 16 37 4 supplemented with folic acid and vitamin B12.

Laborator supplemented with folic acid and vitamin B12.

Laboratory Laboratory Hematol Table 4: Adverse Reactions in Fully Supplemented Hematologic Table 4: Adverse Reactions in Fully Supplemented Hematologic a Anemia Patients Receiving 6 3 15 Anemia a ALIMTA plus Cisplatin in NSCLC Patients Receiving ALIMTA plus Cisplatin in NSCLC 1 6 3 15 Anemia 0 Neutrop 3 6 Neutropenia3 ALIMTA/cisplatin Gemcitabine/cisplatin 0 0 6 Neutropenia ALIMTA/cisplatin b Gemcitabine/cisplatin 1 Clinical (N=839) (N=830) Reaction 1 2 1 6 6 Leukopenia2 Leukopenia (N=839) (N=830) Reactionb Constitu Hepatic All GradesGradeGrade All Grades Grade 3-4 All Grades Grade 3-4 All Grades 3-4 3-4 Hepatic Increased ALT 10 0 4 Symptom Toxicity (%) Toxicity (%) Toxicity (%) Toxicity (%) Increased ALT 10 0 4 0 Toxicity (%) Toxicity (%) Toxicity (%) Toxicity (%) 4 Fatigue Increased AST 53 8 Increased AST 0 4 8 0 0 91 Gastroin All Adverse Reactions 90All Adverse Reactions 37 91 90 53 37 Clinical Clinical Laboratory Nausea Constitutional Laboratory Constitutional Hematologic Vomitin Symptoms Hematologic Symptoms 10 46 Mucosi Fatigue 25 5 11 10 6 46 33 33 Anemia 6 Anemia Fatigue 25 5 11 1 27 38 General 27 15 38 29 15 29 Neutropenia Neutropenia Gastrointestinal 8 21 Gastrointestinal 8 5 21 18 18 Leukopenia5 Leukopenia 6 Edema Nausea 1 13 27 4 10 Thrombocytopenia 1 1 6 19 19 Nausea 13 27 4 10 Thrombocytopenia 5 a Adverse re 2 19 Anorexia 0 5 2 19 Anorexia Renal 1 adverse re 0 9 Vomiting 0 Renal 0 1 9 Vomiting 7 1 2 to those re Creatinine elevation 10 Creatinine elevation 1 7 10 1 1 0 1 2 7 1 7 Mucositis/stomatitis Mucositis/stomatitis 3 b NCI CTCA 1 5 Diarrhea 1 Clinical 0 3 5 Diarrhea Clinical Constitutional Infection 5 2 2 Adm Constitutional Infection 5 2 2 0 Symptoms erythropoie Symptoms Neurology 45 5 Neurology Fatigue 43 Fatigue 7 45 43 5 7 4 factors (6% Neuropathy-sensory 9 Neuropathy-sensory 1 4 9 0 1 The Gastrointestinal Gastrointestinal Dermatology/Skin 4 53 frequently i Dermatology/Skin 4 7 53 56 56 Nausea 7 Nausea Rash/Desquamation 10 0 3 6 36 Incid Rash/Desquamation 10 0 3 0 6 6 36 40 40 Vomiting 6 Vomiting a 1 24 thisinclusion table a cut of 5% where was used Bl a 1 2 24 27 27 Anorexia 2 Anorexia For the purpose of this table a cut offFor of the 5% purpose was usedoffor of alloffevents the for inclusion of all events 0 20 reporter considered a possible relationship to ALIMTA. G 0 1 20 21 21 Constipation1 Constipation reporter to ALIMTA. b 12 considered a 0possible relationship Refer toeach NCI Grade CTCAEofCriteria version 3.0 for each Grade of toxicity.

Incid b 0 1 12 14 1 14 Stomatitis/Pharyngitis Stomatitis/Pharyngitis Refer to NCI CTCAE Criteria version 3.0 for toxicity.

2 13 No clinically relevant differences in Grade 3/4 adverse reactions were seenCa 2 1 13 12 12 Diarrhea 1 Diarrhea No 3/4 adverse reactions were seen in patients 0 differences in Grade 6 clinically relevant on age,except gender,a ethnic or histology 0 0 6 5 0 5 Dyspepsia/Heartburn Dyspepsia/Heartburn based on age, gender, ethnic origin,based or histology higher origin, incidence of Gradeexcept 3/4 a higher incidence ofG fatigue for Caucasian patients compared to non-Caucasian patients (6.5% versuG Neurology fatigue for Caucasian patients compared to non-Caucasian patients (6.5% versus 0.6%).

Neurology Safety was assessed by exposure for patients who received at least Non Neuropathy-sensory 9 0 12 1 Safety was assessed by exposure for patients who received at least one dose of Neuropathy-sensory 9 0 12 1 c c adverse reactions Re 8 0 ALIMTA9 (N=438). The0incidence ofALIMTA adverse(N=438). reactionsThewasincidence evaluatedof for patients who was evaluated for pat Taste disturbance 8 Taste disturbance 0c 9 0c received to ≤6patients cycles ofwho ALIMTA, and >6 compared patients who received >6 cyclesVa received ≤6 cycles of ALIMTA, and compared received cycles oftoALIMTA. Dermatology/Skin Increases adverse reactions (allexposure; grades) were observed Dermatology/Skin No hr c Increases (all grades) wereinobserved with longer however no with longer exposure; 21 in adverse reactions 1c clinically relevant differences Grade 3/4 adverse reactions were seen.

Alopecia 12 Alopecia 0c 21 12 1c 0 increased in clinically8 relevant differences in Grade 3/4 adverse reactions wereinseen.

Rash/Desquamation 7 0 1 the higher incidence anemia Rash/Desquamation 7 0 8 1 Addi Consistent with the higher incidenceConsistent of anemiawith (all grades) on the ALIMTAofarm, use (all grades) on the ALIMTA a the purpose thisinclusion table a cut of 5%where was used of all events where the of transfusions (mainly RBC) and erythropoiesis stimulating agents (ESAs;Seps ery a For the purpose of this table a cut offFor of 5% was usedoffor of alloffevents the for inclusion of transfusions (mainly RBC) and erythropoiesis stimulating agents (ESAs; erythropoietin reportertoconsidered a possible relationship to ALIMTA. and darbepoetin) were to higher in the ALIMTA arm compared to the placebo armEsop (tr reporter considered a possible relationship ALIMTA. and darbepoetin) were higher in the ALIMTA arm compared the placebo arm (transfusions b Refer to NCI CTC Criteria version 2.0 for each Grade of toxicity.

9.5% versus 3.2%, ESAs 5.9% versus 1.8%). b Refer to NCI CTC Criteria version 2.0 9.5% versus 3.2%, ESAs 5.9% versus 1.8%).

6.2 Post c for each Grade of toxicity. to NCI CTC Criteria 2.0, be thisreported adverse event term should only be reported The following additional adverse reactions were observed in patients with c According to NCI CTC Criteria versionAccording 2.0, this adverse event term version should only The following additional adverse reactions were observed in patients with non-small The as Grade 1 or 2. cell lung cancer who received ALIMTA. as Grade 1 or 2. cell lung cancer who received ALIMTA. ALIMTA. Be No clinically relevant differences in adverse reactions were seen in patients based Incidence 1% to 5% No clinically relevant differences in adverse reactions were seen in patients based Incidence 1% to 5% size, it is n on histology.

Dermatology/Skin — alopecia, pruritus/itching on histology.

Dermatology/Skin — alopecia, pruritus/itching relationship Gastrointestinal — constipation In addition to the lower incidence of hematologic toxicity on the ALIMTA and cisplatin Gastrointestinal — constipation In addition to the lower incidence of hematologic toxicity on the ALIMTA and cisplatin General Disorders — edema, fever (in the absence of neutropenia)Thes arm, useand of hematopoietic transfusions (RBC and factors platelet)was andlower hematopoietic growthGeneral factorsDisorders was lower—inedema, fever (in the absence of neutropenia) arm, use of transfusions (RBC and platelet) growth in combinatio Hematologic — thrombocytopenia the ALIMTA and cisplatin arm compared to the gemcitabine and cisplatin arm.

Hematologic — thrombocytopenia the ALIMTA and cisplatin arm compared to the gemcitabine and cisplatin arm.

Bloo Renal — decreased creatinine clearance, increased creatinine, The following additional adverse reactions were observed in patients with non-small Renal — decreased creatinine clearance, increased creatinine, decreased The following additional adverse reactions were observed in patients with non-small Gast glomerular filtration rate cell lung cancer randomly assigned to receive ALIMTA plus cisplatin. glomerular filtration rate cell lung cancer randomly assigned to receive ALIMTA plus cisplatin.

Gene ALIMTA® (pemetrexed for injection) PV 8927 AMP ALIMTA® (pemetrexed for injection) PV 8 ALIMTA® (pemetrexed for injection) PV 8927 AMP ALIMTA® (pemetrexed for injection) PV 8927 AMP ALIMTA®

ASCOPost.com | JULY 25, 2014

PAGE 33

FDA Update

Orphan Drug Designation Granted for New Agent in Hepatocellular Carcinoma

C

ASI Pharmaceuticals, Inc, announced that its investigational agent ENMD-2076 has received orphan drug designation from the U.S. Food & Drug Administration (FDA) for the treatment of hepatocellular carcinoma. ENMD-2076 is an orally active

Aurora A/angiogenic kinase inhibitor with a unique kinase selectivity profile and multiple mechanisms of action.

The drug has been shown to inhibit a distinct profile of angiogenic tyrosine kinase targets in addition to the Aurora A kinase, which is a key regulator of mi-

tosis and is often overexpressed in human cancers. ENMD-2076 also targets the ­VEGFR, Flt-3, and FGFR3 kinases, which have been shown to play important roles in the pathology of several cancers.

ENMD-2076 previously received orphan drug designation from the FDA

poisoning, procedural — conjunctivitis), ocular surfaceincreased disease (including conjunctivitis), increased Injury, poisoning, and procedural Injury, complications — and Radiation recall complications has been — Radiation recall has been pecial Senses — ocular surface Special disease Senses (including reported in patients who have previously received radiotherapy. lacrimation reported in patients who have previously received radiotherapy. n Respiratory — interstitial pneumonitis Incidence Less than 1% Respiratory — interstitial pneumonitis dence Less than 1% — Bullous conditions, syndrome and toxic epidermal Cardiovascular — supraventricular arrhythmia Skin — Bullous conditions, including Skin Stevens-Johnson syndromeincluding and toxicStevens-Johnson epidermal ardiovascular — supraventricular arrhythmia necrolysis. Some cases were fatal.

Dermatology/Skin — erythema multiforme necrolysis.

Some cases were fatal.

Dermatology/Skin — erythema multiforme General Disorders — febrile neutropenia, allergic reaction/hypersensitivity 7 DRUG INTERACTIONS General Disorders — febrile neutropenia, allergic reaction/hypersensitivity 7 DRUG INTERACTIONS Neurology — motor neuropathy Neurology — motor neuropathy 7.1 Non-Steroidal Anti-Inflammatory Drugs (NSAIDs) Renal — renal failure 7.1 Non-Steroidal Anti-Inflammatory Drugs (NSAIDs) enal — renal failure Although ibuprofen (400 mg the fourclearance times a day) Although ibuprofen (400 mg four times a day) can decrease of can decrease the clearance of Continuation of ALIMTA as Maintenance Following ALIMTA Plus Platinum tinuation of ALIMTA as Maintenance Following ALIMTA Plus Platinum be administered withrenal ALIMTA in patients with normal renal function pemetrexed, it can be administeredpemetrexed, with ALIMTAit incanpatients with normal function Induction Therapy uction Therapy (creatinine clearance ≥80 mL/min). No dose adjustment of ALIMTA is needed with concomitant (creatinine clearance ≥80 mL/min). thereactions frequencyreported and severity of adverse reactions reported in >5% No dose adjustment of ALIMTA is needed with concomitant le 6 provides the frequency and Table 6 severityprovides of adverse in >5% patients with normal renal(12.3)]. function [see Clinical Pharmacology (12.3)].

NSAIDs in patients withof normal renal NSAIDs functionin[see Clinical Pharmacology of the 500 patients with non-squamous NSCLC who received at least one cycle ALIMTA with non-squamous NSCLC who received at least one cycle of ALIMTA Caution should be used when administering dpatients Induction Caution should be used when administering NSAIDs concurrently with ALIMTA NSAIDs concurrently with ALIMTA maintenance (n=333) or placebo (n=167) on the continuation maintenance trial. to patients with mild(creatinine to moderate renal insufficiency ce (n=333) or placebo (n=167) on the continuation maintenance trial. to patients with mild to moderate renal insufficiency clearance from 45 to (creatinine clearance from 45 to The median of maintenance cycles administered to patients receiving one or more 79 mL/min). cycles administered to patients receiving one or more 79 mL/min). d median in >5% of of maintenance doses of maintenance therapy was 4 on both the pemetrexed and placebo arms.

Dose NSAIDs(e.g., with diclofenac, short elimination half-livesshould (e.g., diclofenac, indomethacin) should maintenance 4 on both the pemetrexed and placebo arms. Dose atients with therapy wasreductions NSAIDs arm withand short half-lives indomethacin) occurredarm in 3.3% of patients in the ALIMTA 0.6%elimination in be avoided for of, a period of 2 days before, the day of, and 2 days following administration for adverse events occurred in 3.3%for of adverse patients events in the ALIMTA and 0.6% in be avoided for a period of 2 days before, the day and 2 days following administration the placebo Doseindelays forpatients adverseinevents occurred in 22% of patients in the ALIMTA of ALIMTA. o arm. Dose delays for adverse eventsarm. occurred 22% of the ALIMTA num-based of ALIMTA. arm and 16% study in thearms placebo arm.

Patients in both study with folic In theinteraction absence ofbetween data regarding interaction 6% in the placebo arm.

Patients in both were supplemented with folic arms wereInsupplemented s were fully the absence of data regarding potential ALIMTA potential and NSAIDs with between ALIMTA and NSAIDs with acid and vitamin B .

12 longer half-lives (e.g., meloxicam, nabumetone), patients taking these NSAIDs should interrupt tamin B12. longer half-lives (e.g., meloxicam, nabumetone), patients taking these NSAIDs should interrupt a b at 2 days least 5 days before, the day of, and 2 days Table of for Patients b 6: Selected Adverse Reactions Occurring in ≥5% dosing at leastReceiving 5 days before, thedosing day of,forand following ALIMTA administration.

If following ALIMTA administration. If 6: Selecteda Adverse Reactions Occurring in ≥5% of Patients Receiving cebo administration of NSAIDs is necessary, should be monitored closely for ALIMTA inALIMTA Nonsquamous NSCLCInduction FollowingTherapy ALIMTA Plusconcomitant Cisplatin Induction Therapy administration of NSAIDsconcomitant is necessary, patients should be monitored closelypatients for n Nonsquamous NSCLC Following Plus Cisplatin especially myelosuppression, toxicity, especially myelosuppression,toxicity, renal, and gastrointestinal toxicity. renal, and gastrointestinal toxicity.

ALIMTA Placebo ALIMTA Placebo 7.2 Nephrotoxic Drugs (N=333) (N=167) Drugs Adverse Reaction Organ 7.2 Nephrotoxic (N=333) (N=167) Reaction Organ ALIMTArenally is primarily eliminated unchanged renally as a result of glomerular filtration a a a is primarily eliminated a System and Term ALIMTA unchanged as a result of glomerular filtration All Grades Grade 3-4 All Grades Grades 3-4 m and All Gradesa Grade 3-4a All Gradesa Grades 3-4a and tubular secretion.

Concomitant of nephrotoxic drugs could result in rade 3-4Term and tubular(%)secretion.

Concomitant administration of nephrotoxic drugsadministration could result in Toxicity (%) Toxicity (%) Toxicity Toxicity (%) Toxicity (%) Toxicity (%) Toxicity (%) Toxicity (%) delayed clearance of ALIMTA. Concomitant administration of substances that are also xicity (%) delayed34clearance of 4.8 ALIMTA. Concomitant administration of substances that are also secretedresult (e.g.,inprobenecid) could potentially se4Reactions 53All Adverse Reactions 17 34 53 4.8 17 tubularly secreted (e.g., probenecid) tubularly could potentially delayed clearance of ALIMTA.result in delayed clearance of ALIMTA. Laboratory 8 USE IN SPECIFIC POPULATIONS ry 8 USE IN SPECIFIC POPULATIONS Hematologic logic 8.1 Pregnancy 8.1 Pregnancy 4.8 0.6 a 1 15 Anemia 4.8 4.8 15 0.6 4.8 Teratogenic Effects - Pregnancy Category D [see Warnings and Precautions (5.6)].

Teratogenic Effects 0.6 0 - Pregnancy Category D [see Warnings and Precautions (5.6)]. penia 9 Neutropenia 3.9 0.6 9 0 3.9 Based on mechanism of action, ALIMTA can cause fetal harm when administered 0 Based on its mechanism of action, ALIMTA canitscause fetal harm when administered Clinical to adequate a pregnantandwoman.

There arestudies no adequate and inwell controlled studies of ALIMTA in 1 to a pregnant woman.

There are no well controlled of ALIMTA Constitutional pregnant women.

Pemetrexed was embryotoxic, fetotoxic, and teratogenic in mice. In utional pregnant women.

Pemetrexed was embryotoxic, fetotoxic, and teratogenic in mice.

In Symptoms mice, repeated intraperitoneal doses oforganogenesis pemetrexed when given during organogenesis ms0 mice, repeated intraperitoneal doses of pemetrexed when given during 11 0.6 caused fetal malformations ossification of talus and skull bone; about 1/833rd e 0 18 Fatigue 4.5 11 18 0.6 4.5 caused fetal malformations (incomplete ossification of talus and(incomplete skull bone; about 1/833rd the dose recommended intravenous human dose on a mg/m2 basis), and cleft palate (1/33rd 2 Gastrointestinal the recommended intravenous human on a mg/m basis), and cleft palate (1/33rd ntestinal the recommended intravenous dose onwas a mg/m2 basis). Embryotoxicity was 2 0 2.4 the recommended intravenous human dose on a mg/m basis). human Embryotoxicity 0 0.3 2.4 12 12 Nausea 0.3 a characterized by increased embryo-fetal deaths and 0 1.8 0 6 Vomiting characterized by increased embryo-fetal deaths and reduced litter sizes. If ALIMTA is usedreduced litter sizes. If ALIMTA is used 0 1.8 0 6 ng during pregnancy, if thetaking patient 0.3 5 Mucositis/stomatitis during2.4 pregnancy, or if0the patient becomes pregnant orwhile thisbecomes drug, thepregnant patient while taking this drug, the patient 0 2.4 0.3 5 itis/stomatitis 1 the potential hazard topotential the fetus. Women of childbearing potential should be apprised of the potential should hazardbeto apprised the fetus.ofWomen of childbearing General Disorders should be advised to use contraceptive measures Disorders should3.6 be advised to use measures to effective prevent pregnancy during the to prevent pregnancy during the 0 effective contraceptive treatment with ALIMTA. 5 Edema 0 3.6 5 0 0 1 treatment with ALIMTA. a reactions of anyfrequently severity (all(≥5%) grades) occurring (≥5%) or Grade 3-4 0 of any severity (all Adverse 8.3 Nursing Mothers eactions grades) occurring more or Grade 3-4 more8.3frequently Nursing Mothers adverse reactions occurring more frequently (≥2%) in ALIMTA-treated patients compared 0 It oris itsnotmetabolites known whether ALIMTA inor human its metabolites are excreted in human eactions occurring more frequently (≥2%) in ALIMTA-treated patients compared It is not known whether ALIMTA are excreted to those receiving placebo 0 milk. Because many drugs are excreted inpotential human for milk, and because of the potential for eceiving placebo b milk. Because many drugs are excreted in human milk, and because of the NCI CTCAE Criteria version 3.0 0 serious adverse reactions in nursing infants from ALIMTA, a decision should be made to AE Criteria version 3.0 seriousversus adverse in nursing infants from ALIMTA, a decision should be made to Administration RBC (13% and platelet (1.5% 0.6%)reactions transfusions, discontinue nursing or discontinue the drug,oftaking into account the importance of the drug 0 ministration of RBC (13% versus 4.8%) and plateletof(1.5% versusversus 0.6%)4.8%) transfusions, discontinue nursing or discontinue the drug, taking into account the importance the drug erythropoiesis stimulating agents (12% 7%), and granulocyte colony stimulating for the mother. esis stimulating agents (12% versus 7%), and granulocyte colonyversus stimulating for the mother. factors (6% arm versus 0) weretohigher in the ALIMTA % versus compared the placebo arm. arm compared to the placebo arm.

8.4 Pediatric Use 0 0) were higher in the ALIMTA 8.4 Pediatric Use The following additional Grade 3 or 4 adverse reactions were observed more following additional Grade 3 or 4 adverse reactions were observed more Efficacy in pediatric patients not been demonstrated. ALIMTA was Efficacy of ALIMTA in pediatric patients hasofnotALIMTA been demonstrated.

ALIMTAhaswas frequently in the ALIMTA arm. administered an intravenous 10 minutes on Day 1 of a 21 day cycle to in the ALIMTA arm. administered as an intravenous infusion over 10 as minutes on Day 1 infusion of a 21 over day cycle to Incidence 1% to 5% 0 with1 study recurrent tumors Phase 1 study (32 patients) and a Phase dence 1% to 5% pediatric patients with recurrent solidpediatric tumors patients in a Phase (32 solid patients) andina aPhase Blood/Bone Marrow — thrombocytopenia 2 study (72 patients). with All patients with vitamin B12 and folic acid slood/Bone where theMarrow — thrombocytopenia 2 study (72 patients). All patients received pretreatment vitaminreceived B12 and pretreatment folic acid General Disorders — febrile neutropenia supplementation and dexamethasone.

The dose escalation in the Phase 1 study determined General Disorders — febrile neutropenia supplementation and dexamethasone.

The dose escalation in the Phase 1 study determined Incidence Less than 1% 2 the maximum tolerated dose(orwas 1910 mg/m and this dose (or 60 mg/kg for patients dence Less than 1% the maximum tolerated dose was 1910 mg/m2 and this dose 60 mg/kg for patients Cardiovascular <12 months old) was evaluated in the Phase 2 study nardiovascular in patients — ventricular tachycardia, syncope — ventricular tachycardia, syncope<12 months old) was evaluated in the Phase 2 study of patients with relapsed or refractoryof patients with relapsed or refractory General Disorders — pain osteosarcoma, sarcoma/peripheral PNET, rhabdomyosarcoma, neuroblastoma, Grade Disorders 3/4 General — pain PNET, Ewing rhabdomyosarcoma, neuroblastoma, Gastrointestinal — gastrointestinal obstruction osteosarcoma, Ewing sarcoma/peripheral ependymoma, medulloblastoma/supratentorial PNET, or nonbrainstem high grade glioma. us 0.6%).

Gastrointestinal — gastrointestinal obstruction ependymoma, medulloblastoma/supratentorial PNET, or nonbrainstem high grade glioma.

Neurologic — depression No responses were observed among the most 72 patients in this Phase 2 trial. The most common ne dose of— depression Neurologic No responses were observed among the 72 patients in this Phase 2 trial.

The common Renal — renal failure toxicities reported were hematological (leukopenia, neutropenia/granulocytopenia, anemia, tients enal —who renal failure toxicities reported were hematological (leukopenia, neutropenia/granulocytopenia, anemia, thrombocytopenia, and lymphopenia), liver ALT/AST), function abnormalities (increased ALT/AST), of ALIMTA. ascular — pulmonary embolism Vascular — pulmonary embolism thrombocytopenia, lymphopenia), liver function abnormalities (increased effect for ALIMTA safety due to gender race was identified,and except an fatigue, and nausea. however no for ALIMTA safety No relevant effect duerelevant to gender or race was identified, except an orfatigue, and nausea. increased incidence of rash in men (24%) compared to women (16%). pharmacokinetics ALIMTA administered in doses ranging ncidence of rash in men (24%) compared to women (16%).

The single dose pharmacokineticsTheof single ALIMTAdose administered in dosesofranging 2 from 400 to 2480 mg/m were evaluated(13in males the Phase TAitional arm,Experience use 2 Across ClinicalAdditional Trials Experience Across Clinical Trials from 400 to 2480 mg/m were evaluated in the Phase 1 trial in 22 patients and 1 trial in 22 patients (13 males and Sepsis, whichininapproximately some cases was occurred in approximately 1% of patients.

9 females) aged 4 to Pemetrexed 18 years (average age(AUC 12 years).

Pemetrexed exposure (AUC and ythropoietin sis, which in some cases was fatal, occurred 1% fatal, of patients.

9 females) aged 4 to 18 years (average age 12 years). exposure and Cmax) appeared to The increase proportionally with dose. The average pemetrexed clearance ransfusions phagitis occurred in less than 1%Esophagitis of patients.occurred in less than 1% of patients. Cmax) appeared to increase proportionally with dose. average pemetrexed clearance 2 (2.30inL/h/m ) andpatients half-lifewere (2.3 comparable hours) in pediatric (2.30 L/h/m2) and half-life (2.3 hours) pediatric to valuespatients were comparable to values tmarketing Experience 6.2 Postmarketing Experience reported in adults. h non-small The following adverse reactions have been identified during post-approval use of reported in adults. following adverse reactions have been identified during post-approval use of ALIMTA. Because thesefrom reactions are reported voluntarily from a population of uncertain 8.5 Geriatric Use ecause these reactions are reported voluntarily a population of uncertain 8.5 Geriatric Use a causal size, it estimate is not always possible toorreliably estimate their frequency or establish known to be substantially not always possible to reliably their frequency establish a causal ALIMTA is known to be substantiallyALIMTA excretedis by the kidney, and the risk excreted of adverseby the kidney, and the risk of adverse relationship to drug exposure. reactions to this drug may be greater in patients with impaired renal function. Renal function p to drug exposure. reactions to this drug may be greater in patients with impaired renal function. Renal function These when reactions with ALIMTAandwhen as a single-agent and in monitoring is recommended with administration of ALIMTA. No dose reductions other than se reactions occurred with ALIMTA usedoccurred as a single-agent in used monitoring is recommended with administration of ALIMTA. No dose reductions other than combination therapies. those recommended for all65 years patients ofareage necessary for patients 65 years of age or older [see on therapies. those recommended for all patients are necessary for patients or older [see Blood and Lymphatic System – Immune-mediated hemolytic anemia Dosage and Administration (2.4)]. Dosage and Administration (2.4)]. oddecreased and Lymphatic System – Immune-mediated hemolytic anemia Of 3,946 patients across the five clinical trials [see Clinical Gastrointestinal — colitis, pancreatitis Of 3,946 patients (34.0% ≥65) studied across the five(34.0% clinical≥65) trialsstudied [see Clinical trointestinal — colitis, pancreatitis (14.1, 14.2, 14.3, and 14.4)], effect of ALIMTA on survival was similar in patients Disorders—andedema Administration Site ConditionsStudies — edema (14.1, 14.2, 14.3, and 14.4)],Studies the effect of ALIMTA on survival was the similar in patients eral Disorders and AdministrationGeneral Site Conditions 8927 AMP ALIMTA® (pemetrexed for injection) PV 8927 AMP ALIMTA® (pemetrexed for injection) PV 8927 AMP (pemetrexed for injection) PV 8927 AMP ALIMTA® (pemetrexed for injection) PV 8927 AMP

019517_elalns_PM90249_oncTIMES_ja_fa3.indd 6

5/2/14 10:24 AM

for the treatment of ovarian cancer, multiple myeloma, and acute myeloid leukemia. Phase II studies of ENMD2076 in ovarian cancer, triple-negative breast cancer, metastatic soft-tissue sarcoma, and advanced ovarian clear cell carcinomas are currently underway. n

The ASCO Post | JULY 25, 2014

PAGE 34

FDA Update

FDA Approves Belinostat for Relapsed or Refractory Peripheral T-Cell Lymphoma

T

he U.S. Food and Drug Administration (FDA) has granted accelerated approval to belinostat (Beleodaq), a histone deacetylase inhibitor, for the treatment of patients with re-

lapsed or refractory peripheral T-cell lymphoma, a rare and fast-growing type of non-Hodgkin lymphoma (NHL).

“This is the third drug that has been approved since 2009 for the treatment

of peripheral T-cell lymphoma,” said Richard Pazdur, MD, Director of the Office of Hematology and Oncology Products in the FDA’s Center for Drug Evaluation and Research. “Today’s ap-

<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

Trial Details The safety and effectiveness of belinostat was evaluated in a multicenter, single-arm clinical trial of 120 evaluable patients with relapsed or refractory peripheral T-cell lymphoma. The median age of patients was 64 years (range, 29–81), 52% of patients were male, and the median number of prior treatments

was two (range, 1-8). Patients received intravenous belinostat at 1,000 mg/m2 once daily on days 1 to 5 of a 21-day cycle. All participants were treated with belinostat until their disease progressed or side effects became unacceptable.

Overall response rate, the primary trial endpoint was 25.8% (95% confidence interval = 18.3–34.6), with 10.8% of patients achieving complete response and 15.0% achieving partial response.

The median response duration was 8.4 months (95% CI = 4.5–29.4)

Adverse Events The most common side effects seen in belinostat-treated participants were nausea, fatigue, pyrexia, anemia, and vomiting. Serious adverse events were reported in 47% of patients. The most common serious adverse reactions were pneumonia, pyrexia, infection, anemia, increased creatinine, thrombocytopenia, and multiorgan failure. One treatment-related death due to hepatic failure was reported.

As a condition of this accelerated approval, FDA requires the sponsor to conduct a dose-finding trial of belinostat when combined with CHOP (cyclophosphamide, vincristine, doxorubicin, and prednisone) and a subsequent phase III trial to characterize the comparative efficacy and safety of belinostat in combination with CHOP vs CHOP alone. n

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)

019517_elalns_PM90249_oncTIMES_ja_fa3.indd 7

proval expands the number of treatment options available to patients with serious and life-threatening diseases.”

The FDA granted accelerated approval to pralatrexate (Folotyn) in 2009 for use in patients with relapsed or refractory peripheral T-cell lymphoma and romidepsin (Istodax) in 2011 for the treatment of peripheral T-cell lymphoma in patients who received at least one prior therapy.

For more on belinostat, see page 65.

PV 8927 AMP

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PAGE 35

ASCO Annual Meeting Genitourinary Oncology

Investigational Immunotherapy Demonstrates Response in Patients With PD-L1–Positive Metastatic Bladder Cancer

T

he investigational immunotherapy agent MPDL3280A (also known as anti-PDL1) produced an overall response rate of 43% in a phase I study of patients previously treated for metastatic urothelial bladder cancer whose tumors were characterized as programmed death ligand 1 (PDL1)-positive. Results of the study were presented at the 2014 ASCO Annual Meeting by Thomas Powles, MD,

Thomas Powles, MD

Clinical Professor of Genitourinary Oncology, Barts Cancer Institute at the Queen Mary University of London, United Kingdom.1 Daniel P. Petrylak, MD, Professor of Medicine and Urology at Yale Cancer Center and Yale School of Medicine, was the senior author of the study.

The anti–PD-L1 agent ­MPDL3280A is an investigational monoclonal antibody designed to interfere with the PD‑L1 protein. MPDL3280A is designed to target PD-L1 expressed on tumor cells and tumor-infiltrating immune cells, preventing it from binding to PD-1 and B7.1 on the surface of T cells. By inhibiting PD-L1, ­MPDL3280A may enable the activation of T cells, restoring their ability to effectively detect and kill tunor cells.

Study Details and Results

Safety and Toxicity

Dr. Powles presented results from the phase I single-arm, multicenter, open-label trial, which included a cohort of 68 people with previously treated, meta­ static bladder cancer.

Thirty patients were identified as having tumors positive for PD-L1 (immunohistochemistry [IHC] 2/3) using an investigational PD-L1 diagnostic test being developed by Roche. Patients received 15 mg/kg of MPDL3280A intravenously every 3 weeks for up to 1 year.

After 6 weeks of follow-up, the objective response rate for the entire

Treatment-related grade 3 adverse events occurred in 4% (3/68) of people in the study. These included asthenia in 2%, thrombocytopenia in 2%, and blood phosphorus decrease in 2%). The most common adverse events observed to date occurring in more than 5% of people in the study were decreased appetite (12%), fatigue (12%), nausea (12%), fever (9%), and asthenia (7%).

Metastatic urothelial bladder cancer is associated with a poor prognosis and limited treatment options.

[The study results] point to a new era in cancer treatment for a disease that has not seen a major advancement since the introduction of cisplatinbased combination chemotherapy in the 1980s.

—Daniel P. Petrylak, MD

study population (both PD-L1–positive and PD-L1–negative), as measured

by RECIST criteria was 43% (13/30).

After 12 weeks, the objective response rate was 52% (13/25) in people with PD-L1–positive tumors. A complete response (no radiographic evidence of tumor) was observed in 7% of patients with PD-L1–positive tumors (2/30).

The objective response rate was 11% (4/35) in people whose tumors were identified as PD-L1–negative (IHC 0/1) by the investigational test. The median time to response was 42 days.

According to the American Cancer Society, it is estimated that more than 74,000 Americans will be diagnosed with bladder cancer in 2014, with approximately 15,000 new diagnoses made when the disease is in advanced stages.

The study results in advanced bladder cancer patients “point to a new era in cancer treatment for a disease that has not seen a major advancement since the introduction of cisplatinbased combination chemotherapy in the 1980s,” said Dr. P ­ etrylak.

FDA Grants Breakthrough Therapy Designation The U.S. Food and Drug Administration (FDA) has granted MPDL3280A Breakthrough Therapy designation to expedite the development and review of the drug and to help ensure patients have access to it

Sandra Horning, MD

through FDA approval as soon as possible. The agent is being evaluated in a broad range of tumors, noted Sandra Horning, MD, Chief Medical Officer and Head of Global Product Development for Genentech. Dr. Horning noted that MPDL3280A pivotal studies including a diagnostic test have been started in lung and bladder ­cancers. n Disclosure: Dr. Powles has served in a consultant or advisory role for Genentech and GlaxoSmithKline. Dr. Petrylak has received honoraria from Genentech. For disclosure information for all study authors, visit meetinglibrary.asco.org/abstracts.

Reference 1. Powles T, Vogelzang NJ, Fine GD, et al: Inhibition of PD-L1 by ­MPDL3280A and clinical activity in patients with metastatic urothelial bladder cancer. Abstract 5011. Presented at the 2014 ASCO Annual Meeting, May 31, 2014.

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The ASCO Post | JULY 25, 2014

PAGE 36

ASCO Annual Meeting Clinical Trials

Federally Funded Trials Praised—and Underfunded

By Caroline Helwick

A

ll four studies presented at the 2014 ASCO Annual Meeting Plenary Session were at least partially funded by federal dollars, bringing long overdue attention to the value of federally supported cancer research. Perhaps because of this high visibility, ASCO leaders took to the soapbox to sound the alarm about the decline in such funding.

“Critically important, clinically relevant research” is being jeopardized be-

other concerning figures. When adjusted for inflation and the effects of sequestration, the National Institutes of Health (NIH) budget is actually lower today than it was in 2003. As a result, the NIH funded 2,110 fewer grants in 2013 than a decade ago.

“Who knows which of these might have led to the next breakthrough in cancer prevention or treatment?” Dr. Schilsky asked. The impressive progress

The question that we are now facing is who is going to plan, launch, and complete these kinds of trials in the future. This answer, honestly, remains to be seen.

—Clifford A. Hudis, MD, FACP

cause of a lack of federal funding to the NCI, ASCO Immediate Past President Clifford A. Hudis, MD, FACP, said at a press briefing.

“While our country has had a longstanding commitment to funding cancer research, this commitment appears to be diminishing,” said Dr. Hudis, Professor of Medicine at Weill Cornell Medical College and Chief of the Breast Cancer Medicine Service at Memorial Sloan Kettering Cancer Center, New York.

“In this, our 50th year of continued progress against cancer, it is pretty clear that the national clinical trial system that Americans and others around the world have come to depend on to advance clinical research is changing,” he observed.

Dr. Hudis had the numbers to back this up: for ASCO 2014, the number of submitted abstracts that received federal funding dropped from 575 in 2008 to only 169 for this year’s meeting. He called this “a real—and we think disturbing—bit of evidence about the impact of the reduction in this federal support.”

Funding Inadequate for Progress Richard L. Schilsky, MD, FASCO, Chief Medical Officer of ASCO, had

against cancer is in jeopardy of being stalled, just when the opportunities and also the needs are greatest, he added.

The National Cancer Institute (NCI) plans to reduce trial enrollment over the next 2 to 3 years to 12,000 adult patients per year (approximately 50% of previous highs), he indicated, the result being the lowest participation

Richard L. Schilsky, MD, FASCO

in clinical trials in a decade. Fewer definitive phase III randomized trials are also being initiated.

Currently, NIH funding stands at $29.9 billion, while the NCI appropriation is $4.92 billion—increases of just 3.5% and 3.0%, respectively, over last year’s postsequestration funding.

“This level of funding is simply inadequate to accelerate progress against

cancer in the years ahead,” Dr. Schilsky emphasized.

ASCO and many other advocates for biomedical research are urging Congress to halt the NIH spending decline by budgeting at least $32 billion for the next fiscal year. However, advocates are concerned because neither the House nor the Senate appropriations committees have passed a bill to fund NIH for the fiscal year that begins October 1, potentially setting up a repeat of the gridlock that has plagued the funding process for several years.

Trials of Less Interest to Industry The four studies in the Plenary Session “are further testimony to the strides we are making to improve cancer care, and the results answer critical questions that people with cancer and their doctors face every single day,” Dr. Hudis said. “All four studies received funding from the National Institutes of Health.

This is a critically important point that may not be fully appreciated by everybody out there in broader ­society.”

The fact that these studies were made possible through federal dollars does not suggest that the outlook on funding is improving. They were all begun years ago, at a time when the U.S. government was better able to support these kinds of studies.

Publicly funded trials are important because they typically address areas of research that may be of less interest to the pharmaceutical industry than to physicians and their patients: cancer screening and prevention, quality of life and symptom control, comparative effectiveness of similar agents, new indications for older generic drugs, and combined modalities of treatment.

“These are often studies that industry is less interested in performing,” Dr. Hudis noted.

Less Biased Approach Publicly funded trials are also important because they contrib-

ute to a position of neutrality, noted Alan P. ­Venook, MD, who presented the CALGB/SWOG 80405 study. Dr. Venook is the Madden Family Distinguished Professor in Medical Oncology

Alan P. Venook, MD

and Translational Research at the University of California, San Francisco.

CALGB/SWOG 80405, designed in 2004, was a herculean effort. It was designed to compare the relative efficacy and toxicity of bevacizumab (Avastin) and cetuximab (Erbitux), which had been recently approved for advanced colorectal cancer.

The results of the trial were highly anticipated, since the previous FIRE-3 trial, reported at the 2013 ASCO Annual Meeting, found that cetuximab improved overall survival but not progressionfree survival—a result that puzzled many experts. In contrast, CALGB/SWOG 80405 found no survival differences between the arms, with an “unprecedented” median overall survival of 29 months in each arm.

“These patients are doing a little better, and I believe this represents a less biased approach. This is what cooperative groups do: treat patients in studies for which companies are not paying the bill,” Dr. Venook commented.

Dr. Hudis also lauded the study for this reason, and added, “The question that we are now facing is who is going to plan, launch, and complete these kinds of trials in the future. This answer, honestly, remains to be seen.” n Disclosure: Dr. Hudis reported no potential conflicts of interest. Dr. Venook reported research support from Genentech/Roche, BMS, and Lilly.

The Value of Federally Funded Cancer Research ASCO has created a badge to raise awareness of the importance of federally funded biomedical research that improves the lives of people worldwide.

The plenary presentations at ASCO’s Annual Meeting all were the result of federally funded research. To call attention to the value of federal funds, The ASCO Post has printed this badge alongside reports on data resulting from federally funded research.

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The ASCO Post | JULY 25, 2014

PAGE 38

American Society of Pediatric Hematology/Oncology Annual Meeting

ASPHO Abstracts Cover Broad Range of Topics

By Charlotte Bath

M

ore than 400 abstracts—a record—were submitted for the 27th Annual Meeting of the American Society of Pediatric Hematology/Oncology in Chicago. Here is a small sampling of those studies, with comments from the abstract authors.

Token Economy to Improve Compliance BMT Bucks form the basis of a token economy created at Children’s Mercy Hospital in Kansas City, Missouri, to improve patient compliance with the often grueling, lengthy hospital experience for children undergoing bone marrow transplantation (BMT). Patients earn $1, $5, and $10 bills personalized with their photo for cooperating with daily hospital tasks, such as taking medicine on time, brushing their teeth, and permitting unpleasant procedures such as dressing changes (Abstract 2056).

Ronald Jones, physician assistant, author of the abstract and the original grant funding the program, now retired, explained that the hospital’s Child Life staff interview patients and their parents to determine what items patients

Ronald Jones

would want and bring those items to the hospital where patients can “purchase” the items with BMT bucks. For a young child, it could be a toy, and for adolescents and young adults, it could be iTunes.

The price is not based on real dollars, but rather, BMT bucks as determined by the Child Life staff. The program is funded by a nonprofit organization at the hospital—the Cancer Care Committee—and available to every patient receiving BMT, which Mr. Jones estimated was about 45 to 50 patients per year.

“Changes in the emotional atmosphere of the BMT Unit were immediate and dramatic. What had been a stressful environment became a positive one where the children themselves expressed pride in their accomplishments. Although initially designed as

a pilot study, nursing staff and parents were insistent on continuing the BMT Bucks program,” according to the study abstract.

Another advantage of the program is that it provides structure to the patient’s experience. “One of the ideas of a token economy is for the child to place value on something that for him has no inherent value,” such as taking a pill or bath, Mr. Jones explained to The ASCO Post.

For now, the evidence on outcome is anecdotal, Mr. Jones said. “Obviously, if someone takes all their medicines on time, their transplant is going to go smoother and they are going to have fewer problems.” Controlled research “may reveal what we currently suspect—that not only is the experience enhanced, but that by improving compliance, outcomes may also be improved,” the abstract noted. “The hard part is you would have to study that with and without the Bucks program,” Mr. Jones said. “In our case, once the Bucks program was in place for that pilot year, nobody wanted to stop it.”

Fertility Preservation Among Girls In a study presented by Chicago researchers, histologic samples of ovarian tissue from 25 pediatric patients undergoing ovarian tissue cryopreservation found preantral follicles in all samples (Abstract 2059). The patients ranged in age from 2 to 17 years and exhibited a wide distribution of both cancer and noncancer diagnoses, including solid tumors (24%), leukemias/lymphomas/ myelodysplastic syndromes (56%), and hematologic disorders (16%). At the time of cryopreservation, 52% had received previous therapy (surgery, chemotherapy, radiation).

“These findings are promising for fertility preservation using [ovarian tissue cryopreservation] and suggest that ovarian tissue from a pediatric population is likely to contain follicles regardless of age, disease diagnosis, treatment history, and specimen processing methods,” the authors concluded.

Ovarian research tissue was obtained from the Oncofertility Consortium’s National Physician’s Cooperative under institutional review board–approved protocols, with 80% of the removed tissue for each patient cryopreserved for future clinical use and the remaining 20% designated for research after informed consent.

“We use that tissue to do basic research to further understand these tissues and how best to use them for these patients,” the study’s lead author, Francesca E. Duncan, PhD, of the Department of Obstetrics and Gynecology, Northwestern University, Feinberg School of Medicine, Chicago, explained in an interview with The ASCO Post.

Francesca E. Duncan, PhD

“Fertility preservation in a female pediatric population is challenging because standard assisted reproductive technologies may not be possible due to premenarchal status or the inability to delay cancer treatment. For these patients, ovarian tissue cryopreservation to preserve the primordial follicles within the ovarian cortex may be the only option. This tissue can potentially be used for transplantation to restore endocrine function and/or fertility,” the abstract authors noted.

Study coauthor Sherif M. Badawy, MD, of Ann & Robert H. Lurie Children’s Hospital, Northwestern University, Feinberg School of Medicine, told The ASCO Post that more families are becoming aware of the challenges of preserving fertility in young children treated for cancer, and in the long-run, new fertility options being studied could change the standard of care for young patients.

Transplantation of tissue could be contraindicated in some cases, such as ovarian cancer, “because you could potentially reintroduce the cancer,” Dr. Duncan stated. For those cases, “we are also developing new technologies, where you actually remove the follicles from the tissues completely and grow

Sherif M. Badawy, MD

them in an artificial ovary. That would get rid of any contaminating cancer cells. This technique is in the emerging stages and has only been performed in a research setting,” she noted.

Obesity Risk in ALL Survivors Although obesity is a well-established late effect following treatment of acute lymphoblastic leukemia (ALL) in childhood, and a major source of morbidity and reduced quality of life, parents are often unaware of the risks.

“Unlike other late effects of therapy, obesity is potentially modifiable, making it critical to ensure that patients and families are aware of these risks,” according to a study by Gary L. Jones, DO, of Children’s Mercy Hospital, Kansas City, Missouri, and colleagues (Abstract 2043).

Data were collected during routine follow-up in the hematology/oncology clinic for 99 patients who completed ALL therapy. Median time from the end of therapy was 34 months.

One hundred and twenty-one parents completed a questionnaire while in

Gary L. Jones, DO

clinic to evaluate their thoughts on their child’s diet, weight, activity level, and the obesity education provided by their practitioners. At the time of survey, 52 patients (53%) met Centers for Disease Control criteria for overweight (≥ 85th percentile), with 26 (26%) meeting criteria for obesity (≥ 95th percentile).

Forty-two of the overweight patients (80%) were identified as “overweight” by their parents.

The majority of the parents of overweight and obese children (93% and 64%, respectively) did not recall discussing weight with their medical team following therapy. Of all 121 parents, 60% did not recall a discussion regarding obesity risk in ALL survivors, including 82% of the parents of obese children.

“I think the discussion does occur, but we probably need to change how we address it or the emphasis we place on

ASCOPost.com | JULY 25, 2014

PAGE 39

American Society of Pediatric Hematology/Oncology Annual Meeting it,” Dr. Jones told The ASCO Post. “That is going to be our next step.”

One of the problems, he said, is that during therapy, children often don’t want to eat, so parents will give the children whatever they will eat, including junk food, which can establish a pattern that contributes to obesity in the long-run. Continuing discussions about weight, diet, and maintaining activity throughout the term of care could remind parents about avoiding obesity risks.

Substituting Intrathecal Cytarabine for Methotrexate Intrathecal cytarabine “appears to be a tolerable substitution for intrathecal methotrexate when necessary” to reduce neurotoxicity, according to a study by Suzanne Lewis, MD, and colleagues from The University of Texas Health Science Center at San Antonio (Abstract 2048).

In a retrospective chart review of 400 oncology patients treated at the Health Science Center between 1997 and 2013, the medical records for each patient were searched individually for documented central nervous sys-

Suzanne Lewis, MD

tem (CNS) toxicity from intrathecal methotrexate and subsequent use of cytarabine. “There was quite a variety of neurotoxicty that patients had—from seizures to loss of bladder control—and all patients seemed to tolerate the [cytarabine],” Dr. Lewis said in an interview with The ASCO Post.

Charts were available for 10 of the 14 patients (3.5%) identified as having experienced a CNS event attributed to intrathecal methotrexate and subsequently switched to intrathecal cytarabine. None of those patients experienced any neurotoxic events subsequent to the intrathecal cytarabine. Eight of those patients completed therapy with cytarabine as the prophylactic intrathecal agent, and seven were in their first clinical remis-

sion, with an average of 3.6 years off therapy.

“The only relapse we had was a bone marrow relapse, which as far as we could tell was unrelated to the intrathecal therapy,” Dr. Lewis noted. Two patients were still receiving chemotherapy, including intrathecal cytarabine injections without complications.

Dr. Lewis said that a new formulation of cytarabine has different absorption properties, and it is unclear how these results will apply to the new ­formulation.

Zoledronic Acid in Osteosarcoma Patients A retrospective study suggests that maintenance chemotherapy with zoledronic acid may offer a survival benefit

Amina Rafique, MD

to patients with high-risk osteosarcoma (Abstract 2102). Zoledronic acid was well tolerated in the study, and 10 of 15 patients are alive at a median follow-up of 42 months.

The study involved 15 high-risk pediatric patients (10 males) with osteosarcoma considered “high risk” and treated with zoledronic acid as maintenance therapy after completion of chemotherapy over the past 5 years.

“We defined ‘high risk’ as poor histologic response, relapse < 24 months since diagnosis, multiple relapses, metastatic disease, or unresectable disease,” Amina Rafique, MD, of Rush University Medical Center, Chicago, explained.

All patients had documented osteopenia, and all were treated with a dose of 2.3 mg/m2 (to a maximum of 4 mg).

A total of 159 doses of zoledronic acid were administered, with a mean of 10.6 doses, and the average age at start was 17.

“The next step is to calculate eventfree survival,” Dr. Rafique told The ASCO Post, “and how many of these patients are actually disease-free.” n Disclosure: Drs. Duncan and G.L. Jones reported no potential conflicts of interest.

Don’t Miss These Important Reports in This Issue of The ASCO Post Howard A. Fine, MD, and Martin J. van den Bent, MD, on RTOG 9802 glioma study see page 16

Wendy Demark-Wahnefried, PhD, RD, on breast cancer-related benefits of weight loss see page 26

Jean-Yves Douillard, MD, PhD, on colorectal cancer see page 43

Clifford A. Hudis, MD, FACP, Alan P. Venook, MD, and Richard L. Schilsky, MD, FASCO, on federally funded clinical trials see page 36

Marcia S. Brose, MD, PhD, and Maria E. Cabanillas, MD, FACE, on thyroid cancer see pages 56 and 57

Visit The ASCO Post online at ASCOPost.com

Dan Labriola, ND, and Robert B. Livingston, MD, on antioxidant-drug interactions during cancer treatment see page 97

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-40138 January 2014.

The ASCO Post | JULY 25, 2014

PAGE 42

FDA Update

FDA Grants Breakthrough Therapy Designation to Blinatumomab for Acute Lymphoblastic Leukemia

T

he U.S. Food and Drug Administration (FDA) has granted breakthrough therapy designation to blinatumomab for adults with Philadelphia chromosome–negative relapsed/re-

fractory B-precursor acute lymphoblastic leukemia (ALL).

Blinatumomab is an investigational bispecific T-cell engager antibody designed to direct the body’s cell-destroy-

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.

ing T cells against target cells expressing CD19, a protein found on the surface of B-cell–derived leukemias and lymphomas. Bispecific T-cell engager antibodies are a type of immunotherapy in which

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-40189 January 2014 This brief summary is based on TBO-003 GRANIX full Prescribing Information.

modified antibodies are designed to engage two different targets simultaneously, thereby placing the T cells within reach of the targeted cancer cell.

The Breakthrough Therapy designation was based on the results of a phase II trial of 189 adult patients with Philadelphia chromosome–negative relapsed/refractory B-precursor ALL

treated with blinatumomab. Data from the phase II trial were most recently presented at the 50th Annual Meeting of the American Society of Clinical Oncology and the 19th Congress of the European Hematology Association.

Breakthrough Therapy designation is intended to expedite the development and review of drugs for serious or life-threatening conditions. The designation requires preliminary clinical evidence demonstrating that the drug may have substantial improvement on at least one clinically significant endpoint over available therapy. n

FDA Drug Safety Communication: Docetaxel May Cause Symptoms of Alcohol Intoxication

T

he U.S. Food and Drug Administration (FDA) has issued a drug safety communication to health-care professionals warning that docetaxel contains ethanol, which may cause patients to experience intoxication during and after treatment. FDA is revising the labels of all docetaxel drug products to warn about this risk.

The FDA has recommended that health-care professionals should consider the alcohol content of docetaxel when prescribing or administering the drug to patients, particularly in those whom alcohol intake should be avoided or minimized and when using it in conjunction with other medications. Health-care professionals and patients are encouraged to report adverse events or side effects related to the use of these products to the FDA’s MedWatch Safety Information and Adverse Event Reporting Program at www.fda.gov/MedWatch/report.htm n

ASCOPost.com | JULY 25, 2014

PAGE 43

ESMO 16th World Congress on GI Cancers

Phase III Trial Shows Improved Survival With TAS-102 in Metastatic Colorectal Cancer Refractory to Standard Therapies

T

he new combination agent TAS102 can improve overall survival compared to placebo in patients whose metastatic colorectal cancer is refractory to standard therapies, researchers reported at the ESMO 16th World Congress on Gastrointestinal Cancer in Barcelona.1 “Around 50% of patients with colorectal cancer develop metastases, but eventually many of them do not respond to standard therapies,” said Takayuki Yoshino, MD, of the National Cancer Centre Hospital East in Chiba, Japan, lead author of the phase III ­RECOURSE trial. “The RECOURSE trial shows that TAS-102 improves overall survival in these pa-

The RECOURSE study shows that TAS-102 improves overall survival in these patients compared to placebo. I believe that this agent will become one of the standards of care in the refractory setting of metastatic colorectal cancer in Japan and worldwide.

—Takayuki Yoshino, MD

tients compared to placebo. I believe that this agent will become one of the standards of care in the refractory setting of metastatic colorectal cancer in Japan and worldwide.”

TAS-102 is a novel nucleoside antitumor agent consisting of trifluridine

EXPERT POINT-OF-VIEW

C

ommenting on the RECOURSE data,1 ESMO spokesperson Jean-Yves Douillard, MD, PhD, Professor of Medical Oncology, Institut de Cancérologie de l’Ouest (ICO) René Gauducheau, Saint-Herblain, France, said, “The phase III trial of TAS-102 is a global study and confirms the results of the phase II study in Japanese patients, whose response to fluoropyrimidine is slightly different to patients in Europe and the Jean-Yves Douillard, MD, PhD United States.2 It is good to know that the magnitude of benefit shown in the smaller phase II trial is confirmed in the larger phase III trial and that the results apply to Asians and Caucasians alike.”

Dr. Douillard concluded, “In RECOURSE, TAS-102 was tested in patients who had received all types of chemotherapy available for colorectal cancer. I would probably move this drug into an earlier line of treatment and I would also combine it with either irinotecan or oxaliplatin.” n Disclosure: Dr. Douillard reported no potential conflicts of interest.

References 1. Yoshino T, Mayer R, Falcone A, et al: Results of a multicenter, randomized, double-blind, phase III study of TAS-102 vs placebo, with best supportive care in patients with metastatic colorectal cancer refractory to standard therapies. Ann Oncol 25(suppl 2):114, 2014.

2. Yoshino T, Mizunuma N, Yamazaki K, et al: TAS-102 monotherapy for pretreated metastatic colorectal cancer: A double-blind, randomized, placebo-controlled phase II trial. Lancet Oncol 13(10):993-1001, 2012.

and tipiracil hydrochloride. Trifluridine is the active component of TAS102 and is directly incorporated into DNA, leading to DNA dysfunction.

However, when trifluridine is taken orally it is largely degraded to an inactive form. Tipiracil hydrochloride prevents the degradation of trifluridine.

This mechanism of action is different from that of a fluoropyrimidine, oxaliplatin, and i­ rinotecan.

The phase II trial of TAS-102 had found an overall survival benefit in Japanese patients with metastatic colorectal cancer refractory to the fluoropyrimidine fluorouracil (5-FU), irinotecan, and oxaliplatin.2

RECOURSE Trial The current RECOURSE trial was a global phase III trial conducted in 13 countries at 114 centers. Patients had metastatic colorectal cancer refractory to all standard therapies including fluoropyrimidines, oxaliplatin, irinotecan, and bevacizumab (Avastin); and cetuximab (Erbitux), or panitumumab (Vectibix) for patients who had wildtype KRAS tumors. Patients were randomly assigned 2:1 to TAS-102 (n =

534) or placebo (n = 266). The primary endpoint was overall survival.

The researchers found that TAS-102 prolonged overall survival compared to placebo (hazard ratio [HR] = 0.68); median overall survival was 7.1 months for TAS-102 and 5.3 months for placebo.

TAS-102 also improved progressionfree survival compared to placebo (HR = 0.48), which was a secondary endpoint.

Dr. Yoshino said, “We found a statistically significant difference in overall and progression-free survival, and a clinically meaningful improvement.”

TAS-102 had a mild safety profile.

The most common grade > 3 adverse events were neutropenia (37.9%), leukopenia (21.4%), and anemia (18.2%).

Febrile neutropenia was observed in 3.8% of patients receiving TAS-102.

“Patients with metastatic colorectal cancer refractory to standard therapies now have a strong treatment option,” Dr. Yoshino said. n

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

References 1. Yoshino T, Mayer R, Falcone A, et al: Results of a multicenter, randomized, double-blind, phase III study of TAS-102 vs placebo, with best supportive care in patients with metastatic colorectal cancer refractory to standard therapies. Ann Oncol 25(suppl 2):114, 2014.

2. Yoshino T, Mizunuma N, Yamazaki K, et al: TAS-102 monotherapy for pretreated metastatic colorectal cancer: A double-blind, randomized, placebocontrolled phase II trial. Lancet Oncol 13(10):993-1001, 2012.

TAS-102 in Metastatic Colorectal Cancer ■■ TAS-102 prolonged overall survival by 1.8 months compared to placebo in patients with metastatic colorectal cancer refractory to standard therapy.

■■ TAS-102 also improved progression-free survival compared to placebo.

■■ The drug was well tolerated, and side effects were mild.

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PAGE 44

ESMO 16th World Congress on GI Cancers

Adding Novel Agent to Standard Therapy Improves Survival in Patients With Pancreatic Cancer After Prior Gemcitabine-Based Therapy

T

he addition of the novel agent MM-398 to standard treatment improved overall survival in patients with metastatic pancreatic cancer who have already received gemcitabine, according to a phase III trial reported at the ESMO 16th World Congress on Gastrointestinal Cancer in Barcelona.1

at the tumor site. “MM-398 therefore generates higher antitumor activity and is more effective than conventional irinotecan alone in the preclinical setting,” Dr. Wang-Gillam said, who noted that

one of the biggest challenges in pancreatic cancer is drug delivery.

A phase II study had previously demonstrated the antitumor activity of MM-398 monotherapy as second-line

treatment in patients with metastatic pancreatic cancer refractory to gemcitabine.

NAPOLI-1 Trial The current NAPOLI-1 trial was a

This was a positive trial and will provide a new treatment option for patients with metastatic pancreatic cancer.

—Andrea Wang-Gillam, MD, PhD

“Patients with metastatic pancreatic cancer or pancreatic cancer in general have very limited options,” said one study author Andrea Wang-Gillam, MD, PhD, Assistant Professor in the Division of Oncology at Washington University in St. Louis. “These patients just simply don’t do well. This was a positive trial and will provide a new treatment option for patients with metastatic pancreatic cancer.”

MM-398 is a novel encapsulation of irinotecan in a nanoliposome, a delivery system that allows longer drug exposure in circulation and more accumulation of the drug and its active metabolite

MM-398 in Metastatic Pancreatic Cancer ■■ MM-398 plus fluorouracil/ leucovorin significantly improved overall survival and progression-free survival in patients with metastatic pancreatic cancer who had progressed or received prior gemcitabine-based therapy.

■■ The combination regimen provides a new second-line treatment option for patients with metastatic pancreatic cancer.

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PAGE 45

ESMO 16th World Congress on GI Cancers global randomized phase III trial at more than 100 sites. Patients were randomly assigned to receive either MM-398 alone, standard treatment with fluorouracil (5-FU)/leucovorin, or MM-398 plus 5-FU/leucovorin. The trial included 417 patients who had progressed or received prior gemcitabine-based therapy, and the primary endpoint was overall survival.

Overall survival was significantly improved with the combination therapy of MM-398 plus 5-FU/leucovorin compared to 5-FU/leucovorin alone. Median overall survival was 6.1 months in the MM-398 plus 5-FU/leucovorin group compared to 4.2 months in the group receiving standard treatment with 5-FU/leucovorin alone (hazard ratio [HR] = 0.67, P = .012).

Progression-free survival also improved significantly, from 1.5 months with the standard therapy to 3.1 months in patients receiving MM-398 plus 5-FU/ leucovorin (HR = .56, P < .001). MM398 alone did not provide any additional survival benefit over standard therapy.

“The results are very exciting because the trial met its primary endpoint and

found a highly statistically significant benefit of MM-398 plus 5-FU/leucovorin on overall survival and progressionfree survival compared to 5-FU/leucovorin alone. We also found a significant benefit of the combination therapy on overall response rate and biochemical response,” said Dr. Wang-Gillam.

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continued on page 46

The ASCO Post | JULY 25, 2014

PAGE 46

ESMO 16th World Congress on GI Cancers Pancreatic Cancer continued from page 45

Combination therapy led to more gastrointestinal side effects than standard treatment alone. Diarrhea occurred in 12.8%, 21.1%, and 4.5% of the MM-398 plus 5-FU/leucovorin, MM-398 alone, and 5-FU/leucovorin alone groups, respectively. Vomiting occurred in 11.1%,

13.6% and 3.0%, respectively, and fatigue in 13.7%, 6.1% and 3.7%, respectively.

New Option “Our results are indicative of a successful effort in developing new drugs toward pancreatic cancer. We now have another viable option in this devastating disease,” Dr. Wang-Gillam said.

ESMO spokesperson Roberto ­Labianca, MD, Director of the Cancer Centre, Ospedale Giovanni XXIII in Bergamo, Italy, said, “This trial has important clinical implications in a difficult setting, because we will be able to add the new drug to standard treatment and increase activity and efficacy.” He concluded, “NAPOLI-1 demonstrated that [MM-398]

plus 5-FU/leucovorin was an effective second-line therapy in metastatic pancreatic cancer. Future trials should evaluate this combination as first-line treatment and in locally advanced pancreatic cancer.” n Reference 1. Von Hoff D, et al: Ann Oncol 25 (suppl 2):105-106, 2014.

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ASCOPost.com | JULY 25, 2014

PAGE 47

ESMO 16th World Congress on GI Cancers

Second-Line Regorafenib Improves Survival in Metastatic Colorectal Cancer

I

n the phase III double-blind, placebocontrolled ­CONCUR trial,1 previously treated patients with stage IV adenocarcinoma of the colon or rectum had increased overall survival, the primary endpoint, when treated with regorafenib (Stivarga).

Regorafenib also improved progression-

free survival, a secondary endpoint.

The study enrolled 204 patients in 25 centers in China, Hong Kong, Taiwan, Republic of Korea, and Vietnam. Patients were randomly assigned to receive best supportive care plus either oral regorafenib at 160 mg daily or placebo in the first 3

weeks of each 4-week cycle. Treatment was stopped at disease progression, unacceptable toxicity, or consent withdrawal.

Median overall survival was 8.8 months with regorafenib vs 6.3 months with placebo (hazard ratio [HR] = 0.550, P = .0002). Progression-free sur-

vival was 3.2 vs 1.7 months (HR = 0.311, P < .0001), and disease control rates were 52% vs 7%, respectively. n Reference 1. Li J, et al: CONCUR. Ann Oncol 25(suppl 2):114, 2014.

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PAGE 48

Issues in Oncology Value in Cancer Care continued from page 1

School of Medicine and The Wharton School at the University of Pennsylvania, Philadelphia, noted that the United States spent $3 trillion on health care in 2013. “That’s larger than the economy of France,” he pointed out. An estimated 5% of this total—$150 billion

or more—goes to cancer care, amounting to 10 times the “pockets” of the five largest insurance companies, he added.

“The high cost of cancer care threatens to increase disparities in care and outcomes,” added session Chair Neal J. Meropol, MD, Chief of Hematology and Oncology at University Hospitals–Seidman Cancer Center and Case

Western Reserve University, Cleveland.

These costs are incurred in multiple ways—through lack of insurance, copays/coinsurance, tiered formularies, the Medicare part D “donut hole,” and oncology drug shortages—but perhaps most sensationally by the cost of new agents, as illustrated by five new drugs that were approved in 2013 (Table 1).

Dr. Emanuel noted that even older, established agents are getting more expensive. The price of imatinib (Gleevec), for example, has tripled since it first reached the market, despite the launch of competitors.

Not Just About ‘Value’ While the world expects therapeutic breakthroughs, the fact that significant amounts of money are spent for small gains is becoming universally unacceptable. The controversy is not just about “value” but about “cost,” Dr. Emanuel maintained.

It’s difficult for oncologists to be gatekeepers on cost, but they should become gatekeepers for value.

—Neal J. Meropol, MD

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“If you doubt that, look at the new drugs for hepatitis C. We are talking about $80,000 for a disease cure, and it’s still controversial. Any educated person would acknowledge that a one-time curative treatment is good value, yet there is still consternation,” Dr. Emanuel observed. “Yes, we are concerned about value, but we are also concerned about absolute total costs.”

Oncologists Need to Do More Total cost is determined by multiplying price times volume, Dr. Emanuel said, and oncologists have some control over both. He suggested that oncologists examine both the volume and the price of their cancer interventions.

Many may be guilty, he suggested, of being poor stewards of the cancer care budget through unnecessary testing, frequent use of drugs off label and off guidelines, and prescriptions for expensive drugs when less expensive ones are available.

Advanced gastric cancer is a good example of the wide variation in cost and in practice, he said, as there is a 50-fold difference in the price of the National Comprehensive Cancer Network’s preferred regimens.

ASCOPost.com | JULY 25, 2014

PAGE 49

Issues in Oncology

“We have to ask ourselves what do we have to do with this story?” Dr. Emanuel continued. “Oncologists have an obligation to avoid unnecessary testing and to prescribe the lower-cost option if it is equivalent to a more expensive drug. And we have an obligation to expose practices that are not adding value,” he said.

“I remind you, your patients are paying for this, and you are paying for this with increases in insurance. We all are—it is not a victimless crime,” he commented.

Much of the reticence over cutting costs pertains to the current reimbursement formulas, he pointed out.

“We won’t get out of this box unless we stop paying doctors for testing more and giving more treatments. We have an obligation to advance off the fee-for-service model. And we should want to get out of this system so we can focus on patients, and actually spend time talking with them, as we claim we want to do. We can’t reach common ground until we have payment reform, but between now and then, we need to do our part.”

ASCO Is Addressing Value ASCO is beginning to address the issue of value, according to Lowell E. Schnipper MD, Berenson Professor in Medicine, Harvard Medical School, Chief of Hematology/Oncology at Beth Israel Deaconess Medical Center, Boston, and Chair of the ASCO Task Force on Value in Cancer Care.

Lowell E. Schnipper MD

The problem is not so much the absolute dollars expended, but what these dollars buy for the patients who may be experiencing financial as well as physical toxicity, Dr. Schnipper suggested. “It’s what we are buying, and not buying, with the health-care dollars

that we expend,” he said. Table 1: Oncology Agents Approved by the U.S. Food and Drug Administration in 2013 “The amount of overuse Drug Indication Route Price for 28 days and waste in the system First-line metastatic non–small cell lung Oral $6,216 is astonishing. We are not Afatinib cancer with an EGFR mutation getting enough for the Dabrafenib Unresectable or metastatic melanoma Oral $8,512 money.” with BRAF V600E mutation ASCO is now addressing the multiple elements Ibrutinib Mantle cell lymphoma, previously Oral $12,245 that comprise value: untreated wanted variation in qualChronic lymphocytic leukemia (with ity and outcome, harm to Obinutuzumab chlorambucil), previously untreated Intravenous $12,384 patients, waste and failure Unresectable or metastatic melanoma Oral $9,744 to maximize value, health Trametinib with BRAF V600E mutation inequalities and inequities, and failure to prevent idea was for the patient “to pause and discern the value of a given treatment— disease. Efforts are underway through the Quality Oncology ask, ‘Is this worth the money?’” he said. is expected to be a major barrier to getPractice Initiative (QOPI), Cancer- In many situations, patients don’t think ting value-based insurance in place, he LinQ, the Choosing Wisely campaign, so, he noted. His company has docu- predicted. and participation in experimental mod- mented a 58% compliance rate among Dr. Newcomer also discussed site patients with $50 copays for a $5,000-a- of care as an important component of els of payment reform.

In addition, ASCO’s Value Initiative month drug. “That’s concerning to me,” value, indicating that the shift in canis seeking to create a transparent, clini- he commented. cer care from community practices into A value-based insurance design hospitals is an obstacle that is already cally driven, methodologically sound method for defining and assessing rela- would create a fair differential be- costing the commercial payers a lot of tive value of cancer care options. “We tween high-value services and low- money. want to give oncology providers the On average, UnitedHealthcare skills and tools to assess the relative valpays the Centers for Medicare & ue of therapies and use these in discussMedicaid Services (CMS) rate plus ing treatment options with patients,” 22% for chemotherapy delivered in Dr. Schnipper said. the oncologist’s office. When the Such a tool will allow individuals same chemotherapy is delivered by to compare treatments based on their the same oncologist practicing in a benefits, toxicities, and costs, allowing hospital-owned facility, the company treatments to be categorized according pays the CMS rate plus 146%—nearly to low, medium, and high value—with seven times more for the same serLee N. Newcomer, MD, MHA nuance and distinguishability among vice, he noted. regimens. value ones. A high-value service Working Together Value-Based Insurance, might offer complete coverage, with to Find Solutions Site of Service Dr. Meropol suggested the tasks no requirement for the patient’s fiPayers are certainly committed to nancial participation, while a low- ahead for the major stakeholders infurthering value in cancer care, added value service would mandate that the clude the following: Lee N. Newcomer, MD, MHA, Senior patient contribute, say, one-third or • The payers must align payment with Vice President of Oncology, Women’s one-half—even 100% if the proceoutcomes, and support this with eviHealth and Genetics for UnitedHealth- dure lacks proven value. dence. care. “We have to start having discusThe challenge will be in establishing • The manufacturers must bring innosions about value, and we are going to meaningful, nonbiased thresholds, crevations of high value, and avoid the have to say that there are certain things ating computer programs that can hanpromotion of marginal advances. that should not be covered. The issue is dle the complexity, and educating pa- • The patients must expect high-value how to do this in a way that will be ra- tients. “Where do we say that one thing care and participate in research. tional and fair,” he said.

“It’s difficult for oncologists to be should be free, and another should have Copays were never intended to be 30% participation?” Dr. Newcomer gatekeepers on cost, but they should belarge enough to keep patients from re- asked. “No matter where we draw the come gatekeepers for value,” he said. n Disclosure: Drs. Hudis, Schnipper, and ceiving important, high-value care, but line, someone will be unhappy.” to keep them from selecting lower-valTrying to make this concept under- Newcomer reported no potential conflicts of ue care, Dr. Newcomer explained. The standable to consumers—helping them interest.

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The ASCO Post | JULY 25, 2014

PAGE 50

Direct From ASCO

Illumination to Innovation: Transforming Data Into Learning Introducing Dr. Peter Yu’s 2014-2015 Presidential Theme Featured commentary from the online column of ASCO President Peter Yu, MD, FASCO

“I

llumination” is a provocative word, evoking as it does the banishment of the darkness of ignorance by the light of new knowledge. Today, we are benefiting from a steady stream of new knowledge about the molecular basis of cancer and the interaction between host and tumor immunology. The concept of patient-centered care is illuminating how we view the role of patients in shared decision-making, the definition of quality of care, and the professional responsibility of physicians.

Reassessing Global Cancer Care Needs At the same time, the challenge of delivering cancer care that incorporates Dr. Yu is the 2014-2015 President of ASCO. He is a medical oncologist and hematologist, Director of Cancer Research at Palo Alto Medical Foundation, and a member of the Alliance for Clinical Trials in Oncology and the Gynecologic Oncology Group (GOG). He is also the Chair of ASCO’s Research, Policy & Practice Subcommittee, an ASCO Liaison to the College of American Pathologists Cancer Biomarker Reporting Committee, and Past Chair of the ASCO HIT Working Group.

Follow Dr. Yu on Twitter @YupOnc.

these advances in thinking, both in the United States and globally, are significant societal hurdles. Innovation—the imaginative and creative use of illumination to transform how we improve the lives of cancer patients in a sustainable and scalable manner—is the necessary companion to illumination.

We are the American Society of Clinical Oncology and not the American Society of Oncology. That distinction is critical because it tells the world that we are focused on patients who have or are at special risk for cancer, and that at the end of the day, our goal is not the accumulation of knowledge for its own sake, but rather the application of knowledge to patient care. Learning is simply that, another word for innovation.

We are also the American Society of Clinical Oncology and not the International Society of Clinical Oncology. Yet one-third of our members are international, and I can only assume that is because ASCO is a rich source of learning.

But it can and should go both ways; there are opportunities to improve cancer care in America by learning about cancer care in other cultures, ethnicities, and geographies. Indeed, the evolving demographics in the United States are expanding the range of health-care disparity populations with cancer, populations whose unique attributes may be more readily discerned by sharing the global experience.

Over the next 18 months, a task force

of domestic and international ASCO leadership will undertake a comprehensive examination of global cancer needs, which in turn provides opportunities for ASCO to work with our sister professional societies across the world to help address those needs and inculcate aware-

practice and clinical research will depend on meeting these challenges successfully.

At the same time, demands on academic oncologists to increase practice revenues have decreased satisfaction with the balance of academic and clinical work. Now is a time when a willingness to design and

If change is inevitable, let us go out in front of it and lead.

—ASCO President Peter Yu, MD, FASCO

ness of ethnography across the Society.

While we will not change our name, we will define our place in the global effort to improve the lives of cancer patients.

Rapid Learning Health Systems Today in the United States, we are challenged to reinvent how we practice medicine in response to society’s demand for higher quality and more affordable health care and a more efficient clinical research enterprise. A shift from reimbursement models based on production to models based on quality and outcomes has started. The survival of existing and the success of developing models of community

carefully study new models of providing cancer care will hold us in good stead. If change is inevitable, let us get out in front of it and lead.

As physician-scientists, we are accustomed to using data to generate and test new models. Propitiously, the arrival of digital health has provided an invaluable source of new data from which to generate knowledge and learning. The blending of big health data and medical informatics now gives us a tool with which to accelerate learning, a concept described as “Rapid Learning Health Systems.” These data sets are derived continued on page 52

ASCO’s 50th Anniversary: Past Presidents Recall Top Issues During Their Terms

I

n a series of articles on the American Society of Clinical Oncology’s CancerProgress.Net website, past ASCO presidents are sharing their recollections of the major issues during their terms.

Emil J Freireich, MD, FASCO, (1980–1981), remembered that during his presidency, ASCO began the process of starting a new scientific journal, the Journal of Clinical Oncology, he “was personally very confident that the journal would be a success,” despite the concerns by many that the journal would fail. “More importantly, I felt it would be an important service to our members to have such a journal,” Dr. Freireich wrote. Another accomplishment that Dr. Freireich recalled was instituting the commercial exhibits at the ASCO Annual Meeting, which has served as an important

source of information and resources for ASCO. Bernard Fisher, MD, FASCO, (1992–1993), recalled discussions during his presidency over whether ASCO’s mission related to cancer research or cancer practice. “I expressed my view that a widening gap between physicians and investigators could not only threaten the welfare of patients, but that, as clinicians got further away from science, the hope for progress in curing and preventing cancer would diminish,” Dr. Fisher wrote.

Paul A. Bunn Jr, MD, FASCO, (2002–2003), remembered his presidential year as a challenging one, dealing with massive growth in membership and the size of the Annual Meeting, growth in international membership, the growing interest in disease-oriented multidisciplinary re-

Emil J Freireich, MD, FASCO

Bernard Fisher, MD, FASCO

search, and how to meet the needs of patients and advocates, among other issues. As ASCO grew, many more stakeholders began looking to ASCO to meet their needs, he recalled. ASCO addressed these needs in a number of ways, including launching diseaseoriented meetings and collaborative symposia with international organizations, as well as increasing work with advocacy organizations.

Paul A. Bunn Jr., MD, FASCO

ASCO Past Presidents who have yet to submit their reflections can still send an article for posting on CancerProgress.Net. Articles should be 500 to 1,500 words, and can include photographs (current or contemporary to the time period), and may be sent to CancerProgress@asco.org n © 2014. American Society of Clinical Oncology. All rights reserved.

ASCOPost.com | JULY 25, 2014

PAGE 51

Direct From ASCO

ASCO’s Cancer Survivorship Compendium Offers Oncologists Help With Survivorship Care

I

t has been almost 10 years since the Institute of Medicine released its influential report, “From Cancer Patient to Cancer Survivor: Lost in Transition,” in which it stressed that all patients completing cancer treatment should receive a survivorship care plan.

Since then, the need to help transi-

Kevin C. Oeffinger, MD

tion cancer survivors back to primary care treatment has only grown. In 2012, the American Cancer Society estimated that there were about 13.7 million cancer survivors in the United States, and it estimated that this number would increase to about 18 million by 2022.

New Online Toolkit To help support its member implementation or improvement of their survivorship care, ASCO has recently launched its Cancer Survivorship Compendium, an online repository of tools and resources for the survivorship care of patients who have completed curative treatment or who have transitioned to maintenance or prophylactic therapy.

“We thought it would be useful to oncologists if we developed a survivorship toolkit that included resources to help develop a survivorship program, expand a program, or fill needs within an existing program aimed at improving the care of cancer survivors throughout the country,” said Kevin C. Oeffinger, MD, Director of the Adult Long-Term Follow-up Program at Memorial Sloan Kettering Cancer Center, and Immediate Past Chair of ASCO’s Cancer Survivorship Committee.

The Survivorship Compendium is broken down into two easy-to-navigate sections, “Putting Survivorship Care into Practice” and “Additional Online Resources,” both of which offer valuable information for growing survivorship care.

Volume 7, Issue 3

Survivorship Care Plan Among the most valuable information is the Clinical Tools and Resources link that points to ASCO’s survivorship care planning tools. Later this year, the tools will be updated to include a new template for a Survivorship Care Plan. According to Dr. Oeffinger, this updated plan is designed to provide oncologists with a streamlined version of a care plan that is a much more efficient template for creating cancer treatment summaries and a follow-up care plan.

The Compendium also offers information on a variety of phases of the development of a survivorship care program. Oncologists can browse information discussing a variety of mod-

ing to Dr. Oeffinger. The Compendium offers quick access to ASCO’s resources on coverage and reimbursement information for survivorship care services.

“This version of the Compendium is only the ‘1.0’ version,” said Dr. Oeffinger. “As we add to and grow the Compendium, we hope that people will continue to find these tools useful, and come back and visit the site as a source for information about how to deliver high quality care to survivors.”

Visit the Cancer Survivorship Compendium at asco.org/survivorship. n

els of long-term follow-up care, and can access a needs assessment that will help to determine what survivorship resources are already available at their practices, and what additional resources may need to be added in order to build a successful program.

Finally, oncologists can visit the Compendium to access information on reimbursement as it relates to survivorship care. Although survivorship care has been identified as an important component of cancer care, many oncology practices and hospitals are still struggling to incorporate the work associated with survivorship care planning into their business plans, accord-

May 2011

Journal of oncology Practice

© 2014. American Society of Clinical Oncology. All rights reserved.

Top 5 articles Top 10 most-accessed recently published articles published in 2011 in in Journal of Oncology Practice Journal of Clinical Oncology

The Authoritative Resource for Oncology Practices

Report on the ASCO 2010 Provider-Payer Initiative Meeting

By Michael N. Neuss, MD, et al Subspecialization in Community Oncology: Option or Necessity?

By Dean H. Gesme, MD, et al Current Hepatitis B Screening Practices and Clinical Experience of Reactivation in Patients Undergoing Chemotherapy for Solid Tumors: A Nationwide Survey of Medical Oncologists

By Fiona L. Day, FRACP, et al Barriers to Recruitment of Rural Patients in Cancer Clinical Trials

By Shamsuddin Virani, MB, BS, et al Partners and Partnerships: Trends in Private Oncology Practice

By Thomas A. Paivanas, MHSA

www.jop.ascopubs.org

What’s Hot in

JOP

JOP.ascopubs.org Cancer Clinical Research: Return on Investment in the Era of Value-Based Purchasing

by Randall F. Holcombe

Balancing Incentives and Professionalism in Health Care Payment Reform

by Barry Meisenberg

ASCO Invites Widespread Use of Federally Funded Research Badge

T

o raise awareness of the importance of federally funded biomedical research that improves the lives of people worldwide, ASCO has created a badge that organizations and individuals can use to publicize research that has received federal funding.

To use the Federally Funded Research badge, organizations and individuals are invited to fill out ASCO’s badge request form. Upon submitting the form, the user will be able to download graphic files with web- and print-quality ver-

sions of the trademarked badge.

To complete the badge request form and for further information from ASCO on the need for greater federal investment in cancer research, visit www.asco.org/ NIHfunding. n

Quality Measures for Palliative Care in Patients With Cancer: A Systematic Review

by Arif H. Kamal, et al

Radiation Oncology: A Perspective on Health Reform and Value-Based Initiatives

by Najeeb Mohideen, et al

Colorectal Cancer Survivors’ Needs and Preferences for Survivorship Information

by Talya Salz, et al

© 2014. American Society of Clinical Oncology. All rights reserved.

The ASCO Post | JULY 25, 2014

PAGE 52

Direct From ASCO Illumination to Innovation

(PD-0332991)

NOW ENROLLING Palbociclib Clinical Trials

If we are able to match these data sets LinQ will provide insights for the design continued from page 50 with data on patient outcomes and con- of new models of cancer care delivery from real-world patient experiences, sumption ofPaloma medical will beR. Panariello that are sustainable andx 9.75” that address sociCODE: PAL-14 2B PUB/POST: 3 Singleresources, Page Ad-3 Sizeswe PRODUCTION: LIVE: 6.75” and consequently, the data they contain positioned etal objectives, provide DESCRIPTION: Paloma 3 Single Page Ad-Sizesto B contribute new knowledge WORKORDER #: 006627 TRIM: 7” x 10”supportive mechreflect patients FILE: are02A-006578-02C-743829-B-SIZE-PALOMA.indd treated to the health-care reform discussion. a 7.875” thriving Delivery how Support:cancer 212.237.7000 SAP #: S.TEMP.02365anisms to sustain BLEED: x 10.75”community in the daily practice of medicine, the CancerLinQ™ is ASCO’s version of a practice base, and allow the voice of the benefit and harm patients experience, Rapid Learning Health System applied physician to be resonant. By sharing our the efficiency of care delivery, and most to oncology and the first such innovation data, we all receive in return something interestingly, the variation in all of this. in medicine. We anticipate that Cancer- that is greater than the sum of the parts.

Palbociclib, an oral CDK4/6 inhibitor, in combination with fulvestrant vs fulvestrant alone in the treatment of women with HR+/HER2- locally advanced or metastatic breast cancer A phase 3, randomized, double-blind, multicenter study in patients with HR+/HER2metastatic breast cancer, regardless of menopausal status, whose disease has progressed on or after prior endocrine therapy N=417

Study 1023 Women of any menopausal status with HR+/HER2- breast cancer who progressed on or after prior endocrine therapy

Palbociclib

2:1 R A N D O M I Z A T I O N

125 mg QD (21 days on/7 days off) + Fulvestrant 500 mg (Days 1 & 15 of Cycle 1; Day 1 of each subsequent 28-day cycle)

Placebo (21 days on/7 days off) + Fulvestrant 500 mg (Days 1 & 15 of Cycle 1; Day 1 of each subsequent 28-day cycle)

ENDPOINTS PRIMARY: Progression-free survival KEY SECONDARY: Overall survival, objective response, clinical benefit response, duration of response, safety, pharmacokinetics, patient-reported outcomes, tumor tissue biomarkers KEY INCLUSION CRITERIA • Adult women (≥18 years) with metastatic or locally advanced disease, not amenable to curative therapy • Confi rmed diagnosis of HR+/HER2breast cancer • Post- or pre-/perimenopausal • Progressed ≤12 months from prior adjuvant therapy or progressed while on or ≤1 month after prior advanced/ metastatic breast cancer therapy.

One previous line of chemotherapy for metastatic disease is allowed • Pre/perimenopausal patients must be on an LHRH agonist for ≥28 days AND willing to switch to goserelin (Zoladex®) at time of randomization if initiated on an LHRH agonist other than goserelin

• Measurable disease defined by RECIST version 1.1 or bone-only disease • Eastern Cooperative Oncology Group (ECOG) PS 0-1 • Prior treatment with any CDK inhibitor, fulvestrant, everolimus or agent that inhibits the PI3K-mTOR pathway • Patients with advanced/metastatic, symptomatic visceral disease • Known uncontrolled or symptomatic CNS metastases • Major surgery or any anticancer therapy within 2 weeks of randomization • Prior stem cell or bone marrow transplantation • Use of potent CYP3A4 inhibitors or inducers

The PALOMA-3 trial is part of the (Cyclin-Dependent Kinase inhibitor in cancer) clinical trial program of Pfizer Oncology. For more information about this trial, please visit www.pfizercancertrials.com and www.clinicaltrials.gov (NCT01942135).

PS=performance status; CDK=cyclin-dependent kinase; CNS=central nervous system; DFI=disease-free interval CDK664413-01 © 2014 Pfizer Inc. All rights reserved.

My Presidential theme for our 51st year is Illumination to Innovation: Transforming Data into Learning. With the transformation of data into knowledge and thence from knowledge to learning lies an unprecedented opportunity to move our health-care delivery and research systems forward. It begins with a willingness to share our data and involves analysis of that data in ways that will seem foreign and new, along with the agile thinking to accept the knowledge and apply it. The most difficult part will be the recognition that the authority of conventions is often derived more from the comfort of habit than it is from reason.

Illumination and innovation are how the most adaptable will survive in a changing environment. As oncologists, we have always been and always will be at the forefront of creativity and disruptive change; it is the nature of who we are, and why we endeavor in this most difficult of medical specialties to illuminate the path forward. n Originally published in ASCO Connection. © American Society of Clinical Oncology. “Illumination to Innovation: Transforming Data into Learning.” connection. asco.org. June 2, 2014. All rights reserved.

To comment, visit ASCOconnection.org and select “Commentary.”

Look for Changes to Cancer.Net’s Design and Navigation

KEY EXCLUSION CRITERIA

Palbociclib (PD-0332991) is an investigational compound.

This information is current as of June 2014.

Illuminating the Way in Oncology

C

ancer.Net, ASCO’s patient information website, is in the process of updating the design and is now offering an easier way to navigate the site.

Based on extensive testing, the site’s new look and feel is designed to improve each user’s experience. The changes will keep Cancer.Net up-to-date with the newest trends in web design, offering a useful and clean look to help the site’s users quickly find the information they need. Watch out for the latest changes at www.cancer.net. n © 2014. American Society of Clinical Oncology. All rights reserved.

ASCOPost.com | JULY 25, 2014

PAGE 53

Direct From ASCO

Conquer Cancer Foundation Past Grant Recipients Present Research Advances in Melanoma and Ovarian Cancer at 2014 ASCO Annual Meeting

T

he Conquer Cancer Foundation has an excellent track record of finding and funding the most promising young investigators. Past recipients Joyce F. Liu, MD, MPH, and Antoni Ribas, MD, PhD, received

fective alternative to standard chemotherapy,” said Dr. Liu. Dr. Liu is the recipient of a Conquer Cancer Foundation of ASCO 2008 Young Investigator Award (YIA).

“Receiving the award was enormously

Receiving the [Young Investigator Award] was enormously helpful and motivated me to continue on the cancer research path. I learned an immense amount about how to approach cancer biology through my YIA research.

Antoni Ribas, MD, PhD

the Conquer Cancer Foundation to investigate alpha fetoprotein–based immunotherapy for hepatocellular carcinoma. As Dr. Ribas explained, “it is really hard for someone coming out of a fellowship to receive a grant

that will support their salary and give them the protected time to develop new concepts. So, it is really important that the YIA and CDA awards are maintained because it allows the awardees to dedicate the appropriate time and effort to clinical and patientoriented research.”

The Conquer Cancer Foundation is currently accepting applications for the 2015 YIA and CDA programs. Learn more and apply online at www.conquercancerfoundation.org. n © 2014. American Society of Clinical Oncology. All rights reserved.

—Joyce F. Liu, MD, MPH

funding from the Conquer Cancer Foundation early in their career and at the 2014 ASCO Annual Meeting presented research on important advances for patients with recurrent ovarian cancer and advanced melanoma.

Olaparin and Cedirinib in Ovarian Cancer Dr. Liu presented study findings showing that a combination of the PARP inhibitor olaparib and the antiangiogenic drug cediranib delays recurrent ovarian cancer progression by more than 8 months compared with olaparib alone.

This marks the first time these two types of targeted drugs have ever been combined and could fill an important gap in the treatment of ovarian cancer.

“The significant activity that we saw with the combination suggests that this could potentially be an ef-

helpful and motivated me to continue on the cancer research path. I learned an immense amount about how to approach cancer biology through my YIA research,” she reflected.

Anti–PD-L1 Antibody Shows Promise in Melanoma Dr. Ribas presented findings from a phase I study of 411 patients with advanced melanoma, which demonstrated that the PD-1 targeting antibody pembrolizumab (MK-3475) yields longterm responses in a high percentage of patients. The 1-year overall survival was 69% across all patient subgroups, and responses were ongoing in 88% of patients at analysis, after a median followup of 12 months.

“We were excited to see that [pembrolizumab] was effective in previously untreated patients as well as in those who had multiple prior therapies, including ipilimumab [Yervoy],” said Dr. Ribas. “These are early data, but they tell us we are on to something really important.”

Dr. Ribas received a 2000 Career Development Award (CDA) from

Save the Date Best of ASCO® Boston August 8-9, 2014 Renaissance Boston Waterfront Hotel Boston, Massachusetts

Best of ASCO® Chicago August 15-16, 2014 Hilton Chicago Chicago, Illinois

Best of ASCO® Seattle August 22-23, 2014 The Westin Seattle Seattle, Washington

The ASCO Post | JULY 25, 2014

PAGE 56

Journal Spotlight Head and Neck Cancer

Sorafenib Improves Progression-Free Survival in Progressive Radioactive Iodine–Refractory Differentiated Thyroid Cancer

By Matthew Stenger

P

atients with radioactive iodine–­ refractory locally advanced or metastatic differentiated thyroid cancer have a poor prognosis. In the double-blind phase III DECISION trial reported in The Lancet, Marcia S. Brose, MD, PhD, of Abramson Cancer Center of the University of Pennsylvania, and colleagues found that sorafenib (Nexavar) increased progression-free survival in this setting.1 The DECISION trial supported the approval of sorafenib in this indication in November 2013.

RET/PTC translocations, BRAF V600E mutations, RAS mutations, and increased expression of vascular endothelial growth factor (VEGF) and its receptors (VEGFRs) have been implicated in the pathogenesis and poor outcome of thyroid carcinoma. Sorafenib is a kinase inhibitor of VEGFR-1, VEGFR-2, and VEGFR-3, RET (including RET/ PTC), RAF (including BRAF V600E), and platelet-derived growth factor receptor–beta.

Study Details In the trial, 417 patients with radioactive iodine-refractory locally advanced or metastatic differentiated thyroid cancer that had progressed within the past 14 months from 77 centers in 18 countries were randomly assigned to receive sorafenib at 400 mg twice daily (n = 207) or placebo (n = 210). Patients had to have at least one measurable lesion on computed tomography or magnetic resonance imaging, Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 2, adequate bone marrow, liver, and renal function, and serum thyroid-stimulating hormone concentration < 0.5 mIU/L. The primary endpoint was progression-free survival assessed every 8 weeks

61% white, 23% and 25% Asian), metastases (distant in 97% and 96%), time from diagnosis (median, 66 and 67 months), ECOG performance status (0 in 63% and 62%, 1 in 33% and 35%, 2 in 3% and 3%), histology (eg, papillary in 57% in both, follicular-oncocytic in 18% in both, poorly differentiated in 12% and 8%), metastatic sites (eg, lung

These results suggest that sorafenib is a new treatment option for patients with progressive radioactive iodinerefractory differentiated thyroid cancer.

—Marcia S. Brose, MD, PhD, and colleagues

in 86% in both, lymph nodes in 55% and 48%, bone in 28% and 27%), FDG uptake (positive in 78% and 76%), and previous treatment (median cumulative radioiodine activity, 400 and 376 mCi; systemic therapy in 3% in both; radiotherapy in 40% and 43%).

Prolonged Progression-Free Survival Median follow-up was 16.2 months.

Median progression-free survival was 10.8 months in the sorafenib group vs 5.8 months in the placebo group (hazard ratio [HR] = 0.59, P < .0001). Progressionfree survival was improved with sorafenib in all prespecified clinical and genetic biomarker subgroups, irrespective of mutation status.

Tumor mutation data, available for 60% of patients, showed BRAF mutations in 27.0% of sorafenib patients vs 33.1% of placebo patients and RAS mutations in 19.0% vs 20.0%. BRAF mutation

Sorafenib in Thyroid Cancer ■■ Sorafenib reduced risk of progression or death by 41%.

■■ Sorafenib prolonged progression-free survival in patients with and without BRAF mutation and in those with and without RAS mutation.

by central independent review. Patients in the placebo group could cross over to sorafenib at disease progression.

The sorafenib and placebo groups were generally balanced for age (median, 63 years in both), sex (50% and 55% female), ethnicity (eg, 59% and

and both in those with RAS mutations (5.5 vs 3.5 months, HR = 0.49, P = .045) and those with wild-type RAS (10.8 vs 5.8 months, HR = 0.60, P = .004). Neither BRAF nor RAS mutation status was predictive of sorafenib benefit (P = .653 and P = .422 for interactions).

Multivariate analyses showed that only histology (papillary vs poorly differenti-

frequency was highest in papillary thyroid carcinoma. Median progression-free survival was prolonged with sorafenib both among patients with BRAF mutations (20.5 vs 9.4 months, HR = 0.46, P = .02) and in those with wild-type BRAF (8.9 vs 3.8 months, HR = 0.55, P < .001)

ated), age, and sorafenib treatment were independent predictors of progressionfree survival and that mutation status was not an independent predictor when analysis was restricted to papillary tumors.

Sorafenib also significantly improved progression-free survival irrespective of high or low thyroglobulin concentration.

Objective response rate (all partial responses) was 12.2% vs 0.5% (P < .0001), and median duration of response in the sorafenib group was 10.2 months. Overall survival did not differ between the groups (HR = 0.80, P = .14), and median overall survival had not been reached at the time of data cutoff. Overal1, 71% of placebo patients crossed over to receive open-label sorafenib at disease progression, and 20% of sorafenib patents and 9% of placebo patients received other ­anticancer treatment after progression.

Safety Analysis Most adverse events were mild to moderate and tended to occur early in treatment. The most frequent adverse events of any grade in the sorafenib group were hand-foot skin reaction (76% vs 10% in placebo group), diarrhea (69% vs 15%), alopecia (67% vs 8%), rash or desquamation (50% vs 12%), fatigue (50% vs 25%), weight loss (47% vs 14%), hypertension (41% vs 12%), and anorexia (32% vs 5%). The most common grade 3 or 4 adverse events were hand-foot skin reaction (20% vs 0%), hypertension (10% vs 2%), hypocalcemia (9% vs 2%), weight loss (6% vs 1%), fatigue (6% vs 1%), and diarrhea (6% vs 1%).

Serious adverse events occurred in 37% of sorafenib patients vs 26% of those receiving placebo, with the most common being secondary malignancy (4.3% vs 1.9%), dyspnea (3.4% vs 2.9%), and pleural effusion (2.9% vs 1.9%). The increased serious adverse event rate on the sorafenib arm was likely affected, in part, by the fact that patients received sorafenib twice as long as patients in the other arm received placebo. In patients receiving sorafenib, secondary malignancies included squamous cell carcinoma of the skin in 6 patients, melanoma in 1 patient, and single cases of acute myeloid leukemia and bladder cancer. In patients receiving placebo, single cases of bladder cancer, colon carcinoma, pulmonary carcinoid tumors, and gastric cancer were reported.

Adverse events resulted in dose interruption in 66% vs 26% of patients, reduction in 64% vs 9%, and withdrawal in 19% vs 4%. Hand-foot skin reaction was the most common cause of sorafenib dose interruption (27%), reduction (34%), and withdrawal (5%).

Death occurred in 12 sorafenib patients (due to underlying disease in 7, unknown cause in 2, and lung infection, chronic obstructive lung disease, and myocardial infarction in 1 each) and in 6 placebo patients (due to underlying disease in 4 and pulmonary embolism and subdural hematoma in 1 each). Death from myocardial infarction in a sorafenib patient and from subdural hematoma in a placebo patient were considered related to study drug.

The investigators concluded, “Sorafenib significantly improved progression-free survival compared with placebo in patients with progressive radioactive iodinerefractory differentiated thyroid cancer.

Adverse events were consistent with the known safety profile of sorafenib. These results suggest that sorafenib is a new treatment option for patients with progressive radioactive iodine-refractory differentiated thyroid cancer.” n

Disclosure: The study was funded by Bayer HealthCare Pharmaceuticals and Onyx Pharmaceuticals (an Amgen subsidiary). For full disclosures of the study authors, visit www.thelancet.com.

Reference 1. Brose MS, Nutting CM, Jarzab B, et al: Sorafenib in radioactive iodine-refractory, locally advanced or metastatic differentiated thyroid cancer: A randomised, doubleblind, phase 3 trial. Lancet. April 23, 2014 (early release online).

ASCOPost.com | JULY 25, 2014

PAGE 57

Perspective

Progress in Differentiated Thyroid Cancer

By Maria E. Cabanillas, MD, FACE

T

reatment of differentiated thyroid cancer has been slow to advance. Three decades lapsed between the description of the first differentiated thyroid cancer patient being cured by radioactive iodine in the 1940s1 and the report of the study that led to the approval of doxorubicin in the 1970s.2 The approval of doxorubicin was based on scanty evidence of efficacy, and this agent was eventually deemed ineffective and abandoned as a treatment option in this setting. For several decades, the standard of care for these patients was thyroid-stimulating hormone (TSH)-suppressive therapy and observation or referral to clinical trials, which were few and far between.

It was not until 2004 that the first trials with targeted multikinase inhibitors were started in differentiated thyroid cancer, bringing new hope for thyroid cancer patients with advanced radioactive iodine–refractory disease. Thanks to the efforts of several thyroid cancer experts, the U.S. Food and Drug Administration (FDA) has permitted phase III thyroid cancer trials to randomly assign patients to the standard of care, observation (ie, placebo), instead of to the more toxic option, doxorubicin. The culmination of these efforts came in 2013, when the FDA approved sorafenib (Nexavar) for differentiated thyroid cancer on the basis of the landmark DECISION trial.3

DECISION Trial This trial, recently reported by Brose et al in The Lancet and reviewed in this issue of The ASCO Post, enrolled patients with chemotherapynaive disease that had progressed within the past 14 months and randomly assigned them to sorafenib or placebo. The trial allowed for crossover from placebo to sorafenib in case of disease progression, and the primary endpoint of the study was progression-free survival, as opposed to overall survival.

The investigators found an absoDr. Cabanillas is Associate Professor and Faculty Director of Clinical Research, Department of Endocrine Neoplasia & Hormonal Disorders, The University of Texas MD Anderson Cancer Center, Houston.

lute difference in progression-free survival of 5 months (10.8 in the treatment arm vs 5.8 in the placebo arm, hazard ratio [HR] = 0.59, 95% confidence interval [CI] = 0.45–0.76, P < .0001), satisfying the trial’s primary endpoint. Responses in the treatment arm were surprisingly low, and overall survival benefit was not seen; however, at the time of the primary analysis, the median overall survival had not been reached in either arm.

cancer patients, given that sorafenib was shown to decrease quality of life when compared to placebo.5 The discontinuation, drug hold, and dosereduction rates reported—19%, 64%, and 66%, respectively—were surprisingly higher than those in phase III sorafenib trials in other solid tumors. For example, in renal cell carcinoma, the discontinuation, drug hold, and dose-reduction rates were 10%, 21%, and 13%, respectively, and

Patients should only be treated with these targeted drugs if they have clinically significant, radioactive iodine–refractory, progressive disease. This point cannot be stressed enough, given the drugs’ toxicity, the fact that responses are temporary and not maintained after drug discontinuation, and the lack of a clear overall survival benefit.

—Maria E. Cabanillas, MD, FACE

Furthermore, the trial allowed for crossover, rendering overall survival difficult to assess. Even if crossover had not been permitted, patients might have sought out a commercial supply of sorafenib or another clinical trial, which also could have affected overall survival assessment. An update on overall survival presented at the 2014 ASCO Annual Meeting adjusted for crossover,4 but the results were inconclusive.

Quality-of-Life Considerations The DECISION results are groundbreaking, given that few advances have been made in thyroid cancer for the past several decades.

Brose et al should be commended for their accomplishment in carrying out and completing the first targeted multikinase inhibitor phase III trial in differentiated thyroid cancer.

That being said, it is still not clear whether the progression-free survival advantage without clear-cut evidence of overall survival advantage is truly beneficial to differentiated thyroid

in hepatocellular carcinoma, they were 11%, 44%, and 26%.

These results seem to suggest that sorafenib is more toxic in thyroid cancer patients, a finding that is explained by the recent study presented at the 2014 ASCO Annual Meeting6 showing increased sorafenib exposure (area under the concentration-time curve) in differentiated thyroid cancer patients as compared to those with renal cell carcinoma and hepatocellular carcinoma. Given that these drugs are chronic, continuous therapies that are toxic and in some cases can lead to death, sorafenib and other similar targeted agents should be reserved for patients with clinically significant, progressive, radioactive iodine–refractory differentiated thyroid cancer. In the absence of convincing evidence of an overall survival advantage, cautious use of sorafenib is recommended.

SELECT Trial The search for more effective treatments for advanced thyroid cancer has not ended with the DECISION trial.

Results of the SELECT trial, presented at the 2014 ASCO Annual Meeting by Schlumberger et al,7 represent the most exciting results in a thyroid cancer phase III trial to date. This trial of lenvatinib (E7080), a multikinase inhibitor of VEGFR1-3, FGFR1-4, PDGFRα, RET, and KIT, was also a randomized, placebo-controlled trial that allowed crossover.

The treatment population was quite similar; however, in contrast to the DECISION trial, SELECT allowed for one previous line of chemotherapy, and this group accounted for 25% of the patients on the lenvatinib arm. The progression-free survival results were exciting—a median of 18.3 months in lenvatinib group vs 3.6 months in placebo patients (HR = 0.21, 99% CI = 0.14–0.31, P < .0001). A subgroup analysis showed that previously treated patients had a substantial progression-free survival benefit of approximately 1 year. Response rates were very high (65%), and responses were durable.

As with the DECISION trial, SELECT revealed no overall survival advantage, although the median overall survival has not been reached.

The discontinuation, drug hold, and dose-reduction rates in the lenvatinib arm were 14%, 82%, and 68%, respectively; these are comparable to the sorafenib results and, like the sorafenib results, quite high.

Adverse events were similar to those with sorafenib, but lenvatinibtreated patients had a higher frequency of hypertension and a lower frequency of hand-foot skin reaction. A higher incidence of serious adverse events was reported for lenvatinib (51% in the SELECT lenvatinib-treatment arm and 37% in the DECISION sorafenibtreatment arm). Although head-tohead trial evidence is lacking, these results suggest that lenvatinib may be superior in efficacy to sorafenib, possibly at the cost of more toxicity.

Conclusions Sorafenib and lenvatinib are effective in radioactive iodine–refractory differentiated thyroid cancer; however, observation and TSH-suppressive therapy continue to be the standard treatment for most of these patients. continued on page 61

FOR THE TREATMENT OF PATIENTS WITH METASTATIC CASTRATION-RESISTANT PROSTATE CANCER (mCRPC) WHO HAVE PREVIOUSLY RECEIVED DOCETAXEL

18.4 MONTHS MEDIAN OVERALL SURVIVAL VS 13.6 MONTHS WITH PLACEBO1

XTANDI (enzalutamide) capsules is indicated for the treatment of patients with metastatic castration-resistant prostate cancer (mCRPC) who have previously received docetaxel.

Important Safety Information Contraindications XTANDI can cause fetal harm when administered to a pregnant woman based on its mechanism of action. XTANDI is not indicated for use in women. XTANDI is contraindicated in women who are or may become pregnant.

Warnings and Precautions In the randomized clinical trial, seizure occurred in 0.9% of patients on XTANDI. No patients on the placebo arm experienced seizure. Patients experiencing a seizure were permanently discontinued from therapy. All seizures resolved. Patients with a history of seizure, taking medications known to decrease the seizure threshold, or with other risk factors for seizure were excluded from the clinical trial. Because of the risk of seizure associated with XTANDI use, patients should be advised of the risk of engaging in any activity where sudden loss

of consciousness could cause serious harm to themselves or others.

Adverse Reactions The most common adverse drug reactions (â&#x2030;Ľ 5%) reported in patients receiving XTANDI in the randomized clinical trial were asthenia/fatigue, back pain, diarrhea, arthralgia, hot ďŹ&#x201A;ush, peripheral edema, musculoskeletal pain, headache, upper respiratory infection, muscular weakness, dizziness, insomnia, lower respiratory infection, spinal cord compression and cauda equina syndrome, hematuria, paresthesia, anxiety, and hypertension.

Grade 1-4 neutropenia occurred in 15% of XTANDI patients (1% grade 3-4) and in 6% of patients on placebo (no grade 3-4). Grade 1-4 elevations in bilirubin occurred in 3% of XTANDI patients and 2% of patients on placebo. One percent of XTANDI patients compared to 0.3% of patients on placebo died from infections or sepsis. Falls or injuries related to falls occurred in 4.6% of XTANDI patients vs 1.3% of patients on placebo. Falls were not associated with loss of consciousness or seizure. Fall-related injuries were more severe

Convenient, oral, once-daily administration • Dosed as four 40 mg capsules (160 mg) without food restrictions or steroid requirements. Each capsule should be swallowed whole. Patients should not chew, dissolve, or open the capsules1,2 Comparable overall rate of grade 3-4 adverse reactions • No increased overall rate of grade 3-4 adverse reactions with XTANDI vs placebo (47% vs 53%, respectively)1 37% reduced risk of death • HR = 0.63 (95% CI, 0.53-0.75); P < 0.00011 NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) include enzalutamide (XTANDI) with a category 1 recommendation for use following docetaxel in patients with mCRPC.3

in XTANDI patients and included nonpathologic fractures, joint injuries, and hematomas. Grade 1 or 2 hallucinations occurred in 1.6% of XTANDI patients and 0.3% of patients on placebo, with the majority on opioid-containing medications at the time of the event.

Drug Interactions: Effect of Other Drugs on XTANDI Administration of strong CYP2C8 inhibitors can increase the plasma exposure to XTANDI. Coadministration of XTANDI with strong CYP2C8 inhibitors should be avoided if possible. If coadministration of XTANDI cannot be avoided, reduce the dose of XTANDI. Coadministration of XTANDI with strong or moderate CYP3A4 and CYP2C8 inducers can alter the plasma exposure of XTANDI and should be avoided if possible.

Effect of XTANDI on Other Drugs XTANDI is a strong CYP3A4 inducer and a moderate CYP2C9 and CYP2C19 inducer in humans.

Avoid CYP3A4, CYP2C9, and CYP2C19 substrates with a narrow therapeutic index, as XTANDI may decrease the plasma exposures of these drugs. If XTANDI is

coadministered with warfarin (CYP2C9 substrate), conduct additional INR monitoring.

Please see adjacent pages for Brief Summary of Full Prescribing Information.

References: 1. XTANDI [package insert]. Northbrook, IL: Astellas Pharma US, Inc; 2012. 2. Scher HI, Fizazi K, Saad F, et al. Increased survival with enzalutamide in prostate cancer after chemotherapy. N Engl J Med. 2012;367:1187-1197. 3. Referenced with permission from The NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Prostate Cancer V.2.2013. © National Comprehensive Cancer Network, Inc 2013. All rights reserved. Accessed March 11, 2013. To view the most recent and complete version of the guideline, go online to www.nccn.org. NATIONAL COMPREHENSIVE CANCER NETWORK®, NCCN®, NCCN GUIDELINES®, and all other NCCN Content are trademarks owned by the National Comprehensive Cancer Network, Inc.

Learn L earn m more ore a att X XtandiHCP.com tandiHCP.c com

© 2013 Astellas Pharma US, Inc. All rights reserved. Printed in USA. 013E-076-7984-3 12/13 XTANDI, Astellas, and the flying star logo are trademarks of Astellas Pharma Inc.

XTANDI® (enzalutamide) capsules for oral use Initial U.S. Approval: 2012 BRIEF SUMMARYOF PRESCRIBING INFORMATION The following is a brief summary: please see the package insert for full prescribing information.

INDICATIONS AND USAGE XTANDI is indicated for the treatment of patients with metastatic castration-resistant prostate cancer who have previously received docetaxel.

CONTRAINDICATIONS Pregnancy XTANDI can cause fetal harm when administered to a pregnant woman based on its mechanism of action. XTANDI is not indicated for use in women. XTANDI 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 and the potential risk for pregnancy loss [see Use in Specific Populations].

WARNINGS AND PRECAUTIONS Seizure In the randomized clinical trial, 7 of 800 (0.9%) patients treated with XTANDI 160 mg once daily experienced a seizure. No seizures occurred in patients treated with placebo. Seizures occurred from 31 to 603 days after initiation of XTANDI. Patients experiencing seizure were permanently discontinued from therapy and all seizures resolved. There is no clinical trial experience re-administering XTANDI to patients who experienced seizures.

The safety of XTANDI in patients with predisposing factors for seizure is not known because these patients were excluded from the trial. These exclusion criteria included a history of seizure, underlying brain injury with loss of consciousness, transient ischemic attack within the past 12 months, cerebral vascular accident, brain metastases, brain arteriovenous malformation or the use of concomitant medications that may lower the seizure threshold.

Because of the risk of seizure associated with XTANDI use, patients should be advised of the risk of engaging in any activity where sudden loss of consciousness could cause serious harm to themselves or others.

ADVERSE REACTIONS 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.

In the randomized clinical trial in patients with metastatic castration-resistant prostate cancer who had previously received docetaxel, patients received XTANDI 160 mg orally once daily (N = 800) or placebo (N = 399). The median duration of treatment was 8.3 months with XTANDI and 3.0 months with placebo. All patients continued androgen deprivation therapy. Patients were allowed, but not required, to take glucocorticoids. During the trial, 48% of patients on the XTANDI arm and 46% of patients on the placebo arm received glucocorticoids. All adverse events and laboratory abnormalities were graded using NCI CTCAE version 4.

The most common adverse drug reactions (≥ 5%) reported in patients receiving XTANDI in the randomized clinical trial were asthenia/fatigue, back pain, diarrhea, arthralgia, hot flush, peripheral edema, musculoskeletal pain, headache, upper respiratory infection, muscular weakness, dizziness, insomnia, lower respiratory infection, spinal cord compression and cauda equina syndrome, hematuria, paresthesia, anxiety, and hypertension. Grade 3 and higher adverse reactions were reported among 47% of XTANDI-treated patients and 53% of placebo-treated patients. Discontinuations due to adverse events were reported for 16% of XTANDI-treated patients and 18% of placebo-treated patients. The most common adverse reaction leading to treatment discontinuation was seizure, which occurred in 0.9% of the XTANDI-treated patients compared to none (0%) of the placebo-treated patients.

Table 1 shows adverse reactions reported in the randomized clinical trial that occurred at a ≥ 2% absolute increase in frequency in the XTANDI arm compared to the placebo arm.

Table 1. Adverse Reactions in the Randomized Trial XTANDI N = 800 Grade 1-4 (%) Grade 3-4 (%)

General Disorders Asthenic Conditionsa 50.6 Peripheral Edema 15.4 Musculoskeletal And Connective Tissue Disorders Back Pain 26.4 Arthralgia 20.5 Musculoskeletal Pain 15.0 Muscular Weakness 9.8 Musculoskeletal Stiffness 2.6 Gastrointestinal Disorders Diarrhea 21.8 Vascular Disorders Hot Flush 20.3 Hypertension 6.4 Nervous System Disorders Headache 12.1 Dizzinessb 9.5 Spinal Cord Compression and 7.4 Cauda Equina Syndrome Paresthesia 6.6 Mental Impairment Disordersc 4.3 Hypoesthesia 4.0 Infections And Infestations Upper Respiratory Tract 10.9 Infectiond Lower Respiratory Tract And 8.5 Lung Infectione Psychiatric Disorders Insomnia 8.8 Anxiety 6.5 Renal And Urinary Disorders Hematuria 6.9 Pollakiuria 4.8 Injury, Poisoning And Procedural Complications Fall 4.6 Non-pathologic Fractures 4.0 Skin And Subcutaneous Tissue Disorders Pruritus 3.8 Dry Skin 3.5 Respiratory Disorders Epistaxis 3.3 a b c d e

Placebo N = 399 Grade 1-4 (%) Grade 3-4 (%)

9.0 1.0

44.4 13.3

9.3 0.8

5.3 2.5 1.3 1.5 0.3

24.3 17.3 11.5 6.8 0.3

4.0 1.8 0.3 1.8 0.0

1.1

17.5

0.3

0.0 2.1

10.3 2.8

0.0 1.3

0.9 0.5 6.6

5.5 7.5 4.5

0.0 0.5 3.8

0.0 0.3 0.3

4.5 1.8 1.8

0.0 0.0 0.0

0.0

6.5

0.3

2.4

4.8

1.3

0.0 0.3

6.0 4.0

0.5 0.0

1.8 0.0

4.5 2.5

1.0 0.0

0.3 1.4

1.3 0.8

0.0 0.3

0.0 0.0

1.3 1.3

0.0 0.0

0.1

1.3

0.3

Includes asthenia and fatigue.

Includes dizziness and vertigo.

Includes amnesia, memory impairment, cognitive disorder, and disturbance in attention.

Includes nasopharyngitis, upper respiratory tract infection, sinusitis, rhinitis, pharyngitis, and laryngitis.

Includes pneumonia, lower respiratory tract infection, bronchitis, and lung infection.

Laboratory Abnormalities In the randomized clinical trial, Grade 1-4 neutropenia occurred in 15% of patients on XTANDI (1% Grade 3-4) and in 6% of patients on placebo (no Grade 3-4). The incidence of Grade 1-4 thrombocytopenia was similar in both arms; 0.5% of patients on XTANDI and 1% on placebo experienced Grade 3-4 thrombocytopenia. Grade 1-4 elevations in ALT occurred in 10% of patients on XTANDI (0.3% Grade 3-4) and 18% of patients on placebo (0.5% Grade 3-4). Grade 1-4 elevations in bilirubin occurred in 3% of patients on XTANDI and 2% of patients on placebo.

Infections In the randomized clinical trial, 1.0% of patients treated with XTANDI compared to 0.3% of patients on placebo died from infections or sepsis. Infection-related serious adverse events were reported in approximately 6% of the patients on both treatment arms.

Falls and Fall-related Injuries In the randomized clinical trial, falls or injuries related to falls occurred in 4.6% of patients treated with XTANDI compared to 1.3% of patients on placebo. Falls were not associated with loss of consciousness or seizure. Fallrelated injuries were more severe in patients treated with XTANDI and included non-pathologic fractures, joint injuries, and hematomas.

Hallucinations In the randomized clinical trial, 1.6% of patients treated with XTANDI were reported to have Grade 1 or 2 hallucinations compared to 0.3% of patients on placebo. Of the patients with hallucinations, the majority were on opioid-containing medications at the time of the event. Hallucinations were visual, tactile, or undefined.

DRUG INTERACTIONS Drugs that Inhibit or Induce CYP2C8 Co-administration of a strong CYP2C8 inhibitor (gemfibrozil) increased the composite area under the plasma concentration-time curve (AUC) of enzalutamide plus N-desmethyl enzalutamide in healthy volunteers.

Co-administration of XTANDI with strong CYP2C8 inhibitors should be avoided if possible. If co-administration of XTANDI with a strong CYP2C8 inhibitor cannot be avoided, reduce the dose of XTANDI [see Dosage and Administration (2.2) and Clinical Pharmacology (12.3)].

The effects of CYP2C8 inducers on the pharmacokinetics of enzalutamide have not been evaluated in vivo.

Co-administration of XTANDI with strong or moderate CYP2C8 inducers (e.g., rifampin) may alter the plasma exposure of XTANDI and should be avoided if possible. Selection of a concomitant medication with no or minimal CYP2C8 induction potential is recommended [see Clinical Pharmacology].

Drugs that Inhibit or Induce CYP3A4 Co-administration of a strong CYP3A4 inhibitor (itraconazole) increased the composite AUC of enzalutamide plus N-desmethyl enzalutamide by 1.3 fold in healthy volunteers [see Clinical Pharmacology (12.3)].

The effects of CYP3A4 inducers on the pharmacokinetics of enzalutamide have not been evaluated in vivo.

Co-administration of XTANDI with strong CYP3A4 inducers (e.g., carbamazepine, phenobarbital, phenytoin, rifabutin, rifampin, rifapentine) may decrease the plasma exposure of XTANDI and should be avoided if possible.

Selection of a concomitant medication with no or minimal CYP3A4 induction potential is recommended. Moderate CYP3A4 inducers (e.g., bosentan, efavirenz, etravirine, modafinil, nafcillin) and St. John’s Wort may also reduce the plasma exposure of XTANDI and should be avoided if possible [see Clinical Pharmacology ].

Effect of XTANDI on Drug Metabolizing Enzymes Enzalutamide is a strong CYP3A4 inducer and a moderate CYP2C9 and CYP2C19 inducer in humans. At steady state, XTANDI reduced the plasma exposure to midazolam (CYP3A4 substrate), warfarin (CYP2C9 substrate), and omeprazole (CYP2C19 substrate). Concomitant use of XTANDI with narrow therapeutic index drugs that are metabolized by CYP3A4 (e.g., alfentanil, cyclosporine, dihydroergotamine, ergotamine, fentanyl, pimozide, quinidine, sirolimus and tacrolimus), CYP2C9 (e.g., phenytoin, warfarin) and CYP2C19 (e.g., S-mephenytoin) should be avoided, as enzalutamide may decrease their exposure. If co-administration with warfarin cannot be avoided, conduct additional INR monitoring [see Clinical Pharmacology ].

USE IN SPECIFIC POPULATIONS Pregnancy- Pregnancy Category X [see Contraindications].

XTANDI 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 XTANDI in pregnancy and XTANDI is not indicated for use in women, it is important to know that maternal use of an androgen receptor inhibitor could affect development of the fetus. XTANDI 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 XTANDI. Nursing Mothers XTANDI is not indicated for use in women. It is not known if enzalutamide 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 XTANDI, a decision should be made to either discontinue nursing, or discontinue the drug taking into account the importance of the drug to the mother.

Pediatric Use Safety and effectiveness of XTANDI in pediatric patients have not been established.

Geriatric Use Of 800 patients who received XTANDI in the randomized clinical trial, 71 percent were 65 and over, while 25 percent were 75 and over. No overall differences in safety or effectiveness were observed between these patients and younger patients. Other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out.

Patients with Renal Impairment A dedicated renal impairment trial for XTANDI has not been conducted. Based on the population pharmacokinetic analysis using data from clinical trials in patients with metastatic castration-resistant prostate cancer and healthy volunteers, no significant difference in enzalutamide clearance was observed in patients with pre-existing mild to moderate renal impairment (30 mL/min ≤ creatinine clearance [CrCL] ≤ 89 mL/min) compared to patients and volunteers with baseline normal renal function (CrCL ≥ 90 mL/min). No initial dosage adjustment is necessary for patients with mild to moderate renal impairment. Severe renal impairment (CrCL < 30 mL/min) and end-stage renal disease have not been assessed [see Clinical Pharmacology].

Patients with Hepatic Impairment A dedicated hepatic impairment trial compared the composite systemic exposure of enzalutamide plus N-desmethyl enzalutamide in volunteers with baseline mild or moderate hepatic impairment (Child-Pugh Class A and B, respectively) versus healthy controls with normal hepatic function. The composite AUC of enzalutamide plus N-desmethyl enzalutamide was similar in volunteers with mild or moderate baseline hepatic impairment compared to volunteers with normal hepatic function. No initial dosage adjustment is necessary for patients with baseline mild or moderate hepatic impairment. Baseline severe hepatic impairment (Child-Pugh Class C) has not been assessed [see Clinical Pharmacology].

OVERDOSAGE In the event of an overdose, stop treatment with XTANDI and initiate general supportive measures taking into consideration the half-life of 5.8 days. In a dose escalation study, no seizures were reported at < 240 mg daily, whereas 3 seizures were reported, 1 each at 360 mg, 480 mg, and 600 mg daily. Patients may be at increased risk of seizures following an overdose.

Carcinogenesis, Mutagenesis, Impairment of Fertility Long-term animal studies have not been conducted to evaluate the carcinogenic potential of enzalutamide.

Enzalutamide did not induce mutations in the bacterial reverse mutation (Ames) assay and was not genotoxic in either the in vitro mouse lymphoma thymidine kinase (Tk) gene mutation assay or the in vivo mouse micronucleus assay.

Based on nonclinical findings in repeat-dose toxicology studies, which were consistent with the pharmacological activity of enzalutamide, male fertility may be impaired by treatment with XTANDI. In a 26-week study in rats, atrophy of the prostate and seminal vesicles was observed at ≥ 30 mg/kg/day (equal to the human exposure based on AUC). In 4- and 13-week studies in dogs, hypospermatogenesis and atrophy of the prostate and epididymides were observed at ≥ 4 mg/kg/day (0.3 times the human exposure based on AUC).

PATIENT COUNSELING INFORMATION See FDA-approved patient labeling (PATIENT INFORMATION).

• Instruct patients to take their dose at the same time each day (once daily). XTANDI can be taken with or without food. Each capsule should be swallowed whole. Do not chew, dissolve, or open the capsules.

• Inform patients receiving a GnRH analog that they need to maintain this treatment during the course of treatment with XTANDI. • Inform patients that XTANDI has been associated with an increased risk of seizure. Discuss conditions that may predispose to seizures and medications that may lower the seizure threshold. Advise patients of the risk of engaging in any activity where sudden loss of consciousness could cause serious harm to themselves or others.

• Inform patients that XTANDI may cause dizziness, mental impairment, paresthesia, hypoesthesia, and falls.

• Inform patients that they should not interrupt, modify the dose, or stop XTANDI without first consulting their physician. Inform patients that if they miss a dose, then they should take it as soon as they remember. If they forget to take the dose for the whole day, then they should take their normal dose the next day. They should not take more than their prescribed dose per day.

• Apprise patients of the common side effects associated with XTANDI: asthenia/fatigue, back pain, diarrhea, arthralgia, hot flush, peripheral edema, musculoskeletal pain, headache, upper respiratory infection, muscular weakness, dizziness, insomnia, lower respiratory infection, spinal cord compression and cauda equina syndrome, hematuria, paresthesia, anxiety, and hypertension. Direct the patient to a complete list of adverse drug reactions in PATIENT INFORMATION. • Inform patients that XTANDI may be harmful to a developing fetus. Patients should also be informed that they should use a condom if having sex with a pregnant woman. A condom and another effective method of birth control should be used if the patient is having sex with a woman of child-bearing potential. These measures are required during and for three months after treatment with XTANDI. Manufactured by: Manufactured for and Distributed by: Catalent Pharma Solutions, LLC, Astellas Pharma US, Inc., St. Petersburg, FL 33716 Northbrook, IL 60062 Marketed by: Astellas Pharma US, Inc., Northbrook, IL 60062 Medivation, Inc., San Francisco, CA 94105 Issued: August 2012 12A005-ENZ-BRS Rx Only © 2012 Astellas Pharma US, Inc. XTANDI® is a registered trademark of Astellas Pharma Inc. 0131-076-8930

ASCOPost.com | JULY 25, 2014

PAGE 61

Perspective

Maria E. Cabanillas, MD, FACE continued from page 57

Again, patients should only be treated with these targeted drugs if they have clinically significant, radioactive iodine– refractory, progressive disease. This point cannot be stressed enough, given the drugs’ toxicity, the fact that responses are temporary and not maintained after drug discontinuation, and the lack of a clear overall survival benefit.

Certainly, significant strides in differentiated thyroid cancer treatment have been made over the past 70 years and, without a doubt, will continue to be made. The next challenges are to identify effective treatments for patients in whom first-line therapy fails, to find less

toxic alternatives, to improve quality of life in patients on these systemic therapies, and, ultimately, to find a cure for advanced, radioactive iodine–refractory differentiated thyroid cancer. n Disclosure: Dr. Cabanillas has received research funding and is on the advisory board (uncompensated) for Eisai.

References 1. Seidlin SM, Marinelli LD, Oshry E: Radioactive iodine therapy: Effect on functioning metastases of adenocarcinoma of the thyroid. JAMA 132:838-847, 1946.

2. Gottlieb JA, Hill CS Jr, Ibanez ML, et al: Chemotherapy of thyroid cancer. An evaluation of experience with 37 patients.

Cancer 30:848-853, 1972.

3. Brose MS, Nutting CM, Jarzab B, et

al: Sorafenib in radioactive iodine-refractory, locally advanced or metastatic differentiated thyroid cancer: A randomised, double-blind, phase 3 trial. Lancet. April 23, 2014 (early release online).

4. Brose MS, Jarzab B, Elisei R, et al: Updated overall survival analysis of patients with locally advanced or metastatic radioactive iodine-refractory differentiated thyroid caner (RAI-rDTC) treated with sorafenib in the phase 3 DECISION trial. ASCO Annual Meeting. Abstract 6060. Presented May 31, 2014.

5. Schlumberger M, Jarzab B, Elisei R, et al: Phase III randomized, double-blinded, placebo-controlled trial of sorafenib in locally advanced or metastatic patients with radioactive iodine (RAI)-refractory differentiated

thyroid cancer (DTC): Exploratory analyses of patient-reported outcomes. American Thyroid Association Annual Meeting, Abstract 100. Presented October 18, 2013.

6. Bastholt L, Brose MS, Jarzab B, et al: Population PK modeling and exposure-response analyses of sorafenib in patients with radioactive iodine-refractory differentiated thyroid cancer (RAI-rDTC) in the phase III DECISION trial. ASCO Annual Meeting.

Abstract 6061. Presented May 31, 2014.

7. Schlumberger M, Tahara M, Wirth LJ, et al: A phase 3, multicenter, doubleblind, placebo-controlled trial of lenvatinib (E7080) in patients with 131I-refractory differentiated thyroid cancer (SELECT).

ASCO Annual Meeting. Abstract LBA6008.

Presented June 2, 2014.

Journal Spotlight Gastrointestinal Oncology

Rilotumumab Added to First-Line Chemotherapy May Benefit Patients With Advanced Gastric or Esophagogastric Junction Adenocarcinoma

By Matthew Stenger

H

epatocyte growth factor (HGF) and its receptor MET have been found to promote the proliferation, migration, and survival of tumor cells and to play a role in gastric cancer. In a phase II study reported in The Lancet Oncology, Timothy Iveson, MD, of the University

Study Details In this double-blind study, 121 patients with unresectable disease were randomly assigned to receive rilotumumab at 15 mg/kg (n = 40) or 7.5 mg/ kg (n = 42) or placebo (n = 39) on day 1 in combination with ECX (epirubicin at 50 mg/m2

Rilotumumab plus ECX had no unexpected safety signals and showed greater activity than placebo plus ECX. A phase 3 study of the combination in METpositive gastric and oesophagogastric junction cancer is in progress.

—Timothy Iveson, MD, and colleagues

Hospital Southampton NHS Foundation Trust, United Kingdom, and colleagues found evidence of benefit from adding the investigational anti-HGF monoclonal antibody rilotumumab to epirubicin, cisplatin, and capecitabine (ECX) in first-line treatment of advanced gastric or esophagogastric junction cancer.1

on day 1, cisplatin at 60 mg/m2 on day 1, capecitabine at 625 mg/m2 twice a day on days 1–21) every 3 weeks. The primary endpoint was progression-free survival.

The three treatment groups were genrally balanced for age (median, 59–62 years), sex (68%–79% male), race/ethnicity (69%–83% white), Eastern Coopera-

Rilotumumab in Gastric Cancer ■■ The combined rilotumumab group had significantly prolonged progressionfree survival compared with epirubicin, cisplatin, and capecitabine alone.

■■ Rilotumumab treatment was associated with higher rates of grade 3 or 4 neutropenia and venous thromboembolism.

tive Oncology Group performance status (0 in 36%–48%, 1 in 53%–62%), primary tumor location (gastric in 79%–83%), disease extent (metastatic in 87%–90%), previous curative surgery (15%–23%), previous radiotherapy (2%–8%), and previous adjuvant (3%–5%) and neoadjuvant chemotherapy (5% in all).

Increased Progression-Free Survival Median follow-up was 21.7 months.

Median progression-free survival was 5.1 months in the rilotumumab at 15 mg/kg group (hazard ratio [HR] = 0.69, P = .164, vs placebo), 6.8 months in the 7.5 mg/kg group (HR = 0.53, P = .009), and 5.7 months in the combined groups (HR = 0.60, P = .016) vs 4.2 months in the placebo group.

Objective response occurred in 31%, 48%, 39%, and 21% of patients, in the 15 mg/kg of rilotumumab, 7.5 mg/kg, combined, and placebo groups, respectively.

Median overall survival was 9.7 months (HR = 0.68, P = .149), 11.1 months (HR = 0.79, P = .354), 10.6 months (HR = 0.70, P = .109), and 8.9 months, respectively.

Toxicity Adverse events of any grade that were more common in the rilotumumab combination group than in the placebo group included hematologic adverse events (neutropenia in 54% vs 33%, ane-

mia in 40% vs 28%, and thrombocytopenia in 11% vs 0%), peripheral edema (27% vs 8%), and venous thromboembolism (20% vs 13%). Grade 3 or 4 adverse events that were more common in rilotumumab patients included neutropenia (44% vs 28%) and venous thromboembolism (20% vs 10%).

Serious adverse events were similar in the treatment groups except for a greater frequency of anemia (12% vs 0%) with rilotumumab. Adverse events led to dose reduction or interruption in 14% of the combined rilotumumab group vs 8% of the placebo group and discontinuation of treatment in 27% vs 8%.

The investigators concluded, “Rilotumumab plus ECX had no unexpected safety signals and showed greater activity than placebo plus ECX. A phase 3 study of the combination in MET-positive gastric and oesophagogastric junction cancer is in progress.” n

Disclosure: The study was funded by Amgen Inc. For full disclosures of the study authors, visit www.thelancet.com.

Reference 1. Iveson T, Donehower RC, Davidenko I, et al: Rilotumumab in combination with epirubicin, cisplatin, and capecitabine as firstline treatment for gastric or oesophagogastric junction adenocarcinoma: An open-label, dose de-escalation phase 1b study and a double-blind, randomised phase 2 study. Lancet Oncol. June 23, 2014 (early release online).

The ASCO Post | JULY 25, 2014

PAGE 62

Journal Spotlight Breast Cancer

Swiss Medical Board Members Discuss Recommendation to Phase Out Mammography Screening

By Matthew Stenger

I

n a New England Journal of Medicine “Perspective” article, Nikola BillerAndorno, MD, PhD, of the University of Zurich and Harvard Medical School, and Peter Jüni, MD, of the

mammography screening programs be introduced and that existing programs be subject to a time limit.2 The report also emphasized that the quality of all forms of mammography screening

From an ethical perspective, a public health program that does not clearly produce more benefits than harms is hard to justify. Providing clear, unbiased information, promoting appropriate care, and preventing overdiagnosis and overtreatment would be a better choice.

—Nikola Biller-Andorno, MD, PhD, and Peter Jüni, MD

University of Bern, provide the rationale for a recent report by the Swiss Medical Board advocating the phasing out of mammography screening programs in Switzerland.1 The board recommended that no new systematic

should be evaluated and that women should receive clear and balanced information on the benefits and harms of screening.

Drs. Biller-Andorno and Jüni were members of the nongovernmental

board, the recommendations of which are not legally binding. The authors, a medical ethicist and a clinical epidemiologist, were joined on the board’s expert panel by a clinical pharmacologist, an oncologic surgeon, a nurse scientist, a lawyer, and a health economist.

Benefit and Harm As related by the authors, based on review of available evidence, it is estimated that systematic mammography screening might prevent approximately 1 death from breast cancer for every 1,000 women screened. There is currently no evidence that this benefit has an effect on overall mortality.

Weighed against this benefit is the likelihood of harm. For every breast cancer death prevented in U.S. women over 10 years of annual screening beginning at age 50 years, it is estimated that 490 to 670 women would have a false-positive mammogram with repeat examination, 70 to 100 would undergo unnecessary biopsy, and 3 to 14 would have an overdiagnosed breast cancer that would never have become clinically apparent.3

Old Data The authors note that three major concerns arose during expert panel

review of evidence on the effects of screening. First, evidence of benefits appears to be largely based on a series of re-analyses of predominantly outdated trials, the first of which began 50 years ago and the last of which began in 1991.4 Given that none of the trials include data reflecting the dramatic improvement in prognosis of breast cancer that has occurred in the more modern era of breast cancer treatment, the authors ask, “Could the modest benefit of mammography screening in terms of breast-cancer mortality that was shown in trials initiated between 1963 and 1991 still be detected in a trial conducted today?”

Burden of Harms Second, the authors note being struck by “how nonobvious it was that the benefits of mammography screening outweighed the harms.” They observe that the widely cited relative risk reduction of approximately 20% in breast cancer mortality associated with mammography5 comes at the price of a considerable burden of repeat mammography, subsequent biopsies, and overdiagnosis.

In this regard, they refer to the finding in the recently reported 25year follow-up of the Canadian Na-

Swiss Medical Board Recommendation to End Mammography Screening: A Disturbing Proposal

By Carol H. Lee, MD, FACR

D

espite evidence from a number of prospective, randomized controlled trials showing that screening mammography reduces breast cancer mortality, screening mammography has been the subject of continual debate, controversy, and conflicting guidelines.

Recently, the Swiss Medical Board, tasked with reviewing existing data, took the arguments against screening to their extreme, recommending that no new screening mammography programs be introduced and that existing programs be subject to a time limit. This recommendation, explained in a New Dr. Lee is Attending Radiologist, Memorial Sloan Kettering Cancer Center, Professor of Radiology, Weill Cornell Medical College, New York.

England Journal of Medicine article1 that is reviewed in this issue of The ASCO Post, is a stunning example of how vastly different conclusions can be reached from the same data.

The authors cited three main points as the basis of the board’s recommendation: (1) the use of old data to support benefits of mammography, (2) the lack of evidence that benefits of screening outweigh harms, and (3) misperception of the magnitude of screening benefit among screening candidates.

Old Data The authors note that evidence for the benefit of screening is based on old data, with the first trials conducted more than 50 years ago. In the face of improved treatment, they claim, mod-

ern screening may not perform as well.

This statement is based on conjecture rather than on concrete data and does not take into consideration the fact that imaging technology has improved substantially since the first trials were conducted. It is just as valid to postulate that screening may perform better now than in the trials because marked improvements in the technical quality of mammography may result in greater ability to detect early cancer.

The authors cite the recent update of the Canadian National Breast Screening study that did not show a reduction in breast cancer mortality2 but fail to note that seven other randomized controlled trials did indeed show mortality reduction.3-9 They also fail to note that in the United States,

breast cancer mortality remained unchanged for 50 years but began to decline approximately 5 to 7 years after screening mammography became widespread and is now more than 30% lower than in the prescreening era.

Certainly, some of that benefit is due to improved treatment—but treatment of early-stage breast cancer is successful more often than that of late-stage disease, and mammography remains the best way to detect early breast cancer. In addition, it is interesting to note that breast cancer mortality in males, who are not screened but who receive treatment similar to that for females, has not changed during the same period that breast cancer mortality among women has substantially decreased.10 continued on page 64

ASCOPost.com | JULY 25, 2014

PAGE 63

Journal Spotlight

tional Breast Screening Study that 106 (21.9%) of 484 screen-detected cancers were overdiagnoses. Thus, 106 of the 44,925 healthy women in the screening group in the study were diagnosed with and treated for breast cancer unnecessarily, including unnecessary surgical intervention, radiotherapy, and chemotherapy.6 Further, a Cochrane review of 10 trials involving > 600,000 women indicated no evidence of an effect of screening on overall mortality. This analysis suggested that at best, the small reduction in breast cancer mortality is attenuated by death from other causes and, at worst, the reduction is erased by death due to coexisting conditions or by the harms of screening and associated overtreatment.4 Given these considerations, the authors pose the question, “Did the available evidence, taken together, indicate that mammography screening indeed benefits women?”

the conclusions unethical. They note, “One of the main arguments used against [the report] was that it contradicted the global consensus of leading experts in the field—a criticism that made us appreciate our unprejudiced perspective resulting from our lack of exposure to past consensus-building efforts by specialists in breast cancer

screening. Another argument was that the report unsettled women, but we wonder how to avoid unsettling women, given the available evidence.”

The authors concluded:

Mammography Screening Revisited—Again ■■ The authors indicate that it is not at all obvious that the benefit of screening outweighs the large burden of potential harms.

■■ The authors note that women have mistaken beliefs about the benefits of screening and therefore cannot make informed decisions about whether to be screened.

continued on page 64

We Will

Inaccurate Beliefs About Benefit Third, the authors note that they were “disconcerted by the pronounced discrepancy between women’s perceptions of the benefits of mammography screening and the benefits to be expected in reality.” A survey of U.S. women showed that 71.5% believed that mammography reduced risk of breast cancer death by at least half, and 72.1% believed that 80 deaths would be prevented for every 1,000 women invited for screening.7 In light of data indicating that the relative risk reduction is 20% and that 1 death would be prevented for every 1,000 women screened, the authors ask, “How can women make an informed decision if they overestimate the benefit of mammography so grossly?”

The authors state that the report “caused an uproar” and was rejected by a number of Swiss cancer experts and organizations, with some calling

It is easy to promote mammography screening if the majority of women believe that it prevents or reduces the risk of getting breast cancer and saves

many lives through early detection of aggressive tumors. We would be in favor of mammography screening if these beliefs were valid. Unfortunately, they are not, and we believe that women need to be told so. From an ethical perspective, a public health program that does not clearly produce more benefits

exhaust all possibilities.

We will…because patients are our priority.

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The ASCO Post | JULY 25, 2014

PAGE 64

Perspective

Carol H. Lee, MD, FACR continued from page 63

Benefits vs Harms

Second, the authors emphasize how “nonobvious” it was in their review of data that the benefits of screening outweigh the harms. They note that existing data indicate a mortality reduction of 20%, or roughly 1 breast cancer death averted for every 1,000 women screened. They also observe, however, that there was no decrease in all-cause mortality and that the benefit is outweighed by “harms,” consisting of falsepositive readings and overdiagnosis.

However, none of the randomized trials of screening mammography was designed or powered to evaluate allcause mortality. With regard to falsepositive findings, a recall from screening is resolved in the majority of cases by simply performing a few additional mammographic views and/or ultrasound. In a small proportion of cases, a biopsy is necessary to exclude malignancy, but this is usually achieved by minimally invasive core needle biopsy.

These so-called harms are hardly equal to the possible benefit of having a small, treatable breast cancer detected through screening. Indeed, a survey conducted in the United States found that 63% of women thought that 500 false-positive readings was reasonable to save one life and that 37% would tolerate 10,000 false-positive examinations.11 A recent study showed that the anxiety associated with an abnormal screening mammogram is short-lived and does not result in significant psychological harm or a decreased willingness to participate in future screenings.12

Overdiagnosis vs Overtreatment With regard to “overdiagnosis,” the term is a misnomer. Cancers that are detected are histologically malignant and therefore not, strictly speaking,

Mammography Screening continued from page 63

than harms is hard to justify. Providing clear, unbiased information, promoting appropriate care, and preventing overdiagnosis and overtreatment would be a better choice.

Dr. Biller-Andorno is from the Institute of Biomedical Ethics, University of Zurich, and the Division of Medical Ethics, Department of Global Health and Social Medicine, Harvard Medical School. Dr Jüni is from the Institute

overdiagnosed. Because of the inability to differentiate those cancers that would never progress to become lifethreatening from those that would, all cancers are treated as if they are potentially lethal. Therefore, the more correct term in this setting is “overtreatment.”

The degree to which overtreatment occurs is unclear, with estimates varying widely from < 1% to > 50%. In its analysis of the existing literature, the U.S. Preventive Services Task Force

their patients and encourage shared wdecision-making about whether or not to screen.

The recommendation of the Swiss Medical Board that screening mammography no longer be offered to Swiss women is disturbing. A mortality reduction of 1 per 1,000 may not sound significant, but considering that there are millions of women in the United States who are eligible for screening, even a small reduction in mortality rate translates to thousands

A mortality reduction of 1 per 1,000 may not sound significant, but considering that there are millions of women in the United States who are eligible for screening, even a small reduction in mortality rate translates to thousands of deaths avoided.

—Carol H. Lee, MD, FACR

put the estimate at roughly 10%.13 The answer to overdiagnosis or overtreatment should be to develop cellular or molecular means of separating potentially lethal cancers from innocent ones. It is not reasonable to stop screening in order to avoid overtreating a minority of cases while sacrificing the opportunity to detect and appropriately treat the majority.

Public Misperception Finally, the authors conveyed their uneasiness with the fact that the public seems to have a misperception as to the benefits of screening mammography, with the majority grossly overestimating its ability to reduce breast cancer mortality. This does not seem to be a reason to stop screening, but rather constitutes a call for health-care providers to improve education of of Social and Preventive Medicine and Clinical Trials Unit Bern, Department of Clinical Research, University of Bern.

Dr. Biller-Andorno currently is a member of the expert panel of the Swiss Medical Board, and Dr. Jüni was a member of the panel until August 30, 2013. n

Disclosure: For full disclosures of the Perspective authors, visit www.nejm.org.

References 1. Biller-Andorno N, Jüni P: Abolishing mammography screening programs? A view from the Swiss Medical Board. N Engl

of deaths avoided—and it has been repeatedly demonstrated both by prospective trials and by actual clinical experience that mammography does indeed save lives. n

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

References 1. Biller-Andorno N, Jüni P: Abolishing mammography screening programs?

A view from the Swiss Medical Board. N Engl J Med 370:1965-1967, 2014.

2. Miller AB, Wall C, Baines CJ, et al: Twenty five year follow-up for breast cancer incidence and mortality of the Canadian National Breast Screening Study: Randomised screening trial. BMJ 348:366-376, 2014.

3. Shapiro S, Venet W, Strax P, et al: 10- to 14-year effect of screening on breast cancer mortality. J Natl Cancer Inst 69:349-355, 1982.

J Med. April 16, 2014 (early release online).

2. Swiss Medical Board: [The Board of Experts Swiss Medical Board has approved a report on the “Systematic screening by mammography.”] Press release, February 2, 2014. Available at www.medical-board.ch.

3. Welch HG, Passow HJ: Quantifying the benefits and harms of screening mammography. JAMA Intern Med 174:448454, 2014.

4. Gøtzsche PC, Jørgensen KJ: Screening for breast cancer with mammography. Cochrane Database Syst Rev 6:CD001877, 2013.

5. Independent UK Panel on Breast

4. Nystrom L, Andersson I, Bjurstam N, et al: Long-term effects of mammography screening: Updated overview of the Swedish randomised trials. Lancet 359:909-919, 2002.

5. Andersson I, Janzon L: Reduced breast cancer mortality in women under age 50: Updated results from the Malmo Mammographic Screening Program. J Natl Cancer Inst Monogr 63-67, 1997.

6. Tabar L, Fagerberg G, Chen HH, et al: Efficacy of breast cancer screening by age: New results from the Swedish TwoCounty Trial. Cancer 75:2507-2517, 1995.

7. Frisell J, Lidbrink E: The Stockholm Mammographic Screening Trial: Risks and benefits in age group 40-49 years. J Natl Cancer Inst Monogr (22):49-51, 1997.

8. Bjurstam N, Bjorneld L, Duffy SW, et al: The Gothenburg Breast Cancer Screening Trial: preliminary results on breast cancer mortality for women aged 39-49. J Natl Cancer Inst Monogr (22):53-55, 1997.

9. Alexander FE, Anderson TJ, Brown HK, et al: 14 years of follow-up from the Edinburgh randomised trial of breastcancer screening. Lancet 353:1903-1908, 1999.

10. Centers for Disease Control and Prevention: Cancer Statistics by Cancer Type. Available at www.cdc.gov/cancer/ dcpc/data/types.htm. Accessed June 5, 2014.

11. Schwartz LM, Woloshin S, Sox HC, et al: US women’s attitudes to false positive mammography results and detection of carcinoma in situ: A cross sectional study. BMJ 320:1635-140, 2000.

12. Tosteson ANA, Fryback DG, Hammond CS, et al: Consequences of false-positive screening mammograms.

JAMA Intern Med 174:954-961, 2014.

13. Nelson HD, Tyne K, Naik A, et al: U.S. Preventive Services Task Force.

Screening for breast cancer: An update from the U.S. Preventive Services Task Force. Ann Intern Med 151:727-737, 2009.

Cancer Screening: The benefits and harms of breast cancer screening: An independent review. Lancet 380:1778-1786, 2012.

6. Miller AB, Wall C, Baines CJ, et al: Twenty five year follow-up for breast cancer incidence and mortality of the Canadian National Breast Screening Study: Randomised screening trial. BMJ 348:g366, 2014.

7. Domenighetti G, D’Avanzo B, Egger M, et al: Women’s perception of the benefits of mammography screening: Population-based survey in four countries. Int J Epidemiol 32:816-821, 2003.

ASCOPost.com | JULY 25, 2014

PAGE 65

In the Clinic

Belinostat for Relapsed/Refractory Peripheral T-Cell Lymphoma

By Matthew Stenger

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 July 3, 2014, belinostat (Beleodaq) was granted accelerated approval for the treatment of patients with relapsed or refractory peripheral T-cell lymphoma.1,2 As a condition of accelerated approval, the U.S. Food and Drug Administration requires the sponsor to conduct a dose-finding trial of belinostat combined with CHOP (cyclophosphamide, vincristine, doxorubicin, and prednisone) and a subsequent phase III trial comparing belinostat in combination with CHOP vs CHOP alone. Approval was based on tumor response rate and duration of response. Improvement in survival or disease-related symptoms has not been demonstrated.

Supporting Trial Approval was based on the results of a multicenter, single-arm trial of 120 evaluable patients with peripheral T-cell lymphoma refractory to or relapsing after prior treatment. The

Belinostat was given via intravenous infusion at 1,000 mg/m2 once daily on days 1 to 5 of a 21-day cycle.

The overall response rate on independent review was 25.8% (95% confidence interval [CI] = 18.3%–34.6%), with complete and partial response being observed in 10.8% and 15.0% of patients. Median response duration was 8.4 months (95% CI = 4.5–29.4 months). Patients aged ≥ 65 years had a higher response rate compared with those aged < 65 years (36% vs 16%), with no meaningful difference observed between patients aged ≥ 75 vs < 75 years.

How It Works Belinostat is a histone deacetylase (HDAC) inhibitor. HDACs catalyze the removal of acetyl groups from the lysine residues of histones and some nonhistone proteins. Histones act to package DNA into nucleosomes in eukaryotic cell nuclei, with gene expression being dependent on cellular control of the coiling and uncoiling of DNA around the histones.

Studies in vitro show that belinostat causes the accumulation of acetylated histones and other proteins, affecting gene expression and inducing cell-cycle arrest or apoptosis of transformed cells. Belinostat shows preferential cytotoxicity for tumor

Belinostat in Peripheral T-Cell Lymphoma ■■ Belinostat (Beleodaq) was granted accelerated approval for the treatment of patients with relapsed or refractory peripheral T-cell lymphoma.

■■ The recommended dose of belinostat is 1,000 mg/m2 via intravenous infusion over 30 minutes once daily on days 1 to 5 of a 21-day cycle, repeated until disease progression or unacceptable toxicity.

study included patients with baseline platelet counts < 100,000/µL. They had a median age of 64 years (range, 29–81 years), 52% were male, 88% were white, 77% had Eastern Cooperative Oncology Group performance status of 0 or 1, 83% had a platelet count ≥ 100,000/µL, and peripheral T-cell lymphoma subtypes were unspecified in 64%, angioimmunoblastic T-cell lymphoma in 18%, ALK1-negative anaplastic large cell lymphoma in 11%, and other in 7%.

The median time from peripheral T-cell lymphoma diagnosis was 12 months, and the median number of prior treatments was 2 (range, 1–8).

cells vs normal cells. The drug inhibits HDAC activity at nanomolar concentrations (< 250 nM).

How It Is Given The recommended dose of belinostat is 1,000 mg/m2 via intravenous infusion over 30 minutes once daily on days 1 to 5 of a 21-day cycle. Cycles can be repeated until disease pro-

OF NOTE Belinostat is an HDAC inhibitor that shows preferential cytotoxicity for tumor cells vs normal cells.

gression or unacceptable toxicity.

Patients must have an absolute neutrophil count ≥ 1.0 × 109/L, a platelet count ≥ 50 × 109/L, and nonhematologic toxicity ≤ grade 2 before the start of each cycle and before resuming

OF NOTE Belinostat carries warnings/precautions for thrombocytopenia, leukopenia, anemia, serious and fatal infections, hepatotoxicity, tumor lysis syndrome, and embryo-fetal toxicity.

treatment following interruption for toxicity. The dose should be decreased by 25% to 750 mg/m2 for neutrophil count < 0.5 × 109/L, platelet count < 25 × 109/L, or grade 3 or 4 nonhematologic toxicity. Treatment should be discontinued for recurrence of these events after two dose reductions.

Belinostat is primarily metabolized

by UGT1A1. Concomitant administration with strong inhibitors of UGT1A1 (ie, indinavir and atazanavir) should be avoided and the starting dose should be reduced to 750 mg/ m2 in patients homozygous for the UGT1A1*28 allele. Patients with moderate and severe hepatic impairment were excluded from clinical trials of belinostat, and there are insufficient data to recommend a belinostat dose in such patients. Approximately 40% of the belinostat dose is renally excreted; there are insufficient data to recommend a belinostat dose in patients with creatinine clearance ≤ 39 mL/min.

Safety Profile In the trial supporting approval, the most common adverse events of any grade were nausea (42%), fatigue (37%), pyrexia (35%), anemia (32%), and vomiting (29%); thrombocytopenia occurred in 16%. Grade 3 or 4 adverse events occurred in 61% of patients, with the most common being anemia (11%), thrombocytopenia (7%), dyspnea (6%), and fatigue (5%).

Serious adverse events occurred in 47% of patients, with the most common (> 2%) being pneumonia, pyrexia, infection, anemia, increased creatinine, thrombocytopenia, and multiorgan failure. No clinically meaningful differences in serious adverse events were observed in patients aged < 65 vs ≥ 65 years or < 75 vs ≥ 75 years.

Adverse events led to dose reduction in 12% of patients and to discontinuation of treatment in 19%, with discontinuation most commonly due to anemia, febrile neutropenia, fatigue, and multiorgan failure. One treatmentrelated death due to hepatic failure was reported. One patient with baseline hyperuricemia and bulky disease had grade 4 tumor lysis syndrome during the first cycle of treatment and died due to multiorgan failure. A treatmentrelated death from ventricular fibrillation was reported in another monotherapy clinical trial.

Belinostat carries warnings/precautions for thrombocytopenia, leukopenia (neutropenia and lymphopenia), and anemia; serious and fatal infections (eg, pneumonia and sepsis); hepatotoxicity; tumor lysis syndrome; and embryo-fetal toxicity. Complete blood counts should be monitored at baseline and weekly and serum chemistry tests, including renal and hepatic function tests, should be performed prior to the start of each cycle.

Patients with advanced disease or high tumor burden should be monitored for tumor lysis syndrome, with appropriate precautions taken. Women should be advised of potential harm to the fetus and to avoid pregnancy during treatment. n References 1. U.S. Food and Drug Administration: Belinostat. Available at www.fda. gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm403960.htm. ® 2. BELEODAQ (belinostat) for injection prescribing information, Spectrum Pharmaceuticals, Inc, July 2014. Available at www.accessdata.fda.gov/drugsatfda_ docs/label/2014/206256lbl.pdf.

Report Adverse Events Health-care professionals should report all serious adverse events suspected to be associated with the use of any medicine or device to FDA’s MedWatch Reporting System by completing a form online at www.fda.gov/ medwatch/report.htm, by faxing (800-FDA-0178), by mailing the postage-paid address form provided online, or by telephone (800-FDA-1088).

Now FDA Approved For patients with advanced gastric or gastroesophageal (GE) junction adenocarcinoma who have progressed after prior fluoropyrimidine- or platinum-containing chemotherapy, CYRAMZA is the only FDA-approved antiangiogenic to significantly extend overall survival CYRAMZA as a single agent is indicated for the treatment of patients with advanced or metastatic gastric or GE junction adenocarcinoma with disease progression on or after prior fluoropyrimidine- or platinum-containing chemotherapy.

IMPORTANT SAFETY INFORMATION FOR CYRAMZA WARNING: HEMORRHAGE CYRAMZA increased the risk of hemorrhage, including severe and sometimes fatal hemorrhagic events. Permanently discontinue CYRAMZA in patients who experience severe bleeding.

Warnings and Precautions Hemorrhage • CYRAMZA increased the risk of hemorrhage, including severe and sometimes fatal hemorrhagic events. In Study 1, which evaluated CYRAMZA as a single agent in advanced gastric cancer, the incidence of severe bleeding was 3.4% for CYRAMZA and 2.6% for placebo.

Patients with gastric cancer receiving nonsteroid anti-inflammatory drugs (NSAIDs) were excluded from enrollment in Study 1; therefore, the risk of gastric hemorrhage in CYRAMZA-treated patients with gastric tumors receiving NSAIDs is unknown. Permanently discontinue CYRAMZA in patients who experience severe bleeding.

Arterial Thromboembolic Events • Serious, sometimes fatal, arterial thromboembolic events (ATEs) including myocardial infarction, cardiac arrest, cerebrovascular accident, and cerebral ischemia occurred in clinical trials including 1.7% of 236 patients who received CYRAMZA as a single agent for gastric cancer in Study 1. Permanently discontinue CYRAMZA in patients who experience a severe ATE. Hypertension • An increased incidence of severe hypertension occurred in patients receiving CYRAMZA as a single agent (8%) as compared to placebo (3%). Control hypertension prior to initiating treatment with CYRAMZA. Monitor blood pressure every 2 weeks or more frequently as indicated during treatment. Temporarily suspend CYRAMZA for severe hypertension until medically controlled. Permanently discontinue CYRAMZA if medically significant hypertension cannot be controlled with antihypertensive therapy or in patients with hypertensive crisis or hypertensive encephalopathy.

Infusion-Related Reactions • Prior to the institution of premedication recommendations across clinical trials of CYRAMZA, infusion-related reactions (IRRs) occurred

in 6 out of 37 patients (16%), including 2 severe events. The majority of IRRs across trials occurred during or following a first or second CYRAMZA infusion. Symptoms of IRRs included rigors/tremors, back pain/spasms, chest pain and/or tightness, chills, flushing, dyspnea, wheezing, hypoxia, and paresthesia. In severe cases, symptoms included bronchospasm, supraventricular tachycardia, and hypotension.

Monitor patients during the infusion for signs and symptoms of IRRs in a setting with available resuscitation equipment. Immediately and permanently discontinue CYRAMZA for Grade 3 or 4 IRRs. Gastrointestinal Perforations • CYRAMZA is an antiangiogenic therapy that can increase the risk of gastrointestinal perforation, a potentially fatal event. Four of 570 patients (0.7%) who received CYRAMZA as a single agent in clinical trials experienced gastrointestinal perforation. Permanently discontinue CYRAMZA in patients who experience a gastrointestinal perforation.

Impaired Wound Healing • CYRAMZA has not been studied in patients with serious or nonhealing wounds. CYRAMZA is an antiangiogenic therapy with the potential to adversely affect wound healing. Withhold CYRAMZA prior to surgery.

Resume CYRAMZA following the surgical intervention based on clinical judgment of adequate wound healing. If a patient develops wound healing complications during therapy, discontinue CYRAMZA until the wound is fully healed.

Clinical Deterioration in Child-Pugh B or C Cirrhosis • Clinical deterioration, manifested by new onset or worsening encephalopathy, ascites, or hepatorenal syndrome, was reported in patients with Child-Pugh B or C cirrhosis who received single-agent CYRAMZA. Use CYRAMZA in patients with Child-Pugh B or C cirrhosis only if the potential benefits of treatment are judged to outweigh the risks of clinical deterioration.

Reversible Posterior Leukoencephalopathy Syndrome (RPLS) • RPLS has been reported at a rate of <0.1% in clinical studies with CYRAMZA. Confirm the diagnosis of RPLS with MRI and discontinue CYRAMZA in patients who develop RPLS. Symptoms may resolve or improve within days, although some patients with RPLS can experience ongoing neurologic sequelae or death.

CYRAMZA monotherapy significantly extended overall survival (OS)1

CYRAMZA significantly improved progression-free survival (PFS)1 MAJOR OUTCOME MEASURE

OS PROBABILITY

OVERALL SURVIVAL: MEDIAN – MONTHS (95% CI)1 1.0

CYRAMZA

Placebo

0.8

months

months

(4.4, 5.7)

(2.8, 4.7)

5.2

0.6

The phase III REGARD trial evaluated the efficacy and safety of CYRAMZA vs placebo in patients with locally advanced or metastatic gastric or GE junction adenocarcinoma who had progressed on or after prior fluoropyrimidine- or platinumcontaining chemotherapy. Major efficacy outcome measure was overall survival. Supportive efficacy outcome measure was progression-free survival. All patients were ECOG PS 0 or 1. Prior to enrollment, 85% of patients had progressed during treatment or within 4 months after the last dose of first-line chemotherapy for metastatic disease, and 15% of patients progressed during treatment or within 6 months after the last dose of adjuvant chemotherapy. Patients were randomized 2:1 to CYRAMZA 8 mg/kg q2w + BSC (n=238) or placebo + BSC (n=117).1

3.8

Hazard Ratio=0.78 (0.60, 0.998); P=0.047

0.4

CYRAMZA Placebo

0.2

0.0 0

1

2

3

238 117

5

6

7

8

9

10 11 12 13

14 15 16 17 18 19

20

26

27

28

0 1

0 0

TIME FROM RANDOMIZATION (MONTHS)

Number at Risk CYRAMZA Placebo

4

154 66

92 34

49 20

17 7

7 4

3 2

37%

• Median PFS with CYRAMZA was 2.1 months (95% CI: 1.5, 2.7) vs 1.3 months (95% CI: 1.3, 1.4) with placebo (hazard ratio 0.48 [95% CI: 0.38, 0.62]; P<0.001)1

CI=confidence interval; ECOG=Eastern Cooperative Oncology Group; PS=performance status; BSC=best supportive care.

INCREASE IN MEDIAN OS

Most Common Adverse Reactions

Use in Specific Populations

• The most commonly reported adverse reactions (all grades) occurring in ≥5% of patients receiving CYRAMZA and ≥2% higher than placebo in Study 1 were hypertension (16% vs 8%), diarrhea (14% vs 9%), headache (9% vs 3%), and hyponatremia (6% vs 2%).

• Pregnancy Category C: Based on its mechanism of action, CYRAMZA may cause fetal harm. Advise females of reproductive potential to avoid getting pregnant, including use of adequate contraception, while receiving CYRAMZA and for at least 3 months after the last dose of CYRAMZA. Animal models link angiogenesis, VEGF and VEGF Receptor 2 to critical aspects of female reproduction, embryofetal development, and postnatal development. There are no adequate or well-controlled studies of ramucirumab in pregnant women. 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 a fetus.

• The most common serious adverse events with CYRAMZA in Study 1 were anemia (3.8%) and intestinal obstruction (2.1%). Red blood cell transfusions were given to 11% of CYRAMZA-treated patients vs 8.7% of patients who received placebo.

• Clinically relevant adverse reactions reported in ≥1% and <5% of CYRAMZA-treated patients in Study 1 were: neutropenia (4.7% vs 0.9%), epistaxis (4.7% vs 0.9%), rash (4.2% vs 1.7%), intestinal obstruction (2.1% vs 0%), and arterial thromboembolic events (1.7% vs 0%).

• Across clinical trials of CYRAMZA administered as a single agent, clinically relevant adverse reactions (including Grade ≥3) reported in CYRAMZA-treated patients included proteinuria, gastrointestinal perforation, and infusion-related reactions. In Study 1, according to laboratory assessment, 8% of CYRAMZA-treated patients developed proteinuria vs 3% of placebo-treated patients. Two patients discontinued CYRAMZA due to proteinuria. The rate of gastrointestinal perforation in Study 1 was 0.8% and the rate of infusion-related reactions was 0.4%.

• As with all therapeutic proteins, there is the potential for immunogenicity. In clinical trials, 33/443 (7.4%) CYRAMZA-treated patients with post-baseline serum samples tested positive for antiramucirumab antibodies using an enzyme-linked immunosorbent assay (ELISA). However, this assay has limitations in detecting antiramucirumab antibodies in the presence of ramucirumab; therefore, the incidence of antibody development may not have been reliably determined. Neutralizing antibodies were detected in 1 of the 33 patients who tested positive for anti-ramucirumab antibodies.

Drug Interactions • No formal drug interaction studies have been conducted.

• Nursing Mothers: It is recommended to discontinue nursing or discontinue CYRAMZA due to the potential risks to the nursing infant.

• Females of Reproductive Potential: Advise females of reproductive potential that CYRAMZA may impair fertility.

Please see Brief Summary of Prescribing Information for CYRAMZA, including Boxed Warning for hemorrhage, on next page.

RB HCP ISI 21APR2014 Reference: 1. CYRAMZA (ramucirumab) [package insert]. Indianapolis, IN: Eli Lilly and Company; 2014.

RB89001 05/2014 PRINTED IN USA © Lilly USA, LLC 2014. ALL RIGHTS RESERVED. CYRAMZA™ is a trademark of Eli Lilly and Company.

Visit CYRAMZANowApproved.com

CYRAMZATM (ramucirumab) injection BRIEF SUMMARY: For complete safety, please consult the full Prescribing Information.

WARNING: HEMORRHAGE CYRAMZA increased the risk of hemorrhage, including severe and sometimes fatal hemorrhagic events.

Permanently discontinue CYRAMZA in patients who experience severe bleeding.

INDICATIONS AND USAGE CYRAMZA as a single-agent is indicated for the treatment of patients with advanced or metastatic, gastric or gastroesophageal junction adenocarcinoma with disease progression on or after prior fluoropyrimidine- or platinum-containing chemotherapy.

CONTRAINDICATIONS None.

WARNINGS AND PRECAUTIONS Hemorrhage CYRAMZA increased the risk of hemorrhage, including severe and sometimes fatal hemorrhagic events. In Study 1, the incidence of severe bleeding was 3.4% for CYRAMZA and 2.6% for placebo. Patients with gastric cancer receiving non-steroid anti-inflammatory drugs (NSAIDs) were excluded from enrollment in Study 1; therefore, the risk of gastric hemorrhage in CYRAMZA-treated patients with gastric tumors receiving NSAIDs is unknown. Permanently discontinue CYRAMZA in patients who experience severe bleeding.

Arterial Thromboembolic Events Serious, sometimes fatal, arterial thromboembolic events (ATEs) including myocardial infarction, cardiac arrest, cerebrovascular accident, and cerebral ischemia occurred in clinical trials including 1.7% of 236 patients who received CYRAMZA as a single agent for gastric cancer in Study 1. Permanently discontinue CYRAMZA in patients who experience a severe ATE. Hypertension An increased incidence of severe hypertension occurred in patients receiving CYRAMZA as a single agent (8%) as compared to placebo (3%). Control hypertension prior to initiating treatment with CYRAMZA. Monitor blood pressure every two weeks or more frequently as indicated during treatment. Temporarily suspend CYRAMZA for severe hypertension until medically controlled. Permanently discontinue CYRAMZA if medically significant hypertension cannot be controlled with antihypertensive therapy or in patients with hypertensive crisis or hypertensive encephalopathy.

Infusion Related Reactions Prior to the institution of premedication recommendations across clinical trials of CYRAMZA, infusion related reactions (IRRs) occurred in 6 out of 37 patients (16%), including two severe events. The majority of IRRs across trials occurred during or following a first or second CYRAMZA infusion. Symptoms of IRRs included rigors/tremors, back pain/spasms, chest pain and/or tightness, chills, flushing, dyspnea, wheezing, hypoxia, and paresthesia. In severe cases, symptoms included bronchospasm, supraventricular tachycardia, and hypotension. Monitor patients during the infusion for signs and symptoms of IRRs in a setting with available resuscitation equipment. Immediately and permanently discontinue CYRAMZA for Grade 3 or 4 IRRs. Gastrointestinal Perforations CYRAMZA is an antiangiogenic therapy that can increase the risk of gastrointestinal perforation, a potentially fatal event. Four of 570 patients (0.7%) who received CYRAMZA as a single-agent in clinical trials experienced gastrointestinal perforation.

Permanently discontinue CYRAMZA in patients who experience a gastrointestinal perforation.

Impaired Wound Healing CYRAMZA has not been studied in patients with serious or non-healing wounds. CYRAMZA is an antiangiogenic therapy with the potential to adversely affect wound healing. Withhold CYRAMZA prior to surgery. Resume following the surgical intervention based on clinical judgment of adequate wound healing. If a patient develops wound healing complications during therapy, discontinue CYRAMZA until the wound is fully healed.

Clinical Deterioration in Patients with Child-Pugh B or C Cirrhosis Clinical deterioration, manifested by new onset or worsening encephalopathy, ascites, or hepatorenal syndrome was reported in patients with Child-Pugh B or C cirrhosis who received single-agent CYRAMZA. Use CYRAMZA in patients with Child-Pugh B or C cirrhosis only if the potential benefits of treatment are judged to outweigh the risks of clinical deterioration.

Reversible Posterior Leukoencephalopathy Syndrome (RPLS) RPLS has been reported with a rate of <0.1% in clinical studies with CYRAMZA. Confirm the diagnosis of RPLS with MRI and discontinue CYRAMZA in patients who develop RPLS. Symptoms may resolve or improve within days, although some patients with RPLS can experience ongoing neurologic sequelae or death.

ADVERSE REACTIONS 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.

In Study 1, the most common adverse reactions (all grades) observed in CYRAMZA-treated patients at a rate of ≥10% and ≥2% higher than placebo were hypertension and diarrhea. The most common serious adverse events with CYRAMZA were anemia (3.8%) and intestinal obstruction (2.1%). Red blood cell transfusions were given to 11% of CYRAMZA-treated patients versus 8.7% of patients who received placebo.

Table 1: Adverse Reactions Occurring at Incidence Rate ≥5% and a ≥2% Difference Between Arms in Patients Receiving CYRAMZA in Study 1 CYRAMZA (8 mg/kg) Placebo Adverse Reactions N=236 N=115 a (MedDRA) All Grades Grade 3-4 All Grades Grade 3-4 System Organ Class (Frequency %) (Frequency %) (Frequency %) (Frequency %) Gastrointestinal Disorders Diarrhea 14 1 9 2 Metabolism and Nutrition Disorders Hyponatremia 6 3 2 1 Nervous System Disorders Headache 9 0 3 0 Vascular Disorders Hypertension 16 8 8 3 a MedDRA Version 15.0.

USE IN SPECIFIC POPULATIONS Pregnancy Pregnancy Category C Risk Summary Based on its mechanism of action, CYRAMZA may cause fetal harm. Animal models link angiogenesis, VEGF and VEGF Receptor 2 to critical aspects of female reproduction, embryofetal development, and postnatal development. There are no adequate or well controlled studies of ramucirumab in pregnant women. 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 a fetus.

Animal Data No animal studies have been specifically conducted to evaluate the effect of ramucirumab on reproduction and fetal development. In mice, loss of the VEGFR2 gene resulted in embryofetal death and these fetuses lacked organized blood vessels and blood islands in the yolk sac. In other models, VEGFR2 signaling was associated with development and maintenance of endometrial and placental vascular function, successful blastocyst implantation, maternal and feto-placental vascular differentiation, and development during early pregnancy in rodents and non-human primates.

Disruption of VEGF signaling has also been associated with developmental anomalies including poor development of the cranial region, forelimbs, forebrain, heart, and blood vessels.

Nursing Mothers It is not known whether CYRAMZA is excreted in human milk. No studies have been conducted to assess CYRAMZA’s impact on milk production or its presence in breast milk. Human IgG is excreted in human milk, but published data suggests that breast milk antibodies do not enter the neonatal and infant circulation in substantial amounts. Because many drugs are excreted in human milk and because of the potential risk for serious adverse reactions in nursing infants from ramucirumab, a decision should be made whether to discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother.

Pediatric Use The safety and effectiveness of CYRAMZA in pediatric patients have not been established. In animal studies, effects on epiphyseal growth plates were identified. In cynomolgus monkeys, anatomical pathology revealed adverse effects on the epiphyseal growth plate (thickening and osteochondropathy) at all doses tested (5-50 mg/kg). Ramucirumab exposure at the lowest weekly dose tested in the cynomolgus monkey was 0.2 times the exposure in humans at the recommended dose of ramucirumab as a single-agent.

Geriatric Use Clinical Trials of CYRAMZA as a single agent did not include sufficient numbers of patients aged 65 and over to determine whether they respond differently from younger patients. Of the 236 patients who received CYRAMZA in Study 1, 35% were 65 and over, while 9% were 75 and over.

Renal Impairment No dedicated clinical studies have been conducted to evaluate the effect of renal impairment on the pharmacokinetics of ramucirumab.

Hepatic Impairment No dedicated clinical studies have been conducted to evaluate the effect of hepatic impairment on the pharmacokinetics of ramucirumab.

Females and Males of Reproductive Potential Fertility Advise females of reproductive potential that CYRAMZA may impair fertility.

Contraception Based on its mechanism of action, CYRAMZA may cause fetal harm. Advise females of reproductive potential to avoid getting pregnant while receiving CYRAMZA and for at least 3 months after the last dose of CYRAMZA. DOSAGE AND ADMINISTRATION Recommended Dose and Schedule The recommended dose of CYRAMZA is 8 mg/kg every 2 weeks administered as an intravenous infusion over 60 minutes.

Continue CYRAMZA until disease progression or unacceptable toxicity. Do not administer CYRAMZA as an intravenous push or bolus.

Premedication Prior to each CYRAMZA infusion, premedicate all patients with an intravenous histamine H1 antagonist (e.g., diphenhydramine hydrochloride). For patients who have experienced a Grade 1 or 2 infusion reaction, also premedicate with dexamethasone (or equivalent) and acetaminophen prior to each CYRAMZA infusion.

Dose Modifications Infusion Related Reactions (IRR) • Reduce the infusion rate of CYRAMZA by 50% for Grade 1 or 2 IRRs. • Permanently discontinue CYRAMZA for Grade 3 or 4 IRRs. Hypertension • Interrupt CYRAMZA for severe hypertension until controlled with medical management.

• Permanently discontinue CYRAMZA for severe hypertension that cannot be controlled with antihypertensive therapy.

Proteinuria • Interrupt CYRAMZA for urine protein levels ≥2 g/24 hours. Reinitiate treatment at a reduced dose of 6 mg/kg every 2 weeks once the urine protein level returns to <2 g/24 hours. If the protein level ≥2 g/24 hours reoccurs, interrupt CYRAMZA and reduce the dose to 5 mg/kg every 2 weeks once the urine protein level returns to <2 g/24 hours.

• Permanently discontinue CYRAMZA for urine protein level >3 g/24 hours or in the setting of nephrotic syndrome.

Wound Healing Complications • Interrupt CYRAMZA prior to scheduled surgery until the wound is fully healed.

Arterial Thromboembolic Events, Gastrointestinal Perforation, or Grade 3 or 4 Bleeding • Permanently discontinue CYRAMZA PATIENT COUNSELING INFORMATION Advise patients: • That CYRAMZA can cause severe bleeding. Advise patients to contact their health care provider for bleeding or symptoms of bleeding including lightheadedness.

• Of increased risk of an arterial thromboembolic event.

• To undergo routine blood pressure monitoring and to contact their health care provider if blood pressure is elevated or if symptoms from hypertension occur including severe headache, lightheadedness, or neurologic symptoms.

• To notify their health care provider for severe diarrhea, vomiting, or severe abdominal pain.

• That CYRAMZA has the potential to impair wound healing. Instruct patients not to undergo surgery without first discussing this potential risk with their health care provider.

• Of the potential risk for maintaining pregnancy, risk to the fetus, or risk to postnatal development during and following treatment with CYRAMZA and the need to avoid getting pregnant, including use of adequate contraception, for at least 3 months following the last dose of CYRAMZA. • To discontinue nursing during CYRAMZA treatment.

Additional information can be found at www.CYRAMZAhcp.com.

Clinically relevant adverse reactions reported in ≥1% and <5% of CYRAMZA-treated patients in Study 1 were: neutropenia (4.7% CYRAMZA versus 0.9% placebo), epistaxis (4.7% CYRAMZA versus 0.9% placebo), rash (4.2% CYRAMZA versus 1.7% placebo), intestinal obstruction (2.1% CYRAMZA versus 0% placebo), and arterial thromboembolic events (1.7% CYRAMZA versus 0% placebo).

Across clinical trials of CYRAMZA administered as a single agent, clinically relevant adverse reactions (including Grade ≥3) reported in CYRAMZA-treated patients included proteinuria, gastrointestinal perforation, and infusion-related reactions.

In Study 1, according to laboratory assessment, 8% of CYRAMZA–treated patients developed proteinuria versus 3% of placebo-treated patients. Two patients discontinued CYRAMZA due to proteinuria. The rate of gastrointestinal perforation in Study 1 was 0.8% and the rate of infusion-related reactions was 0.4%.

Immunogenicity As with all therapeutic proteins, there is the potential for immunogenicity. In clinical trials, 33/443 (7.4%) of CYRAMZAtreated patients with post baseline serum samples tested positive for anti-ramucirumab antibodies using an enzyme-linked immunosorbent assay (ELISA). However, this assay has limitations in detecting anti-ramucirumab antibodies in the presence of ramucirumab; therefore, the incidence of antibody development may not have been reliably determined. Neutralizing antibodies were detected in 1 of the 33 patients who tested positive for anti-ramucirumab antibodies. The detection of antibody formation is highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of antibody (including neutralizing antibody) positivity in an assay may be influenced by several factors including assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of incidence of antibodies to CYRAMZA with the incidences of antibodies to other products may be misleading.

DRUG INTERACTIONS No formal drug interaction studies have been conducted.

TM

CYRAMZA (ramucirumab) injection

Eli Lilly and Company, Indianapolis, IN 46285, USA Copyright © 2014, Eli Lilly and Company. All rights reserved.

RB HCP BS 21APR2014

PA000IPAM00 – BS 9.25x13.25

CYRAMZATM (ramucirumab) injection

PA000IPAM00 – BS 9.25x13.25

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PAGE 69

JCO Spotlight Health-Care Disparities

HIV-Infected People With Early-Stage Cancers Are Up to Four Times More Likely to Go Untreated for Cancer

H

trars from three states—Connecticut, Michigan, and Texas—that provided data to NCI’s HIV/AIDS Cancer Match Study. The researchers used the data to study adults diagnosed with non-Hodgkin lymphoma, Hodgkin lymphoma, or cervical, lung, anal, prostate, colorectal, or breast cancer from 1996 through

prostate cancer, and colorectal cancer were almost twice as likely to be untreated for cancer, even after considering differences in age, gender, race, and stage.

“In my clinical experience, I have seen uncertainty surrounding treatment of HIV-infected cancer patients,”

The results of this study are very concerning and require further investigation to understand why such a substantial proportion of HIV-infected cancer patients are not undergoing lifesaving treatment.

—Gita Suneja, MD

T:14 in

2010. Over 3,000 HIV-infected patients and 1 million uninfected cancer patients were examined.

For early-stage cancers that have the highest chance of cure with appropriate treatment, those with HIV were twice to four times as likely to not receive appropriate cancer treatment, the researchers found. HIV-infected people with lymphoma, lung cancer,

■■ HIV-infected individuals diagnosed with early-stage cancer are two to four times more likely to go untreated for their cancer compared to uninfected cancer patients.

said Dr. Suneja. “Patients with HIV have typically been excluded from clinical trials, and therefore oncologists do not know if the best available treatments are equally safe and effective in those with HIV. Many oncologists rely on guidelines based on such trials for treatment decision-making, and in the absence of guidance, they may elect not to treat HIV-infected cancer patients due to concerns about adverse side effects or poor survival.”

She added, “This could help explain in part why many HIV-positive cancer patients are not receiving appropriate cancer care.”

■■ This treatment disparity may affect survival rates among HIV-infected cancer patients, who generally have worse outcomes than uninfected cancer patients.

Findings Highlight Disparity in Treatment

B:14.25 in

S:13 in

uman immunodeficiency virus (HIV)-infected people diagnosed with cancer are two to four times more likely to go untreated for their cancer compared to uninfected cancer patients, according to a large retrospective study from researchers in Penn Medicine’s Abramson Cancer Center and the National Cancer Institute (NCI). The study by Gita Suneja, MD, Adjunct Assistant Professor in the Department of Radiation Oncology at the Perelman School of Medicine at the University of Pennsylvania and in the Abramson Cancer Center, and colleagues was published in the Journal of Clinical Oncology.1 Life expectancy for HIV-infected people is now similar to that in uninfected people, but survival for HIV patients who develop cancer is not. While many studies have attempted to understand why HIV-infected cancer patients have worse outcomes, the new study, the largest of its size and scope, examined differences in cancer treatment as one potential explanation.

Study Details Dr. Suneja collaborated with researchers at the NCI, as well as regis-

HIV and Cancer Treatment

■■ The authors suggest that clinical trials should begin enrolling HIVinfected patients and cancer management guidelines should incorporate recommendations for HIV-infected patients.

The advent of antiretroviral therapy has changed the outlook in the fight against HIV/AIDS. People with HIV are living longer and healthier lives,

and a disease that was once thought to be universally fatal has now become a chronic and manageable disease like diabetes or hypertension.

In the early era of the HIV epidemic, there were reports of worse toxicity and side effects, but there are now more effective ways to support the immune system, most of them safe, tolerable, and effective. Still, treatments for cancer patients with HIV can be clinically challenging due to drug interactions and the potential increase in immunosuppression from chemotherapy or radiation.

To help close the disparity gap among HIV-positive patients with cancer and those not infected, cancer clinical trials should begin enrolling HIVinfected patients, the authors suggest, and cancer management guidelines should incorporate recommendations for HIV-infected patients.

“The results of this study are very concerning and require further investigation to understand why such a substantial proportion of HIV-infected cancer patients are not undergoing lifesaving treatment,” said Dr. Suneja.

“As cancer becomes an increasingly common cause of death in the HIV population, the issue of cancer treatment in the HIV-infected cancer population will grow in importance.” n

Disclosure: The study was funded by the Intramural Research Program of the National Cancer Institute. The study authors reported no potential conflicts of interest.

Reference 1. Suneja G, Shiels MS, Angulo R, et al: Cancer treatment disparities in HIVinfected individuals in the United States.

J Clin Oncol. June 30, 2014 (early release online).

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PAGE 70

Clinical Trials Resource Guide

Ongoing Clinical Trials Actively Recruiting Children With Cancer Compiled by Jo Cavallo

T

he information in this Clinical Trials Resource Guide includes actively recruiting clinical studies of children with cancer. The studies include pilot and phase I and II studies evaluating new therapies, functional imaging tests, tests to measure the neuropsychological and behavioral function in young patients with cancer, and interventions to improve cognitive late effects from treatment. All of the studies are listed on the National Institutes of Health website at ClinicalTrials.gov.

TRIALS FOR CHILDREN WITH CANCER Study Type: Phase I/II/interventional/nonrandomized Study Title: Phase I and Phase II Study of AZD6244 for Recurrent or Refractory Pediatric Low Grade Glioma Study Sponsor and Collaborators: National Cancer Institute Purpose: AZD6244, an experimental drug designed to prevent tumor growth and shrink existing tumors, has been studied in adults with cancer, but has not been studied in children with cancer. Researchers want to see if AZD6244 is a safe and effective treatment for older children and young adults who have gliomas that have not responded to standard treatments.

Ages Eligible for Study: 3 to 21 years Genders Eligible for Study: Both Accepts Health Volunteers: No Primary Outcome Measures: To estimate the maximum tolerated dose or recommend a phase II dose; to describe the toxicity profile and define the dose-limiting toxicity of AZD6244 in children with recurrent or refractory low-grade gliomas Principal Investigator: Katherine E. Warren, MD, National Cancer Institute, 301-435-4683, warrenk@mail.nih. gov For More Information: Visit ClinicalTrials.gov and refer to this study by its identifier: NCT01386450 Study Type: Phase I/interventional/single-group assignment Study Title: Phase I Study of Single Agent Perifosine for Recurrent Pediatric Solid Tumors

Study Sponsor and Collaborators: Memorial Sloan Kettering Cancer Center Purpose: To test whether perifosine—a drug that inhibits the protein AKT and has had some success in the treatment of adult cancers—is safe and effective in treating cancer. Investigators want to find out what effects the agent has on patients and the cancer. Different dosing schedules of perifosine are planned.

Ages Eligible for Study: Up to 21 years Genders Eligible for Study: Both Accepts Health Volunteers: No Primary Outcome Measures: Maximum tolerated dose of perifosine monotherapy in children with cancer (time frame: conclusion of the study) Principal Investigator: Ira Dunkel, MD, Memorial Sloan Kettering Cancer Center, 212-639-2153 For More Information: Visit ClinicalTrials.gov and refer to this study by its identifier: NCT00776867 Study Type: Interventional/singlegroup assignment Study Title: Development of Radiation Free Whole Body MR Imaging Technique for Staging of Children With Cancer Study Sponsor and Collaborators: Stanford University Purpose: To compare the sensitivity of whole-body magnetic resonance imaging (MRI) and 18F-fluorodeoxyglucose positron-emission tomography (FDG-PET) for detecting metastatic disease in children with malignant lymphomas and malignant sarcomas Ages Eligible for Study: Up to 40 years Genders Eligible for Study: Both Accepts Health Volunteers: No Primary Outcome Measures: Comparison of sensitivity, specificity, and accuracy of whole-body diffusionweighted MRI scans to 18F-FDG-PET scans (time frame: the outcome will be measured after image acquisition) Principal Investigator: Heike Daldrup-Link, MD, Stanford University; contact: Christopher Klenk, 650-7989096, cklenk@stanford.edu For More Information: Visit ClinicalTrials.gov and refer to this study by its identifier: NCT01542879 Study Type: Phase II/interventional/randomized Study Title: A Randomized Con-

trolled Trial Evaluating an Enhanced Physical Activity Intervention to Improve Cognitive Late Effects in Children Treated With Cranial Radiation for Brain Tumors Study Sponsor and Collaborators: National Cancer Institute Purpose: Late effects from cancer treatment in children can cause difficulties in cognitive functions, such as attention and memory. Physical activity has been found to improve the attention and memory skills of children with attention deficit hyperactivity disorder.

Researchers want to see if physical activity can improve cognitive functions in children who had radiation therapy for a brain tumor.

Ages Eligible for Study: 8 to 17 years Genders Eligible for Study: Both Accepts Health Volunteers: No Primary Outcome Measures: Efficacy of 12 weeks physical activity on visual memory (time frame: 12 weeks) Principal Investigator: Pamela L. Wolters, PhD, National Cancer Institute, 301-496-0561, woltersp@mail. nih.gov For More Information: Visit ClinicalTrials.gov and refer to this study by its identifier: NCT02153957 Study Type: Pilot study/observational Study Title: Pilot Study: Functional Imaging of Cerebellar Mutism Syndrome Study Sponsor and Collaborators: Memorial Sloan Kettering Cancer Center, New York Presbyterian Hospital, Columbia University, and Weill Medical College of Cornell University Purpose: To better understand why some children with cancer have difficulty speaking after brain surgery. Difficulty speaking may be due to known complications to the language centers in the brain. These language centers may be located in slightly different places in different people. This study will examine which areas may be damaged.

Ages Eligible for Study: 3 to 21 years Genders Eligible for Study: Both Accepts Health Volunteers: No Primary Outcome Measures: To investigate the feasibility of performing preoperative functional MRI (time frame: 1 year) Principal Investigator: Robert J. Young, MD, Memorial Sloan Kettering Cancer Center, 212-639-8196

For More Information: Visit ClinicalTrials.gov and refer to this study by its identifier: NCT 01733173 Study Type: Interventional/randomized/single-group assignment Study Title: Assessment and Rehabilitation of Cognitive Impairments in Pediatric Survivors of Cancer Study Sponsor and Collaborators: Stanford University Purpose: To assess the cognitive outcome in childhood cancer as well as evaluate a cognitive rehabilitation program for improving learning and problem-solving difficulties in children with cancer.

Ages Eligible for Study: 9 to 16 years Genders Eligible for Study: Both Accepts Health Volunteers: No Primary Outcome Measures: Performance on neuropsychological testing and brain activation patterns measured by functional MRI (time frame: 8 weeks) Principal Investigator: Shelli Kesler, PhD, Stanford University, 650-7230058, skesler@stanford.edu For More Information: Visit ClinicalTrials.gov and refer to this study by its identifier: NCT00490334 Study Type: Observational Study Title: Neuropsychological, Social, Emotional, and Behavioral Outcomes in Children With Cancer Study Sponsor and Collaborators: Children’s Oncology Group, National Cancer Institute Purpose: To study neuropsychological and behavioral testing in young patients with cancer. Collecting information over time from a series of tests may help doctors develop effective tests to measure neuropsychological and behavioral function in young patients with cancer.

Ages Eligible for Study: 1 month to 21 years Genders Eligible for Study: Both Accepts Health Volunteers: No Primary Outcome Measures: Consistent, streamlined, and efficient administration of neuropsychological and behavioral tests (time frame: baseline) Principal Investigator: Leanne Embry, PhD, Children’s Oncology Group, 210-567-7477, embryl@uthscsa.edu For More Information: Visit ClinicalTrials.gov and refer to this study by its identifier: NCT00772200 continued on page 71

ASCOPost.com | JULY 25, 2014

PAGE 71

Expert’s Corner

The Road to Progress in Lung Cancer Treatment A Conversation With Giuseppe Giaccone, MD, PhD

By Ronald Piana

D

espite promising new agents and therapeutic approaches, 5-year lung cancer survival rates have lagged far behind those of most other malignancies. To shed light on some of the important issues facing lung cancer experts, The ASCO Post recently spoke with internationally recognized lung cancer researcher Giuseppe Giaccone, MD, PhD, Associate Director for Clinical Research at the Lombardi Comprehensive Cancer Center, Georgetown University in Washington, DC.

I did my medical training at the Turin Medical School. After that, I spent 2 years, from 1988 to 1990, in the Medical Oncology Branch of the National Cancer Insti-

tute (NCI) under the direction of John Minna, MD. I then moved to the Free University Medical Center in Amsterdam as a senior oncologist, and was appointed

TELL YOUR ADVANCED PRACTICE COLLEAGUES TO

Head of Medical Oncology in 2003.

In 2007, I returned to the NCI as Chief of the Medical Oncology Branch. continued on page 72

REGISTER TODAY!

Career Highlights Please tell the readers a bit about your career before arriving at Georgetown.

I’m originally from Northern Italy.

Clinical Trials continued from page 70

Study Type: Observational/Behavioral: Interview Study Title: A Qualitative Case Study of the Experiences of Children With Cancer as They Learn About Their Diagnosis and Treatment Study Sponsor and Collaborators: St. Jude Children’s Research Hospital Purpose: Little is known about how children with cancer experience learning about their diagnosis and treatment in the hospital setting, or the individuals and materials that may help to facilitate children’s understanding of their diagnosis. This observational study will collect data about how children currently learn about their cancer diagnosis and treatment in the hospital setting to improve how future patients learn about their cancer-related diagnosis.

Ages Eligible for Study: 7 to 11 years Genders Eligible for Study: Both Accepts Health Volunteers: No Primary Outcome Measures: Case study of the ways in which children with cancer learn about their diagnosis and treatment in the hospital setting (time frame: observations collected from diagnosis through 6 months) Principal Investigator: Jessika Boles, MEd, St. Jude Children’s Research Hospital, 866-278-5833, info@ stjude.org For More Information: Visit ClinicalTrials.gov and refer to this study by its identifier: NCT02041689 n

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PAGE 72

Expert’s Corner Giuseppe Giaccone, MD, PhD continued from page 71

The NCI offered a tremendous opportunity for me to do basic research, but clinical research was a bit more challenging due to the amount of government regulation you have to deal with.

I left the NCI at the end of 2012 to join the Lombardi Comprehensive Cancer Center at Georgetown University.

Current Role What is your major function at the Lombardi Comprehensive Cancer Center?

I lead the Medical Thoracic Oncology Section, and my main job is to boost the research efforts at Georgetown University and the MedStar Health Cancer Network, which includes two major hospitals in the DC area and a few other smaller hospitals in Maryland. My focus is largely on increasing the number of investigator-initiated studies in the institution and throughout the network.

My own research is centered on drug development and research on thoracic malignancies in the clinic. I also have a lab where we study mechanisms of resistance and tumor genetics in lung cancer and thymic malignancies. I have made a number of discoveries while at NCI, which we are advancing with our work here. We’re looking at novel genetic targets both in lung cancer and thymic tumors. There’s a lot of work to be done in this field, so I keep very busy.

European Cooperative Groups You served as chair of European Organisation for Research and Treatment of Cancer (EORTC) Lung Cancer Cooperative Group from 1993 to 2000. Please shed light on that experience and how it contrasts with the Cooperative Group system in the United States.

THe European cooperative group system is a lot less structured than the U.S. cooperative groups, in the sense that in Europe there’s really no central nationalized cancer institute. In fact, the EORTC is basically structured around volunteerism, which is driven by the individual interests of the participants.

This creates a collegial environment that

promotes rigorous scientific studies.

However, the culture has changed over the years since I chaired the Lung Cancer Cooperative Group. It’s expensive to run clinical studies on new drugs, and the economic challenges we face have made funding very competitive.

More and more drug companies are running their own studies rather than partnering with cooperative groups, so that adds another challenge for the group system as a whole.

That said, although the U.S. groups face these same issues, the advantage in Europe is the socialized health-care system that funds some of the costs involved in research are being conducted in these groups. For instance, if you’re conducting a trial that requires a computed tomography (CT) scan every two cycles, and that is considered stan-

than it is in the United States. I think culturally there’s less reluctance by the public to participate in a trial in which they might receive a placebo instead of an active drug.

This is important because, for instance, studying the new molecularly targeted agents is different from studying traditional chemotherapy, and in placebo-controlled trials we can detect subtle tumor behavior. Of all the European nations, I think that the northern countries are the most open-minded about placebo-controlled trials.

Screening Challenges Most agree that detecting early-stage lung cancers improves survival. However, whether to screen high-risk populations for lung cancer is still a matter of contentious debate. What’s your take on this issue?

I think we should shift more of our research efforts to earlier-stage disease. Prevention is one area that needs much more attention, and screening plays a part there.

—Giuseppe Giaccone, MD, PhD

dard, the health-care system will pick up that cost. This not only makes it less expensive to run trials, it creates a more dynamic system than we have in the United States.

Accrual Issues Poor accrual is a persistent problem in launching trials in the United States, with only 3% of our adult patients participating in trials. Does the socialized system of European countries have better results in trial accrual?

I believe it does. The socialized health system makes the accrual process less complicated simply because the coverage is universal, which makes the paperwork less onerous. Moreover, in Europe it is easier to accrue patients in studies that are placebo-controlled

This is a major debate, but ultimately I believe CT screening in high-risk individuals will be approved by Medicare and move forward. That said, it will present huge challenges because once you begin population screening you need to deal with the risks involved in overdetection of benign nodules.

Even specialized centers will be challenged by the harms to patients associated with inevitable overdiagnosis. Once approved, it will take years to ensure that all screening centers are equipped to meet standardized criteria.

Epidemiology Shift Is there any significant change in lung cancer epidemiology that researchers and clinicians need to be aware of?

The most striking changes are in the

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populations now presenting with lung cancer. When I began working in this disease, it was almost always a tumor that presented in long-term smokers. But over the past decade we’ve seen a dramatic shift, whereby the majority of new cases present in nonsmokers and exsmokers.

I’ve noticed an alarming number of nonsmokers and young people, especially young women who come into the center with a diagnosis of lung cancer.

We really don’t understand what’s driving this epidemiologic shift. We need to spend more time studying this phenomenon so we are prepared to treat these new groups of patients.

Future Directions What direction should we take in this very difficult disease?

First, the drug industry puts tremendous emphasis on developing new drugs that treat advanced cancer.

However, at least in lung cancer, this is probably no longer a viable strategy.

We’ve tried it for decades now. I think we should shift more of our research efforts to earlier-stage disease. Prevention is one area that needs much more attention, and screening plays a part there.

We also need to move as fast as possible in developing agents that work in the adjuvant setting. There has been some work in this area, but unfortunately it takes many years for results. So we should try to develop some mechanisms by which we can test novel ideas in the adjuvant setting without having to wait years for the results.

Although targeted therapies have increased survival in patients with advanced disease, the increase has remained very small at best. The challenge remains to find something that will have a major impact for the whole population. But even with the new therapies, including the addition of immunotherapy, it doesn’t look like we’re going to be able to achieve cures in these patients.

So moving these advances upfront to after or even before surgery, could be the way to progress in the future. n Disclosure: Dr. Giaccone reported no potential conflicts of interest.

The ASCO Post | JULY 25, 2014

PAGE 74

ASCO Annual Meeting Thoracic Oncology

Lung-MAP Trial Debuts—Other Personalized Studies Will Follow

By Caroline Helwick

O

ncologists now have a means of bringing personalized medicine to advanced squamous cell carcinoma, and it involves a biomarker-driven clinical trial that maximizes the chance of successful treatment and new drug approvals.

Lung-MAP (Lung Cancer Master Protocol) is a unique concept in which the government, private foundations, advocacy groups and industry are working together to match molecular profiles of tumors to novel agents, possibly enhancing the efficacy of secondline treatment and accelerating the approval of promising drugs. It is noteworthy for its collaborative nature and scope.

Partners include the National Cancer Institute (NCI), SWOG Cancer Research, Friends of Cancer Research, the Foundation for the National Institutes of Health, five pharmaceutical companies—Amgen, Genentech, Pfizer, AstraZeneca PLC, and AstraZeneca’s global biologics research and development arm, MedImmune, and two diagnostic companies—Foundation Medicine and Clarient, Inc. Other companies have supported the development portion of the protocol.

cians don’t want to wait for the results.

And in squamous cell disease, almost no patients are profiled since no driver mutations are known. Lung-MAP gives us an opportunity to potentially help these patients in real time and develop new agents for the future,” he said.

The trial will be conducted at more than 200 medical centers by the NCI’s newly formed National Clinical Trials Network (NCTN), said Jeffrey S. Abrams, MD, Associate Director of

Jeffrey S. Abrams, MD

NCI’s Cancer Therapy Evaluation Program. “The restructuring and consolidation of NCI’s large trial treatment program, resulting in the formation of the NCTN, is quite timely, as it can now offer an ideal platform for bringing the benefits of more-precise molecular diagnostics to cancer patients in communities large and small.”

Benefits of More-Precise Diagnostics

Calling All Clinicians

“Lung-MAP advances personalized medicine, and it is a faster way to get drugs to patients,” said one of the study’s leaders Roy S. Herbst, MD, PhD, Chief of Medical Oncology at the Yale Cancer Center, New Haven, Connecticut.

He emphasized that far too few pa-

Any oncologist with access to cooperative group clinical trials can enroll patients, Dr. Herbst said. The aim is to ultimately involve as many as 500 centers and to enroll as many as 1,000 patients a year for 5 years.

Physicians have good reasons to enroll their patients with squamous

Lung-MAP advances personalized medicine, and it is a faster way to get potentially active drugs to patients, which is our primary goal.

—Roy S. Herbst, MD, PhD

tients are undergoing molecular profiling. Even in the case of non–small cell lung cancer (NSCLC) patients with non-squamous histology, who may have actionable mutations in ALK or EGFR, perhaps only 50% to 60% of tumors are tested. “It’s clearly not 100%.

Either the test is not available, or clini-

cell NSCLC on Lung-MAP, he said.

Considering that these tumors lack the known actionable mutations for which drugs are currently available in NSCLC, enrollment “will provide access to drugs they otherwise could not obtain,” he pointed out.

Enrollment is also made attractive

by the fact that capitation per patient is “double the usual” for a cooperative group trial, that molecular profiling is provided free of charge, with no reimbursement issues, he added.

“It’s a multiple win for patients and oncologists,” he said.

In spite of these features, Dr. Herbst emphasizes the need to closely monitor the study—along with ­Ellen V. Sigal, PhD, of Friends of Cancer Research, he cochairs the Oversight Committee—to ensure that LungMAP will meet its accrual target.

Squamous cell disease represents only 20% to 30% of all NSCLC cases, and while this still amounts to 60,000 patients a year, “we need patients who have suitable performance status and are motivated for the study,” he indicated. “It will take a full cooperative effort to make this work.”

More information on patient eligibility and enrollment is available online at www.lung-map.org.

Study Design Patients will be screened by Foundation Medicine for more than 200 cancer-related genes. Based on their molecular characteristics—with test results returned within 2 weeks—they will be assigned to one of five groups testing a relevant novel agent. Within that group, patients will be randomly assigned to standard second-line chemotherapy or chemotherapy plus the experimental drug. Drugs showing promise can rapidly move into phase III testing, ineffective drugs can be eliminated, and new compounds can be added to the protocol as they emerge.

For the initial round of testing, the drugs include the following: GDC0032, a PI3K inhibitor provided by Genentech; palbociclib, an oral cyclindependent kinase (CDK) inhibitor believed to selectively inhibit CDK-4 and CDK-6, from Pfizer; AZD4547, an oral fibroblast growth factor receptor (FGFR) inhibitor from AstaZeneca; rilotumumab, an antibody to human hepatocyte growth factor (HGF) from Amgen that will be given along with erlotinib (Tarceva); and MED14736, a monoclonal antibody binding to the programmed death receptor ligand (PD-L1) by MedImmune.

“These drugs were selected because they gave us hints of efficacy in this setting,” Dr. Herbst said.

The phase II endpoint is an improve-

ment of at least 2 to 2.5 months in median progression-free survival, to be determined after 56 events. At that point, the drug will either move to phase III or be discontinued. The final analysis will be based on 290 progression-free survival events and 256 deaths. The trial is being led by SWOG. Dr. Herbst predicted that the “next generation arms” of Lung-MAP (they are modular) will include more combinations, as this first set of agents prove their worth. “We envision that we will want to target multiple pathways,” he said.

Model for Future Clinical Testing “Lung-MAP represents the first of several planned large, genomically driven treatment trials that will be conducted by the NCTN,” Dr. Abrams reported in a session on clinical trials at the ASCO Annual Meeting.

ALCHEMIST (Adjuvant Lung Cancer Enrichment Marker Identification and Sequencing Trial), which will be conducted by the Alliance and the Eastern Cooperative Oncology Group (ECOG), is set to launch this summer in non–squamous cell NSCLC. It will test the efficacy of drugs targeting ALK rearrangements (crizotinib [Xalkori]) and EGFR mutations (erlotinib) in the adjuvant setting.

ALCHEMIST also has a research component that will examine such aspects of the tumor as circulating DNA and white cells. “We also hope to be able to follow the natural genomic history of this tumor through serial biopsies. We want to develop a rich public resource with genomic characterization that is tied to detailed clinical outcomes, with long-term follow-up,” he indicated.

Up to 8,000 patients will need to be screened to identify 400 with an ALK or EGFR abnormality. The primary endpoints for the separate trials testing ALK or EGFR abnormalities will be a hazard ratio of 0.67 for overall survival.

NCI Match Study The third NCTN biomarker-driven multiarm phase II trial is the NCI Match study. This trial will identify mutations, amplifications, and gene fusions in advanced-disease patients with solid tumors or lymphomas (25% will continued on page 75

ASCOPost.com | JULY 25, 2014

PAGE 75

Announcements

Head and Neck Societies Proclaim July 27th ‘World Head and Neck Cancer Day’

T

he International Federation of Head and Neck Oncologic Societies ­(IFHNOS), as part of the opening ceremonies of its 5th World Congress, and in collaboration with the annual meeting of the American Head and Neck Society (AHNS), will proclaim July 27th as “World Head and Neck Cancer Day.” The announcement on Sunday, July 27th will kick off the World Congress of Head and Neck Cancer, held jointly by IFHNOS and AHNS in celebration of the 100-year anniversary of the establishment of the first head and neck cancer surgery service at Memorial Sloan Kettering Cancer Center. This opening session will include remarks from former President Bill Clinton, actor and producer Michael Douglas and experts in head and neck cancer.

“Head and neck squamous cell carcinoma (head and neck cancer) is the leading cause of death and disability

in many parts of the world,” said Jatin Shah, MD, IFHNOS Congress Chairman, Chief of the Head and Neck Service at Memorial Sloan Kettering Cancer Center and AHNS Past President.

“The vast majority of these cancers can be prevented or can be cured if detect-

ed early; however, millions suffer from delayed diagnosis, inadequate treatment, inappropriate rehabilitation and palliation,” Dr. Shah said. The collaborative effort will call upon the World Health Organization (WHO) and the Union for International Cancer Control

(UICC), to also recognize July 27th as World Head and Neck Cancer Day and to join the international movement to increase awareness and promote education and training in the diagnosis, treatment, outcomes and research in head and neck cancer. n

WHAT CREATES A GREAT SURVIVAL CURVE?

L E V I N E C A N C E R INS TITUTE’S MO DEL OF C ARE

Lung-MAP Trial continued from page 74

have uncommon malignancies without a standard treatment). Based on their actionable mutations, patients will be assigned an agent using a “rules-based approach.”

Upon disease progression, they will be retested for subsequent mutations and assigned another study agent accordingly or discontinued if no additional mutations are found.

Sequential tumor biopsies will help to illuminate mechanisms of resistance. The trial may also include whole-exome sequencing in selected patients to further study mechanisms of resistance.

“NCI Match is a discovery trial that is a partnership between the NCTN and a large number of pharmaceutical companies. We will use a national network of academic sequencing centers, and we will make the information available to researchers around the world,” Dr. Abrams said.

“I am pretty fired up about this trial.

I think it could change the landscape significantly and bring a personalized medicine approach to community centers around the country,” he added.

“These new trials are good examples of how researchers are partnering, and not working in separate silos.”

Plans for similar study approaches in colon cancer and pediatric solid tumors are being considered. n

Hematologic Oncology and Blood Disorders Program The Hematologic Oncology and Blood Disorders program at Levine Cancer Institute, part of Carolinas HealthCare System, has built its foundation not only on providing excellent care, but on changing the delivery model of that care. Reaching patients – no matter where they live – through the newest treatments delivered by world-class oncologists has been its priority since day one. The result?

Improving the survival curve and changing the course of cancer itself.

CLINICAL EXPERTISE More than a dozen of the Institute’s nationally recruited physicians, from the top cancer programs in the country, are dedicated to hematology and blood cancers.

This team of subspecialists provides cutting-edge care and expertise in specific malignancies, including leukemia, plasma cell disorders, transplantation and lymphoma, and non-malignant hematology.

Our Leadership Team Ed Copelan, MD, FACP CHAIR

Hematologic Oncology and Blood Disorders program

Belinda Avalos, MD VICE-CHAIR

Hematologic Oncology and Blood Disorders program

TRANSPLANTATION In addition to multiple care locations across the Carolinas, Levine Cancer Institute opened a new transplantation unit in early 2014.

Staffed by some of the world’s foremost experts in hematological malignancies, the 16-bed unit also includes:

CLINICAL TRIALS AND RESEARCH Physicians at the Institute participate in leading-edge clinical trials related to most types of blood cancers and blood disorders. The Institute is expected to be one of the leading enrolling sites for blood cancer clinical trials in the country by the end of 2014. Our specialized Phase 1 unit provides:

• Six-bed apheresis unit, adjacent to the transplant unit, to obtain stem • First-in-man clinical trials testing cells for peripheral blood transplants novel therapies and treatment options • Four ICU beds integrated with Carolinas HealthCare System’s • Access to high-quality care, and virtual ICU, which provides 24/7 expertise from physicians who oversight of all patients subspecialize in treating specific • Patient support, including familydiseases friendly patient rooms, an exercise • The ability to enroll patients in room, a laundry room and lounge the newest, most promising trials, • Patient navigation whether that patient lives down the street or out of state, through the Institute’s decentralized model of care

Disclosure: Drs. Herbst and Abrams reported no potential conflicts of interest.

For more information, visit CarolinasHealthCare.org/ModelOfCare

The ASCO Post | JULY 25, 2014

PAGE 76

Dermatologic Events in Oncology How to Recognize and Manage Intertriginous Eruptions Related to Doxorubicin

By Lida Zheng, BS, and Milan J. Anadkat, MD

I

ntertriginous areas refer to skin folds (such as axillae, inguinal creases, and inframammary creases), which are characterized by increased friction, temperature, and occlusion. Intertriginous drug reactions are an underrecognized side effect associated with pegylated liposomal doxorubicin therapy, occurring in approximately 3% to 12% of patients who receive such treatment.

mildly pruritic, but it occasionally can be tender or even develop painful erosive lesions.

The exact mechanism is unproven, but the leading hypothesis on why pegylated liposomal doxorubicin is the chemotherapy agent most associated with intertriginous eruptions involves its long half-life and hydrophilic coating. This coating decreases cardiotoxici-

GUEST EDITOR

Mario E. Lacouture, MD

Dermatologic Events in Oncology is guest edited by Mario E. Lacouture, MD, Associate Member in the Division of Dermatology, Department of Medicine, at Memorial Sloan-Kettering Cancer Center, New York. He is a board-certified dermatologist with a special interest in dermatologic conditions that result from cancer treatments.

Differential Diagnosis and Treatment

Recognition of intertriginous eruptions is important in order to exclude more serious reactions and to initiate treatment for this potentially dose-limiting toxicity.

—Lida Zheng, BS, and Milan J. Anadkat, MD

Onset of the eruption can occur anywhere from 1 to 25 days after treatment.

No predilection exists for sex, age, underlying malignancy, or preexisting skin condition.

Clinical Manifestation The rash typically consists of red papules as the primary lesion, later developing into confluent beefy red or violaceous patches that are primarily centered in the axillary and inguinal folds. Areas that are less commonly affected include inframammary creases (see Fig. 1), abdominal folds, back of the neck, antecubital fossa, and other areas under occlusion.

In most cases, the rash progresses to mild superficial skin sloughing and eventual spontaneous resolution with postinflammatory hyper- or hypopigmentation. The eruption is typically

ty but may increase its ability to concentrate within skin, particularly in eccrine sweat glands.

The association of liposomal doxorubicin with palmar-plantar erythrodysesthesia, or hand-foot syndrome, has been well documented in the literature and was described by Beth McLellan, MD, in the June 25, 2013, issue of The ASCO Post. In both conditions—handfoot syndrome and intertriginous eruptions—local microtrauma and vasodilation may promote drug extravasation, leading to increased drug concentration.

While intertriginous eruptions may share a similar pathogenesis with handfoot syndrome, it is less common, and thus may be less recognized by oncologists. It should be noted that intertriginous eruptions are seen with or without concomitant hand-foot syndrome.

Although intertriginous eruptions often self-resolve, recognition is important to distinguish them from bacterial fungal infections (intertrigo due to Candida) or more serious reactions such as a drug hypersensitivity.

Treatment should focus on both preventive and supportive approaches. Preventive methods include avoidance of trauma, pressure, tight clothing, and heat. A simple measure is to apply nonmedicated powders within intertriginous sites. However, once the rash occurs, treatment with topical steroids is generally recommended.

Given that intertriginous skin is fairly thin and subject to occlusion (which increases topical steroid potency), strength of topical steroids should be limited to mild-potency (hydrocortisone 2.5%) or mid-potency (triamcinolone 0.1%) agents. High-

potency topical steroids (clobetasol 0.05%) should be reserved for very severe cases for short-duration use.

If pain develops, skin superinfection should be excluded with a culture. Appropriate antibiotics (topical [ie, silver sulfadiazine, mupirocin] or oral) or antifungals (ie, ciclopirox, econazole) can then be prescribed as necessary.

Recognition of intertriginous eruptions is important in order to exclude more serious reactions and to initiate treatment for this potentially doselimiting toxicity. In most cases, this toxicity will improve with topical management, which allows for consistent dosing. Rarely, dose interruptions and decreases may be necessary along with topical corticosteroids/antibiotics, in order to maintain quality of life. n Disclosure: Ms. Zheng and Dr. Anadkat reported no potential conflicts of interest.

Fig. 1: Ill-defined erythematous plaques and maculopapules in the inframammary areas of a patient receiving liposomal doxorubicin.

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The ASCO Post | JULY 25, 2014

PAGE 78

ASCO State Affiliates Focus on the Ohio Hematology Oncology Society

By Jo Cavallo

Slobodan M. Stanisic, MD

T

he Ohio Hematology Oncology Society (OHOS) was formed 2 decades ago to advocate for and provide educational seminars and networking opportunities to hematologists and medical oncologists throughout the states of Ohio and West Virginia. Today, the society is focused on the needs of its nearly 200 members in Ohio (West Virginia formed its own ASCO State Affiliate, the West Virginia Oncology Society, in 2008) in bringing the highest-quality care to patients.

OHOS is very active in the state legislature. In 2011, a bill created by the Society updating Ohio’s regulations on off-label drug indications so it could mirror federal standards was signed into law. The Society has already had two legislative successes this year with the passage of Ohio’s oral chemotherapy parity law, which is awaiting the governor’s signature, and passage of the first state law to prohibit “brown bagging” of chemotherapy drugs—whereby insurers require drug purchase from and/

or preparation by designated low-cost pharmacies that ship the drugs directly to patients, disrupting the chain of safe preparation and delivery.

OHOS also helped establish the Ohio Legislative Cancer Caucus, which educates legislators about the myriad issues involved in cancer care, including the need for clinical research and improving patient access to treatment. The Caucus also helps advance state policies in developing strategies for cancer prevention and more effective diagnosis and treatment.

The ASCO Post talked with OHOS President Slobodan M. Stanisic, MD, about the Society’s legislative achievements, its challenges, and its goals for the future.

Similar Local and National Issues Why was it important for OHOS to become an ASCO State Affiliate and form its own oncology society?

Oncology care nationwide is facing

rising administrative burdens from government and private health insurers, so it’s important for all of the State Affiliates to share ideas.

A solution to a problem in one state could be an option for a society in another state.

It’s important to share experiences about dealing with issues like getting oncology medications covered and helping patients get financial assistance if necessary. The more ideas that can be generated to solve problems in our practices or for our patients, the stronger all our societies will be.

Also, being affiliated with ASCO gives each state society a certain amount of clout we otherwise wouldn’t have. Instead of having 50 lone voices in the dark, being an ASCO affiliate gives us one larger and stronger voice. Many of our local legislative issues, such as

As we head into our 21st year as a society, we want oncologists to know that OHOS is here to help them improve their practices so they can offer their patients the best care possible.

—Slobodan M. Stanisic, MD

the same business problems and challenges that we are facing on a local level, including declining reimbursement rates, increasing patient workload, and

Fast Facts ■■ The Ohio Hematology Oncology Society (OHOS) was founded in 1994.

■■ The current President is Slobodan M. Stanisic, MD. ■■ The founding President was Dale H. Cowan, MD. ■■ The Society has 184 members, including physicians, nurse practitioners, physician assistants, and administrative staff members.

■■ The Society’s mission is to promote excellence in the care of patients afflicted with cancer and hematologic disorders; advance the sciences of hematology and oncology and improve patient care; safeguard the rights of patients; serve as a spokesperson and liaison to governmental agencies and managed care organizations; and disseminate information regarding legislative and regulatory developments affecting the issues of common concern to hematologists and oncologists.

■■ Each year, the Society holds three meetings—a spring and fall meeting for OHOS members and a combined spring meeting of OHOS and the Kentucky Association of Medical Oncology. In addition to the three annual meetings, OHOS holds quarterly conference calls with members. The meetings provide a forum for professional networking and the exchange of ideas on issues paramount to oncologists.

oral chemotherapy parity, are the same issues being confronted on a national level, and being part of ASCO gives us the ability to improve cancer care both locally and nationally.

Practice Setting Are most of your members in private practice?

Yes. More and more community practices are becoming hospital owned, but most of our members are in private practice.

Legislative Activities Please talk about your legislative and advocacy efforts.

A major concern of ours has been the practice of brown bagging chemotherapies, in which drugs are shipped directly to the patient rather than to the oncologist’s office, and patients bring their chemotherapies to the oncologist for treatment. The problem is you can’t be sure of what you are getting or whether the drugs were properly pre-

pared, but as physicians, we bear the responsibility if something with the drug preparation goes wrong.

We have worked with other interested parties and insurers for several years to pass legislation to ban the practice of brown bagging in Ohio and were successful this year with the passage of Senate Bill 230. We were also involved in getting an oral chemotherapy parity bill passed after several years of effort.

On a federal level, we are supporting ASCO’s efforts to reduce instability in federal payment systems and eliminate barriers that prevent oncology practices from improving quality oncology care, including reversing sequestration cuts to Medicare payments, removing prompt pay discounts in the average sale price formula, and repealing the sustainable growth rate formula.

We’ve had two other major legislative successes: We worked with the Medicare Carrier Advisory Committee to modify Medicare’s policies on chemotherapy and nonchemotherapy infusion and were able to convince payors to increase reimbursement levels and pay for more than one infusion on a specific date of service. Several years ago, we also got legislation enacted that exempts the purchase of chemotherapy drugs from the state sales tax in Ohio.

Remaining Relevant What are your greatest challenges?

Our challenges are the same ones other societies are facing, including shrinking reimbursements and the site of care moving away from outpatient centers to academic centers. Recently, we have seen a drop off in membership due in part to the perception of salaried physicians, who don’t have to contend with reimbursement issues, that there is little value in belonging to a state society.

As more oncology physicians leave private practice and become employed

ASCOPost.com | JULY 25, 2014

PAGE 79

ASCO State Affiliates in hospital-based and university settings, there is the presumption that they are protected from the issues confronting community oncologists. I don’t know if that is the case, but there is less advocacy of the physician’s individual practice when he or she becomes part of a larger entity.

We have to find solutions to overcome these misperceptions and remain relevant to all oncologists regardless of whether they are in the community, academic, or hospital setting.

Ongoing Objectives What are your future goals?

We would like to expand our membership and continue to grow as a society. To accomplish this goal, OHOS

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

is fostering cooperation between our members and physicians at the major cancer centers in our state, such as the Cleveland Clinic and The Ohio State University Comprehensive Cancer Center. We continue to upgrade our communication efforts to keep members updated on the rapidly changing world of oncology. In addition, we are

reaching out to employers to educate them on the appropriate support for employees diagnosed with cancer.

Closing Thoughts What else would you like ASCO members to know about OHOS? As we head into our 21st year as a society, we want oncologists to know

that OHOS is here to help them improve their practices so they can offer their patients the best care possible.

Our overarching goal is to provide educational programs and networking opportunities members won’t find anywhere else. n Disclosure: Dr. Stanisic reported no potential conflicts of interest.

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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.

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The ASCO Post | JULY 25, 2014

PAGE 80

From Ireland to America and Back, Patrick G. Johnston, MD, PhD, Thrives on Bringing Research Findings to Clinical Practice

By Ronald Piana

P

atrick G. Johnston, MD, PhD, FMedSci, Professor of Oncology and President and Vice-Chancellor of Queen’s University Belfast, grew up in Derry, a city in Northern Ireland.

Derry is distinct in being Ireland’s only remaining fully intact walled city, considered one of the finest examples of a walled city in all of Europe.

Career Path “My father was a teacher, as were a number of my aunts and uncles. I also had very good teachers in grade school and high school, so I was fortunate to have grown up in an atmosphere of education,” said Dr. Johnston. It was during his high school days at St. Columb’s College when Dr. Johnston’s future career path began to take shape.

“I was about 14 years old when I first thought about becoming a doctor. My decision was probably influenced by a mixture of things—an early interest in chemistry and biology, seeing people suffering and dying of diseases such as cancer, wanting to make a difference, and having relatives who were in the nursing profession,” said Dr. Johnston.

He added, “At a young age, I also saw the positive effect a family doctor had on a sick person’s life.”

In 1976, at age 18, Dr. Johnston entered the University College Dublin, receiving his undergraduate degree with distinction in 1982. He stayed on at the Dublin University Hospitals to pursue further medical studies, and it was during that intense academic period that he said his critical thinking and clinical skills were honed. Dr. Johnston’s interest in pursuing a career in cancer care arose during his residency working with oncologists (Dr. Desmond Carney [Desmond N. Carney, MD, now at Mater Misericordiae University Hospital, Dublin] and Dr. Peter Daly [Peter A. Daly, MB, FRCPI, now at St. James’s Hospital, Dublin]) and cancer patients in the mid-1980s.

“In Ireland, cancer care was still quite underdeveloped. Seeing the challenges and suffering that cancer patients had to undergo motivated me to enter the field. But also, as I began to read the

medical and scientific literature, I realized that the cancer field was rapidly evolving in other places, like the United States,” said Dr. Johnston.

“It was a time of high-dose chemotherapies for leukemia and lymphoma, and the first cures in testicular cancer, leukemias, and lymphomas were being recorded. It was a very different era from the one we inhabit now, but it was nonetheless exciting because, for the first time, patients were surviving cancers that had once been a death sentence,” he commented.

Research Calls Yearning to participate in the new bench-to-bedside era of oncology, Dr. Johnston applied for a fellowship at the epicenter of cancer research and clinical trials, the National Cancer Institute (NCI). He was accepted and joined the Institute in 1987.

Massachusetts General Hospital Cancer Center, Boston] and Dr. Carmen Allegra [Carmen J. Allegra, MD, now Professor of Medicine and Chief of Hematology/Oncology at the University of Florida, Gainesville] as mentors.

They remain close friends to this day,” said Dr. Johnston.

His early scientific work at NCI primarily involved understanding drug resistance and developing biomarkers to identify patients who wouldn’t benefit from chemotherapy, which at that time was quite revolutionary.

“I worked on the enzyme thymidylate synthase, which is the target enzyme for fluoropyrimidines. I also developed a number of bioassays to measure target enzymes and began working with the clinical trial cooperative groups, mainly the National Surgical Adjuvant Breast and Bowel Project (NSABP). We quantified the enzymes

During the past decade, cancer care in Ireland has been transformed….

Northern Ireland now has the best cancer outcomes in the United Kingdom, and among the best in all of Europe.

—Patrick G. Johnston, MD, PhD, FRCP, FRCPI

“The most important part of my fellowship at the NCI was the exposure to basic science and research and further clinical training in integrated cancer care. My fellowship at the NCI was where large elements of my later career were defined,” said Dr. Johnston.

Dr. Johnston was at the NCI for almost 10 years, and during that period, he developed as a clinician-scientist.

“The approach of bringing knowledge obtained in research to clinical practice has been the foundation of my career.

While at the NCI, I was fortunate to have had Dr. Bruce Chabner [Bruce A. Chabner, MD, now Professor of Medicine at Harvard Medical School and Director of Clinical Research at

in tissues, actually showing how we could detect certain groups of patients who would never benefit from fluorouracil. At that time this work was considered cutting-edge science and got quite a bit of recognition in the United States,” said Dr. Johnston.

A Call From Ireland In 1996, Dr. Johnston received a telephone call from Ireland, prompting a career-changing decision. “I was asked if I would consider a position a Queen’s University Belfast, which essentially would be charged with redeveloping cancer services in Northern Ireland. I was reluctant at first because my research at the NCI was going very

well. But when I flew back to Ireland for a visit, I saw the opportunity to build a comprehensive cancer program in Northern Ireland and truly make an impact on cancer care throughout the country. After some reflection, I accepted the position,” noted Dr. Johnston. In 1996, Dr. Johnston became Chair of the Department of Oncology at Queen’s University Belfast.

“I started the development of a cancer program that would reach throughout all Northern Ireland, and part of the project included building a new cancer center. With the help of Dr. Richard Klausner [Richard D. Klausner, MD, now Senior Vice President and Chief Medical Officer at Illumina], who was Director of the NCI at the time, and Dr. Edison Liu [Edison T. Liu, MD, now Chief Executive Officer of The Jackson Laboratory], we set up a unique cancer consortium agreement between Northern and Southern Ireland and the U.S. Department of Health and Human Services to work together in creating cancer programs across all of the island of Ireland,” explained Dr. Johnston.

Launched in 1999, The Ireland– Northern Ireland–NCI Cancer Consortium set a number of goals, such as strengthening the capacity of cancer centers in Ireland, conducting cancer clinical trials, and enhancing opportunities for patients to participate in trials, as a way of improving care and reducing cancer mortality.

“The program brought about training opportunities and new linkages for nurses, psychologists, social workers, and physicians, and became a huge catalyst for the development of local cancer programs and registries. It is still flourishing; in fact, plans are underway for the fourth Ireland–Northern Ireland–NCI Cancer Consortium to be held next year,” said Dr. Johnston.

Dramatically Improved Outcomes Reflecting on the progress in cancer care in Ireland, Dr. Johnston said, “During the past decade, cancer care in Ireland has been transformed. The number of oncologists has increased six- to eight-

ASCOPost.com | JULY 25, 2014

fold. Moreover, cancer surgery is now being performed by specialists in surgical oncology—a drastic shift from a decade ago, when this very difficult surgery was performed by general surgeons. We now have a mature and well-developed referral pathways system with registry data that are linked to hospital records measuring population outcomes and a well-run clinical trial network with 15% of patients on clinical trials. And because of these innovative programs that monitor population outcomes, Northern Ireland now has the best cancer outcomes in the United Kingdom, and among the best in all of Europe.”

Asked why the NCI would take interest in such a large undertaking in a small European country, Dr. Johnston replied, “The NCI leadership recognized the importance of what we were doing, the enormous clinical impact, and our ability to measure patient outcomes in a population-based system in a relatively short time frame. Having NCI leaders such as Drs. Chabner, Klausner, Liu, and Allegra as such strong advocates who helped us from a distance also gave those in Ireland the needed conviction to tackle such a large and complex undertaking. It changed the culture here. You no longer have to

convince people; they’re championing these innovative programs themselves.”

More recently, Dr. Johnston has built on the lessons learned from developing the cancer programs in Northern Ireland. Along with his colleagues and friends, Dr. Martin Murphy [Martin J. Murphy, DMedSc, PhD, FASCO, Executive Director of The Oncologist and previous Chairman of Conquer Cancer Foundation ASCO], Dr. Thierry le Chevalier [Thierry le Chevalier, MD, Director of the Institute of Thoracic Oncology, Gustave-Roussy, Paris], and many oncology colleagues and patient groups from across Europe, he has led the European Cancer Coalition and developed a “Patient’s Bill of Rights” as a charter and catalyst for cancer care across Europe.1,2

Recognition for Leadership In 2013, Dr. Johnston was awarded the Bob Pinedo Cancer Care Prize [named for H.M. (Bob) Pinedo, MD, PhD, Professor Emeritus of the VU University Medical Center (VUmc), Amsterdam] in recognition of his pioneering work in cancer research and for his leadership in establishing a comprehensive cancer care and research program in Northern Ireland. Dr. Johnston re-

PAGE 81

marked that the Pinedo Prize was doubly gratifying, as Dr. Pinedo was one of his close colleagues and mentors in Europe.

“When I returned to Europe from the NCI, one of the first things I did was sit down with Bob. I’d known him through the NCI EORTC [European Organisation for Research and Treatment of Cancer] program,” he recounted. “Bob was very helpful when I first began the comprehensive overhaul of the Northern Irish cancer system. His success in the Netherlands was well known, so when people saw him as my advocate and collaborator, it gave the whole project a can-do feel of optimism. Another thing that was important to me about Bob was his drive to make sure that his scientific work in the lab would ultimately benefit his patients. That ultimately became my overriding philosophy.”

Balancing the Lab and the Desk Along with his hefty administrative work as President and Vice-Chancellor of Queen’s University Belfast, Dr. Johnston’s current research work is focused on understanding signaling pathways that are key determinants in drug resistance and trying to identify novel therapeutic targets.

“In my lab, we’re working on a protein called the FLICE-inhibitory protein, which regulates cell death,” he said.

“We’re in the process of developing some possibly important therapeutic molecules related to that protein. I’ve also been active in developing new platforms using a disease-specific genomic approach to develop molecular stratifiers for prognosis in certain tumors, such as colorectal cancer.”

Dr. Johnston commented that due to the multiple hats he now wears, he doesn’t put his lab coat on as often these days, leaving the bulk of the dayto-day work to his well-trained staff.

What does the super-busy Vice-Chancellor-scientist do to wind down? “I cycle in the hills of Donegal,” said Dr. Johnston. n

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

References 1. Lawler M, Le Chevalier T, Banks I, et al: A Bill of Rights for patients with cancer in Europe. Lancet Oncol 15:258-260, 2014.

2. Lawler M, Le Chevalier T, Murphy MJ Jr, et al: A catalyst for change: The European Cancer Patient’s Bill of Rights. Oncologist 19:217-224, 2014.

Journal Spotlight

Surgical Biopsy Proves Safe for Selected Patients With Late-Stage Lung Cancer

R

esearchers at the University of California Davis have determined that surgical biopsies can be safely performed on select patients with latestage non-small cell lung cancer, which should enhance their access to drugs that target specific genetic mutations such as epidermal growth factor receptor (EGFR).

The findings, published recently in The Journal of Thoracic and Cardiovascular Surgery,1 address the common problem in treatment for advanced lung cancer, namely insufficient tumor tissue available for molecular analysis.

“We will be allowing more people to be eligible for clinical trials, and ultimately that will provide value to the patient and access to treatments they may not have had otherwise,” said David T. Cooke, MD, lead author of the study and Assistant Pro-

fessor and Head of General Thoracic Surgery at UC Davis Medical Center.

In many cases of late-stage lung cancer, surgical biopsy is deemed too dangerous, so less invasive approaches are used, including fine-needle aspiration and core-needle biopsies.

“With clinical trials of new targeted therapies, an exhausting level of testing is performed,” Dr. Cooke said. “With less invasive biopsies, sometimes there is not enough volume of cells collected to do the molecular testing.”

Study Details Dr. Cooke and colleagues retrospectively examined the records of 25 patients whose cases were discussed at a multidisciplinary thoracic oncology conference or clinic and who had known or suspected stage IV non-small cell lung cancer. All elected to have sur-

gical biopsies, most of which were done using video-assisted thoracic surgery.

Of the cases, five experienced a complication; three of them were minor.

Surgical biopsy led to the identification of potentially targetable molecular information in more than half, with 10 of the 25 patients also determined to be eligible for enrollment into a therapeutic targeted clinical trial. “Patients who have been reviewed in a multidisciplinary manner and determined that less invasive biopsies might not be successful, could be appropriate for surgical biopsy, even at stage IV,” Dr. Cooke said. He emphasized that the approach should only be used when the case has been reviewed by a team of experts, including a pulmonologist, radiologist, surgeon, and medical oncologist, and the best biopsy strategy is selected.

“I think this will change the game,” he

said. “It will empower thoracic surgeons to work closely with multidisciplinary tumor boards and participate in the care of patients with late-stage lung cancer.”

Other study authors included David R. Gandara, MD, Philip C. Mack, MD, Primo N. Lara, Jr, MD, and Elizabeth A. David, MD, all of UC Davis; Royce F. Calhoun, MD, formerly of UC Davis and now with Rideout Health; and Neal C. Goodwin, MD, formerly of Jackson Laboratory-West and now with Champions Oncology, Inc. n Disclosure: No potential conflicts of interest were reported.

Reference 1. Cooke DT, Gandara DR, Goodwin NC, et al: Outcomes and efficacy of thoracic surgery biopsy for tumor molecular profiling in patients with advanced lung cancer J Thorac Cardiovasc Surg 148:36-40, 2014.

NOW

IN THE FIRST LINE FOR PATIENTS WITH WT KRAS mCRC

Indication Vectibix® is indicated for the treatment of patients with wild-type KRAS (exon 2 in codons 12 or 13) metastatic colorectal cancer (mCRC) as determined by an FDA-approved test for this use: • As first-line therapy in combination with FOLFOX • As monotherapy following disease progression after prior treatment with fluoropyrimidine-, oxaliplatin-, and irinotecan-containing chemotherapy Vectibix® is not indicated for the treatment of patients with KRAS-mutant mCRC or for whom KRAS mutation status is unknown. mCRC = metastatic colorectal cancer; OS = overall survival.

Boxed WARNING: DERMATOLOGIC TOXICITY Dermatologic Toxicity: Dermatologic toxicities occurred in 90% of patients and were severe (NCI-CTC grade 3 and higher) in 15% of patients receiving Vectibix® monotherapy [see Dosage and Administration (2.3), Warnings and Precautions (5.1), and Adverse Reactions (6.1)].

Important Safety Information

• In Study 1, dermatologic toxicities occurred in 90% of patients and

were severe (NCI-CTC grade 3 and higher) in 15% of patients with mCRC receiving Vectibix®. The clinical manifestations included, but were not limited to, acneiform dermatitis, pruritus, erythema, rash, skin exfoliation, paronychia, dry skin, and skin fissures.

• Monitor patients who develop dermatologic or soft tissue toxicities while receiving Vectibix® for the development of inflammatory or infectious sequelae. Life-threatening and fatal infectious complications including necrotizing fasciitis, abscesses, and sepsis have been observed in patients treated with Vectibix®. Rare cases of StevensJohnson syndrome and toxic epidermal necrolysis have been reported in patients treated with Vectibix® in the postmarketing setting. Lifethreatening and fatal bullous mucocutaneous skin disease has also been observed in patients treated with Vectibix®. Withhold or discontinue Vectibix® for dermatologic or soft tissue toxicity associated with severe or life-threatening inflammatory or infectious complications. Dose modifications for Vectibix® concerning dermatologic toxicity are provided in the product labeling.

• Determination of KRAS mutational status in colorectal tumors using an FDA-approved test indicated for this use is necessary for selection of patients for treatment with Vectibix®. Vectibix® is indicated only for the treatment of patients with KRAS wild-type mCRC. Vectibix® is not indicated for the treatment of patients with colorectal cancer that harbor somatic mutations in codons 12 and 13 (exon 2) as determined by an FDA-approved test for this use. In Study 3, 221 patients with KRAS-mutant mCRC tumors receiving Vectibix® in combination with FOLFOX experienced shorter overall survival (OS) compared to 219 patients receiving FOLFOX alone (HR = 1.24, 95% CI: 0.98-1.57).

Perform the assessment for KRAS mutational status in colorectal cancer in laboratories with demonstrated proficiency in the specific technology being utilized. Improper assay performance can lead to unreliable test results. Refer to an FDA-approved test’s package

insert for instructions on the identification of patients eligible for treatment with Vectibix®.

• Progressively decreasing serum magnesium levels leading to severe (Grade 3-4) hypomagnesemia occurred in up to 7% in Study 2.

Monitor patients for hypomagnesemia and hypocalcemia prior to initiating Vectibix® treatment, periodically during Vectibix® treatment, and for up to 8 weeks after the completion of treatment. Other electrolyte disturbances, including hypokalemia, have also been observed. Replete magnesium and other electrolytes as appropriate.

• In Study 1, 4% of patients experienced infusion reactions and 1% of patients experienced severe infusion reactions (NCI-CTC grades 3-4). Infusion reactions, manifesting as fever, chills, dyspnea, bronchospasm, and hypotension, can occur following Vectibix® administration. Fatal infusion reactions occurred in postmarketing experience. Terminate the infusion for severe infusion reactions.

• Severe diarrhea and dehydration, leading to acute renal failure and other complications, have been observed in patients treated with Vectibix® in combination with chemotherapy.

• Fatal and non-fatal cases of interstitial lung disease (ILD) (1%) and pulmonary fibrosis have been observed in patients treated with Vectibix®. Pulmonary fibrosis occurred in less than 1% (2/1467) of patients enrolled in clinical studies of Vectibix®. In the event of acute onset or worsening of pulmonary symptoms, interrupt Vectibix® therapy.

Discontinue Vectibix® therapy if ILD is confirmed.

• In patients with a history of interstitial pneumonitis or pulmonary fibrosis, or evidence of interstitial pneumonitis or pulmonary fibrosis, the benefits of therapy with Vectibix® versus the risk of pulmonary complications must be carefully considered.

• Exposure to sunlight can exacerbate dermatologic toxicity. Advise patients to wear sunscreen and hats and limit sun exposure while receiving Vectibix®.

The only biologic approved in combination with FOLFOX in the FIRST LINE based on improved OS in patients with wild-type KRAS mCRC1-4 • The PRIME study is a phase 3, open-label, randomized, multicenter study of 1,183 previously untreated patients with mCRC who

were treated with Vectibix® Q2W + FOLFOX or FOLFOX Q2W alone • Prespecified major efficacy measure was PFS (Vectibix® + FOLFOX 9.6 months vs FOLFOX alone 8.0 months [HR = 0.80; 95% CI: 0.66, 0.97], P = 0.02) • Exploratory analysis of OS was conducted based on events in 82% of patients with wild-type KRAS mCRC • Median OS for the Vectibix® + FOLFOX arm (n = 325) was 23.8 months vs 19.4 months for the FOLFOX-alone arm (n = 331) (HR = 0.83; 95% CI: 0.70, 0.98) • There were no OS or PFS benefits in Vectibix®-treated patients with mutant KRAS mCRC

• Keratitis and ulcerative keratitis, known risk factors for corneal • Because many drugs are excreted into human milk and because of

perforation, have been reported with Vectibix® use. Monitor for evidence the potential for serious adverse reactions in nursing infants from of keratitis or ulcerative keratitis. Interrupt or discontinue Vectibix® for Vectibix®, a decision should be made whether to discontinue nursing acute or worsening keratitis. or to discontinue the drug, taking into account the importance of • In an interim analysis of an open-label, multicenter, randomized the drug to the mother. If nursing is interrupted, it should not be clinical trial in the first-line setting in patients with mCRC, the resumed earlier than 2 months following the last dose of Vectibix®. addition of Vectibix® to the combination of bevacizumab and ® chemotherapy resulted in decreased OS and increased incidence • Women who become pregnant during Vectibix treatment are of NCI-CTC grade 3-5 (87% vs 72%) adverse reactions. NCI-CTC encouraged to enroll in Amgen’s Pregnancy Surveillance Program. grade 3-4 adverse reactions occurring at a higher rate in Vectibix®- Women who are nursing during Vectibix® treatment are encouraged treated patients included rash/acneiform dermatitis (26% vs 1%), to enroll in Amgen’s Lactation Surveillance Program. Patients or diarrhea (23% vs 12%), dehydration (16% vs 5%; primarily occurring their physicians should call 1-800-77-AMGEN (1-800-772-6436) in patients with diarrhea), hypokalemia (10% vs 4%), stomatitis/ to enroll. mucositis (4% vs < 1%), and hypomagnesemia (4% vs 0). ® • NCI-CTC grade 3-5 pulmonary embolism occurred at a higher rate • In Study 1, the most common adverse reactions (≥ 20%) with Vectibix in Vectibix®-treated patients (7% vs 3%) and included fatal events were skin rash with variable presentations, paronychia, fatigue, nausea, and diarrhea. The most common (> 5%) serious adverse reactions in three (< 1%) Vectibix®-treated patients.

• As a result of the toxicities experienced, patients randomized to in the Vectibix® arm were general physical health deterioration and Vectibix®, bevacizumab, and chemotherapy received a lower mean intestinal obstruction. relative dose intensity of each chemotherapeutic agent (oxaliplatin, • In Study 3, the most commonly reported adverse reactions (≥ 20%) irinotecan, bolus 5-FU, and/or infusional 5-FU) over the first in patients with wild-type KRAS mCRC receiving Vectibix® 24 weeks on study, compared with those randomized to bevacizumab (6 mg/kg every 2 weeks) and FOLFOX therapy (N = 322) were and chemotherapy.

• Advise patients of the need for adequate contraception in both males diarrhea, stomatitis, mucosal inflammation, asthenia, paronychia, and females while receiving Vectibix® and for 6 months after the last anorexia, hypomagnesemia, hypokalemia, rash, acneiform dermatitis, dose of Vectibix® therapy. Vectibix® may be transmitted from the pruritus, and dry skin. Serious adverse reactions (≥ 2% difference mother to the developing fetus, and has the potential to cause fetal between treatment arms) in Vectibix®-treated patients with wild-type KRAS mCRC were diarrhea and dehydration. harm when administered to pregnant women.

References: 1. Vectibix® (panitumumab) prescribing information, Amgen. 2. Avastin® (bevacizumab) prescribing information, Genentech, Inc. 3. Erbitux® (cetuximab) prescribing information, Bristol-Myers Squibb/Eli Lily and Company. 4. Zaltrap® (ziv-aflibercept) prescribing information, sanofi-aventis.

Avastin is a registered trademark of Genentech, Inc. Erbitux is a registered trademark of ImClone LLC, a wholly-owned subsidiary of Eli Lilly and Company. Zaltrap is a registered trademark of Regeneron Pharmaceuticals, Inc. Please see Brief Summary of full Prescribing Information on adjacent page. ©2014 Amgen Inc. All rights reserved. 05/14 80389-R1-V1

Visit www.vectibix.com

Vectibix® (panitumumab) Brief Summary of full PreScriBing information Warning: Dermatologic toXicity Dermatologic toxicity: Dermatologic toxicities occurred in 90% of patients and were severe (nci-ctc grade 3 and higher) in 15% of patients receiving Vectibix® monotherapy [see Dosage and Administration (2.3), Warnings and Precautions (5.1), and Adverse Reactions (6.1)]. inDicationS anD uSage metastatic colorectal cancer Vectibix® is indicated for the treatment of patients with wild-type KRAS (exon 2 in codons 12 or 13) metastatic colorectal cancer (mCRC) as determined by an FDA-approved test for this use: • As first-line therapy in combination with FOLFOX [see Clinical Studies 14.2 in Full Prescribing Information].

• As monotherapy following disease progression after prior treatment with fluoropyrimidine-, oxaliplatin-, and irinotecan-containing chemotherapy [see Clinical Studies (14.1) in Full Prescribing Information]. limitation of use Vectibix® is not indicated for the treatment of patients with KRAS-mutant mCRC or for whom KRAS mutation status is unknown [see Dosage and Administration (2.1), Warnings and Precautions (5.2), and Clinical Pharmacology (12.1) in Full Prescribing Information].

DoSage anD aDminiStration Patient Selection Prior to initiation of treatment with Vectibix®, assess KRAS mutational status in colorectal tumors and confirm the absence of a KRAS mutation using an FDA-approved test [see Warnings and Precautions (5.2)]. Information on FDA-approved tests for the detection of KRAS mutations in patients with metastatic colorectal cancer is available at: http://www.fda.gov/CompanionDiagnostics. recommended Dose The recommended dose of Vectibix® is 6 mg/kg, administered as an intravenous infusion over 60 minutes, every 14 days. If the first infusion is tolerated, administer subsequent infusions over 30 to 60 minutes.

Administer doses higher than 1000 mg over 90 minutes [see Dosage and Administration (2.4)].

Appropriate medical resources for the treatment of severe infusion reactions should be available during Vectibix® infusions [see Warnings and Precautions (5.4)].

Dose modifications Dose Modifications for Infusion Reactions [see Warnings and Precautions (5.4) and Adverse Reactions (6.1, 6.3)] • Reduce infusion rate by 50% in patients experiencing a mild or moderate (grade 1 or 2) infusion reaction for the duration of that infusion.

• Terminate the infusion in patients experiencing severe infusion reactions. Depending on the severity and/or persistence of the reaction, permanently discontinue Vectibix®.

Dose Modifications for Dermatologic Toxicity [see Boxed Warning, Warnings and Precautions (5.1), and Adverse Reactions (6.1, 6.3)] • Upon first occurrence of a grade 3 (NCI-CTC/CTCAE) dermatologic reaction, withhold 1 to 2 doses of Vectibix®. If the reaction improves to < grade 3, reinitiate Vectibix ® at the original dose.

• Upon the second occurrence of a grade 3 (NCI-CTC/CTCAE) dermatologic reaction, withhold 1 to 2 doses of Vectibix®. If the reaction improves to < grade 3, reinitiate Vectibix ® at 80% of the original dose.

• Upon the third occurrence of a grade 3 (NCI-CTC/CTCAE) dermatologic reaction, withhold 1 to 2 doses of Vectibix®. If the reaction improves to < grade 3, reinitiate Vectibix® at 60% of the original dose.

• Upon the fourth occurrence of a grade 3 (NCI-CTC/CTCAE) dermatologic reaction, permanently discontinue Vectibix®.

Permanently discontinue Vectibix® following the occurrence of a grade 4 dermatologic reaction or for a grade 3 (NCI-CTC/CTCAE) dermatologic reaction that does not recover after withholding 1 or 2 doses.

Preparation and administration Do not administer Vectibix® as an intravenous push or bolus. contrainDicationS None.

WarningS anD PrecautionS Dermatologic and Soft tissue toxicity In Study 1, dermatologic toxicities occurred in 90% of patients and were severe (NCI-CTC grade 3 and higher) in 15% of patients with mCRC receiving Vectibix ®. The clinical manifestations included, but were not limited to, acneiform dermatitis, pruritus, erythema, rash, skin exfoliation, paronychia, dry skin, and skin fissures.

Monitor patients who develop dermatologic or soft tissue toxicities while receiving Vectibix® for the development of inflammatory or infectious sequelae. Life-threatening and fatal infectious complications including necrotizing fasciitis, abscesses, and sepsis have been observed in patients treated with Vectibix®. Life-threatening and fatal bullous mucocutaneous skin disease has also been observed in patients treated with Vectibix®. Rare cases of Stevens-Johnson syndrome and toxic epidermal necrolysis have been reported in patients treated with Vectibix® in the postmarketing setting. Withhold or discontinue Vectibix® for dermatologic or soft tissue toxicity associated with severe or life-threatening inflammatory or infectious complications [see Boxed Warning and Adverse Reactions (6.1, 6.3)]. Dose modifications for Vectibix® concerning dermatologic toxicity are provided [see Dosage and Administration (2.3)]. increased tumor Progression, increased mortality, or lack of Benefit in Patients with KRAS-mutant mcrc Determination of KRAS mutational status in colorectal tumors using an FDA-approved test indicated for this use is necessary for selection of patients for treatment with Vectibix®. Vectibix® is indicated only for the treatment of patients with KRAS wild-type mCRC. Vectibix® is not indicated for the treatment of patients with colorectal cancer that harbor somatic mutations in codons 12 and 13 (exon 2) as determined by an FDA-approved test for this use [see Indications and Usage (1.2), Dosage and Administration (2.1), Clinical Pharmacology (12.1), and Clinical Studies (14) in Full Prescribing Information]. In Study 3, 221 patients with KRAS-mutant mCRC tumors receiving Vectibix® in combination with FOLFOX experienced shorter overall survival (OS) compared to 219 patients receiving FOLFOX alone (HR = 1.24, 95% CI: 0.98-1.57).

Perform the assessment for KRAS mutational status in colorectal cancer in laboratories with demonstrated proficiency in the specific technology being utilized. Improper assay performance can lead to unreliable test results. Refer to an FDA-approved test’s package insert for instructions on the identification of patients eligible for the treatment of Vectibix®. electrolyte Depletion/monitoring Progressively decreasing serum magnesium levels leading to severe (grade 3-4) hypomagnesemia occurred in up to 7% (in Study 2) of patients across clinical trials. Monitor patients for hypomagnesemia and hypocalcemia prior to initiating Vectibix® treatment, periodically during Vectibix® treatment, and for up to 8 weeks after the completion of treatment. Other electrolyte disturbances, including hypokalemia, have also been observed. Replete magnesium and other electrolytes as appropriate. infusion reactions In Study 1, 4% of patients experienced infusion reactions and 1% of patients experienced severe infusion reactions (NCI-CTC grade 3-4).

Infusion reactions, manifesting as fever, chills, dyspnea, bronchospasm, and hypotension, can occur following Vectibix® administration [see Adverse Reactions (6.1), 6.3)]. Fatal infusion reactions occurred in postmarketing experience. Terminate the infusion for severe infusion reactions [see Dosage and Administration (2.3)]. acute renal failure in combination with chemotherapy Severe diarrhea and dehydration, leading to acute renal failure and other complications, have been observed in patients treated with Vectibix® in combination with chemotherapy.

Pulmonary fibrosis/interstitial lung Disease (ilD) Fatal and nonfatal cases of interstitial lung disease (ILD) (1%) and pulmonary fibrosis have been observed in patients treated with Vectibix®. Pulmonary fibrosis occurred in less than 1% (2/1467) of patients enrolled in clinical studies of Vectibix®. In the event of acute onset or worsening of pulmonary symptoms, interrupt Vectibix® therapy. Discontinue Vectibix® therapy if ILD is confirmed.

In patients with a history of interstitial pneumonitis or pulmonary fibrosis, or evidence of interstitial pneumonitis or pulmonary fibrosis, the benefits of therapy with Vectibix® versus the risk of pulmonary complications must be carefully considered.

Photosensitivity Exposure to sunlight can exacerbate dermatologic toxicity. Advise patients to wear sunscreen and hats and limit sun exposure while receiving Vectibix®. ocular toxicities Keratitis and ulcerative keratitis, known risk factors for corneal perforation, have been reported with Vectibix® use. Monitor for evidence of keratitis or ulcerative keratitis. Interrupt or discontinue Vectibix® therapy for acute or worsening keratitis. increased mortality and toxicity with Vectibix® in combination with Bevacizumab and chemotherapy In an interim analysis of an open-label, multicenter, randomized clinical trial in the first-line setting in patients with mCRC, the addition of Vectibix® to the combination of bevacizumab and chemotherapy resulted in decreased OS and increased incidence of NCI-CTC grade 3-5 (87% vs 72%) adverse reactions. NCI-CTC grade 3-4 adverse reactions occurring at a higher rate in Vectibix®-treated patients included rash/acneiform dermatitis (26% vs 1%), diarrhea (23% vs 12%), dehydration (16% vs 5%), primarily occurring in patients with diarrhea, hypokalemia (10% vs 4%), stomatitis/mucositis (4% vs < 1%), and hypomagnesemia (4% vs 0).

NCI-CTC grade 3-5 pulmonary embolism occurred at a higher rate in Vectibix®-treated patients (7% vs 3%) and included fatal events in three (< 1%) Vectibix®-treated patients.

As a result of the toxicities experienced, patients randomized to Vectibix®, bevacizumab, and chemotherapy received a lower mean relative dose intensity of each chemotherapeutic agent (oxaliplatin, irinotecan, bolus 5-FU, and/or infusional 5-FU) over the first 24 weeks on study compared with those randomized to bevacizumab and chemotherapy. aDVerSe reactionS The following adverse reactions are discussed in greater detail in other sections of the label: • Dermatologic and Soft Tissue Toxicity [see Boxed Warning, Dosage and Administration (2.3), and Warnings and Precautions (5.1)] • Increased Tumor Progression, Increased Mortality, or Lack of Benefit in KRAS-Mutant mCRC [see Indications and Usage (1.2) and Warnings and Precautions (5.2)]

• Electrolyte Depletion/Monitoring [see Warnings and Precautions (5.3)] • Infusion Reactions [see Dosage and Administration (2.3), and Warnings and Precautions (5.4)] • Acute Renal Failure in Combination with Chemotherapy [see Warnings and Precautions (5.5)] • Pulmonary Fibrosis/Interstitial Lung Disease (ILD) [see Warnings and Precautions (5.6)] • Photosensitivity [see Warnings and Precautions (5.7)] • Ocular Toxicities [see Warnings and Precautions (5.8)] • Increased Mortality and Toxicity with Vectibix® in combination with Bevacizumab and Chemotherapy [see Warnings and Precautions (5.9)] clinical trials experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates in the clinical trials of a drug cannot be directly compared to rates in clinical trials of another drug and may not reflect the rates observed in practice. The adverse reaction information from clinical studies does, however, provide a basis for identifying the adverse events that appear to be related to drug use and for approximating rates.

Safety data are available from two clinical trials in which patients received Vectibix®: Study 1, an open-label, multinational, randomized, controlled, monotherapy clinical trial (N = 463) evaluating Vectibix® with best supportive care (BSC) versus BSC alone in patients with EGFR-expressing mCRC and Study 3, a randomized, controlled trial (N = 1183) in patients with mCRC that evaluated Vectibix® in combination with FOLFOX chemotherapy versus FOLFOX chemotherapy alone. Safety data for Study 3 are limited to 656 patients with wild-type KRAS mCRC. Vectibix® Monotherapy In Study 1, the most common adverse reactions (≥ 20%) with Vectibix® were skin rash with variable presentations, paronychia, fatigue, nausea, and diarrhea.

The most frequently reported (> 5%) serious adverse reactions in the Vectibix® arm were general physical health deterioration and intestinal obstruction. The most frequently reported adverse reactions for Vectibix® leading to withdrawal were general physical health deterioration (n = 2) and intestinal obstruction (n = 2).

For Study 1, the data described in Table 1 and in other sections below, except where noted, reflect exposure to Vectibix® administered to patients with mCRC as a single agent at the recommended dose and schedule (6 mg/kg every 2 weeks). table 1: adverse reactions (≥ 5% Difference) observed in Patients treated with Vectibix® monotherapy and Best Supportive care compared to Best Supportive care alone (Study 1)

SyStem organ claSS Preferred Term eye DiSorDerS Growth of eyelashes gaStrointeStinal DiSorDerS Nausea Diarrhea Vomiting Stomatitis general DiSorDerS anD aDminiStration Site conDitionS Fatigue Mucosal inflammation infectionS anD infeStationS Paronychia reSPiratory, tHoracic, anD meDiaStinal DiSorDerS Dyspnea Cough SKin anD SuBcutaneouS tiSSue DiSorDerS Erythema Pruritus Acneiform dermatitis Rash Skin fissures Exfoliative rash Acne Dry skin Nail disorder Skin exfoliation Skin ulcer

Study 1 Vectibix® Plus Best Supportive care Best Supportive care (n = 234) (n = 229) Any Grade Grade 3-4 Any Grade Grade 3-4 n (%) n (%) n (%) n (%) 13 (6) 52 (23) 49 (21) 43 (19) 15 (7)

2 (< 1) 4 (2) 6 (3)

37 (16) 26 (11) 28 (12) 2 (< 1)

1 (< 1)

60 (26) 15 (7)

10 (4) 1 (< 1)

34 (15) 2 (< 1)

7 (3)

57 (25)

4 (2)

41 (18) 34 (15)

12 (5) 1 (< 1)

30 (13) 17 (7)

8 (3)

150 (66) 132 (58) 131 (57) 51 (22) 45 (20) 41 (18) 31 (14) 23 (10) 22 (10) 21 (9) 13 (6)

13 (6) 6 (3) 17 (7) 3 (1) 3 (1) 4 (2) 3 (1)

2 (< 1) 4 (2) 2 (< 1) 2 (< 1) 1 (< 1)

2 (< 1)

2 (< 1) 1 (< 1)

Adverse reactions in Study 1 that did not meet the threshold criteria for inclusion in Table 1 were conjunctivitis (4.8% vs < 1%), dry mouth (4.8% vs 0%), pyrexia (16.6% vs 13.2%), chills (3.1% vs < 1%), pustular rash (4.4% vs 0%), papular rash (1.7% vs 0%), dehydration (2.6% vs 1.7%), epistaxis (3.9% vs 0%), and pulmonary embolism (1.3% vs 0%).

In Study 1, dermatologic toxicities occurred in 90% of patients receiving Vectibix®. Skin toxicity was severe (NCI-CTC grade 3 and higher) in 15% of patients. Ocular toxicities occurred in 16% of patients and included, but were not limited to, conjunctivitis (5%). One patient experienced an NCI-CTC grade 3 event of mucosal inflammation. The incidence of paronychia was 25% and was severe in 2% of patients [see Warnings and Precautions (5.1)].

In Study 1 (N = 229), median time to the development of dermatologic, nail, or ocular toxicity was 12 days after the first dose of Vectibix®; the median time to most severe skin/ocular toxicity was 15 days after the first dose of Vectibix®; and the median time to resolution after the last dose of Vectibix® was 98 days. Severe toxicity necessitated dose interruption in 11% of Vectibix®-treated patients [see Dosage and Administration (2.3)].

Subsequent to the development of severe dermatologic toxicities, infectious complications, including sepsis, septic death, necrotizing fasciitis, and abscesses requiring incisions and drainage were reported.

Vectibix® in Combination with FOLFOX Chemotherapy The most commonly reported adverse reactions (≥ 20%) in patients with wild-type KRAS mCRC receiving Vectibix® (6 mg/kg every 2 weeks) and FOLFOX therapy (N = 322) in Study 3 were diarrhea, stomatitis, mucosal inflammation, asthenia, paronychia, anorexia, hypomagnesemia, hypokalemia, rash, acneiform dermatitis, pruritus, and dry skin (Table 2). Serious adverse reactions (≥ 2% difference between treatment arms) in Vectibix®-treated patients with wild-type KRAS mCRC were diarrhea and dehydration. The commonly reported adverse reactions (≥ 1%) leading to discontinuation in patients with wild-type KRAS mCRC receiving Vectibix® were rash, paresthesia, fatigue, diarrhea, acneiform dermatitis, and hypersensitivity. One grade 5 adverse reaction, hypokalemia, occurred in a patient who received Vectibix®. table 2: adverse reactions (≥ 5% Difference) observed in Patients with Wild-type (Wt) KRAS tumors treated with Vectibix® and folfoX chemotherapy compared to folfoX chemotherapy alone (Study 3)

SyStem organ claSS Preferred Term eye DiSorDerS Conjunctivitis gaStrointeStinal DiSorDerS Diarrhea Stomatitis general DiSorDerS anD aDminiStration Site conDitionS Mucosal inflammation Asthenia infectionS anD infeStationS Paronychia inVeStigationS Weight decreased metaBoliSm anD nutrition DiSorDerS Anorexia Hypomagnesemia Hypokalemia Dehydration reSPiratory, tHoracic, anD meDiaStinal DiSorDerS Epistaxis

Vectibix® Plus folfoX (n = 322) Any Grade Grade 3-4 n (%) n (%)

folfoX alone (n = 327) Any Grade Grade 3-4 n (%) n (%)

58 (18)

5 (2)

10 (3)

201 (62) 87 (27)

59 (18) 15 (5)

169 (52) 42 (13)

29 (9) 1 (< 1)

82 (25) 79 (25)

14 (4) 16 (5)

53 (16) 62 (19)

1 (< 1) 11 (3)

68 (21)

11 (3)

58 (18)

3 (< 1)

116 (36) 96 (30) 68 (21) 26 (8)

46 (14)

14 (4) 21 (7) 32 (10) 8 (2)

SyStem organ claSS Preferred Term SKin anD SuBcutaneouS tiSSue DiSorDerS Rash Acneiform dermatitis Pruritus Dry skin Erythema Skin fissures Alopecia Acne Nail disorder Palmar-plantar erythrodysesthesia syndrome

Vectibix® Plus folfoX (n = 322) Any Grade Grade 3-4 n (%) n (%)

179 (56) 104 (32) 75 (23) 68 (21) 50 (16) 50 (16) 47 (15) 44 (14) 32 (10)

55 (17) 33 (10) 3 (< 1) 5 (2) 7 (2) 1 (< 1) 10 (3) 4 (1)

14 (4) 13 (4) 14 (4) 1 (< 1) 30 (9) 1 (< 1) 4 (1)

30 (9)

6 (2) 1 (< 1) 15 (5) 5 (2)

24 (7)

30 (9)

4 (1)

9 (3)

1 (< 1)

2 (< 1)

Adverse reactions that did not meet the threshold criteria for inclusion in Table 2 were abdominal pain (28% vs 23%), localized infection (3.7% vs < 1%), cellulitis (2.5% vs 0%), hypocalcemia (5.6% vs 2.1%), and deep vein thrombosis (5.3% vs 3.1%).

Infusion Reactions Infusional toxicity manifesting as fever, chills, dyspnea, bronchospasm or hypotension was assessed within 24 hours of an infusion during the clinical study. Vital signs and temperature were measured within 30 minutes prior to initiation and upon completion of the Vectibix ® infusion. The use of premedication was not standardized in the clinical trials. Thus, the utility of premedication in preventing the first or subsequent episodes of infusional toxicity is unknown. Across clinical trials of Vectibix® monotherapy, 3% (24/725) experienced infusion reactions of which < 1% (3/725) were severe (NCI-CTC grade 3-4). In one patient, Vectibix® was permanently discontinued for a serious infusion reaction [see Dosage and Administration (2.2, 2.3)]. immunogenicity As with all therapeutic proteins, there is potential for immunogenicity. The immunogenicity of Vectibix® has been evaluated using two different screening immunoassays for the detection of binding anti-panitumumab antibodies: an acid dissociation bridging enzyme-linked immunosorbent assay (ELISA) detecting high-affinity antibodies and a Biacore ® biosensor immunoassay detecting both high- and low-affinity antibodies. For patients whose sera tested positive in screening immunoassays, an in vitro biological assay was performed to detect neutralizing antibodies.

Monotherapy: The incidence of binding anti-panitumumab antibodies (excluding preexisting and transient positive patients) was 0.4% (5/1123) as detected by the acid dissociation ELISA and 3.2% (36/1123) as detected by the Biacore® assay. The incidence of neutralizing anti-panitumumab antibodies (excluding preexisting and transient positive patients) was 0.8% (9/1123). There was no evidence of altered pharmacokinetic or safety profiles in patients who developed antibodies to Vectibix®.

In combination with chemotherapy: The incidence of binding anti-panitumumab antibodies (excluding preexisting positive patients) was 0.9% (12/1297) as detected by the acid dissociation ELISA and 0.7% (9/1296) as detected by the Biacore® assay. The incidence of neutralizing antipanitumumab antibodies (excluding preexisting positive patients) was 0.2% (2/1297). No evidence of an altered safety profile was found in patients who developed antibodies to Vectibix®.

The detection of antibody formation is highly dependent on the sensitivity and specificity of the assay.

Additionally, the observed incidence of antibody (including neutralizing antibody) positivity in an assay may be influenced by several factors, including assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies to panitumumab with the incidence of antibodies to other products may be misleading.

Postmarketing experience The following adverse reactions have been identified during post-approval use of Vectibix ®.

Because these reactions are reported in a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

• Skin and subcutaneous tissue disorders: Stevens-Johnson syndrome, toxic epidermal necrolysis, skin necrosis, angioedema [see Boxed Warning, Dosage and Administration (2.3), and Warnings and Precautions (5.1)] • Immune system disorders: Infusion reaction [see Dosage and Administration (2.3) and Warnings and Precautions (5.4)] • Eye disorders: Keratitis/ulcerative keratitis [see Warnings and Precautions (5.8)] Drug interactionS No formal drug-drug interaction studies have been conducted between Vectibix® and oxaliplatin or fluoropyrimidine. uSe in SPecific PoPulationS Pregnancy Pregnancy category c. There are no studies of Vectibix® in pregnant women. Reproduction studies in cynomolgus monkeys treated with 1.25 to 5 times the recommended human dose of panitumumab resulted in significant embryolethality and abortions; however, no other evidence of teratogenesis was noted in offspring [see Nonclinical Toxicology (13.3)]. Vectibix® should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Based on animal models, EGFR is involved in prenatal development and may be essential for normal organogenesis, proliferation, and differentiation in the developing embryo. Human IgG is known to cross the placental barrier; therefore, panitumumab may be transmitted from the mother to the developing fetus, and has the potential to cause fetal harm when administered to pregnant women.

Women who become pregnant during Vectibix® treatment are encouraged to enroll in Amgen’s Pregnancy Surveillance Program. Patients or their physicians should call 1-800-77-AMGEN (1-800-772-6436) to enroll. nursing mothers It is not known whether panitumumab is excreted into human milk; however, human IgG is excreted into human milk. Published data suggest that breast milk antibodies do not enter the neonatal and infant circulation in substantial amounts. Because many drugs are excreted into human milk and because of the potential for serious adverse reactions in nursing infants from Vectibix®, 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. If nursing is interrupted, based on the mean half-life of panitumumab, nursing should not be resumed earlier than 2 months following the last dose of Vectibix® [see Clinical Pharmacology (12.3)].

Women who are nursing during Vectibix® treatment are encouraged to enroll in Amgen’s Lactation Surveillance Program. Patients or their physicians should call 1-800-77-AMGEN (1-800-7726436) to enroll.

Pediatric use The safety and effectiveness of Vectibix® have not been established in pediatric patients. The pharmacokinetic profile of Vectibix® has not been studied in pediatric patients. geriatric use Of the 737 patients who received Vectibix® monotherapy in Study 1 and 2, 36% were 65 and over while 8% were 75 and over. No overall differences in safety or efficacy were observed in elderly patients (≥ 65 years of age) treated with Vectibix® monotherapy.

Of the 322 patients in Study 3 who received Vectibix® plus FOLFOX, 128 (40%) were 65 and over while 8% were 75 and over. Patients older than 65 years of age experienced an increased incidence of serious adverse events (52% vs 36%) and an increased incidence of serious diarrhea (15% vs 5%) as compared to younger patients. oVerDoSage Doses up to approximately twice the recommended therapeutic dose (12 mg/kg) resulted in adverse reactions of skin toxicity, diarrhea, dehydration, and fatigue.

Patient counseling information Advise patients to contact a healthcare professional for any of the following: • Skin and ocular/visual changes [see Boxed Warning, Dosage and Administration (2.3), Warnings and Precautions (5.1, 5.8), and Adverse Reactions (6.1, 6.3)] • Signs and symptoms of infusion reactions, including fever, chills, or breathing problems [see Dosage and Administration (2.3), Warnings and Precautions (5.4), and Adverse Reactions (6.1, 6.3)] • Diarrhea and dehydration [see Warnings and Precautions (5.5)] • Persistent or recurrent coughing, wheezing, dyspnea, or new-onset facial swelling [see Warnings and Precautions (5.6) and Adverse Reactions (6.1)] • Pregnancy or nursing [see Use in Specific Populations (8.1, 8.3)] Advise patients of the need for: • Periodic monitoring of electrolytes [see Warnings and Precautions (5.3)] • Limitation of sun exposure (use of sunscreen, wear hats) while receiving Vectibix® and for 2 months after the last dose of Vectibix® therapy [see Warnings and Precautions (5.7)] • Adequate contraception in both males and females while receiving Vectibix ® and for 6 months after the last dose of Vectibix® therapy [see Use in Specific Populations (8.1, 8.3)]

22 (7)

85 (26) 26 (8) 42 (13) 10 (3)

folfoX alone (n = 327) Any Grade Grade 3-4 n (%) n (%)

This brief summary is based on the Vectibix® Prescribing Information v20, 5/14.

Vectibix® (panitumumab) Manufactured by: Amgen Inc. One Amgen Center Drive Thousand Oaks, CA 91320-1799 USA Patent: http://pat.amgen.com/vectibix/ © 2006-2014 Amgen Inc. All rights reserved. v20 05/14

ASCOPost.com | JULY 25, 2014

PAGE 85

Perspective Genitourinary Oncology

Prostate Cancer Biomarkers: Improvement in Predicting Clinically Significant Disease

By Richard J. Boxer, MD, FACS

P

rostate cancer will be diagnosed in 233,000 American men in 2014. It is one of the leading causes of death by a cancer (killing ~29,500 men annual-

Richard J. Boxer, MD, FACS

ly).1 Hundreds of thousands of men undergo prostate biopsies each year, most for either benign disease or for a cancer that will never lead to their death. Basic and clinical scientists have been focused on discovering or refining tumor markers that can differentiate between benign and malignant prostate disease and between prostate cancer that will cause death and that which will never have a serious impact on the patient’s life. American men have a 16% chance of being diagnosed, but only a 3% chance of dying from prostate cancer.

Search for Tumor Markers Each year, nearly 30 million Americans have a prostate-specific antigen (PSA) blood test. It has been hailed and reviled by PSA researcher Richard J. Ablin, PhD, DSc (Hon), Professor of Pathology at the University of Arizona, Tucson.2 “In approving the procedure, the Food and Drug Administration [FDA] relied heavily on a study that showed testing could detect 3.8 percent of prostate cancers, which was a better rate than the standard method, a digital rectal exam,” he wrote.

The race for discovery of more accurate tumor markers (ie, resulting in fewer false-positives and false-negatives, or greater accuracy for clinically significant disease) has produced many new markDr. Boxer is Visiting Professor of Urology and Scholar in Residence (Business of Science Center) at the David Geffen School of Medicine at UCLA. He is also a Professor of Clinical Urology at the University of Wisconsin–Madison.

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

ers or combinations of markers that will lead to better predictive value.

Prostate Health Index The Prostate Health Index (phi), approved by the FDA in 2012, combines the measurements of protein-free and protein-attached PSA along with a subcategory of free PSA, known as proPSA. “The phi can play a valuable role in determining whether an elevated PSA is likely due to prostate cancer or benign changes,” said Brant Thrasher, MD, Chair of Urology, University of Kansas Medical Center, Kansas City. “This option may prevent patients from potentially undergoing unnecessary biopsies.”

PCA3 Test The test for prostate cancer antigen 3 (PCA3) gene (formerly known as DD3) has not been approved by the FDA, but some research and reference laboratories are offering it. The PCA3 urine test measures a non–protein-coding messenger RNA that is highly overexpressed in prostate cancer tissue as compared to benign prostate tissue. The proposed uti-

Urologist-in-Chief at Johns Hopkins Medicine, Baltimore, said this about the PCA3 test: “If the score was greater than 60, the positive predictive value of having prostate cancer—meaning you should get a biopsy—was 80%, and that is pretty good for a biomarker. And those of us who have been using PCA3 for years now realize there are 10% to 15% of the people coming in the door with values that are above 60.”

4Kscore The 4Kscore is a blood test developed by OPKO Diagnostics that measures the serum levels of four different prostate-derived kallikrein proteins: total PSA, free PSA, intact PSA, and hK2.3 Levels of these biomarkers are combined with a patient’s age and digital rectal exam status using a proprietary algorithm to calculate the probability of finding aggressive prostate cancer.

The 4Kscore test is based on over a decade of research of the four-kallikrein panel of biomarkers conducted by scientists at Memorial Sloan Kettering Cancer Center and leading research centers

The doctor needs to balance the results of the markers with the common sense and clinical judgment of treating only those whose life will be impacted more by the disease than by the treatment.

—Richard J. Boxer, MD, FACS

lization for the PCA3 test is to help decide whether to biopsy or rebiopsy and whether a positive biopsy should lead to curative therapy (surgery or radiation).

Recent reports describe the use of PCA3 testing to identify patients with aggressive vs indolent prostate cancer.

Results of studies have been mixed. If the PCA3 test is found to correlate with disease prognosis, it could be a valuable tool in identifying patients who are better treated with expectant management (eg, aggressive follow-up of the tumor without radical treatment intervention) vs those better treated with curative therapy (eg, surgery or radiation therapy).

Speaking at the recent International Prostate Cancer Symposium in Vail, Colorado, Alan W. Partin, MD, PhD, Chairman of the James Buchanan Brady Urological Institute and David Hall McConnell Professor, Director, and

in Europe on over 10,000 patients. The information provided by the 4Kscore test has been reported to facilitate the shared decision-making process between urologist and patient in determining the advisability of a prostate biopsy.

Stephen M. Zappala, MD, FACS, of Andover Urology, Andover, Massachusetts, recently stated, “The 4Kscore test offers new information on the probability of having a Gleason score ≥ 7 cancer prior to undergoing a prostate biopsy. This is important, because we know that besides the potential side effects of biopsy such as bleeding and infection, up to 80% of prostate biopsies will either be negative for prostate cancer or will indicate a low-grade disease that may be better monitored than treated. The 4Kscore test will offer both the urologist and patient new information for the shared decision-making dis-

cussion about whether or not to have a prostate biopsy.”

TMPRSS2-ERG Fusion Transcript The test for the TMPRSS2-ERG gene fusion measures an androgenregulated transcription factor found in the urine. Through a rearrangement on chromosome 21, TMPRSS2 can get fused to ERG, which is a member of the ETS oncogene family. This is found to be an early event in prostatic intraepithelial neoplasia and atypia, as well as prostate cancer.

Dr. Partin, quoting data from Jack Groskopf, PhD, Senior Director, Research and Development at Hologic Gen-Probe,4 said that by coupling these two assays—PCA3 score and TMPRSS2-ERG score—“you come up with a level between 1 and 5 to determine what your probabilities [of having prostate cancer] are. So if you are at level 5 for both of those assays, you are up at around a 75% to 80% chance of having cancer, a 75% to 80% chance of significant cancer, and over a 40% chance that it’s higher than grade 6.”

Single Nucleotide Polymorphisms As described by the National Institutes of Health (NIH),5 “single nucleotide polymorphisms, frequently called SNPs (pronounced ‘snips’), are the most common type of genetic variation among people. Each SNP represents a difference in a single DNA building block, called a nucleotide. For example, a SNP may replace the nucleotide cytosine (C) with the nucleotide thymine (T) in a certain stretch of DNA.” The NIH reference continues: SNPs occur normally throughout a person’s DNA. They occur once in every 300 nucleotides on average, which means there are roughly 10 million SNPs in the human genome. Most commonly, these variations are found in the DNA between genes.

They can act as biologic markers, helping scientists locate genes that are associated with disease. When SNPs occur within a gene or in a regulatory region near a gene, they may play a more direct role in disease by affecting the gene’s function.

Most SNPs have no effect on health or development. Some of these genetic difcontinued on page 86

The ASCO Post | JULY 25, 2014

PAGE 86

Letters to the Editor

Do We Need So Much Emphasis on ‘Quality Care’?

U

nfortunately, when I see The ASCO Post, my first impression is that you enable a group of researchers (part-time clinicians) to pontificate about their own agendas. The agenda that seems to be missing is the presentation of information that either supports or refutes the freight train of “quality care” reporting that seems to

be mandated at the national level.

Is all this reporting really necessary? As a physician, I am part of the most intensely educated group in the world. Despite my education, a pervading emphasis on documenting quality care and quality care metrics seems to suggest (1) I am not to be trusted, (2) I cannot do my job, (3) I

am enabled by no one to perform efficiently, and (4) I require the oversight of every [less educated] regulatory body in this country.

It is nice of you to focus on the scientific progress (remarkable and truly appreciated). But your service does not enable me to provide my service.

How about getting your quality

care team to update us on the pros and cons of all the extra data collection?

—James R. Gould, MD Paducah, Kentucky

Prostate Cancer Biomarkers

blood, urine, and cerebrospinal fluid, and from which high-quality RNA and DNA can be extracted and purified for analysis. Exosomes are shed by cells under both normal and pathologic conditions.

In an article published online in Frontiers in Genetics,7 exosomal microRNAs (miRNAs) were identified as possible markers with great specificity for prostate cancer. The authors explained:

Science and Common Sense

than by the treatment. The biomarkers described above are pushing back the lack of specificity and sensitivity to give both the patient and the doctor what they need. n

continued from page 85

ferences, however, have proven to be very important in the study of human health.

Researchers have found SNPs that may help predict an individual’s response to certain drugs, susceptibility to environmental factors such as toxins, and risk of developing particular diseases. SNPs can also be used to track the inheritance of disease genes within families.

SNPs have been investigated as a marker for prostate cancer. William ­Isaacs, PhD, Professor of Urology at Johns Hopkins Medical School and researchers at the Karolinska Institute in Sweden as well as researchers at deCODE Genetics in Reykjavik, Iceland, have studied SNPs as a marker for prostate cancer.6 Dr. Isaacs found five SNPs—three on chromosome 8 and two on chromosome 17—that relate to prostate cancer.

If a patient had all five of those SNPs, the odds ratio for developing prostate cancer was ninefold higher.

The Karolinska group looked at 5,000 men using this SNP technology and found that they could avoid prostate biopsy in 22% of the patients, about the same as when using the PCA3 and TMPRSS2-ERG tests. However, using SNPs did not miss the aggressive cancers.

The researchers at deCODE Genetics, looking at 300,000 SNPs in 23,000 Icelanders, could predict prostate cancer.

This was repeated in the United States in 15,000 men in seven different cohorts, and the predictive results were confirmed.

According to Dr. Partin, “[The results of evaluating the appropriate area of the genome for SNPs has demonstrated that] if you have none of the SNPs, there is a 5% risk of prostate cancer, … and if you have all eight of them, there is an 80% risk you are going to develop prostate cancer.”

Exosomes Exosomes are one of many different subpopulations of microvesicles that can be isolated from biofluids such as

miRNAs are small non-coding RNAs that finely regulate gene expression in cells. Alterations in miRNA expression have been associated with development of cancer, and miRNAs are now being investigated as biomarkers for cancer as well as other diseases. Extracellular miRNAs exist in different forms—associated with Ago2 proteins, loaded into extracellular vesicles (exosomes, microvesicles, or apoptotic bodies) or into high density lipoprotein particles. These extracellular miRNAs are probably products of distinct cellular processes, and might therefore play different roles.

However, their functions in vivo are currently unknown. In spite of this, they are considered as promising, non-invasive diagnostic, and prognostic tools.

Cancer biomarkers are extraordinarily important to initial diagnosis and follow-up care. They are measured for accuracy by their specificity and sensitivity. Sensitivity measures the proportion of actual positives that are correctly identified as such, whereas specificity measures the proportion of negatives that are correctly identified as such. A perfect predictor would be 100% sensitive (ie, predicting all people from the sick group as sick) and 100% specific (ie, not predicting anyone from the healthy group as sick).

Prostate cancer markers have evolved from acid phosphatase decades ago that commonly indicated metastatic disease, to PSA that has led to too many biopsies and curative treatments and does not distinguish clinically significant disease, to the more sophisticated markers described in this commentary. What the patient needs is a marker that will determine whether clinically significant disease is present. The doctor needs to balance the results of the markers with the common sense and clinical judgment of treating only those whose life will be impacted more by the disease

Disclaimer: Letters to the Editor represent the views of the author and may not necessarily reflect the views of ASCO.

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

References 1. American Cancer Society: Cancer Facts & Figures 2014. Atlanta, American Cancer Society, 2014. Available at www. cancer.org.

2. Ablin RJ: The great prostate mistake.

New York Times. March 9, 2010. Available at www.nytimes.com.

3. OPKO Health, Inc, website. Available at www.opko.com.

4. Hologic Gen-Probe website. Available at http://www.gen-probe.com 5. National Institutes of Health: What are single nucleotide polymorphisms (SNPs)? Available at http://ghr.nlm.nih. gov/handbook/genomicresearch/snp.

6. deCODE genetics website. Available at http://www.decode.com 7. Hessvik NP, Sandvig K, Llorente A: Exosomal miRNAs as biomarkers for prostate cancer. Front Genet. March 21, 2013 (early release online).

Contact The ASCO Post Editorial Correspondence

Rates, reprints, or supplements

James O. Armitage, MD Editor-in-Chief e-mail: Editor@ASCOPost.com

Leslie Dubin e-mail: Leslie@harborsidepress.com Phone: 631.935.7660

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

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ASCOPost.com | JULY 25, 2014

PAGE 87

Patient’s Corner

Coping With the Aftermath of Cancer

Although I’m now cancer-free, the lingering effects of my breast cancer have impacted both my financial and physical well-being.

By Marie Krejci, as told to Jo Cavallo Editor’s note: In the July 10 issue of The ASCO Post, this article by Marie Krejci as told to Jo Cavallo was published; however, the published version was incomplete in that it did not reflect important updates made by Ms. Krejci. We apologize to Ms. Krejci for this error and to our readers for any confusion. Herewith we are reprinting the complete and up-to-date version of Ms. Krejci’s experience, “Coping With the Aftermath of Cancer.”

E

ven now, 3 years after I was diagnosed with breast cancer, I’m still struggling with how it is possible to have a normal mammogram and 6 months later be confronted with stage II estrogen/progesterone–positive, HER2-positive breast cancer. The news was especially devastating to hear because it arrived 6 weeks before my wedding, and at a time in my life when I was the happiest I have ever been. In an instant, my whole world was turned upside down, and I knew I was going to be in for the fight of my life.

Because the cancer was so aggressive, my oncologist recommended that I postpone the wedding and immediately undergo treatment: first a mastectomy, followed by a grueling chemotherapy regimen of carboplatin, trastuzumab (Herceptin), and docetaxel. Although the cancer was confined to my right breast, I also opted to have a contralateral prophylactic mastectomy.

I could see the looks of concern on the faces of my medical team and knew I had to act fast. After talking it over with my fiancé, Scott, we decided to cancel the wed-

ding festivities, but moved up our wedding date so it wouldn’t interfere with the start of my treatment. We were married the day before my surgery.

The Cost of Cancer My treatment was difficult. In addition to the 4½ months of chemotherapy and an additional year of trastuzumab, I underwent seven surgeries, including breast reconstruction surgeries. I was so sick most of that time, I had to take a medical leave from work. With the loss of my income, the bills began piling up, and I’m still recovering financially.

So many things about having cancer are devastating. Certainly, the immediate fear

complete assignments, and my ability to multitask—a skill I was so proficient at before—is now completely gone. Complex situations that I used to handle with ease now leave me feeling bewildered and overwhelmed. In addition to my cognitive issues, I also have a lot of joint pain from anastrozole, the aromatase inhibitor I’m taking to prevent a cancer recurrence, so I also have physical limitations to contend with as well.

All of these problems have left me unable to continue my career in a full-time capacity. Having to make such a drastic change in my profession is concerning.

I’ve been with the same company for 29 years and love what I do, so having to cur-

Cancer changes everything: your outlook on life, your career goals, and your priorities. And while cancer has taken a lot away from me, it has also given me a lot, including a desire to help other survivors going through a similar experience.

—Marie Krejci

rection from my medical team; now I feel like I’m on my own, and it’s a little scary.

I realize there are support programs out there to help survivors transition back to their “normal” lives; however, I do not feel that patients are ever prepared enough for that transition.

Your life is anything but normal after a cancer experience. Some experiences may not be as drastic as others, but I really feel that there should be some type of counselor or social worker assigned to survivors to help them get back to their lives, particularly for patients who have had body parts removed.

Patients are given a list of resources, but in my particular case, I experienced severe anxiety and depression and was in no shape to be calling around for information.

I was so secluded for almost 2 years during treatment and surgeries that I developed a social phobia—I didn’t want to go out of the house, and I couldn’t bring myself to make any phone calls. I was later diagnosed with post-traumatic stress disorder.

These are the aftermaths that people don’t usually hear about and for which available assistance tends to be insufficient.

Renewed Sense of Purpose that you could lose your life is at the top of the list. But what has been the most difficult to cope with is the aftermath of cancer.

I’m thrilled to say that the treatment was successful and I’m now cancer-free, but it has not been easy trying to resume the life I had before my diagnosis—and I am realizing with every day that passes, I never will have that life again.

The treatment has left me with serious cognition problems. I struggle at work to

tail my workload and relinquish some of my responsibilities has been difficult. On a more basic level, I’m worried about how reducing my work hours will affect my retirement fund and my ability to recover financially from my treatment expenses.

Survivorship Support At times, cancer’s aftermath has also left me feeling somewhat abandoned.

During treatment, I received constant di-

Patient Guides Available Through ASCO University Bookstore • 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.

• 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.

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

Cancer changes everything: your outlook on life, your career goals, and your priorities. And while cancer has taken a lot away from me, it has also given me a lot, including a desire to help other survivors going through a similar experience.

Cancer has also given me a renewed sense of purpose, and now I live every day to the fullest and never take anything for granted.

That’s a valuable lesson for us all. 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

The ASCO Post | JULY 25, 2014

PAGE 88

2014–2015 Oncology Meetings July

5th World Congress of International Federation of Head and Neck Oncologic Societies Annual Meeting of American Head and Neck Society July 26-30 • New York, New York For more information: www.ahns.info/meetings/index.php

AACR/ASCO Methods in Clinical Cancer Research Workshop July 26-August 1 • Vail, Colorado For more information: www.aacr.org

August

Hematology and Medical Oncology Best Practices August 14-21 • Arlington, Virginia For more information: smhs.gwu.edu/ cehp/activities/courses/hemonc

Breast Cancer Symposium September 4-6 • San Francisco, California For more information: breastcasym.org

Best of ASCO® Chicago August 15-16 • Chicago, Illinois For more information: boa.asco.org

2014 APAO Annual Conference September 10-14, 2014 • Austin, Texas Sheraton Austin at the Capitol For more information: www.apao.cc/node/9

16th Annual Scientific Meeting: AGITG Trials in Action August 20-22 • Brisbane, Australia For more information: www.agitg.asnevents.com.au 6th Latin American Conference on Lung Cancer August 21-23 • Lima, Peru For more information: www.lalca2014.org ISEH Society for Hematology and Stem Cells 43rd Annual Scientific Meeting August 21-24 • Montreal, Canada For more information: www.iseh.org Best of ASCO® Seattle August 22-23 • Seattle, Washington For more information: boa.asco.org

Best of ASCO® Boston August 8-9 • Boston, Massachusetts For more information: boa.asco.org ASH Meeting on Lymphoma Biology August 10-13 • Colorado Springs, Colorado For more information: www.hematology.org/LymphomaBiology/

2014-2015

6th Mayo Clinic Angiogenesis Symposium August 22-24 • Rochester, Minnesota For more information: www.mayo.edu/cme/ hematology-and-oncology-2014r606

September Association of Pediatric Hematology/Oncology Nurses 38th Annual Conference September 4-6 • Portland, Oregon For more information: www.aphon.org

American Society for Radiation Oncology Annual Meeting September 14-17 • San Francisco, California For more information: www.astro.org Academy of Oncology Nurse and Patient Navigators 5th Annual Conference September 18-21 • Orlando, Florida For more information: www.aonnonline.org NCCN 9th Annual Congress: Hematologic Malignancies™ September 19-20 • New York, New York For more information: www.nccn.org/professionals/ meetings/hematological/ Advances in Melanoma: From Biology to Therapy September 20-23 • Philadelphia, Pennsylvania For more information: www.aacr.org/home/scientists/ meetings--workshops/specialconferences/advances-in-melanomafrom-biology-to-therapy.aspx European Society for Medical Oncology 2014 Congress September 26-30 • Madrid, Spain For more information: www.esmo.org/Conferences/ESMO2014-Congress

Critical Issues in Tumor Microenvironment, Angiogenesis and Metastasis: From Bench to Bedside to Biomarkers September 29-October 2 • Cambridge, Massachusetts For more information: steelelab.mgh.harvard.edu

October ACCC 31st National Oncology Conference October 8-11 • San Diego, California For more information: www.accc-cancer.org International Cancer Imaging Society Meeting and 14th Annual Teaching Course October 9-11 • Heidelberg, Germany For more information: www.icimagingsociety.org.uk/index. cfm?task=meetings&meetingid=37 11th Meeting of the European Association of NeuroOncology (EANO) October 9-12 • Turin, Italy For more information: www.eano.eu/mee_welcome.php 2nd Annual Breast Cancer Symposium October 11 • Miami, Florida For more information: cme.baptisthealth.net/breastcancer/ pages/index.aspx 18th SIS World Congress on Breast Healthcare October 16-19 • Orlando, Florida For more information: www2.kenes.com/sis/Pages/Home. aspx

continued on page 96

For Your NPs and PAs A CE/CME/CEU Conference for Advanced Practitioners in Oncology

October 30th – November 2nd Loews Royal Pacific Hotel at Universal Orlando, FL apsho.org/jadprolive

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 doselimiting 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 (cont’d) 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

• 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 Non–Small Cell Lung Cancer (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 ≥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 • 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

ABRAXANE® is a registered trademark of Celgene Corporation. © 2014 Celgene Corporation 04/14 US-ABR140005

Pancreatic Adenocarcinoma Study • See next page for most common adverse reactions • 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%), 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

For more information, please visit www.abraxane.com.

ABRAXANE® is indicated for the first-line treatment of patients with metastatic adenocarcinoma of the pancreas (MPAC), in combination with gemcitabine.

in first-line MPAC

ignite survival ABRAXANE + gemcitabine significantly increased overall survival vs gemcitabine alone 1.0

Median OS

0.9

ABRAXANE + gemcitabine (n=431)

Proportion of survival

0.8 0.7

Gemcitabine (n=430)

0.6 0.5

8.5

months (95% CI: 7.9-9.5)

6.7

months (95% CI: 6.0-7.2)

0.4 0.3

HR: 0.72 (95% CI: 0.62-0.83)a

0.2

P<0.0001b

0.1 0.0 Patients at risk A+G: G:

0

3

6

9

12

15

18

21

24

27

30

33

36

39

431 430

357 340

269 220

169 124

108 69

67 40

40 26

27 15

16 7

9 3

4 1

1 0

1 0

0 0

Time (months)

A+G=ABRAXANE + gemcitabine; G=gemcitabine; HR=hazard ratio; KPS=Karnofsky Performance Status; OS=overall survival.

Stratified Cox proportional hazard model. b Stratified log-rank test stratified by geographic region (North America vs Others), KPS (70-80 vs 90-100), and presence of liver metastasis (yes vs no). a

STUDY DESIGN The multinational, randomized, phase 3 MPACT trial compared ABRAXANE (125 mg/m2) + gemcitabine (1000 mg/m2) on Days 1, 8, and 15 of each 28-day cycle vs gemcitabine alone (1000 mg/m2 administered weekly for 7 weeks, followed by a 1-week rest period in Cycle 1, then on Days 1, 8, and 15 of each subsequent 28-day cycle) in 861 patients with MPAC. The primary end point was OS.

Most common adverse reactions in the 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%)

ABRAXANE is also indicated in MBC and NSCLC 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.

• The primary end point in the metastatic breast cancer (MBC) phase 3 trial was reconciled target lesion response rate (recTLRR) vs paclitaxel injection 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.

• The primary end point in the NSCLC phase 3 trial was overall response rate (ORR) vs paclitaxel injection + carboplatin

Overall survival (secondary end point) was not statistically significant in the MBC and NSCLC trials vs comparator arms.

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 100 800 1st dose reduction 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 260 mg/m2 over 30 min 175 mg/m2 over 3 hb (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 8 4 Severe Symptomsd Asthenia Any Symptoms 47 39 8 3 Severe Symptomsd 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 2 25 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 227 (54%) 70 (17%) 51 (13%) 3 (1%) neuropathya 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 47 (11%) 10 (2%) 20 (5%) 1 (<1%) infectionsb 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 continued from page 88

2014 Quality Care Symposium October 17-18 • Boston, Massachusetts For more information: quality.asco.org Atlanta Lung Cancer Symposium October 18 • Atlanta, Georgia For more information: www.phillipsgilmore.com/alcs2014 16th World Congress of Psycho-Oncology and Psychosocial Academy October 20-24 • Lisbon, Portugal For more information: www.ipos2014.com 14th Annual Conference of SIOG October 23-25 • Lisbon, Portugal For more information: www.siog.org ASCO’s Palliative Care in Oncology Symposium October 24-25 • Boston. Massachusetts For more information: www.palliative.asco.org 11th International Conference of the Society for Integrative Oncology October 26-28 • Houston, Texas For more information: www.integrativeonc.org American College of Surgeons Clinical Congress October 26-30 • San Francisco, California For more information: www.facs.org/meetings_events/ future_congress/future

20th Annual Cancer Institute Symposium October 30 • Hershey, Pennsylvania For more information: www.pennstatehershey.org/web/ce/ home/programs/physicians

19th Annual Meeting of the Society for Neuro-Oncology November 13-16 • Miami Beach, Florida For more information: www.soc-neuro-onc.org/

2014 Chicago Multidisciplinary Symposium in Thoracic Oncology October 30-November 1 • Chicago, Illinois For more information: http://thoracicsymposium.org

EORTC-NCI-AACR International Symposium on Molecular Targets and Cancer Therapeutics November 18-21 • Barcelona, Spain For more information: www.aacr.org

3rd Annual Global Biomarkers Consortium Conference October 31 – November 1 • San Francisco, California For more information: www.globalbiomarkersconsortium .com

November Chemotherapy Foundation Symposium November 4 - 8 • New York, New York For more information: www.chemotherapyfoundation symposium.org Diagnostic Error in Medicine 5th International Conference November 11-14 • Baltimore, Maryland For more information: www.hopkinscme.edu/ CourseDetail.aspx/80028747 CNS Anticancer Drug Discovery/ Development Conference November 12-13 • Miami Beach, Florida For more information: www.soc-neuro-onc.org

3rd Annual World Cutaneous Malignancies Congress October 29-31 • San Francisco, California For more information: www.cutaneousmalignancies.com

2014-2015

Multidisciplinary Update in Breast Disease 2014 November 12-15 • Atlantic Beach, Florida For more information: www.mayo.edu/cme/surgicalspecialties-2014s306

European Multidisciplinary Colorectal Cancer Congress (EMCCC) November 23-25 • Amsterdam, The Netherlands For more information: www.dccg.nl

37th Annual San Antonio Breast Cancer Symposium December 9-13 • San Antonio, Texas For more information: www.sabcs.org

January 2015 Gastrointestinal Cancers Symposium January 15-17 • San Francisco, California For more information: www.gicasym.org

RSNA 2014: Radiological Society of North America November 30 - December 5 • Chicago, Illinois For more information: www.rsna.org

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

December

February

American Association for Cancer Research: Tumor Immunology December 1-4 • Orlando, Florida 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

UICC World Cancer Congress December 3-6 • Melbourne, Australia For more information: www.worldcancercongress.org ASH Annual Meeting and Exposition December 6-9 • San Francisco, California For more information: hematology.org

Genitourinary Cancers Symposium February 26-28 • Orlando, Florida For more information: www.gucasym.org

March 13th International Congress on Targeted Anticancer Therapies March 2-4 • Paris, France For more information: www.tatcongress.org

ASCOPost.com | JULY 25, 2014

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Integrative Oncology Avoiding Antioxidant-Drug Interactions During Cancer Treatment

By Dan Labriola, ND, and Robert B. Livingston, MD

M

any potential drug-nutrient interactions can affect cancer treatment. It is important to consider these interactions given the significant use of supplements and other self-treatment options during cancer care. Antioxidants account for a large portion of the $32 billion in supplement industry sales,1 and thus, patients frequently have questions about them. The challenges for oncology professionals are to determine which supplement–cancer treatment combinations are safe and to explain the risks to patients.

The solution is not to rely on drugnutrient interaction references, as these are not as mature or reliable as drug-drug interaction science reports for consistently accurate answers.

Moreover, telling the patient to stop all supplements or even to just stop antioxidants is problematic, since patients are reluctant to give up agents that they believe will produce better outcomes and reduced adverse effects, as typically cited in aggressive marketing.

Understanding the Controversy The numerous contradictory reports about antioxidants in the cancer treatment setting are understandable and more easily explained to patients if we revisit the pharmacology of these agents.

We focus here solely on the interactions between antioxidants and those cancer treatments that utilize reactive oxygen species for their cytotoxic effects. Characterized by an unpaired set of electrons in their outer orbital ring, reactive oxygen species are a well-known mechanism by which radiotherapy and some chemotherapy agents preferentially induce apoptosis in cancer cells.

Antioxidants gained their fame with cancer patients as a result of their ability to quench reactive oxygen species, the free radicals that can result in some cancers. It is also well recognized that they can quench the reactive oxygen species created by cancer treatments.2 These interactions, however, occur only when the antioxidant and chemotherapy are matched. If the molecules do not match, Dr. Labriola is Director, Northwest Natural Health Specialty Care Clinic, and Medical Director, Naturopathic Services, Swedish Cancer Institute, Swedish Medical Center, Seattle. Dr. Livingston is Professor of Medicine and Hematology, University of Arizona Cancer Center, Tucson.

the antioxidant will not interact and therefore will not affect treatment.

Different cancer treatments utilize a variety of different, unique reactive oxygen species for their cytotoxicity, even though they are frequently referred to as if all chemotherapy or cancer treatments were the same. The antioxidants from dietary, botanical, and other available sources come in many different forms as well. Some combinations of antioxidants and cancer treatments will interact, some will not, and as of today, we are not able to accurately predict which do or do not interact.

When an interaction occurs, it has the net effect of reducing the dosage by reducing the number of reactive oxy-

about all antioxidant–reactive oxygen species interactions based on these single combinations tested are misleading. In fact, it may not even be accurate to predict the interaction of a specific combination that’s been tested when applied to a different patient or condition until we have a greater knowledge of the independent variables that can affect outcome.

Explaining Potential Risks to Patients When the patient comes in with antioxidant recommendations based on data that appear to be too good to be true, consider that there may be other factors at play. The most obvious explanation is

It is recommended that patient supplement treatments be limited to those whose actions and interactions are understood; when there is doubt, one should err on the side of caution.

The potential benefits of reduced side effects frequently do not outweigh the potential risk of a poor outcome.

—Dan Labriola, ND, and Robert B. Livingston, MD

gen species delivered by the treatment.

Since most of these treatments have a narrow therapeutic index and efficacy that is proportional to dose, even a modest decrease in reactive oxygen species can have a significant effect on outcome including reduction in disease-free survival,3 especially where long-term outcome is a clinical objective.

The published literature regarding concurrent chemotherapy or radiation with antioxidants reach a wide variety of conclusions, some showing improved survival and status and others, a reduction in survival. A convenient list was published by Ladas et al.4 When viewed in light of the governing pharmacology, however, these apparently contradictory results are understandable. Some combinations interacted, and others did not.

Unfortunately, the generalizations

that an inadvertent dose reduction from an antioxidant–reactive oxygen species interaction will likely reduce adverse effects, no different from administering a reduced dose. Also, supplements with anti-inflammatory activity may improve patient status and give the appearance of tumor response in the short term even with reduced effective dosage.

Trial data from short-term or salvage therapy, where a reduced tumor response resulting from an interaction may not be noticeable, should be viewed with caution. This is especially important in patients where long-term disease-free survival is a clinical objective, as the same interference may dramatically interfere with survival if the net effect of treatment falls below the therapeutic index.

In the sole long-term, randomized, placebo-controlled prospective trial to have addressed this topic, Bairati et al

administered antioxidants with radiotherapy for 540 stage I and II squamous cell head and neck patients and found a significant increase in relapse rate for the antioxidant arm.5 The same authors published again, this time adjusting for patients who continued to smoke after treatment,6 and suggested that the differences could be resolved by removing smokers from the randomization. However, this adjustment has been controversial, and the authors concede that antioxidants do, in fact, interact with radiotherapy.

Minimizing and Managing Interactions In terms of patient management and safety, the evidence is clear that chemotherapy agents that rely on reactive oxygen species mechanisms for their cytotoxicity, including alkylators, antitumor antibiotics, and others, should be considered potentially vulnerable to interference from antioxidant supplementation greater than dietary levels. If antioxidants are to be used with these patients, interaction can be minimized by separating dosage by at least 4 halflives for the drug and a return to normal dietary serum levels for the antioxidant. Both the antioxidant and the drug multicompartment pharmacokinetics should be considered. The same principles apply to radiotherapy.

The pharmacokinetics of the vulnerable chemotherapy treatments and antioxidants, including strategies for managing these interactions, has been reviewed in greater detail and can be helpful.7 When looking for supplement information, unfortunately not all Internet websites and database services are accurate, but one reliable source is the evidence-based Memorial Sloan Kettering Cancer Center Integrative Medicine website.8 Broader, patientfriendly explanations of the many oncology-nutrient interactions including antioxidants are also available.9,10

Frequently Asked Questions Chemotherapy and radiation therapy are powerful treatments. How is it that a few vitamins or other relatively benign substances can interfere?

Cytotoxic treatments are indeed powerful, but their efficacy is governed by a relatively narrow therapeutic index, which means that dosage is already close to the upper or lower limit. The trial by Bairati et al5 used a modest 400 IU of vitamin E and continued on page 98

The ASCO Post | JULY 25, 2014

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Integrative Oncology Antioxidant-Drug Interactions continued from page 97

30 mg of beta-carotene. Patients frequently self-treat with much higher dosages.

Can the risk for an unwanted interaction be avoided by instructing the patient to avoid antioxidants within 24 hours of chemotherapy or radiation?

The answer depends on the treatments and the patient. The rule of thumb is to separate interacting agents by at least 4 terminal half-lives of the cancer treatment and, for the supplemental antioxidant, return to normal serum levels. For example, it is unlikely that the cytotoxicity of busulfan (Busulfex, Myleran), with a terminal half-life of approximately 3 hours, would have a meaningful interaction after 24 hours, whereas oxaliplatin, whose terminal half-life is more than 50 hours, would be vulnerable to interference the next day and longer.

When the route of administration is other than intravenous, the appropriate compartment pharmacokinetics is also important. You would not use firstcompartment kinetics with intrathecal methotrexate.

The pharmacokinetics of the antioxidant is important as well. The half-life of vitamin E, for example, is approximately 48 hours, which puts it well beyond 24 hours for even modest dosages.

What are the most common sources of antioxidants?

Vitamins A (including beta-carotene), B6, C, and E are powerful antioxidants.

Minerals zinc and selenium also have significant antioxidant activity. Since these are life-sustaining nutrients that cannot be manufactured by the body, they must still be available at reasonable levels in the diet and/or with supplementation.

There are also many plant-based antioxidant sources including some fruits, vegetables, and herbal medicines.

Is it safe for patients to take just a multiple vitamin during treatment?

Not all multiple vitamin products are appropriate. Many have 2,000% or more of the daily value of some ingredients. It is best to find a multiple vitamin that has approximately 100% of daily values for all ingredients.

Are herbal medicines a potential source of antioxidant interference?

Some botanicals have more than 50 pharmacologically active alkaloids, many of which have antioxidant activity. Those that have been scientifically tested, standardized for their active ingredients, and manufactured with good

quality control will behave predictably.

For others, we simply don’t yet have enough data to know all of their actions.

When uncertain, the safest course is to assume the agent has antioxidant activity and separate it from treatment.

Can diet be a potential source of interference?

A normal, varied diet should not be a problem. It is useful, however, to caution patients to avoid practices that can concentrate antioxidants such as severe “mono-diets” and juicing vegetables.

Also, some sports drinks and protein supplements are fortified with levels of nutrients that may interfere with treatment. Consult the label.

Many other complementary and alternative medicine products such as homeopathic treatments and traditional Chinese medicine herbs are promoted for use with cancer treatment. Are these a potential source for antioxidant interference?

Traditional homeopathics are very dilute and unlikely to interact. Some products labelled as homeopathic, however, have other ingredients that are not dilute and may pose a risk.

The botanicals associated with traditional Chinese medicine and other Asian healing arts face the same challenges as Western herbs, namely that we do not always know how much antioxidant activity they contain. The same cautions are recommended.

Are there any other concerns when combining supplements with cancer treatments that are vulnerable to antioxidant interference?

There are many evidence-based complementary and alternative medicine therapies with demonstrated benefit11 when delivered in a disciplined, integrative care setting, but there are also risks for interference with treatment efficacy, increasing adverse effects, and creating new problems when administered incorrectly. Providers of these treatments frequently do not understand the technology of modern cancer care and, as a result, do not recognize potentially negative interactions.

Patients are also confused when the interactions produce results that are not intuitive. In cases where a supplement treatment reduces side effects, it can be difficult for the patient to understand that this may not be a wholly positive event in relationship to outcome. Patients who are anxious to do something on their own to improve the cancer journey are frequently baffled when normally healthful strategies such as juicing vegetables and fruits are described as risky.

GUEST EDITOR

I

ntegrative Oncology is guest edited by Barrie R. Cassileth, MS, PhD, Chief of the Integrative Medicine Service and Laurance S. Rockefeller Chair in Integrative Medicine at Memorial Sloan Kettering Cancer Center, New York.

The Integrative Medicine Service at Memorial Sloan Kettering Cancer Center developed and maintains a free website—About Herbs (www.mskcc.

Barrie R. Cassileth, MS, PhD org/aboutherbs)—that provides objective and unbiased information about herbs, vitamins, minerals, and other dietary supplements, and unproved anticancer treatments. Each of the 269 and growing number of entries offer health-care professional and patient versions, and entries are regularly updated with the latest research findings.

In addition, the About Herbs app, Memorial Sloan Kettering Cancer Center’s very first mobile application, is compatible with iPad, iPhone, and iPod Touch devices, and can be downloaded at http://itunes.apple.com/us/app/ about-herbs/id554267162?mt=8.

Summary It is recommended that patient supplement treatments be limited to those whose actions and interactions are understood; when there is doubt, one should err on the side of caution. The potential benefits of reduced side effects frequently do not outweigh the potential risk of a poor outcome. It is important to note that antioxidants represent just one of many complementary and alternative medicine treatments with the potential to interact with oncology care.

Patient compliance and satisfaction are improved if these interactions can be explained rather than “just saying no.”

Compliance will be even better if a safe substitute can be prescribed in place of a supplement that is risky, especially for patients who are seriously committed to using these products during treatment.

Patients appreciate receiving knowledgeable guidance from their oncology team, especially when they have been receiving conflicting information.

Initial patient screening for possible interactions can be accomplished by a midlevel provider with appropriate training.

For patients who want a treatment plan using complementary and alternative medicine therapies, a competent integrative oncology service is strongly recommended.

For the future, as we advance our knowledge with new research, it is possible that dietary and botanical antioxidants will find a place in conventional oncology care. n

Disclosure: Drs. Livingston and Labriola reported no potential conflicts of interest.

References 1. Lariviere D: Nutritional supplements flexing muscles as growth industry. Forbes, April 2013. Available at www.forbes.com.

Accessed June 30, 2014.

2. Erhola M, Kellokumpu-Lehtinen P, Metsa-Ketela T, et al: Effect of anthracycline-based chemotherapy on total plasma antioxidant capacity in small-cell lung cancer patients. Free Radic Biol Med 21:383390, 1996.

3. Budman DR, Berry DA, Cirrincione CT, et al: Dose and dose intensity as determinants of outcome in the adjuvant treatment of breast cancer. J Natl Cancer Inst 90:12051211, 1998.

4. Ladas EJ, Jacobson JS, Kennedy DD, et al: Antioxidants and cancer therapy: A systematic review. J Clin Oncol 22:517-528, 2004.

5. Bairati I, Meyer F, Gélinas M, et al: Randomized trial of antioxidant vitamins to prevent acute adverse effects of radiation therapy in head and neck cancer patients. J Clin Oncol 23:5805-5813, 2005.

6. Meyer F, Bairati I, Fortin A, et al: Interaction between antioxidant vitamin supplementation and cigarette smoking during radiation therapy in relation to long-term effects on recurrence and mortality: A randomized trial among head and neck cancer patients. Int J Cancer 122:1679-1683, 2008.

7. Labriola D, Livingston R: Possible interactions between dietary antioxidants and chemotherapy. Oncology (Williston Park) 13:1003-1008, 1999.

8. Memorial Sloan Kettering Cancer Center: Integrative Medicine. Available at www. mskcc.org/cancer-care/integrative-medicine.

Accessed June 30, 2014.

9. Cassileth B: Survivorship: Living Well During and After Cancer. Ann Arbor, Michigan, Spry Publishing, 2014.

10. Labriola D: Complementary Cancer Therapies. New York, Three Rivers Press, 2000.

11. Integrating conventional and naturopathic medicine. Swedish Medical Center Update, March 2011. Available at www.nwnaturalhealth.com/holmstrom-article.pdf. Accessed June 30, 2014.

ASCOPost.com | JULY 25, 2014

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Announcements

David C. Beyer, MD, FASTRO, Named President-Elect, ASTRO Board of Directors

M

embers of the American Society for Radiation Oncology (­ ASTRO) have elected David C. Beyer, MD, ­FASTRO, President-Elect of the ASTRO

David C. Beyer, MD, FASTRO

Board of Directors. Dr. Beyer will begin his term at the Annual Business Meeting in September during ASTRO’s 56th Annual Meeting in San Francisco.

Colleen A.F. Lawton, MD, ­FASTRO, Chair of ASTRO’s Board of Directors, said “[Dr. Beyer] brings an extensive amount of valuable experience and knowledge that will significantly impact our work on behalf of cancer patients worldwide.

Moffitt Receives $1.6 Million Grant for Lung Cancer Screenings

M

offitt Cancer Center Thoracic Oncology Department Chair Scott Antonia, MD, PhD, received an Infrastructure Grant Florida’s James and Esther King Biomedical Research Program. The grant will help fund Moffitt’s comprehensive lung screening program. Earlier this year the U.S. Preventive Services Task Force approved guidelines recommending low-dose CT scans annually for older smokers. The grant will provide funding in the amount of $1,600,000 over a 3-year period.

The award will be carried out under the direction of a Community Advisory Committee and 10 Moffitt staff members. Research will focus on radiomics, proteogenomics, epidemiology and smoking cessation. It will also help to provide a more comprehensive blood and plasma data bank for future research.

Moffitt offers a comprehensive lung cancer screening program, which includes assessment of lung CT scans by a team of multispecialty medical experts. Insurance coverage for screenings varies. For plans that do not cover the screening, the scan will cost $150. n

Dr. Beyer is the Medical Director of Arizona Oncology Services in Scottsdale. He is an active clinician ­ with a primary focus on prostate cancer. He served ASTRO as a Member of the Board of Directors (2007–2011) as the Vice-Chair and then the Chair of

the Health Policy Council; as Co-Chair of the Best Practices Committee and the Health Policy Committee; and as a Member of the CPT/RUC Advisors Workgroup, the Clinical Affairs and Quality Committee and the Nominating Committee.

Dr. Beyer has spent his career at Arizona Oncology Services, joining the practice in 1985. He specializes in prostate brachytherapy, including seed implants and high-dose-rate brachytherapy, as well as intensity-modulated radiation therapy and image-guided radiation therapy. n

Reserve Your Seat Today at NCCN.org/hem

Register Now!

Scan QR code to go to NCCN.org/hem

NCCN 9th Annual Congress:

Hematologic Malignancies

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September 19 – 20, 2014 New York Marriott Marquis 1535 Broadway • New York, New York

Registe

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y Friday, August th 15 for early bird rat e!

Additio nal available discounts Member for NCCN Institutio ns

Moderator:

Andrew D. Zelenetz, MD, PhD Memorial Sloan Kettering Cancer Center

Highlights include*: • AML: Current Management

• Molecular Monitoring in CML

• Changing Paradigms in the Management of CLL

• Molecular Prognostication in CLL from FISH to Next Generation Sequencing: Implications for Clinical Management

• Chimeric Antigen Receptor (CAR) Modified T Cells for ALL • Current Management of Adult ALL • Diffuse Large B Cell Lymphoma: Treatment Beyond R-CHOP • Evolving Therapy of Mantle Cell Lymphoma • Follicular Lymphoma and the Role of Maintenance • Is There a Role for Upfront Transplant in the Current Management of Symptomatic Multiple Myeloma?

• Management of Hodgkin Lymphoma in the Elderly

• Myeloid Growth Factors Revisited • Optimal Management of CML without Breaking the Bank • Role of Molecular Advances in the Classification and Prognosis of MDS • Targeted Therapy in Indolent Lymphoma • The Continuum of MGUS and Smoldering Myeloma • Updates on the Prevention and Treatment of Cancer-Related Infections

*Subject to change.

This activity will be approved for AMA PRA Category 1 Credit(s)™ for physicians and will also be accredited for nurses, pharmacists, and other health care professionals. Please refer to the complete accreditation details for more information.

Sponsorship and exhibit opportunities available!

For more information, contact Jennifer Tredwell at tredwell@nccn.org.

JNCCN-N-0195-0714

The ASCO Post | JULY 25, 2014

PAGE 100

Lab Notes

Ongoing Molecular Research in the Science of Oncology NOVEL MECHANISMS MTH1 Inhibition Blocks Sanitation of Deoxyribonucleotide Triphosphate Pool and Causes Cancer Cell Death Dysfunctional redox regulation in cancer results in production of reactive oxygen species, damaging DNA and free deoxyribonucleotide triphosphates (dNTPs). The MTH1 protein, which is nonessential in normal cells, sanitizes oxidized dNTP pools, preventing incorporation of damaged bases during DNA replication in cancer cells.

As reported in Nature, Gad and colleagues found that cancer cells require MTH1 activity to avoid incorporation of oxidized dNTPs, which would result in DNA damage and cell death.

First-in-class nudix hydrolase family small-molecule inhibitors (TH287 and TH588) were shown to potently and selectively engage and inhibit the MTH1 protein in vitro, with protein co-crystal structures showing that the agents bind in the active site of MTH1.

The inhibitors caused incorporation of oxidized dNTPs in cancer cells, resulting in DNA damage, cytotoxicity, and antitumor response in patient-derived mouse xenografts.

The investigators concluded, “This study exemplifies the non-oncogene addiction concept for anticancer treatment and validates MTH1 as being cancer phenotypic lethal.”

Gad H, et al: Nature 508:215-221, 2014.

RISK FACTORS High Macrophage Inhibitory Cytokine-1 Levels and Colorectal Cancer Risk Chronic inflammation is implicated in the development of colorectal cancer, and the plasma inflammatory biomarker macrophage inhibitory cytokine-1 (MIC-1, GDF15) may have a direct role in tumorigenesis.

As reported in Journal of the National Cancer Institute, Mehta and colleagues found that subjects in the highest (5th) quintile of plasma MIC1 as measured by enzyme-linked immunosorbent assay had significantly increased risk of colorectal cancer (relative risk [RR] = 1.93, P = .004 for trend) compared with the lowest quintile on multivariate analysis in a nested case-control study.

Further, for patients in the four highest MIC-1 quintiles, regular use vs nonuse of aspirin or nonsteroidal antiinflammatory drugs (NSAIDs) was associated with significantly reduced risk of prostaglandin-endoperoxide synthase 2 (PTGS2)/cyclooxygenase-2 (COX-2)–positive colorectal cancer (RR = 0.60, 95% confidence interval [CI] = 0.41– 0.88) but not PTGS2-negative colorectal cancer (RR = 1.21, 95% CI = 0.71–2.07).

Aspirin and NSAID use was not associated with a significantly altered risk of PTGS2-positive colorectal cancer (RR = 0.57, 95% CI = 0.21–1.54) or PTGS2-negative colorectal cancer (RR = 1.41, 95% CI = 0.47–4.23) in

©Charles Barsotti/The New Yorker Collection/www.cartoonbank.com

patients in the lowest MIC-1 quintile.

The investigators concluded, “Our results support an association between higher levels of circulating MIC-1 (GDF15) and [colorectal cancer]. Aspirin/NSAID use appeared to lower risk of PTGS2-positive cancers, particularly among individuals with high levels of circulating MIC-1.”

Mehta RS, et al: J Natl Cancer Inst 106(4):dju016, 2014.

IMMUNOTHERAPY EGFR Activation Increases Cancer Cell ‘Visibility’ for Cytotoxic T Lymphocytes The antitumor activities of cytolytic T lymphocytes and natural killer cells are being increasingly investigated and exploited in cancer immunotherapy. One mechanism by which these cells recognize tumor cells is by engagement of NKG2D, an activating receptor on cytolytic T lymphocytes and natural killer cells,

by MICA/B and ULBP family stress antigens.

In a study reported in Science Translational Medicine, Vantourout and colleagues showed that activation of EGFR is responsible for surface upregulation of NKG2D ligands in human epithelial cells in response to ultraviolet irradiation, osmotic shock, oxidative stress, and growth factor exposure. EGFR activation results in intracellular relocalization of adenylate-uridylate (AU)rich element RNA-binding protein 1 (AUF1); AUF1 proteins normally destabilize NKG2D ligand mRNAs by targeting an AU-rich element that is conserved in the 3′ ends of most human, but not murine, NKG2D ligand genes. NKG2D ligand expression was positively correlated with EGFR expression in primary human carcinomas and was reduced by treatment with clinically available EGFR inhibitors.

Thus, as noted by the investigators, stress-induced activation of EGFR both regulates cell growth and modulates immunologic visibility of cancer cells. They concluded, “[T] herapeutics designed to limit cancer cell growth should also be considered in terms of their impact on immunosurveillance.”

Vantourout P, et al: Sci Transl Med 6:231ra49, 2014.

COMBINATION THERAPY Vaccine Targeting Tumor Antigen to Dendritic Cell Receptors Induces AntigenSpecific Immunity Anticancer immunity may be enhanced by harnessing the ability of dendritic cells to initiate T-cell immunity through efficient uptake and presentation of endocytosed material. In preclinical models, delivery of tumorassociated antigens to dendritic cells using receptor-specific monoclonal antibodies in the presence of dendritic cell–activating agents has produced marked antigen-specific immune responses.

CDX-1401 is a vaccine consisting of a monoclonal antibody specific for DEC-205, a molecule expressed on dendritic cells that is active in antigen processing and presentation, fused to the full-length tumor antigen NYESO-1. In a phase I trial reported in Science Translational Medicine, Dhodapkar and colleagues assessed the safety, immunogenicity, and clinical activity of escalating doses of CDX1401 along with administration of Toll-like receptor (TLR) agonists resiquimod (TLR7/8) and Hiltonol (poly-ICLC, TLR3) in 45 patients with advanced malignancies refractory to available therapies.

Vaccine was associated with humoral and cellular immunity to NYESO-1 in patients with NY-ESO-1– expressing tumors across various dose levels and adjuvant combinations. No dose-limiting or grade 3 toxicities were reported. Stable disease was observed in 13 patients, with a median duration of 6.7 months (range = 2.4+ to 13.4 months), and 2 patients had approximately 20% shrinkage in target lesions.

Six of eight patients who received TLR inhibitors within 3 months after vaccine administration had objective tumor regression.

The investigators concluded, “This first-in-human study of a protein vaccine targeting [dendritic cells] demonstrates its feasibility, safety, and biological activity and provides rationale for combination immunotherapy strategies including immune checkpoint blockade.”

Dhodapkar NV, et al: Sci Transl Med 6:232ra51, 2014.

Lab Notes is compiled and written for The ASCO Post by Matthew Stenger.

ASCOPost.com | JULY 25, 2014

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Survivorship Issues in Oncology

Cancer Survivors Face Unique Challenges Reentering the Workforce

By Jo Cavallo

A

n online survey of 201 unemployed cancer survivors looking for work found that a majority—61%—are at least somewhat concerned that a potential employer would find out about their cancer diagnosis and not hire them. In this survey conducted by Cancer and Careers, 66% of participants said they needed more information to balance their health and work life, and 54% agreed that health-care professionals could do a better job of advising patients about these demands.

Opportunity for Dialogue “There is an opportunity for dialogue that might help survivors stay at work if that’s what they want or go back to work with a realistic understanding of what they can and can’t do following their cancer treatment,” said Rebecca V. Nellis, MPP, Vice President of Programs and Strategy for Cancer and Careers, an organization dedicated to serving the needs of working people during and after cancer treatment.

“And oncologists and the supportive oncology universe is the key to that [dialogue].”

The survey, conducted between No-

Finances were a driving factor to look for a job, but underneath that were [concerns] more about identity and the desire to contribute.

—Rebecca V. Nellis, MPP

vember 2013 and February 2014, included male and female survivors, aged 18 and older, 79% of whom have been looking for work for up to 3 years. While all cancer types were represented in the survey, the majority of respondents were survivors of breast cancer, followed by skin and gynecologic cancers; 14% were survivors of penile, prostate, or testicular cancers. More than half of the respondents (52%) had finished their treatment no longer than 5 years earlier.

More than half of respondents said that cancer impacted their work life in some way, causing 63% to either take time off from work or quit their job altogether.

The primary reason for returning to work For resources on how to help cancer survivors manage treatment and returning to work, visit the Cancer and Careers website at­ ­ www. cancerandcareers.org.

cited by 79% of respondents was “financial concerns”; however, many survivors also said they wanted to “feel as normal as possible” and that “work keeps me feeling productive and busy, so I’m not always

worrying about the cancer diagnosis.”

“A cancer diagnosis doesn’t just bring with it questions of mortality, but also questions of identity, and so many people define themselves by what they do,” said

Ms. Nellis. “Of course, finances were a driving factor to look for a job, but underneath that reason were all these [concerns] that were more about identity and the desire to contribute.” n

The ASCO Post | JULY 25, 2014

PAGE 102

In Memoriam

International Leader in Urology, Professor John Fitzpatrick, Dies

By Ronald Piana

“I

have too many positive memories of John to regale you with here,” said Roger Kirby, MD, in a tribute to his close friend and colleague, John Michael Fitzpatrick, MCh, FRCSI, who died suddenly on May 14, 2014, at the age of 65.

“Climbing Mount Kilimanjaro (he never tired of reminding me that he reached the summit before me), trekking in Nepal, cycling in Sicily, Malawi, and Madagascar— John was always ‘up for it’…. Everywhere he went he made friends, took interest in everyone he met, and communicated in his own unique, eloquent, and quintessentially Irish style.”

Early Education Born on July 15, 1948, Dr. Fitzpatrick became one of Europe’s most highly regarded medical opinion leaders. During an interview, he said that one of the factors that had a great influence on his life was being educated by Jesuits during his undergraduate studies at Gonzaga College, Dublin. At Gonzaga, Dr. Fitzpatrick developed his lifelong love of history and literature, especially William Shakespeare.

Following his undergraduate studies, Dr. Fitzpatrick intended to go to Oxford to follow his passion for literature, but a sudden change in plans led to his entering the University College Dublin to study medicine. He did his clinical internship at St. Vincent’s Hospital in Dublin, where he was strongly influenced by the head of surgery, Patrick FitzGerald, MD. “He helped me develop an interest in scientific pursuits

and showed me that a surgeon could also make a meaningful contribution in the scientific field—another lesson that I never forgot,” said Dr. Fitzpatrick.

While doing his residency at St. Vincent’s, he decided to become a urologist, largely due to the influence of two mentors, noted urologic surgeons Drs. Frank Duff and Dan Kelly. “They were both superb surgeons and I was able to learn outstanding technique and the beauty of urologic surgery,” said Dr. Fitzpatrick.

and Trinity College Dublin. He maintained a high surgical workload along with laboratory research. While there, a short posting of several months in Mainz, Germany, launched what would become a career-long interest in urologic research.

In 1986, he was appointed Professor of Surgery and consultant urologist in the Mater Hospital and University College Dublin. Although he was gregarious and well liked, his independent spirit

Academic urology is a great and also very enjoyable pastime. When you have made a name for yourself, remember that people listen to you. You owe it to them to maintain the same good and honorable principles that have guided you through your life and speak the truth as you see it, even if some people may not like what you are saying.

Photo courtesy of Roger Kirby, MD.

His life was gentle, and the elements So mixed in him that Nature might stand up And say to all the world, “This was a man!”

—William Shakespeare

—John M. Fitzpatrick, MCh, FRCSI

In 1977, seeing a need to further his education as a surgeon, he moved to the Institute of Urology at St. Peter’s Hospital in London. He looked back at his period in London with fondness, remembering all the mentors and friends, especially his boss, John Wickham, MD. “He was my mentor and a close friend.

His sense of innovation and his wish to change dogma was something I had not seen before,” noted Dr. Fitzpatrick.

Career-Long Interest

Editor’s Note: Visit a tribute to Professor John Fitzpatrick by Dr. Roger Kirby at www.bjuinternational.com/bjui-blog/ professor-john-fitzpatrick-1948-2014 or the QR code here.

After completing his training in London, Dr. Fitzpatrick returned to Dublin in 1981 as a consultant urologist and senior lecturer in Urology in the Meath and St. James’s Hospitals

and enthusiasm for initiating change would lead to confrontations with more conservative doctors.

“I would recommend for young urologists to have a balanced view about everything, but if you believe in something, you must proceed with it to try to bring it about. Do not let confrontation prevent you from bringing what you believe to be important into reality. There are many reasons why people might try to hinder you, but if you believe something to be right, then run with that idea,” said Dr. Fitzpatrick during an interview.

Not one to let confrontation deter him, he remained on as Professor and Chairman for 25 years at the Department of Surgery, Mater Hospital, and the University College in Dublin. He also served as registrar and consultant in various hospitals and universities in Dublin and London.

Other Roles Dr. Fitzpatrick once described his tenure as Editor-in-Chief of BJU International from 2003 to 2012 in the following way: “There have been many aspects of my career that I have enjoyed and felt fulfilled by, but none more so than leading the BJU International. It has been a post where creativity can be allowed to run riot.”

Dr. Fitzpatrick also served as President of the British Association of Urological Surgeons and the Irish Society of Urology. From January 2012 until his death, he was Head of Research for the Irish Cancer Society. Aside form his numerous awards from prominent medical societies, he wrote and coauthored nearly 20 books, more than 90 book chapters, and over 400 scientific and scholarly papers published in international, peer-reviewed journals on a wide range of urologic topics.

Immediately following the announcement of his death, tributes poured in from around the world, such as one from Prokar Dasgupta, MD, who called Dr. Fitzpatrick one of his heroes: “He was on my Professorial interview panel and asked me very tricky questions. Some of them were impossible to answer at the time but now bring a smile to my face. He literally helped me down Mount Etna on an ultra difficult trip to Sicily. Afterwards he showed me a rather embarrassing photograph of me asleep on the slopes of this mountain. I hadn’t even realized that I had dozed off.”

Dr. Fitzpatrick ended an essay in Legends of Urology with the following passage: “I have one final thing to say.

Academic urology is a great and also very enjoyable pastime. When you have made a name for yourself, remember that people listen to you. You owe it to them to maintain the same good and honorable principles that have guided you through your life and speak the truth as you see it, even if some people may not like what you are saying.” n

 In Memoriam

John Michael Fitzpatrick, MCh, FRCSI July 15, 1948 – May 14, 2014

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The ASCO Post | JULY 25, 2014

PAGE 104

In the Literature

Emerging Clinical Data on Cancer Management BREAST CANCER Women With Small, Node-Negative Breast Tumors Have Excellent Prognosis Without Chemotherapy Women who have small (≤ 1 cm), node-negative breast tumors “have an excellent prognosis without chemotherapy,” concluded the authors of a prospective cohort study involving 4,113 women with T1a,b, N0, M0 breast cancer. “Size and tumor subtype may identify patients in whom the rate of recurrence justifies consideration of chemotherapy,” the authors added. “These patients represent an optimal group for evaluating less toxic adjuvant regimens to maintain efficacy while minimizing short- and long-term risks.”

Patients were identified through the National Comprehensive Cancer Network database and treated between 2000 and 2009. Eight centers nationwide contributed data to the analysis.

“There were striking differences in chemotherapy use between tumor subtypes,” the researchers noted in the Journal of Clinical Oncology. “Chemotherapy was rarely administered in patients with [hormone receptor]-positive/HER2-negative tumors [8%], and their pattern of care was unchanged over the last decade.” In contrast, 52% of those with HER2-positive or [hormone receptor]-negative/HER2negative breast cancers received chemotherapy. There was an increase in the use of chemotherapy with or without trastuzumab [Herceptin] among patients with HER2-positive disease and in patients with T1a [hormone receptor]-negative/HER2negative tumors over the past decade.

Survival Outcomes “Survival outcomes diverged by subtype and size, but the 5-year distant relapse–free survival did not exceed 10% in any subgroup,” the researchers reported. The 5-year distant relapse–free survival was 97% for patients with T1a tumors untreated with chemotherapy and 95% for patients with T1b tumors.

“Patients with [hormone receptor]positive/HER2-negative disease had the best [distant relapse–free survival] estimates, and patients with [hormone receptor]-negative/HER2-negative tumors had the lowest,” the investigators noted. The 5-year distant relapse–free survival was 100% for treated patients with hormone receptor–negative/ HER2-negative T1a tumors and 96% for T1b tumors.

“This observational, nonrandomized

cohort study calls into question what type of treatment is justified and appropriate for these patients,” the authors wrote. “In making decisions regarding adjuvant chemotherapy, the potential absolute benefits of treatment must be weighed against the treatment-related risks.”

They added, “Although the risk of death during breast cancer adjuvant chemotherapy is less than 1%, it is not absent, and there is a non-negligible risk of hospitalization or need for urgent evaluation for serious adverse effects related to chemotherapy. Other serious and lasting adverse effects include cardiomyopathy, secondary leukemias, and neuropathy.”

For most patients with T1a,b, N0, M0 breast tumors, the absolute benefit of chemotherapy with or without trastuzumab is relatively small, and “potential toxicities should be a factor in treatment decisions, which ultimately should be driven by a well-informed patient,” the researchers noted. “In the long run, we need to develop better ways to identify patients at the highest risk of recurrence while simultaneously trying to minimize treatment-related toxicity.”

Vaz-Luis I, et al: J Clin Oncol. June 2, 2014 (early release online).

COLORECTAL CANCER Colorectal Cancer Survivors Prefer More Information on Late Effects of Treatment and Recurrence Risks Survivors of nonmetastatic colorectal cancer, when surveyed about their needs and preferences for survivorship information, responded that they would prefer receiving more information about late effects of treatment, challenges to expect, general health maintenance, and risks of recurrence. Most of those surveyed indicated that they would like to receive survivorship information early on; 59% volunteered that they would have like to receive survivorship information during treatment and another 21% said that preferred to receive such information immediately after treatment.

The survey was designed “to evaluate the information survivors may need and want from a survivorship care plan,” according to an article in the Journal of Oncology Practice. The Institute of Medicine proposed the use of survivorship care plans, containing personalized cancer treatment summaries, as well as recommendations for ongoing care from oncologists, primary care or other providers,

to improve coordination of care and promote optimal post-treatment care.

A telephone survey was completed by 175 patients identified through hospital databases and medical records from two New York metropolitan area hospitals, Memorial Sloan Kettering Cancer Center (170 patients) and Queens Cancer Center (5 patients). Patients were 18 years or older at the time of diagnosis with stage I to III colorectal cancer and had completed treatment 6 to 24 months before and had not received a survivorship care plan.

Key Findings Most survivors knew whether their disease was in their colon and rectum, and close to 100% knew the types of treatment received. Fewer survivors knew their risks of local recurrence (69%), distant recurrence (77%), or developing a new colorectal cancer (40%).

“Most respondents reported receiving information about the importance of visiting an oncologist (77%), the need for tests to monitor for recurrence (82%), and information about diet and exercise (66%),” the researchers reported. “Only 38% reported being told of the importance of visiting a primary care provider after treatment completion.” The investigators found this “troubling.”

“If oncology providers are not providing this information to survivors, it may, in part, indicate a confidence on the part of the oncologist that survivors are already being seen by a primary care provider,” they continued. “Nevertheless, coordinated post-treatment care depends on active participation of both oncology and primary care providers to ensure comprehensive, nonduplicative care.”

Survey questions about additional types of information survivors would have liked to receive elicited 62 comments about late effects and challenges to expect, 22 comments concerning general health and diet issues, and 12 about recommended follow-up and tests. Asked to identify one of more preferred ways get information about survivorship, 93% said in a conversation with their doctor, 75% from a personalized printed document, and 61% from a website.

“In the absence of [a survivorship care plan], [colorectal cancer] survivors still generally understood their cancer history.

However, many lacked knowledge of ongoing risks and prevention,” investigators concluded.

Salz T, et al: J Oncol Pract. June 3, 2014 (early release online).

MULTIPLE MYELOMA High Response Rate and Good Safety Profile for Carfilzomib Plus Cyclophosphamide and Dexamethasone A multicenter, open-label phase II trial found that the selective proteasome inhibitor carfilzomib (Kyprolis), in combination with cyclophosphamide and dexamethasone produced high complete response rates and was associated with low toxicity in patients with newly diagnosed multiple myeloma. “Responses were rapid and deep, and showed improvement over time,” according to the results, published in Blood.

The 58 patients in the trial were all aged ≥ 65 years or were ineligible for autologous stem cell transplantation and enrolled from 10 centers in Italy. Study participants received cyclophosphamide/dexamethasone/carfilzomib for up to nine 28-day cycles, followed by maintenance with carfilzomib until progression or intolerance. A total of 55 patients were evaluable for response, and 56 for safety. The median age of the patients was 71 years.

Major Outcomes “After a median of 9 [cyclophosphamide/dexamethasone] induction cycles (range, 1–9), 95% of patients achieved at least a partial response, 71% achieved at least a very good partial response, 49% achieved at least a near complete response, and 20% achieved stringent complete response,” according to the investigators.

The median time to achieve a partial response was 1 month, and 94% of patients who achieved a complete response did so during induction. At a median follow-up of 18 months, 2-year progression-free survival was 76% and 2- year overall survival was 87%.

“The most frequent grade 3–5 toxicities were neutropenia (20%), anemia (11%), and cardiopulmonary adverse events (7%). Peripheral neuropathy was limited to grade 1–2 (9%),” the researchers stated. Adverse events led 14% of patients to discontinue treatment and 21% to have the carfilzomib dose reduced. Seven patients died while on the study.

The authors noted that this is the first study of carfilzomib in combination with an alkylating agent in elderly patients with newly diagnosed multiple myeloma. n Bringhen S, et al: Blood. May 22, 2014 (early release online).

In the Literature is compiled and written for The ASCO Post by Charlotte Bath.

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Perspective Clifford A. Hudis, MD, FACP continued from page 1

different from how I perceived the Society as a volunteer and member, Committee Chair, or even as Treasurer. I never fully grasped the enormous potential ASCO possesses to influence the world around us. That is why I chose the theme of “Science and Society” for this year’s Annual Meeting. These are not separate worlds.

What we do in “Science” is what changes the world and “Society” for the better.

But we cannot do this without the wholehearted support of the society we serve.

I see ASCO as integral to increasing this support. In fact, I see ASCO as the leader for many people in our society in this way.

Receiving a diagnosis of cancer can be one of the most dramatic events in a person’s life. At that moment, even those who have lived outside of the scientific world can become immersed in some part of science.

With treatment, patients are receiving the fruits of our labor. That’s an opportunity.

This is one of those teachable moments when we can bring more people into the fold to support what we do at ASCO. I think ASCO needs to engage the broader public—government, media, everybody—even more fully than we have in the past. We at ASCO have an amazing story to tell, and I think if we tell it well, we will have an unusual opportunity to make a favorable impression on the world and change things.

In each of their various areas of responsibility, the staff’s breadth and depth of knowledge is really unparalleled. They work tirelessly behind the scenes with not that much recognition outside of the office of their work. The strength of resources that we have assembled is remarkable, and this strength extends beyond the staff to our volunteers, which now number approximately 1,600.

A Force for Big Changes Where do you think ASCO is going?

Where should it go?

I always liked the Yogi Berra phrase, “making predictions is really hard, especially about the future.” I don’t know where we’re going, but we have been really fortunate. We’ve been very, very successful—much more so than ASCO’s founders probably ever imagined.

We’ve built a powerful tool with tremendous potential. Moving forward, I hope we’re going to engage the broader world even more overtly than we have in

using data and technology to improve cancer care may not lead from point A to point B in all the ways we might predict, but they are certainly going to take us someplace better than where we are now.

Global Responsibility Almost everything presented at the Annual Meeting applies to the United States, Canada, Western Europe, Japan, Australia, and maybe increasingly China, but much of the world thinks about this level of cancer research and treatment as a far-off dream. Do we have any responsibility for that?

I have a personal and, maybe, institutional answer for that. One of the first things that I did early in my career was work in infectious disease in Brazil. This was many years ago, before HIV was fully understood, and I saw what it was like to live in a health-care system where the majority of people can’t access care, even currently available treatments.

A poignant memory for me was the experience of seeing an infant dying of

We at ASCO have an amazing story to tell, and I think if we tell it well, we will have an unusual opportunity to make a favorable impression on the world and change things.

—Clifford A. Hudis, MD, FACP

Strength in Resources What do you think was the best thing about being President of ASCO? It was working with our dedicated volunteers and staff leadership. It sounds pat when people say that. But the thing that I wish could be conveyed to all of ASCO’s 35,000 members is the unbelievable work our staff does each day.

Long-term International Fellowship (LIFe) Award

T

he Long-term International Fellowship (LIFe) provides early-career oncologists in developing nations the support and resources needed to advance their training by deepening their relationship with a U.S. or Canadian colleague and his or her institution.

The fellowship was first awarded to a single investigator in 2010. Recipients of the 2014 LIFe award were Daniel Fontes Santos De Teive E Argolo, MD, of Brazil, Gevorg Tamamyan, MD, of Armenia, and Zhen Wang, PhD, of China. n

the past. I hope that we are going to be a force for big changes, not just in cancer science but in medicine generally, and even in society.

We are already stepping in that direction in a couple of different ways. We are leading a really difficult discussion on value in cancer care, and that was one of the hottest topics at this year’s Annual Meeting. Having the courage to speak out in society and lead this discussion, we will make it a better one. Similarly, we are engaging in some of the big public health problems, such as obesity and other lifestyle issues, and hopefully that will provide us with a means of helping to prevent some cancers in the future.

Finally, there is “big data.” One of the things that just can’t help but bother physicians is how far we lag behind the rest of the digital economy. This shortcoming brings with it a very big expense.

There must be untold billions of dollars wasted in productivity every year because of the way we keep records and fail to learn from what we do.

ASCO’s CancerLinQ initiative is an unprecedented attempt to try to leapfrog us into the 21st century. These efforts at

meningococcal meningitis. The doctor knew that all the infant needed was penicillin, but it was not available, and both he and the infant’s family accepted this fact.

That was a shocking moment for me.

I’ve also spent time in Africa and other low-income parts of the world. I try to be sensitive to the disparities that result from such economic conditions. There are parts of the world where in a wealthy neighborhood, the average breast cancer is a very small screen-detected tumor, and a kilometer away, the average breast cancer presentation is locally advanced, unresectable disease. And it is just access to care making the difference—not biology, nothing more than obstacles to equity and fairness.

ASCO has a huge global impact now, with a substantial number of members being in the international category and comprising a large number of the attendees at the Annual Meeting. With this comes global responsibility. More than 1,000 individuals have been through ASCO’s training programs. We have the LIFe [Long-term International Fellowship] awardees (see sidebar) that we bring to the United States and teach so that they, in turn, can take their knowledge back to their home coun-

tries and apply what they have learned. I actually think that training and education on an international level represents a growth area for ASCO, not necessarily in terms of financial growth, but with regard to global impact on society.

The potential to make transformative changes in low-resource countries is incredibly rewarding. Compared to some of the battles we face, the ability to make these changes is not so hard. If we could get the expertise and a modicum of supplies into some of those low-resource areas, lives could change significantly and quickly.

Return on Investment What final message would you like to share with readers of The ASCO Post?

One thing that everybody should know is that the return on investment— when we spend money in scientific research and medical research and cancer medical research, specifically—is actually unmatchable. This is one of the reasons for the belief sometimes referred to as American Exceptionalism: America has made a unique investment in science and technology since the end of World War II. That investment is currently challenged.

I hope that one message all attendees might have taken away from this year’s Annual Meeting is an even clearer appreciation for the outsize return we have gotten on that investment and, importantly, the urgent need to increase our investment in research. We need to keep pace with the growing opportunities that molecular biology and technology now offer.

Bipartisan Collaboration It seems that investment in research is something that shouldn’t be political. That is, this is not a Republican or Democratic idea; rather, this should be something that everyone can agree on.

I couldn’t agree more. One of the points I made in my presidential talk was the “0.1%” concept. There is $1 in $1,000 of the federal budget every year that is apportioned to the good work at the National Cancer Institute (NCI). That is just not commensurate to the challenge that we face in confronting all of these diseases that we call cancer. I can’t imagine the rate of progress we would have if we actually had the resources that we put into other areas of economic development.

No matter what side of the aisle you’re on, if you spend a dollar on NCI-sponsored research in any local community in America, it has an economic multiplier effect of about 2.5. This is good economic policy. This is good scientific policy. And it’s patriotic. n Disclosure: Dr. Hudis reported no potential conflicts of interest.

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The ASCO Post | JULY 25, 2014

Viewpoints

Peer-to-Peer Viewpoints on Issues in Oncology Visit ASCOPost.com to view the series

Recorded Live at ASCO’s 50th Annual Meeting, Chicago The ASCO Post is pleased to present a special video series of interviews by and with leaders in oncology as recorded live at ASCO’s 50th Annual Meeting in Chicago. Visit ASCOPost.com/video or use the QR code to access the program and view these one-on-one interviews: James O. Armitage, MD, speaks with: ■■

Franco Cavalli, MD: Important Data in Lymphoma Presented at ASCO 2014

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Richard I. Fisher, MD: Standard of Care in Mantle Cell Lymphoma

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Clifford A. Hudis, MD, FACP: ASCO Today: Science and Society

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Michael Pfreundschuh, MD: Diffuse Large B-Cell Lymphoma

Nancy E. Davidson, MD, speaks with: ■■

Lisa Carey, MD: Anti-HER2 Therapy for Breast Cancer

Derek Raghavan, MD, PhD, speaks with: ■■

Karim Fazizi, MD: French Genitourinary Tumor Group Studies

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Maha Hussein, MD: Prostate Cancer, Bladder Cancer

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Daniel Petrylak, MD: Bladder Cancer: Neoadjuvant and Adjuvant Therapy

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David I. Quinn, MD: Prostate Cancer, Bladder Cancer, Adrenocortical Carcinoma

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Brian I. Rini, MD: Advances in Renal Cell Carcinoma

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Siu-Long Yao, MD: Prostate Cancer: A Statistician’s Perspective

James L. Mulshine, MD, speaks with: ■■

Carolyn Aldige: Issues in Lung Cancer Screening: An Advocate’s Perspective

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Fred R. Hirsch, MD, PhD: Issues in the Early Detection of Lung Cancer

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Natasha Leighl, MD: Issues in Lung Cancer Screening

Plus, the following presentations: ■■

Halle C.F. Moore, MD, on Fertility Preservation in Young Women With Breast Cancer

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John F. Smyth, MD, on Improving the Efficacy of Developing New Medicines—and Finding Solutions to Making Them More Affordable

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Alok A. Khorana, MD, on Colorectal Cancer: Results From CALGB/SWOG 80405

James O. Armitage, MD (right), Editor-in-Chief of The ASCO Post speaks with ASCO Immediate Past President Clifford A. Hudis, MD, FACP (left) following a one-on-one interview during ASCO’s Annual Meeting. Visit ASCOPost.com/video to view the interview.

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AVASTIN® (bevacizumab) Solution for intravenous infusion Initial U.S. Approval: 2004 This is a brief summary of information about AVASTIN. Before prescribing, please see full Prescribing Information.

WARNING: GASTROINTESTINAL PERFORATIONS, SURGERY AND WOUND HEALING COMPLICATIONS, and HEMORRHAGE Gastrointestinal Perforations The incidence of gastrointestinal perforation, some fatal, in Avastin‑treated patients ranges from 0.3 to 2.4%. Discontinue Avastin in patients with gastrointestinal perforation. [See Dosage and Administration (2.4), Warnings and Precautions (5.1).]

Surgery and Wound Healing Complications The incidence of wound healing and surgical complications, including serious and fatal complications, is increased in Avastin‑treated patients. Discontinue Avastin in patients with wound dehiscence. The appropriate interval between termination of Avastin and subsequent elective surgery required to reduce the risks of impaired wound healing/wound dehiscence has not been determined. Discontinue at least 28 days prior to elective surgery. Do not initiate Avastin for at least 28 days after surgery and until the surgical wound is fully healed. [See Dosage and Administration (2.4), Warnings and Precautions (5.2), Adverse Reactions (6.1).]

Hemorrhage Severe or fatal hemorrhage, including hemoptysis, gastrointestinal bleeding, central nervous systems (CNS) hemorrhage, epistaxis, and vaginal bleeding occurred up to five‑fold more frequently in patients receiving Avastin. Do not administer Avastin to patients with serious hemorrhage or recent hemoptysis. [See Dosage and Administration (2.4), Warnings and Precautions (5.3), Adverse Reactions (6.1).]

1 INDICATIONS AND USAGE 1.1 Metastatic Colorectal Cancer (mCRC) Avastin is indicated for the first‑ or second‑line treatment of patients with metastatic carcinoma of the colon or rectum in combination with intravenous 5‑fluorouracil–based chemotherapy.

Avastin, in combination with fluoropyrimidine‑irinotecan‑ or fluoropyrimidine‑ oxaliplatin‑based chemotherapy, is indicated for the second‑line treatment of patients with metastatic colorectal cancer who have progressed on a first‑line Avastin‑containing regimen.

Limitation of Use: Avastin is not indicated for adjuvant treatment of colon cancer. [See Clinical Studies (14.2).]

1.2 Non‑Squamous Non–Small Cell Lung Cancer (NSCLC) Avastin is indicated for the first‑line treatment of unresectable, locally advanced, recurrent or metastatic non–squamous non–small cell lung cancer in combination with carboplatin and paclitaxel.

1.3 Glioblastoma Avastin is indicated for the treatment of glioblastoma with progressive disease in adult patients following prior therapy as a single agent.

The effectiveness of Avastin in glioblastoma is based on an improvement in objective response rate. There are no data demonstrating an improvement in disease‑related symptoms or increased survival with Avastin. [See Clinical Studies (14.4).]

1.4 Metastatic Renal Cell Carcinoma (mRCC) Avastin is indicated for the treatment of metastatic renal cell carcinoma in combination with interferon alfa.

4 CONTRAINDICATIONS None.

5 WARNINGS AND PRECAUTIONS 5.1 Gastrointestinal Perforations Serious and sometimes fatal gastrointestinal perforation occurs at a higher incidence in Avastin treated patients compared to controls. The incidence of gastrointestinal perforation ranged from 0.3 to 2.4% across clinical studies. [See Adverse Reactions (6.1).]

The typical presentation may include abdominal pain, nausea, emesis, constipation, and fever. Perforation can be complicated by intra‑abdominal abscess and fistula formation. The majority of cases occurred within the first 50 days of initiation of Avastin.

Discontinue Avastin in patients with gastrointestinal perforation. [See Boxed Warning, Dosage and Administration (2.4).]

5.2 Surgery and Wound Healing Complications Avastin impairs wound healing in animal models. [See Nonclinical Toxicology (13.2).] In clinical trials, administration of Avastin was not allowed until at least 28 days after surgery. In a controlled clinical trial, the incidence of wound healing complications, including serious and fatal complications, in patients with mCRC who underwent surgery during the course of Avastin treatment was 15% and in patients who did not receive Avastin, was 4%. [See Adverse Reactions (6.1).]

Avastin should not be initiated for at least 28 days following surgery and until the surgical wound is fully healed. Discontinue Avastin in patients with wound healing complications requiring medical intervention.

The appropriate interval between the last dose of Avastin and elective surgery is unknown; however, the half‑life of Avastin is estimated to be 20 days. Suspend Avastin for at least 28 days prior to elective surgery. Do not administer Avastin until the wound is fully healed. [See Boxed Warning, Dosage and Administration (2.4).]

Necrotizing fasciitis including fatal cases, has been reported in patients treated with Avastin; usually secondary to wound healing complications, gastrointestinal perforation or fistula formation. Discontinue Avastin therapy in patients who develop necrotizing fasciitis. [See Adverse Reactions (6.3).]

5.3 Hemorrhage Avastin can result in two distinct patterns of bleeding: minor hemorrhage, most commonly Grade 1 epistaxis; and serious, and in some cases fatal, hemorrhagic events. Severe or fatal hemorrhage, including hemoptysis, gastrointestinal bleeding, hematemesis, CNS hemorrhage, epistaxis, and vaginal bleeding occurred up to five‑fold more frequently in patients receiving Avastin compared to patients receiving only chemotherapy. Across indications, the incidence of Grade ≥ 3 hemorrhagic events among patients receiving Avastin ranged from 1.2 to 4.6%. [See Adverse Reactions (6.1).]

Serious or fatal pulmonary hemorrhage occurred in four of 13 (31%) patients with squamous cell histology and two of 53 (4%) patients with non‑squamous non‑small cell lung cancer receiving Avastin and chemotherapy compared to none of the 32 (0%) patients receiving chemotherapy alone.

In clinical studies in non–small cell lung cancer where patients with CNS metastases who completed radiation and surgery more than 4 weeks prior to the start of Avastin were evaluated with serial CNS imaging, symptomatic Grade 2 CNS hemorrhage was documented in one of 83 Avastin‑treated patients (rate 1.2%, 95% CI 0.06%–5.93%).

Intracranial hemorrhage occurred in 8 of 163 patients with previously treated glioblastoma; two patients had Grade 3–4 hemorrhage.

Do not administer Avastin to patients with recent history of hemoptysis of ≥ 1/2 teaspoon of red blood. Discontinue Avastin in patients with hemorrhage. [See Boxed Warning, Dosage and Administration (2.4).]

AVASTIN® (bevacizumab) 5.4 Non‑Gastrointestinal Fistula Formation Serious and sometimes fatal non‑gastrointestinal fistula formation involving tracheo‑esophageal, bronchopleural, biliary, vaginal, renal and bladder sites occurs at a higher incidence in Avastin‑treated patients compared to controls. The incidence of non‑gastrointestinal perforation was ≤ 0.3% in clinical studies. Most events occurred within the first 6 months of Avastin therapy.

Discontinue Avastin in patients with fistula formation involving an internal organ. [See Dosage and Administration (2.4).]

5.5 Arterial Thromboembolic Events Serious, sometimes fatal, arterial thromboembolic events (ATE) including cerebral infarction, transient ischemic attacks, myocardial infarction, angina, and a variety of other ATE occurred at a higher incidence in patients receiving Avastin compared to those in the control arm. Across indications, the incidence of Grade ≥ 3 ATE in the Avastin containing arms was 2.6% compared to 0.8% in the control arms. Among patients receiving Avastin in combination with chemotherapy, the risk of developing ATE during therapy was increased in patients with a history of arterial thromboembolism, diabetes, or age greater than 65 years. [See Use in Specific Populations (8.5).]

The safety of resumption of Avastin therapy after resolution of an ATE has not been studied. Discontinue Avastin in patients who experience a severe ATE. [See Dosage and Administration (2.4).]

5.6 Hypertension The incidence of severe hypertension is increased in patients receiving Avastin as compared to controls. Across clinical studies the incidence of Grade 3 or 4 hypertension ranged from 5‑18%.

Monitor blood pressure every two to three weeks during treatment with Avastin. Treat with appropriate anti‑hypertensive therapy and monitor blood pressure regularly. Continue to monitor blood pressure at regular intervals in patients with Avastin‑induced or ‑exacerbated hypertension after discontinuation of Avastin.

Temporarily suspend Avastin in patients with severe hypertension that is not controlled with medical management. Discontinue Avastin in patients with hypertensive crisis or hypertensive encephalopathy. [See Dosage and Administration (2.4).]

5.7 Reversible Posterior Leukoencephalopathy Syndrome (RPLS) RPLS has been reported with an incidence of < 0.1% in clinical studies.

The onset of symptoms occurred from 16 hours to 1 year after initiation of Avastin. RPLS is a neurological disorder which can present with headache, seizure, lethargy, confusion, blindness and other visual and neurologic disturbances. Mild to severe hypertension may be present. Magnetic resonance imaging (MRI) is necessary to confirm the diagnosis of RPLS. Discontinue Avastin in patients developing RPLS. Symptoms usually resolve or improve within days, although some patients have experienced ongoing neurologic sequelae. The safety of reinitiating Avastin therapy in patients previously experiencing RPLS is not known. [See Dosage and Administration (2.4).]

5.8 Proteinuria The incidence and severity of proteinuria is increased in patients receiving Avastin as compared to controls. Nephrotic syndrome occurred in < 1% of patients receiving Avastin in clinical trials, in some instances with fatal outcome. [See Adverse Reactions (6.1).] In a published case series, kidney biopsy of six patients with proteinuria showed findings consistent with thrombotic microangiopathy.

Monitor proteinuria by dipstick urine analysis for the development or worsening of proteinuria with serial urinalyses during Avastin therapy.

Patients with a 2 + or greater urine dipstick reading should undergo further assessment with a 24‑hour urine collection.

Suspend Avastin administration for ≥ 2 grams of proteinuria/24 hours and resume when proteinuria is < 2 gm/24 hours. Discontinue Avastin in patients with nephrotic syndrome. [See Dosage and Administration (2.4).]

Data from a postmarketing safety study showed poor correlation between UPCR (Urine Protein/Creatinine Ratio) and 24 hour urine protein (Pearson Correlation 0.39 (95% CI 0.17, 0.57). [See Use in Specific Populations (8.5).]

5.9 Infusion Reactions Infusion reactions reported in the clinical trials and post‑marketing experience include hypertension, hypertensive crises associated with neurologic signs and symptoms, wheezing, oxygen desaturation, Grade 3 hypersensitivity, chest pain, headaches, rigors, and diaphoresis. In clinical studies, infusion reactions with the first dose of Avastin were uncommon (< 3%) and severe reactions occurred in 0.2% of patients.

Stop infusion if a severe infusion reaction occurs and administer appropriate medical therapy. [See Dosage and Administration (2.4).]

5.10 Ovarian Failure The incidence of ovarian failure was higher (34% vs. 2%) in premenopausal women receiving Avastin in combination with mFOLFOX chemotherapy as compared to those receiving mFOLFOX chemotherapy alone for adjuvant treatment for colorectal cancer, a use for which Avastin is not approved. Inform females of reproductive potential of the risk of ovarian failure prior to starting treatment with Avastin. [See Adverse Reactions (6.1), Use in Specific Populations (8.6).]

6 ADVERSE REACTIONS The following serious adverse reactions are discussed in greater detail in other sections of the label: • Gastrointestinal Perforations [See Boxed Warning, Dosage and Administration (2.4), Warnings and Precautions (5.1).]

• Surgery and Wound Healing Complications [See Boxed Warning, Dosage and Administration (2.4), Warnings and Precautions (5.2).]

• Hemorrhage [See Boxed Warning, Dosage and Administration (2.4), Warnings and Precautions (5.3).]

• Non‑Gastrointestinal Fistula Formation [See Dosage and Administration (2.4), Warnings and Precautions (5.4).]

• Arterial Thromboembolic Events [See Dosage and Administration (2.4), Warnings and Precautions (5.5).]

• Hypertensive Crisis [See Dosage and Administration (2.4), Warnings and Precautions (5.6).]

• Reversible Posterior Leukoencephalopathy Syndrome [See Dosage and Administration (2.4), Warnings and Precautions (5.7).]

• Proteinuria [See Dosage and Administration (2.4), Warnings and Precautions (5.8).]

• Ovarian Failure [See Warnings and Precautions (5.10), Use in Specific Populations (8.6).]

The most common adverse reactions observed in Avastin patients at a rate > 10% and at least twice the control arm rate, are epistaxis, headache, hypertension, rhinitis, proteinuria, taste alteration, dry skin, rectal hemorrhage, lacrimation disorder, back pain and exfoliative dermatitis.

Across all studies, Avastin was discontinued in 8.4 to 21% of patients because of 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 data below reflect exposure to Avastin in 4599 patients with CRC, non‑squamous NSCLC, glioblastoma, or mRCC trials including controlled (Studies 1, 2, 4, 5 and 8) or uncontrolled, single arm (Study 6) treated at the recommended dose and schedule for a median of 8 to 23 doses of Avastin.

[See Clinical Studies (14).] The population was aged 18‑89 years (median 60 years), 45.4% male and 85.8% (3729/4345) White. The population included 2184 first‑ and second‑line mCRC patients who received a median of 10 doses of Avastin, 480 first‑line metastatic NSCLC patients who received a median of 8 doses of Avastin, 163 glioblastoma patients who received a median of

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AVASTIN® (bevacizumab) 9 doses of Avastin, and 337 mRCC patients who received a median of 16 doses of Avastin. These data also reflect exposure to Avastin in 363 patients with metastatic breast cancer (MBC) who received a median of 9.5 doses of Avastin, 669 female adjuvant CRC patients who received a median of 23 doses of Avastin and exposure to Avastin in 403 previously untreated patients with diffuse large B‑cell lymphoma (DLBCL) who received a median of 8 doses of Avastin. Avastin is not approved for use in MBC, adjuvant CRC, or DLBCL. Surgery and Wound Healing Complications The incidence of post‑operative wound healing and/or bleeding complications was increased in patients with mCRC receiving Avastin as compared to patients receiving only chemotherapy. Among patients requiring surgery on or within 60 days of receiving study treatment, wound healing and/or bleeding complications occurred in 15% (6/39) of patients receiving bolus‑IFL plus Avastin as compared to 4% (1/25) of patients who received bolus‑IFL alone.

In Study 6, events of post‑operative wound healing complications (craniotomy site wound dehiscence and cerebrospinal fluid leak) occurred in patients with previously treated glioblastoma: 3/84 patients in the Avastin alone arm and 1/79 patients in the Avastin plus irinotecan arm. [See Boxed Warning, Dosage and Administration (2.4), Warnings and Precautions (5.2).]

Hemorrhage The incidence of epistaxis was higher (35% vs. 10%) in patients with mCRC receiving bolus‑IFL plus Avastin compared with patients receiving bolus‑IFL plus placebo. All but one of these events were Grade 1 in severity and resolved without medical intervention. Grade 1 or 2 hemorrhagic events were more frequent in patients receiving bolus‑IFL plus Avastin when compared to those receiving bolus‑IFL plus placebo and included gastrointestinal hemorrhage (24% vs. 6%), minor gum bleeding (2% vs. 0), and vaginal hemorrhage (4% vs. 2%). [See Boxed Warning, Dosage and Administration (2.4), Warnings and Precautions (5.3).]

Venous Thromboembolic Events The overall incidence of Grade 3–4 venous thromboembolic events in Study 1 was 15.1% in patients receiving bolus‑IFL plus Avastin and 13.6% in patients receiving bolus‑IFL plus placebo. In Study 1, more patients in the Avastin containing arm experienced deep venous thrombosis (34 vs.

19 patients ) and intra‑abdominal venous thrombosis (10 vs. 5 patients).

The risk of developing a second thromboembolic event while on Avastin and oral anticoagulants was evaluated in two randomized studies. In Study 1, 53 patients (14%) on the bolus‑IFL plus Avastin arm and 30 patients (8%) on the bolus‑IFL plus placebo arm received full dose warfarin following a venous thromboembolic event (VTE). Among these patients, an additional thromboembolic event occurred in 21% (11/53) of patients receiving bolus‑IFL plus Avastin and 3% (1/30) of patients receiving bolus‑IFL alone.

In a second, randomized, 4‑arm study in 1401 patients with mCRC, prospectively evaluating the incidence of VTE (all grades), the overall incidence of first VTE was higher in the Avastin containing arms (13.5%) than the chemotherapy alone arms (9.6%). Among the 116 patients treated with anticoagulants following an initial VTE event (73 in the Avastin plus chemotherapy arms and 43 in the chemotherapy alone arms), the overall incidence of subsequent VTEs was also higher among the Avastin treated patients (31.5% vs. 25.6%). In this subgroup of patients treated with anticoagulants, the overall incidence of bleeding, the majority of which were Grade 1, was higher in the Avastin treated arms than the chemotherapy arms (27.4% vs. 20.9%). [See Dosage and Administration (2.4).]

Ovarian Failure The incidence of new cases of ovarian failure (defined as amenorrhoea lasting 3 or more months, FSH level ≥ 30 mIU/mL and a negative serum β‑HCG pregnancy test) was prospectively evaluated in a subset of 179 women receiving mFOLFOX chemotherapy alone (n = 84) or with Avastin (n = 95). New cases of ovarian failure were identified in 34% (32/95) of women receiving Avastin in combination with chemotherapy compared with 2% (2/84) of women receiving chemotherapy alone [relative risk of

a

Arm 2 IFL+ + Avastin (n = 392) 87%

7% 5% 5%

10% 8% 8%

2% 5% 1% 1%

12% 9% 3% 3%

25% 2%

34% 4%

31% 14%

37% 21%

AVASTIN® (bevacizumab) In patients receiving Avastin alone (N = 84), the most frequently reported adverse events of any grade were infection (55%), fatigue (45%), headache (37%), hypertension (30%), epistaxis (19%) and diarrhea (21%). Of these, the incidence of Grade ≥ 3 adverse events was infection (10%), fatigue (4%), headache (4%), hypertension (8%) and diarrhea (1%). Two deaths on study were possibly related to Avastin: one retroperitoneal hemorrhage and one neutropenic infection.

In patients receiving Avastin alone or Avastin plus irinotecan (N = 163), the incidence of Avastin‑related adverse events (Grade 1–4) were bleeding/ hemorrhage (40%), epistaxis (26%), CNS hemorrhage (5%), hypertension (32%), venous thromboembolic event (8%), arterial thromboembolic event (6%), wound‑healing complications (6%), proteinuria (4%), gastrointestinal perforation (2%), and RPLS (1%). The incidence of Grade 3–5 events in these 163 patients were bleeding/hemorrhage (2%), CNS hemorrhage (1%), hypertension (5%), venous thromboembolic event (7%), arterial thromboembolic event (3%), wound‑healing complications (3%), proteinuria (1%), and gastrointestinal perforation (2%).

Metastatic Renal Cell Carcinoma (mRCC) All grade adverse events were collected in Study 8. Grade 3–5 adverse events occurring at a higher incidence ( ≥ 2%) in 337 patients receiving interferon alfa (IFN‑α) plus Avastin compared to 304 patients receiving IFN‑α plus placebo arm were fatigue (13% vs. 8%), asthenia (10% vs. 7%), proteinuria (7% vs. 0%), hypertension (6% vs. 1%; including hypertension and hypertensive crisis), and hemorrhage (3% vs. 0.3%; including epistaxis, small intestinal hemorrhage, aneurysm ruptured, gastric ulcer hemorrhage, gingival bleeding, haemoptysis, hemorrhage intracranial, large intestinal hemorrhage, respiratory tract hemorrhage, and traumatic hematoma).

Grade 1–5 adverse events occurring at a higher incidence ( ≥ 5%) in patients receiving IFN‑α plus Avastin compared to the IFN‑α plus placebo arm are presented in Table 3.

Table 3 NCI‑CTC Grades 1−5 Adverse Events in Study 8 (Occurring at Higher Incidence [≥ 5%] in IFN‑α + Avastin vs. IFN‑α + Placebo) System Organ Class/ IFN‑α + Placebo Preferred terma (n = 304) Gastrointestinal disorders Diarrhea 16% General disorders and administration site conditions Fatigue 27% Investigations Weight decreased 15% Metabolism and nutrition disorders Anorexia 31% Musculoskeletal and connective tissue disorders Myalgia 14% Back pain 6% Nervous system disorders Headache 16% Renal and urinary disorders Proteinuria 3% Respiratory, thoracic and mediastinal disorders Epistaxis 4% Dysphonia 0% Vascular disorders Hypertension 9%

Central laboratories were collected on Days 1 and 21 of each cycle.

Neutrophil counts are available in 303 patients in Arm 1 and 276 in Arm 2.

Grade 1–4 adverse events which occurred at a higher incidence ( ≥ 5%) in patients receiving bolus‑IFL plus Avastin as compared to the bolus‑IFL plus placebo arm are presented in Table 2. Grade 1–4 adverse events were collected for the first approximately 100 patients in each of the three treatment arms who were enrolled until enrollment in Arm 3 (5‑FU/LV + Avastin) was discontinued.

Table 2 NCI‑CTC Grade 1‑4 Adverse Events in Study 1 (Occurring at Higher Incidence [≥ 5%] in IFL + Avastin vs. IFL) Arm 1 Arm 2 Arm 3 IFL + Placebo IFL + Avastin 5‑FU/LV + Avastin (n = 98) (n = 102) (n = 109) Body as a Whole Pain Abdominal Pain Headache Cardiovascular Hypertension Hypotension Deep Vein Thrombosis Digestive Vomiting Anorexia Constipation Stomatitis Dyspepsia GI Hemorrhage Weight Loss Dry Mouth Colitis Hemic/Lymphatic Thrombocytopenia Nervous Dizziness Respiratory Upper Respiratory Infection Epistaxis Dyspnea Voice Alteration Skin/Appendages Alopecia Skin Ulcer Special Senses Taste Disorder Urogenital Proteinuria

55% 55% 19%

61% 61% 26%

62% 50% 26%

14% 7% 3%

23% 15% 9%

34% 7% 6%

47% 30% 29% 18% 15% 6% 10% 2% 1%

52% 43% 40% 32% 24% 24% 15% 7% 6%

47% 35% 29% 30% 17% 19% 16% 4% 1%

0%

5%

5%

20%

26%

19%

39% 10% 15% 2%

47% 35% 26% 9%

40% 32% 25% 6%

26% 1%

32% 6%

6% 6%

9%

14%

21%

24%

36%

36%

IFN‑α + Avastin (n = 337) 21% 33% 20% 36% 19% 12% 24% 20% 27% 5% 28%

Adverse events were encoded using MedDRA, Version 10.1.

a

Avastin in Combination with FOLFOX4 in Second‑line mCRC Only Grade 3‑5 non‑hematologic and Grade 4–5 hematologic adverse events related to treatment were collected in Study 2. The most frequent adverse events (selected Grade 3–5 non‑hematologic and Grade 4–5 hematologic adverse events) occurring at a higher incidence (≥2%) in 287 patients receiving FOLFOX4 plus Avastin compared to 285 patients receiving FOLFOX4 alone were fatigue (19% vs. 13%), diarrhea (18% vs. 13%), sensory neuropathy (17% vs. 9%), nausea (12% vs. 5%), vomiting (11% vs. 4%), dehydration (10% vs. 5%), hypertension (9% vs. 2%), abdominal pain (8% vs.

5%), hemorrhage (5% vs. 1%), other neurological (5% vs. 3%), ileus (4% vs.

1%) and headache (3% vs. 0%). These data are likely to under‑estimate the true adverse event rates due to the reporting mechanisms used in Study 2.

Avastin in Combination with Fluoropyrimidine‑Irinotecan or Fluoropyrimidine‑ Oxaliplatin Based Chemotherapy in Second‑line mCRC Patients who have Progressed on an Avastin Containing Regimen in First‑line mCRC: No new safety signals were observed in Study 4 when Avastin was administered in second line mCRC patients who progressed on an Avastin containing regimen in first line mCRC. The safety data was consistent with the known safety profile established in first and second line mCRC. Unresectable Non‑Squamous Non‑Small Cell Lung Cancer (NSCLC) Only Grade 3‑5 non‑hematologic and Grade 4‑5 hematologic adverse events were collected in Study 5. Grade 3–5 non‑hematologic and Grade 4–5 hematologic adverse events (occurring at a higher incidence (≥2%) in 427 patients receiving PC plus Avastin compared with 441 patients receiving PC alone were neutropenia (27% vs. 17%), fatigue (16% vs.

13%), hypertension (8% vs. 0.7%), infection without neutropenia (7% vs.

3%), venous thrombus/embolism (5% vs. 3%), febrile neutropenia (5% vs.

2%), pneumonitis/pulmonary infiltrates (5% vs. 3%), infection with Grade 3 or 4 neutropenia (4% vs. 2%), hyponatremia (4% vs. 1%), headache (3% vs. 1%) and proteinuria (3% vs. 0%).

Glioblastoma All adverse events were collected in 163 patients enrolled in Study 6 who either received Avastin alone or Avastin plus irinotecan. All patients received prior radiotherapy and temozolomide. Avastin was administered at 10 mg/kg every 2 weeks alone or in combination with irinotecan.

Avastin was discontinued due to adverse events in 4.8% of patients treated with Avastin alone.

The following adverse events were reported at a 5‑fold greater incidence in the IFN‑α plus Avastin arm compared to IFN‑α alone and not represented in Table 3: gingival bleeding (13 patients vs. 1 patient); rhinitis (9 vs.0 ); blurred vision (8 vs. 0); gingivitis (8 vs. 1); gastroesophageal reflux disease (8 vs.1 ); tinnitus (7 vs. 1); tooth abscess (7 vs.0); mouth ulceration (6 vs. 0); acne (5 vs. 0); deafness (5 vs. 0); gastritis (5 vs. 0); gingival pain (5 vs. 0) and pulmonary embolism (5 vs. 1).

6.2 Immunogenicity As with all therapeutic proteins, there is a potential for an immune response to Avastin. In clinical trials of adjuvant colon carcinoma, 14 of 2233 evaluable patients (0.63%) tested positive for treatment‑emergent anti‑bevacizumab antibodies detected by an electrochemiluminescent (ECL) based assay. Among these 14 patients, three tested positive for neutralizing antibodies against bevacizumab using an enzyme‑linked immunosorbent assay (ELISA). The clinical significance of these anti‑product antibody responses to bevacizumab is unknown.

Immunogenicity assay results are highly dependent on the sensitivity and specificity of the test method and may be influenced by several factors, including sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies to Avastin 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 Avastin. 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.

Body as a Whole: Polyserositis Cardiovascular: Pulmonary hypertension, RPLS, Mesenteric venous occlusion Eye disorders (from unapproved intravitreal use for treatment of various ocular disorders): Permanent loss of vision; Endophthalmitis (infectious and sterile); Intraocular inflammation; Retinal detachment; Increased intraocular pressure; Hemorrhage including conjunctival, vitreous hemorrhage or retinal hemorrhage; Vitreous floaters; Ocular hyperemia; Ocular pain or discomfort Gastrointestinal: Gastrointestinal ulcer, Intestinal necrosis, Anastomotic ulceration Hemic and lymphatic: Pancytopenia Hepatobiliary disorders: Gallbladder perforation Infections and infestations: Necrotizing fasciitis, usually secondary to wound healing complications, gastrointestinal perforation or fistula formation Musculoskeletal: Osteonecrosis of the jaw Renal: Renal thrombotic microangiopathy (manifested as severe proteinuria) Respiratory: Nasal septum perforation, dysphonia Systemic Events (from unapproved intravitreal use for treatment of various ocular disorders): Arterial thromboembolic events, Hypertension, Gastrointestinal perforation, Hemorrhage 7 DRUG INTERACTIONS A drug interaction study was performed in which irinotecan was administered as part of the FOLFIRI regimen with or without Avastin. The results demonstrated no significant effect of bevacizumab on the pharmacokinetics of irinotecan or its active metabolite SN38.

In a randomized study in 99 patients with NSCLC, based on limited data, there did not appear to be a difference in the mean exposure of either carboplatin or paclitaxel when each was administered alone or in combination with Avastin.

However, 3 of the 8 patients receiving Avastin plus paclitaxel/carboplatin had substantially lower paclitaxel exposure after four cycles of treatment (at Day 63) than those at Day 0, while patients receiving paclitaxel/carboplatin without Avastin had a greater paclitaxel exposure at Day 63 than at Day 0.

In Study 8, there was no difference in the mean exposure of interferon alfa administered in combination with Avastin when compared to interferon alfa alone.

AVASTIN® (bevacizumab) 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Pregnancy Category C There are no adequate or well controlled studies of bevacizumab in pregnant women. While it is not known if bevacizumab crosses the placenta, human IgG is known to cross the placenta Reproduction studies in rabbits treated with approximately 1 to 12 times the recommended human dose of bevacizumab demonstrated teratogenicity, including an increased incidence of specific gross and skeletal fetal alterations.

Adverse fetal outcomes were observed at all doses tested. Other observed effects included decreases in maternal and fetal body weights and an increased number of fetal resorptions. [See Nonclinical Toxicology (13.3).]

Because of the observed teratogenic effects of bevacizumab in animals and of other inhibitors of angiogenesis in humans, bevacizumab should be used during pregnancy only if the potential benefit to the pregnant woman justifies the potential risk to the fetus.

8.3 Nursing Mothers It is not known whether Avastin is secreted in human milk. Human IgG is excreted in human milk, but published data suggest that breast milk antibodies do not enter the neonatal and infant circulation in substantial amounts. Because many drugs are secreted in human milk and because of the potential for serious adverse reactions in nursing infants from bevacizumab, a decision should be made whether to discontinue nursing or discontinue drug, taking into account the half‑life of the bevacizumab (approximately 20 days [range 11–50 days]) and the importance of the drug to the mother. [See Clinical Pharmacology (12.3).]

8.4 Pediatric Use The safety, effectiveness and pharmacokinetic profile of Avastin in pediatric patients have not been established.

Antitumor activity was not observed among eight children with relapsed glioblastoma treated with bevacizumab and irinotecan. There is insufficient information to determine the safety and efficacy of Avastin in children with glioblastoma.

Juvenile cynomolgus monkeys with open growth plates exhibited physeal dysplasia following 4 to 26 weeks exposure at 0.4 to 20 times the recommended human dose (based on mg/kg and exposure). The incidence and severity of physeal dysplasia were dose‑related and were partially reversible upon cessation of treatment.

8.5 Geriatric Use In Study 1, severe adverse events that occurred at a higher incidence (≥ 2%) in patients aged ≥ 65 years as compared to younger patients were asthenia, sepsis, deep thrombophlebitis, hypertension, hypotension, myocardial infarction, congestive heart failure, diarrhea, constipation, anorexia, leukopenia, anemia, dehydration, hypokalemia, and hyponatremia. The effect of Avastin on overall survival was similar in elderly patients as compared to younger patients.

In Study 2, patients aged ≥ 65 years receiving Avastin plus FOLFOX4 had a greater relative risk as compared to younger patients for the following adverse events: nausea, emesis, ileus, and fatigue.

In Study 5, patients aged ≥65 years receiving carboplatin, paclitaxel, and Avastin had a greater relative risk for proteinuria as compared to younger patients. [See Warnings and Precautions (5.8).]

Of the 742 patients enrolled in Genentech‑sponsored clinical studies in which all adverse events were captured, 212 (29%) were age 65 or older and 43 (6%) were age 75 or older. Adverse events of any severity that occurred at a higher incidence in the elderly as compared to younger patients, in addition to those described above, were dyspepsia, gastrointestinal hemorrhage, edema, epistaxis, increased cough, and voice alteration.

In an exploratory, pooled analysis of 1745 patients treated in five randomized, controlled studies, there were 618 (35%) patients aged ≥ 65 years and 1127 patients < 65 years of age. The overall incidence of arterial thromboembolic events was increased in all patients receiving Avastin with chemotherapy as compared to those receiving chemotherapy alone, regardless of age. However, the increase in arterial thromboembolic events incidence was greater in patients aged ≥ 65 years (8.5% vs. 2.9%) as compared to those < 65 years (2.1% vs. 1.4%). [See Warnings and Precautions (5.5).]

8.6 Females of Reproductive Potential Avastin increases the risk of ovarian failure and may impair fertility.

Inform females of reproductive potential of the risk of ovarian failure prior to starting treatment with Avastin. Long term effects of Avastin exposure on fertility are unknown.

In a prospectively designed substudy of 179 premenopausal women randomized to receive chemotherapy with or without Avastin, the incidence of ovarian failure was higher in the Avastin arm (34%) compared to the control arm (2%). After discontinuation of Avastin and chemotherapy, recovery of ovarian function occurred in 22% (7/32) of these Avastin‑treated patients. [See Warnings and Precautions (5.10), Adverse Reactions (6.1).]

10 OVERDOSAGE The highest dose tested in humans (20 mg/kg IV) was associated with headache in nine of 16 patients and with severe headache in three of 16 patients.

17 PATIENT COUNSELING INFORMATION Advise patients: • To undergo routine blood pressure monitoring and to contact their health care provider if blood pressure is elevated.

• To immediately contact their health care provider for unusual bleeding, high fever, rigors, sudden onset of worsening neurological function, or persistent or severe abdominal pain, severe constipation, or vomiting.

• Of increased risk of wound healing complications during and following Avastin.

• Of increased risk of an arterial thromboembolic event.

• Of the potential risk to the fetus during and following Avastin and the need to continue adequate contraception for at least 6 months following last dose of Avastin.

• Of the increased risk for ovarian failure following Avastin treatment.

Avastin® (bevacizumab) Manufactured by: Genentech, Inc. A Member of the Roche Group 1 DNA Way South San Francisco, CA 94080‑4990

03/14 AVA0000765907 Initial U.S. Approval: February 2004 Code Revision Date: March 2014 Avastin® is a registered trademark of Genentech, Inc. © 2014 Genentech, Inc.

S:12.5"

Congestive Heart Failure (CHF) The incidence of Grade ≥ 3 left ventricular dysfunction was 1.0% in patients receiving Avastin compared to 0.6% in the control arm across indications. In patients with metastatic breast cancer (MBC), an indication for which Avastin is not approved, the incidence of Grade 3–4 CHF was increased in patients in the Avastin plus paclitaxel arm (2.2%) as compared to the control arm (0.3%). Among patients receiving prior anthracyclines for MBC, the rate of CHF was 3.8% for patients receiving Avastin as compared to 0.6% for patients receiving paclitaxel alone.

The safety of continuation or resumption of Avastin in patients with cardiac dysfunction has not been studied.

In previously untreated patients with diffuse large B‑cell lymphoma (DLBCL), an indication for which Avastin is not approved, the incidence of CHF and decline in left‑ventricular ejection fraction (LVEF) were significantly increased in the Avastin plus R‑CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) arm (n=403) compared to the placebo plus R‑CHOP arm (n=379); both regimens were given for 6 to 8 cycles. At the completion of R‑CHOP therapy, the incidence of CHF was 10.9% in the Avastin plus R‑CHOP arm compared to 5.0% in the R‑CHOP alone arm [relative risk (95% CI) of 2.2 (1.3, 3.7)]. The incidence of a LVEF event, defined as a decline from baseline of 20% or more in LVEF or a decline from baseline of 10% or more to a LVEF value of less than 50%, was also increased in the Avastin plus R‑CHOP arm (10.4%) compared to the R‑CHOP alone arm (5.0%).

Time to onset of left‑ventricular dysfunction or CHF was 1‑6 months after initiation of therapy in at least 85% of the patients and was resolved in 62% of the patients experiencing CHF in the Avastin arm compared to 82% in the control arm.

NCI‑CTC Grade 3‑4 Events Body as a Whole Asthenia Abdominal Pain Pain Cardiovascular Hypertension Deep Vein Thrombosis Intra‑Abdominal Thrombosis Syncope Digestive Diarrhea Constipation Hemic/Lymphatic Leukopenia Neutropeniaa

Arm 1 IFL+ + Placebo (n = 396) 74%

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Proteinuria Grade 3–4 proteinuria ranged from 0.7 to 7.4% in Studies 1, 2, 4, 5 and 8.

The overall incidence of proteinuria (all grades) was only adequately assessed in Study 8, in which the incidence was 20%. Median onset of proteinuria was 5.6 months (range 15 days to 37 months) after initiation of Avastin. Median time to resolution was 6.1 months (95% CI 2.8 months, 11.3 months). Proteinuria did not resolve in 40% of patients after median follow up of 11.2 months and required permanent discontinuation of Avastin in 30% of the patients who developed proteinuria (Study 8).

In an exploratory, pooled analysis of 8,273 patients treated in 7 randomized clinical trials, 5.4% (271 of 5037) of patients receiving Avastin in combination with chemotherapy experienced Grade ≥ 2 proteinuria. The Grade ≥ 2 proteinuria resolved in 74.2% (201 of 271) of patients. Avastin was re‑initiated in 41.7% (113 of 271) of patients. Of the 113 patients who re‑initiated Avastin, 47.8% (54 of 113) experienced a second episode of Grade ≥ 2 proteinuria. [See Warnings and Precautions (5.8).]

Metastatic Colorectal Cancer (mCRC) The data in Table 1 and Table 2 were obtained in Study 1, a randomized, double‑blind, controlled trial comparing chemotherapy plus Avastin with chemotherapy plus placebo. Avastin was administered at 5 mg/kg every 2 weeks.

All Grade 3–4 adverse events and selected Grade 1–2 adverse events (hypertension, proteinuria, thromboembolic events) were collected in the entire study population. Severe and life‑threatening (Grade 3–4) adverse events, which occurred at a higher incidence ( ≥ 2%) in patients receiving bolus‑IFL plus Avastin as compared to bolus‑IFL plus placebo, are presented in Table 1.

Table 1 NCI‑CTC Grade 3−4 Adverse Events in Study 1 (Occurring at Higher Incidence [ ≥ 2 %] Avastin vs. Control)

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Neutropenia and Infection The incidences of neutropenia and febrile neutropenia are increased in patients receiving Avastin plus chemotherapy compared to chemotherapy alone. In Study 1, the incidence of Grade 3 or 4 neutropenia was increased in mCRC patients receiving IFL plus Avastin (21%) compared to patients receiving IFL alone (14%). In Study 5, the incidence of Grade 4 neutropenia was increased in NSCLC patients receiving paclitaxel/carboplatin (PC) plus Avastin (26.2%) compared with patients receiving PC alone (17.2%).

Febrile neutropenia was also increased (5.4% for PC plus Avastin vs. 1.8% for PC alone). There were 19 (4.5%) infections with Grade 3 or 4 neutropenia in the PC plus Avastin arm of which 3 were fatal compared to 9 (2%) neutropenic infections in patients receiving PC alone, of which none were fatal. During the first 6 cycles of treatment, the incidence of serious infections including pneumonia, febrile neutropenia, catheter infections and wound infections was increased in the PC plus Avastin arm [58 patients (13.6%)] compared to the PC alone arm [29 patients (6.6%)].

In Study 6, one fatal event of neutropenic infection occurred in a patient with previously treated glioblastoma receiving Avastin alone. The incidence of any grade of infection in patients receiving Avastin alone was 55% and the incidence of Grade 3–5 infection was 10%.

AVASTIN® (bevacizumab) 14 (95% CI 4, 53)]. After discontinuation of Avastin treatment, recovery of ovarian function at all time points during the post‑treatment period was demonstrated in 22% (7/32) of the Avastin‑treated women. Recovery of ovarian function is defined as resumption of menses, a positive serum β‑HCG pregnancy test, or a FSH level < 30 mIU/mL during the post‑ treatment period. Long term effects of Avastin exposure on fertility are unknown. [See Warnings and Precautions (5.10), Use in Specific Populations (8.6).]

Think Avastin

Clinically meaningful activity in 4 distinct tumor types1

Confronting a common threat across approved indications Indications

Avastin is indicated for the treatment of metastatic renal cell carcinoma in combination with interferon alfa.

Avastin is indicated for the treatment of glioblastoma as a single agent for adult patients with progressive disease following prior therapy. The effectiveness of Avastin in glioblastoma is based on an improvement in objective response rate. There are no data demonstrating an improvement in disease-related symptoms or increased survival with Avastin.

Avastin is indicated for the first-line treatment of unresectable, locally advanced, recurrent or metastatic non–squamous non–small cell lung cancer in combination with carboplatin and paclitaxel.

Avastin is indicated for the first- or second-line treatment of patients with metastatic carcinoma of the colon or rectum in combination with intravenous 5-fluorouracil–based chemotherapy.

Avastin, in combination with fluoropyrimidine-irinotecan- or fluoropyrimidine-oxaliplatin-based chemotherapy, is indicated for the second-line treatment of patients with metastatic colorectal cancer who have progressed on a first-line Avastin-containing regimen.

Limitation of Use: Avastin is not indicated for adjuvant treatment of colon cancer.

Boxed WARNINGS

Gastrointestinal (GI) perforation — Serious and sometimes fatal GI perforation occurs at a higher incidence in Avastin-treated patients compared to controls — The incidences of GI perforation ranged from 0.3% to 2.4% across clinical studies — Discontinue Avastin in patients with GI perforation Surgery and wound healing complications — The incidence of wound healing and surgical complications, including serious and fatal complications, is increased in Avastin-treated patients — Do not initiate Avastin for at least 28 days after surgery and until the surgical wound is fully healed. The appropriate interval between termination of Avastin and subsequent elective surgery required to reduce the risks of impaired wound healing/wound dehiscence has not been determined — Discontinue Avastin at least 28 days prior to elective surgery and in patients with wound healing complications requiring medical intervention Hemorrhage — Severe or fatal hemorrhage, including hemoptysis, GI bleeding, hematemesis, central nervous system hemorrhage, epistaxis, and vaginal bleeding, occurred up to 5-fold more frequently in patients receiving Avastin. Across indications, the incidence of grade ≥3 hemorrhagic events among patients receiving Avastin ranged from 1.2% to 4.6% — Do not administer Avastin to patients with serious hemorrhage or recent hemoptysis (≥1/2 tsp of red blood) — Discontinue Avastin in patients with serious hemorrhage (ie, requiring medical intervention)

Additional serious adverse events

Additional serious and sometimes fatal adverse events with increased incidence in the Avastin-treated arm vs control included — Non-GI fistula formation (≤0.3%) — Arterial thromboembolic events (grade ≥3, 2.6%) — Proteinuria (nephrotic syndrome, <1%) Additional serious adverse events with increased incidence in the Avastin-treated arm vs control included — Hypertension (grade 3–4, 5%–18%) — Reversible posterior leukoencephalopathy syndrome (RPLS) (<0.1%) Infusion reactions with the first dose of Avastin were uncommon (<3%), and severe reactions occurred in 0.2% of patients Inform females of reproductive potential of the risk of ovarian failure prior to starting treatment with Avastin

Most common adverse events

Across indications, the most common adverse reactions observed in Avastin patients at a rate >10% and at least twice the control arm rate were — Epistaxis — Rhinitis — Dry skin — Back pain — Headache — Proteinuria — Rectal hemorrhage — Exfoliative dermatitis — Hypertension — Taste alteration — Lacrimation disorder Across all studies, Avastin was discontinued in 8.4% to 21% of patients because of adverse reactions

©2013 Genentech USA, Inc.

All rights reserved.

AVA0000488404

Printed in USA.

(12/13)

Pregnancy warning

Avastin may impair fertility Based on animal data, Avastin may cause fetal harm Advise patients of the potential risk to the fetus during and following Avastin and the need to continue adequate contraception for at least 6 months following the last dose of Avastin For nursing mothers, discontinue nursing or Avastin, taking into account the importance of Avastin to the mother

Indication-specific adverse events

In mRCC, the most common grade 3–5 adverse events in AVOREN, occurring at a ≥2% higher incidence in Avastin-treated patients vs controls, were fatigue (13% vs 8%), asthenia (10% vs 7%), proteinuria (7% vs 0%), hypertension (6% vs 1%), and hemorrhage (3% vs 0.3%) In GBM Study AVF3708g, in patients receiving Avastin alone, the most frequently reported adverse events were infection (55%), fatigue (45%), headache (37%), hypertension (30%), epistaxis (19%), and diarrhea (21%). Of these, the incidence of grade ≥3 adverse events was infection (10%), fatigue (4%), headache (4%), hypertension (8%), and diarrhea (1%).

Two deaths were possibly related to Avastin: 1 retroperitoneal hemorrhage and 1 neutropenic infection In GBM patients receiving Avastin alone or Avastin plus irinotecan,* the incidences of Avastinrelated adverse events (grade 1–4) were bleeding/hemorrhage (40%), epistaxis (26%), CNS hemorrhage (5%), hypertension (32%), venous thromboembolic events (8%), arterial thromboembolic events (6%), wound healing complications (6%), proteinuria (4%), GI perforation (2%), and RPLS (1%). The incidences of grade 3–5 events in these 163 patients were bleeding/hemorrhage (2%), CNS hemorrhage (1%), hypertension (5%), venous thromboembolic events (7%), arterial thromboembolic events (3%), wound healing complications (3%), proteinuria (1%), and GI perforation (2%). Intracranial hemorrhage occurred in 8 of 163 patients; 2 patients had grade 3–4 hemorrhage In NSCLC, grade 3–5 (nonhematologic) and grade 4–5 (hematologic) adverse events in Study E4599 occurring at a ≥2% higher incidence in Avastin-treated patients vs controls were neutropenia (27% vs 17%), fatigue (16% vs 13%), hypertension (8% vs 0.7%), infection without neutropenia (7% vs 3%), venous thrombus/embolism (5% vs 3%), febrile neutropenia (5% vs 2%), pneumonitis/pulmonary infiltrates (5% vs 3%), infection with grade 3 or 4 neutropenia (4% vs 2%), hyponatremia (4% vs 1%), headache (3% vs 1%), and proteinuria (3% vs 0%) In first-line MCRC, the most common grade 3–4 events in Study 2107, which occurred at a ≥2% higher incidence in the Avastin plus IFL vs IFL groups, were asthenia (10% vs 7%), abdominal pain (8% vs 5%), pain (8% vs 5%), hypertension (12% vs 2%), deep vein thrombosis (9% vs 5%), intra-abdominal thrombosis (3% vs 1%), syncope (3% vs 1%), diarrhea (34% vs 25%), constipation (4% vs 2%), leukopenia (37% vs 31%), and neutropenia (21% vs 14%) In second-line MCRC, the most common grade 3–5 (nonhematologic) and 4–5 (hematologic) events in Study E3200, which occurred at a higher incidence (≥2%) in the Avastin plus FOLFOX4 vs FOLFOX4 groups, were diarrhea (18% vs 13%), nausea (12% vs 5%), vomiting (11% vs 4%), dehydration (10% vs 5%), ileus (4% vs 1%), neuropathy–sensory (17% vs 9%), neurologic–other (5% vs 3%), fatigue (19% vs 13%), abdominal pain (8% vs 5%), headache (3% vs 0%), hypertension (9% vs 2%), and hemorrhage (5% vs 1%). These data are likely to underestimate the true adverse event rates due to the reporting mechanisms used in this study When continued beyond first progression in MCRC, no new safety signals were observed in the TML study (ML18147) when Avastin was administered in second-line MCRC patients who progressed on an Avastin containing regimen in first-line MCRC. The safety data was consistent with the known safety profile established in first- and second-line MCRC *Avastin is not approved for use in combination with irinotecan or any other combination regimens.

You may report side effects to the FDA at (800) FDA-1088 or www.fda.gov/medwatch.

You may also report side effects to Genentech at (888) 835-2555.

Please see accompanying brief summary of Prescribing Information, including Boxed WARNINGS, for additional important safety information.

Reference: 1. Avastin Prescribing Information.

Genentech, Inc. March 2013.

www.avastin-hcp.com