TAP Vol 6 Issue 7 by Harborside Press LLC

Postoperative Pain in Breast Cancer

| Aging Population and Cancer Care

| Too Young for Cancer: A Patient’s Story

VOLUME 6, ISSUE 7

APRIL 25, 2015

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

Journal Spotlight

Radiotherapy or Not in Older Women Receiving Breast-Conserving Surgery and Endocrine Treatment? Study shows omitting radiotherapy may increase local recurrence risk but has no effect on survival

By Chandrakanth Are, MBBS, MBA, FRCS, FACS

By Matthew Stenger

n the phase III PRIME II trial, designed to assess whether whole-breast irradiation could be omitted in women aged ≥ 65 years with early-stage breast cancer undergoing breast-conserving surgery and receiving adjuvant endocrine treatment, Ian H. Kunkler, MB BChir, FRCR, of Western General Hospital, Edinburgh, and colleagues found an increased risk of ipsilateral recurrence in women not receiving radiotherapy.1 No significant differences between radiotherapy and no-radiotherapy groups were observed for regional recurrence, distant metastases, contralateral breast cancers, new breast cancers, or overall survival. The study is reported in Lancet Oncology.

Study Details In the trial, 1,326 women from 76 centers in the Unit-

ed Kingdom, Greece, Australia, and Serbia were randomly assigned between April 2003 and December 2009 to receive radiotherapy at 40 to 50 Gy in 15 to 25 fractions (n = 658) or no radiotherapy (n = 668). Patients were considered to be at low risk Ian H. Kunkler, of recurrence on the basis of MB BChir, FRCR hormone receptor–positive and axillary node–negative disease, T1 to T2 disease ≤ 3 cm at the longest dimension, and clear margins. Patients could have grade 3 tumor histology or lymphovascular invasion, but not both. The primary endpoint was ipsilatcontinued on page 3

Oncology Worldwide

Noncommunicable Diseases Are the Leading Cause of Death in Low- and Middle-Income Countries By Jo Cavallo

Heal Thy Patient … Reflections on the Human Side of Medicine Physician Perspective

he greatest health threat to people living in lowand middle-income countries is no longer infectious diseases like HIV/AIDS, which has seen a 33% decline in the global rate of new infections since 2001.1 It is the rise of noncommunicable diseases (including cancer, cardiovascular disease, and diabetes), which are now the leading cause of death and disability in

low- and middle-income countries, killing more than 8 million people before the age of 60 in 2013 alone, according to a new report by the Council on Foreign Relations (CFR), an independent nonprofit think tank headquartered in New York.2 In many of these countries, especially those in Africa, the proportion rises to 80% or higher, the report found. Over the past 15 years, mortality rates from nonWe need more oncologists and communicable diseases physicians from related fields to in these countries have increased 53%—significollaborate on cancer control. We’ve cantly faster than the rate made so much progress in cancer of population growth—fueled by a constellation of and heart disease in high-income factors, including urbancountries, but it is not being extended ization, limited access to preventive care, greater in developing countries. exposure to air pollution, —Thomas J. Bollyky

he first time I met Mrs. X and her husband was to discuss the surgical treatment options for pancreatic cancer. She had just been diagnosed with pancreatic cancer at her local hospital and was being referred to a tertiary care center for operative management. Mrs. X and her husband were no different than the approximately 45,000 patients diagnosed with pancreatic cancer on an annual basis in the United States. They were anxious, as is expected, but maintained a calm grace and dignified composure. They were in their 60s and were extremely polite and courteous, despite continued on page 80

Dr. Are is Associate Professor of Surgical Oncology, Vice Chair of Education, and Program Director of the General Surgery Residency Program at the University of Nebraska Medical Center, Omaha. Disclaimer: This commentary represents the views of the author and may not necessarily reflect the views of ASCO.

MORE IN THIS ISSUE Oncology Meetings Coverage National Comprehensive Cancer Network �� 13 Patrick I. Borgen, MD, on Postoperative Pain in Breast Cancer �� 21 Aspirin and COX-2 Inhibitors in Colon Cancer ��26 High Cost of Novel Cancer Drugs ��30 Geriatrics for the Oncologist �� 40 Direct From ASCO �� 42–45 Coping With Stress, Burnout, Fatigue ��50 Improving Cancer Care Globally ��54 Hope Rugo, MD, on Avoiding Hair Loss During Chemotherapy �� 74

continued on page 54

ASCO Annual Meeting, May 29 - June 2, 2015, Chicago

A Harborside Press® Publication

The ASCO Post | APRIL 25, 2015

PAGE 2

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ASCOPost.com | APRIL 25, 2015

PAGE 3

Journal Spotlight PRIME II Trial continued from page 1

eral breast tumor recurrence. Follow-up in the trial continues. The no-radiotherapy and radiotherapy groups were generally balanced for age (median, 70 and 69 years), margins (1–5 mm in 47% and 45%, > 5 mm in 34% and 36%), tumor grade (1 in 41% and 44%, 2 in 55% and 53%, 3 in 3% and 2%), tumor side (left breast for 54% and 52%), lymphovascular invasion (5% and 4%), axillary surgery (sentinel node biopsy only in 33% and 30%, sample only in 26% and 32%, both in 16% in both), preoperative endocrine treatment (9% and 8%), and estrogen receptor (ER) status (rich in 89% and 91%).

Risk of Ipsilateral Recurrence After a median follow-up of 5 years, ipsilateral breast tumor recurrence was observed in 4.1% of patients in the noradiotherapy group vs 1.3% in the radiotherapy group (hazard ratio [HR] = 5.19, P = .0007). On multivariate analysis including pathologic tumor size, margin status, tumor grade, age, presence of lymphovascular invasion, ER status, and use of radiotherapy, omission of radiotherapy was the only significant predictor of local recurrence (HR = 4.87, P = .0013); ER-

poor status and grade 3 tumors were of borderline significance (both P = .06). The absolute risk reduction in ipsilateral recurrence at 5 years with radiotherapy was 2.9% (95% confidence interval [CI] = 1.1%–4.8%). The number needed to treat to prevent a case of recurrence was calculated at 31.8 (95%

local recurrence, four had local recurrence only and one had local and regional recurrence. Among 23 patients in the no-radiotherapy group and 4 in the radiotherapy group with local recurrence who had such data available, mastectomy was performed in 12 vs 2 and wide local excision was performed in 11 vs 2.

Postoperative whole-breast radiotherapy after breast-conserving surgery and adjuvant endocrine treatment resulted in a significant but modest reduction in local control for women aged 65 years or older with early breast cancer 5 years after randomisation. However, the 5-year rate of ipsilateral breast tumour recurrence is probably low enough for omission of radiotherapy to be considered for some patients. —Ian H. Kunkler, MB BChir, FRCR

CI = 27.4–55.0), yielding an adjusted absolute risk reduction of 3.1% (95% CI = 1.8%–3.6%). Local recurrence occurred in 26 patients in the no-radiotherapy group, with 18 having local recurrence only, 6 both local and regional recurrences, and 2 local recurrence with distant spread. Of five women in the radiotherapy group with

Radiotherapy and Recurrence in Early Breast Cancer ■■ Risk of local recurrence was significantly greater in women not receiving radiotherapy. ■■ Five-year overall survival was similar in the two groups.

In an unplanned subgroup analysis by ER score, local recurrence was observed in 20 (3%) of 593 patients in the no-radiotherapy group vs 5 (< 1%) of 601 in the radiotherapy group with ER-rich status, with 5-year ipsilateral recurrence of 3.3% vs 1.1% (P = .002). In women with ER-poor status, local recurrence was observed in 6 (9%) of 65 women in the noradiotherapy group vs 0 of 55 in the radiotherapy group, with 5-year ipsilateral recurrence of 10.3% vs 0% (P = .026).

Additional Recurrences, Survival For the no-radiotherapy vs radiotherapy groups, respectively, regional

recurrence was observed in 1.5% vs 0.5%; distant recurrence, in 1.0% vs 0.5%; contralateral breast cancer, in 0.7% vs 1.5%; and new nonbreast cancer, in 4.3% vs 3.7%. Five-year overall survival was 93.9% in both groups (P = .34) and 5-year breast cancer-free survival was 94.5% vs 97.6%. Among 49 patients in the noradiotherapy group and 40 in the radiotherapy group who died, 8 and 4 died from breast cancer. The investigators concluded: Postoperative whole-breast radiotherapy after breast-conserving surgery and adjuvant endocrine treatment resulted in a significant but modest reduction in local control for women aged 65 years or older with early breast cancer 5 years after randomisation. However, the 5-year rate of ipsilateral breast tumour recurrence is probably low enough for omission of radiotherapy to be considered for some patients. n Disclosure: The study was funded by the Chief Scientist Office of the Scottish Government and Breast Cancer Institute at Western General Hospital, Edinburgh. Prof. Kunkler reported no potential conflicts of interest. For full disclosures of the other study authors, visit www.thelancet.com.

Reference 1. Kunkler IH, Williams LJ, Jack WJ, et al: Breast-conserving surgery with or without irradiation in women aged 65 years or older with early breast cancer (PRIME II): A randomised controlled trial. Lancet O ncol 16:266-273, 2015.

PRIME II and the Omission of Radiation Therapy in Low-Risk, Elderly Patients Undergoing Breast Conservation: The Time Has Come By Meena S. Moran, MD

espite the high prevalence of breast cancer worldwide, it is important to recognize that > 40% of all cases occur in women aged 65 years or older in both the United States and the United Kingdom.1,2 Breast cancers in older patients are more often associated with indolent features and with overall better outcomes than those in younger patients. Thus, use of breast-conservation therapy may be preferable as the surgical treatment pathway to that of mastectomy, particularly for low-risk elderly patients with comor-

Dr. Moran is Associate Professor, Yale University School of Medicine, Department of Therapeutic Radiology, New Haven, Connecticut.

bidities, given the shorter recovery time and lower perioperative morbidity risk with more-limited surgery. The standard approach for breastconservation therapy has traditionally added whole-breast radiation therapy after a limited breast-conserving approach to remove the primary tumor, based on a large body of level I data with long-term follow-up. Furthermore, meta-analysis of the trials providing these data suggest that whole-breast radiation therapy not only provides a significant benefit in decreasing local relapse (relative benefit reduction of approximately two-thirds), but also adds a modest—but statistically significant—long-term improvement in breast cancer–specific survival

(absolute benefit of approximately 3% at 15 years in N0 patients).3 While these data are routinely extrapolated across all subgroups of patients, the more indolent natural history of low-risk elderly patients and limited representation of these patients in the original breast-conservation therapy trials (with many of the protocols excluding patients ≥ 70 years of age) bring to question the practice of routine delivery of radiation therapy in low-risk elderly patients undergoing breast-conservation therapy.

Practice-Changing Studies Thus, trials such as the PRIME II trial—recently reported by Kunkler and colleagues4 and reviewed in this

issue of The ASCO Post—are major, practice-changing studies regarding low-risk elderly patients treated with breast-conservation therapy. This trial, along with the Cancer and Leukemia Group B (CALGB) 9343 trial,5 should be changing the paradigm of routine use of whole-breast radiation therapy in low-risk elderly patients. In the PRIME II trial, patients ≥ 65 years with tumors < 3 cm in size with primarily grade I/II disease, all estrogen receptor (ER)-positive and pathologically node-negative, were randomly assigned to whole-breast radiation therapy plus hormone therapy vs hormone therapy alone. The findings parcontinued on page 4

The ASCO Post | APRIL 25, 2015

PAGE 4

Perspective

Meena S. Moran, MD continued from page 3

allel those of CALGB 9343, which included an even lower-risk cohort of patients (≥ 70 years with tumors ≤ 2 cm, clinically node-negative, ER-positive). Both studies have similarly reported local relapse rates for cohorts treated with or without whole-breast radiation therapy that were acceptable (PRIME II 5-year rate of 4.1% with no whole-breast radiation therapy vs 1.3% with whole-breast radiation therapy, P = .0002; CALGB 9343 10-year rate of 10% with no whole-breast radiation therapy vs 2% with whole-breast radiation therapy, P < .001). Though these differences in local relapse between the arms of each study were statistically significant, the addition of whole-breast radiation therapy did not result in differences in axillary recurrence, distant metastasis, or breast cancer–specific survival. In fact, the majority of deaths in both the PRIME II and CALGB trials were non–breast cancer–related events.5

Similar Findings In addition to these two studies, others have similarly reported findings that suggest whole-breast radiation therapy may be omitted in subsets of patients at low risk for local relapse. For example, the 2×2 designed randomized BASO II trial included 1,135 women aged < 70 years.6 With a median age of only 57 years (range, 33–69 years), the study reported 10-year local relapse-free survival of 93% for the whole-breast radiation therapy–alone arm and 93% for the tamoxifen-alone arm (P = .90). For patients on the whole-breast radiation therapy/tamoxifen arm, local control was 100% and dropped significantly to 83% for the arm receiving no tamoxifen and no whole-breast radiation therapy.6 It is important to keep in mind that many patients in the trials cited herein received tamoxifen, whereas current practice standards recommend aromatase inhibitors in postmenopausal women. Due to the added (albeit small) further decrease in local relapse associated with aromatase inhibitors, it is highly likely that failure rates in low-risk elderly patients receiving hormone therapy alone will be slightly lower than those reported in these trials. Furthermore, the improved toxicity profile, better tolerability, and array of aromatase inhibitor choices relative to tamoxifen make compliance less of an issue in clinical practice.

Together, these data suggest that in highly selected subsets of low-risk patients such as those older than 65 or 70 years with hormone receptor–positive disease and/or other favorable factors, breast cancer–specific survival is not affected by the omission of whole-breast radiation therapy. Yet, the uptake of these data into our clinical practices has been slow. Recently, a study using the National Cancer Institute–Surveillance, Epidemiology, and End Results (SEER) database to compare use of radiation in a low-risk elderly population ≥ 70 years old from 2000 to 2004 (pre-CALGB 9343) vs 2005 to 2009 (post-CALGB) demonstrated that use of radiation therapy declined by < 7% (from 68.6% pre-CALGB to 61.7% post-CALGB, P < .001). Though the use of externalbeam radiotherapy specifically went

iting significant distress and anxiety for the patients and their families irrespective of the fact that the relapse does not ultimately affect breast cancer survival, and that this trauma is mostly avoidable given the excellent tolerability of whole-breast radiation therapy. Patients, in turn, also report more distress in clinical follow-up when choosing to omit radiation.8 In light of all of the above, and particularly in countries such as the United States, where physicians/institutions must face the direct consequences of omission of any treatment with regard to fee-for-service reimbursements and the monitoring of “relative value units” on individual physicians’ “productivity,” the slow acceptance and integration of omission of radiation into clinical practice for low-risk elderly patients are not surprising.

We now have a growing body of level I data supporting routine treatment of low-risk elderly patients undergoing breast conservation with surgery and hormone therapy alone. —Meena S. Moran, MD

down from 66% to 54% (P < .001), an unexpected and fascinating finding was a simultaneous increase in implantbased radiotherapy from 1.4% to 6.2%, which diminished the overall effect of omitting radiation in these low-risk elderly patients.7

Reasons for Slow Adoption Why are these level I data so slow to be adopted into clinical practice, particularly relative to other breast cancer practices such as the use of implantbased radiotherapy (accelerated partialbreast irradiation) for which similar published level I data with adequate follow-up remain limited? One can only postulate that despite the availability of data, we as a medical community may respond differently to implementing data supporting the withholding of established treatments compared with data that support the implementation of new therapies into clinical practice. Furthermore, despite the lack of its benefits in survival endpoints, some physicians argue that there is an immeasurable psychological detriment when patients sustain local relapse, elic-

Time for Change Nevertheless, the time has come. We now have a growing body of level I data supporting routine treatment of low-risk elderly patients undergoing breast conservation with surgery and hormone therapy alone. Along with the emergence of additional data supporting omission of radiation in selected subsets of low-risk patients, we have started to see the more routine use of biomarkers, gene assays, and other innovative methods for assessing an individual’s risk for local relapse; a shift in guideline recommendations from national organizations such as the National Comprehensive Cancer Network (NCCN) incorporating new standards for breast-conservation therapy (without radiation) in selected subsets of patients9; more clinical awareness and monitoring of physicians’ choices as part of national initiatives such as the Choosing Wisely campaign10; and national health-care reform evolving to reward physicians for quality over quantity of care. Given all these factors, we should anticipate a more drastic increase in

omission of radiation therapy for lowrisk elderly patients undergoing breast conservation in our country. n Disclosure: Dr. Moran reported no potential conflicts of interest.

References 1. Cancer Research UK: Breast cancer incidence statistics. Available at www. cancerresearchuk.org/cancer-info/cancerstats/types/breast/. Accessed April 9, 2015. 2. American Cancer Society: Breast Cancer Facts & Figures, 2011-2012. Available at www. cancer.org/acs/groups/content/@epidemiologysurveilance/documents/document/acspc-030975.pdf. Accessed April 9, 2015. 3. Early Breast Cancer Trialists’ Collaborative Group: Effect of radiotherapy after breast-conserving surgery on 10-year recurrence and 15-year breast cancer death: Meta-analysis of individual patient data for 10,801 women in 17 randomised trials. Lancet 378:1707-1716, 2011. 4. Kunkler IH, Williams LJ, Jack WJL, et al: Breast-conserving surgery with or without irradiation in women aged 65 years or older with early breast cancer (PRIME II). Lancet Oncol 16:266-273, 2015. 5. Hughes KS, Schnaper LA, Bellon JR, et al: Lumpectomy plus tamoxifen with or without irradiation in women age 70 years or older with early breast cancer: Long-term follow-up of CALGB 9343. J Clin Oncol 31:2382-2387, 2013. 6. Blamey RW, Bates T, Chetty U, et al: Radiotherapy or tamoxifen after conserving surgery for breast cancers of excellent prognosis: British Association of Surgical Oncology (BASO) II trial. Eur J Cancer 49:22942302, 2013. 7. Palta M, Palta P, Bhavsar NA, et al: The use of adjuvant radiotherapy in elderly patients with early-stage breast cancer: Changes in practice patterns after publication of Cancer and Leukemia Group B 9343. Cancer 121:188-193, 2015. 8. Prescott R, Kunkler I, Williams L, et al: A randomised controlled trial of postoperative radiotherapy following breastconserving surgery in a minimum-risk older population: The PRIME trial. Health Technol Assess 11:1-149, 2007. 9. National Comprehensive Cancer Network: Breast cancer (version 2.2015). Available at www.nccn.org/professionals/physician_gls/recently_updated.asp. Accessed April 9, 2015. 10. American Society for Radiation Oncology: Choosing Wisely: [10 Things] Physicians and Patients Should Question. Available at www.choosingwisely.org/ wp-content/uploads/2013/09/ASTRO5things-List_092013.pdf. Accessed April 9, 2015.

The first and only FDA-approved combination therapy Indicated for the treatment of patients with unresectable or metastatic melanoma with BRAF V600E or V600K mutations, as detected by an FDA-approved test. This indication is based on the demonstration of durable response rate. Improvement in disease-related symptoms or overall survival has not been demonstrated for TAFINLAR in combination with MEKINIST. Limitation of use: TAFINLAR is not indicated for treatment of patients with wild-type BRAF melanoma.

2 AGENTS. 1 THERAPY.

DEMONSTRATED DURABLE RESPONSE RATE IN A PHASE II STUDY 1,2

Investigator-assessed analysis

TAFINLAR + MEKINIST

150 mg twice daily

2 mg once daily

in combination TAFINLAR

as a single agent

overall response rate1 overall response rate1

76 54%

% (95% CI: 62, 87)

median duration of response1

(95% CI: 40, 67)

median duration of response1

10.5 5.6

months

(95% CI: 7, 15)

months

(95% CI: 5, 7)

Important Safety Information for TAFINLAR and MEKINIST when used in combination New Primary Malignancies. New primary malignancies, cutaneous and non-cutaneous, can occur when TAFINLAR is used in combination with MEKINIST. Cutaneous Malignancies: In Trial 2, the incidence of basal cell carcinoma was increased in patients receiving TAFINLAR in combination with MEKINIST: 9% (5/55) of patients receiving TAFINLAR in combination with MEKINIST compared with 2% (1/53) of patients receiving TAFINLAR as a single agent. The range of time to diagnosis of basal cell carcinoma was 28 to 249 days in patients receiving TAFINLAR in combination with MEKINIST and was 197 days for the patient receiving TAFINLAR as a single agent. Cutaneous squamous cell carcinoma, including keratoacanthoma, (cuSCC) occurred in 7% of patients receiving TAFINLAR in combination with MEKINIST and 19% of patients receiving TAFINLAR as a single agent. The range of time to diagnosis of cuSCC was 136 to 197 days in the combination arm and was 9 to 197 days in the arm receiving TAFINLAR as a single agent. New primary melanoma occurred in 2% (1/53) of patients receiving TAFINLAR as a single agent and in none of the 55 patients receiving TAFINLAR in combination with MEKINIST. Perform dermatologic evaluations prior to initiation of TAFINLAR in combination with MEKINIST, every 2 months while on therapy, and for up to 6 months following discontinuation of TAFINLAR. No dose modifications of

TAFINLAR or MEKINIST are required in patients who develop new primary cutaneous malignancies. Non-cutaneous Malignancies: In patients receiving TAFINLAR in combination with MEKINIST four cases of non-cutaneous malignancies were identified: KRAS mutation-positive pancreatic adenocarcinoma (n=1), recurrent NRAS mutation-positive colorectal carcinoma (n=1), head and neck carcinoma (n=1), and glioblastoma (n=1). Monitor patients receiving the combination closely for signs or symptoms of non-cutaneous malignancies. Permanently discontinue TAFINLAR for RAS mutation-positive non-cutaneous malignancies. If used in combination with MEKINIST, no dose modification of MEKINIST is required for patients who develop non-cutaneous malignancies. Tumor Promotion in BRAF Wild-Type Melanoma. In vitro experiments have demonstrated paradoxical activation of MAP-kinase signaling and increased cell proliferation in BRAF wild-type cells that are exposed to BRAF inhibitors. Confirm evidence of BRAF V600E or V600K mutation status prior to initiation of TAFINLAR in combination with MEKINIST. To learn more, visit TAFINLARMEKINISTHCP.com Please see additional Important Safety Information for TAFINLAR and MEKINIST when used in combination on the following pages. Please see Brief Summary of Prescribing Information for TAFINLAR and MEKINIST on the following pages.

TAFINLAR + MEKINIST demonstrated a 76% overall response rate1 Major efficacy outcome: Investigator-assessed response rate1 Overall Response

54%

(95% CI: 40, 67)

Overall Response

76%

(95% CI: 62, 87)

67%

80 70

50%

Response Rates

Study Design: Trial 2 was a multicenter, open-label, randomized (1:1:1) dose-ranging trial designed to evaluate the clinical activity and safety of TAFINLAR in combination with MEKINIST (at 2 different doses) and to compare the safety with TAFINLAR as a single agent in 162 patients with BRAF V600E or V600K mutationpositive, unresectable or metastatic melanoma. Patients were permitted to have had one prior chemotherapy regimen and prior aldesleukin; patients with prior exposure to BRAF or MEK inhibitors were ineligible. Patients were randomized to receive TAFINLAR 150 mg orally twice daily with MEKINIST 2 mg orally once daily (N=54), TAFINLAR 150 mg orally twice daily with MEKINIST 1 mg orally once daily (N=54), or TAFINLAR 150 mg orally twice daily (N=54). Treatment continued until disease progression or unacceptable toxicity.1

50 40 30 20 10 0

Complete Response

Partial Response

TAFINLAR as a single agent (N=54)

Complete Response

TAFINLAR

150 mg twice daily

Partial Response

MEKINIST

2 mg once daily

(N=54)

Important Safety Information for TAFINLAR and MEKINIST when used in combination (cont'd) Hemorrhage. Hemorrhages, including major hemorrhages defined as symptomatic bleeding in a critical area or organ, can occur when TAFINLAR is used in combination with MEKINIST. In Trial 2, treatment with TAFINLAR in combination with MEKINIST resulted in an increased incidence and severity of any hemorrhagic event: 16% (9/55) of patients treated with TAFINLAR in combination with MEKINIST compared with 2% (1/53) of patients treated with TAFINLAR as a single agent. The major hemorrhagic events of intracranial or gastric hemorrhage occurred in 5% (3/55) of patients treated with TAFINLAR in combination with MEKINIST compared with none of the 53 patients treated with TAFINLAR as a single agent. Intracranial hemorrhage was fatal in 4% (2/55) of patients receiving TAFINLAR in combination with MEKINIST. Permanently discontinue TAFINLAR and MEKINIST for all Grade 4 hemorrhagic events and for any Grade 3 hemorrhagic events that do not improve. Withhold TAFINLAR for Grade 3 hemorrhagic events; if improved resume at a lower dose level. Withhold MEKINIST for up to 3 weeks for Grade 3 hemorrhagic events; if improved, resume at a lower dose level. Venous Thromboembolism. In Trial 2, treatment with TAFINLAR in combination with MEKINIST resulted in an increased incidence of deep venous thrombosis (DVT) and pulmonary embolism (PE): 7% (4/55) of patients treated with TAFINLAR in combination with MEKINIST compared with none of the 53 patients treated with TAFINLAR as a single agent. Pulmonary embolism was fatal in 2% (1/55) of patients receiving TAFINLAR in combination with MEKINIST. Advise patients to immediately seek medical care if they develop symptoms of DVT or PE, such as shortness of breath, chest pain, or arm or leg swelling. Permanently discontinue TAFINLAR and MEKINIST for life-threatening PE. Withhold MEKINIST and continue TAFINLAR at the same dose for uncomplicated DVT or PE; if improved within 3 weeks, MEKINIST may be resumed at a lower dose level. Cardiomyopathy. In Trial 2, cardiomyopathy occurred in 9% (5/55) of patients treated with TAFINLAR in combination with MEKINIST

and in none of the patients treated with TAFINLAR as a single agent. The median time to onset of cardiomyopathy in patients treated with TAFINLAR in combination with MEKINIST was 86 days (range: 27 to 253 days). Cardiomyopathy was identified within the first month of treatment with TAFINLAR in combination with MEKINIST in 2 of 5 patients. Development of cardiomyopathy resolved in all 5 patients following dose reduction (4/55) and/or dose interruption (1/55). Across clinical trials of TAFINLAR in combination with MEKINIST (N=202), 2% demonstrated a decrease in LVEF below institutional lower limits of normal with an absolute decrease in LVEF of â&#x2030;Ľ20% below baseline. Assess LVEF by echocardiogram or multigated acquisition (MUGA) scan before initiation of TAFINLAR in combination with MEKINIST, one month after initiation, and then at 2- to 3-month intervals while on treatment with the combination. Withhold treatment with MEKINIST and continue TAFINLAR at the same dose if absolute LVEF value decreases by 10% from pretreatment values and is less than the lower limit of normal. For symptomatic cardiomyopathy or persistent, asymptomatic LV dysfunction that does not resolve within 4 weeks, permanently discontinue MEKINIST and withhold TAFINLAR. Resume TAFINLAR at the same dose level upon recovery of cardiac function. Ocular Toxicities. Retinal Vein Occlusion (RVO): Across all clinical trials of MEKINIST, the incidence of RVO was 0.2% (4/1,749). RVO may lead to macular edema, decreased visual function, neovascularization, and glaucoma. Urgently (within 24 hours) perform ophthalmological evaluation for patient-reported loss of vision or other visual disturbances. Permanently discontinue MEKINIST in patients with documented RVO. If MEKINIST is used in combination with TAFINLAR, do not modify dose of TAFINLAR. Retinal Pigment Epithelial Detachment (RPED): Retinal pigment epithelial detachments (RPED) can occur when TAFINLAR is used in combination with MEKINIST and with MEKINIST as a single agent. Retinal detachments resulting from MEKINIST are often

TAFINLAR + MEKINIST achieved a median duration of response of 10.5 months1 Efficacy outcome: Investigator-assessed median duration of response1

TAFINLAR

+ MEKINIST

150 mg twice daily 2 mg once daily (N=54)

10.5

months

(95% CI: 7, 15)

Months Months TAFINLAR as a single agent (N=54)

5.6

months

(95% CI: 5, 7)

Independent Radiology Review Committee (IRRC) analyses were supportive of investigator-assessed results1 • 57% overall response rate (ORR) (95% CI: 43, 71) with TAFINLAR 150 mg twice daily + MEKINIST 2 mg once daily; 46% ORR (95% CI: 33, 60) with TAFINLAR as a single agent1 – Complete response (CR) with TAFINLAR 150 mg twice daily + MEKINIST 2 mg once daily: 9%; CR with TAFINLAR as a single agent: 7% – Partial response (PR) with TAFINLAR 150 mg twice daily + MEKINIST 2 mg once daily: 48%; PR with TAFINLAR as a single agent: 39% • Median duration of response of 7.6 months (95% CI: 7, not reported) with TAFINLAR 150 mg twice daily + MEKINIST 2 mg once daily; median duration of response of 7.6 months (95% CI: 6, not reported) with TAFINLAR as a single agent1

Important Safety Information for TAFINLAR and MEKINIST when used in combination (cont'd) bilateral and multifocal, occurring in the macular region of the retina. In Trial 2, ophthalmologic examinations including retinal evaluation were performed pretreatment and at regular intervals during treatment. RPED occurred in 2% (1/55) of patients receiving TAFINLAR in combination with MEKINIST. Perform ophthalmological evaluation at any time a patient reports visual disturbances and compare with baseline, if available. If TAFINLAR is used in combination with MEKINIST, do not modify the dose of TAFINLAR. Withhold MEKINIST if RPED is diagnosed. If resolution of the RPED is documented on repeat ophthalmological evaluation within 3 weeks, resume MEKINIST at a lower dose level. Discontinue MEKINIST if no improvement after 3 weeks. Uveitis and Iritis: Uveitis (including iritis) occurred in 1% (6/586) of patients treated with TAFINLAR as a single agent and in 1% (2/202) of patients treated with TAFINLAR in combination with MEKINIST. Symptomatic treatment employed in clinical trials included steroid and mydriatic ophthalmic drops. Monitor patients for visual signs and symptoms of uveitis (eg, change in vision, photophobia, eye pain). If diagnosed, withhold TAFINLAR for up to 6 weeks until uveitis/iritis resolves to Grade 0-1. If TAFINLAR is used in combination with MEKINIST, do not modify the dose of MEKINIST. Interstitial Lung Disease. In clinical trials of MEKINIST (N=329) as a single agent, ILD or pneumonitis occurred in 2% of patients. Withhold MEKINIST in patients presenting with new or progressive pulmonary symptoms and findings including cough, dyspnea, hypoxia, pleural effusion, or infiltrates, pending clinical investigations. Permanently discontinue MEKINIST for patients diagnosed with treatment-related ILD or pneumonitis. If MEKINIST is used in combination with TAFINLAR, do not modify the dose of TAFINLAR. Serious Febrile Drug Reactions. The incidence and severity of pyrexia are increased when TAFINLAR is used in combination

with MEKINIST compared with TAFINLAR as a single agent. In Trial 2, the incidence of fever (serious and non-serious) was 71% (39/55) in patients treated with TAFINLAR in combination with MEKINIST and 26% (14/53) in patients treated with TAFINLAR as a single agent. Serious febrile reactions and fever of any severity complicated by hypotension, rigors, or chills occurred in 25% (14/55) of patients treated with TAFINLAR in combination with MEKINIST compared with 2% (1/53) of patients treated with TAFINLAR as a single agent. Fever was complicated with chills/rigors in 51% (28/55), dehydration in 9% (5/55), renal failure in 4% (2/55), and syncope in 4% (2/55) of patients in Trial 2. In patients treated with TAFINLAR in combination with MEKINIST, the median time to initial onset of fever was 30 days compared with 19 days in patients treated with TAFINLAR as a single agent; the median duration of fever was 6 days with the combination compared with 4 days with TAFINLAR as a single agent. To learn more, visit TAFINLARMEKINISTHCP.com Please see additional Important Safety Information for TAFINLAR and MEKINIST when used in combination on the following pages. Please see Brief Summary of Prescribing Information for TAFINLAR and MEKINIST on the following pages.

(dabrafenib) 50 mg, 75 mg capsules

(trametinib) 0.5 mg, 1 mg, 2 mg tablets

Important Safety Information for TAFINLAR and MEKINIST when used in combination (cont'd) Across clinical trials of TAFINLAR in combination with MEKINIST (N=202), the incidence of pyrexia was 57% (116/202). Withhold TAFINLAR for fever of 101.3ºF or higher. Withhold MEKINIST for any fever higher than 104ºF. Withhold TAFINLAR, and MEKINIST if used in combination, for any serious febrile reaction or fever complicated by hypotension, rigors or chills, dehydration, or renal failure, and evaluate for signs and symptoms of infection. Refer to Table 2 of the Prescribing Information for TAFINLAR for recommended dose modifications. Prophylaxis with antipyretics may be required when resuming TAFINLAR or MEKINIST. Serious Skin Toxicity. In Trial 2, the incidence of any skin toxicity was similar for patients receiving TAFINLAR in combination with MEKINIST (65% [36/55]) compared with patients receiving TAFINLAR as a single agent (68% [36/53]). The median time to onset of skin toxicity in patients treated with TAFINLAR in combination with MEKINIST was 37 days (range: 1 to 225 days) and median time to resolution of skin toxicity was 33 days (range: 3 to 421 days). No patient required dose reduction or permanent discontinuation of TAFINLAR or MEKINIST for skin toxicity. Across clinical trials of TAFINLAR in combination with MEKINIST (N=202), severe skin toxicity and secondary infections of the skin requiring hospitalization occurred in 2.5% (5/202) of patients treated with TAFINLAR in combination with MEKINIST. Withhold TAFINLAR, and MEKINIST if used in combination, for intolerable or severe skin toxicity. TAFINLAR and MEKINIST may be resumed at lower dose levels in patients with improvement or recovery from skin toxicity within 3 weeks. Hyperglycemia. In Trial 2, the incidence of Grade 3 hyperglycemia based on laboratory values was 5% (3/55) in patients treated with TAFINLAR in combination with MEKINIST compared with 2% (1/53) in patients treated with TAFINLAR as a single agent. Monitor serum glucose levels as clinically appropriate when TAFINLAR is used in combination with MEKINIST in patients with pre-existing diabetes or hyperglycemia. Advise patients to report symptoms of severe hyperglycemia, such as excessive thirst or any increase in the volume or frequency of urination. Glucose-6-Phosphate Dehydrogenase Deficiency. TAFINLAR, which contains a sulfonamide moiety, confers a potential risk of hemolytic anemia in patients with glucose-6-phosphate dehydrogenase (G6PD) deficiency. Closely observe patients with G6PD deficiency for signs of hemolytic anemia. Embryofetal Toxicity. TAFINLAR and MEKINIST both can cause fetal harm when administered to a pregnant woman. Advise female patients of reproductive potential to use highly effective non-hormonal contraception during treatment with TAFINLAR and MEKINIST in combination and for 4 months after treatment, since TAFINLAR can render hormonal contraceptives ineffective. Advise patients to contact their healthcare provider if they become pregnant, or if pregnancy is suspected, while taking TAFINLAR and MEKINIST. Most Common Adverse Reactions. The most common (≥20%) adverse reactions in Trial 2 (all grades) for TAFINLAR 150 mg twice daily and MEKINIST 2 mg once daily, TAFINLAR 150 mg

twice daily and MEKINIST 1 mg once daily, and TAFINLAR as a single agent, respectively, included: pyrexia (fever) (71%, 69%, 26%), chills (58%, 50%, 17%), fatigue (53%, 57%, 40%), rash (45%, 43%, 53%), nausea (44%, 46%, 21%), vomiting (40%, 43%, 15%), diarrhea (36%, 26%, 28%), abdominal pain (33%, 24%, 21%), peripheral edema (31%, 28%, 17%), cough (29%, 11%, 21%), headache (29%, 37%, 28%), arthralgia (27%, 44%, 34%), night sweats (24%, 15%, 6%), decreased appetite (22%, 30%, 19%), constipation (22%, 17%, 11%) and myalgia (22%, 24%, 23%). The most common (≥5%) serious adverse reactions in Trial 2 (grades 3 or 4) for TAFINLAR 150 mg twice daily and MEKINIST 2 mg once daily, TAFINLAR 150 mg twice daily and MEKINIST 1 mg once daily, and TAFINLAR as a single agent, respectively, included: renal failure (7%, 0%, 0%), pyrexia (5%, 9%, 0%), back pain (5%, 0%, 2%), and hemorrhage (5%, 0%, 0%). Drug Interactions Effects of Other Drugs on Dabrafenib. Dabrafenib is primarily metabolized by CYP2C8 and CYP3A4. Strong inhibitors of CYP3A4 or CYP2C8 may increase concentrations of dabrafenib and strong inducers of CYP3A4 or CYP2C8 may decrease concentrations of dabrafenib. Substitution of strong inhibitors or strong inducers of CYP3A4 or CYP2C8 is recommended during treatment with TAFINLAR. If concomitant use of strong inhibitors (eg, ketoconazole, nefazodone, clarithromycin, gemfibrozil) or strong inducers (eg, rifampin, phenytoin, carbamazepine, phenobarbital, St John’s wort) of CYP3A4 or CYP2C8 is unavoidable, monitor patients closely for adverse reactions when taking strong inhibitors or loss of efficacy when taking strong inducers. Effects of Dabrafenib on Other Drugs. Dabrafenib induces CYP3A4 and CYP2C9. Dabrafenib decreased the systemic exposures of midazolam (a CYP3A4 substrate), S-warfarin (a CYP2C9 substrate), and R-warfarin (a CYP3A4/CYP1A2 substrate). Monitor international normalized ratio (INR) levels more frequently in patients receiving warfarin during initiation or discontinuation of dabrafenib. Coadministration of TAFINLAR with other substrates of these enzymes, including dexamethasone or hormonal contraceptives, can result in decreased concentrations and loss of efficacy. Substitute for these medications or monitor patients for loss of efficacy if use of these medications is unavoidable. Effects of the Combination of Dabrafenib with Trametinib. Coadministration of TAFINLAR 150 mg twice daily and MEKINIST 2 mg once daily resulted in no clinically relevant pharmacokinetic drug interactions. To learn more, visit TAFINLARMEKINISTHCP.com Please see Brief Summary of Prescribing Information for TAFINLAR and MEKINIST on the following pages. Please see full Prescribing Information and Medication Guide for TAFINLAR and full Prescribing Information and Patient Information Leaflet for MEKINIST.

References: 1. TAFINLAR [package insert]. Research Triangle Park, NC: GlaxoSmithKline; 2014. 2. Flaherty KT, Infante JR, Daud A, et al. N Engl J Med. 2012;367:1694-1703. TAFINLARMEKINISTHCP.com TAFINLAR and MEKINIST are registered trademarks of the GSK group of companies. ©2014 GSK group of companies. All rights reserved. Printed in USA. MEL156R0 July 2014

(dabrafenib) 50 mg, 75 mg capsules

(trametinib) 0.5 mg, 1 mg, 2 mg tablets

BRIEF SUMMARY TAFINLAR® (dabrafenib) capsules, for oral use MEKINIST® (trametinib) tablets, for oral use The following is a brief summary only; see Full Prescribing Information for each product to view the complete product information 1 INDICATIONS AND USAGE TAFINLAR, in combination with MEKINIST, is indicated for the treatment of patients with unresectable or metastatic melanoma with BRAF V600E or V600K mutations, as detected by an FDA-approved test. This indication is based on the demonstration of durable response rate. Improvement in disease-related symptoms or overall survival has not been demonstrated for TAFINLAR in combination with MEKINIST. Limitation of use: TAFINLAR is not indicated for treatment of patients with wild-type BRAF melanoma. 5 WARNINGS AND PRECAUTIONS 5.1 New Primary Malignancies New primary malignancies, cutaneous and non-cutaneous, can occur when TAFINLAR is administered as a single agent or when used in combination with MEKINIST. Cutaneous Malignancies: In Trial 2, the incidence of basal cell carcinoma was increased in patients receiving TAFINLAR in combination with MEKINIST: 9% (5/55) of patients receiving TAFINLAR in combination with MEKINIST compared with 2% (1/53) of patients receiving TAFINLAR as a single agent. The range of time to diagnosis of basal cell carcinoma was 28 to 249 days in patients receiving TAFINLAR in combination with MEKINIST and was 197 days for the patient receiving TAFINLAR as a single agent. Cutaneous squamous cell carcinoma (SCC), including keratoacanthoma, occurred in 7% of patients receiving TAFINLAR in combination with MEKINIST and 19% of patients receiving TAFINLAR as a single agent. The range of time to diagnosis of cuSCC was 136 to 197 days in the combination arm and was 9 to 197 days in the arm receiving TAFINLAR as a single agent. New primary melanoma occurred in 2% (1/53) of patients receiving TAFINLAR as a single agent and in none of the 55 patients receiving TAFINLAR in combination with MEKINIST. Perform dermatologic evaluations prior to initiation of TAFINLAR as a single agent or in combination with MEKINIST, every 2 months while on therapy, and for up to 6 months following discontinuation of TAFINLAR. No dose modifications of TAFINLAR or MEKINIST are required in patients who develop new primary cutaneous malignancies. Non-cutaneous Malignancies: Based on its mechanism of action, TAFINLAR may promote the growth and development of malignancies with activation of RAS through mutation or other mechanisms [see Warnings and Precautions (5.2)]. In patients receiving TAFINLAR in combination with MEKINIST four cases of non-cutaneous malignancies were identified: KRAS mutation-positive pancreatic adenocarcinoma (n = 1), recurrent NRAS mutation-positive colorectal carcinoma (n = 1), head and neck carcinoma (n = 1), and glioblastoma (n = 1). Monitor patients receiving the combination closely for signs or symptoms of non-cutaneous malignancies. Permanently discontinue TAFINLAR for RAS mutation-positive non-cutaneous malignancies. If used in combination with MEKINIST, no dose modification of MEKINIST is required for patients who develop non-cutaneous malignancies. 5.2 Tumor Promotion in BRAF Wild-Type Melanoma In vitro experiments have demonstrated paradoxical activation of MAP-kinase signaling and increased cell proliferation in BRAF wild-type cells which are exposed to BRAF inhibitors. Confirm evidence of BRAF V600E or V600K mutation status prior to initiation of TAFINLAR [see Indications and Usage (1)]. 5.3 Hemorrhage Hemorrhages, including major hemorrhages defined as symptomatic bleeding in a critical area or organ, can occur when TAFINLAR is used in combination with MEKINIST. In Trial 2, treatment with TAFINLAR in combination with MEKINIST resulted in an increased incidence and severity of any hemorrhagic event: 16% (9/55) of patients treated with TAFINLAR in combination with MEKINIST compared with 2% (1/53) of patients treated with TAFINLAR as a single agent. The major hemorrhagic events of intracranial or gastric hemorrhage occurred in 5% (3/55) of patients treated with TAFINLAR in combination with MEKINIST compared with none of the 53 patients treated with TAFINLAR as a single agent. Intracranial hemorrhage was fatal in 4% (2/55) of patients receiving TAFINLAR in combination with MEKINIST. Permanently discontinue TAFINLAR and MEKINIST for all Grade 4 hemorrhagic events and for any Grade 3 hemorrhagic events that do not improve. Withhold TAFINLAR for Grade 3 hemorrhagic events; if improved resume at a lower dose level. Withhold MEKINIST for up to 3 weeks for Grade 3 hemorrhagic events; if improved, resume at a lower dose level. 5.4 Venous Thromboembolism Venous thromboembolism can occur when TAFINLAR is used in combination with MEKINIST. In Trial 2, treatment with TAFINLAR in combination with MEKINIST resulted in an increased incidence of deep venous thrombosis (DVT) and pulmonary embolism (PE): 7% (4/55) of patients treated with TAFINLAR in combination with MEKINIST compared with none of the 53 patients treated with TAFINLAR as a single agent. Pulmonary embolism was fatal in 2% (1/55) of patients receiving TAFINLAR in combination with MEKINIST. Advise patients to immediately seek medical care if they develop symptoms of DVT or PE, such as shortness of breath, chest pain, or arm or leg swelling. Permanently discontinue TAFINLAR and MEKINIST for life-threatening PE. Withhold MEKINIST and continue TAFINLAR at the same dose for uncomplicated DVT or PE; if improved within 3 weeks, MEKINIST may be resumed at a lower dose level. 5.5 Cardiomyopathy Cardiomyopathy can occur when TAFINLAR is used in combination with MEKINIST and with

MEKINIST as a single agent [refer to Full Prescribing Information for MEKINIST]. In Trial 2, cardiomyopathy occurred in 9% (5/55) of patients treated with TAFINLAR in combination with MEKINIST and in none of patients treated with TAFINLAR as a single agent. The median time to onset of cardiomyopathy in patients treated with TAFINLAR in combination with MEKINIST was 86 days (range: 27 to 253 days). Cardiomyopathy was identified within the first month of treatment with TAFINLAR in combination with MEKINIST in two of five patients. Development of cardiomyopathy resolved in all five patients following dose reduction (4/55) and/or dose interruption (1/55). Across clinical trials of TAFINLAR administered in combination with MEKINIST (N = 202), 8% of patients developed evidence of cardiomyopathy (decrease in LVEF below institutional lower limits of normal with an absolute decrease in LVEF ≥10% below baseline). Two percent demonstrated a decrease in LVEF below institutional lower limits of normal with an absolute decrease in LVEF of ≥20% below baseline. Assess LVEF by echocardiogram or multigated acquisition (MUGA) scan before initiation of TAFINLAR in combination with MEKINIST, one month after initiation, and then at 2- to 3-month intervals while on treatment with the combination. Withhold treatment with MEKINIST and continue TAFINLAR at the same dose if absolute LVEF value decreases by 10% from pretreatment values and is less than the lower limit of normal. For symptomatic cardiomyopathy or persistent, asymptomatic LV dysfunction that does not resolve within 4 weeks, permanently discontinue MEKINIST and withhold TAFINLAR. Resume TAFINLAR at the same dose level upon recovery of cardiac function. 5.6 Ocular Toxicities Retinal Vein Occlusion (RVO): Across all clinical trials of MEKINIST, the incidence of RVO was 0.2% (4/1,749). RVO may lead to macular edema, decreased visual function, neovascularization, and glaucoma. Urgently (within 24 hours) perform ophthalmological evaluation for patient-reported loss of vision or other visual disturbances. Permanently discontinue MEKINIST in patients with documented RVO. If MEKINIST is used in combination with TAFINLAR, do not modify TAFINLAR dose. Retinal Pigment Epithelial Detachment (RPED): Retinal pigment epithelial detachments (RPED) can occur when TAFINLAR is used in combination with MEKINIST and with MEKINIST as a single agent [refer to Full Prescribing Information for MEKINIST]. Retinal detachments resulting from MEKINIST are often bilateral and multifocal, occurring in the macular region of the retina. In Trial 2, ophthalmologic examinations including retinal evaluation were performed pretreatment and at regular intervals during treatment. RPED occurred in 2% (1/55) of patients receiving TAFINLAR in combination with MEKINIST. Across clinical trials of TAFINLAR administered in combination with MEKINIST (N = 202), the incidence of RPED was 1% (2/202). Perform ophthalmological evaluation at any time a patient reports visual disturbances and compare with baseline, if available. If TAFINLAR is used in combination with MEKINIST, do not modify the dose of TAFINLAR. Withhold MEKINIST if RPED is diagnosed. If resolution of the RPED is documented on repeat ophthalmological evaluation within 3 weeks, resume MEKINIST at a lower dose level. Discontinue MEKINIST if no improvement after 3 weeks. Uveitis and Iritis: Uveitis and iritis can occur when TAFINLAR is administered as a single agent or when used in combination with MEKINIST. Uveitis (including iritis) occurred in 1% (6/586) of patients treated with TAFINLAR as a single agent and uveitis occurred in 1% (2/202) of patients treated with TAFINLAR in combination with MEKINIST. Symptomatic treatment employed in clinical trials included steroid and mydriatic ophthalmic drops. Monitor patients for visual signs and symptoms of uveitis (e.g., change in vision, photophobia, eye pain). If diagnosed, withhold TAFINLAR for up to 6 weeks until uveitis/iritis resolves to Grade 0-1. If TAFINLAR is used in combination with MEKINIST, do not modify the dose of MEKINIST. 5.6 Interstitial Lung Disease In clinical trials of MEKINIST (N = 329) as a single agent, ILD or pneumonitis occurred in 2% of patients. In Trial 1, 2% (5/211) of patients treated with MEKINIST developed ILD or pneumonitis; all five patients required hospitalization. The median time to first presentation of ILD or pneumonitis was 160 days (range: 60 to 172 days). Withhold MEKINIST in patients presenting with new or progressive pulmonary symptoms and findings including cough, dyspnea, hypoxia, pleural effusion, or infiltrates, pending clinical investigations. Permanently discontinue MEKINIST for patients diagnosed with treatment-related ILD or pneumonitis. If MEKINIST is used in combination with TAFINLAR, do not modify the dose of TAFINLAR. 5.7 Serious Febrile Reactions The incidence and severity of pyrexia are increased when TAFINLAR is used in combination with MEKINIST compared with TAFINLAR as a single agent [see Adverse Reactions (6.1)]. In Trial 2, the incidence of fever (serious and non-serious) was 71% (39/55) in patients treated with TAFINLAR in combination with MEKINIST and 26% (14/53) in patients treated with TAFINLAR as a single agent. Serious febrile reactions and fever of any severity complicated by hypotension, rigors or chills occurred in 25% (14/55) of patients treated with TAFINLAR in combination with MEKINIST compared with 2% (1/53) of patients treated with TAFINLAR as a single agent. Fever was complicated with chills/rigors in 51% (28/55), dehydration in 9% (5/55), renal failure in 4% (2/55), and syncope in 4% (2/55) of patients in Trial 2. In patients treated with TAFINLAR in combination with MEKINIST, the median time to initial onset of fever was 30 days compared with 19 days in patients treated with TAFINLAR as a single agent; the median duration of fever was 6 days with the combination compared with 4 days with TAFINLAR as a single agent. Across clinical trials of TAFINLAR administered in combination with MEKINIST (N = 202), the incidence of pyrexia was 57% (116/202). Withhold TAFINLAR for fever of 101.3°F or higher. Withhold MEKINIST for any fever higher than 104°F.

Withhold TAFINLAR, and MEKINIST if used in combination, for any serious febrile reaction or fever complicated by hypotension, rigors or chills, dehydration, or renal failure and evaluate for signs and symptoms of infection. Refer to Table 2 for recommended dose modifications for adverse reactions. Prophylaxis with antipyretics may be required when resuming TAFINLAR or MEKINIST. 5.8 Serious Skin Toxicity Serious skin toxicity can occur when TAFINLAR is used in combination with MEKINIST and with MEKINIST as a single agent [refer to Full Prescribing Information for MEKINIST]. In Trial 2, the incidence of any skin toxicity was similar for patients receiving TAFINLAR in combination with MEKINIST (65% [36/55]) compared with patients receiving TAFINLAR as a single agent (68% [36/53]). The median time to onset of skin toxicity in patients treated with TAFINLAR in combination with MEKINIST was 37 days (range: 1 to 225 days) and median time to resolution of skin toxicity was 33 days (range: 3 to 421 days). No patient required dose reduction or permanent discontinuation of TAFINLAR or MEKINIST for skin toxicity. Across clinical trials of TAFINLAR in combination with MEKINIST (N = 202), severe skin toxicity and secondary infections of the skin requiring hospitalization occurred in 2.5% (5/202) of patients treated with TAFINLAR in combination with MEKINIST. Withhold TAFINLAR, and MEKINIST if used in combination, for intolerable or severe skin toxicity. TAFINLAR and MEKINIST may be resumed at lower dose levels in patients with improvement or recovery from skin toxicity within 3 weeks. 5.9 Hyperglycemia Hyperglycemia can occur when TAFINLAR is administered as a single agent or when used in combination with MEKINIST. In Trial 2, the incidence of Grade 3 hyperglycemia based on laboratory values was 5% (3/55) in patients treated with TAFINLAR in combination with MEKINIST compared with 2% (1/53) in patients treated with TAFINLAR as a single agent. Monitor serum glucose levels as clinically appropriate when TAFINLAR is administered as a single agent or when used in combination with MEKINIST in patients with pre-existing diabetes or hyperglycemia. Advise patients to report symptoms of severe hyperglycemia such as excessive thirst or any increase in the volume or frequency of urination. 5.10 Glucose-6-Phosphate Dehydrogenase Deficiency TAFINLAR, which contains a sulfonamide moiety, confers a potential risk of hemolytic anemia in patients with glucose-6-phosphate dehydrogenase (G6PD) deficiency. Closely observe patients with G6PD deficiency for signs of hemolytic anemia. 5.11 Embryofetal Toxicity TAFINLAR and MEKINIST both can cause fetal harm when administered to a pregnant woman. Advise female patients of reproductive potential to use a highly effective non-hormonal contraception during treatment with TAFINLAR and MEKINIST in combination and for 4 months after treatment, since TAFINLAR can render hormonal contraceptives ineffective. Advise patients to contact their healthcare provider if they become pregnant, or if pregnancy is suspected, while taking TAFINLAR or MEKINIST. 6 ADVERSE REACTIONS The following adverse reactions are discussed in greater detail in another section of the label: • New Primary Malignancies [see Warnings and Precautions (5.1)] • Tumor Promotion in BRAF Wild-Type Melanoma [see Warnings and Precautions (5.2)] • Hemorrhage [see Warnings and Precautions (5.3)] • Venous Thromboembolism [see Warnings and Precautions (5.4)] • Cardiomyopathy [see Warnings and Precautions (5.5)] • Ocular Toxicities [see Warnings and Precautions (5.6)] • Interstitial Lung Disease [see Warnings and Precautions (5.6)] • Serious Febrile Reactions [see Warnings and Precautions (5.7)] • Serious Skin Toxicity [see Warnings and Precautions (5.8)] • Hyperglycemia [see Warnings and Precautions (5.9)] • Glucose-6-Phosphate Dehydrogenase Deficiency [see Warnings and Precautions (5.10)] 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The data described in the Warnings and Precautions section and below reflect exposure to TAFINLAR as a single agent and in combination with MEKINIST. BRAF V600E or V600K Unresectable or Metastatic Melanoma: The safety of TAFINLAR in combination with MEKINIST was evaluated in Trial 2 and other trials consisting of a total of 202 patients with BRAF V600 mutation-positive unresectable or metastatic melanoma who received TAFINLAR 150 mg orally twice daily in combination with MEKINIST 2 mg orally once daily until disease progression or unacceptable toxicity. Among these 202 patients, 66 (33%) were exposed to TAFINLAR and 68 (34%) were exposed to MEKINIST for greater than 6 to 12 months while 40 (20%) were exposed to TAFINLAR and 36 (18%) were exposed to MEKINIST for greater than one year. The median age was 54 years, 57% were male, and >99% were white. Table 5 presents adverse reactions from Trial 2, a multicenter, open-label, randomized trial of 162 patients with BRAF V600E or V600K mutation-positive melanoma receiving TAFINLAR 150 mg

twice daily in combination with MEKINIST 2 mg orally once daily (n = 55), TAFINLAR 150 mg orally twice daily in combination with MEKINIST 1 mg once daily (n = 54), and TAFINLAR as a single agent 150 mg orally twice daily (n = 53) [see Clinical Studies (14.2)]. Patients with abnormal LVEF, history of acute coronary syndrome within 6 months, current evidence of Class II or greater congestive heart failure (New York Heart Association), history RVO or RPED, QTc interval ≥480 msec, treatment refractory hypertension, uncontrolled arrhythmias, history of pneumonitis or interstitial lung disease, or a known history of G6PD deficiency were excluded. The median duration of treatment was 10.9 months for both TAFINLAR and MEKINIST (2-mg orally once-daily treatment group) when used in combination, 10.6 months for both TAFINLAR and MEKINIST (1-mg orally once-daily treatment group) when used in combination, and 6.1 months for TAFINLAR as a single agent. In Trial 2, 13% of patients receiving TAFINLAR in combination with MEKINIST experienced adverse reactions resulting in permanent discontinuation of trial medication(s). The most common adverse reaction resulting in permanent discontinuation was pyrexia (4%). Adverse reactions led to dose reductions in 49% and dose interruptions in 67% of patients treated with TAFINLAR in combination with MEKINIST. Pyrexia, chills, and nausea were the most common reasons cited for dose reductions and pyrexia, chills, and decreased ejection fraction were the most common reasons cited for dose interruptions of TAFINLAR and MEKINIST when used in combination. Table 5. Common Adverse Drug Reactions Occurring in ≥10% at (All Grades) or ≥5% (Grades 3 or 4) of Patients Treated With TAFINLAR in Combination With MEKINIST in Trial 2 TAFINLAR plus TAFINLAR plus MEKINIST 2 mg MEKINIST 1 mg TAFINLAR N = 55 N = 54 N = 53 All All Grades Adverse Reactions Gradesa 3 and 4 Gradesa General disorders and administrative site conditions Pyrexia 71 5 69 Chills 58 2 50 Fatigue 53 4 57 b 31 0 28 Edema peripheral Skin and subcutaneous tissue disorders 45 0 43 Rashc Night Sweats 24 0 15 Dry skin 18 0 9 Dermatitis acneiform 16 0 11 Actinic keratosis 15 0 7 Erythema 15 0 6 Pruritus 11 0 11 Gastrointestinal disorders Nausea 44 2 46 Vomiting 40 2 43 Diarrhea 36 2 26 33 2 24 Abdominal paind Constipation 22 0 17 Dry mouth 11 0 11 Nervous system disorders Headache 29 0 37 Dizziness 16 0 13 Respiratory, thoracic, and mediastinal disorders Cough 29 0 11 Oropharyngeal pain 13 0 7 Musculoskeletal, connective tissue, and bone disorders Arthralgia 27 0 44 Myalgia 22 2 24 Back pain 18 5 11 Muscle spasms 16 0 2 Pain in extremity 16 0 11 Metabolism and nutritional disorders Decreased appetite 22 0 30 Dehydration 11 0 6 Psychiatric Disorders Insomnia 18 0 11 Vascular disorders 16 5 11 Hemorrhagee Infections and infestations Urinary tract infection 13 2 6 Renal and urinary disorders 7 7 2 Renal failuref

Grades 3 and 4

All Gradesa

Grades 3 and 4

9 2 2 0

26 17 40 17

0 0 6 0

2 0 0 0 0 0 0

53 6 6 4 9 2 13

0 0 0 0 0 0 0

6 4 0 2 2 0

21 15 28 21 11 6

0 0 0 2 0 0

2 0

28 9

0 0

21 0

0 0

0 0 0 0 2

34 23 11 4 19

0 2 2 0 0

0 2

19 2

0 0

National Cancer Institute Common Terminology Criteria for Adverse Events, version 4. Includes the following terms: peripheral edema, edema, and lymphedema. c Includes the following terms: rash, rash generalized, rash pruritic, rash erythematous, rash papular, rash vesicular, rash macular, and rash maculo-papular. d Includes the following terms: abdominal pain, abdominal pain upper, abdominal pain lower, and abdominal discomfort. e Includes the following terms: brain stem hemorrhage, cerebral hemorrhage, gastric hemorrhage, epistaxis, gingival hemorrhage, hematuria, vaginal hemorrhage, hemorrhage intracranial, eye hemorrhage, and vitreous hemorrhage. f Includes the following terms: renal failure and renal failure acute. Other clinically important adverse reactions (N = 202) observed in <10% of patients treated with TAFINLAR in combination with MEKINIST were: Eye Disorders: Vision blurred, transient blindness. Gastrointestinal Disorders: Stomatitis, pancreatitis. General Disorders and Administration Site Conditions: Asthenia. Infections and Infestations: Cellulitis, folliculitis, paronychia, rash pustular. Neoplasms Benign, Malignant, and Unspecified (including cysts and polyps): Skin papilloma. Skin and Subcutaneous Tissue Disorders: Palmar-plantar erythrodysesthesia syndrome, hyperkeratosis, hyperhidrosis. Vascular Disorders: Hypertension. Table 6. Treatment-Emergent Laboratory Abnormalities Occurring at ≥10% (All Grades) or ≥2% (Grades 3 or 4)] of Patients Treated With TAFINLAR in Combination With MEKINIST in Trial 2 TAFINLAR plus TAFINLAR plus MEKINIST 2 mg MEKINIST 1 mg TAFINLAR N = 55 N = 54 N = 53 a

All All All Grades Grades Grades Grades 3 and 4 Grades 3 and 4 Grades 3 and 4a Tests Hematology Leukopenia 62 5 46 4 21 0 Lymphopenia 55 22 59 19 40 6 Neutropenia 55 13 37 2 9 2 Anemia 55 4 46 7 28 0 Thrombocytopenia 31 4 31 2 8 0 Liver Function Tests Increased AST 60 5 54 0 15 0 Increased alkaline 60 2 67 6 26 2 phosphatase Increased ALT 42 4 35 4 11 0 Hyperbilirubinemia 15 0 7 4 0 0 Chemistry Hyperglycemia 58 5 67 6 49 2 Increased GGT 56 11 54 17 38 2 Hyponatremia 55 11 48 15 36 2 Hypoalbuminemia 53 0 43 2 23 0 Hypophosphatemia 47 5 41 11 40 0 Hypokalemia 29 2 15 2 23 6 Increased creatinine 24 5 20 2 9 0 Hypomagnesemia 18 2 2 0 6 0 Hyperkalemia 18 0 22 0 15 4 Hypercalcemia 15 0 19 2 4 0 Hypocalcemia 13 0 20 0 9 0 a No Grade 4 events were reported in patients receiving TAFINLAR as a single agent. ALT = Alanine aminotransferase; AST = Aspartate aminotransferase; GGT = Gamma glutamyltransferase. QT Prolongation: In Trial 2, QTcF prolongation to >500 msec occurred in 4% (2/55) of patients treated with TAFINLAR in combination with MEKINIST and in 2% (1/53) of patients treated with TAFINLAR as a single agent. The QTcF was increased more than 60 msec from baseline in 13% (7/55) of patients treated with TAFINLAR in combination with MEKINIST and 2% (1/53) of patients treated with TAFINLAR as a single agent. 7 DRUG INTERACTIONS 7.1 Effects of Other Drugs on Dabrafenib Dabrafenib is primarily metabolized by CYP2C8 and CYP3A4. Strong inhibitors of CYP3A4 or CYP2C8 may increase concentrations of dabrafenib and strong inducers of CYP3A4 or CYP2C8 may decrease concentrations of dabrafenib [see Clinical Pharmacology (12.3)]. Substitution of strong inhibitors or strong inducers of CYP3A4 or CYP2C8 is recommended during treatment with TAFINLAR. If concomitant use of strong inhibitors (e.g., ketoconazole, nefazodone, clarithromycin, gemfibrozil) or strong inducers (e.g., rifampin, phenytoin, carbamazepine, phenobarbital, St John’s wort) of CYP3A4 or CYP2C8 is unavoidable, monitor patients closely for adverse reactions when taking strong inhibitors or loss of efficacy when taking strong inducers.

7.2 Effects of Dabrafenib on Other Drugs Dabrafenib induces CYP3A4 and CYP2C9. Dabrafenib decreased the systemic exposures of midazolam (a CYP3A4 substrate), S-warfarin (a CYP2C9 substrate), and R-warfarin (a CYP3A4/CYP1A2 substrate) [see Clinical Pharmacology (12.3)]. Monitor international normalized ratio (INR) levels more frequently in patients receiving warfarin during initiation or discontinuation of dabrafenib. Coadministration of TAFINLAR with other substrates of these enzymes, including dexamethasone or hormonal contraceptives, can result in decreased concentrations and loss of efficacy [see Use in Specific Populations (8.1, 8.6)]. Substitute for these medications or monitor patients for loss of efficacy if use of these medications is unavoidable. 7.3 Trametinib Coadministration of TAFINLAR 150 mg twice daily and trametinib 2 mg once daily resulted in no clinically relevant pharmacokinetic drug interactions [see Clinical Pharmacology (12.3)]. 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy TAFINLAR Pregnancy Category D Risk Summary: Based on its mechanism of action, TAFINLAR can cause fetal harm when administered to a pregnant woman. Dabrafenib was teratogenic and embryotoxic in rats at doses three times greater than the human exposure at the recommended clinical dose of 150 mg twice daily based on AUC. If this drug is used during pregnancy or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to a fetus [see Warnings and Precautions (5.11)]. Animal Data: In a combined female fertility and embryofetal development study in rats, developmental toxicity consisted of embryo-lethality, ventricular septal defects, and variation in thymic shape at a dabrafenib dose of 300 mg/kg/day (approximately three times the human exposure at the recommended dose based on AUC). At doses of 20 mg/kg/day or greater (equivalent to the human exposure at the recommended dose based on AUC), rats demonstrated delays in skeletal development and reduced fetal body weight. MEKINIST Pregnancy Category D Risk Summary: MEKINIST can cause fetal harm when administered to a pregnant woman. Trametinib was embryotoxic and abortifacient in rabbits at doses greater than or equal to those resulting in exposures approximately 0.3 times the human exposure at the recommended clinical dose. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus [see Warnings and Precautions (5.10)]. Animal Data: In reproductive toxicity studies, administration of trametinib to rats during the period of organogenesis resulted in decreased fetal weights at doses greater than or equal to 0.031 mg/kg/day (approximately 0.3 times the human exposure based on AUC at the recommended dose). In rats, at a dose resulting in exposures 1.8-fold higher than the human exposure at the recommended dose, there was maternal toxicity and an increase in post-implantation loss. In pregnant rabbits, administration of trametinib during the period of organogenesis resulted in decreased fetal body weight and increased incidence of variations in ossification at doses greater than or equal to 0.039 mg/kg/day (approximately 0.08 times the human exposure at the recommended dose based on AUC). In rabbits administered trametinib at 0.15 mg/kg/day (approximately 0.3 times the human exposure at the recommended dose based on AUC) there was an increase in postimplantation loss, including total loss of pregnancy, compared with control animals. 8.3 Nursing Mothers It is not known whether this drug is present in human milk. Because many drugs are present in human milk and because of the potential for serious adverse reactions from TAFINLAR and MEKINIST in nursing infants, a decision should be made whether to discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother. 8.4 Pediatric Use The safety and effectiveness of TAFINLAR and MEKINIST have not been established in pediatric patients. In a repeat-dose toxicity study of dabrafenib in juvenile rats, an increased incidence of kidney cysts and tubular deposits were noted at doses as low as 0.2 times the human exposure at the recommended adult dose based on AUC. Additionally, forestomach hyperplasia, decreased bone length, and early vaginal opening were noted at doses as low as 0.8 times the human exposure at the recommended adult dose based on AUC. 8.5 Geriatric Use One hundred and twenty-six (22%) of 586 patients in clinical trials of TAFINLAR administered as a single agent and 40 (21%) of the 187 patients receiving TAFINLAR in Trial 1 were ≥65 years of age. No overall differences in the effectiveness or safety of TAFINLAR were observed in the elderly in Trial 1. Across all clinical trials of TAFINLAR administered in combination with MEKINIST, there was an insufficient number of patients aged 65 years and over to determine whether they respond differently from younger patients. In Trial 2, 11 patients (20%) were 65 years of age and older, and 2 patients (4%) were 75 years of age and older. 8.6 Females and Males of Reproductive Potential TAFINLAR Contraception: Females: Advise female patients of reproductive potential to use highly effective contraception during treatment and for at least 2 weeks after the last dose of TAFINLAR or at least 4 months after the last dose of TAFINLAR taken in combination with MEKINIST. Counsel patients to use a non-hormonal method of contraception since TAFINLAR can render hormonal contraceptives

ineffective. Advise patients to contact their healthcare provider if they become pregnant, or if pregnancy is suspected, while taking TAFINLAR [see Warnings and Precautions (5.11), Drug Interactions (7.1), Use in Specific Populations (8.1)]. Infertility: Females: Increased follicular cysts and decreased corpora lutea were observed in female rats treated with trametinib. Advise female patients of reproductive potential that TAFINLAR taken in combination with MEKINIST may impair fertility in female patients. Males: Effects on spermatogenesis have been observed in animals. Advise male patients of the potential risk for impaired spermatogenesis, and to seek counseling on fertility and family planning options prior to starting treatment with TAFINLAR [see Nonclinical Toxicology (13.1)]. MEKINIST Contraception: Females: MEKINIST can cause fetal harm when administered during pregnancy. Advise female patients of reproductive potential to use highly effective contraception during treatment and for 4 months after the last dose of MEKINIST. When MEKINIST is used in combination with TAFINLAR, counsel patients to use a non-hormonal method of contraception since dabrafenib can render hormonal contraceptives ineffective. Advise patients to contact their healthcare provider if they become pregnant, or if pregnancy is suspected, while taking MEKINIST [see Use in Specific Populations (8.1)]. Infertility: Females: MEKINIST may impair fertility in female patients [see Nonclinical Toxicology (13.1)]. Males: Effects on spermatogenesis have been observed in animals treated with dabrafenib. Advise male patients of the potential risk for impaired spermatogenesis, and to seek counseling on fertility and family planning options prior to starting treatment with MEKINIST in combination with TAFINLAR. 8.7 Hepatic Impairment TAFINLAR No formal pharmacokinetic trial in patients with hepatic impairment has been conducted. Dose adjustment is not recommended for patients with mild hepatic impairment based on the results of the population pharmacokinetic analysis. As hepatic metabolism and biliary secretion are the primary routes of elimination of dabrafenib and its metabolites, patients with moderate to severe hepatic impairment may have increased exposure. An appropriate dose has not been established for patients with moderate to severe hepatic impairment [see Clinical Pharmacology (12.3)]. MEKINIST No formal clinical trial has been conducted to evaluate the effect of hepatic impairment on the pharmacokinetics of trametinib. No dose adjustment is recommended in patients with mild hepatic impairment based on a population pharmacokinetic analysis [see Clinical Pharmacology (12.3)]. The appropriate dose of MEKINIST has not been established in patients with moderate or severe hepatic impairment. 8.8 Renal Impairment No formal pharmacokinetic trial for TAFINLAR or MEKINIST has been conducted in patients with renal impairment. Dose adjustment is not recommended for patients with mild or moderate renal impairment based on the results of the population pharmacokinetic analysis. An appropriate dose has not been established for patients with severe renal impairment [see Clinical Pharmacology (12.3)]. 10 OVERDOSAGE There is no information on overdosage of TAFINLAR. Since dabrafenib is highly bound to plasma proteins, hemodialysis is likely to be ineffective in the treatment of overdose with TAFINLAR. There were no reported cases of overdosage with MEKINIST. The highest doses of MEKINIST evaluated in clinical trials were 4 mg orally once daily and 10 mg administered orally once daily on 2 consecutive days followed by 3 mg once daily. In seven patients treated on one of these two schedules, there were two cases of retinal pigment epithelial detachments for an incidence of 28%. Since trametinib is highly bound to plasma proteins, hemodialysis is likely to be ineffective in the treatment of overdose with MEKINIST. 17 PATIENT COUNSELING INFORMATION See FDA-approved patient labeling (Medication Guide) for TAFINLAR. See FDA-approved patient labeling (Patient Information) for MEKINIST. Inform patients of the following: • Evidence of BRAF V600E mutation in the tumor specimen is necessary to identify patients for whom treatment with TAFINLAR as a single agent is indicated and evidence of BRAF V600E or V600K mutation in tumor specimens is necessary to identify patients for whom treatment with TAFINLAR in combination with MEKINIST is indicated. • TAFINLAR administered in combination with MEKINIST can result in the development of new primary cutaneous and non-cutaneous malignancies. Advise patients to contact their doctor immediately for any new lesions, changes to existing lesions on their skin, or other signs and symptoms of malignancies [see Warnings and Precautions (5.1)]. • TAFINLAR administered in combination with MEKINIST increases the risk of intracranial and gastrointestinal hemorrhage. Advise patients to contact their healthcare provider to seek immediate medical attention for signs or symptoms of unusual bleeding or hemorrhage [see Warnings and Precautions (5.3)]. • TAFINLAR administered in combination with MEKINIST increases the risks of pulmonary embolism and deep venous thrombosis. Advise patients to seek immediate medical attention for sudden onset of difficulty breathing, leg pain, or swelling [see Warnings and Precautions (5.4)]. • TAFINLAR administered in combination with MEKINIST can cause cardiomyopathy. Advise patients to immediately report any signs or symptoms of heart failure to their healthcare provider [see Warnings and Precautions (5.5)]. • TAFINLAR and MEKINIST can cause visual disturbances that can lead to blindness. Advise patients to

contact their healthcare provider if they experience any changes in their vision [see Warnings and Precautions (5.6)]. • MEKINIST can cause interstitial lung disease (or pneumonitis). Advise patients to contact their healthcare provider as soon as possible if they experience signs such as cough or dyspnea [see Warnings and Precautions (5.6)]. • TAFINLAR administered as a single agent and in combination with MEKINIST can cause pyrexia including serious febrile reactions. Inform patients that the incidence and severity of pyrexia are increased when TAFINLAR is given in combination with MEKINIST. Instruct patients to contact their doctor if they develop fever while taking TAFINLAR [see Warnings and Precautions (5.7)]. • TAFINLAR in combination with MEKINIST can cause serious skin toxicities which may require hospitalization. Advise patients to contact their healthcare provider for progressive or intolerable rash [see Warnings and Precautions (5.8)]. • TAFINLAR can impair glucose control in diabetic patients resulting in the need for more intensive hypoglycemic treatment. Advise patients to contact their doctor to report symptoms of severe hyperglycemia [see Warnings and Precautions (5.9)]. • TAFINLAR may cause hemolytic anemia in patients with glucose-6-phosphate dehydrogenase (G6PD) deficiency. Advise patients with known G6PD deficiency to contact their doctor to report signs or symptoms of anemia or hemolysis [see Warnings and Precautions (5.10)]. • MEKINIST causes hypertension. Advise patients that they need to undergo blood pressure monitoring and to contact their healthcare provider if they develop symptoms of hypertension such as severe headache, blurry vision, or dizziness. • MEKINIST often causes diarrhea which may be severe in some cases. Inform patients of the need to contact their healthcare provider if severe diarrhea occurs during treatment. • TAFINLAR and MEKINIST can cause fetal harm if taken during pregnancy. Instruct female patients to use non-hormonal, highly effective contraception during treatment and for 4 months after discontinuation of treatment with TAFINLAR in combination with MEKINIST. Advise patients to contact their doctor if they become pregnant, or if pregnancy is suspected, while taking TAFINLAR and MEKINIST [see Warnings and Precautions (5.11), Use in Specific Populations (8.1)]. • Nursing infants may experience serious adverse reactions if the mother is taking TAFINLAR or MEKINIST during breastfeeding. Advise breastfeeding mothers to discontinue nursing while taking TAFINLAR or MEKINIST [see Use in Specific Populations (8.3)]. • Male patients are at an increased risk for impaired spermatogenesis [see Use in Specific Populations (8.6)]. • TAFINLAR and MEKINIST should be taken either at least 1 hour before or at least 2 hours after a meal. TAFINLAR is a registered trademark of GlaxoSmithKline. MEKINIST is a registered trademark of GlaxoSmithKline.

GlaxoSmithKline Research Triangle Park, NC 27709

ASCOPost.com | APRIL 25, 2015

PAGE 13

National Comprehensive Cancer Network Annual Conference Reflections

20 Years of NCCN: The Best Is Yet to Come A Conversation With Robert W. Carlson, MD By Caroline Helwick

Robert W. Carlson, MD

s the National Comprehensive Cancer Network (NCCN) celebrates its 20th year, The ASCO Post asked its Chief Executive Officer, Robert W. Carlson, MD, to reflect on the organization’s accomplishments, mission, and future and on the role he may have played in its success.

The Early Years You became CEO in January 2013, but you’ve been involved in NCCN since its inception. What were those first years like? NCCN was founded by a group of visionary leaders who came together 20 years ago to assure access of patients to high-quality cancer care. Interestingly, they were from 13 different academic centers that traditionally competed for funding, faculty, students, and patients—now working together. That commitment and focus on the patient were central to the founding of NCCN, and it continues today, with our alliance of 26 cancer centers. We developed our first set of NCCN Guidelines in Oncology in 1996, as a result of tremendous threats we saw to the practice of oncology, especially in academic centers. The health maintenance organization movement was in full swing. There were forces aimed at dictating to physicians and patients the care that would be provided. The NCCN member institutions saw clinical practice guidelines as a means of assuring that cancer centers would have an optimal role in deciding what that care should be. Our aim was to convince payers that we provided effective and efficient care. What were those original Guidelines like? The first Guidelines were both complicated and visionary and, compared to the current Guidelines, very simple. The

scientific basis and rigor with which they were developed have rapidly evolved since then. For example, the original 7 adult panel Guidelines were backed up by a total of 104 references. In those same 7 Guidelines, for the current versions, we now cite 3,772 references. Some of our initial decisions have proven to be visionary. We provided the Guidelines free of charge on the Internet. As a result, in 2014 alone, there were 6 million downloads. Our decision to publish the Guidelines seems so logical now, but the original intent was for member institutions to use them as a business advantage. We included in our original panels not only experts from multiple disciplines, but fully empowered patient advocates who kept the Guidelines grounded to the patients’ needs. We displayed our recommendations graph-

transplant advocates, “This meeting is over” and headed for the door. Rodger Winn, head of the Guidelines program, locked the door in front of me and said, “We are not leaving.” Somehow, we went back to the table and formed a solution. Ultimately, transplant was not added to the main pathway, but we indicated that very high-risk or metastatic patients were candidates for clinical trials. This outcome ultimately proved to be fully appropriate. This story is really about the patient. Although the bone marrow transplant lacked high-level evidence, we still gave patients access to a potentially important treatment. This story also illustrates a continuing theme for our organization: assessment of the evidence by experts, patient access, high-quality care, and patient-centric

Our Guidelines and the NCCN Drugs & Biologics Compendium are used by more payers than any other documents. They have a breadth and depth that others lack and are efficient enough to be used at the point of care. —Robert W. Carlson, MD

ically, across the continuum of care, which was logical, intuitive, and critical to their rapid adoption and clinical usefulness. And we assigned our recommendations categories of evidence, which differentiated them as scientific, evidence-based documents. Some of these decisions proved to be inflection points in the history of the NCCN.

Assessment of Evidence by Experts Back then, and now, not all recommendations are made without a sprinkling of controversy, right? That’s very true. Remember the controversy surrounding the use of highdose chemotherapy with bone marrow transplant in high-risk or metastatic breast cancer? There were major differences of opinion between the NCCN breast cancer panel and bone marrow transplant panel, and when the breast cancer panel declined to place this in the original Guidelines, there was an outcry. Our two panels met (I was on the breast cancer panel) and had a contentious and heated discussion. I remember thinking we would never reach consensus. At one point, I said to the

decisions. They continue to be central to the heartbeat of the NCCN.

Informing Coverage Decisions What makes the NCCN Guidelines stand apart from others? Our Guidelines and the NCCN Drugs & Biologics Compendium are used by more payers than any other documents. They have a breadth and depth that others lack and are efficient enough to be used at the point of care. In 2008, the Centers for Medicare and Medicaid and UnitedHealthcare recognized our Guidelines and Compendium as a means of informing their coverage decisions. This was a big change! When NCCN was founded, payers were challenging physicians and telling them what they would cover. Now, major payers were saying, “We think you got it right. Use your Guidelines, and you can tell us what to cover.” That was remarkable!

Future Initiatives What new initiatives can the oncology world look forward to from NCCN? As strong and as good as the Guidelines may be, we are not satisfied with where we are. Over the next few years,

you will see us develop (working with IBM) a digitally based database that will move beyond the current graphical document, which cannot be processed by a computer-based system. This will give us the ability to incorporate the Guidelines into clinical decision-making systems to an extent that we have not been able to do with the graphical display. We are well along in this process and hope to debut this in 2016. You will also start seeing enhanced descriptions of efficacy, safety, data quality, and cost in the Guidelines. And we will have “evidence blocks,” which employ a 5-point scale (for efficacy, safety, data quality, data consistency, and affordability) to help providers and patients understand and select among treatment options, based on the factors that matter most to the individual. One of our most important initiatives is “resource stratification” of the Guidelines. Almost half our users reside outside the United States, many in low- to intermediate-resource areas. We will customize recommendations in accordance with basic, limited, enhanced, and maximal resources—always preserving the context of the full Guidelines. This will make the Guidelines relevant in almost all parts of the world.

Molecular Profiling How will the Guidelines incorporate the growing number of molecular profiles that are starting to guide treatment selection? Using molecular profiling for decision-making will be very complicated, but I also think that—once the evidence exists—our Guideline panels are uniquely positioned to respond to that challenge. Many of our institutions are using multigene testing, mainly for research purposes, and are learning how to use it in patient care. Although we have been incorporating molecular profiling for some time—using HER2, ALK, EGFR, RAF, and others—we know that the smaller the subset, the greater the statistical challenges, and the smaller the cohort, the less confidence we can have in the findings.

Value and Cost in Cancer Care Achieving “value” in cancer care is increasingly important. How will the Guidelines deal with this imperative? Value is in the eyes of the beholder, and that’s one of the challenges when we continued on page 14

The ASCO Post | APRIL 25, 2015

PAGE 14

National Comprehensive Cancer Network Annual Conference Robert W. Carlson, MD continued from page 13

prioritize oncology treatments. Different patients will have different value systems, expectations, and resources. So our approach to value is to provide as much information as we can about the effectiveness of treatment, toxicity, and then cost and allow the patient to take that information and make a decision. The “evidence blocks” will be very helpful for this. Will NCCN ever consider the actual cost of a drug in constructing its list of preferred regimens? Yes and no. As our capability of looking at cost-effectiveness becomes greater, the Guideline panels will almost certainly begin to incorporate cost in some way. The challenge is that in this country (as opposed to countries with national health systems), cost of treatment varies. It may depend on the drug, the region, the institution where the patient is treated, the physician, the payer, and so forth. Within the U.S. healthcare system, cost is complicated, and our estimates will be inexact, but I think it’s likely we will use cost to inform our preferred regimens in the future.

Financial Stability of NCCN Speaking of costs, the financial challenges of maintaining NCCN and promoting new initiatives must be great. NCCN is exceptionally strong financially. We have a robust and diversified revenue stream and are becoming more diversified with time. We are not at risk of a financial crisis in the foreseeable future!

Personal Style and Accomplishments On a more personal note, how do you think your own leadership style has impacted NCCN? The most fundamental thing is that I’m the first physician to lead the organization as CEO. So I bring the medical model with me—what’s needed at the point of care—and I bring some awareness of the patient experience. From my days at Stanford, I think I’m a strong collaborator, someone who can develop high-performing teams and who is open to examining all sides of an issue. I have no problem with being challenged! Sometimes that’s necessary. These are the characteristics I’ve brought to NCCN. What are your proudest accomplishments as CEO of NCCN? I am proud of a family of accomplishments, starting with the Board of Directors. We adopted a 5-year strate-

gic plan in November 2012, and I came along in January 2013. Since then, we have achieved the vast majority of tasks within that plan and exceeded most of the metrics—not because they were set too low, but because this organization is vibrant and dynamic. We also have a staff that shares the mission and vision and can accomplish things efficiently.

A Look Backward Finally, as much as you love this job, you must miss some things about your former life as a Stanford academic and clinician. Yes. I miss the people. Over 40 years at Stanford, I grew up with many people professionally, and they are very close friends. I had a very

active academic clinical practice and miss each one of my patients. There is a relationship that develops that is very important. It’s gratifying to still see and hear from many of these patients, and I am still here for them if they need me. n

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

BLEED TRIM:

LIVE: 1

ASCOPost.com | APRIL 25, 2015

PAGE 15

National Comprehensive Cancer Network Annual Conference

D: 15.4” 15.15”

14.15”

Remembering Dr. Jane Weeks’ Pioneering Work and NCCN’s Outcomes Research Initiative

ane Carrie Weeks, MD, MSc, a prominent researcher at Dana-Farber Cancer Center, died of cancer on September 10, 2013, at the age of 61. At the time of her death, Dr. Weeks

was Professor of Medicine at Harvard Medical School, Professor of Health Policy and Management at the Harvard School of Public Health, Director of the Mc-Gaw-Patterson Center

for Population Sciences, and Chief of the Division of Population Sciences in the Department of Medical Oncology at Dana-Farber. In 1995, Dr. Weeks founded Dana-

Jane Carrie Weeks, MD, MSc

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Making the human connection

BLEED: 10.825”

LIVE: 9.575”

Introducing

TRIM: 10.575”

Farber’s Center for Outcomes and Policy Research, which fosters crossdisciplinary health services research in cancer, and in 2001 Dr. Weeks helped create Dana-Farber’s Initiative to Eliminate Cancer Disparities (IECD). She was also somewhat ahead of her time in appreciating the need to add “value” to the clinical care continuum, and she therefore pioneered comparative effectiveness research and maintained that clinicians should know a thing or two about cost-effectiveness as well. Dr. Weeks’ groundbreaking work in these fields will have a long-lasting impact on cancer care, said Robert W. Carlson, MD, Chief Executive Officer of the NCCN. Although outcomes research is a heady discipline of macroanalysis and statistics, it all boils down to delivering better and more equitable care for patients with cancer, taking into consideration their experiences and preferences. This area of work, therefore, dovetails completely with the NCCN’s patient-centered mission, according to Dr. Carlson. Dr. Carlson reflected on Dr. Weeks’ substantial contribution to the NCCN. “One of the early programs was an NCCN outcomes database. It was a very robust database of patient information in terms of demographics, disease characteristics, treatments, and so forth from participating NCCN institutions. There were well over 100,000 patients in it,” he said. “It was an incredible source of information for research purposes and also for producing feedback about compliance, to our member institutions. That program existed because Jane spearheaded it.” The database has been inactive for a while, but there are plans to “resurrect it,” Dr. Carlson added. “It would have been great to have Jane here for that endeavor.” n

The ASCO Post | APRIL 25, 2015

PAGE 16

JCO Spotlight Breast Cancer

Analysis Shows No Link Between Aromatase Inhibitor–Related Musculoskeletal/Vasomotor Symptoms and Relapse-Free Survival By Matthew Stenger

etrospective analyses of the ATAC, TEAM, and BIG 1-98 adjuvant endocrine therapy trials in breast cancer have suggested that treatment-emergent endocrine symptoms may be associated with superior survival outcomes. In a study reported in the Journal of Clinical Oncology, Vered Stearns, MD, Professor of Oncology and Co-Director of the Breast Cancer Program at Johns Hopkins Medicine, Baltimore, and colleagues found no association of new or worsening vasomotor or musculoskeletal symptoms with relapse-free survival in patients receiving adjuvant aromatase inhibitor therapy with anastrozole or exemestane in the National Cancer Institute of Canada Clinical Trials Group (NCIC CTG) MA.27 trial.1

Study Details In the MA.27 trial, 7,576 postmenopausal women with breast cancer were randomly assigned to 5 years of anastrozole or exemestane. There was no difference in efficacy or treatment adherence between treatment groups. Patient-reported symptoms were collected using Common Terminology Criteria for Adverse Events version 3.0 at protocol-specified baseline and 6and 12-month visits. Landmark analyses excluding patients who had already experienced recurrence were used to assess the effects of new or worsening symptoms on subsequent relapse-free survival by evaluating the effect of having vs not having such symptoms at 3, 6, or 12 months after randomization. The effects of symptoms at 3 months were assessed using unplanned clinic visits due to severe toxicity within the first 3 months.

Frequency of Symptoms A total of 7,344 patients were alive without relapse at 3 months; 96% were evaluable at both 6 and 12 months, and 34% of patients had vasomotor or joint symptoms at baseline in the evaluable populations at all three time points.

Patients were categorized into three groups: those without either baseline vasomotor or grade 3 or 4 musculoskeletal symptoms at baseline (n = 5,645), those without any vasomotor or musculoskeletal symptoms at baseline (n = 4,877), and all patients. The frequency of onset or worsening of symptoms was 19.2%, 25.4%, and 26.4% at 6 months and 38.0%, 52.9%, and 52.9% at 12 months in the three groups. The frequency of early severe toxicity clinical visits at 3 months was 3.9%, 5.2%, and 5.5% in the three groups. There were numerous differences in baseline characteristics between patients with or without baseline symp-

Aromatase Inhibitors, Symptoms, and Survival ■■ Among patients without baseline vasomotor or musculoskeletal symptoms, 25% and 52% had new symptoms by 6 and 12 months. ■■ Neither treatment-emergent nor baseline symptoms significantly affected relapse-free survival in patients with or without baseline symptoms.

relapse-free survival hazard ratios for those developing vasomotor symptoms or grade 3 or 4 musculoskeletal symptoms vs those not developing such symptoms were 0.62 (95% confidence interval [CI] = 0.33–1.18, P = .15) at 3 months, 0.80 (95% CI = 0.59–1.07, P = .13) at 6 months, and 0.81 (95% CI = 0.63–1.03, P = .09) at 12 months. Among all patients, irrespective of

Our study, examining two [aromatase inhibitors], failed to show an association between new or worsening symptoms and outcome. —Vered Stearns, MD, and colleagues

toms who did or did not develop new or worsening symptoms at 3, 6, or 12 months; most notable was an effect of age, with development or worsening of symptoms being significantly more common in women aged ≤ 55 years. There were no significant differences between the anastrozole and exemestane treatment groups in time to discontinuation of therapy among patients with or without new or worsening vasomotor or musculoskeletal symptoms by 12 months.

No Effect on Relapse-Free Survival New or worsening vasomotor or joint symptoms did not significantly affect relapse-free survival on univariate analysis at any time point for any of the three groups. Among patients without baseline vasomotor or grade 3 or 4 musculoskeletal symptoms, the

baseline symptoms, the relapse-free survival hazard ratios for those developing new or worsened symptoms vs those not developing new or worsened symptoms were 0.88 (95% CI = 0.55–1.35, P = .5595) at 3 months, 0.84 (95% CI = 0.67–1.05, P = .1307) at 6 months, and 0.93 (95% CI = 0.76–1.14, P = .4803) at 12 months. In multivariate models including treatment and significant patient baseline characteristics and stratified by use of celecoxib, aspirin, and trastuzumab (Herceptin) and by lymph node status and prior chemotherapy, neither treatment nor new or worsening symptoms (P > .10) had a significant effect on relapse-free survival irrespective of the presence or absence of baseline symptoms. The investigators noted that the high event-free survival rates (91% with exemestane and 91.2% with anastrozole

at 4 years) in the MA.27 trial may have made it more difficult to demonstrate differences in relapse-free survival in landmark analyses in which events are excluded. The investigators concluded: [T]he majority of studies of patients who received tamoxifen or [aromatase inhibitor] reported a relationship between emergence of vasomotor and musculoskeletal symptoms and survival outcomes. Our study, examining two [aromatase inhibitors], failed to show an association between new or worsening symptoms and outcome. Predictive factors are required to determine treatment efficacy and treatment-emergent symptoms. Future prospective analyses of symptoms in [aromatase inhibitor] trials should ensure that symptoms are collected in a similar way to both the positive and negative trials to resolve the issue. Until then, treatment-emergent symptoms should be managed as effectively as possible to support treatment continuation, and it is premature to counsel patients on whether to continue or change their adjuvant [aromatase inhibitor] therapy based on symptoms.” n Disclosure: The study was supported by the Canadian Cancer Society Research Institute, U.S. National Cancer Institute, International Breast Cancer Study Group, Pfizer, Susan G. Komen for the Cure, and Avon Foundation New York. For full disclosures of the study authors, visit jco.ascopubs.org.

Reference 1. Stearns V, Chapman JA, Ma CX, et al: Treatment-associated musculoskeletal and vasomotor symptoms and relapse-free survival in the NCIC CTG MA.27 adjuvant breast cancer aromatase inhibitor trial. J Clin Oncol 33:265-271, 2015.

Should We Be Worried If Patients Tolerate Endocrine Therapy Well? N. Lynn Henry, MD, PhD, of the University of Michigan Medical School, Ann Arbor, offers her perspective on the MA.27 trial discussed above. See page 18.

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References: 1. Referenced with permission from The NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Non-Small Cell Lung Cancer V.4.2015. © National Comprehensive Cancer Network, Inc 2015. All rights reserved. Accessed February 16, 2015. To view the most recent and complete version of the guidelines, go online to http://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. 2. From Ferlay J., Soerjomataram I, Ervik M., Dikshit R., Eser S., Mathers C., Rebelo M., Parkin D.M., Forman D., Bray, F. GLOBOCAN 2012 v1.0, Cancer Incidence and Mortality Worldwide: IARC CancerBase No. 11 [Internet]. Lyon, France: International Agency for Research on Cancer; 2013. Available from: http://globocan.iarc.fr, accessed on 23/02/2015. 3. American Cancer Society. What is non-small cell lung cancer? http://www.cancer.org/cancer/lungcancer-non-smallcell/detailedguide/ non-small-cell-lung-cancer-what-is-non-small-cell-lung-cancer. Accessed February 16, 2015. 4. Hoang T, Dahlberg SE, Schiller JH, et al. Does histology predict survival of advanced non-small cell lung cancer patients treated with platin-based chemotherapy? An analysis of the Eastern Cooperative Oncology Group Study E1594. Lung Cancer. 2013;81(1):47-52. 5. Ellis LM, Bernstein DS, Voest EE, et al. American Society of Clinical Oncology perspective: raising the bar for clinical trials by defining clinically meaningful outcomes. J Clin Oncol. 2014;32(12):1277-1280.

MARCH 2015

GLOONC00009a

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PAGE 18

Perspective

Should We Be Worried If Patients Tolerate Endocrine Therapy Well? By N. Lynn Henry, MD, PhD

hen meeting with patients to discuss adjuvant endocrine therapy for breast cancer, the question often arises, “How will I know that the treatment is working?” While the efficacy of these treatments has been demonstrated for the majority of patients in multiple large randomized clinical trials, they are ineffective for others. We remain unable to determine whether the treatment will be, or is, effective for the individual patient sitting in front of us in the clinic. Researchers have sought to identify predictors of response to adjuvant

flashes and/or arthralgias within the first 3 months of treatment were less likely to experience breast cancer recurrence compared with those who did not report either symptom. Similar findings were reported from other large clinical trial cohorts, including the Breast International Group (BIG) 1-98 and Tamoxifen Exemestane Adjuvant Multinational (TEAM) trials.2-4 There has been some discordance in the findings, however, since not all symptoms (vasomotor, arthralgia, and vulvovaginal) have been associated with

More research is required to fully understand the association between symptom development and benefit from treatment, and analyses that include the patient’s perspective will be invaluable. —N. Lynn Henry, MD, PhD

endocrine therapy that can be used to guide treatment decisions, either between different classes of endocrine therapy—ie, selective estrogen receptor modulators and aromatase inhibitors—or among different aromatase inhibitors. Studies assessing standard cancer-related factors, including pathologic characteristics of the tumor, have not yet identified a useful predictive marker for endocrine therapy selection.

Patient-Reported Outcomes Evaluation of other outcomes that are potential surrogates for adjuvant endocrine therapy activity and that could be used as predictors of response has therefore been considered. One such outcome that has been assessed retrospectively in multiple clinical trials is patient-reported symptoms. The first reported finding was from the Arimidex, Tamoxifen, Alone or in Combination (ATAC) randomized trial of anastrozole vs tamoxifen for adjuvant endocrine therapy in postmenopausal women with newly diagnosed breast cancer.1 This retrospective analysis concluded that patients who developed hot Dr. Henry is Associate Professor, Internal Medicine, University of Michigan Medical School, Ann Arbor.

improved survival in every study. In contrast to these findings, the recent report by Stearns et al from the MA.27 randomized trial of anastrozole vs exemestane, reviewed in this issue of The ASCO Post, did not identify any associations between development of symptoms during therapy and improvement in breast cancer disease outcomes.5 The investigators examined associations between worsening of symptoms at 6 and 12 months following treatment initiation and event-free survival, with a median follow-up of 4.1 years. No differences in event-free survival were noted, regardless of whether symptoms were present at baseline. One of the key limitations of all these studies is the lack of validated patientreported outcomes. The trials used physician-reported toxicity or obtained data from patients in a nonstandardized manner. Reliance on physician reporting of toxicity has been shown to result in underestimation of symptom burden in aromatase inhibitor–treated women.6 Therefore, the data used for the analyses of associations between treatmentemergent toxicity and breast cancer outcomes are likely incomplete, which could affect the findings. There are other potential limitations, as discussed by Stearns et al, including exclusion of patients with

baseline symptoms; omission of symptom severity information; and lack of information about concomitant medications, including analgesics. Patients treated with aromatase inhibitor therapy are postmenopausal and generally have a baseline symptom burden that is fairly high due to arthritis and other age-related conditions. The lack of data about the effect of baseline symptoms on the findings and the omission of concomitant medication data influence the findings and, more importantly, limit the applicability of the results to the typical patient population. Overall, these concerns about the quality and completeness of data used for the various retrospective analyses could account for the discordance in findings among studies.

Future Directions There is a movement afoot to increase the patient voice in oncology trials. Symptom presence and severity are subjective, not objective, and the patient’s perception of his or her symptoms is vital. Ethan Basch and colleagues have called for the incorporation of patient-reported outcomes into clinical trials to improve the accuracy of clinician-reported adverse events.7 One argument against collection of patient-reported outcomes in trials is the cost and inconvenience. In response, the National Institutes of Health has developed tools such as the Patient-Reported Outcomes Measurement Information System (PROMIS) in order to facilitate collection of patient-reported outcomes.8 The PROMIS short-form questionnaires are being used in the ongoing ECOG-ACRIN E1Z11 observational clinical trial of anastrozole, which is specifically assessing toxicity of aromatase inhibitor therapy (Clinicaltrials.gov NCT01824836). It will be interesting to see both the uptake of electronic reporting of patient-reported outcomes, which would streamline data collection, and the concordance between patientand physician-reported symptoms in this prospective clinical trial. The ability to accurately predict the efficacy of adjuvant endocrine therapy for an individual patient is crucial to optimizing the benefit-risk ratio of treatment. For now, it remains uncertain

whether we should be concerned if a patient fails to develop toxicity from adjuvant endocrine therapy. More research is required to fully understand the association between symptom development and benefit from treatment, and analyses that include the patient’s perspective will be invaluable. n

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

References 1. Cuzick J, Sestak I, Cella D, et al: Treatment-emergent endocrine symptoms and the risk of breast cancer recurrence: A retrospective analysis of the ATAC trial. Lancet Oncol 9:1143-1148, 2008. 2. Fontein DB, Houtsma D, Hille ET, et al: Relationship between specific adverse events and efficacy of exemestane therapy in early postmenopausal breast cancer patients. Ann Oncol 23:30913097, 2012. 3. Fontein DB, Seynaeve C, Hadji P, et al: Specific adverse events predict survival benefit in patients treated with tamoxifen or aromatase inhibitors: An international tamoxifen exemestane adjuvant multinational trial analysis. J Clin Oncol 31:22572264, 2013. 4. Huober J, Cole BF, Rabaglio M, et al: Symptoms of endocrine treatment and outcome in the BIG 1-98 study. Breast Cancer Res Treat 143:159-169, 2014. 5. Stearns V, Chapman JA, Ma CX, et al: Treatment-associated musculoskeletal and vasomotor symptoms and relapsefree survival in the NCIC CTG MA.27 adjuvant breast cancer aromatase inhibitor trial. J Clin Oncol 33:265-271, 2015. 6. Oberguggenberger A, Hubalek M, Sztankay M, et al: Is the toxicity of adjuvant aromatase inhibitor therapy underestimated? Complementary information from patient-reported outcomes (PROs). Breast Cancer Res Treat 128:553-561, 2011. 7. Basch E, Bennett A, Pietanza MC: Use of patient-reported outcomes to improve the predictive accuracy of clinicianreported adverse events. J Natl Cancer Inst 103:1808-1810, 2011. 8. Cella D, Riley W, Stone A, et al: The Patient-Reported Outcomes Measurement Information System (PROMIS) developed and tested its first wave of adult self-reported health outcome item banks: 2005-2008. J Clin Epidemiol 63:11791194, 2010.

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.

GRANIX® is an option in short-acting G-CSF therapy » A 71% reduction in duration of severe neutropenia vs placebo (1.1 days vs 3.8 days, p<0.0001)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 » The safety of GRANIX was established in 3 Phase III trials, with 680 patients receiving chemotherapy for either breast cancer, lung cancer, or non-Hodgkin lymphoma (NHL)1 » Now offering a new presentation for self-administration

Indication » GRANIX 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. » 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. » Capillary leak syndrome (CLS): CLS can occur in patients receiving hG-CSFs and is characterized by hypotension, hypoalbuminemia, edema and hemoconcentration. Episodes vary in frequency, severity and may be life-threatening if treatment is delayed. Patients who develop symptoms of CLS should be closely monitored and receive standard symptomatic treatment, which may include a need for intensive care. » 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. » 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® (tbo-filgrastim) Injection Prescribing Information. North Wales, PA: Teva Pharmaceuticals; 2014.

©2015 Cephalon, Inc., a wholly-owned subsidiary of Teva Pharmaceutical Industries Ltd. GRANIX is a registered trademark of Teva Pharmaceutical Industries Ltd. All rights reserved. GRX-40582 January 2015.

The ASCO Post | APRIL 25, 2015

PAGE 20

Clinical Brief Gynecologic Oncology

Complete Regression of Metastatic Cervical Cancer Is Observed After Treatment With HPV-Targeted Tumor-Infiltrating T Cells By Matthew Stenger

s reported in Journal of Clinical Oncology,1 researchers at the National Cancer Institute observed complete regression of metastatic cervical tumors

in two patients following a single infusion of human papillomavirus (HPV)targeted tumor-infiltrating T cells. In the protocol, nine patients with

metastatic cervical cancer who had received platinum-based chemotherapy or chemoradiotherapy received a single infusion of tumor-infiltrating

T cells, grown from tumor fragments following excision of the tumor, selected when possible for HPV E6 and E7 reactivity. Patients underwent lymphocyte-depleting chemotherapy prior to infusion and received aldesleukin after infusion.

Complete Responses Observed

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 nonmyeloid 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 Capillary Leak Syndrome Capillary leak syndrome (CLS) can occur in patients receiving human granulocyte colonystimulating factors and is characterized by hypotension, hypoalbuminemia, edema and hemoconcentration. Episodes vary in frequency, severity and may be life-threatening if treatment is delayed. Patients who develop symptoms of capillary leak syndrome should be closely monitored and receive standard symptomatic treatment, which may include a need for intensive care. 5.6 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)] • Capillary Leak Syndrome [see Warnings and Precautions (5.5)] • Potential for Tumor Growth Stimulatory Effects on Malignant Cells [see Warnings and Precautions (5.6)] 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.

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-USapproved 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. Additional Adverse Reactions Other adverse reactions known to occur following administration of human granulocyte colony-stimulating factors include myalgia, headache, vomiting, Sweet’s syndrome (acute febrile neutrophilic dermatosis), cutaneous vasculitis and thrombocytopenia. 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 Risk Summary There are no adequate and well-controlled studies of GRANIX in pregnant women. In animal reproduction studies, treatment of pregnant rabbits with tbo-filgrastim resulted in increased spontaneous abortion and fetal malformations at systemic exposures substantially higher than the human exposure. GRANIX should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Animal Data In an 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 (AUC) 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. ©2014 Cephalon, Inc., a wholly-owned subsidiary of Teva Pharmaceutical Industries Ltd. All rights reserved. GRANIX is a registered 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-40581 January 2015 This brief summary is based on TBO-004 GRANIX full Prescribing Information.

Objective response was observed in three of the nine patients, including two complete responses that were ongoing at 15 and 22 months after treatment. The partial response was 3 months in duration. HPV reactivity of T cells in the infusion was positively correlated with likelihood of response on interferon gamma production,

HPV-Targeted T Cells in Metastatic Cervical Cancer ■■ Durable complete response was observed in two of nine patients. ■■ Response was correlated with HPV reactivity of T cells in the infusion and with persistence of HPV-reactive T cells in peripheral blood.

enzyme-linked immunospot, and CD137 upregulation assays (P = .02 for all three assays). The level of HPVreactive T cells in peripheral blood at 1 month after treatment was also positively associated with likelihood of response (P = .02). The investigators concluded: “Durable, complete regression of metastatic cervical cancer can occur after a single infusion of HPV-[tumor-infiltrating lymphocytes]. Exploratory studies suggest a correlation between HPV reactivity of the infusion product and clinical response. Continued investigation of this therapy is warranted.” Christian S. Hinrichs, MD, of the National Cancer Institute-Surgery Branch, is the corresponding author for the Journal of Clinical Oncology article. n Disclaimer: The study was supported by the National Institutes of Health and the Milstein Family Foundation.

Reference 1. Stevanovic S, Draper LM, Langhan MM, et al: Complete regression of metastatic cervical cancer after treatment with human papillomavirus-targeted tumorinfiltrating T cells. J Clin Oncol. March 30, 2015 (early release online).

ASCOPost.com | APRIL 25, 2015

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Expert’s Corner Breast Cancer

Opioid-Reduction Strategy for Postoperative Pain After Breast Cancer Surgery A Conversation With Patrick I. Borgen, MD By Ronald Piana

Patrick I. Borgen, MD

ne persistent and potentially debilitating problem breast cancer patients suffer with is postoperative pain. Studies show that proper pain management is an essential component in the healing process, but undertreatment of pain symptoms remains an ongoing issue in the oncology community. Opioids, which are the mainstay of cancer pain management, have a variety of negative side effects, such as constipation, nausea, altered mental status, and respiratory depression, and may play a role in increasing the likelihood of cancer recurrence. At the recent 32nd Annual Miami Breast Cancer Conference, pain management following breast surgery was an integral part of the program. The ASCO Post spoke with Conference Chairman Patrick I. Borgen, MD, who has been a vocal advocate for reducing the use of opioids in the postoperative breast surgery setting.

Meet Dr. Borgen Please introduce yourself to our readers. I’m currently the Chairman of the Department of Surgery at Maimonides Medical Center in Brooklyn, New York. I also founded what we call the Brooklyn Breast Cancer Project, which is the only dedicated multidisciplinary breast cancer center in Brooklyn, a city of 3 million people; most cities the size of Brooklyn have a dozen or so breast cancer programs. The leadership at Maimonides saw an unmet need and invested heavily in Brooklyn’s cancer needs. We’re set to celebrate our 10-year anniversary. Prior to Maimonides, I was the Chief Breast Surgeon at Memorial Sloan Kettering Cancer Center from 1993 until 2006.

Revolutionizing the Postoperative Experience Please tell the readers about the successful management of postoperative pain without opioids?

During my years at Memorial Sloan Kettering, we focused heavily on extending our patients’ lives and made significant advances, which I am very proud of. Now that those advances are a reality, it is time to pay more attention to extending our patients’ quality of life. One of the easiest ways to accomplish this is by employing state-of-the-art, multimodality pain management strategies in patients undergoing breast surgery. The nidus of this opioid-reduction story begins at this year’s annual Miami Breast Cancer Conference, which featured several talks on new painmanagement approaches that reduce or eliminate the need for opioids after breast surgery. It’s important to note, this was the 32nd Annual Miami Breast Cancer Conference, and it was the first in which we focused on the patient experience related to their pain, which speaks volumes about how this issue has been somewhat neglected by the oncology community. I chaired several practical sessions on opioid-sparing pain control, and part of what has made this strategy possible is a vast improvement in local-regional anesthesia techniques, particularly the development of a time-released local anesthetic called liposomal bupivacaine (Exparel), which is a multivesicular liposomal-encased bupivacaine formulation. I began using this in my own practice a year ago, and it completely revolutionized the postoperative experience in my patients…irrespective of whether they had mastectomy, lymph node dissection, or lumpectomy. This agent is a long-acting drug that offers substantial pain relief for up to 72 hours after surgery, obviating the need for opioid analgesics. My patients then escape all of the opioid-driven side effects such as constipation and nausea. Using opioid-sparing techniques such as liposomal bupivacaine also shortens hospital stays, which is another valueadded benefit for our patients.

‘A Technique That Surgeons Need to Learn’ Has this particular opioid-sparing method of postoperative pain management been widely used? The short answer is —not widely enough—but that is changing very rapidly. When we look at patient-reported pain data recorded over the past decade, we see that we have actually gotten worse in our efforts to properly manage pain in the postopera-

tive setting. We attack the pain problem by adding more opioids and other narcotics, which just does not work. It’s a strategy that has very untoward side effects and just does not get to the root of the problem. By creating an anesthetic field prior to creating the trauma of surgery with a drug that lasts for 72 hours, we are preventing the whole inflammatory-cytokine–related pain cycle from starting. That’s key. We’ve found that our patients who undergo bupivacaine therapy go home with a prescription for oxycodone and never break the seal on the bottle. For breast cancer patients undergoing surgery, it’s

breast surgery, you want to bridge the initial 3-day period of pain symptoms, at which point our patients generally move to acetaminophen or nonsteroidal anti-inflammatory drugs. And that’s what we see, which leaves me ecstatic.

Unanimous and Enthusiastic Approval What’s been the reaction from your colleagues in the surgical oncology community about this relatively new drug technique? Unanimous and enthusiastic approval. In the past, we had to spend a lot of time warning our patients about postopera-

For breast cancer patients undergoing surgery, it’s really been a game-changer—they wake up from surgery pain free. —Patrick I. Borgen, MD

really been a game-changer—they wake up from surgery pain free. We first use bupivacaine that’s not liposomal-encased to get the immediate pain relief and then the liposomal bupivacaine injection, which kicks during the hours following surgery. So we bridge the patients with local anesthesia and then the long-acting drug. It’s a technique that surgeons need to learn because it is a methodical injection process of the surgical field. We’re also using this technique in cardiac surgery and colorectal procedures.

Downstream Cost-Effectiveness Is bupivacaine treatment a cost-effective way to treat postoperative pain? The treatment is in a single 20-mL vile that can be diluted by a factor of three or four. The vile of bupivacaine we use in Brooklyn costs us about $300, which on the surface seems expensive. But when you consider that these postoperative patients leave the recovery room and go home quicker without bowel dysfunction or nausea, and with no need for opioids, we realize the downstream cost-effectiveness of the treatment. Moreover, medical reimbursement is increasingly impacted by patient satisfaction. Patients in postoperative pain are rarely “satisfied.” Pain treatment is largely about staying ahead of the pain curve. One of the main benefits of bupivacaine therapy is that we stop the cytokine-driven inflammatory process before it starts. In

tive pain and discomfort, especially for procedures like mastectomy with reconstruction, in which about 10% to 15% of patients will go into a chronic pain syndrome that impacts every aspect of their daily lives. So we’re quite content preventing that very serious side effect. Moreover, by using opioid-sparing painmanagement therapy, we’re enabling our patients to have a much quicker transition to their next course of therapy, whether its radiation therapy or chemotherapy.

Getting the Word Out Besides the Miami Breast Conference, do you plan to actively get the word out to the surgical community about the benefits of opioid sparing postoperative pain management? Yes, because it’s an important advance in the quality-of-life arena, and that is good for our patients. I’ve been in this wonderful field for about 25 years, and during that time, I’ve come to realize the power of breast cancer advocacy groups. So we plan reach out to these organizations and make them aware of how opioid-sparing strategies can enhance the outcomes of women undergoing breast cancer surgery. The postoperative experience is the beginning of the next step of treatment. It’s an important transition point, and we can make that transition much less difficult and much less stressful by actively employing opioid-sparing techniques. We just have to get the word out. n Disclosure: Dr. Borgen reported no potential conflicts of interest.

The ASCO Post | APRIL 25, 2015

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Clinical Brief Risk Factors

Overweight Girls Face Increased Risk of Colorectal Cancer Later in Life

irls who are overweight as young children and teens may face increased risk for colorectal cancer decades later, regardless of what they weigh as adults, suggests a new study published by Xuehong Zhang, MD, ScD, Instructor at Harvard Medical School, and colleagues in Cancer Epidemiology, Biomarkers & Prevention.1 “Our study supports the growing evidence that early-life body size can influence risk of colorectal cancer many decades later,” said senior study author Esther K. Wei, ScD, Scientist at the California Pacific

search, it’s too early to conclude that this association does not exist in men.” Disentangling the independent link between being overweight as a youth and as an adult is challenging. For adults, there is a clear link between being obese and increased risk of colorec-

tal cancer as well as many other cancers. Excess body fat can cause high levels of insulin and insulin-like hormones, which may fuel colorectal cancer. The role of excess body fat and cancer risk over a lifetime is an emerging and important area of research. Approximately a

third of children and adolescents are overweight or obese, according to the Centers for Disease Control and Prevention. n Reference 1. Zhang X, et al: Cancer Epidemiol Biomarkers Prev 24:690-697, 2015.

ADVERTORIAL

Our study supports the growing evidence that early-life body size can influence risk of colorectal cancer many decades later. —Esther K. Wei, ScD

Medical Center. “Although we don’t need any additional evidence to encourage obesity prevention and increased physical activity in children, this study adds additional imperative to prioritizing children’s health.”

Cancer Stem Cells

Understanding

Study Details Researchers pulled data from two large and long-term cohorts: 75,238 women who were part of the Nurses’ Health Study, and 34,533 men from the Health Professionals Follow-Up Study. In 1988, participants were presented with a set of nine diagrams of body shapes, ranging from the most slender to the most overweight. Participants selected what his or her body shape looked like at ages 5, 10, 20, 30, and 40, along with their current age. Then everyone regularly answered questionnaires about their weight, activity, diet, and other lifestyle habits. During an average of 22 years, 2,100 people had developed colorectal cancer. After adjusting for adult weight, the researchers found that women who were overweight as young children had a 28% higher risk of colorectal cancer compared to those who were most lean at those ages. Women who were overweight as adolescents had a 27% increased risk.Unexpectedly, the same link for overweight boys and adult colorectal cancer was not found. Not seeing the similar link among men could be due to faulty recall, chance, or unknown biology, said Dr. Wei. “We really don’t know why we only observed the association in women and not in men, but since this is still a relatively new area of re-

Signal Pathways

alignancies, like normal adult tissue, have been shown to contain a subset of cells that have the capacity to both selfrenew and produce more differentiated progeny. Pre-clinical research suggests that these “cancer stem cells”, while a minority of the total cancer cell population, are part of a hierarchical structure within the tumor mass that retains the highest malignant potential.1,2 Cancer stem cells are also highly resistant to conventional chemotherapeutic drugs.3

Cancer stem cells may originate from either normal stem cells as a result of mutation or from daughter cells which are a progeny of stem cells that have acquired the ability to self-renew as a result of genetic and/or epigenetic changes. Cells that reproduce themselves are more likely

EDU-NPS-0009

12/2014

to live long enough to accumulate the mutations that lead to cancer.4 It has also been demonstrated that non-stem cancer cells can acquire stemness properties to become cancer stem cells.5,6 Our understanding of the role of cancer stem cells in the natural history of cancer is evolving. Cancer stem cells may not only lead to the development of the primary tumor, but migrate to distant sites and cause metastasis.7 Cancer stem cells not eradicated during chemotherapy may also lead to regrowth or recurrence. Cancer stem cells have been positively identified and isolated from a variety of human cancers, including hematological malignancies as well as solid tumors.8 Most chemotherapeutics target actively

ASCOPost.com | APRIL 25, 2015

PAGE 23

Announcements

Richard Pazdur, MD, and Anthony S. Fauci, MD, Included in Fortune’s List of the World’s 50 Greatest Leaders

ichard Pazdur, MD, Director of the Office of Oncology and Hematology Products at the U.S. Food and Drug Administration (FDA) was named one of the world’s 50 great-

est leaders by Fortune Magazine. The list also included names such as Pope Francis, Apple CEO Tim Cook, Chief Justice of the United States Supreme Court John Roberts Jr, and Facebook

Chairman and CEO Mark Zuckerberg. Dr. Pazdur was praised by the publication for his effort to quicken the process of getting medications on the market and to patients. According to

Richard Pazdur, MD

Under Dr. Pazdur’s leadership, the FDA has been more responsive to the needs of cancer patients. —J. Leonard Lichtenfeld, MD, MACP

Regrowth

Metastasis

Cancer Stem Cells proliferating cells, resulting in bulk tumor shrinkage; however these agents are not as effective at killing relatively slowly proliferating cancer stem cells. Moreover, it has been shown that conventional chemotherapy and radiation therapy can induce stemness properties in non-stem cancer cells.9,10 Cancer stem cells at primary and metastatic sites can be activated by signals from the tumor microenvironment.11 Targeting these signaling pathways may disrupt aberrant signaling in cancer stem cells while reducing the toxicity to normal tissues associated with chemotherapy.12

1. Chen J, Li Y, Yu TS, et al. A restricted cell population propagates glioblastoma growth after chemotherapy. Nature. 2012;488:522-526. 2. Bonnet D, Dick JE. Human acute myeloid leukemia is organized as a hierarchy that originates from a primitive hematopoietic cell. Nat Med. 1997;3(7):730-737. 3. Dean M, Fojo T, Bates S. Tumour stem cells and drug resistance. Nat Rev Cancer. 2005;5(4):275-285. 4. Al-Hajj M, Becker MW, Wicha M, Weissman I, Clarke MF. Therapeutic implications of cancer stem cells. Curr Opin Genet Dev. 2004;14(1):43-47. 5. Gupta PB, Chaffer CL, Weinberg RA. Cancer stem cells: mirage or reality? Nat Med. 2009;15(9):1010-1012. 6. Gupta PB, Fillmore CM, Jiang G, et al. Stochastic state transitions give rise to phenotypic equilibrium in populations of cancer cells. Cell. 2011;146(4):633-644. 7. Jordan CT, Guzman ML, Noble M. Cancer stem cells. N Engl J Med. 2006;355(12):1253-1261. 8. Korkaya H, Wicha MS. Selective targeting of cancer stem cells: a new concept in cancer therapeutics. BioDrugs. 2007;21(5):299-310. 9. Hu X, Ghisolfi L, Keates AC, et al. Induction of cancer cell stemness by chemotherapy. Cell Cycle. 2012;11(14):2691-2698. 10. Ghisolfi L, Keates AC, Hu X, Lee DK, Li CJ. Ionizing radiation induces stemness in cancer cells. PLoS One. 2012;7(8):e43628. 11. Wicha MS, Liu S, Dontu G. Cancer stem cells: an old idea – a paradigm shift. Cancer Res. 2006;66(4):1883-1890. 12. Boman BM, Huang E. Human colon cancer stem cells: a new paradigm in gastrointestinal oncology. J Clin Oncol. 2008;26(17):2828-2838.

Boston Biomedical’s mission is to develop the next generation of cancer therapeutics by creating drugs designed to target cancer stem cell pathways.

Fortune, “in 2014 the FDA approved the greatest number of novel [oncology] drugs in almost 20 years.” J. Leonard Lichtenfeld, MD, MACP, Deputy Chief Medical Officer of the American Cancer Society, said under Dr. Pazdur’s leadership, “the FDA has been more responsive to the needs of cancer patients.” Also featured in the rankings was Anthony S. Fauci, MD, Director of the National Institute of Allergy and Infectious Diseases at the National Institutes

Anthony S. Fauci, MD

of Health. Dr. Fauci was lauded for his work on HIV/AIDS research and therapies, as well as for his advice to the American government and media during the Ebola crisis. n

The ASCO Post Wants to Hear From You

Write to The ASCO Post at editor@ASCOPost.com

www.bostonbiomedical.com

The ASCO Post | APRIL 25, 2015

PAGE 24

Perspective Breast Cancer

Breast Cancer Management in Review

Part 2. Metastatic Disease and Survivorship Issues By Jame Abraham, MD, FACP

ith the field of breast oncology as complex as ever, a brief update of the latest findings impacting breast cancer treatment seems timely. To that end, I have assembled highlights from a collection of newsworthy studies featured over the past year and into early 2015. Part 1 of this review, which appeared in the April 10, 2015, issue of The ASCO Post, focused on genetics and adjuvant therapies in breast cancer. In Part 2 of this two-part series, I will focus on newer therapeutic options for metastatic disease (fulvestrant [Faslodex], palbociclib [Ibrance], pertuzumab [Perjeta], and pictilisib) as well as several survivorship issues (fertility preservation, diet, and exercise).

for toxicity, more cases of grade 3/4 neutropenia (54% vs 1%), leukopenia (19% vs 0%), and fatigue (4% vs 1%) were reported with the addition of palbociclib. Clinical Perspective: The FDA approval of palbociclib is significant for two reasons. To begin with, this is the first CDK inhibitor approved for breast

PALOMA-1/TRIO-18 Trial On February 3, 2015, palbociclib, an oral, highly selective inhibitor of cyclindependent kinase (CDK) 4 and 6, was granted accelerated approval by the U.S. Food and Drug Administration (FDA) in combination with letrozole for the initial endocrine-based treatment of postmenopausal women with estrogen receptor–positive, HER2-negative metastatic breast cancer (see Table 1). The supporting data for this approval came from the randomized phase II PALOMA-1/TRIO-18 trial, which included 165 women.1 Key Findings: The median progression-free survival was 20.2 months (95% confidence interval [CI] = 13.8– 27.5) for the combination-treatment group and 10.2 months (95% CI = 5.7–12.6) for the letrozole-only group (hazard ratio [HR] = 0.488, 95% CI = 0.319–0.748, one-sided P = .0004). As Dr. Abraham is Director of Breast Medical Oncology at Taussig Cancer Institute and Co-Director of the Comprehensive Breast Cancer Program at the Cleveland Clinic, Cleveland, Ohio.

Pertuzumab in combination with trastuzumab (Herceptin) and docetaxel was approved for the treatment of patients with HER2-positive metastatic breast cancer who have not received prior anti-HER2 therapy or chemotherapy for metastatic disease. This approval was based on the CLEOPATRA

The FIRST study is the second trial to show an overall survival advantage for fulvestrant (500 mg) over another endocrine therapy. If the phase III FALCON study confirms these findings, Robertson and colleagues believe that fulvestrant should be considered for approval as a first-line agent in the treatment of advanced breast cancer.

Therapeutic Options for Metastatic Disease Recent progress in drug development and the understanding of tumor biology has resulted in a variety of new treatment options for metastatic breast cancer. The following key trials demonstrate that although metastatic breast cancer remains incurable, patient survival in this setting continues to be extended.

CLEOPATRA Study

—Jame Abraham, MD, FACP

cancer treatment. Second, and most important, based on PALOMA-1/ TRIO-18, palbociclib is a highly active drug for patients with estrogen receptor–positive breast cancer. Ongoing and completed trials will establish and further define the role of palbociclib in breast cancer treatment.

FIRST Study The randomized, phase II FIRST study compared 500 mg of fulvestrant with anastrozole in 205 patients with advanced hormone receptor–positive breast cancer.2 These women had not received prior endocrine therapy for their advanced disease. Key Findings: The median overall survival was longer in those given fulvestrant than in those given anastrozole (54.1 vs 48.4 months; HR = 0.70, 95% CI = 0.50–0.98, P = .041). The frequency of serious adverse events was similar between the two groups (between 21% and 24%). Clinical Perspective: According to the investigators, the FIRST study is the second trial to show an overall survival advantage for fulvestrant (500 mg) over another endocrine therapy. If the phase III FALCON study confirms these findings, Robertson and colleagues believe that fulvestrant should be considered for approval as a first-line agent in the treatment of advanced breast cancer.2

study, which reported improvement in progression-free survival in more than 800 women.3 Key Findings: The results of the final overall survival analysis from the CLEOPATRA study were reported at the 2014 ESMO Congress4 and published recently in The New England Journal of Medicine.5 First-line treatment with the three-drug combination significantly improved overall survival in these women compared with trastuzumab, docetaxel, and placebo (56.5 vs 40.8 months). This 15.7-month difference was a statistically significant im-

provement in overall survival in favor of the pertuzumab arm (HR = 0.68, 95% CI = 0.56–0.84, P = .0002). Clinical Perspective: “The median overall survival of 56.5 months is unprecedented in first-line, and this substantial improvement confirms the pertuzumab-containing regimen as standard of care in this setting,” stated Sandra Swain, MD, Medical Director of the Washington Cancer Institute at MedStar Washington Hospital Center, Washington, DC, in a press release.

OPPORTUNE Study Schmid and colleagues presented the first report of a preoperative window of opportunity study evaluating the PI3K inhibitor pictilisib in combination with anastrozole in the treatment of women with estrogen receptor–positive, HER2-negative operable breast cancer at the 2014 San Antonio Breast Cancer Symposium.6 In the OPPORTUNE study, 73 postmenopausal patients were randomly assigned to receive 2-week preoperative treatment; two-thirds were given anastrozole and pictilisib, and the other third, anastrozole alone. Key Findings: In this patient population, the antiproliferative response to anastrozole was increased with the addition of pictilisib over anastrozole alone. According to a preplanned subgroup analysis, there also seemed to be an interaction in response to the twodrug treatment with molecular subtype and Ki67 level. Furthermore, patients who had luminal B tumors had a higher Ki67 response with anastrozole and pic-

Table 1: A closer look at palbociclib FDA approval

February 3, 2015

Indication

In combination with letrozole for initial endocrinebased treatment of postmenopausal women with estrogen receptor–positive, HER2-negative metastatic breast cancer

Mechanism of action

Inhibits cyclin-dependent kinase 4 and 6 Reduces cellular proliferation of estrogen receptor– positive breast cancer cell lines by blocking the progression of cells from the G1 into the S phase of the cell cycle

Recommended dose

Palbociclib: 125 mg/d orally, days 1–21, 28-day cycle Letrozole: 2.5 mg/d continuously throughout 28-day cycle

Common side effects

Neutropenia, fatigue, anemia, stomatitis, diarrhea, thrombocytopenia, peripheral neuropathy

ASCOPost.com | APRIL 25, 2015

PAGE 25

Perspective

tilisib than with anastrozole alone (83% vs 38%), according to subset analyses. As for patients who had luminal A tumors, the Ki67 response appeared to be similar for both treatment groups. Clinical Perspective: Preoperative studies such as the OPPORTUNE trial have emerged as a strategy to evaluate novel treatments in women with estrogen receptor–positive breast cancer.6 Such studies may potentially help to characterize the optimal target population for such treatments.

Survivorship Issues Although improved diagnostics and therapeutics have led to longer lives for a greater number of breast cancer survivors, issues such as fertility, diet, and exercise and their roles in survival and quality of life for these patients are still being clarified. The following studies addressed some of these issues.

POEMS-SWOG S0230 The randomized phase III POEMSSWOG S0230 trial evaluated whether premature ovarian failure could be reduced by the administration of a luteinizing hormone–releasing hormone analog (goserelin [Zoladex]) with chemotherapy in women with earlystage, hormone receptor–negative breast cancer.7,8 A total of 257 patients (younger than age 50) with stages I to IIIA disease received standard cyclophosphamide-containing chemotherapy with or without monthly goserelin. Key Findings: Moore and colleagues presented their data on the 218 patients evaluated thus far during a Plenary Session at the 2014 ASCO Annual Meeting7 and recently published their findings in The New England Journal of Medicine.8 They found more success in attempting and achieving pregnancy with the addition of goserelin, with premature ovarian failure rates of 22% with standard chemotherapy and 8% with the addition of goserelin. In addition, there were 13 pregnancies among those who received standard chemotherapy and 22 pregnancies among those who received goserelin (odds ratio = 2.22, 95% CI = 1.00– 4.92, P = .05). Clinical Perspective: Not only were there fewer cases of premature ovarian failure and more pregnancies with the addition of goserelin to standard chemotherapy, an exploratory analysis suggested potential improvement

in both disease-free and overall survival as well.7 This is clearly a practicechanging study with significant clinical implications.

Women’s Intervention Nutrition Study The final survival analysis of this trial was presented at the 2014 San Antonio Breast Cancer Symposium.9 Of the more than 2,400 women between the ages of 48 and 79 years with early-stage breast cancer who took part in the trial, 975 patients received dietary intervention (targeting fat intake reduction [target 15% calories from fat] while maintaining nutritional adequacy) along with their standard cancer therapy, and the others did not.

Arthralgia Treatment The final study centers on the impact of exercise vs usual care for aromatase inhibitor–induced arthralgia in previously inactive breast cancer survivors.10 Irwin and colleagues conducted this yearlong randomized trial, which included 121 breast cancer survivors who received an aromatase inhibitor and reported arthralgia. Half of these women received usual care, and the others underwent aerobic exercise sessions (up to 90 minutes per week with no strength training). Key Findings: The worst joint pain scores decreased by 1.6 points (29%) at 12 months among the exercising women, compared with a 0.2-point increase (3%) among those receiving usual care

Clinical Trials in Breast Cancer ■■ Palbociclib and letrozole yielded a higher median progression-free survival than letrozole alone (20.2 vs 10.2 months) in women with advanced estrogen receptor–positive, HER2-negative breast cancer. ■■ The median overall survival was longer with fulvestrant than with anastrozole (54.1 vs 48.4 months) in women with advanced breast cancer, according to the FIRST study results. ■■ Pertuzumab-containing therapy improved overall survival in the first-line treatment of women with HER2-positive metastatic breast cancer vs non– pertuzumab-containing treatment (56.5 vs 40.8 months), based on the final results of the CLEOPATRA study. ■■ The addition of the PI3K inhibitor pictilisib to anastrozole improved response over anastrozole alone in women with operable estrogen receptor–positive, HER2-negative breast cancer, with a higher Ki67 response reported with the combination therapy in those with luminal B tumors. ■■ In women younger than age 50 with early-stage, hormone receptor– negative breast cancer, the addition of goserelin to chemotherapy resulted in premature ovarian failure rates of 8%, vs 22% with standard chemotherapy. ■■ Dietary intervention in women with early-stage breast cancer and exercise in women with aromatase inhibitor–induced arthralgia may be of benefit, according to two clinical trials.

The dietary intervention consisted of eight biweekly individual counseling sessions by centrally trained registered dietitians, with subsequent every-3-month dietitian contacts. Key Findings: After a median follow-up of 15 years, the lifestyle dietary intervention was associated with weight loss but not a significant increase in overall survival in women with resected breast cancer who received conventional cancer therapy.9 However, exploratory analyses suggested a favorable lifestyle influence on survival in the hormone receptor– negative subgroup and during active intervention.

(P < .001). In addition, pain scores on other standard indices and questionnaires decreased at 12 months in women randomly assigned to exercise. Clinical Perspective: We clearly know that diet and lifestyle play a key role in breast cancer incidence, survival, and quality of life. Although we are awaiting confirmatory data, all breast cancer survivors should be counseled about the importance of diet and exercise. n Disclosure: Dr. Abraham reported no potential conflicts of interest.

References 1. Finn RS, Crown JP, Lang I, et al: The cyclin-dependent kinase 4/6 inhibitor pal-

bociclib in combination with letrozole versus letrozole alone as first-line treatment of oestrogen receptor-positive, HER2-negative, advanced breast cancer (PALOMA-1/ TRIO-18): A randomized phase 2 study. Lancet Oncol 16:25-35, 2015. 2. Robertson JFR, Llombart-Cussac A, Feltl D, et al: Fulvestrant 500 mg versus anastrozole as first-line treatment for advanced breast cancer: Overall survival from the phase II ‘first’ study. 2014 San Antonio Breast Cancer Symposium. Abstract S6-04. Presented December 12, 2014. 3. Baselga J, Cortés J, Kim SB, et al: Pertuzumab plus trastuzumab plus docetaxel for metastatic breast cancer. N Engl J Med 366:109-119, 2012. 4. Swain S, Kim S, Cortés J, et al: Final overall survival analysis from the CLEOPATRA study of first-line pertuzumab, trastuzumab, and docetaxel in patients with HER2-positive metastatic breast cancer. 2014 ESMO Congress. Abstract 350O. Presented September 28, 2014. 5. Swain SM, Baselga J, Kim SB, et al: Pertuzumab, trastuzumab, and docetaxel in HER2-positive metastatic breast cancer. N Engl J Med 372:724-734, 2015. 6. Schmid P, Pinder SE, Wheatley D, et al: Preoperative window of opportunity study of the PI3K inhibitor pictilisib (GDC-0941) plus anastrozole vs anastrozole alone in patients with ER+, HER2-negative operable breast cancer (OPPORTUNE study). 2014 San Antonio Breast Cancer Symposium. Abstract S2-03. Presented December 10, 2014. 7. Moore HCF, Unger JM, Phillips K-A, et al: Phase III trial (Prevention of Early Menopause Study [POEMS]-SWOG S0230) of LHRH analog during chemotherapy to reduce ovarian failure in early-stage, hormone receptor-negative breast cancer: An international intergroup trial of SWOG, IBCSG, ECOG, and CALGB (Alliance). 2014 ASCO Annual Meeting. Plenary Session. Abstract LBA505. Presented May 31, 2014. 8. Moore HCF, Unger JM, Phillips KA, et al: Goserelin for ovarian protection during breast-cancer adjuvant chemotherapy. N Engl J Med 372:923-932, 2015. 9. Chlebowski RT, Blackburn GL: Final survival analysis from the randomized Women’s Intervention Nutrition Study (WINS) evaluating dietary intervention as adjuvant breast cancer therapy. 2014 San Antonio Breast Cancer Symposium. Abstract S5-08. Presented December 12, 2014. 10. Irwin ML, Cartmel B, Gross CP, et al: Randomized exercise trial of aromatase inhibitor-induced arthralgia in breast cancer survivors. J Clin Oncol. December 1, 2014 (early release online).

The ASCO Post | APRIL 25, 2015

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Journal Spotlight Gastrointestinal Oncology

Evidence of Recurrence-Free, Disease-Free, and Overall Survival Benefit of Aspirin and COX‑2 Inhibitor Use in Stage III Colon Cancer By Matthew Stenger

n an analysis from the Cancer and Leukemia Group B (CALGB) 89803 adjuvant trial reported in the Journal of the National Cancer Institute, Kimmie Ng, MD, MPH, of Dana-Farber Cancer Institute, Boston, and colleagues found consistent trends suggesting benefit of aspirin use and cyclo-oxygenase-2

pirin use reported at both time points, and COX-2 inhibitor use was defined as any use reported at the second time point. Multivariate analysis was adjusted for age (continuous variable), sex, race, adjuvant treatment in the trial, family history of colorectal cancer, per-

[T]his observational study of stage III colon cancer patients found statistically significant associations between aspirin and COX-2 inhibitor use and reduced cancer recurrence and mortality…. Further exploration of predictive biomarkers of aspirin and COX-2 inhibitor activity is warranted. —Kimmie Ng, MD, MPH, and colleagues

(COX-2) inhibitor use on recurrencefree, disease-free, and overall survival in patients with stage III colon cancer.1

Study Details This prospective observational study involved 799 patients in the CALGB 89803 trial evaluating the addition of irinotecan to adjuvant fluorouracil-leucovorin. The trial showed no difference in outcomes between the study groups. A self-administered questionnaire assessing diet, lifestyle, and medication use was conducted midway through chemotherapy and 6 months after chemotherapy. In the current analysis, consistent aspirin use was defined as any as-

formance status, depth of tumor invasion through the bowel wall, number of positive lymph nodes, tumor grade, body mass index at 6 months after chemotherapy, and physical activity at 6 months after chemotherapy. Overall, 9.4% of patients were aspirin users and 7.0% were COX-2 inhibitor users. Aspirin users were older and more likely to be male, and COX-2

inhibitor users were less likely to have a family history of cancer, had higher body mass index, and reported more acetaminophen use.

Aspirin Use Recurrence-free, disease-free, and overall mortality events were observed in 182, 214, and 156 of 724 patients with nonconsistent aspirin use and in 12, 19, and 14 of 75 consistent aspirin users. On multivariate analysis, hazard ratios (HRs) for consistent aspirin use vs nonconsistent use were 0.51 (95% confidence interval [CI] = 0.28–0.95) for recurrence-free survival, 0.68 (95% CI = 0.42–1.11) for disease-free survival, and 0.63 (95% CI = 0.35–1.12) for overall survival. In an analysis censored at 5 years to minimize the effects of noncancer deaths, hazard ratios were 0.61 (95% CI = 0.36–1.04) for diseasefree survival and 0.48 (95% CI = 0.23– 0.99) for overall survival.

COX-2 Inhibitor Use Recurrence-free, disease-free, and overall mortality events were observed in 198, 237, and 179 of 784 patients not using COX-2 inhibitors and in 9, 12, and 7 of 59 COX-2 inhibitor users. On multivariate analysis, hazard ratios for COX-2 inhibitor users vs nonus-

Aspirin/COX-2 Inhibitors and Colon Cancer ■■ Evidence of a benefit of aspirin use was observed for recurrence-free, disease-free, and overall survival. ■■ Similar benefits were observed with COX-2 inhibitor use.

ers were 0.53 (95% CI = 0.27–1.04) for recurrence-free survival, 0.60 (95% CI = 0.33–1.08) for disease-free survival, and 0.50 (95% CI = 0.23-1.07) for overall survival. In an analysis censored at 5 years, hazard ratios were 0.47 (95% CI = 0.24–0.91) for disease-free survival and 0.26 (95% CI = 0.08–0.81) for overall survival. The ongoing phase III Alliance for Clinical Trials in Oncology CALGB 80702 trial and the Aspirin for Dukes C and High Risk Dukes B Colorectal Cancers study (ASCOLT) are examining the effects of celecoxib and aspirin in colorectal cancer, but results will not be available for several years. The investigators concluded: “This observational study of stage III colon cancer patients found statistically significant associations between aspirin and COX-2 inhibitor use and reduced cancer recurrence and mortality. Results from the ongoing CALGB 80702 and ASCOLT trials are eagerly awaited. Further exploration of predictive biomarkers of aspirin and COX-2 inhibitor activity is warranted.” n

Disclosure: The study was supported by the National Cancer Institute, Conquer Cancer Foundation of the American Society of Clinical Oncology, Damon Runyan Cancer Research Foundation, and the Pharmacia and Upjohn Company, now Pfizer Oncology. For full disclosures of the study authors, visit jnci. oxfordjournals.org.

Reference 1. Ng K, Meyerhardt JA, Chan AT, et al: Aspirin and COX-2 inhibitor use in patients with stage III colon cancer. J Natl Cancer Inst 107(1):dju345, 2015.

Aspirin as Adjuvant Therapy for Colon Cancer: Is the Time Right? By Alfred I. Neugut, MD, PhD

spirin has long proved to be a multipotent drug, with efficacy as a pain reliever, anti-inflammatory agent, antiplatelet agent, and cardioprotective agent. In the cancer Dr. Neugut is Myron M. Studner Professor of Cancer Research, Professor of Medicine and Epidemiology, Associate Director of Population Sciences for the Herbert Irving Comprehensive Cancer Center, Columbia University College of Physicians and Surgeons, New York.

world, a large literature has accumulated demonstrating its ability to prevent various epithelial malignancies, most notably colorectal cancer,1 primarily by its inhibitory effect on cyclo-oxygenase-2 (COX2). Despite this effect, neither aspirin nor other COX-2 inhibitors are recommended for general use as chemopreventive agents because of the fairly common adverse effects of aspirin, mainly upper gastrointestinal toxicity, including gastritis and

gastrointestinal bleeding, and the risk of hemorrhagic stroke.

Five Observational Studies Since 2009, at least five observational studies have reported a significant survival benefit from the use of aspirin in the therapeutic setting for colorectal cancer.2-6 These studies focused on the initiation of aspirin use in patients with stage III colorectal cancer who have generally also had standard adjuvant chemotherapy.

Thus, the benefit of the aspirin on survival has been over and above that of conventional chemotherapy. Furthermore, those who were using aspirin prior to the cancer diagnosis generally were aspirin-resistant, similar to what happens with the use of tamoxifen as a chemopreventive agent.7,8 While one may have a reasonable sense of skepticism for the utilization of observational studies (vs prospective trials) as evidence in the evaluation of a therapeutic intervention, this

ASCOPost.com | APRIL 25, 2015

PAGE 27

Perspective

is usually because of concern about confounding, selection bias, and the use of retrospectively collected data. In the observational studies regarding aspirin, however, the benefits of the adjuvant aspirin were generally limited to those who were COX-2– positive2,6 or PIK3CA mutation–negative.5,6,9 These observations are very reassuring that this is a true effect of the drug and not due to confounding or selection bias. Furthermore, most of the studies used prospectively rather than retrospectively collected data.

tients in the intervening years before these trials reach maturity? I have argued previously16 that the observational evidence is strong enough to make adjuvant aspirin a standard of care, in light of its consistent efficacy and low-toxicity profile, as illustrated in the studies cited above. In my view, the Ng study10 just adds more evidence to this argument. Some ob-

The observational evidence is strong enough to make adjuvant aspirin a standard of care, in light of its consistent efficacy and lowtoxicity profile.

Sixth Study As reported in this issue of The ASCO Post, Ng and colleagues have now presented a sixth study to add to the prior mix. This prospectively collected observational study, published in the Journal of the National Cancer Institute,10 included patients who were entered in the randomized CALGB 89803 trial of adjuvant therapy for stage III colon cancer, which enrolled 843 patients between 1999 and 2001.11 Aspirin and nonsteroidal antiinflammatory drug use was determined by questionnaire, and improved survival was reported at the Annual ASCO Meeting in 2005 at 2.7 years of follow-up.12 So, in truth, this was the first of the studies to discover the therapeutic benefits of aspirin. Now, the investigators report the 5-year follow-up results and find continued significant improvements in survival for those who used aspirin, including in overall survival at 5 years. Marker studies were not included in this study. There are now randomized trials in progress to assess aspirin13,14 and celecoxib15 as adjuvant therapy for colorectal cancer. But what of pa-

References 1. Rothwell PM, Wilson M, Elwin CE, et al: Long-term effect of aspirin on colorectal cancer incidence and mortality: 20-year follow-up of five randomised trials. Lancet 376:1741-1750, 2010. 2. Chan AT, Ogino S, Fuchs CS: Aspirin use and survival after diagnosis of colorectal cancer. JAMA 302:649-658, 2009. 3. Bastiaannet E, Sampieri K, Dekkers

—Alfred I. Neugut, MD, PhD

servers, however, in considering the same evidence, suggest awaiting the results of the randomized trials now in progress.

Closing Thoughts In oncology, we often treat patients with toxic chemotherapy based on phase II trials that show partial remission benefits and have no comparison arms. Here, at least in theory, we have an agent that can reduce mortality in several patients per hundred of those treated. Certainly, the evidence adduced here for aspirin—a relatively nontoxic agent—for reducing mortality in stage III colon cancer merits serious consideration for adoption as adjuvant therapy in stage III colorectal cancer patients who have not previously been on aspirin and have no contraindications to aspirin therapy. n Disclosure: Dr. Neugut is a paid consultant for Pfizer, Otsuka, Teva, and United Biosource Corporation.

OM, et al: Use of aspirin postdiagnosis improves survival for colon cancer patients. Br J Cancer 106:1564-1570, 2012. 4. McCowan C, Munro AJ, Donnan PT, et al: Use of aspirin post-diagnosis in a cohort of patients with colorectal cancer and its association with all-cause and colorectal cancer specific mortality. Eur J Cancer 49:1049-1057, 2013. 5. Domingo E, Church DN, Sieber O, et al.: Evaluation of PIK3CA mutation as a predictor of benefit from nonsteroidal antiinflammatory drug therapy in colorectal cancer. J Clin Oncol 31:4297-4305, 2013. 6. Reimers MS, Bastiaannet E, Langley RE, et al: Expression of HLA class I antigen, aspirin use, and survival after a diagnosis of colon cancer. JAMA Intern Med 174:732-739, 2014. 7. Esserman LJ, Ozanne EM, Dowsett M, et al: Tamoxifen may prevent both ER+ and ER- breast cancers and select for ERcarcinogenesis: An alternative hypothesis. Breast Cancer Res 7:R1153-R1158, 2005. 8. Fisher B, Costantino JP, Wicker-

ham DL, et al: Tamoxifen for prevention of breast cancer: Report of the National Surgical Adjuvant Breast and Bowel Project P-1 Study. J Natl Cancer Inst 90:13711388, 1998. 9. Liao X, Lochhead P, Nishihara R, et al: Aspirin use, tumor PIK3CA mutation, and colorectal-cancer survival. N Engl J Med 367:1596-1606, 2012. 10. Ng K, Meyerhardt JA, Chan AT, et al: Aspirin and COX-2 inhibitor use in patients with stage III colon cancer. J Natl Cancer Inst 107(1):dju345, 2015. 11. Saltz LB, Niedzwiecki D, Hollis D, et al: Irinotecan and fluorouracil plus leucovorin is not superior to fluorouracil plus leucovorin alone as adjuvant treatment for stage III colon cancer: Results of CALGB 89803. J Clin Oncol 25:3456-3461, 2007. 12. Fuchs C, Meyerhardt JA, Heseltine DL, et al: Influence of regular aspirin use on survival for patients with stage III colon cancer: Findings from Intergroup trial CALGB 89803. J Clin Oncol 23(suppl 16):3530, 2005. 13. Ali R, Toh HC, Chia WK: The utility of aspirin in Dukes C and high risk Dukes B colorectal cancer—the ASCOLT study: Study protocol for a randomized controlled trial. Trials 12:261, 2011. 14. Langley RE, Wilson RH, Ring AE, et al: Add-Aspirin trial: A phase III, doubleblind, placebo-controlled, randomized trial assessing the effects of aspirin on disease recurrence and survival after primary therapy in common nonmetastatic solid tumors. J Clin Oncol 32(15 suppl):TPS1617, 2014. 15. Oxaliplatin, leucovorin calcium, and fluorouracil with or without celecoxib in treating patients with stage III colon cancer previously treated with surgery. Available at clinicaltrials.gov/show/NCT01150045. Accessed March 16, 2015. 16. Neugut AI: Aspirin as adjuvant therapy for stage III colon cancer: Standard of care? JAMA Intern Med 174:739741, 2014.

Visit The ASCO Post website at ASCOPost.com

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Polycythemia Polycythemia Vera: Vera:

Are AreSome SomePatients Patientsat atIncreased IncreasedRisk? Risk?

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Phlebotomy Phlebotomy Phlebotomyisisisusually usually usuallythe the thestarting starting startingpoint point pointof ofoftreatment treatment treatmentin ininpatients patients patients 2,11 2,11 2,11 with with withPV, PV, PV,in ininaddition addition additionto tototherapy therapy therapywith with withlow-dose low-dose low-doseaspirin. aspirin. aspirin. LowLowLowdose dose doseaspirin aspirin aspirinhas has hasbeen been beenshown shown shownto totoprevent prevent preventboth both botharterial arterial arterialand and andvenous venous venous 18 1818 thrombotic thrombotic thromboticcomplications complications complicationsin ininpatients patients patientswith with withPV. PV. PV. Cytoreductive Cytoreductive Cytoreductivetherapy therapy therapywith with withhydroxyurea hydroxyurea hydroxyureaor ororinterferon-alpha interferon-alpha interferon-alphamay may may also also alsobe be behelpful helpful helpfulin ininpatients patients patientswho who whohave have havediffi diffi diffi culty culty cultywith with withphlebotomy, phlebotomy, phlebotomy, who who whohave have havesymptomatic symptomatic symptomaticor ororprogressive progressive progressivesplenomegaly splenomegaly splenomegalyor ororwho who who 11 1111 experience experience experience severe severe severe symptoms. symptoms. symptoms. Although Although Although treatment treatment treatment with with with hydroxyurea hydroxyurea hydroxyureamay may maybe be betolerated tolerated toleratedby by bymost most mostpatients, patients, patients,itititisisisimportant important important to totoconsider consider considerthat that thatapproximately approximately approximately25% 25% 25%of ofofpatients patients patientswith with withPV PV PVdevelop develop develop 19, 19, 19, 20 2020 resistance resistance resistanceto totoor ororintolerance intolerance intoleranceof ofofhydroxyurea hydroxyurea hydroxyurea(Table (Table (Table1). 1). 1). Table Table Table1. 1.1. Assessment Assessment Assessmentof ofofhydroxyurea hydroxyurea hydroxyurea(HU) (HU) (HU)resistance resistance resistance and and andintolerance intolerance intolerance HU HU HUResistance Resistance Resistance

HU HU HUIntolerance Intolerance Intolerance

After After After12 12 12weeks weeks weeksof ofofHU HU HUat atat At At Atleast least least111of ofofthe the thefollowing: following: following: aaatotal total totaldose dose doseof ofof≥2 ≥2 ≥2g/day g/day g/dayor oror •••Neutropenia Neutropenia Neutropenia(absolute (absolute (absolute neutrophil neutrophil neutrophilcount count countof ofof at atatthe the themaximum maximum maximumtolerated tolerated tolerated 99 9 dose, dose, dose,ififif<2 <2 <2g/day g/day g/day <1.0 <1.0 <1.0xxx10 10 10/L) /L) /L) •••Need Need Needfor for forphlebotomy phlebotomy phlebotomy •••Platelet Platelet Plateletcount count countof ofof 99 9 to totomaintain maintain maintainHct Hct Hctlevel level level /L /L/L <100 <100 <100xxx10 10 10 at atat<45% <45% <45%or oror •••Hgb Hgb Hgblevel level levelof ofof<10 <10 <10g/dL g/dL g/dL •••Elevated Elevated Elevatedplatelet platelet plateletand and andwhite white white •••Leg Leg Legulcers ulcers ulcersor ororother other other blood blood bloodcell cell cellcounts counts countsor oror unacceptable unacceptable unacceptable •••<50% <50% <50%reduction reduction reductionin inin nonhematologic nonhematologic nonhematologic splenomegaly splenomegaly splenomegaly HU-related HU-related HU-relatedtoxicity toxicity toxicity Hct, Hct, Hct, hematocrit; hematocrit; hematocrit; Hgb, Hgb, Hgb, hemoglobin. hemoglobin. hemoglobin. 191919 Modifi Modifi Modifi ed ed ed from from from Barosi Barosi Barosi et etet al. al. al.

Despite Despite Despite current current current approaches, approaches, approaches, including including including phlebotomy, phlebotomy, phlebotomy, lowlowlowdose dose doseaspirin, aspirin, aspirin,interferon-alpha interferon-alpha interferon-alphaor ororcytoreductive cytoreductive cytoreductivetherapy therapy therapywith with with hydroxyurea, hydroxyurea, hydroxyurea,some some somepatients patients patientswill will willnot not notbe be beable able ableto totogain gain gainand and andmaintain maintain maintain 19,20 19,20 19,20 hematocrit hematocrit hematocritlevels levels levelsof ofof<45% <45% <45% (Figure (Figure (Figure 2). 2). 2). For For Forsome some somepatients patients patientswhose whose whosehematocrit hematocrit hematocritlevels levels levelsremain remain remainelevated, elevated, elevated, and and andfor for forthose those thosewho who whocontinue continue continueto totoexperience experience experienceclinical clinical clinicalsigns signs signs and and and symptoms symptoms symptoms such such such as as as fatigue, fatigue, fatigue, pruritus, pruritus, pruritus, night night night sweats sweats sweats 11,20 11,20 11,20 or oror splenomegaly, splenomegaly, splenomegaly, PV PV PV remains remains remains uncontrolled. uncontrolled. uncontrolled. Recently, Recently, Recently, standardized standardized standardizedcriteria criteria criteriafor for formonitoring monitoring monitoringand and andassessing assessing assessingresponse response response in ininPV PV PVhave have havebeen been beendeveloped developed developedfor for forclinical clinical clinicalresearch. research. research.Evaluation Evaluation Evaluation of ofof response response response includes includes includes such such such parameters parameters parameters as as as resolution resolution resolution of ofof splenomegaly splenomegaly splenomegalyand and andother other otherdisease-related disease-related disease-relatedsigns, signs, signs,hematocrit hematocrit hematocritof ofof <45%, <45%, <45%,blood blood bloodcount count countremission, remission, remission,absence absence absenceof ofofthrombotic thrombotic thromboticevents events events 21 2121 and and andbone bone bonemarrow marrow marrowhistology. histology. histology.

Hydroxyurea Hydroxyurea Hydroxyurea(HU) (HU) (HU)or or orinterferon-alpha interferon-alpha interferon-alphaas as as aa a first-line first-line first-linecytoreductive cytoreductive cytoreductivetherapy therapy therapyat at atany any anyage age age

••Patients •Patients Patients are are are intolerant intolerant intolerant of ofof or oror resistant resistant resistant to toto HU HU HU

Unmet Unmet Unmetneed need needexists exists existsfor for foraaasubset subset subsetof of ofpatients patients patients not not notmanaged managed managedappropriately appropriately appropriatelyby by bycurrent current currenttreatment treatment treatment strategies strategies strategies(alone (alone (aloneor or orin inincombination) combination) combination) Hct, Hct, Hct,hematocrit. hematocrit. hematocrit. aa a

All All All patients patients patients should should should be be be managed managed managed aggressively aggressively aggressively for for for their their their generic generic generic cardiovascular cardiovascular cardiovascular risk risk risk factors. factors. factors. HU HU HU should should should be be be used used used with with with caution caution caution in inin patients patients patients <40 <40 <40 years years years of ofof age; age; age; busulfan busulfan busulfan may may may be be be considered considered considered in inin elderly elderly elderly patients patients patients (>70 (>70 (>70 years). years). years).

111111 Figure Figure Figure 2.2.2. AAA practical practical practical management management management algorithm. algorithm. algorithm.

Learn Learn Learnmore more moreabout about aboutunderstanding understanding understanding the the theburden burden burdenof of ofPolycythemia Polycythemia PolycythemiaVera Vera Vera at at atwww.MPNConnect.com www.MPNConnect.com www.MPNConnect.com References References References 1.1.1. Vannucchi Vannucchi Vannucchi AM, AM, AM, Guglielmelli Guglielmelli Guglielmelli P,P,P, Tefferi Tefferi Tefferi A. A.A. CA CA CA Cancer Cancer Cancer JJClin. JClin. Clin. 2009;59:171-191. 2009;59:171-191. 2009;59:171-191. 2. 2.2. Marchioli Marchioli Marchioli R, R,R, Finazzi Finazzi Finazzi G, G,G, Specchia Specchia Specchia GGG et etet al. al.al. NNN Engl Engl Engl JJMed. JMed. Med. 2013;368:22-33. 2013;368:22-33. 2013;368:22-33. 3. 3.3. Tefferi Tefferi Tefferi A. A.A. Am Am Am JJHematol. JHematol. Hematol. 2013;88:507-516. 2013;88:507-516. 2013;88:507-516. 4. 4.4. Spivak Spivak Spivak JL. JL. JL. Blood. Blood. Blood. 2002;100:4272-4290. 2002;100:4272-4290. 2002;100:4272-4290. 5. 5.5. Spivak Spivak Spivak JL. JL. JL. Ann Ann Ann Intern Intern Intern Med. Med. Med. 2010;152:300-306. 2010;152:300-306. 2010;152:300-306. 6. 6.6. Tefferi Tefferi Tefferi A, A,A, Rumi Rumi Rumi E, E,E, Finazzi Finazzi Finazzi GGG et etet al. al.al. Leukemia. Leukemia. Leukemia. 2013;27:1874-1881. 2013;27:1874-1881. 2013;27:1874-1881. 7.7.7. Gruppo Gruppo Gruppo Italiano Italiano Italiano Studio Studio Studio Policitemia. Policitemia. Policitemia. Ann Ann Ann Intern Intern Intern Med. Med. Med. 1995;123:656-664. 1995;123:656-664. 1995;123:656-664. 8. 8.8. Data Data Data on on on fifile. fi le.le. Incyte Incyte Incyte Corporation. Corporation. Corporation. 9. 9.9. Verstovsek Verstovsek Verstovsek S. S.S. Postgrad Postgrad Postgrad Med. Med. Med. 2013;125:128-135. 2013;125:128-135. 2013;125:128-135. 10. 10. 10. Staerk Staerk Staerk J,J,J, Kallin Kallin Kallin A, A,A, Demoulin Demoulin Demoulin JB JB JB et etet al. al.al. JJBiol JBiol Biol Chem. Chem. Chem. 2005;280:41893-41895. 2005;280:41893-41895. 2005;280:41893-41895. 11. 11. 11. Barbui Barbui Barbui T,T,T, Barosi Barosi Barosi G, G,G, Birgegard Birgegard Birgegard GGG et etet al. al.al. JJClin JClin Clin Oncol. Oncol. Oncol. 2011;29:761-770. 2011;29:761-770. 2011;29:761-770. 12. 12. 12. Passamonti Passamonti Passamonti F.F.F. Blood. Blood. Blood. 2012;120:275-284. 2012;120:275-284. 2012;120:275-284. 13. 13. 13. Hultcrantz Hultcrantz Hultcrantz M, M, M, Kristinsson Kristinsson Kristinsson SY, SY, SY, Andersson Andersson Andersson TML TML TML et etet al. al.al. JJClin JClin Clin Oncol. Oncol. Oncol. 2012;30:2995-3001. 2012;30:2995-3001. 2012;30:2995-3001. 14. 14. 14. Falanga Falanga Falanga A, A,A, Marchetti Marchetti Marchetti M. M. M. Hematology Hematology Hematology Am Am Am Soc Soc Soc Hematol Hematol Hematol Educ Educ Educ Program. Program. Program. 2012;2012:571-581. 2012;2012:571-581. 2012;2012:571-581. 15. 15. 15. Marchioli Marchioli Marchioli R, R,R, Finazzi Finazzi Finazzi G, G,G, Landolfi Landolfi Landolfi RRR et etet al. al.al. JJClin JClin Clin Oncol. Oncol. Oncol. 2005;23:2224-2232. 2005;23:2224-2232. 2005;23:2224-2232. 16. 16. 16. De De De Stefano Stefano Stefano V, V,V, Za Za Za T,T,T, Rossi Rossi Rossi EEE et etet al. al.al. Haematologica. Haematologica. Haematologica. 2008;93:372-380. 2008;93:372-380. 2008;93:372-380. 17. 17. 17. Mesa Mesa Mesa RA, RA, RA, Niblack Niblack Niblack J,J,J, Wadleigh Wadleigh Wadleigh M MM et etet al. al.al. Cancer. Cancer. Cancer. 2007;109:68-76. 2007;109:68-76. 2007;109:68-76. 18. 18. 18. Landolfi Landolfi Landolfi R, R,R, Marchioli Marchioli Marchioli R, R,R, Kutti Kutti Kutti JJet Jetet al. al.al. NNN Engl Engl Engl JJMed. JMed. Med. 2004;350:114-124. 2004;350:114-124. 2004;350:114-124. 19. 19. 19. Barosi Barosi Barosi G, G,G, Birgegard Birgegard Birgegard G, G,G, Finazzi Finazzi Finazzi GGG et etet al. al.al. Br BrBr JJHaematol. JHaematol. Haematol. 2010;148:961-963. 2010;148:961-963. 2010;148:961-963. 20. 20. 20. Alvarez-Larrán Alvarez-Larrán Alvarez-Larrán A, A,A, Pereira Pereira Pereira A, A,A, Cervantes Cervantes Cervantes FFet Fetet al. al.al. Blood. Blood. Blood. 2012;119:1363-1369. 2012;119:1363-1369. 2012;119:1363-1369. 21. 21. 21. Barosi Barosi Barosi G, G,G, Mesa Mesa Mesa R, R,R, Finazzi Finazzi Finazzi GGG et etet al. al.al. Blood. Blood. Blood. 2013;121:4778-4781. 2013;121:4778-4781. 2013;121:4778-4781.

The ASCO Post | APRIL 25, 2015

PAGE 30

Perspective Issues in Oncology

In Search of ‘Just’ Prices: Questioning the High Cost of New Cancer Drugs A Conversation With Hagop M. Kantarjian, MD By Ronald Piana

Hagop M. Kantarjian, MD

s the oncology community begins the slow and often difficult-to-define transition from volume to value in the delivery of cancer care, the relationship between the price and value of certain high-priced cancer drugs is getting more scrutiny. We generally correlate the efficacy of a new drug and its price by complicated cost-efficacy ratios or quality-adjusted life-years. To shed light on this important issue, The ASCO Post recently spoke with nationally regarded leukemia expert Hagop M. Kantarjian, MD, Professor, Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston.

Defining Benefit In our cost-constrained health-care system, what counts as a benefit in cancer treatment? Even as we are looking at treatment value, it is important to note that in most cancers we are far from curing patients with effective and optimal therapies that produce maximum efficacy with minimal toxicity. Therefore, I would consider a benefit in cancer treatment as any metric that improves survival or other parameters important to the patient, such as improved wellbeing and quality-of-life measures. We should not restrict our evaluation of benefit to one parameter. It needs to be an across-the-board assessment of multiple clinical endpoints that determine the treatment’s overall contribution to the condition of the patient.

Cost and Decision-Making How much should cost of oncologic agents factor into a physician’s treatment decisions? Disclaimer: This commentary represents the views of the author and may not necessarily reflect the views of ASCO.

The data show that cancer patients want their oncologists to make treatment decisions based on the most effective treatment, regardless of the price. Everyone understands that the rising costs of cancer treatments contribute to the fiscal dangers faced by our health-care system. But in the intimate doctor-patient setting, it’s all about delivering the best care to our vulnerable cancer patients. Cost discussions should be reserved for the larger public forum. It is an essential public health debate, because currently there is little correlation between the actual cost of a cancer drug and its price.

Free-Market Pricing A growing number of oncologists have been questioning the high costs of new cancer drugs. What’s your opinion on this difficult issue of pricing in a free-market system? In many cases, pharmaceutical companies make excessive profits on the cancer drugs marketed in the United States. For example, U.S. drug companies make very good margins in Europe and elsewhere, despite the fact that most coun-

are priced at more than $100,000 per year. In my opinion, no cancer drug should cost more than $40,000 per year. That would be an equitable price for a drug that prolongs life for 1 year and would offer the drug company reasonable profits without crossing the line into profiteering from an unjust price. The current drugs that cost more than $100,000 are priced in excess of their value, and this unwarranted pricing trend is harming our patients and causing personal and social injustice. Depending on the value in survival and/or quality of life, cancer drugs should be priced from about $10,000 to $40,000.

Research and Development Costs Pharmaceutical companies routinely justify the high costs of their drugs as necessary to defray the large investment in research and development (R&D). Do you feel that explanation accurately explains the costs of new cancer therapies? I believe that the R&D outlay as it relates to drug costs is misinformation. Many companies have used $1 billion

As physicians guided by the Hippocratic oath, it is up to us to stand up for our patients and counter the people and institutions that have a vested interest in keeping cancer drugs priced at an artificially inflated rate. —Hagop M. Kantarjian, MD

tries outside the United States have government- and other entity-sponsored negotiations to reduce and control the price of cancer drugs. We have no such price controls in the United States. At the recent American Society of Hematology (ASH) meeting, an expert contended that the cost for cancer drugs outside the United States is only 30% lower than in the United States. This is a misleading data point, because it conflates the prices of both patented and generic drugs. Outside the United States, generic drugs are indeed more expensive because they don’t use the average sales price-plus-6% formula in their cost valuation. No matter how you spin the data, U.S. cancer patients pay 50% to 300% more for patented cancer drugs than cancer patients in Europe and other regions. Furthermore, many of the patented cancer drugs entering the U.S. market

as their cost to bring a drug from the lab to the market; however, many pharmaceutical company CEOs are now backtracking from that extraordinary number because it includes, among other things, 11% compounded interest annually for 15 years. It also includes government rebates for such things as orphan drugs, and it cites the mean cost of developing the drug as opposed to the median, which increases the cost by another 30%. I’ve studied and written on this subject, and I’d venture that the cost of R&D is about 10% of what numerous companies cite. Instead of justifying high costs of drugs because of R&D expenses, companies should be exploring ways to reduce their R&D costs, such as developing more intelligent trial designs, having discussions with the U.S. Food and Drug Administration (FDA) about reducing unnecessary administrative

work, and other factors that slow the process and add superfluous costs. There are many ways to reduce cost that won’t compromise the quality of the drug development process.

Bar for Approval Many of the new biologics have been approved based on endpoints other than overall survival, such as objective response or progression-free survival. Some argue that these endpoints allow drugs with little true benefit for survival or symptom relief to reach the market; therefore, we should raise the bar for approval. What is your opinion on this issue? I would argue the opposite; I think we should lower the approval bar and get more drugs to the market. For example, in acute myeloid leukemia (AML), because the approval bar has been raised so high, the FDA has not approved a single drug for AML in more than 3 decades. I believe that overall survival should not be the only endpoint for approval. We should consider event-free survival, response rate, quality-of-life parameters, and other factors. We should have as many FDA-approved agents on the market as possible, because once drugs are approved, they are available to outside investigators to explore using the drugs in different combinations and other tumors, which could lead to discoveries that were missed by the original researchers.

Out-of-Pocket Expenses Medical debt is a growing problem in today’s health-care environment. Out-ofpocket copays for expensive cancer drugs are a real challenge for many patients. Is there a way to challenge the status quo that sets the prices of cancer drugs? As mentioned, most of the new drugs being approved cost more than $100,000 per year, so out-of-pocket copay expenses for, say, the average family income of $48,000 is a crushing financial burden. If you look at seniors, whose average annual income is about $32,000, their copays for cancer drugs have driven many into bankruptcy. In short, out-of-pocket expenses for cancer care are preventing some patients from accessing care and harming many others. In my opinion, we should vigorously find ways to totally eliminate out-ofpocket expenses for cancer patients. This isn’t a unique idea. For example, in my home country of Lebanon, cancer care is delivered without any out-of-pocket excontinued on page 32

The goal seemed insurmountable: to find a way to unleash the immune system’s power to fight cancer.

And we achieved it at Dana-Farber.

To many physician-researchers and scientists, finding a way to get the body’s immune system to attack cancer cells is a momentous achievement. And Dana-Farber researchers helped make it happen. We found that some cancer cells elude the body’s immune defenses by cloaking themselves in the proteins PD-L1 and PD-L2. This discovery led to the development of several immunotherapies that are already demonstrating promising results and better quality of life for some people with deadly cancers. In fact, the new therapies have improved outcomes for many patients with advanced metastatic melanoma, kidney cancer, Hodgkin lymphoma, bladder cancer, stage IV lung cancer, and more. And the sky is the limit. Videos, whitepapers and more at DiscoverCareBelieve.org/PD-1.

The ASCO Post | APRIL 25, 2015

PAGE 32

Clinical Brief Sarcoma

Persistence of HER2-Specific CAR T Cells in HER2-Positive Sarcoma By Matthew Stenger

n a phase I/II study reported in the Journal of Clinical Oncology,1 Nabil Ahmed, MD, MSc, of Baylor College of Medicine, Houston, and colleagues, found that infusion of T cells expressing HER2-specific chimeric antigen

ated, with no dose-limiting toxicities being observed. At doses of ≥ 1×105/m2, HER2-CAR T cells were detected by quantitative polymerase chain reaction at 3 hours after infusion in 14 of 16 patients. HER2-CAR T cells persisted for

CAR T Cells in HER2-Positive Sarcoma ■■ HER2-CAR T cells persisted for ≥ 6 weeks in some patients with HER2-positive recurrent/refractory sarcoma. ■■ Extensive necrosis was observed in one tumor.

receptor (CAR) with a CD28.ζ signaling domain (HER2-CAR T cells) could produce persistent CAR T cell levels for ≥ 6 weeks in patients with HER2-positive recurrent/refractory sarcoma. In the study, 19 patients received escalating HER2-CAR T doses of 1×104/ m2 to 1×108/m2. Infusions were well toler-

≥ 6 weeks in 7 of 9 evaluable patients who received a dose > 1×106/m2 (P = .005). HER2-CAR T cells were identified at tumor sites of each of two patients examined. Among 17 evaluable patients, 4 had stable disease for 12 weeks to 14 months. Three of these patients received no additional therapy

and had residual tumor removed, with the tumor from one patient exhibiting ≥ 90% necrosis. At the time of analysis, all three patients remained in remission at 6 to 16 months with no further treatment. Median overall survival of all 19 patients receiving infusion was 10.3 months (range = 5.1–29.1 months). The investigators concluded: “This first evaluation of the safety and efficacy of HER2-CAR T cells in patients with cancer shows the cells can persist for 6 weeks without evident toxicities, setting the stage for studies that combine HER2-CAR T cells with other immunomodulatory approaches to enhance their expansion and persistence.” Stephen Gottschalk, MD, of Baylor College of Medicine is the correspond-

High Cost of Cancer Drugs

It’s not as complicated an issue as it might seem. But as a growing number of oncologists voice concern about the costs of cancer drugs, we’ll see a public relations campaign by the pharmaceutical industry to justify the prices of these drugs. The central argument is that if they are constrained in pricing, it will stifle valuable innovation. The reality is that since 2000, the pharmaceutical industry

has discarded their social responsibility to provide cancer therapies at a just pricing level that patients can afford. Nobody is against reasonable profit, but since the Medicare Modernization Act of 2003 and the legislation of Medicare Part D, which made drug companies the sole arbiter on pricing, we’ve seen an alarming increase in drug prices that is harming our patients and our

This first evaluation of the safety and efficacy of HER2-CAR T cells in patients with cancer shows the cells can persist for 6 weeks without evident toxicities, setting the stage for studies that combine HER2-CAR T cells with other immunomodulatory approaches to enhance their expansion and persistence. —Nabil Ahmed, MD, MSc, and colleagues

continued from page 30

penses. If patients can’t pay for the drugs, the government foots the bill. I think in the United States, we should find a way to achieve zero out-of-pocket expenses for patented cancer drugs.

Social Responsibility Any last thoughts on drug pricing?

ing author for the Journal of Clinical Oncology article. n

Disclosure: The study was supported by the V Foundation for Cancer Research, Cancer Prevention and Research Institute of Texas, Hoag Foundation, Alliance for Cancer Gene Therapy, Alex’s Lemonade Stand Foundation for Childhood Cancer, Stand Up To Cancer St. Baldrick’s Pediatric Dream Team, Clinical Research Center at Texas Children’s Hospital, and Dan L. Duncan Institute for Clinical and Translational Research at Baylor College of Medicine. For full disclosures of the study authors, visit jco.ascopubs.org.

Reference 1. Ahmed N, Brawley VS, Hedge M, et al: Human epidermal growth factor receptor 2 (HER2)-specific chimeric antigen receptor–modified T cells for the immunotherapy of HER2-positive sarcoma. J Clin Oncol. March 23, 2015 (early release online).

health-care system. As physicians guided by the Hippocratic oath, it is up to us to stand up for our patients and counter the people and institutions that have a vested interest in keeping cancer drugs priced at an artificially inflated rate. As doctors, we should be strong advocates for our patients. n Disclosure: Dr. Kantarjian reported no potential conflicts of interest.

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For patients with metastatic squamous non-small cell lung cancer (NSCLC) with progression on or after platinum-based chemotherapyâ&#x20AC;Ś

What if You Could Do More?

Expect More. Do More.

Proven Superior Survival With the Only Immuno-Oncology Therapy in Previously Treated Metastatic Squamous NSCLC INDICATION OPDIVO速 (nivolumab) is indicated for the treatment of patients with metastatic squamous non-small cell lung cancer (NSCLC) with progression on or after platinum-based chemotherapy.

SELECT IMPORTANT SAFETY INFORMATION OPDIVO is associated with the following Warnings and Precautions including immune-mediated: pneumonitis, colitis, hepatitis, nephritis and renal dysfunction, hypothyroidism, hyperthyroidism, other adverse reactions; and embryofetal toxicity.

For patients with metastatic squamous non-small cell lung cancer with progression on or after platinum-based chemotherapy

OPDIVO Demonstrated Superior Survival vs Standard of Care1-5 100

MEDIAN OS 9.2 MONTHS vs 6.0 MONTHS

Probability of Survival (% of Patients)

(95% CI: 7.3-13.3 vs 5.1-7.3) HR=0.59; 95% CI: 0.44-0.79; P=0.00025

70 60 50 40 30 20 10 0 0

Number at risk OPDIVO 135 137 DOCETAXEL

113 103

86 68

69 45

31 14

15 7

7 2

0 0

OS (Months) 52 30

Refer to Figure 1 in the Full Prescribing Information for data on censored patients. CI=confidence interval; HR=hazard ratio; IV=intravenous; OS=overall survival; PD-1=programmed death-1; PD-L1=programmed death ligand 1.

Study design: OPDIVO was evaluated in a randomized (1:1), open-label, phase 3 study of OPDIVO 3 mg/kg IV every 2 weeks (n=135) vs docetaxel 75 mg/m2 IV every 3 weeks (n=137). The primary endpoint of the study was overall survival.1,6 Results were based on the prespecified interim analysis conducted when 199 events (86% of the planned number of events for final analysis) were observed (86 in the OPDIVO arm and 113 in the docetaxel arm).1 ■

This study included patients regardless of PD-L1 status; PD-L1 testing is not required for a treatment decision

Based on the unprecedented results, OPDIVO achieved the benchmark goal of improving overall survival in metastatic squamous NSCLC The safety of OPDIVO (3 mg/kg IV over 60 minutes every 2 weeks) was evaluated in CHECKMATE 063 (Trial 3), a singlearm study of 117 patients with metastatic squamous NSCLC who had progressed after receiving a platinum-based therapy and at least one additional systemic treatment regimen.1,7 Twenty-nine percent of patients receiving OPDIVO had a drug delay for an adverse reaction.

Serious Adverse Reactions ■

In Trial 3, serious adverse reactions occurred in 59% of patients receiving OPDIVO. The most frequent serious adverse drug reactions reported in ≥2% of patients were dyspnea, pneumonia, chronic obstructive pulmonary disease exacerbation, pneumonitis, hypercalcemia, pleural effusion, hemoptysis, and pain.

Common Adverse Reactions ■

The most common adverse reactions (≥20%) reported with OPDIVO in Trial 3 were fatigue (50%), dyspnea (38%), musculoskeletal pain (36%), decreased appetite (35%), cough (32%), nausea (29%), and constipation (24%).

Please see additional Important Safety Information on the following page.

Responding to Your Needs in 24 Hours or Less

IMPORTANT SAFETY INFORMATION Immune-Mediated Pneumonitis Severe pneumonitis or interstitial lung disease, including fatal cases, occurred with OPDIVO treatment. Across the clinical trial experience in 691 patients with solid tumors, fatal immunemediated pneumonitis occurred in 0.7% (5/691) of patients receiving OPDIVO; no cases occurred in Trial 3. In Trial 3, immunemediated pneumonitis occurred in 6% (7/117) of patients receiving OPDIVO including five Grade 3 and two Grade 2 cases. Monitor patients for signs and symptoms of pneumonitis. Administer corticosteroids for Grade 2 or greater pneumonitis. Permanently discontinue OPDIVO for Grade 3 or 4 and withhold OPDIVO until resolution for Grade 2. Immune-Mediated Colitis In Trial 3, diarrhea occurred in 21% (24/117) of patients receiving OPDIVO. Grade 3 immune-mediated colitis occurred in 0.9% (1/117) of patients. Monitor patients for immune-mediated colitis. Administer corticosteroids for Grade 2 (of more than 5 days duration), 3, or 4 colitis. Withhold OPDIVO for Grade 2 or 3. Permanently discontinue OPDIVO for Grade 4 colitis or recurrent colitis upon restarting OPDIVO. Immune-Mediated Hepatitis In Trial 3, the incidences of increased liver test values were AST (16%), alkaline phosphatase (14%), ALT (12%), and total bilirubin (2.7%). Monitor patients for abnormal liver tests prior to and periodically during treatment. Administer corticosteroids for Grade 2 or greater transaminase elevations. Withhold OPDIVO for Grade 2 and permanently discontinue OPDIVO for Grade 3 or 4 immunemediated hepatitis. Immune-Mediated Nephritis and Renal Dysfunction In Trial 3, the incidence of elevated creatinine was 22%. Immunemediated renal dysfunction (Grade 2) occurred in 0.9% (1/117) of patients. Monitor patients for elevated serum creatinine prior to and periodically during treatment. For Grade 2 or 3 serum creatinine elevation, withhold OPDIVO and administer corticosteroids; if worsening or no improvement occurs, permanently discontinue OPDIVO. Administer corticosteroids for Grade 4 serum creatinine elevation and permanently discontinue OPDIVO. Immune-Mediated Hypothyroidism and Hyperthyroidism

In Trial 3, hypothyroidism occurred in 4.3% (5/117) of patients

receiving OPDIVO. Hyperthyroidism occurred in 1.7% (2/117) of patients including one Grade 2 case. Monitor thyroid function prior to and periodically during treatment. Administer hormone replacement therapy for hypothyroidism. Initiate medical management for control of hyperthyroidism.

Other Immune-Mediated Adverse Reactions

The following clinically significant immune-mediated adverse

administered at doses 3 mg/kg and 10 mg/kg, additional clinically significant, immune-mediated adverse reactions were identified: hypophysitis, diabetic ketoacidosis, hypopituitarism, GuillainBarré syndrome, and myasthenic syndrome. Based on the severity of adverse reaction, withhold OPDIVO, administer high-dose corticosteroids, and, if appropriate, initiate hormone-replacement therapy. Embryofetal Toxicity

Based on its mechanism of action, OPDIVO can cause fetal harm

when administered to a pregnant woman. Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with OPDIVO and for at least 5 months after the last dose of OPDIVO.

Lactation

It is not known whether OPDIVO is present in human milk. Because

many drugs, including antibodies, are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from OPDIVO, advise women to discontinue breastfeeding during treatment.

Serious Adverse Reactions

In Trial 3, serious adverse reactions occurred in 59% of patients

receiving OPDIVO. The most frequent serious adverse drug reactions reported in ≥2% of patients were dyspnea, pneumonia, chronic obstructive pulmonary disease exacerbation, pneumonitis, hypercalcemia, pleural effusion, hemoptysis, and pain.

Common Adverse Reactions

The most common adverse reactions (≥20%) reported

with OPDIVO in Trial 3 were fatigue (50%), dyspnea (38%), musculoskeletal pain (36%), decreased appetite (35%), cough (32%), nausea (29%), and constipation (24%).

Please see brief summary of Full Prescribing Information on the following pages. References: 1. OPDIVO [package insert]. Princeton, NJ: Bristol-Myers Squibb Company; 2015. 2. Taxotere [package insert]. Bridgewater, NJ: sanofi-aventis U.S. LLC; 2014. 3. Referenced with permission from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) Non-Small Cell Lung Cancer V.4.2015. ©2015 National Comprehensive Cancer Network, Inc. All rights reserved. Accessed February 3, 2015. To view the most recent and complete version of the NCCN 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. 4. Garassino MC, Martelli O, Broggini M, et al; on behalf of the TAILOR trialists. Erlotinib versus docetaxel as second-line treatment of patients with advanced non-small-cell lung cancer and wild-type EGFR tumours (TAILOR): a randomised controlled trial. Lancet Oncol. 2013;14(10):981-988. 5. Kawaguchi T, Ando M, Asami K, et al. Randomized phase III trial of erlotinib versus docetaxel as second- or third-line therapy in patients with advanced nonsmall-cell lung cancer: Docetaxel and Erlotinib Lung Cancer Trial (DELTA). J Clin Oncol. 2014;32(18):19021908. 6. Bristol-Myers Squibb. Study of BMS-936558 (nivolumab) compared to docetaxel in previously treated advanced or metastatic squamous cell non-small cell lung cancer (NSCLC) (CheckMate 017). Identifier: NCT01642004. https://clinicaltrials.gov/ct2/show/NCT01642004. Updated December 31, 2014. Accessed February 5, 2015. 7. Rizvi NA, Mazières J, Planchard D, et al. Activity and safety of nivolumab, an anti-PD-1 immune checkpoint inhibitor, for patients with advanced, refractory squamous non-small-cell lung cancer (CheckMate 063): a phase 2, single-arm trial. Lancet Oncol. 2015;16:257-265.

reactions occurred in <2% of OPDIVO-treated patients: adrenal insufficiency, uveitis, pancreatitis, facial and abducens nerve paresis, demyelination, autoimmune neuropathy, motor dysfunction and vasculitis. Across clinical trials of OPDIVO OPDIVO® and the related logo are trademarks of Bristol-Myers Squibb Company. ©2015 Bristol-Myers Squibb Company. All rights reserved. Printed in USA. 1506US15BR00482-02-01 03/15

OPDIVO® (nivolumab) injection, for intravenous use Brief Summary of Prescribing Information. For complete prescribing information consult official package insert. INDICATIONS AND USAGE OPDIVO® (nivolumab) is indicated for the treatment of patients with metastatic squamous non-small cell lung cancer (NSCLC) with progression on or after platinum-based chemotherapy [see Clinical Studies (14.2) in full Prescribing Information]. CONTRAINDICATIONS None. WARNINGS AND PRECAUTIONS Immune-Mediated Pneumonitis Severe pneumonitis or interstitial lung disease, including fatal cases, occurred with OPDIVO treatment. Across the clinical trial experience in 691 patients with solid tumors, fatal immune-mediated pneumonitis occurred in 0.7% (5/691) of patients receiving OPDIVO. No cases of fatal pneumonitis occurred in Trial 3; all five fatal cases occurred in a dose-finding study with OPDIVO doses of 1 mg/kg (two patients), 3 mg/kg (two patients), and 10 mg/kg (one patient). In Trial 3, pneumonitis occurred in 6% (7/117) of patients receiving OPDIVO, including five Grade 3 and two Grade 2 cases, all immune-mediated. The median time to onset was 3.3 months (range: 1.4 to 13.5 months). All seven patients discontinued OPDIVO for pneumonitis or another event and all seven patients experienced complete resolution of pneumonitis following receipt of high-dose corticosteroids (at least 40 mg prednisone equivalents per day). Monitor patients for signs and symptoms of pneumonitis. Administer corticosteroids at a dose of 1 to 2 mg/kg/day prednisone equivalents for Grade 2 or greater pneumonitis, followed by corticosteroid taper. Permanently discontinue OPDIVO for severe (Grade 3) or life-threatening (Grade 4) pneumonitis and withhold OPDIVO until resolution for moderate (Grade 2) pneumonitis [see Dosage and Administration (2.2) in full Prescribing Information]. Immune-Mediated Colitis In Trial 3, diarrhea occurred in 21% (24/117) of patients. Immune-mediated colitis (Grade 3) occurred in 0.9% (1/117) of patients. The time to onset in this patient was 6.7 months. The patient received high-dose corticosteroids and was permanently discontinued from OPDIVO (nivolumab). Complete resolution occurred. Monitor patients for immune-mediated colitis. Administer corticosteroids at a dose of 1 to 2 mg/kg/day prednisone equivalents followed by corticosteroid taper for severe (Grade 3) or life-threatening (Grade 4) colitis. Administer corticosteroids at a dose of 0.5 to 1 mg/kg/day prednisone equivalents followed by corticosteroid taper for moderate (Grade 2) colitis of more than 5 days duration; if worsening or no improvement occurs despite initiation of corticosteroids, increase dose to 1 to 2 mg/kg/day prednisone equivalents. Withhold OPDIVO for Grade 2 or 3 immune-mediated colitis. Permanently discontinue OPDIVO for Grade 4 colitis or for recurrent colitis upon restarting OPDIVO [see Dosage and Administration (2.2) in full Prescribing Information]. Immune-Mediated Hepatitis In Trial 3, the incidences of increased liver test values were AST (16%), alkaline phosphatase (14%), ALT (12%), and total bilirubin (2.7%). No cases of immunemediated hepatitis occurred in this trial. Monitor patients for abnormal liver tests prior to and periodically during treatment. Administer corticosteroids at a dose of 1 to 2 mg/kg/day prednisone equivalents for Grade 2 or greater transaminase elevations, with or without concomitant elevation in total bilirubin. Withhold OPDIVO for moderate (Grade 2) and permanently discontinue OPDIVO for severe (Grade 3) or life-threatening (Grade 4) immune-mediated hepatitis [see Dosage and Administration (2.2) in full Prescribing Information and Adverse Reactions]. Immune-Mediated Nephritis and Renal Dysfunction In Trial 3, the incidence of elevated creatinine was 22%. Immune-mediated renal dysfunction (Grade 2) occurred in 0.9% (1/117) of patients. The time to onset in this patient was 0.8 months. The patient received high-dose corticosteroids. OPDIVO was withheld, and the patient discontinued due to disease progression prior to receiving additional OPDIVO. Immune-mediated renal dysfunction was ongoing. Monitor patients for elevated serum creatinine prior to and periodically during treatment. Administer corticosteroids at a dose of 1 to 2 mg/kg/day prednisone equivalents followed by corticosteroid taper for life-threatening (Grade 4) serum creatinine elevation and permanently discontinue OPDIVO. For severe (Grade 3) or moderate (Grade 2) serum creatinine elevation, withhold OPDIVO and administer

corticosteroids at a dose of 0.5 to 1 mg/kg/day prednisone equivalents followed by corticosteroid taper; if worsening or no improvement occurs, increase dose of corticosteroids to 1 to 2 mg/kg/day prednisone equivalents and permanently discontinue OPDIVO (nivolumab) [see Dosage and Administration (2.2) in full Prescribing Information and Adverse Reactions]. Immune-Mediated Hypothyroidism and Hyperthyroidism In Trial 3, patients were evaluated for thyroid function at baseline, first day of treatment, and every 6 weeks. Hypothyroidism occurred in 4.3% (5/117) of patients. The median time to onset for these five cases was 4.1 months (range: 1.4 to 4.6 months). All five patients with hypothyroidism received levothyroxine. Complete resolution of hypothyroidism occurred in one patient allowing discontinuation of levothyroxine. Interruption of OPDIVO did not occur in these five patients. Hyperthyroidism occurred in 1.7% (2/117) of patients. One patient experienced Grade 2 hyperthyroidism 5.2 months after the first dose of OPDIVO, requiring treatment with high-dose corticosteroids and methimazole. Thyroid laboratory tests returned to normal 4.7 months later. Monitor thyroid function prior to and periodically during treatment. Administer hormone replacement therapy for hypothyroidism. Initiate medical management for control of hyperthyroidism. There are no recommended dose adjustments of OPDIVO for hypothyroidism or hyperthyroidism. Other Immune-Mediated Adverse Reactions Other clinically significant immune-mediated adverse reactions can occur. Immune-mediated adverse reactions may occur after discontinuation of OPDIVO therapy. The following clinically significant, immune-mediated adverse reactions occurred in less than 2% of OPDIVO-treated patients (n=385): adrenal insufficiency, uveitis, pancreatitis, facial and abducens nerve paresis, demyelination, autoimmune neuropathy, motor dysfunction, and vasculitis. Across clinical trials of OPDIVO administered at doses of 3 mg/kg and 10 mg/kg the following additional clinically significant, immune-mediated adverse reactions were identified: hypophysitis, diabetic ketoacidosis, hypopituitarism, GuillainBarré syndrome, and myasthenic syndrome. For any suspected immune-mediated adverse reactions, exclude other causes. Based on the severity of the adverse reaction, withhold OPDIVO, administer highdose corticosteroids, and if appropriate, initiate hormone-replacement therapy. Upon improvement to Grade 1 or less, initiate corticosteroid taper and continue to taper over at least 1 month. Consider restarting OPDIVO after completion of corticosteroid taper based on the severity of the event [see Dosage and Administration (2.2) in full Prescribing Information]. Embryofetal Toxicity Based on its mechanism of action and data from animal studies, OPDIVO can cause fetal harm when administered to a pregnant woman. In animal reproduction studies, administration of nivolumab to cynomolgus monkeys from the onset of organogenesis through delivery resulted in increased abortion and premature infant death. Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with OPDIVO and for at least 5 months after the last dose of OPDIVO [see Use in Specific Populations]. ADVERSE REACTIONS The following adverse reactions are discussed in greater detail in other sections of the labeling. • Immune-Mediated Pneumonitis [see Warnings and Precautions] • Immune-Mediated Colitis [see Warnings and Precautions] • Immune-Mediated Hepatitis [see Warnings and Precautions] • Immune-Mediated Nephritis and Renal Dysfunction [see Warnings and Precautions] • Immune-Mediated Hypothyroidism and Hyperthyroidism [see Warnings and Precautions] • Other Immune-Mediated Adverse Reactions [see Warnings and Precautions] 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. The data described in the WARNINGS and PRECAUTIONS section and below reflect exposure to OPDIVO in Trial 3, a single-arm trial in patients with metastatic squamous non-small cell lung cancer (NSCLC).

Clinically significant adverse reactions were evaluated in a total of 691 patients enrolled in Trials 1, 3, or an additional dose finding study (n=306) administering OPDIVO (nivolumab) at doses of 0.1 to 10 mg/kg every 2 weeks [see Warnings and Precautions]. Metastatic Squamous Non-Small Cell Lung Cancer The safety of OPDIVO was evaluated in Trial 3, a single-arm multinational, multicenter trial in 117 patients with metastatic squamous NSCLC and progression on both a prior platinum-based therapy and at least one additional systemic therapy [see Clinical Studies (14.2) in full Prescribing Information]. Patients received 3 mg/kg of OPDIVO administered intravenously over 60 minutes every 2 weeks. The median duration of therapy was 2.3 months (range: 1 day to 16.1+ months). Patients received a median of 6 doses (range: 1 to 34). Trial 3 excluded patients with active autoimmune disease, symptomatic interstitial lung disease, or untreated brain metastasis. The median age of patients was 65 years (range: 37 to 87) with 50% ≥65 years of age and 14% ≥75 years of age. The majority of patients were male (73%) and white (85%). All patients received two or more prior systemic treatments. Baseline disease characteristics of the population were recurrent Stage IIIb (6%), Stage IV (94%), and brain metastases (1.7%). Baseline ECOG performance status was 0 (22%) or 1 (78%). OPDIVO was discontinued due to adverse reactions in 27% of patients. Twenty-nine percent of patients receiving OPDIVO had a drug delay for an adverse reaction. Serious adverse reactions occurred in 59% of patients receiving OPDIVO. The most frequent serious adverse reactions reported in at least 2% of patients were dyspnea, pneumonia, chronic obstructive pulmonary disease exacerbation, pneumonitis, hypercalcemia, pleural effusion, hemoptysis, and pain. Table 1 summarizes adverse reactions that occurred in at least 10% of patients. The most common adverse reactions (reported in at least 20% of patients) were fatigue, dyspnea, musculoskeletal pain, decreased appetite, cough, nausea, and constipation. Table 1:

Adverse Reactions Occurring in ≥10% of Patients for All NCI CTCAE* Grades or ≥5% for Grades 3-4 (Trial 3)

Table 1: (Continued)

Adverse Reactions Occurring in ≥10% of Patients for All NCI CTCAE* Grades or ≥5% for Grades 3-4 (Trial 3) OPDIVO (nivolumab) (n=117)

Adverse Reaction

All Grades

Investigations Decreased weight Infections and Infestations Pneumoniag

0.9

*a National Cancer Institute Common Terminology Criteria for Adverse Events, Version 4.0.

Includes face edema, peripheral edema, local swelling, localized edema, lymphoedema. Includes chest discomfort and noncardiac chest pain. Includes back pain, bone pain, musculoskeletal chest pain, myalgia, neck pain, pain in extremity, spinal pain. d Includes arthritis and osteoarthritis. e Includes abdominal pain lower, abdominal pain upper, gastrointestinal pain. f Includes maculopapular rash, rash erythematous, erythema, dermatitis, dermatitis exfoliative, and dermatitis acneiform. g Includes lung infection and pneumonia aspiration. b c

Other clinically important adverse reactions in less than 10% of patients in Trial 3 were: General Disorders and Administration Site Conditions: stomatitis Nervous System Disorders: peripheral neuropathy Infections and Infestations: bronchitis, upper respiratory tract infection Table 2:

Laboratory Abnormalities Worsening from Baseline Occurring in ≥10% of Patients for all NCI CTCAE Grades or ≥2% for Grades 3-4 (Trial 3) Percentage of Patients with Worsening Laboratory Test from Baselinea

Grades 3-4

Percentage (%) of Patients General Disorders and Administration Site Conditions Fatigue Asthenia Edemaa Pyrexia Chest painb Pain Respiratory, Thoracic, and Mediastinal Disorders Dyspnea Cough Musculoskeletal and Connective Tissue Disorders Musculoskeletal painc Arthralgiad Metabolism and Nutrition Disorders Decreased appetite Gastrointestinal Disorders Nausea Constipation Vomiting Diarrhea Abdominal paine Skin and Subcutaneous Tissue Disorders Rashf Pruritus

Grades 3-4

Percentage (%) of Patients

OPDIVO (n=117) Adverse Reaction

All Grades

50 19 17 17 13 10

7 1.7 1.7 0 0 2.6

38 32

9 1.7

36 13

6 0

2.6

29 24 19 18 16

1.7 0 0.9 2.6 1.7

16 11

0.9 0.9 (Continued)

Test Chemistry Hyponatremia Increased creatinine Hypercalcemia Hypokalemia Hypomagnesemia Hypocalcemia Hyperkalemia Increased AST Increased alkaline phosphatase Increased ALT Hematology Lymphopenia Anemia Thrombocytopenia a

All Grades

Grades 3-4

38 22 20 20 20 18 18 16 14 12

10 0 2.6 2.6 0 1.8 4.4 0.9 0 0

47 28 14

16 2.6 0

Each test incidence is based on the number of patients who had both baseline and at least one on-study laboratory measurement available (range 111 to 114 patients).

Immunogenicity As with all therapeutic proteins, there is a potential for immunogenicity. Of 281 patients who were treated with OPDIVO 3 mg/kg every 2 weeks and evaluable for the presence of anti-product antibodies, 24 patients (8.5%) tested positive for treatment-emergent anti-product antibodies by an electrochemiluminescent (ECL) assay. Neutralizing antibodies were detected in two patients (0.7%). There was no evidence of altered pharmacokinetic profile or toxicity profile with anti-product binding antibody development based on the population pharmacokinetic and exposure-response analyses. 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 OPDIVO (nivolumab) with the incidences of antibodies to other products may be misleading. DRUG INTERACTIONS No formal pharmacokinetic drug-drug interaction studies have been conducted with OPDIVO. USE IN SPECIFIC POPULATIONS

Hepatic Impairment Based on a population pharmacokinetic analysis, no dose adjustment is recommended for patients with mild hepatic impairment. OPDIVO (nivolumab) has not been studied in patients with moderate or severe hepatic impairment [see Clinical Pharmacology (12.3) in full Prescribing Information]. OVERDOSAGE There is no information on overdosage with OPDIVO.

Pregnancy

PATIENT COUNSELING INFORMATION

Risk Summary Based on its mechanism of action [see Clinical Pharmacology (12.1) in full Prescribing Information] and data from animal studies, OPDIVO can cause fetal harm when administered to a pregnant woman [see Clinical Pharmacology (12.1) in full Prescribing Information]. In animal reproduction studies, administration of nivolumab to cynomolgus monkeys from the onset of organogenesis through delivery resulted in increased abortion and premature infant death [see Data]. Human IgG4 is known to cross the placental barrier and nivolumab is an immunoglobulin G4 (IgG4); therefore, nivolumab has the potential to be transmitted from the mother to the developing fetus. The effects of OPDIVO are likely to be greater during the second and third trimesters of pregnancy. There are no available human data informing the drug-associated risk. Advise pregnant women of the potential risk to a fetus. The background risk of major birth defects and miscarriage for the indicated population is unknown; however, the background risk in the U.S. general population of major birth defects is 2% to 4% and of miscarriage is 15% to 20% of clinically recognized pregnancies. Data

Advise the patient to read the FDA-approved patient labeling (Medication Guide). Inform patients of the risk of immune-mediated adverse reactions that may require corticosteroid treatment and interruption or discontinuation of OPDIVO, including: • Pneumonitis: Advise patients to contact their healthcare provider immediately for any new or worsening cough, chest pain, or shortness of breath [see Warnings and Precautions]. • Colitis: Advise patients to contact their healthcare provider immediately for diarrhea or severe abdominal pain [see Warnings and Precautions]. • Hepatitis: Advise patients to contact their healthcare provider immediately for jaundice, severe nausea or vomiting, pain on the right side of abdomen, lethargy, or easy bruising or bleeding [see Warnings and Precautions]. • Nephritis and Renal Dysfunction: Advise patients to contact their healthcare provider immediately for signs or symptoms of nephritis including decreased urine output, blood in urine, swelling in ankles, loss of appetite, and any other symptoms of renal dysfunction [see Warnings and Precautions]. • Hypothyroidism and Hyperthyroidism: Advise patients to contact their healthcare provider immediately for signs or symptoms of hypothyroidism and hyperthyroidism [see Warnings and Precautions]. Advise patients of the importance of keeping scheduled appointments for blood work or other laboratory tests [see Warnings and Precautions]. Advise females of reproductive potential of the potential risk to a fetus and to inform their healthcare provider of a known or suspected pregnancy [see Warnings and Precautions, Use in Specific Populations]. Advise females of reproductive potential to use effective contraception during treatment with OPDIVO and for at least 5 months following the last dose of OPDIVO [see Use in Specific Populations]. Advise women not to breastfeed while taking OPDIVO [see Use in Specific Populations].

Animal Data A central function of the PD-1/PD-L1 pathway is to preserve pregnancy by maintaining maternal immune tolerance to the fetus. Blockade of PD-L1 signaling has been shown in murine models of pregnancy to disrupt tolerance to the fetus and to increase fetal loss. The effects of nivolumab on prenatal and postnatal development were evaluated in monkeys that received nivolumab twice weekly from the onset of organogenesis through delivery, at exposure levels of between 9 and 42 times higher than those observed at the clinical dose of 3 mg/kg of nivolumab (based on AUC). Nivolumab administration resulted in a non-doserelated increase in spontaneous abortion and increased neonatal death. Based on its mechanism of action, fetal exposure to nivolumab may increase the risk of developing immune-mediated disorders or altering the normal immune response and immune-mediated disorders have been reported in PD-1 knockout mice. In surviving infants (18 of 32 compared to 11 of 16 vehicle-exposed infants) of cynomolgus monkeys treated with nivolumab, there were no apparent malformations and no effects on neurobehavioral, immunological, or clinical pathology parameters throughout the 6-month postnatal period. Lactation Risk Summary It is not known whether OPDIVO is present in human milk. Because many drugs, including antibodies are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from OPDIVO, advise women to discontinue breastfeeding during treatment with OPDIVO. Females and Males of Reproductive Potential Contraception Based on its mechanism of action, OPDIVO can cause fetal harm when administered to a pregnant woman [see Use in Specific Populations]. Advise females of reproductive potential to use effective contraception during treatment with OPDIVO and for at least 5 months following the last dose of OPDIVO. Pediatric Use The safety and effectiveness of OPDIVO have not been established in pediatric patients. Geriatric Use Clinical studies of OPDIVO did not include sufficient numbers of patients aged 65 years and older to determine whether they respond differently from younger patients. Of the 117 patients treated with OPDIVO in Trial 3, 50% of patients were 65 years or older and 14% were 75 years or older. Renal Impairment Based on a population pharmacokinetic analysis, no dose adjustment is recommended in patients with renal impairment [see Clinical Pharmacology (12.3) in full Prescribing Information].

Manufactured by: Bristol-Myers Squibb Company Princeton, NJ 08543 USA U.S. License No. 1713 1321663A1

Revised: March 2015 1506US15BR00210-02-01

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Geriatrics for the Oncologist

Preparing for the ‘Silver Tsunami’ and the Impact of an Aging Population on Cancer Care By Jimmie Holland, MD, and Mindy Greenstein, PhD “Older adults constitute the only increasing natural resource in the entire world.” —Linda Fried, PhD, Columbia School of Public Health

he good and bad news about our changing demographic world is that the population of older adults is increasing in the United States and worldwide. While it is good news that people are living longer and healthier, this increasing

14 million cancer survivors in the country, 59% are over 65. These circumstances are evolving in the context of increasingly expensive and complex treatments for cancer, which will have to be delivered by a workforce that is likely to remain the same. Geriatric oncology must take the lead in planning ahead to weaken the force of the approaching “silver tsunami,” preparing oncologists and their teams, who will take the most direct hit.

Geriatric oncology must take the lead in planning ahead to weaken the force of the approaching ‘silver tsunami,’ preparing oncologists and their teams, who will take the most direct hit. —Jimmie Holland, MD, and Mindy Greenstein, PhD

number of older people will also need health care for largely chronic diseases, especially cancer. In 2013, the Institute of Medicine suggested that we prepare for this change,1 given the aging population, increase in cancer incidence, and the fact that of the Dr. Holland is Attending Psychiatrist and Wayne E. Chapman Chair at Memorial Sloan Kettering Cancer Center and Professor of Psychiatry, Weill Medical College of Cornell University in New York. Dr. Greenstein is a clinical psychologist and consultant to the geriatric group in the Department of Psychiatry at Memorial Sloan Kettering.

Attitudes of Oncology Teams This population will be cared for by a younger oncology team who may have had little experience with older adults since their personal experience with elders is often limited today. This problem is compounded by negative societal attitudes toward older people; young house staff may even develop derogatory terms for elders. We are impressed by the number of older patients whose only trip outside their home over the course of a week is to their doctors’ offices. They may leave feeling cheered by a warm interaction or saddened by the negative attitudes

that are evident to them, especially if they move slowly, hear poorly, or have any trouble understanding. We must include in our “tsunami planning” the training of oncology teams in how to speak kindly and respectfully to older patients. Also, treatment decisions should be made based on level of functioning rather than chronologic age, even if it takes more time to take the history. Demakos et al found that patients with myelodysplastic syndrome— largely an older population—are frequently not treated with the optimal number of cycles of hypomethylating agents, which contributes to poor posttreatment prognosis.2 Ageism may contribute to this early discontinuation. We can all remember when protocols routinely excluded patients over 65, before it was discovered that many older patients tolerated treatment well. At the Communication Skills Laboratory at Memorial Sloan Kettering Cancer Center, we have developed a teaching module for oncology staff to appropriately evaluate older patients and learn how to include a family member when the patient needs assistance in decisions about treatment.

Older Patients’ Attitudes and Coping In the 1990s, psychologists began to focus not only on psychopathology, but on the positive attributes that help us cope. An extensive review of current and past religions and philosophies found a consistent group of core character strengths that have sustained people into old age: courage, wisdom, humanity, social justice, temperance, and transcendence.3 Philosopher and ethicist Sissela Bok noted that these qualities “allow the human animal to struggle against and to triumph over what is darkest within

For more information, visit www.siog.org

GUEST EDITOR

Stuart M. Lichtman, MD

r. Lichtman is an Attending Physician at Memorial Sloan Kettering Cancer Center, Commack, New York, and Professor of Medicine, Weill Cornell Medical College, New York. He is also President Elect of the International Society of Geriatric Oncology (www.siog.org). us.”4 For example, older people speak with pride about moments of courage or sacrifices made for beloved causes, which gave their lives a sense of purpose and meaning. Recent research by gerontologists is expanding our knowledge of the psychology of elders. While there is a decline in recall of names and a slowing of cognition, older people counter this with better emotional regulation. They react to a cancer diagnosis with less distress than younger patients, as if to say, “I’ve been through a lot—what’s one more?” It is interesting that despite the problems of aging, reported well-being actually goes up in our early 50s and continues to rise into our 80s.5 This may be related to the “wisdom” that comes with the realization that life ahead is short, and, thus, more appreciated, making it easier to enjoy the simple pleasures, like family. There is less fear of what others think and an

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Geriatrics for the Oncologist

enhanced sense of living in the now, at the same time that it becomes important to pass on values and hard-won knowledge to the young. There are some similarities in coping between cancer patients and older people facing old age. Both must maintain their daily lives while living with uncertainty and vulnerability about the future. Both need to identify what is most meaningful to accomplish in the time left. They do this by using the character strengths they have developed and finetuned over the years—with older people having had more time to hone them.

Loneliness Among Elders

Society has moved from small, close-knit multigenerational communities to big cities where it is easy to feel lonely, even (or especially) in a crowd, particularly when serious illness strikes. This situation arises for elders more today than in the past because children and family are scattered across the country. It is not uncommon for older people to describe not seeing another person for days at a time. Home health aides are a godsend to many; often, the aide begins to be

perceived as a family member. We are social animals; contact with others is a critical part of life. Counseling must be available to older patients with cancer. The telephone is a critical link when geographic closeness isn’t possible. We have developed a psychotherapy for patients that can be delivered by telephone. The contact, over five sessions, reduces feelings of loneliness, depression, and anxiety and brings a sense of meaning back to their lives [for information, contact the authors]. Another challenge is to find ways to counter boredom and depression for the elder staring at the same four walls all day. We began encouraging those who were able to join in reading literary classics for our monthly Vintage Readers Book Club (see The ASCO Post, January 15, 2013, page 83). Even those who can’t attend can join by phone or just keep up with the readings. We have had lively discussions of such classics as Cicero’s Essay on Old Age from 44 BC and The Autobiography of Ben Franklin. The discussions discourage focus on self and illness and encourage taking a fresh look at life’s universals.6

In Summary We must prepare for the coming increase of older patients with cancer. We must understand and inoculate against negative societal attitudes by adding psychosocial issues to geriatric oncology curricula. It is important both to identify lonely elders with cancer and help set up social contact for them in any way possible. Finding something meaningful to engage in is very useful. Phone therapy is one way to establish regular contact; encouraging interactions through reading and social exchanges is another. It is also important to note models of older people who cope well, thanks to character strengths honed over many years. n “Beautiful young people are accidents of nature, but beautiful old people are works of art.” —Eleanor Roosevelt

sis. Washington, DC, National Academies Press, 2008. 2. Demakos EP, Silverman LR, Lawrence ME, et al: Incidence and treatment of myelodysplastic syndrome in the US: Treatment approaches, optimization of care and the need for additional therapeutic agents. 2014 ASH Annual Meeting. Abstract 1287. Presented December 6, 2014. 3. Peterson C, Seligman M: Character Strengths and Virtues. Oxford University Press, New York, 2004. 4. Bok S: Common Values. Columbia, Missouri, University of Missouri Press, 1995. 5. Stone AA, Schwartz JE, Broderick JE, et al: A snapshot of the age distribution of psychological well-being in the United States. Proc Natl Acad Sci USA 107:99859990, 2010. 6. Greenstein M, Holland J: Lighter as We Go: Virtues, Character Strengths, and Aging. New York, Oxford University Press, 2014.

Disclosure: Drs. Holland and Greenstein reported no potential conflicts of interest.

References 1. Levit L, Balogh E, Nass S, et al (eds): Delivering High-Quality Cancer Care: Charting a New Course for a System in Cri-

Announcements

Michael E. Jung, PhD, Charles Sawyers, MD, and Howard I. Scher, MD, Receive Team Science Award From American Association for Cancer Research

ichael E. Jung, PhD, Distinguished Professor of Chemistry and Biochemistry and Member at UCLA Jonsson Comprehensive Cancer Center; Charles Sawyers, MD, Human Oncology and Pathogenesis Program Director at Memorial Sloan Kettering Cancer Center; and Howard I. Scher, MD, Chief of the Genitourinary Oncology Service and D. Wayne Calloway Chair in Urologic Oncology at Memorial Sloan Kettering, received the 9th annual American Association for

Cancer Research (AACR) 2015 Team Science Award. Presented by the AACR annually, the Team Science Award recognizes prominent researchers for their innovative scientific work in the detection, diagnosis, prevention, and/or treatment of cancer. Drs. Jung, Sawyers, and Scher are being recognized for their groundbreaking work in the discovery and development of the antiandrogen drug enzalutamide (Xtandi). Based on the results from the clinical trials conducted worldwide, enzalutamide has been shown to extend progression-free survival by several months in men battling the disease. In the initial studies, Dr. Sawyers determined that androgen overexpression was responsible for fueling the growth and survival of castration-re-

Michael E. Jung, PhD

Charles Sawyers, MD

sistant prostate cancers. A team of chemists and biologists then used preclinical models to identify novel androgen receptor antagonists that blocked the growth of tumors, and it was these studies that led to the clinical development of enzalutamide. Following a phase III clinical trial, managed by Dr. Scher, which showed that

Howard I. Scher, MD

the drug significantly extended survival among patients with metastatic castrationresistant prostate cancer that had failed to respond to chemotherapy, enzalutamide received U.S. Food and Drug Administration approval in August 2012. This is the first time the AACR has given this award to such a small group of researchers. n

The ASCO Post | APRIL 25, 2015

PAGE 42

Direct From ASCO

Triple Negative Breast Cancer Foundation Works to Change the Treatment Landscape of an Aggressive Form of Breast Cancer

ayley Dinerman, Cofounder and Executive Director of the Triple Negative Breast Cancer Foundation, remembers how she and a group of close female friends first learned about the devastating effects of triple-negative breast cancer. It was 2005 when these new mothers, who had recently formed a playgroup for their young children, learned that their

When Ms. Block-Zenna’s insurer unexpectedly covered the treatment, the group wanted to honor the promise to the donors that their funds would help patients with triple-negative breast cancer. The group applied the money as seed funding for the Triple Negative Breast Cancer Foundation. “The cause resonated with a lot of people,” Ms. Dinerman said. “They were

Our audience is hungry for information and interactions with people in the know about triple-negative breast cancer. —Hayley Dinerman

friend Nancy Block-Zenna had triplenegative breast cancer, which accounts for about 15% to 20% of diagnosed breast cancers. Triple-negative breast cancer is a fast-growing cancer, more likely to recur and spread to other organs than other types of breast cancer. “Nancy came to the playgroup one day saying that she found a lump in her breast,” Ms. Dinerman said. “We didn’t know anything about triple-negative breast cancer. We did know breast cancer is curable if found early, but we didn’t understand the gravity of triple-negative breast cancer.” The concerned friends went online for more information and had difficulty finding resources. “We found [Eric P. Winer, MD,] of the Dana-Farber Cancer Institute, mentioned in an article, and decided to send him an email to learn more,” Ms. Dinerman said. Dr. Winer responded immediately. This initial correspondence lead to a long-term partnership, with Dr. Winer helping the group form the first foundation to raise funds and awareness, underwrite research, and support patients and caregivers who are faced with triple-negative breast cancer.

A Foundation Built on Friendship The Triple Negative Breast Cancer Foundation was founded in 2006, with Ms. Block-Zenna named as the honorary founder. Initial funding for the foundation was raised in a grassroots fashion. When Ms. Block-Zenna believed that part of her breast cancer treatment would not be covered by insurance, her friends rallied around her. They created a “peace, love, and cure” campaign to raise funds by producing and selling beach towels printed with a peace sign, heart, and pink ribbon. The campaign raised $8,000.

moved to support the fight against an aggressive breast cancer that tends to strike younger women.” Sadly, Ms. Block-Zenna passed away in 2007 at the age of 37, only 2 1/2 years after she was diagnosed. Her devastated family and friends renewed their resolve to help those affected by this aggressive disease . Dr. Winer, along with Lisa A. Carey, MD, of the University of North Carolina, Chapel Hill, and George W. Sledge, Jr, MD, of Stanford University, formed the foundation’s first Scientific Advisory Board. The first triple-negative breast cancer symposium, held in 2007, was attended by 35 researchers from around the world and led to the first white paper on the state of triple-negative breast cancer. Today, the Triple Negative Breast Cancer Foundation provides funds and services for researchers and patients, including symposia, CME courses, research grants, webinars, and teleconferences on the latest treatments, and an online discussion forum for patients. The foundation also provides grants to help patients with treatment-related transportation and childcare costs. “We offer a telephone helpline staffed by oncology social workers specially trained to deal with triple-negative breast cancer issues,” Ms. Dinerman said. “We have heard from our community that a triple-negative breast cancer diagnosis can be isolating, as other groups do not typically gear the information on their sites specifically to triple-negative breast cancer. On our online discussion forums, patients can speak with hundreds of people who are going through what they are going through. They get not only peer support, but also practical information on managing side effects and other specific information related to diagnosis and treatment.”

Partnership With the Conquer Cancer Foundation

search grant funding for YIA recipient Karen Cadoo, MD, of Memorial Sloan Kettering Cancer Center. Dr. Cadoo’s project seeks better treatment for advanced-stage HER2-positive and triple-negative breast cancers. Hsp90 is found in both normal and cancer cells, but it is more active in cancer cells. Based on results from previous studies, Dr. Cadoo will test the combination of an Hsp90 inhibitor with anti-HER2 therapy and chemotherapy to determine the effect of the triplet combination and the associated side effects in patients with HER2-positive breast cancer. For patients with advanced triple-negative breast cancer, she is testing the combination of an Hsp90 inhibitor and chemotherapy. She hopes that her project will help to inform

The foundation frequently collaborates with other organizations, including Living Beyond Breast Cancer, which is hosting a conference in Denver in Fall 2015. The Triple Negative Breast Cancer Foundation’s role is providing expertise in support of the conference’s triple-negative breast cancer track, funding travel grants for those diagnosed with the disease, and promoting the track among the community. In 2014, the Triple Negative Breast Cancer Foundation became a new supporter of the Conquer Cancer Foundation of ASCO’s Young Investigator Award (YIA) program. The Triple Negative Breast Cancer Foundation provided reVolume 7, Issue 3

May 2011

Journal of oncology Practice

Top 10 most-accessed Top 5 articles articles recently published in 2011 in in published 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 Barriers to Physician Adherence to Evidence-Based Monitoring Guidelines in Chronic Myelogenous Leukemia by Stuart L. Goldberg, et al

Supporting Commission on Cancer–Mandated Psychosocial Distress Screening With Implementation Strategies by Mark Lazenby, et al

Randomized Controlled Trial of Shared Care for Patients With Cancer Involving General Practitioners and Cancer Specialists by Claire E. Johnson, et al

Priorities for Quality Care in Pediatric Oncology Supportive Care by Lillian Sung

Improving Documentation of Oral Chemotherapy at a Community Cancer Center by Katherine Enright, et al

ASCOPost.com | APRIL 25, 2015

PAGE 43

Direct From ASCO further drug development in triple-negative breast cancer and help to understand why some tumors respond well to therapy, whereas others do not. “We’re very proud of our research investments,” Ms. Dinerman said. “We’re not a large organization, but we have been able to leverage our support for large-scale projects. We have tremendous respect for ASCO and for the Conquer Cancer Foundation’s grants review process. We also love the idea of providing start-up funding and protected research time to a talented researcher at the start of her career.”

Raising Awareness for a Devastating Disease The foundation’s many achievements in its brief history include the unique ways it helped raise the profile of triplenegative breast cancer. For example, the foundation worked to establish March 3 as Triple-Negative Breast Cancer Day and was invited to ring the bell of the New York Stock Exchange in 2014. “Triple-Negative Breast Cancer Day was the brainchild of Lori Redmer, the foundation’s former Executive Director, who lost her life to triple-negative breast cancer,” Ms. Dinerman said. Ms. Dinerman plans to expand upon and perfect the foundation’s current programming. A member of the Metastatic Breast Cancer Alliance, the foundation seeks to further focus on metastatic triplenegative breast cancer disease. When asked about opportunities for ASCO members to get involved with the foundation, Ms. Dinerman said, “We are always looking for speakers for

Direct Your Patients to Cancer.Net for Informative Videos

ancer.Net offers patient-friendly videos produced by ASCO to give people with cancer and their families and friends an additional option for oncologist-approved information. Topics covered include side effects, treatments, tests and procedures, quality of life, survivorship, cancer research news, information for young adults, and much more. Visit Cancer.Net/videos for a complete list, or Cancer.Net’s YouTube page at www.youtube.com/cancerdotnet. n © 2015. American Society of Clinical Oncology. All rights reserved.

our various education programs. Our audience is hungry for information and interactions with people in the know about triple-negative breast cancer. We would welcome with open arms any ASCO members who are interested in helping us fulfill our mission. “I want ASCO members to know how grateful we are to have been so

readily accepted into the breast cancer advocacy world,” Ms. Dinerman said. “We are grateful for the advancements that we have seen since we were founded in 2006. It’s a completely different landscape now, and that wouldn’t be the case if it weren’t for ASCO members who are working to understand triple-negative breast cancer and to find

targeted treatments for this disease.” For further information about the Triple Negative Breast Cancer Foundation, please visit tnbcfoundation.org. Visit ConquerCancerFoundation.org to learn more about the Conquer Cancer Foundation. n © 2015. American Society of Clinical Oncology. All rights reserved.

The ASCO Post | APRIL 25, 2015

PAGE 44

Direct From ASCO

Cancer Control in Primary Care Courses Offered in India

SCO International’s mission is to optimize care for every patient with cancer in the world. To achieve that goal, it is critical to establish collaborations in all sectors of the health-care system. ASCO International’s newest course, Cancer Control in Primary Care, helps to address this need by offering primary health-care providers with practical and specific knowledge that can be put into daily practice. The course was hosted in India, for the first time, this March. In the following interview, we speak to Prince John, MBBS, MPAC, about the course and how it will help evolve cancer care in the region.

How would you describe the current state of cancer care in India? Cancer care in the country is developing at a very fast pace. There are more than 250 comprehensive cancer centers. In fact, partial treatments such as surgery, chemotherapy, and radiotherapy are offered at even more places. For instance, there are more than 300 radiation facilities in India—some of which function in the absence of a com-

prehensive center. Treatment is offered at government institutions, private hospitals, and not-for-profit organizations. The distribution of the cancer facilities

and prevention to primary physicians. We have selected the trainees who are working at primary-level district hospitals. These doctors are part of the pri-

We envision the [Cancer Care in Primary Care course] as being the beginning of a new approach to provide knowledge and skills to doctors practicing at the grassroots level. —Prince John, MBBS, MPAC

is, unfortunately, not uniform. Around 85% of these centers are situated in and around the major cities, thus leaving a major gap in services throughout the country. Per the World Health Organization’s requirement, there is still a need for many more centers. What are your goals for the Cancer Control in Primary Care course? The main goal of the course is to bring knowledge of early detection

mary health-care system of the government, and hence, act as the first point of contact for a large number of patients. However, many of these physicians lack the necessary skills in prevention and screening. The majority of patients from these regions are from low-income populations and really deserve better care. How do you hope to use this opportunity to further develop cancer care? The state of Madhya Pradesh in cen-

tral India has already embarked on a unique project of cancer care delivery at the grassroots level. This additional knowledge of early detection will help cure more patients and offer standardized treatment to all. We envision the program as being the beginning of a new approach to provide knowledge and skills to doctors practicing at the grassroots level—thus, easing the pressures of the tertiary centers, where these efforts are being focused currently. Dr. John is a Palliative Care Consultant at the Asian Institute of Oncology. Following his MBBS training, he worked in the Department of Palliative Medicine at Tata Memorial Hospital. For the past 9 years, Dr. John has devoted his career to palliative care and is one of the first full-time palliative medicine practitioners in private practice in India. n Originally printed in ASCO Connection. © American Society of Clinical Oncology. “New ‘Cancer Control in Primary Care’ Courses Offered in India.” ASCO Connection, March 2015: 25. All rights reserved.

Researcher Spotlight on Conquer Cancer Foundation International Innovation Grant Recipient Mya Thida, MBBS

n 2014, Mya Thida, MBBS, of Myanmar, was awarded one of the first-ever Conquer Cancer Foundation of ASCO International Innovation Grants. This grant was created to fund novel research projects that may significantly improve cancer control in lowand middle-income countries. One year later, Dr. Thida’s research is already having a powerful impact on the lives of women in her country.

After decades of isolation, Myanmar is still catching up in many critical areas, including access to modern health care. The majority of women in Myanmar forgo routine cervical cancer screenings that are widely available in more developed nations. In fact, this preventable, treatable disease is the second most common cancer affecting women in Myanmar. Dr. Thida, Head of Obstetrics and Gynecology at the University of Medi-

Dr. Thida (fourth from right) and her team with their mobile cryotherapy unit.

cine 1, Yangon, knows all too well what life is like for women she treats with latestage cervical cancer, who often aren’t seen until little can be done to save their

helped provide cervical cancer screening to more than 1,370 women in Taikkyi Township and Gyophyu Village. Forty cases of cancer were treated with

Thanks to the Conquer Cancer Foundation, instead of just managing cervical cancer, we can prevent it and save more women and their families from immense suffering. —Mya Thida, MBBS

lives. To change this, she created a breakthrough single-visit model for cervical cancer detection to serve rural villages, using visual screening and immediate cryotherapy provided in mobile units. “We know it’s possible to prevent the suffering and death we see in our country from cervical cancer,” said Dr. Thida. “Now, as Myanmar is working to build health-care resources for everyone, this is the moment to create a sustainable, cost-effective program that can be shared wherever it’s needed.” The essential seed funds from Dr. Thida’s grant enabled her to purchase a mobile cryotherapy unit and train a dozen local midwives. These assets

life-saving cryotherapy. “Thanks to the Conquer Cancer Foundation, we have a starting point for cervical cancer screening in our country, and we are very grateful,” said Dr. Thida. “Instead of just managing cervical cancer, we can prevent it, and save more women and their families from immense suffering.” Visit www.conquercancerfoundation.org to learn about funding opportunities and to make a donation that will directly impact people with cancer worldwide. n © 2015. American Society of Clinical Oncology. All rights reserved.

ASCOPost.com | APRIL 25, 2015

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Direct From ASCO

FDA’s Biosimilar Product Approval Process: A Closer Look

n March, the U.S. Food and Drug Administration (FDA) approved filgrastim-sndz (Zarxio) as a biosimilar to U.S.-licensed filgrastim (Neupogen). It is the first biosimilar product to be approved in the United States and will increase treatment options for people living with cancer. The FDA considers a biosimilar to be a biologic product that is highly similar to a product that has already been approved and licensed for use in the United States. In 2010, a streamlined process for the approval of biosimilar products was created as part of the Patient Protection and Affordable Care Act. A biosimilar product is required to have the same active mechanisms, conditions of use, and administration method and dosage as the approved product. Only minor differences in clinically inactive components are allowable. To submit a biosimilar product for FDA review, manufacturers must com-

plete an application that includes the following data as evidence of a product’s biosimilarity: • analytical studies • animal studies (including a toxicity assessment) • clinical studies (or a single clinical study) demonstrating the product’s safety, purity, and potency in at least one of the conditions for which the already licensed product is approved

for use (eg, an immunogenicity and pharmacokinetics or pharmacodynamics assessment) For additional information on biosimilar products and the approval process, view the following FDA resources: Biosimilar Biological Products Presentation: www.fda.gov/downloads/ Drugs/DevelopmentApprovalProcess/HowDrugsareDevelopedandApproved/ApprovalApplications/

TherapeuticBiologicApplications/ Biosimilars/UCM292463.pdf FDA’s Biosimilars Webpage: www .fda.gov/Drugs/DevelopmentApprovalProcess/HowDrugsareDevelopedandApproved/ApprovalApplications/ TherapeuticBiologicApplications/ Biosimilars/default.htm n © 2015. American Society of Clinical Oncology. All rights reserved.

ASCO’s Oncology Interoperability Standard Highlighted in AMIA’s Bioinformatics Journal Club Webinar

SCO’s oncology-specific interoperability electronic data-sharing standard for communicating and coordinating care throughout the cancer journey was featured in the American Medical Informatics Association’s Bioinformatics Journal Club webinar, a live production jointly sponsored by the Division of Bio-

medical Informatics at the UC San Diego School of Medicine (DBMI-UCSD) and Integrating Data for Analysis, Anonymization, and Sharing (iDASH). The presenters described the work required to translate the Society’s previously released paper-based treatment plan and summary templates

into a technical standard that provides the ability to electronically exchange clinical information. To listen to the webinar, visit www.scivee.tv/node/63528. n © 2015. American Society of Clinical Oncology. All rights reserved.

Ann Partridge, MD, MPH, Confronts Challenges Facing Young Women With Breast Cancer With Support From Conquer Cancer Foundation Improving Cancer Care Grant

nn Partridge, MD, MPH, Associate Professor of Medicine at Harvard Medical School and Founding Director of the Program for Young Women With Breast Cancer at the Dana-Farber Cancer Institute, received a 2010 Im-

this stage in life are parenting young children, trying to start a family, completing education, and developing a career. They often feel isolated and lack information, which contributes to greater emotional distress in this patient group.

Young Women’s Intervention Program

Ann Partridge, MD, MPH

proving Cancer Care Grant (ICCG) for her project “Improving the Care of Young Women with Breast Cancer,” to address the critical issues and concerns facing young women who are receiving breast cancer treatment. Young women undergoing breast cancer treatment have a variety of unique concerns compared to older women. For instance, many women at

To address this, Dr. Partridge and her team at Dana-Farber developed a comprehensive pilot program called the Young Women’s Intervention (YWI) to provide additional care, support, and education for young women with breast cancer, as well as their oncology providers. Building on the success of the program, Dr. Partridge sought to export a sustainable educational and support intervention outside of a comprehensive cancer center to the community setting, where most young women with breast cancer receive treatment. With the support of the ICCG, Dr. Partridge led a nationwide randomized controlled trial to compare the YWI program to a physical activity intervention to determine if the YWI program

content improved attention to fertility issues, quality of care, satisfaction, and quality of life. She also looked at how the physical activity intervention affected exercise behaviors. In the trial, 40 community and 14 academic sites across the United States were randomly assigned to the YWI or physical activity intervention arm. Each site met its minimum recruitment goal, and 467 women enrolled in the trial and completed the intervention. Dr. Partridge and her team are currently collecting follow-up surveys and medical records, after which they will conduct a final outcomes analysis.

New Model to Improve Care, Overcome Barriers Dr. Partridge believes this work will not only improve care for young wom-

en with breast cancer, but will also serve as a novel model to overcome barriers to delivering optimal care for unique groups of patients in community settings. At $1.35 million, the Improving Cancer Care Grant, supported by Susan G. Komen, is the largest ever in the history of the Conquer Cancer Foundation Grants and Awards Program, which has now given more than $90 million in Grants and Awards funding since its inception. Dr. Partridge is a 2001 Young Investigator Award and 2003 Career Development Award recipient. Receiving the 2010 ICCG made her the first Conquer Cancer Foundation tripleaward recipient. Visit ConquerCancerFoundation.org to learn more about the CCF Grants and Awards Program and to make a donation to support cancer research. n © 2015. American Society of Clinical Oncology. All rights reserved.

The ASCO Post | APRIL 25, 2015

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FDA Update Gynecologic Oncology

FDA Grants Breakthrough Therapy Designation to Rucaparib in Advanced Ovarian Cancer With BRCA Mutations

he U.S. Food and Drug Administration (FDA) has granted Breakthrough Therapy designation to Clovis Oncology’s investigational agent rucaparib as monotherapy treatment of advanced ovarian cancer in patients who have received at least two lines of prior platinum-containing therapy, with B RCA-mutated tumors, inclusive of both germline BRCA and somatic BRCA mutations. Rucaparib is an oral, potent inhibitor of PARP1 and PARP2 being developed for the treatment of platinumsensitive ovarian cancer, specifically in patients with tumors with BRCA muta-

tions and other DNA repair deficiencies beyond BRCA, commonly referred to as “BRCA-like” or “BRCAness.” The Breakthrough Therapy designation was granted based on interim efficacy and safety results from two ongoing phase II studies of rucaparib in ovarian cancer, including a phase II study in women with germline BRCA mutations, and the ARIEL2 treatment study.

Clinical Data A clinical data update from the ARIEL2 study presented at the 2015 Annual Meeting on Women’s Cancer demonstrated that 70% of evaluable patients with BRCA-mutant tumors achieved a RECIST and/or CA-125 response, and 65% achieved a RECIST response. Responses were observed in both germline and somatic BRCAmutant tumors. In addition, Clovis’ proprietary BRCA-like DNA signature, run by its partner Foundation Medicine, successfully predicted which ovarian cancer patients would respond to rucaparib therapy. In patients with normal BRCA genes, rucaparib activity was substantially higher for those with the prospectively defined BRCA-like homologous recombination deficiency (HRD) signature vs biomarker-negative patients. Forty-eight percent of patients with the BRCA-like signature achieved a RECIST and/or CA-125 response, and 40% achieved a R ECIST response. In biomarker-negative patients, 8% of patients achieved a RECIST and/or CA-125 response.

These data also demonstrate that rucaparib is well tolerated. At the recommended phase II dose, the most common treatment-related adverse events reported in ≥ 15% of all patients included nausea,

fatigue, transient alanine transaminase/ aspartate transaminase elevations, dysgeusia, constipation,S:6.75” anemia/low hemoglobin, decreased appetite, vomiting, and diarrhea. These events were mostly grade

1/2; the only common grade 3/4 toxicity was anemia/low hemoglobin. The next update of rucaparib clinical data will be presented at the 2015 ASCO Annual Meeting. n

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

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

Important Safety Information WARNING: PERFORATIONS AND FISTULAS, and HEMORRHAGE

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

Perforations and Fistulas: Serious gastrointestinal (GI) perforations and fistulas were reported, of which one GI fistula was fatal. Non-GI fistulas including tracheal/esophageal were reported in 4% of COMETRIQ-treated patients. Two of these were fatal. Monitor patients for symptoms of perforations and fistulas. Hemorrhage: Serious and sometimes fatal hemorrhage occurred with COMETRIQ. Events ≥ Grade 3 occurred in 3% of COMETRIQ patients vs 1% receiving placebo. Do not administer COMETRIQ to patients with a recent history of hemorrhage or hemoptysis. Thrombotic Events: COMETRIQ treatment results in an increased incidence vs placebo of venous thromboembolism (6% vs 3%) and arterial thromboembolism (2% vs 0%). Discontinue COMETRIQ in patients who develop an acute myocardial infarction or any other clinically significant arterial thromboembolic complication.

Wound Complications: Wound complications have been reported with COMETRIQ. Stop treatment with COMETRIQ at least 28 days prior to scheduled surgery. Resume COMETRIQ therapy after surgery based on clinical judgment of adequate wound healing. Withhold COMETRIQ in patients with dehiscence or wound healing complications requiring medical intervention. Hypertension: COMETRIQ treatment results in an increased incidence of treatment-emergent hypertension vs placebo (61% vs 30%). Monitor blood pressure prior to initiation and regularly during COMETRIQ treatment. Withhold COMETRIQ for hypertension that is not adequately controlled with medical management; when controlled, resume COMETRIQ at a reduced dose. Discontinue COMETRIQ for severe hypertension that cannot be controlled with anti-hypertensive therapy. Osteonecrosis of the Jaw (ONJ): ONJ occurred in 1% of COMETRIQ-treated patients. ONJ can manifest as jaw pain, osteomyelitis, osteitis, bone erosion, tooth or periodontal infection, toothache, gingival ulceration or erosion, persistent jaw pain or slow healing of the mouth or jaw after dental surgery. Perform an oral examination prior to initiation of COMETRIQ and periodically during COMETRIQ therapy. Advise patients regarding good oral hygiene practices. For invasive dental procedures, withhold COMETRIQ treatment for at least 28 days prior to scheduled surgery, if possible. Palmar-Plantar Erythrodysesthesia Syndrome (PPES): PPES occurred in 50% of patients treated with COMETRIQ and was severe in 13% of patients. Withhold COMETRIQ in patients who develop intolerable Grade 2 PPES or Grade 3-4 PPES until improvement to Grade 1; resume COMETRIQ at a reduced dose.

05/14 [COM-0086]

B:17

T:1

PAGE 47

FDA Update Hematology

FDA Grants Priority Review to Carfilzomib Supplemental New Drug Application for Relapsed Multiple Myeloma

he U.S. Food and Drug Administration (FDA) has accepted Amgen’s supplemental New Drug Application (sNDA) for carfilzomib (Kyprolis) injection for the treatment

of patients with relapsed multiple myeloma who have received at least one S:6.75” prior therapy. The sNDA is designed to support the conversion of accelerated approval to full approval and expand

the current carfilzomib indication. As part of the acceptance, the FDA granted carfilzomib priority review with a Prescription Drug User Fee Act target continued on page 48

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

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

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

PFS

1.0

COMETRIQ® (n=219) Placebo (n=111)

0.9 0.8 0.6

HR=0.28 95% CI: 0.19, 0.40 P<0.0001

0.7 0.5 0.4

median

4.0 4.0

0.3

11.2 11.2 months months

months months

0.2

Probability of patients who are progression free

AE/AS

72% reduction in risk of progression was seen in patients receiving COMETRIQ® vs placebo

31 3

12 2

2 0

1 0

Months 219 111

121 35

78 11

55 6

Proteinuria: Proteinuria was observed in 2% of patients receiving COMETRIQ (vs 0% receiving placebo), including 1 with nephrotic syndrome. Monitor urine protein regularly during COMETRIQ treatment. Discontinue COMETRIQ in patients who develop nephrotic syndrome. Reversible Posterior Leukoencephalopathy Syndrome (RPLS): RPLS occurred in 1 patient. Perform an evaluation for RPLS in any patient presenting with seizures, headache, visual disturbances, confusion, or altered mental function. Discontinue COMETRIQ in patients who develop RPLS. Drug Interactions: Avoid administration of COMETRIQ with agents that are strong CYP3A4 inducers or inhibitors. Hepatic Impairment: COMETRIQ is not recommended for use in patients with moderate or severe hepatic impairment. Embryo-fetal Toxicity: COMETRIQ can cause fetal harm when administered to a pregnant woman. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus. Adverse Reactions: The most commonly reported adverse drug reactions (≥25% and ≥5% difference from placebo) were diarrhea (63% vs 33%), stomatitis (51% vs 6%), PPES (50% vs 2%), decreased weight (48% vs 10%), decreased appetite (46% vs 16%), nausea (43% vs 21%), fatigue (41% vs 28%), oral pain (36% vs 6%), hair color changes (34% vs 1%), dysgeusia (34% vs 6%), hypertension (33% vs 4%), abdominal pain (27% vs 13%), and constipation (27% vs 6%). The most common laboratory abnormalities (≥25%) were increased AST (86% vs 35%), increased ALT (86% vs 41%), lymphopenia (53% vs 51%),

Results of the international, multicenter, randomized, double-blind EXAM study in patients with progressive, metastatic MTC (N=330). Primary endpoint: PFS; secondary endpoints included: objective response rate (ORR) and OS.1

increased ALP (52% vs 35%), hypocalcemia (52% vs 27%), neutropenia (35% vs 15%), thrombocytopenia (35% vs 4%), hypophosphatemia (28% vs 10%), and hyperbilirubinemia (25% vs 14%). Increased levels of thyroid stimulating hormone (TSH) were observed in 57% of patients receiving COMETRIQ (vs 19% receiving placebo). In clinical trials, the dose was reduced in 79% of patients receiving COMETRIQ compared to 9% of patients receiving placebo. The median number of dosing delays was one in patients receiving COMETRIQ compared to none in patients receiving placebo. Adverse reactions led to study treatment discontinuation in 16% of patients receiving COMETRIQ and in 8% of patients receiving placebo. Please see accompanying brief summary of Prescribing Information, including Boxed Warnings. You are encouraged to report negative side effects of prescription drugs to the FDA. Visit www.FDA.gov/medwatch or call 1-800-FDA-1088. Reference: 1. Elisei R, Schlumberger MJ, Müller SP, et al. Cabozantinib in progressive medullary thyroid cancer. J Clin Oncol. 2013;31:3639-3646.

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action date of July 26, 2015. Carfilzomib is currently approved by the FDA for the treatment of patients with multiple myeloma who have received at least two prior therapies, including bortezomib (Velcade) and an immunomodulatory agent,

and have demonstrated disease progression on or within 60 days of completion of the last therapy.

ASPIRE Trial The sNDA is based on data from the international randomized phase III ASPIRE trial, which evaluated carfilzomib in combination with le-

nalidomide (Revlimid) and low-dose dexamethasone vs lenalidomide and low-dose dexamethasone alone, in 792 patients with relapsed multiple myeloma following treatment with one to three prior regimens. The primary endpoint S:6.75” of the trial was progression-free survival. Secondary endpoints included overall survival,

COMETRIQ® (cabozantinib) capsules BRIEF SUMMARY OF PRESCRIBING INFORMATION Initial U.S. Approval: 2012 WARNING: PERFORATIONS AND FISTULAS, and HEMORRHAGE See full prescribing information for complete boxed warning. Perforations and Fistulas: Gastrointestinal perforations occurred in 3% and fistula formation in 1% of COMETRIQ-treated patients. Discontinue COMETRIQ in patients with perforation or fistula. (5.1) Hemorrhage: Severe, sometimes fatal, hemorrhage including hemoptysis and gastrointestinal hemorrhage occurred in 3% of COMETRIQ-treated patients. Monitor patients for signs and symptoms of bleeding. Do not administer COMETRIQ to patients with severe hemorrhage. (5.2)

1. INDICATIONS AND USAGE COMETRIQ is indicated for the treatment of patients with progressive, metastatic medullary thyroid cancer (MTC). 2. DOSAGE AND ADMINISTRATION 2.1 Recommended Dose: The recommended daily dose of COMETRIQ is 140 mg (one 80-mg and three 20-mg capsules). Do not administer COMETRIQ with food. Instruct patients not to eat for at least 2 hours before and at least 1 hour after taking COMETRIQ. Continue treatment until disease progression or unacceptable toxicity occurs. Swallow COMETRIQ capsules whole. Do not open COMETRIQ capsules. Do not take a missed dose within 12 hours of the next dose. Do not ingest foods (e.g., grapefruit, grapefruit juice) or nutritional supplements that are known to inhibit cytochrome P450 during COMETRIQ. 2.2 Dosage Adjustments: For Adverse Reactions : Withhold COMETRIQ for NCI CTCAE Grade 4 hematologic adverse reactions, Grade 3 or greater non-hematologic adverse reactions or intolerable Grade 2 adverse reactions. Upon resolution/improvement of the adverse reaction (i.e., return to baseline or resolution to Grade 1), reduce the dose as follows: • If previously receiving 140-mg daily dose, resume treatment at 100 mg daily (one 80-mg and one 20-mg capsule) • If previously receiving 100-mg daily dose, resume treatment at 60 mg daily (three 20-mg capsules) • If previously receiving 60-mg daily dose, resume at 60 mg if tolerated, otherwise, discontinue COMETRIQ Permanently discontinue COMETRIQ for any of the following: development of visceral perforation or fistula formation; severe hemorrhage; serious arterial thromboembolic event (e.g., myocardial infarction, cerebral infarction); nephrotic syndrome; malignant hypertension, hypertensive crisis, persistent uncontrolled hypertension despite optimal medical management; osteonecrosis of the jaw; or reversible posterior leukoencephalopathy syndrome. In Patients With Hepatic Impairment : COMETRIQ is not recommended for use in patients with moderate and severe hepatic impairment. In Patients Taking CYP3A4 Inhibitors : Avoid the use of concomitant strong CYP3A4 inhibitors (e.g., ketoconazole, itraconazole, clarithromycin, atazanavir, nefazodone, saquinavir, telithromycin, ritonavir, indinavir, nelfinavir, voriconazole) in patients receiving COMETRIQ. For patients who require treatment with a strong CYP3A4 inhibitor, reduce the daily COMETRIQ dose by 40 mg (for example, from 140 mg to 100 mg daily or from 100 mg to 60 mg daily). Resume the dose that was used prior to initiating the CYP3A4 inhibitor 2 to 3 days after discontinuation of the strong inhibitor. In Patients Taking Strong CYP3A4 Inducers : Avoid the chronic use of concomitant strong CYP3A4 inducers (e.g., phenytoin, carbamazepine, rifampin, rifabutin, rifapentine, phenobarbital) if alternative therapy is available. Do not ingest foods or nutritional supplements (e.g., St. John’s Wort [Hypericum perforatum]) that are known to induce cytochrome P450 activity. For patients who require treatment with a strong CYP3A4 inducer, increase the daily COMETRIQ dose by 40 mg (for example, from 140 mg to 180 mg daily or from 100 mg to 140 mg daily) as tolerated. Resume the dose that was used prior to initiating the CYP3A4 inducer 2 to 3 days after discontinuation of the strong inducer. The daily dose of COMETRIQ should not exceed 180 mg. 4. CONTRAINDICATIONS None. 5. WARNINGS AND PRECAUTIONS 5.1 Perforations and Fistulas: Gastrointestinal (GI) perforations and fistulas were reported in 3% and 1% of COMETRIQ-treated patients, respectively. All were serious and one GI fistula was fatal (<1%). Non-GI fistulas including tracheal/esophageal were reported in 4% of COMETRIQ-treated patients. Two (1%) of these were fatal. Monitor patients for symptoms of perforations and fistulas. Discontinue COMETRIQ in patients who experience a perforation or a fistula. 5.2 Hemorrhage: Serious and sometimes fatal hemorrhage occurred with COMETRIQ. The incidence of Grade ≥3 hemorrhagic events was higher in COMETRIQ-treated patients compared with placebo (3% vs. 1%). Do not administer COMETRIQ to patients with a recent history of hemorrhage or hemoptysis. 5.3 Thrombotic Events: COMETRIQ treatment results in an increased incidence of thrombotic events (venous thromboembolism: 6% vs. 3% and arterial thromboembolism: 2% vs. 0% in COMETRIQ-treated and placebo-treated patients, respectively). Discontinue COMETRIQ in patients who develop an acute myocardial infarction or any other clinically significant arterial thromboembolic complication.

overall response rate, duration of response, disease control rate, healthrelated quality of life, and safety. The ASPIRE data were presented at the 56th Annual Meeting of the American Society of Hematology in December 2014 and published in The New England Journal of Medicine. n

5.4 Wound Complications: Wound complications have been reported with COMETRIQ. Stop treatment with COMETRIQ at least 28 days prior to scheduled surgery. Resume COMETRIQ therapy after surgery based on clinical judgment of adequate wound healing. Withhold COMETRIQ in patients with dehiscence or wound healing complications requiring medical intervention. 5.5 Hypertension: COMETRIQ treatment results in an increased incidence of treatment-emergent hypertension with Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (modified JNC criteria) stage 1 or 2 hypertension identified in 61% of COMETRIQ-treated patients compared with 30% of placebo-treated patients in the randomized trial. Monitor blood pressure prior to initiation and regularly during COMETRIQ treatment. Withhold COMETRIQ for hypertension that is not adequately controlled with medical management; when controlled, resume COMETRIQ at a reduced dose. Discontinue COMETRIQ for severe hypertension that cannot be controlled with anti-hypertensive therapy. 5.6 Osteonecrosis of the Jaw (ONJ): Osteonecrosis of the jaw (ONJ) occurred in 1% of COMETRIQ-treated patients. ONJ can manifest as jaw pain, osteomyelitis, osteitis, bone erosion, tooth or periodontal infection, toothache, gingival ulceration or erosion, persistent jaw pain or slow healing of the mouth or jaw after dental surgery. Perform an oral examination prior to initiation of COMETRIQ and periodically during COMETRIQ therapy. Advise patients regarding good oral hygiene practices. For invasive dental procedures, withhold COMETRIQ treatment for at least 28 days prior to scheduled surgery, if possible. 5.7 Palmar-Plantar Erythrodysesthesia Syndrome: Palmar-plantar erythrodysesthesia syndrome (PPES) occurred in 50% of patients treated with cabozantinib and was severe (≥Grade 3) in 13% of patients. Withhold COMETRIQ in patients who develop intolerable Grade 2 PPES or Grade 3-4 PPES until improvement to Grade 1; resume COMETRIQ at a reduced dose. 5.8 Proteinuria: Proteinuria was observed in 4 (2%) patients receiving COMETRIQ, including one with nephrotic syndrome, as compared to none of the patients receiving placebo. Monitor urine protein regularly during COMETRIQ treatment. Discontinue COMETRIQ in patients who develop nephrotic syndrome. 5.9 Reversible Posterior Leukoencephalopathy Syndrome: Reversible Posterior Leukoencephalopathy Syndrome (RPLS), a syndrome of subcortical vasogenic edema diagnosed by characteristic finding on MRI, occurred in one (<1%) patient. Perform an evaluation for RPLS in any patient presenting with seizures, headache, visual disturbances, confusion or altered mental function. Discontinue COMETRIQ in patients who develop RPLS. 5.10 Drug Interactions: Avoid administration of COMETRIQ with agents that are strong CYP3A4 inducers or inhibitors. 5.11 Hepatic Impairment: COMETRIQ is not recommended for use in patients with moderate or severe hepatic impairment. 5.12 Embryo-Fetal Toxicity: COMETRIQ can cause fetal harm when administered to a pregnant woman. Cabozantinib was embryolethal in rats at exposures below the recommended human dose, with increased incidences of skeletal variations in rats and visceral variations and malformations in rabbits. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus. 6. ADVERSE REACTIONS 6.1 Clinical Trial Experience: Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The safety of COMETRIQ was evaluated in 330 patients with progressive, metastatic medullary thyroid cancer randomized to receive 140 mg of COMETRIQ (n=214) or placebo (n=109) administered daily until disease progression or intolerable toxicity occurred in a randomized, double-blind, controlled trial. The data described below reflect a median exposure to COMETRIQ for 204 days. The population exposed to COMETRIQ was 70% male, 90% white, and had a median age of 55 years. Adverse reactions which occurred in ≥25% of COMETRIQ-treated patients occurring more frequently in the COMETRIQ arm with a between-arm difference of ≥5% included, in order of decreasing frequency: diarrhea, stomatitis, palmar-plantar erythrodysesthesia syndrome (PPES), decreased weight, decreased appetite, nausea, fatigue, oral pain, hair color changes, dysgeusia, hypertension, abdominal pain, and constipation. The most common laboratory abnormalities (>25%) were increased AST, increased ALT, lymphopenia, increased alkaline phosphatase, hypocalcemia, neutropenia, thrombocytopenia, hypophosphatemia, and hyperbilirubinemia. Grade 3-4 adverse reactions and laboratory abnormalities which occurred in ≥5% of COMETRIQ-treated patients occurring more frequently in the COMETRIQ arm with a between-arm difference of ≥2% included, in order of decreasing frequency: diarrhea, PPES, lymphopenia, hypocalcemia, fatigue, hypertension, asthenia, increased ALT, decreased weight, stomatitis, and decreased appetite (see Table 1, Table 2). Fatal adverse reactions occurred in 6% of patients receiving COMETRIQ and resulted from hemorrhage, pneumonia, septicemia, fistulas, cardiac arrest, respiratory failure, and unspecified death. Fatal adverse reactions occurred in 5% of patients receiving placebo and resulted from septicemia, pneumonia, and general deterioration. The dose was reduced in 79% of patients receiving COMETRIQ compared to 9% of patients receiving placebo. The median number of dosing delays was one in patients receiving COMETRIQ compared to none in patients receiving placebo. Adverse reactions led to study treatment discontinuation in 16% of patients receiving COMETRIQ and in 8% of patients receiving placebo. The most frequent adverse reactions leading to permanent discontinuation in patients treated with COMETRIQ were: hypocalcemia, increased lipase, PPES, diarrhea, fatigue, hypertension, nausea, pancreatitis, tracheal fistula formation, and vomiting. Increased levels of thyroid stimulating hormone (TSH) were observed in 57% of patients receiving COMETRIQ after the first dose compared to 19% of patients receiving placebo (regardless of baseline value). Ninety-two percent (92%) of patients on the COMETRIQ arm had a prior thyroidectomy, and 89% were taking thyroid hormone replacement prior to the first dose.

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

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Awards

Owen N. Witte, MD, Recognized With AACR G.H.A. Clowes Memorial Award

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Dr. Witte’s innovative work helped revolutionize modern cancer treatment by defining tyrosine kinases as crucial drug targets in human disease. Most notably, he pinpointed the molecular consequences of the Philadelphia chromosome abnormality present in chronic myelogenous leukemia and related types of leukemia and defined the tyrosine kinase activity of the ABL gene product. These findings played a crucial role in the subsequent development of ABL kinase–targeted therapies. In addition to his research involving ABL, Dr. Witte also codiscovered Bruton agammaglobulinemia tyrosine kinase. This kinase is essential for B-cell maturation and, when mutated, results in the onset of the immunodeficiency disease, X-linked agammaglobulinemia. More recently, Dr. Witte’s work has focused on defining the epithelial stem cell populations that contribute to prostate cancer. He is currently using mass spectrometry approaches to identify kinases that could be potential therapeutic targets for human prostate cancer. “Much progress has been made in the area of personalized cancer medicine, due to the dedication of scientists and physicians around the world,” said Dr. Witte. “But much more work is needed as we seek to understand cancer, which is not a single disease but rather many diseases that develop differently. I thank the AACR for its leadership in this effort and am honored to receive the Clowes Memorial Award.” n

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tributions to the understanding of human leukemias, immune disorders, and epithelial cancer stem cells. Dr. Witte’s work, which contributed to the development of several approved targeted therapies, has transformed the lives of patients with Philadelphia chromosome–positive leukemias and B-cell malignancies.

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Owen N. Witte, MD

Table 3. Per-Patient Incidence of Hypertension in Protocol XL184-301 COMETRIQ HYPERTENSION, JNC1 STAGE N=2113 (%) Normal: Grade 0: Systolic 4 <120 mmHg and Diastolic <80 mmHg Pre-hypertension: Systolic 34 ≥120 mmHg or Diastolic ≥80 mmHg Stage 1: Systolic ≥140 mmHg or 46 Diastolic ≥90 mmHg

7. DRUG INTERACTIONS 7.1 Effect of CYP3A4 Inhibitors: Administration of a strong CYP3A4 inhibitor, ketoconazole (400 mg daily for 27 days) to healthy subjects increased single-dose plasma cabozantinib exposure (AUC0-inf) by 38%. Avoid taking a strong CYP3A4 inhibitor (e.g., ketoconazole, itraconazole, clarithromycin, atazanavir, indinavir, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin, voriconazole) when taking COMETRIQ. 7.2 Effect of CYP3A4 Inducers: Administration of a strong CYP3A4 inducer, rifampin (600 mg daily for 31 days) to healthy subjects decreased single-dose plasma cabozantinib exposure (AUC0-inf) by 77%. Avoid chronic coadministration of strong CYP3A4 inducers (e.g., dexamethasone, phenytoin, carbamazepine, rifampin, rifabutine, rifapentine, phenobarbital, St. John’s Wort) with COMETRIQ. 8. USE IN SPECIFIC POPULATIONS 8.1 Pregnancy: Pregnancy Category D. Risk Summary : Based on its mechanism of action, COMETRIQ can cause fetal harm when administered to a pregnant woman. Cabozantinib was embryolethal in rats at exposures below the recommended human dose, with increased incidences of skeletal variations in rats and visceral variations and malformations in rabbits. If this drug is used during pregnancy or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus. Animal Data: In an embryo-fetal development study in which pregnant rats were administered daily doses of cabozantinib during organogenesis, increased loss of pregnancy compared to controls was observed at doses as low as 0.03 mg/kg (less than 1% of the human exposure by AUC at the recommended dose). Findings included delayed ossifications and skeletal variations at doses equal to or greater than 0.01 mg/kg/day (approximately 0.03% of the human exposure by AUC at the recommended dose). In pregnant rabbits administered cabozantinib daily during organogenesis, there were findings of visceral malformations and variations including reduced splenic size and missing lung lobe at 3 mg/kg (approximately 11% of the human exposure by AUC at the recommended dose). 8.2 Nursing Mothers: It is unknown whether cabozantinib or its metabolites are excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from COMETRIQ, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. 8.3 Pediatric Use: The safety and effectiveness of COMETRIQ in pediatric patients have not been studied. 8.4 Geriatric Use: Clinical studies of COMETRIQ did not include sufficient numbers of patients aged 65 years and over to determine whether they respond differently from younger patients. 8.5 Females and Males of Reproductive Potential: Contraception: Use effective contraception during treatment with COMETRIQ and up to 4 months after completion

of therapy. Infertility : There are no data on the effect of COMETRIQ on human fertility. Cabozantinib impaired male and female fertility in animal studies. 8.6 Hepatic Impairment: Cabozantinib pharmacokinetics has not been studied in patients with hepatic impairment. There are limited data in patients with liver impairment (serum bilirubin greater than 1.5 times the upper limit of normal). COMETRIQ is not recommended for use in patients with moderate or severe hepatic impairment, as safety and efficacy have not been established. 8.7 Renal Impairment: No dose adjustment is recommended for patients with mild or moderate renal impairment. There is no experience with COMETRIQ in patients with severe renal impairment. 10. OVERDOSAGE One case of overdosage was reported in a patient who inadvertently took twice the intended dose (200 mg daily) for nine days. The patient suffered Grade 3 memory impairment, Grade 3 mental status changes, Grade 3 cognitive disturbance, Grade 2 weight loss, and Grade 1 increase in BUN. The extent of recovery was not documented. 17. PATIENT COUNSELING INFORMATION See FDA-approved patient labeling (Patient Information and Instructions for Use). Inform patients of the following: • COMETRIQ often causes diarrhea which may be severe in some cases. Inform patients of the need to contact their healthcare provider if severe diarrhea occurs during treatment with COMETRIQ. • COMETRIQ often causes palmar-plantar erythrodysesthesia syndrome. Advise patients to contact their healthcare provider for progressive or intolerable rash. • COMETRIQ often causes sores in the mouth, oral pain, changes in taste, nausea or vomiting. Advise patients to contact their healthcare provider if any of these symptoms are severe or prevent patients from eating and drinking. • COMETRIQ often causes weight loss which may be significant in some cases. Advise patients to report significant weight loss. • To contact their healthcare provider before any planned surgeries, including dental procedures. • COMETRIQ may interact with other drugs; advise patients to inform their healthcare provider of all prescription or nonprescription medication or herbal products that they are taking. • Patients of childbearing potential must use effective contraception during therapy and for at least four months following their last dose of COMETRIQ. • Breast-feeding mothers must discontinue nursing while receiving COMETRIQ therapy. • COMETRIQ should not be taken with food. Instruct patients not to eat for at least 2 hours before and at least 1 hour after taking COMETRIQ. COMETRIQ capsules should not be opened or crushed but should be taken with a full glass (at least 8 ounces) of water. • Patients should not consume grapefruits or grapefruit juice while taking COMETRIQ treatment. Reference ID: 3223542 Distributed by Exelixis, Inc. 11/2012

Dr. Witte, who is also a Howard Hughes Medical Institute Investigator and an Elected Fellow of the AACR Academy, is being recognized for con-

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

Malignant: Diastolic 0 0 ≥120 mmHg 1 Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure, JAMA 2003:289:2560. Criteria applied were modified, as multiple readings were not available per timepoint, and therefore not averaged. 2 Subjects classified by highest category based on all recorded blood pressure readings beginning after the first dose through 30 days after last dose. 3 Subjects with at least two blood pressure measurements after the first dose.

Memorial Award in 1961 to honor G.H.A. Clowes, PhD, a founding member of the AACR and Research Director at Eli Lilly. The award recognizes an individual with outstanding recent accomplishments in basic cancer research.

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

Molecular Genetics at the University of California, Los Angeles (UCLA), with the 55th Annual AACR G.H.A. Clowes Memorial Award at the AACR Annual Meeting 2015.S:6.75” The AACR and Eli Lilly and Company established the G.H.A. Clowes

he American Association for Cancer Research (AACR) honored Owen N. Witte, MD, Founding Director of the Eli & Edythe Broad Center of Regenerative Medicine & Stem Cell Research, and Distinguished Professor of Microbiology, Immunology, and

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Integrative Oncology Staff Support Sessions in an Oncology Setting By Michele Schuman, LMSW, LMT

ork-related issues such as coping skills, stress management, burnout, and compassion fatigue are among the challenges faced by clinical and other staff in cancer treatment centers. Given the emotional consequences of professional caregiving, staff support group meetings are valuable resources for health-care providers. Such meetings provide a safe environment for employees to express emotions, share experiences, build resilience, and balance work responsibilities. Although support groups vary in intention and composition, they are typically voluntary and led professionally or chaired by colleagues with similar experiences and challenges. The objective is to provide emotional comfort and information in a strictly confidential setting. Formal support group meetings may be traced back to Alcoholics Anonymous (AA). Established in 1935, this self-help group aims to assist recovery from alcoholism. Extended families, fraternal organizations, guilds, and informal social gathering formed the basis of AA’s contemporary groups. In today’s hospital settings, support groups accommodate patients, staff, family members, and caregivers, offering in-house as well as online gatherings.

common professional challenges.6 Research illustrates that oncology staff including physicians, allied health professionals, and support staff display emotional exhaustion, feelings of depersonalization, and thoughts of leaving the oncology field.7 Interventions such as Care for the Professional Caregiver Program, a group discussion module that addresses burnout, coping with grief, loss and trauma, and self-care strategies, effectively decrease oncology professionals’ emotional exhaustion.8 Additional interventions such as the Compassion Fatigue Resiliency Program9 and a self-organized monthly nurse support group10 demonstrate the importance of helping oncology workers manage their professional stressors. Interventions such as an ongoing educational course11 modeled after mindfulness-based stress reduction demonstrated reduction in burnout and increased mental well-being for health-care providers including doctors from diverse specialties, and a biweekly physician discussion group12

Ms. Schuman is a member of the Integrative Medicine Service at Memorial Sloan Kettering Cancer Center, New York.

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 Barrie R. Cassileth, MS, PhD maintains a free website—About Herbs (www. mskcc.org/aboutherbs)—that provides objective and unbiased information about herbs, vitamins, minerals, and other dietary supplements, and unproved anticancer treatments. Each of the close to 300 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, can be downloaded at http://itunes.apple. com/us/app/about-herbs/id554267162?mt=8. The app is compatible with iPad, iPhone, and iPod Touch devices. vey of physicians both in training and practice found personal growth techniques such as self-awareness, prioritizing, setting limits, and cultivating a personal philosophy are successful self-care tools for coping.16 Also illustrative, pediatric and medicine resi-

Staff support groups support employees’ patient care efforts, reinforcing the intentions and skills of its members so that their work is consistent, exemplary, and true to the mission of caregiving.

Oncology Support Groups Reduce Stress Research documents the many stresses experienced by oncology nurses and physicians. They include compassion fatigue, which results from the trauma of long-term care of the ill and suffering1; burnout syndrome, the occupational chronic stress that results from emotional exhaustion2; feelings of low personal accomplishment3; and reduced ability to cope with patients’ pain and death.4,5 Oncology professionals contribute significantly to patients’ well-being. Their ability to manage grief and loss, and to sustain their own psychological and physical health while maintaining optimal relationships with patients, represents a major challenge. Sustaining quality of work and the determination to remain in their jobs are

GUEST EDITOR

—Michele Schuman, LMSW, LMT

resulted in increased work satisfaction and reduced feelings of depersonalization with results that lasted for more than a year. Additional interventions such as peer support,13 panel discussions involving topics such as balancing work and personal life, and mentoring and professional support groups are helpful,14 and Communication Skills Training shows promise for improved professional communication skills and effectiveness.15

Variety of Support Group Measures The development and impact of support group meetings for oncology staff in a variety of settings have demonstrated the use of diverse coping mechanisms. For example, a sur-

dents respond positively to half-day stress management workshops that focus on interpersonal skill building; balancing educational, personal, and work demands; developing a positive outlook and awareness; and cultivating adaptive behavioral responses.17 An interdisciplinary team of an oncology pediatric service participated in a weekly narrative writing instruction class for 6 weeks.18 By writing about their attachment to patients and how they felt emotionally about their relationships with patients and families, there was a definite increase in empathy. This reinforced team building and led to a better understanding of their colleagues with the potential to improve clinical care and professional experiences.

Nursing staff support groups assist in reducing stress, promoting member cohesiveness, and reducing interdisciplinary conflicts and perceived lack of support from nursing administration.19 One inpatient oncology unit initiated a bereavement support group to combat compassion fatigue and promote staff support.20 A remembrance tree was displayed in an area for staff only and changed seasonally. The intervention permitted staff to discuss patients who passed away, remember them, and bring closure to the experience. Schwartz Center Rounds21 provide the opportunity for interdisciplinary staff members to support one another as they discuss patient cases, explore the emotional and human components of clinical care, build team cohesiveness, and improve patient care.

Support Group Structure In 2011, we established support group meetings for the Memorial Sloan Kettering Integrative Medicine Service. They are monthly meetings open to all staff members. Guidelines were established to maintain a focus on patient-centered interactions. The meetings often begin with a meditation and a selected reading or discussion, but they also may begin immediately. The role of the facilitator is to support attendees as they introduce topics, respond to the discussion, encourage interaction, and maintain sensitivity to each member’s needs.22 In our group, the facilitator is a licensed social worker employee who can readily understand member concerns.

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Integrative Oncology Support Group Participants Core attendees of our support group meetings are the Memorial Sloan Kettering Integrative Medicine massage therapists, all licensed professionals, each with many years of experience. Massage therapists play an important role, supporting inpatients and outpatients throughout each stage of the patient’s medical journey. Patients report reduced pain, nausea, fatigue, procedural anxiety, and stress after receiving massage therapy. A massage therapist may provide care on an ongoing basis, sometimes for years. Such long-term relationships may profoundly affect the therapist, due in part to the special nature of the interaction. The therapist’s oneto-one relationship with the patient is devoid of machines and medicine, and it is hands-on. We are touching, feeling, communicating with the patient, as does the physician, but specifically and exclusively to provide comfort in quiet and peaceful circumstances. During their sessions, patients speak of their fears, money troubles, family dynamics, spiritual concerns, and other personal matters.

Professional Boundaries We are trained to adhere to professional boundaries, to care deeply, but to avoid emotional attachments. If a patient fails to thrive, dies, or is transferred to another facility, our grieving and the loss we may feel cannot impact our job effectiveness or our mission to help patients. The support group helps us maintain these boundaries. By sharing our experiences with colleagues who have similar experiences, we feel less isolated and less emotionally fatigued. We learn from suggestions and comments, and we benefit from the group’s teamwork and communication. The group sessions also provide an opportunity to reflect on and assess our work.23

Workplace Dynamics What are the dynamics of working in this environment? We work with patients of all ages, from the pediatric to the geriatric population. Often, depending on a family’s structure, an inpatient child may not have a guardian, and an older patient may have no family members who visit. In treating such people on a regular basis, a therapist may feel like a surrogate family member. The death of such a patient results in a sense of painful loss. Some therapists may feel as though they have lost their own

child. If a patient relapses or dies, how does the therapist integrate this information, give a voice to these thoughts and ideas, and share this with colleagues? The support group performs these functions. As therapists, we have access to a patient’s medical records and the results of their tests. Sometimes, we know the results before patients receive such news from their physicians. If it is not good news, we hold this information in confidence and make sure it does not interfere with treatment. For example, many times a patient has said, “I know I’m okay; I’m nervous about the results, but I feel so good, I know it’s going to be fine,” and we know otherwise. A young newly married patient in the intensive care unit with her husband at bedside may share with the therapist their plans for the future, and this includes having a family. The therapist has read her medical records indicating that the cancer has spread. Or a patient who you have massaged for many years at our outpatient center has relapsed, with accompanying metastases. Her oncologists urged chemotherapy, but her partner tells her to decline chemotherapy and try an “alternative” therapy, which she does. Over time, you watch her grow weaker until she passes away. Although you have maintained professional boundaries, it feels as though you have lost a very close friend. The support group is a forum for sharing these experiences, validating your feelings, offering insight to coping mechanisms, and suggesting self-care strategies. On a day-to-day basis, our massage therapists hold hands or feet while inpatients receive painful procedures or apply a very gentle massage as a patient is dying with family members looking on, or we share in the joy of learning that a patient is in remission and is going home. These are very private moments, and yet we are invited to bear witness. Core staff members attend our support group meetings on a monthly basis. Other employees attend following a particular situation that has put them into crisis mode. Consider the staff person who schedules our therapists for all inpatient work—massage therapy, music therapy, acupuncture, mind-body therapies, yoga, etc—and is familiar with patients, their medical histories, and current status. She has never met them face-to-face, but she feels as if she knows these patients. If that patient has a lengthy hospital stay and passes away,

scheduling staff also may experience a profound sense of loss.

Other Stressors In monthly meetings, our own lives enter into the discussions: we may address aging parents, their medical needs, finances, and end-of-life care; family members with cancer and how best to manage their illness, emotionally and physically; the joys and fears of upcoming parenthood; our own aging; spouses with a history of cancer, and how to cope with anxiety each time a spouse goes for a test or checkup; and team members with a history of cancer, who must be mindful of maintaining boundaries between their own experience and the needs of their patients. Once the discussion is underway, we offer suggestions for coping. We provide different points of view without judgment, acknowledging feelings and encouraging strategies for problemsolving. Our staff support group helps therapists not to feel alone in their work. Shared experiences and perspectives are reassuring and very helpful. This improves workplace satisfaction and promotes comfortable communication among staff and between staff and patients.

Ongoing Benefits The Memorial Sloan Kettering Integrative Medicine Service support group is held monthly regardless of how many people attend. Integrative Medicine Service staff employees are aware that if they require support, encouragement, suggestions for self-care, or camaraderie, or if they just want to talk, there is a group of people who want to listen. This is important for mental health and stability anytime, but it is critical in a workplace environment that confronts issues of health, suffering, and death and dying on a regular basis.6 Research has demonstrated the benefits of support groups for promoting self-care, refining communication strategies, and processing loss.10 It is reassuring to be among coworkers who share similar commitments and experience.24 The ability to make connections with other people in the group is helpful because it is necessary to connect with patients and their families. As health-care providers, we want to help our patients. Employees feel best when they are compassionate, when patients appear to be helped by our efforts, when patients show their appreciation, and when they are recognized in the workplace5 for doing a good job.

References 1. Sabo B: Reflecting on the concept of compassion fatigue. Online J Issues Nurs 16:1, 2011. 2. Demirci S, Yildirim YK, Ozsaran Z, et al: Evaluation of burnout syndrome in oncology employees. Med Oncol 27:968-974, 2010. 3. Blanchard P, Truchot D, AlbigesSauvin L, et al: Prevalence and causes of burnout amongst oncology residents: A comprehensive nationwide cross-sectional study. Eur J Cancer 46:2708-2715, 2010. 4. Potter P, Deshields T, Divanbeigi J, et al: Compassion fatigue and burnout: Prevalence among oncology nurses. Clin J Oncol Nurs 14:E56-E62, 2010. 5. Cashavelly BJ, Donelan K, Binda KD, et al: The forgotten team member: Meeting the needs of oncology support staff. Oncologist 13:530-538, 2008. 6. Wenzel J, Shaha M, Klimmek R, et al: Working through grief and loss: Oncology nurses’ perspectives on professional bereavement. Oncol Nurs Forum 38:E272E282, 2011. 7. Grunfeld E, Whelan TJ, Zitzelsberger L, et al: Cancer care workers in Ontario: Prevalence of burnout, job stress and job satisfaction. CMAJ 163:166-169, 2000. 8. Edmonds C, Lockwood GM, Bezjak A, et al: Alleviating emotional exhaustion in oncology nurses: An evaluation of Wellspring’s Care for the Professional Caregiver Program. J Cancer Educ 27:27-36, 2012. 9. Back AL, Deignan PF, Potter PA: Compassion, compassion fatigue, and burnout: Key insights for oncology professionals. Am Soc Clin Oncol Educ Book:e454e459, 2014. 10. Wittenberg-Lyles E, Goldsmith J, Reno J: Perceived benefits and challenges of an oncology nurse support group. Clin J Oncol Nurs 18:E71-E76, 2014. 11. Goodman MJ, Schorling JB: A mindfulness course decreases burnout and improves well-being among healthcare providers. Int J Psychiatry Med 43:119-128, 2012. 12. West CP, Dyrbye LN, Rabatin JT, et al: Intervention to promote physician wellbeing, job satisfaction, and professionalism: A randomized clinical trial. JAMA Intern Med 174:527-533, 2014. 13. Hu YY, Fix ML, Hevelone ND, et al: Physicians’ needs in coping with emotional stressors: The case for peer support. Arch continued on page 52

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Integrative Oncology Staff Support Sessions continued from page 51

Surg 147:212-217, 2012. 14. Eckleberry-Hunt J, Van Dyke A, Lick D, et al: Changing the conversation from burnout to wellness: Physician well-being in residency training programs. J Grad Med Educ 1:225-230, 2009. 15. Kissane DW, Bylund CL, Banerjee SC, et al: Communication skills training for oncology professionals. J Clin Oncol 30:1242-1247, 2012. 16. Quill TE, Williamson PR: Healthy approaches to physician stress. Arch Intern Med 150:1857-1861, 1990. 17. McCue JD, Sachs CL: A stress management workshop improves residents’ coping skills. Arch Intern Med 151:2273-2277, 1991.

18. Sands SA, Stanley P, Charon R: Pediatric narrative oncology: Interprofessional training to promote empathy, build teams, and prevent burnout. J Support Oncol 6:307-312, 2008. 19. Guillory BA, Riggin OZ: Developing a nursing staff support group model. Clin Nurse Spec 5:170-173, 1991. 20. Fetter KL: We grieve too: One in-

patient oncology unit’s interventions for recognizing and combating compassion fatigue. Clin J Oncol Nurs 16:559-561, 2012. 21. Gibson S: Schwartz Center Rounds: Focusing on the patient-caregiver relationship. This national model offers emotional support to doctors and other medical professionals. Health Prog 89:40-43, 2008.

22. Zabalegui A, Sanchez S, Sanchez PD, et al: Nursing and cancer support groups. J Adv Nurs 51:369-381, 2005. 23. Barnes K: Staff stress in the children’s hospice: Causes, effects and coping strategies. Int J Palliat Nurs 7:248-254, 2001. 24. Lederberg MS: Staff support groups for high-stress medical environments. Int J Group Psychother 48:275-304, 1998.

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Learn more about the unmet needs in EGFRm+ NSCLC at targetEGFR.com

ASCOPost.com | APRIL 25, 2015

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Announcements

Recipients of the 2015 Conquer Cancer Foundation’s Innovation Grants By Jo Cavallo

he Conquer Cancer Foundation’s 2015 International Innovation Grants were awarded to the following five organizations conducting research in India, Mexico, Nigeria, Romania, and Uganda:

• Tata Medical Center (Kolkata, India). This grant is funding a randomized clinical study testing the success of text message intervention to improve chemotherapy protocol compliance

and reduce toxicity in patients. Principal investigator: Tanuj Chawla, MD, MBBS. • Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán

We want to change the face of EGFR-targeted therapy Cutaneous toxicities are caused by inhibition of wild-type epidermal growth factor receptor (EGFR) and can be debilitating1,2 Inhibition of wild-type and mutant EGFR in non–small cell lung cancer (NSCLC)

Cutaneous toxicities can be dose-limiting

Normal, or wild-type, EGFR is highly expressed on epithelial cells in the skin, liver, and gastrointestinal tract.3-5 Current EGFR tyrosine kinase inhibitors (TKIs) target not only the oncogenic mutant forms of EGFR, but also wild-type EGFR, which may lead to cutaneous toxicities including rash, stomatitis, and paronychia.1,2,6-8

The symptoms and psychosocial impact of cutaneous toxicities can negatively affect both patient quality of life and patient compliance.11,12 In some studies, rash and paronychia were among the most frequent causes of dose modification, combining to cause dose reductions in as many as 33% of patients.7,8

90% of patients treated with approved EGFR TKIs experience rash7,8

The future of EGFR inhibition

The skin is dependent on wild-type EGFR signaling for normal growth and differentiation.1,9,10 Druginduced inhibition of wild-type EGFR disrupts its normal function and can cause cutaneous inflammation and injury. This accounts for the high incidence of cutaneous toxicities associated with EGFR TKIs.1,9

Strategies that eliminate inhibition of wild-type EGFR may be most effective at mitigating cutaneous toxicities and maintaining optimal dosing.9 At Clovis Oncology, we’re committed to exploring new approaches in EGFR therapy to advance the fight against NSCLC.

Clovis Oncology is leading the fight

REFERENCES: 1. Lynch TJ Jr et al. Epidermal growth factor receptor inhibitor–associated cutaneous toxicities: an evolving paradigm in clinical management. Oncologist. 2007;12(5):610-621. 2. Pérez-Soler R et al. HER1/EGFR inhibitor-associated rash: future directions for management and investigation outcomes from the HER1/EGFR Inhibitor Rash Management Forum. Oncologist. 2005;10(5):345-356. 3. Harandi A et al. Clinical efficacy and toxicity of anti-EGFR therapy in common cancers. J Clin Oncol. 2009;2009:567486. doi:10.1155/2009/567486. 4. Natarajan A et al. The EGF receptor is required for efficient liver regeneration. Proc Natl Acad Sci U S A. 2007;104(43):17081-17086. 5. Tissue atlas: EGFR. The Human Protein Atlas website. http://www.proteinatlas.org /ENSG00000146648-EGFR/tissue. Accessed February 17, 2015. 6. Antonicelli A et al. EGFR-targeted therapy for non-small cell lung cancer: focus on EGFR oncogenic mutation. Int J Med Sci. 2013;10(3):320-330. 7. Tarceva [package insert]. Northbrook, IL: Astellas Pharma US Inc; 2014. 8. Gilotrif [package insert]. Ridgefield, CT: Boehringer Ingelheim Pharmaceuticals Inc; 2014. 9. Lacouture ME. Mechanisms of cutaneous toxicities to EGFR inhibitors. Nat Rev Cancer. 2006;6(10):803-812. 10. Melosky B et al. Management of common toxicities in metastatic NSCLC related to anti-lung cancer therapies with EGFR–TKIs. Front Oncol. 2014;4:238. doi:10.3389/fonc.2014.00238. 11. White KJ et al. Psychosocial impact of cutaneous toxicities associated with epidermal growth factor receptor–inhibitor treatment. Clin J Oncol Nurs. 2011;15(1):88-96. 12. National Cancer Institute. Common Terminology Criteria for Adverse Events (CTCAE), Version 4.0. http://evs.nci .nih.gov/ftp1/CTCAE/CTCAE_4.03_2010-06-14_QuickReference_8.5x11.pdf. Published May 28, 2009. Updated June 14, 2010. Accessed February 2, 2015.

(Mexico City, Mexico). This award is funding a breast health educational program for rural adolescents to increase knowledge of breast health and promote help-seeking behaviors. Principal investigator: Yanin Chávarri Guerra, MD, MSc. • College of Medicine, University of Ibadan (Ibadan, Nigeria). The study is investigating community-level intervention strategies to recruit and train local health providers to prevent, detect, and treat cervical cancer. Principal investigator: Olutosin Alaba Awolude, MBBS, MS. • The Oncology Institute “Prof. Dr. Ion Chiricuţă” (Cluj-Napoca, Romania). Although patients with breast cancer in Romania have access to many standard therapies, they have worse outcomes than patients in developed countries receiving the same therapies. This award will support the implementation of a telemedicine Web-based platform to enable an experienced multidisciplinary breast tumor board to review cases and improve treatment decisions for patients in small, remote cancer centers. Principal investigator: Alexandru E. Eniu, MD, PhD.

• Hutchinson Centre Research Institute of Uganda (Kampala, Uganda). This project involves a 9-month pilot study to test the impact and acceptability of an integrated cervical screening program on identifying early-stage invasive cervical cancer in a high-volume HIV clinic. Principal investigator: Mugume Mugisha, MPH, MBChB. n The 2014 and 2015 International Innovation Grants were made possible by the generous support of ASCO International, AstraZeneca, Conquer Cancer Foundation Mission Endowment, Doris Duke Charitable Foundation, Roche, Thomas G. Roberts, Jr, MD, and Susan M. DaSilva. If you would like to make a donation to the International Innovation Grant program or to learn more about other initiatives to improve cancer care in lowand middle-income countries, please visit Conquer Cancer Foundation at conquercancerfoundation.org.

The ASCO Post | APRIL 25, 2015

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Oncology Worldwide Noncommunicable Diseases continued from page 1

Unfortunate Byproduct of Success

poor nutrition, and increasing rates of tobacco use caused by limited tax and regulatory systems. According to the report, the increase in cigarette smoking in low- and middle-income countries, including India, Indonesia, Pakistan, and Vietnam, has made lung cancer the most common cancer and cause of death from cancer. Deaths from other cancers are on the rise, too, including ones that are largely treatable, curable, and on the decline in the United States and in other high-income countries. The report found that in poorer countries between 1990 and 2013, premature deaths from breast cancer and leukemia grew an astounding 90% and 25%, respectively, largely the result of too little access to diagnostic and curative care. (Approximately two-thirds of all cancer deaths occur in low- and middle-income countries, where the 5-year survival rates are lower than in high-income countries.3)

While increasing incomes and reductions in infectious diseases like HIV/AIDS, malaria, and tuberculosis in poor countries have resulted in people living long enough to die of diseases that typically affect older people, they do not explain why so many are developing noncommunicable diseases at much younger ages and with such worse outcomes than populations in wealthier countries. The reason for the shift, say experts, is that noncommunicable diseases are outpacing the ability of developing nations to put into place the health-care systems necessary to prevent and treat these chronic diseases. “Fewer infants and children are dying, and people in developing countries are living longer, but those improvements in longevity have happened without the same gains in wealth and improvements in health-care systems you saw in higher-income countries,” said Thomas J. Bollyky, Senior Fellow for Global Health, Economics, and De-

velopment at the Council on Foreign Relations, and Project Director of The Emerging Global Health Crisis: Noncommunicable Diseases in Low- and MiddleIncome Countries report. “All the governments of sub-Saharan Africa spend about as much on health care per year as the government of Poland—about $30 billion,” he continued. “The same factors that drive other global health problems are driving noncommunicable diseases in these countries: persistent poverty and limited health-care systems.”

Halting the Epidemic In addition to the human toll that rising rates of noncommunicable diseases will inflict on poor countries—including large numbers of people who will get sick, suffer longer, require more medical care, and die young—the economic consequences in these countries are equally staggering. According to the CFR report, the World Economic Forum projects that the noncommunicable disease epidemic will result in a loss of $21.3 trillion

in developing countries over the next 2 decades—a cost that is nearly equal to the total aggregate economic output of these countries in 2013 ($24.5 trillion). The remedies to blunt the noncommunicable disease epidemic, said Mr. Bollyky, are well known and have been successfully used in the United States and other high-income countries to curtail these diseases, especially cancer. “Our task force looked at the interventions to reduce [noncommunicable diseases] in low-income countries, and the ones that are relevant for cancer include establishing better tobacco control; increasing vaccination rates for human papillomavirus (HPV) and hepatitis B, which are relevant for cervical cancer and liver cancer; and adapting chemotherapeutics and diagnostic tools to the lower-resource setting,” he said. Devoting more resources to the development of population-based registries to track the incidence, mortality, and survival rates of different types of cancer are also fundamental to improving cancer prevention and treatment, he added.

How the International Innovation Grant Is Improving Cancer Care for Women in Myanmar By Jo Cavallo

n 2014, the Conquer Cancer Foundation awarded four inaugural International Innovation Grants to aid novel research projects in Colombia, Myanmar, Nigeria, and Tanzania. The program, which supports a 1-year research grant of up to $20,000 to a nonprofit organization or governmental agency in a low- and middle-income country, is designed to fund projects to improve cancer care in local communities, as well as have the potential to be transferable to settings in other developing countries. Each grant is associated with a principal investigator who is an ASCO member, is affiliated with the grantee organization, and is a resident of a low- or middle-income country. Recently, W. Charles Penley, MD, FASCO, Chair of the Conquer Cancer Foundation Board of Directors and a medical oncologist in Nashville, paid a visit to the University of Medicine 1 in Yangon, Myanmar, to see firsthand how the grant is being utilized. The project, “Effectiveness of a visual inspection with acetic acid and cryotherapy-based single-visit approach to cervical cancer prevention in Taikkyi Township,” is led by principal investigator Mya Thida, MBBS, PhD, Professor and Head of the Ob-

stetrics and Gynecology Department at the University of Medicine 1. The program uses an economical “screenand-treat” method for the prevention of cervical cancer, a disease that kills 300,000 women—mostly young women—in low- and middle-income countries each year. “Because physicians don’t have access to pathology resources, widespread Pap smear screening is not done. Dr. Thida’s program follows

the area, eliminating the suspicious tissue. The patient is then offered a repeat examination in 6 months.”

Taking Screening to Women Where They Live In addition to having a screening facility at Central Women’s Hospital in Yangon, where she also conducts public education in cervical cancer prevention, Dr. Thida takes medical equipment, including disposable

Dr. Thida and her colleagues are using the resources they have in the most imaginative and efficient way. The Conquer Cancer Foundation is proud to support the work of this dedicated team. —W. Charles Penley, MD, FASCO

the approach of screening through visual inspection of the cervix with acetic acid,” explained Dr. Penley. “If a potential problem is identified, Dr. Thida and her colleagues take it a step further. With the permission of the patient, they use cryotherapy to freeze

speculums and portable cryotherapy units; brochures in cervical cancer prevention; and a staff of physicians, nurses, and midwives who have been trained in cervical cancer screening, to communities throughout Myanmar. Although it is too early to measure

the full impact Dr. Thida’s International Innovation Grant has had on preventing cervical cancer in women in Taikkyi Township, Dr. Penley said in just a few months screening rates have increased from a baseline of 0.9% prior to Dr. Thida’s program to nearly 20% today. The hope is that with repeat visits by the team, the rate will increase further. The program is reproducible not just in other cities in Myanmar, but in other developing countries as well. “What I witnessed is such quality work being done,” said Dr. Penley. “Dr. Thida and her colleagues are using the resources they have in the most imaginative and efficient way. I was very impressed. The Conquer Cancer Foundation is proud to support the work of this dedicated team.” The screen-and-treat program is already so successful, said Dr. Penley, he has encouraged Dr. Thida and her medical research fellows and students to apply for other Conquer Cancer Foundation funding opportunities, including the International Development and Education Award and the Young Investigator Award. n See related story on page 44.

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Oncology Worldwide Collaborating to Reduce Cancer Rates Leveraging resources to address the health-care needs of low- and middleincome countries is the goal of the National Cancer Institute’s Center for Global Health. Established in 2011, the Center is tasked with improving global health outcomes through sharing knowledge gained in cancer research and cancer control, and developing research networks to facilitate collaboration to reduce cancer rates in developing countries. “What we are trying to do is make sure that what we already know about reducing cancer globally is rolled out to these countries as effectively as possible, and that dovetails with the findings in the Council on Foreign Relations report,” said Edward J. Trimble, MD, MPH, Director of the Center for Global Health. “We need to help countries integrate into their public health practices what we already know about how to prevent cancer, how to screen for cancer, and how to treat cancer.”

Edward J. Trimble, MD, MPH

However, lack of funding to combat noncommunicable diseases in these countries—the United States does not have a dedicated program or budget to address noncommunicable diseases globally—threaten to slow these efforts. “Unfortunately, much of the budget of the government agencies tasked with disease prevention, such as the Centers for Disease Control and Prevention and the [U.S. Agency for International Development], is earmarked for specific categories. It can be hard for them to transfer money out of those categories

without congressional approval,” said Dr. Trimble. “We looked at the 49 countries where the United States invests $5 million or more annually in global health aid, and we found that the premature mortality from [noncommunicable diseases] in these countries is 3.5 times the rate of premature mortality from HIV,” added Mr. Bollyky. “In fact, it is almost twice the rate of premature mortality from HIV, tuberculosis, and malaria combined.”

Conquer Cancer Foundation Funding Recognizing the health crises noncommunicable diseases are causing in low- and middle-income countries, 2 years ago the Conquer Cancer Foundation of ASCO announced the establishment of the International Innovation Grant program to help stem the trend. The program awards 1-year grants of up to $20,000 to fund novel and innovative research projects that can have a significant impact on cancer control in these countries. The inaugural grants were awarded in January 2014 and supported research projects in Colombia, Myanmar, Nigeria, and Tanzania (see “How the International Innovation Grant Is Improving Cancer Care for Women in Myanmar,” on page 54). Earlier this year, the Foundation announced the five recipients of the 2015 International Innovation Grant. They include organizations in India, Mexico, Nigeria, Romania, and Uganda conducting research on cervical cancer screening and treatment, breast health education and breast cancer treatment, and chemotherapy compliance (see “Recipients of the 2015 International Innovation Grants” on page 53). “Our goal is not to dictate the methods that physicians in other countries use to improve screening or treatment for the patients they serve,” said W. Charles Penley, MD, FASCO, Chair of the Conquer Cancer Foundation Board of Directors and a medical oncologist in

International Innovation Grant Enables Screen and Treat Program in Myanmar: W. Charles Penley, MD, FASCO (top row, third from left), and Mya Thida, MBBS, PhD (top row, second from right), are shown with health-care workers at the Central Women’s Hospital in Yangon, Myanmar, where Dr. Thida and her colleagues conduct public education in cervical cancer prevention in addition to providing cervical cancer screening through visual inspection of the cervix with acetic acid and treatment if needed.

Nashville. “Only physicians familiar with local practices and resources know best how to address the local care needs. A $20,000 grant sounds rather small, but it can make a world of difference where there is great need. Our grant selection committee reviews the proposals that we receive in the context of the current health status in a particular country, considering the impact that successful completion of the project will have on the local population, then steps back and allows the physicians and nurses on the ground to do the good work.”

Saving Lives Mr. Bollyky agrees that the participation of cancer organizations and societies is vital to providing on-the-ground support to reduce noncommunicable disease prevalence. “It will take a combination of things to improve care. One way is to have ongoing global health initiatives to integrate interventions or programs to address cancer in lowerand middle-income countries. Certainly, we need more oncologists and physicians from related fields to collaborate on cancer control. We’ve made so much progress in cancer and heart disease in

high-income countries, but it is not being extended in developing countries. In many of these settings, everything is missing, including personnel, equipment, and basic chemotherapies,” said Mr. Bollyky. To overcome these challenges, the CFR report recommends that the United States and its international partners examine their global health priorities and develop a sustainable plan for collective action on noncommunicable diseases in developing countries. n

Disclosure: Mr. Bollyky, Dr. Penley, and Dr. Trimble reported no potential conflicts of interest.

References 1. UNAIDS: AIDS by the numbers, 2013. Available at unaids.org. Accessed April 7, 2015. 2. Independent Task Force on Noncommunicable Diseases: The Emerging Global Health Crisis: Noncommunicable Diseases in Low- and Middle-Income Countries, Task Force Report No. 72. New York, Council on Foreign Relations Press, 2014. 3. Patel JD, Galsky MD, Chagpar AB, et al: Role of American Society of Clinical Oncology in low- and middle-income countries. J Clin Oncol 29:3097-3102, 2011.

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SHAPE PROGRESSION-FREE SURVIVAL WITH CONTINUOUS TREATMENT Continuous REVLIMID + dex until progression showed a PFS and OS benefit in patients with newly diagnosed multiple myeloma vs MPT

WARNING: EMBRYO-FETAL TOXICITY, HEMATOLOGIC TOXICITY, and VENOUS and ARTERIAL THROMBOEMBOLISM See full prescribing information for complete boxed warning. EMBRYO-FETAL TOXICITY • Lenalidomide, a thalidomide analogue, caused limb abnormalities in a developmental monkey study similar to birth defects caused by thalidomide in humans. If lenalidomide is used during pregnancy, it may cause birth defects or embryo-fetal death. • Pregnancy must be excluded before start of treatment. Prevent pregnancy during treatment by the use of two reliable methods of contraception. REVLIMID is available only through a restricted distribution program called the REVLIMID REMS® program (formerly known as the “RevAssist® program”). HEMATOLOGIC TOXICITY. REVLIMID can cause significant neutropenia and thrombocytopenia. • For patients with del 5q myelodysplastic syndromes, monitor complete blood counts weekly for the first 8 weeks and monthly thereafter. VENOUS AND ARTERIAL THROMBOEMBOLISM • Significantly increased risk of deep vein thrombosis (DVT) and pulmonary embolism (PE), as well as risk of myocardial infarction and stroke in patients with multiple myeloma receiving REVLIMID with dexamethasone. Anti-thrombotic prophylaxis is recommended.

REVLIMID is only available through a restricted distribution program, REVLIMID REMS®. Please see additional Important Safety Information and Brief Summary, including Boxed WARNINGS, on the following pages. Learn more at www.REVLIMID.com

Median Progression-Free Survival (PFS) Rd Continuous (n=535) 25.5 mo (95% CI 20.7, 29.4) Rd18 (n=541) 20.7 mo (95% CI 19.4, 22.0) MPT (n=547) 21.2 mo (95% CI 19.3, 23.2)

100

Survival Probability (%)

80 Rd Continuous vs MPT Rd Continuous vs Rd18 Rd18 vs MPT

Logrank P value (2-sided) HR (95% CI) 0.72 (0.61, 0.85) P<0.0001 0.70 (0.60, 0.82) 1.03 (0.89, 1.20)

Planned duration of treatment in the Rd18 40 and MPT arms was 18 months 20

Progression-Free Survival (Years) •535 PFS Rd Continuous Rd18 541 MPT MM-020 547 Study design: The

Events: (52.0%), (64.3%), MPT=334/547 400Rd Continuous=278/535 319 265 218 Rd18=348/541 168 105 55 19 (61.1%)2 391 380 (FIRST)

319 265 167 304 244 compared REVLIMID170+

108 116 low-dose

56 30 58 28 (Rd) dexamethasone

7 2 6 1 Continuous until

0 0 0 progression,

trial fixed-cycle MPT, and fixed-cycle Rd18. MM-020 was a Phase 3, randomized, multicenter, open-label, 3-arm study enrolling 1623 newly diagnosed Number of Subjects at mg Risk patients who did not receive a stem cell transplant (SCT). REVLIMID was given 25 once daily orally on Days 1 to 21 of 28-day cycles, PFS Events: Rd Continuous=278/535 (52.0%), Rd18=348/541 (64.3%), MPT=334/547 (61.1%) ≤75 years and 20 mg for patients and dex was dosed once daily orally on Days 1, 8, 15, and 22 of each 28-day cycle (40 mg for patients >75 years). The primary endpoint in the trial was progression-free survival (PFS), as the time from randomization to the first documentation of disease progression as determined by Independent Response Adjudication Committee (IRAC), based on International Myeloma Working Group (IMWG) criteria, or death due to any cause, whichever occurred first during the study until the end of the PFS follow-up phase. For the efficacy analysis of all endpoints, the primary comparison was between Rd Continuous and MPT arms.

58.9 months median overall survival (OS) with Rd Continuous until progression in an interim analysis, compared with 48.5 months with MPT (HR 0.75 [95% CI 0.62, 0.90]) and 56.7 months with Rd18 (HR 0.91 [95% CI 0.75, 1.09]) • At median follow-up of 45.5 months, only 78% of prespecified events had occurred (697/896 of the final OS events) • OS is defined as the time from randomization to death from any cause ADVERSE REACTIONS Multiple Myeloma • In newly diagnosed patients the most frequently reported Grade 3 or 4 adverse reactions in Arm Rd Continuous included neutropenia (27.8%), anemia (18.2%), thrombocytopenia (8.3%), pneumonia (11.3%), asthenia (7.7.%), fatigue (7.3%), back pain (7%), hypokalemia (6.6%), rash (7.3%), cataract (5.8%), dyspnea (5.6%), DVT (5.6%), hyperglycemia (5.3%), lymphopenia and leukopenia. The frequency of infections in Arm Rd Continuous was 75% Adverse reactions reported in ≥20% of NDMM patients in Arm Rd Continuous: diarrhea (45.5%), anemia (43.8%), neutropenia (35%), fatigue (32.5%), back pain (32%), insomnia (27.6%), asthenia (28.2%), rash (26.1%), decreased appetite (23.1%), cough (22.7%), pyrexia (21.4%), muscle spasms (20.5%), and abdominal pain (20.5%). The frequency of onset of cataracts increased over time with 0.7% during the first 6 months and up to 9.6% by the second year of treatment with Arm Rd Continuous CONTRAINDICATIONS Pregnancy: REVLIMID can cause fetal harm when administered to a pregnant female and is contraindicated in females who are pregnant. 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 Allergic Reactions: REVLIMID is contraindicated in patients who have demonstrated hypersensitivity (e.g., angioedema, StevensJohnson syndrome, toxic epidermal necrolysis) to lenalidomide

Treatment is a science. Patient care is your art.

REVLIMID® (lenalidomide) in combination with dexamethasone (dex) is indicated for the treatment of patients with multiple myeloma (MM) REVLIMID is not indicated and is not recommended for the treatment of patients with chronic lymphocytic leukemia (CLL) outside of controlled clinical trials

Important Safety Information WARNING: EMBRYO-FETAL TOXICITY, HEMATOLOGIC TOXICITY, and VENOUS and ARTERIAL THROMBOEMBOLISM Embryo-Fetal Toxicity Do not use REVLIMID during pregnancy. Lenalidomide, a thalidomide analogue, caused limb abnormalities in a developmental monkey study. Thalidomide is a known human teratogen that causes severe life-threatening human birth defects. If lenalidomide is used during pregnancy, it may cause birth defects or embryo-fetal death. In females of reproductive potential, obtain 2 negative pregnancy tests before starting REVLIMID treatment. Females of reproductive potential must use 2 forms of contraception or continuously abstain from heterosexual sex during and for 4 weeks after REVLIMID treatment. To avoid embryo-fetal exposure to lenalidomide, REVLIMID is only available through a restricted distribution program, the REVLIMID REMS® program (formerly known as the “RevAssist®” program). Information about the REVLIMID REMS® program is available at www.celgeneriskmanagement.com or by calling the manufacturer’s toll-free number 1-888423-5436. Hematologic Toxicity (Neutropenia and Thrombocytopenia) REVLIMID can cause significant neutropenia and thrombocytopenia. Eighty percent of patients with del 5q MDS had to have a dose delay/reduction during the major study. Thirty-four percent of patients had to have a second dose delay/reduction. Grade 3 or 4 hematologic toxicity was seen in 80% of patients enrolled in the study. Patients on therapy for del 5q MDS should have their complete blood counts monitored weekly for the first 8 weeks of therapy and at least monthly thereafter. Patients may require dose interruption and/or reduction. Patients may require use of blood product support and/or growth factors. Venous and Arterial Thromboembolism REVLIMID has demonstrated a significantly increased risk of deep vein thrombosis (DVT) and pulmonary embolism (PE), as well as risk of myocardial infarction and stroke in patients with MM who were treated with REVLIMID and dexamethasone therapy. Monitor for and advise patients about signs and symptoms of thromboembolism. Advise patients to seek immediate medical care if they develop symptoms such as shortness of breath, chest pain, or arm or leg swelling. Thromboprophylaxis is recommended and the choice of regimen should be based on an assessment of the patient’s underlying risks.

CONTRAINDICATIONS Pregnancy: REVLIMID can cause fetal harm when administered to a pregnant female and is contraindicated in females who are pregnant. 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 Allergic Reactions: REVLIMID is contraindicated in patients who have demonstrated hypersensitivity (e.g., angioedema, Stevens-Johnson syndrome, toxic epidermal necrolysis) to lenalidomide WARNINGS AND PRECAUTIONS Embryo-Fetal Toxicity: • REVLIMID is an analogue of thalidomide, a known human teratogen that causes life-threatening human birth defects or embryo-fetal death. An embryo-fetal development study in monkeys indicates that lenalidomide produced malformations in offspring of female monkeys who received drug during pregnancy, similar to birth defects observed in humans following exposure to thalidomide during pregnancy • Females of Reproductive Potential: Must avoid pregnancy for at least 4 weeks before beginning REVLIMID therapy, during therapy, during dose interruptions and for at least 4 weeks after completing therapy. Must commit either to abstain continuously from heterosexual sexual intercourse or to use two methods of reliable birth control beginning 4 weeks prior to initiating treatment with REVLIMID, during therapy, during dose interruptions and continuing for 4 weeks following discontinuation of REVLIMID. Must obtain 2 negative pregnancy tests prior to initiating therapy • Males: Lenalidomide is present in the semen of patients receiving the drug. Males must always use a latex or synthetic condom during any sexual contact with females of reproductive potential while taking REVLIMID and for up to 28 days after discontinuing REVLIMID, even if they have undergone a successful vasectomy. Male patients taking REVLIMID must not donate sperm • Blood Donation: Patients must not donate blood during treatment with REVLIMID and for 1 month following discontinuation of the drug because the blood might be given to a pregnant female patient whose fetus must not be exposed to REVLIMID REVLIMID REMS® Program Because of embryo-fetal risk, REVLIMID is available only through a restricted program under a Risk Evaluation and Mitigation Strategy (REMS) the REVLIMID REMS® program (formerly known as the “RevAssist®” program). Prescribers and pharmacies must be certified with the program and patients must sign an agreement form and comply with the requirements. Further information about the REVLIMID REMS®

program is available at www.celgeneriskmanagement.com or by telephone at 1-888-423-5436 Hematologic Toxicity: REVLIMID can cause significant neutropenia and thrombocytopenia. Monitor patients with neutropenia for signs of infection. Advise patients to observe for bleeding or bruising, especially with use of concomitant medications that may increase risk of bleeding. MM: Patients taking REVLIMID/dex should have their complete blood counts (CBC) assessed every 7 days for the first 2 cycles, on days 1 and 15 of cycle 3, and every 28 days thereafter. Venous and Arterial Thromboembolism: Venous thromboembolic events (DVT and PE) and arterial thromboses are increased in patients treated with REVLIMID. A significantly increased risk of DVT (7.4%) and PE (3.7%) occurred in patients with MM after at least one prior therapy, treated with REVLIMID/dex compared to placebo/dex (3.1% and 0.9%) in clinical trials with varying use of anticoagulant therapies. In NDMM study, in which nearly all patients received antithrombotic prophylaxis, DVT (3.6%) and PE (3.8%) were reported in the Rd continuous arm. Myocardial infarction (MI, 1.7%) and stroke (CVA, 2.3%) are increased in patients with MM after at least 1 prior therapy who were treated with REVLIMID/dex therapy compared with placebo/dex (0.6%, and 0.9%) in clinical trials. In NDMM study, MI (including acute) was reported (2.3%) in the Rd Continuous arm. Frequency of serious adverse reactions of CVA was (0.8%) in the Rd Continuous arm. Patients with known risk factors, including prior thrombosis, may be at greater risk and actions should be taken to try to minimize all modifiable factors (e.g. hyperlipidemia, hypertension, smoking). In controlled clinical trials that did not use concomitant thromboprophylaxis, 21.5% overall thrombotic events occurred in patients with refractory and relapsed MM who were treated with REVLIMID/dex compared to 8.3% thrombosis in the placebo/dex group. Median time to first thrombosis event was 2.8 months. In NDMM study, which nearly all patients received antithrombotic prophylaxis, overall frequency of thrombotic events was 17.4% in combined Rd Continuous and Rd18 arms. Median time to first thrombosis event was 4.37 months. Thromboprophylaxis is recommended and regimen is based on patients underlying risks. ESAs and estrogens may further increase the risk of thrombosis and their use should be based on a benefit-risk decision. See Boxed WARNINGS Increased Mortality in Patients With CLL: In a clinical trial in the first line treatment of patients with CLL, single agent REVLIMID therapy increased the risk of death as compared to single agent chlorambucil. In an interim analysis, there were 34 deaths among 210 patients on the REVLIMID treatment arm compared to 18 deaths among 211 patients in the chlorambucil treatment arm, and hazard ratio for overall survival was 1.92 [95% CI: 1.08-3.41] consistent with a 92% increase in risk of death. Serious adverse cardiovascular reactions, including atrial fibrillation, myocardial infarction, and cardiac failure, occurred more frequently in the REVLIMID

WARNINGS AND PRECAUTIONS (continued) treatment arm. REVLIMID is not indicated and not recommended for use in CLL outside of controlled clinical trials Second Primary Malignancies: In clinical trials in patients with MM receiving REVLIMID, an increase of invasive second primary malignancies (SPM) notably AML and MDS have been observed. The increase of AML and MDS occurred predominantly in NDMM patients receiving REVLIMID in combination with oral melphalan (5.3%) or immediately following high dose intravenous melphalan and ASCT (up to 5.2%). The frequency of AML and MDS cases in the REVLIMID/dex arms was observed to be 0.4%. Cases of B-cell malignancies (including Hodgkin’s Lymphomas) were observed in clinical trials where patients received REVLIMID in the post-ASCT setting. Patients who received REVLIMID-containing therapy until disease progression did not show a higher incidence of invasive SPM than patients treated in the fixed duration REVLIMID-containing arms. Monitor patients for the development of second primary malignancies. Take into account both the potential benefit of REVLIMID and risk of second primary malignancies when considering treatment Hepatotoxicity: Hepatic failure, including fatal cases, has occurred in patients treated with REVLIMID in combination with dex. The mechanism of drug-induced hepatotoxicity is unknown. Pre-existing viral liver disease, elevated baseline liver enzymes, and concomitant medications may be risk factors. Monitor liver enzymes periodically. Stop REVLIMID upon elevation of liver enzymes. After return to baseline values, treatment at a lower dose may be considered Allergic Reactions: Angioedema and serious dermatologic reactions including Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) have been reported. These events can be fatal. Patients with a prior history of Grade 4 rash associated with thalidomide treatment should not receive REVLIMID. REVLIMID interruption or discontinuation should be considered for Grade 2-3 skin rash. REVLIMID must be discontinued for angioedema, Grade 4 rash, exfoliative or bullous rash, or if SJS or TEN is suspected and should not be resumed following discontinuation for these reactions. REVLIMID capsules contain lactose. Risk-benefit of REVLIMID treatment should be evaluated in patients with lactose intolerance Tumor Lysis Syndrome: Fatal instances of tumor lysis syndrome (TLS) have been reported during treatment with lenalidomide. The patients at risk of TLS are those with high tumor burden prior to treatment. These patients should be monitored closely and appropriate precautions taken Tumor Flare Reaction: Tumor flare reaction (TFR) has occurred during investigational use of lenalidomide for CLL and lymphoma, and is characterized by tender lymph node swelling, low grade fever, pain and rash.

Impaired Stem Cell Mobilization: A decrease in the number of CD34+ cells collected after treatment (> 4 cycles) with REVLIMID has been reported. In patients who are autologous stem cell transplant (ASCT) candidates, referral to a transplant center should occur early in treatment to optimize timing of the stem cell collection ADVERSE REACTIONS Multiple Myeloma • In newly diagnosed patients the most frequently reported Grade 3 or 4 adverse reactions in Arm Rd Continuous included neutropenia (27.8%), anemia (18.2%), thrombocytopenia (8.3%), pneumonia (11.3%), asthenia (7.7.%), fatigue (7.3%), back pain (7%), hypokalemia (6.6%), rash (7.3%), cataract (5.8%), dyspnea (5.6%), DVT (5.6%), hyperglycemia (5.3%), lymphopenia and leukopenia. The frequency of infections in Arm Rd Continuous was 75%

Adverse reactions reported in ≥20% of NDMM patients in Arm Rd Continuous: diarrhea (45.5%), anemia (43.8%), neutropenia (35%), fatigue (32.5%), back pain (32%), insomnia (27.6%), asthenia (28.2%), rash (26.1%), decreased appetite (23.1%), cough (22.7%), pyrexia (21.4%), muscle spasms (20.5%), and abdominal pain (20.5%). The frequency of onset of cataracts increased over time with 0.7% during the first 6 months and up to 9.6% by the second year of treatment with Arm Rd Continuous • After at least one prior therapy most adverse reactions and Grade 3 or 4 adverse reactions were more frequent in MM patients who received the combination of REVLIMID/dex compared to placebo/dex. Grade 3 or 4 adverse reactions included neutropenia 33.4% vs 3.4%, febrile neutropenia 2.3% vs 0%, DVT 8.2% vs 3.4% and PE 4% vs 0.9% respectively Adverse reactions reported in ≥15% of MM patients (REVLIMID/dex vs dex/placebo): fatigue (44% vs 42%), neutropenia (42% vs 6%), constipation (41% vs 21%), diarrhea (39% vs 27%), muscle cramp (33% vs 21%), anemia (31% vs 24%), pyrexia (28% vs 23%), peripheral edema (26% vs 21%), nausea (26% vs 21%), back pain (26% vs 19%), upper respiratory tract infection (25% vs 16%), dyspnea (24% vs 17%), dizziness (23% vs 17%), thrombocytopenia (22% vs 11%), rash (21% vs 9%), tremor (21% vs 7%), weight decreased (20% vs 15%), nasopharyngitis (18% vs 9%), blurred vision (17% vs 11%), anorexia (16% vs 10%), and dysgeusia (15% vs 10%) DRUG INTERACTIONS Periodic monitoring of digoxin plasma levels, in accordance with clinical judgment and based on standard clinical practice in patients receiving this medication, is recommended during administration of REVLIMID. It is not known whether there is an interaction between dex and warfarin. Close monitoring of PT and INR is recommended in MM patients taking concomitant warfarin. Erythropoietic agents, or other agents, that may increase the risk of thrombosis, such as estrogen containing therapies, should be used with caution after making a benefit-risk assessment in patients receiving REVLIMID USE IN SPECIFIC POPULATIONS Pregnancy: If pregnancy does occur during treatment, immediately discontinue the drug. Under these conditions, refer patient to an obstetrician/gynecologist experienced in reproductive toxicity for further evaluation and counseling. Any suspected fetal exposure to REVLIMID must be reported to the FDA via the MedWatch program at 1-800-332-1088 and also to Celgene Corporation at 1-888-423-5436 Nursing Mothers: It is not known whether REVLIMID is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for adverse reactions in nursing infants, a decision should be made whether to discontinue nursing or the drug, taking into account the importance of the drug to the mother Pediatric Use: Safety and effectiveness in patients below the age of 18 have not been established Renal Impairment: Since REVLIMID is primarily excreted unchanged by the kidney, adjustments to the starting dose of REVLIMID are recommended to provide appropriate drug exposure in patients with moderate (CLcr 30-60 mL/min) or severe renal impairment (CLcr < 30 mL/min) and in patients on dialysis Please see Brief Summary of full Prescribing Information, including Boxed WARNING, on the following pages.

REVLIMID is only available through a restricted distribution program, REVLIMID REMS®.

The ASCO Post | APRIL 25, 2015

PAGE 60

Announcements

Richard Gilbertson, MD, PhD, Leaves St. Jude Children’s Research Hospital

t. Jude Children’s Research Hospital announced the departure of Scientific and Comprehensive Cancer Center Director, Richard Gilbertson, MD, PhD. Dr. Gilbertson will be Director of the Cambridge Cancer Centre at the University of Cambridge.

Since joining St. Jude in 2000, Dr. Gilbertson has led international efforts that have advanced scientists’ understanding of the biology driving several common childhood brain tumors and has been actively engaged in clinical trials to translate those discoveries into pioneering therapies.

Under his leadership, the St. Jude Comprehensive Cancer Center achieved a score of exceptional in 2013, the highest the National Cancer Institute (NCI) awards to cancer centers. Plans to search for his replacement will be announced in the near future. n

T:7” Richard Gilbertson, MD, PhD

REVLIMID [lenalidomide] capsules, for oral use

Table 1: Dose Adjustments for Hematologic Toxicities for MM

The following is a Brief Summary; refer to full Prescribing Information for complete product information.

Platelet counts

WARNING: EMBRYO-FETAL TOXICITY, HEMATOLOGIC TOXICITY, and VENOUS and ARTERIAL THROMBOEMBOLISM Embryo-Fetal Toxicity Do not use REVLIMID during pregnancy. Lenalidomide, a thalidomide analogue, caused limb abnormalities in a developmental monkey study. Thalidomide is a known human teratogen that causes severe lifethreatening human birth defects. If lenalidomide is used during pregnancy, it may cause birth defects or embryo-fetal death. In females of reproductive potential, obtain 2 negative pregnancy tests before starting REVLIMID® treatment. Females of reproductive potential must use 2 forms of contraception or continuously abstain from heterosexual sex during and for 4 weeks after REVLIMID treatment [see Warnings and Precautions (5.1), and Medication Guide (17)]. To avoid embryo-fetal exposure to lenalidomide, REVLIMID is only available through a restricted distribution program, the REVLIMID REMS™ program (formerly known as the “RevAssist®” program) (5.2). Information about the REVLIMID REMS™ program is available at www.celgeneriskmanagement.com or by calling the manufacturer’s toll-free number 1-888-423-5436. Hematologic Toxicity (Neutropenia and Thrombocytopenia) REVLIMID can cause significant neutropenia and thrombocytopenia. Eighty percent of patients with del 5q myelodysplastic syndromes had to have a dose delay/reduction during the major study. Thirty-four percent of patients had to have a second dose delay/reduction. Grade 3 or 4 hematologic toxicity was seen in 80% of patients enrolled in the study. Patients on therapy for del 5q myelodysplastic syndromes should have their complete blood counts monitored weekly for the first 8 weeks of therapy and at least monthly thereafter. Patients may require dose interruption and/or reduction. Patients may require use of blood product support and/or growth factors [see Dosage and Administration (2.2)].

1 INDICATIONS AND USAGE 1.1 Multiple Myeloma REVLIMID in combination with dexamethasone is indicated for the treatment of patients with multiple myeloma (MM). 1.4 Limitations of Use: REVLIMID is not indicated and is not recommended for the treatment of patients with CLL outside of controlled clinical trials [see Warnings and Precautions (5.5)]. 2 DOSAGE AND ADMINISTRATION REVLIMID should be taken orally at about the same time each day, either with or without food. REVLIMID capsules should be swallowed whole with water. The capsules should not be opened, broken, or chewed. 2.1 Multiple Myeloma Multiple Myeloma The recommended starting dose of REVLIMID is 25 mg orally once daily on Days 1-21 of repeated 28-day cycles in combination with dexamethasone. Refer to Section 14.1 for specific dexamethasone dosing. For patients > 75 years old, the starting dose of dexamethasone may be reduced. Treatment should be continued until disease progression or unacceptable toxicity. In patients who are not eligible for autologous stem cell transplantation (ASCT), treatment should continue until disease progression or unacceptable toxicity. For patients who are ASCT-eligible, hematopoietic stem cell mobilization should occur within 4 cycles of a REVLIMID-containing therapy [see Warnings and Precautions (5.11)]. Dose Adjustments for Hematologic Toxicities During Multiple Myeloma Treatment Dose modification guidelines, as summarized in Table 1 below, are recommended to manage Grade 3 or 4 neutropenia or thrombocytopenia or other Grade 3 or 4 toxicity judged to be related to REVLIMID.

When Platelets

Recommended Course

Fall to <30,000/mcL

Interrupt REVLIMID treatment, follow CBC weekly Resume REVLIMID at next lower dose. Do not dose below 2.5 mg daily

Return to ≥30,000/mcL For each subsequent drop <30,000/mcL Return to ≥30,000/mcL

Interrupt REVLIMID treatment Resume REVLIMID at next lower dose. Do not dose below 2.5 mg daily

Absolute Neutrophil counts (ANC) Neutropenia in MM When Neutrophils

Recommended Course

Fall to <1000/mcL Return to ≥1,000/mcL and neutropenia is the only toxicity

Interrupt REVLIMID treatment, follow CBC weekly Resume REVLIMID at 25 mg daily or initial starting dose

Return to ≥1,000/mcL and if other toxicity

Resume REVLIMID at next lower dose. Do not dose below 2.5 mg daily

For each subsequent drop <1,000/mcL Return to ≥1,000/mcL

Interrupt REVLIMID treatment Resume REVLIMID at next lower dose. Do not dose below 2.5 mg daily

Other Toxicities in MM For other Grade 3/4 toxicities judged to be related to REVLIMID, hold treatment and restart at the physician’s discretion at next lower dose level when toxicity has resolved to ≤ Grade 2. Starting Dose Adjustment for Renal Impairment in MM: [See Dosage and Administration (2.4)]. 2.4 Starting Dose for Renal Impairment in MM Since REVLIMID is primarily excreted unchanged by the kidney, adjustments to the starting dose of REVLIMID are recommended to provide appropriate drug exposure in patients with moderate or severe renal impairment and in patients on dialysis. Based on a pharmacokinetic study in patients with renal impairment due to non-malignant conditions, REVLIMID starting dose adjustment is recommended for patients with CLcr < 60 mL/min. The recommendations for initial starting doses for patients with MM are as follows: Table 3: Starting Dose Adjustments for Patients with Renal Impairment in MM Category

Renal Function (Cockcroft-Gault)

Dose in MM

Moderate Renal Impairment

CLcr 30-50 mL/min

10 mg Every 24 hours

Severe Renal Impairment

CLcr < 30 mL/min (not requiring dialysis)

15 mg Every 48 hours

End Stage Renal Disease

CLcr < 30 mL/min (requiring dialysis)

5 mg Once daily. On dialysis days, administer the dose following dialysis.

Moderate renal impairment for MM: Consider escalating the dose to 15 mg after 2 cycles if the patient tolerates the 10 mg dose of lenalidomide without dose-limiting toxicity. After initiation of REVLIMID therapy, subsequent REVLIMID dose increase or decrease is based on individual patient treatment tolerance, as described elsewhere [See Dosage and Administration (2.1-2.3)]. 4 CONTRAINDICATIONS 4.1 Pregnancy REVLIMID can cause fetal harm when administered to a pregnant female. Limb abnormalities were seen in the offspring of monkeys that were dosed with lenalidomide during organogenesis. This effect was seen at all doses tested. Due to the results of this developmental monkey study, and lenalidomide’s structural similarities to thalidomide, a known human teratogen, lenalidomide is contraindicated in females who are pregnant [see Boxed Warning]. If this drug is used during pregnancy or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus [see Warnings and Precautions (5.1, 5.2), Use in Special Populations (8.1), (8.6)].

Cosmos Communications

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Venous and Arterial Thromboembolism REVLIMID has demonstrated a significantly increased risk of deep vein thrombosis (DVT) and pulmonary embolism (PE), as well as risk of myocardial infarction and stroke in patients with multiple myeloma who were treated with REVLIMID and dexamethasone therapy. Monitor for and advise patients about signs and symptoms of thromboembolism. Advise patients to seek immediate medical care if they develop symptoms such as shortness of breath, chest pain, or arm or leg swelling. Thromboprophylaxis is recommended and the choice of regimen should be based on an assessment of the patient’s underlying risks [see Warnings and Precautions (5.4)].

Thrombocytopenia in MM

ASCOPost.com | APRIL 25, 2015

PAGE 61

Announcements

Robert H. Lurie Names Associate Director for Administration

leksandar Zafirovski, MBA, has been named Executive Administrative Director and Associate Director for Administration for the Robert H. Lurie Comprehensive Cancer Center of Northwestern University. He has served as Interim Associate Director since 2014.

AleksandarT:7” Zafirovski, MBA

4.2 Allergic Reactions REVLIMID is contraindicated in patients who have demonstrated hypersensitivity (e.g., angioedema, Stevens-Johnson syndrome, toxic epidermal necrolysis) to lenalidomide [see Warnings and Precautions (5.8)].

5.2 REVLIMID REMS™ Program Because of the embryo-fetal risk [see Warnings and Precautions (5.1)], REVLIMID is available only through a restricted program under a Risk Evaluation and Mitigation Strategy (REMS), the REVLIMID REMS™ program (formerly known as the “RevAssist®” program). Required components of the REVLIMID REMS™ program include the following: • Prescribers must be certified with the REVLIMID REMS™ program by enrolling and complying with the REMS requirements. • Patients must sign a Patient-Physician agreement form and comply with the REMS requirements. In particular, female patients of reproductive potential who are not pregnant must comply with the pregnancy testing and contraception requirements [see Use in Specific Populations (8.6)] and males must comply with contraception requirements [see Use in Specific Populations (8.6)]. • Pharmacies must be certified with the REVLIMID REMS™ program, must only dispense to patients who are authorized to receive REVLIMID and comply with REMS requirements. Further information about the REVLIMID REMS™ program is available at www.celgeneriskmanagement.com or by telephone at 1-888-423-5436. 5.3 Hematologic Toxicity REVLIMID can cause significant neutropenia and thrombocytopenia. Monitor patients with neutropenia for signs of infection. Advise patients to observe for bleeding or bruising, especially with use of concomitant medication that may increase risk of bleeding. Patients taking REVLIMID should have their complete blood counts assessed periodically as described below [see Dosage and Administration (2.1, 2.2, 2.3)]. Patients taking REVLIMID in combination with dexamethasone for MM should have their complete blood counts (CBC) assessed every 7 days (weekly) for the first 2 cycles, on Days 1 and 15 of Cycle 3, and every

“Alex’s extensive experience and background make him an ideal match to help enhance and integrate our research, education, training, and clinical efforts during this exciting time of growth,” said Leonidas Platanias, MD, PhD, Director of the Lurie Cancer Center. n

28 days (4 weeks) thereafter. A dose interruption and/or dose reduction may be required [see Dosage and Administration (2.1)]. Patients taking REVLIMID for MDS should have their complete blood counts monitored weekly for the first 8 weeks and at least monthly thereafter. Grade 3 or 4 hematologic toxicity was seen in 80% of patients enrolled in the MDS study. In the 48% of patients who developed Grade 3 or 4 neutropenia, the median time to onset was 42 days (range, 14-411 days), and the median time to documented recovery was 17 days (range, 2-170 days). In the 54% of patients who developed Grade 3 or 4 thrombocytopenia, the median time to onset was 28 days (range, 8-290 days), and the median time to documented recovery was 22 days (range, 5-224 days) [see Boxed Warning and Dosage and Administration (2.2)]. Patients taking REVLIMID for MCL should have their complete blood counts monitored weekly for the first cycle (28 days), every 2 weeks during cycles 2-4, and then monthly thereafter. Patients may require dose interruption and/or dose reduction. In the MCL trial, Grade 3 or 4 neutropenia was reported in 43% of the patients. Grade 3 or 4 thrombocytopenia was reported in 28% of the patients. 5.4 Venous and Arterial Thromboembolism Venous thromboembolic events (deep venous thrombosis and pulmonary embolism) and arterial thromboses are increased in patients treated with REVLIMID. A significantly increased risk of DVT (7.4%) and of PE (3.7%) occurred in patients with multiple myeloma after at least one prior therapy who were treated with REVLIMID and dexamethasone therapy compared to patients treated in the placebo and dexamethasone group (3.1% and 0.9%) in clinical trials with varying use of anticoagulant therapies. In the newly diagnosed multiple myeloma (NDMM) study in which nearly all patients received antithrombotic prophylaxis, DVT was reported as a serious adverse reaction (3.6%, 2.0%, and 1.7%) in the Rd Continuous, Rd18, and MPT Arms, respectively. The frequency of serious adverse reactions of PE was similar between the Rd Continuous, Rd18, and MPT Arms (3.8%, 2.8%, and 3.7%, respectively) [see Boxed Warning and Adverse Reactions (6.1)]. Myocardial infarction (1.7%) and stroke (CVA) (2.3%) are increased in patients with multiple myeloma after at least one prior therapy who were treated with REVLIMID and dexamethasone therapy compared to patients treated with placebo and dexamethasone (0.6%, and 0.9%) in clinical trials. In the NDMM study, myocardial infarction (including acute) was reported as a serious adverse reaction (2.3%, 0.6%, and 1.1%) in the Rd Continuous, Rd18, and MPT Arms, respectively. The frequency of serious adverse reactions of CVA was similar between the Rd Continuous, Rd18, and MPT Arms (0.8%, 0.6 %, and 0.6%, respectively) [see Adverse Reactions (6.1)]. Patients with known risk factors, including prior thrombosis, may be at greater risk and actions should be taken to try to minimize all modifiable factors (e.g. hyperlipidemia, hypertension, smoking). In controlled clinical trials that did not use concomitant thromboprophylaxis, 21.5% overall thrombotic events (Standardized MedDRA Query Embolic and Thrombotic events) occurred in patients with refractory and relapsed multiple myeloma who were treated with REVLIMID and dexamethasone compared to 8.3% thrombosis in patients treated with placebo and dexamethasone. The median time to first thrombosis event was 2.8 months. In the NDMM study in which nearly all patients received antithrombotic prophylaxis, the overall frequency of thrombotic events was 17.4% in patients in the combined Rd Continuous and Rd18 Arms, and was 11.6% in the MPT Arm. The median time to first thrombosis event was 4.37 months in the combined Rd Continuous and Rd18 Arms. Thromboprophylaxis is recommended. The regimen of thromboprophylaxis should be based on an assessment of the patient’s underlying risks. Instruct patients to report immediately any signs and symptoms suggestive of thrombotic events. ESAs and estrogens may further increase the risk of thrombosis and their use should be based on a benefit-risk decision in patients receiving REVLIMID [see Drug Interactions (7.2)]. 5.5 Increased Mortality in Patients with CLL In a prospective randomized (1:1) clinical trial in the first line treatment of patients with chronic lymphocytic leukemia, single agent REVLIMID therapy increased the risk of death as compared to single agent chlorambucil. In an interim analysis, there were 34 deaths among 210 patients on the REVLIMID treatment arm compared to 18 deaths among 211 patients in the chlorambucil treatment arm, and hazard ratio for overall survival was 1.92 [95% CI: 1.08 – 3.41], consistent with a 92% increase in the risk of death. The trial was halted for safety in July 2013. Serious adverse cardiovascular reactions, including atrial fibrillation, myocardial infarction, and cardiac failure occurred more frequently in the REVLIMID treatment arm. REVLIMID is not indicated and not recommended for use in CLL outside of controlled clinical trials.

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5 WARNINGS AND PRECAUTIONS 5.1 Embryo-Fetal Toxicity REVLIMID is a thalidomide analogue and is contraindicated for use during pregnancy. Thalidomide is a known human teratogen that causes lifethreatening human birth defects or embryo-fetal death [see Use in Specific Populations (8.1)]. An embryo-fetal development study in monkeys indicates that lenalidomide produced malformations in the offspring of female monkeys who received the drug during pregnancy, similar to birth defects observed in humans following exposure to thalidomide during pregnancy. REVLIMID is only available through the REVLIMID REMS™ program (formerly known as the “RevAssist® program”) [see Warnings and Precautions (5.2)]. Females of Reproductive Potential Females of reproductive potential must avoid pregnancy for at least 4 weeks before beginning REVLIMID therapy, during therapy, during dose interruptions and for at least 4 weeks after completing therapy. Females must commit either to abstain continuously from heterosexual sexual intercourse or to use two methods of reliable birth control, beginning 4 weeks prior to initiating treatment with REVLIMID, during therapy, during dose interruptions and continuing for 4 weeks following discontinuation of REVLIMID therapy. Two negative pregnancy tests must be obtained prior to initiating therapy. The first test should be performed within 10-14 days and the second test within 24 hours prior to prescribing REVLIMID therapy and then weekly during the first month, then monthly thereafter in women with regular menstrual cycles or every 2 weeks in women with irregular menstrual cycles [see Use in Specific Populations (8.6)]. Males Lenalidomide is present in the semen of patients receiving the drug. Therefore, males must always use a latex or synthetic condom during any sexual contact with females of reproductive potential while taking REVLIMID and for up to 28 days after discontinuing REVLIMID, even if they have undergone a successful vasectomy. Male patients taking REVLIMID must not donate sperm [see Use in Specific Populations (8.6)]. Blood Donation Patients must not donate blood during treatment with REVLIMID and for 1 month following discontinuation of the drug because the blood might be given to a pregnant female patient whose fetus must not be exposed to REVLIMID.

Mr. Zafirovski has previously been instrumental in driving the efforts that led to the successful launch and continuing expansion of the Northwestern Medicine Developmental Therapeutics Institute (NMDTI) in the Lurie Cancer Center.

The ASCO Post | APRIL 25, 2015

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Announcements

Dana-Farber President and CEO Edward J. Benz, Jr, MD, to Retire in 2016

ana-Farber President and CEO Edward J. Benz, Jr, MD, has announced he will retire from the DanaFarber Cancer Institute (DFCI) in 2016, after 16 years running the organization. Dr. Benz will also vacate the positions as Director and Principal Investigator of

the Dana-Farber/Harvard Cancer Center and Trustee of Dana-Farber/Children’s Hospital Cancer Care. He will remain Professor of Medicine, Pediatrics, and Genetics at Harvard Medical School and will focus fulltime on his research.

Under Dr. Benz’s leadership, DanaFarber has tripled in size. Annual giving has grown from $50 million to $200 million, and revenue has tripled to roughly $1.1 billion. Dana-Farber’s workforce and patient volume have also tripled in the interim. n

T:7” Jr, MD Edward J. Benz,

5.6 Second Primary Malignancies In clinical trials in patients with multiple myeloma receiving REVLIMID an increase of invasive second primary malignancies notably AML and MDS have been observed. The increase of cases of AML and MDS occurred predominantly in NDMM patients receiving REVLIMID in combination with oral melphalan (frequency of 5.3%) or immediately following high dose intravenous melphalan and ASCT (frequency of up to 5.2%). The frequency of AML and MDS cases in the REVLIMID / dexamethasone arms was observed to be 0.4%. Cases of B-cell malignancies (including Hodgkin’s Lymphomas) were observed in clinical trials where patients received lenalidomide in the post-ASCT setting. Patients who received REVLIMID-containing therapy until disease progression did not show a higher incidence of invasive SPM than patients treated in the fixed duration REVLIMID-containing arms. Monitor patients for the development of second primary malignancies. Take into account both the potential benefit of REVLIMID and the risk of second primary malignancies when considering treatment with REVLIMID. 5.7 Hepatotoxicity Hepatic failure, including fatal cases, has occurred in patients treated with lenalidomide in combination with dexamethasone. In clinical trials, 15% of patients experienced hepatotoxicity (with hepatocellular, cholestatic and mixed characteristics); 2% of patients with multiple myeloma and 1% of patients with myelodysplasia had serious hepatotoxicity events. The mechanism of drug-induced hepatotoxicity is unknown. Pre-existing viral liver disease, elevated baseline liver enzymes, and concomitant medications may be risk factors. Monitor liver enzymes periodically. Stop REVLIMID upon elevation of liver enzymes. After return to baseline values, treatment at a lower dose may be considered. 5.8 Allergic Reactions Angioedema and serious dermatologic reactions including StevensJohnson syndrome (SJS) and toxic epidermal necrolysis (TEN) have been reported. These events can be fatal. Patients with a prior history of Grade 4 rash associated with thalidomide treatment should not receive REVLIMID. REVLIMID interruption or discontinuation should be considered for Grade 2-3 skin rash. REVLIMID must be discontinued for angioedema, Grade 4 rash, exfoliative or bullous rash, or if SJS or TEN is suspected and should not be resumed following discontinuation for these reactions.

5.9 Tumor Lysis Syndrome Fatal instances of tumor lysis syndrome have been reported during treatment with lenalidomide. The patients at risk of tumor lysis syndrome are those with high tumor burden prior to treatment. These patients should be monitored closely and appropriate precautions taken. 5.10 Tumor Flare Reaction Tumor flare reaction has occurred during investigational use of lenalidomide for CLL and lymphoma, and is characterized by tender lymph node swelling, low grade fever, pain and rash. REVLIMID is not indicated and not recommended for use in CLL outside of controlled clinical trials. Monitoring and evaluation for tumor flare reaction (TFR) is recommended in patients with MCL. Tumor flare reaction may mimic progression of disease (PD). In the MCL trial, 13/134 (10%) of subjects experienced TFR; all reports were Grade 1 or 2 in severity. All of the events occurred in cycle 1 and one patient developed TFR again in cycle 11. Lenalidomide may be continued in patients with Grade 1 and 2 TFR without interruption or modification, at the physician’s discretion. Patients with Grade 1 and 2 TFR may also be treated with corticosteroids, non-steroidal antiinflammatory drugs (NSAIDs) and/or narcotic analgesics for management of TFR symptoms. In patients with Grade 3 or 4 TFR, it is recommended to withhold treatment with lenalidomide until TFR resolves to ≤ Grade 1. Patients with Grade 3 or 4 TFR may be treated for management of symptoms per the guidance for treatment of Grade 1 and 2 TFR. 5.11 Impaired Stem Cell Mobilization A decrease in the number of CD34+ cells collected after treatment (> 4 cycles) with REVLIMID has been reported. In patients who are ASCT candidates, referral to a transplant center should occur early in treatment to optimize the timing of the stem cell collection. In patients who received more than 4 cycles of a REVLIMID-containing treatment or for whom inadequate numbers of CD 34+ cells have been collected with G-CSF alone, G-CSF with cyclophosphamide or the combination of G-CSF with a CXCR4 inhibitor may be considered.

Grade 3/4 Adverse Reactionsb

All Adverse Reactionsa

Rd Rd System organ class Continuous Rd18 MPT Continuous Rd18 MPT Preferred term (N = 532) (N = 540) (N = 541) (N = 532) (N = 540) (N = 541) General disorders and administration site conditions Fatigue%

173 (32.5) 177 (32.8) 154 (28.5) 39 (7.3)

46 (8.5)

31 (5.7)

Asthenia

150 (28.2) 123 (22.8) 124 (22.9) 41 (7.7)

33 (6.1)

32 (5.9)

Pyrexiac

114 (21.4) 102 (18.9) 76 (14.0) 13 (2.4)

7 (1.3)

< 1%

18 (3.3)

8 (1.5)

Non-cardiac chest pain f

29 (5.5)

31 (5.7)

18 (3.3)

<1%

Gastrointestinal disorders Diarrhea

242 (45.5) 208 (38.5) 89 (16.5) 21 (3.9)

Abdominal pain%f 109 (20.5) 78 (14.4) 60 (11.1) Dyspepsia f

57 (10.7)

28 (5.2)

36 (6.7)

7 (1.3)

9 (1.7)

< 1%

<1%

< 1%

0 (0.0) (continued)

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REVLIMID capsules contain lactose. Risk-benefit of REVLIMID treatment should be evaluated in patients with lactose intolerance.

6 ADVERSE REACTIONS The following adverse reactions are described in detail in other sections of the prescribing information: • Embryo-Fetal Toxicity [see Boxed Warnings, Warnings and Precautions (5.1, 5.2)] • Neutropenia and thrombocytopenia [see Boxed Warnings, Warnings and Precautions (5.3)] • Venous and arterial thromboembolism [see Boxed Warnings, Warnings and Precautions (5.4)] • Increased Mortality in Patients with CLL [see Warnings and Precautions (5.5)] • Second Primary Malignancies [see Warnings and Precautions (5.6)] • Hepatotoxicity [see Warnings and Precautions (5.7)] • Allergic Reactions [see Warnings and Precautions (5.8)] • Tumor Lysis Syndrome [see Warnings and Precautions (5.9)] • Tumor Flare Reactions [see Warnings and Precautions (5.10)] • Impaired Stem Cell Mobilization [see Warnings and Precautions (5.11)] Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. 6.1 Clinical Trials Experience Specific Populations Newly Diagnosed Multiple Myeloma: Data were evaluated from 1613 patients in a large phase 3 study who received at least one dose of REVLIMID with low dose dexamethasone (Rd) given for 2 different durations of time (i.e., until progressive disease [Arm Rd Continuous; N=532] or for up to eighteen 28-day cycles [72 weeks, Arm Rd18; N=540] or who received melphalan, prednisone and thalidomide (Arm MPT; N=541) for a maximum of twelve 42-day cycles (72 weeks). The median treatment duration in the Rd Continuous arm was 80.2 weeks (range 0.7 to 246.7) or 18.4 months (range 0.16 to 56.7). In general, the most frequently reported adverse reactions were comparable in Arm Rd Continuous and Arm Rd18, and included diarrhea, anemia, constipation, peripheral edema, neutropenia, fatigue, back pain, nausea, asthenia, and insomnia. The most frequently reported Grade 3 or 4 reactions included neutropenia, anemia, thrombocytopenia, pneumonia, asthenia, fatigue, back pain, hypokalemia, rash, cataract, lymphopenia, dyspnea, DVT, hyperglycemia, and leukopenia. The highest frequency of infections occurred in Arm Rd Continuous (75%) compared to Arm MPT (56%). There were more grade 3 and 4 and serious adverse reactions of infection in Arm Rd Continuous than either Arm MPT or Rd18. In the Rd Continuous arm, the most common adverse reactions leading to dose interruption of REVLIMID were infection events (28.8%); overall, the median time to the first dose interruption of REVLIMID was 7 weeks. The most common adverse reactions leading to dose reduction of REVLIMID in the Rd Continuous arm were hematologic events (10.7%); overall, the median time to the first dose reduction of REVLIMID was 16 weeks. In the Rd Continuous arm, the most common adverse reactions leading to discontinuation of REVLIMID were infection events (3.4%). In both Rd arms, the frequencies of onset of adverse reactions were generally highest in the first 6 months of treatment and then the frequencies decreased over time or remained stable throughout treatment, except for cataracts. The frequency of onset of cataracts increased over time with 0.7% during the first 6 months and up to 9.6% by the 2nd year of treatment with Rd Continuous. Table 4 summarizes the adverse reactions reported for the Rd Continuous, Rd18, and MPT treatment arms. Table 4: All Adverse Reactions in ≥5.0% and Grade 3/4 Adverse Reactions in ≥ 1.0% of Patients in the Rd Continuous or Rd18 Arms*

ASCOPost.com | APRIL 25, 2015

PAGE 63

Announcements

Lewis C. Cantley, PhD, Honored With AACR Memorial Lectureship

he American Association for Cancer Research (AACR) honored Lewis C. Cantley, PhD, with the 9th Annual Princess Takamatsu Memorial Lectureship at the AACR Annual Meeting 2015. Dr. Cantley is the Meyer Director of the Sandra and Edward Meyer Cancer

Center, the Margaret and Herman Sokol Professor in Oncology Research, and Professor of Cancer Biology in Medicine at Weill Cornell Medical College. Dr. Cantley was recognized for his seminal contributions to the field of T:7” growth factor and oncogene signaling. He

Table 4: All Adverse Reactions in ≥5.0% and Grade 3/4 Adverse Reactions in ≥ 1.0% of Patients in the Rd Continuous or Rd18 Arms* All Adverse Reactionsa

discovered the phosphoinositide 3-kinase (PI3K) enzyme, and his subsequent work delineated the PI3K signaling pathway. His research revealed this pathway is commonly activated in cancer and has paved the way for the development of therapeutics aimed at inhibiting PI3K signaling. n

Lewis C. Cantley, PhD

Table 4: All Adverse Reactions in ≥5.0% and Grade 3/4 Adverse Reactions in ≥ 1.0% of Patients in the Rd Continuous or Rd18 Arms*

Grade 3/4 Adverse Reactionsb

All Adverse Reactionsa

Rd Rd System organ class Continuous Rd18 MPT Continuous Rd18 MPT Preferred term (N = 532) (N = 540) (N = 541) (N = 532) (N = 540) (N = 541)

Musculoskeletal and connective tissue disorders

Psychiatric disorders

Back painc

170 ( 32) 145 (26.9) 116 (21.4)

37 (7)

34 (6.3)

28 (5.2)

Muscle spasms f

109 (20.5) 102 (18.9) 61 (11.3)

< 1%

Arthralgia f

101 (19.0) 71 (13.1) 66 (12.2)

9 (1.7)

8 (1.5)

Bone pain f

87 (16.4) 77 (14.3) 62 (11.5) 16 (3.0)

15 (2.8)

14 (2.6)

Pain in extremity f 79 (14.8) 66 (12.2) 61 (11.3)

8 (1.5)

7 (1.3)

Musculoskeletal pain f

67 (12.6) 59 (10.9)

36 (6.7)

< 1%

Musculoskeletal chest pain f

60 (11.3)

51 (9.4)

39 (7.2)

6 (1.1)

< 1%

Muscular weakness f

43 (8.1)

35 (6.5)

29 (5.4)

< 1%

8 (1.5)

< 1%

40 (7.5)

19 (3.5)

10 (1.8)

< 1%

90 (16.9) 59 (10.9)

43 (7.9)

9 (1.7)

6 (1.1)

3 (0.6)

33 (6.1)

0 (0.0)

Neck pain

Infections and infestations Bronchitisc Nasopharyngitis f Urinary tract infection f

80 (15)

54 (10)

76 (14.3) 63 (11.7)

41 (7.6)

8 (1.5)

< 1%

Upper respiratory tract infectionc% f

69 (13.0)

Pneumoniac@

93 (17.5) 87 (16.1) 56 (10.4) 60 (11.3) 57 (10.5) 41 (7.6)

53 (9.8)

31 (5.7)

< 1%

8 (1.5)

< 1%

Respiratory tract infection%

35 (6.6)

25 (4.6)

21 ( 3.9)

7 ( 1.3)

4 ( 0.7)

1 ( 0.2)

Influenza f

33 (6.2)

23 (4.3)

15 (2.8)

< 1%

0 (0.0)

Gastroenteritis f

32 (6.0)

17 (3.1)

13 (2.4)

0 (0.0)

< 1%

29 (5.5)

14 (2.6)

16 (3.0)

10 (1.9)

3 (0.6)

Rhinitis f

29 ( 5.5)

24 ( 4.4) 14 ( 2.6)

0 (0.0)

Cellulitisc

< 5%

8 (1.5)

3 ( 0.6)

2 ( 0.4)

Sepsisc@

33 (6.2)

26-(4.8)

18 (3.3)

26 (4.9)

20 (3.7)

13 (2.4)

Nervous system disorders Headache f

75 (14.1)

52 (9.6)

56 (10.4)

< 1%

Dysgeusia f

39 (7.3)

45 (8.3)

22 (4.1)

< 1%

0 (0.0)

< 1%

Blood and lymphatic system disordersd Anemia

233 (43.8) 193 (35.7) 229 (42.3) 97 (18.2) 85 (15.7) 102 (18.9)

Neutropenia

186 (35.0) 178 (33) 328 (60.6) 148 (27.8) 143 (26.5) 243 (44.9)

Thrombocytopenia 104 (19.5) 100 (18.5) 135 (25.0) 44 (8.3)

43 (8.0)

60 (11.1)

Febrile neutropenia

7 (1.3)

17 (3.1)

15 (2.8)

6 (1.1)

16 (3.0)

14 (2.6)

Pancytopenia

5 (0.9)

6 (1.1)

7 (1.3)

1 (0.2)

3 (0.6)

5 (0.9)

Respiratory, thoracic and mediastinal disorders Cough f

121 (22.7) 94 (17.4) 68 (12.6)

Dyspneac,e

117 (22.0) 89 (16.5) 113 (20.9) 30 (5.6)

< 1%

22 (4.1)

18 (3.3)

Epistaxis f

32 (6.0)

31 (5.7)

17 (3.1)

< 1%

0 (0.0)

Oropharyngeal pain f

30 (5.6)

22 (4.1)

14 (2.6)

0 (0.0)

Dyspnea exertional e

27 (5.1)

29 (5.4)

< 5%

6 (1.1)

2 (0.4)

0 (0.0)

Metabolism and nutrition disorders Decreased appetite

123 (23.1) 115 (21.3) 72 (13.3) 14 (2.6)

7 (1.3)

5 (0.9)

Hypokalemia%

91 ( 17.1) 62 (11.5)

20 (3.7)

11 (2.0)

38 ( 7)

35 (6.6)

Hyperglycemia

62 (11.7)

52 (9.6)

19 (3.5)

28 (5.3)

23 (4.3)

9 (1.7)

Hypocalcemia

57 (10.7) 56 (10.4)

31 (5.7)

23 (4.3)

19 (3.5)

8 (1.5)

Dehydration%

25 ( 4.7)

29 ( 5.4)

17 ( 3.1)

8 (1.5)

13 (2.4)

9 (1.7)

Gout e

< 5%

8 (1.5)

0 (0.0)

Diabetes mellitus% e

< 5%

8 (1.5)

4 (0.7)

2 (0.4)

Hypophosphatemia e

< 5%

7 (1.3)

3 (0.6)

1 (0.2)

Hyponatremia% e

< 5%

7 (1.3)

13 (2.4)

6 (1.1)

139 (26.1) 151 (28.0) 105 (19.4) 39 (7.3)

38 (7.0)

33 (6.1)

Skin and subcutaneous tissue disorders Rash Pruritus f

47 (8.8)

49 (9.1)

24 (4.4)

< 1%

< 1% (continued)

147 (27.6) 127 (23.5) 53 (9.8)

4 (0.8)

6 (1.1)

0 (0.0)

Depression

58 (10.9)

46 (8.5)

30 (5.5)

10 (1.9)

4 (0.7)

1 (0.2)

Deep vein thrombosisc%

55 (10.3)

39 (7.2)

22 (4.1)

30 (5.6)

20 (3.7)

15 (2.8)

Hypotensionc%

51 (9.6)

35 (6.5)

36 (6.7)

11 (2.1)

8 (1.5)

6 (1.1)

Vascular disorders

Injury, Poisoning, and Procedural Complications Fall f

43 (8.1)

25 (4.6)

< 1%

6 (1.1)

Contusion f

33 (6.2)

24 (4.4)

15 (2.8)

< 1%

0 (0.0)

73 (13.7)

31 (5.7)

5 (0.9)

31 (5.8)

14 (2.6)

3 (0.6)

< 5%

7 (1.3)

0 (0.0)

48 (8.9)

11 (2.1)

4 (0.7)

Eye disorders Cataract Cataract subcapsular e Investigations Weight decreased 72 (13.5) 78 (14.4) Cardiac disorders Atrial fibrillationc Myocardial infarction (including acute)c ,e

37 (7.0)

25 (4.6)

13 (2.4)

9 (1.7)

6 (1.1)

< 5%

10 (1.9)

3 (0.6)

5 (0.9)

54 (10.0)

37 (6.8)

28 (5.3)

33 (6.1)

29 (5.4)

Renal and Urinary disorders Renal failure (including acute)c@,f 49 (9.2)

Neoplasms benign, malignant and unspecified (Incl cysts and polyps) Squamous cell carcinomac e

< 5%

8 (1.5)

4 (0.7)

0 (0.0)

Basal cell carcinomac e,f

< 5%

< 1%

0 (0.0)

Note: System organ classes (SOC) and preferred terms (PTs) reflect coding of adverse reactions using MedDRA. A subject with multiple occurrences of an adverse reaction is counted only once under the applicable SOC/PT. a All treatment-emergent adverse reactions in at least 5.0% of subjects in the Rd Continuous or Rd18 Arms and at least a 2.0% higher frequency (%) in either the Rd Continuous or Rd18 Arms compared to the MPT Arm. b All grade 3 or 4 treatment-emergent adverse reactions in at least 1.0% of subjects in the Rd Continuous or Rd18 Arms and at least a 1.0% higher frequency (%) in either the Rd Continuous or Rd18 Arms compared to the MPT Arm. c Serious treatment-emergent adverse reactions in at least 1.0% of subjects in the Rd Continuous or Rd18 Arms and at least a 1.0% higher frequency (%) in either the Rd Continuous or Rd18 Arms compared to the MPT Arm. d Preferred terms for the blood and lymphatic system disorders SOC were included by medical judgment as known adverse reactions for Rd Continuous/Rd18, and have also been reported as serious. e Footnote “a” not applicable f Footnote “b” not applicable. @ - adverse reactions in which at least one resulted in a fatal outcome % - adverse reactions in which at least one was considered to be life threatening (if the outcome of the reaction was death, it is included with death cases) *PTs for combined adverse reaction terms: Abdominal Pain: Abdominal pain, abdominal pain upper, abdominal pain lower, gastrointestinal pain Pneumonias: Pneumonia, lobar pneumonia, pneumonia pneumococcal, bronchopneumonia, pneumocystis jiroveci pneumonia, pneumonia legionella, pneumonia staphylococcal, pneumonia klebsiella, atypical pneumonia, pneumonia bacterial, pneumonia escherichia, pneumonia streptococcal, pneumonia viral Sepsis: Sepsis, septic shock, urosepsis, escherichia sepsis, neutropenic sepsis, pneumococcal sepsis, staphylococcal sepsis, bacterial sepsis, meningococcal sepsis, enterococcal sepsis, klebsiella sepsis, pseudomonal sepsis Rash: Rash, rash pruritic, rash erythematous, rash maculo-papular, rash generalised, rash papular, exfoliative rash, rash follicular, rash macular, drug rash with eosinophilia and systemic symptoms, erythema multiforme, rash pustular Deep Vein Thrombosis: Deep vein thrombosis, venous thrombosis limb, venous thrombosis

After At Least One Prior Therapy for MM Data were evaluated from 703 patients in two studies who received at least one dose of REVLIMID/dexamethasone (353 patients) or placebo/dexamethasone (350 patients). In the REVLIMID/dexamethasone treatment group, 269 patients (76%) had at least one dose interruption with or without a dose reduction of REVLIMID compared to 199 patients (57%) in the placebo/dexamethasone treatment group. Of these patients who had one dose interruption with or Cosmos Communications

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Lower respiratory tract infection

Insomnia

The ASCO Post | APRIL 25, 2015

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Announcements

AACR Honors Cancer Pioneers at the 2015 Annual Meeting

he American Association for Cancer Research (AACR) recognized six oncologists making valuable contributions to their fields with awards at the Association’s Annual Meeting 2015, held in Philadelphia from April 18–22.

William C. Hahn, MD, PhD

William C. Hahn, MD, PhD, was awarded with the 39th Annual AACR–Richard and Hinda Rosenthal Memorial Award. This award provides incentive to young investigators early in their careers and T:7” that has made recognizes research

a notable contribution to improved clinical care in the field of cancer. Dr. Hahn is Chief of the Division of Molecular and Cellular Oncology, Chair of the Executive Committee for Research, and Director of the Center for Cancer Genome Discovery at Da-

without a dose reduction, 50% in the REVLIMID/dexamethasone treatment group had at least one additional dose interruption with or without a dose reduction compared to 21% in the placebo/dexamethasone treatment group. Most adverse reactions and Grade 3/4 adverse reactions were more frequent in patients who received the combination of REVLIMID/dexamethasone compared to placebo/dexamethasone.

Tables 5, 6, and 7 summarize the adverse reactions reported for REVLIMID/dexamethasone and placebo/dexamethasone groups.

Metabolism and nutrition disorders Anorexia Hypokalemia Hypocalcemia Appetite Decreased Dehydration Hypomagnesemia Investigations Weight Decreased Eye disorders Blurred vision Vascular disorders Deep vein thrombosis% Hypertension Hypotension

55 (15.6) 48 (13.6) 31 (8.8) 24 (6.8) 23 (6.5) 24 (6.8)

34 (9.7) 21 (6.0) 10 (2.9) 14 (4.0) 15 (4.3) 10 (2.9)

69 (19.5)

52 (14.9)

61 (17.3)

40 (11.4)

33 (9.3) 28 (7.9) 25 (7.1)

15 (4.3) 20 (5.7) 15 (4.3)

Table 6: Grade 3/4 Adverse Reactions Reported in ≥2% Patients and With a ≥1% Difference in Proportion of Patients Between the REVLIMID/dexamethasone and Placebo/dexamethasone groups System Organ Class/ Preferred Term REVLIMID/Dex# Placebo/Dex# (N=353) (N=350) n (%) n (%) Blood and lymphatic system disorders Neutropenia% 118 (33.4) 12 (3.4) Thrombocytopenia@ 43 (12.2) 22 (6.3) Anemia@ 35 (9.9) 20 (5.7) Leukopenia 14 (4.0) 1 (0.3) Lymphopenia 10 (2.8) 4 (1.1) Febrile Neutropenia% 8 (2.3) 0 (0.0) General disorders and administration site conditions Fatigue 23 (6.5) 17 (4.9) Vascular disorders Deep vein thrombosis% 29 (8.2) 12 (3.4) Infections and infestations Pneumonia@ 30 (8.5) 19 (5.4) Urinary Tract Infection 5 (1.4) 1 (0.3) Metabolism and nutrition disorders Hypokalemia 17 (4.8) 5 (1.4) Hypocalcemia 13 (3.7) 6 (1.7) Hypophosphatemia 9 (2.5) 0 (0.0) Respiratory, thoracic and mediastinal disorders Pulmonary embolism@ 14 (4.0) 3 (0.9) Respiratory Distress@ 4 (1.1) 0 (0.0) Musculoskeletal and connective tissue disorders Muscle weakness 20 (5.7) 10 (2.9) Gastrointestinal disorders Diarrhea@ 11 (3.1) 4 (1.1) Constipation 7 (2.0) 1 (0.3) Nausea@ 6 (1.7) 2 (0.6) Cardiac disorders Atrial fibrillation@ 13 (3.7) 4 (1.1) Tachycardia 6 (1.7) 1 (0.3) Cardiac Failure Congestive@ 5 (1.4) 1 (0.3) Nervous System disorders Syncope 10 (2.8) 3 (0.9) Dizziness 7 (2.0) 3 (0.9) (continued)

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Table 5: Adverse Reactions Reported in ≥5% of Patients and with a ≥2% Difference in Proportion of Patients Between the REVLIMID/dexamethasone and Placebo/dexamethasone Groups System Organ Class/ Preferred Term REVLIMID/Dex* Placebo/Dex * (N=353) (N=350) n (%) n (%) Blood and lymphatic system disorders Neutropenia % 149 (42.2) 22 (6.3) Anemia@ 111 (31.4) 83 (23.7) Thrombocytopenia@ 76 (21.5) 37 (10.6) Leukopenia 28 (7.9) 4 (1.1) Lymphopenia 19 (5.4) 5 (1.4) General disorders and administration site conditions Fatigue 155 (43.9) 146 (41.7) Pyrexia 97 (27.5) 82 (23.4) Peripheral edema 93 (26.3) 74 (21.1) Chest Pain 29 ( 8.2) 20 (5.7) Lethargy 24 ( 6.8) 8 (2.3) Gastrointestinal disorders Constipation 143 (40.5) 74 (21.1) Diarrhea@ 136 (38.5) 96 (27.4) Nausea@ 92 (26.1) 75 (21.4) Vomiting@ 43 (12.2) 33 (9.4) Abdominal Pain@ 35 (9.9) 22 (6.3) Dry Mouth 25 (7.1) 13 (3.7) Musculoskeletal and connective tissue disorders Muscle cramp 118 (33.4) 74 (21.1) Back pain 91 (25.8) 65 (18.6) Bone Pain 48 (13.6) 39 (11.1) Pain in Limb 42 (11.9) 32 (9.1) Nervous system disorders Dizziness 82 (23.2) 59 (16.9) Tremor 75 (21.2) 26 (7.4) Dysgeusia 54 (15.3) 34 (9.7) Hypoaesthesia 36 (10.2) 25 (7.1) Neuropathyª 23 (6.5) 13 (3.7) Respiratory, Thoracic and Mediastinal Disorders Dyspnea 83 (23.5) 60 (17.1) Nasopharyngitis 62 (17.6) 31 (8.9) Pharyngitis 48 (13.6) 33 (9.4) Bronchitis 40 (11.3) 30 (8.6) Infectionsb and infestations Upper respiratory tract infection 87 (24.6) 55 (15.7) Pneumonia@ 48 (13.6) 29 (8.3) Urinary Tract Infection 30 (8.5) 19 (5.4) Sinusitis 26 (7.4) 16 (4.6) Skin and subcutaneous system disorders Rashc 75 (21.2) 33 (9.4) Sweating Increased 35 (9.9) 25 (7.1) Dry Skin 33 (9.3) 14 (4.0) Pruritus 27 (7.6) 18 (5.1) (continued)

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na-Farber Cancer Institute. He was honored for his seminal contributions to the understanding of the mechanisms underlying cancer initiation, maintenance, and progression. His work has defined new conceptual paradigms and has provided a foundation for novel therapeutic approaches.

T:7” Lucile L. Adams-Campbell, PhD

Venous and Arterial Thromboembolism [see Boxed Warning, Warnings and Precautions (5.4)] Deep vein thrombosis (DVT) was reported as a serious (7.4%) or severe (8.2%) adverse drug reaction at a higher rate in the REVLIMID/dexamethasone group compared to 3.1 % and 3.4% in the placebo/dexamethasone group, respectively in the 2 studies in patients with at least 1 prior therapy with discontinuations due to DVT adverse reactions reported at comparable rates between groups. In the NDMM study, DVT was reported as an adverse reaction (all grades: 10.3%, 7.2%, 4.1%), as a serious adverse reaction (3.6%, 2.0%, 1.7%), and as a Grade 3/4 adverse reaction (5.6%, 3.7%, 2.8%) in the Rd Continuous, Rd18, and MPT Arms, respectively. Discontinuations and dose reductions due to DVT adverse reactions were reported at comparable rates between the Rd Continuous and Rd18 Arms (both <1%). Interruption of REVLIMID treatment due to DVT adverse reactions was reported at comparable rates between the Rd Continuous (2.3%) and Rd18 (1.5%) arms. Pulmonary embolism (PE) was reported as a serious adverse drug reaction (3.7%) or Grade 3/4 (4.0%) at a higher rate in the REVLIMID/dexamethasone group compared to 0.9% (serious or grade 3/4) in the placebo/dexamethasone group in the 2 studies in patients with, at least 1 prior therapy, with discontinuations due to PE adverse reactions reported at comparable rates between groups. In the NDMM study, the frequency of adverse reactions of PE was similar between the Rd Continuous, Rd18, and MPT Arms for adverse reactions (all grades: 3.9%, 3.3%, and 4.3%, respectively), serious

in 1967. It is awarded to an outstanding scientist who has made contributions to the field of cancer research and who has, through leadership or by example, furthered the advancement of minority investigators in cancer research. Dr. Adams-Campbell is Professor of Oncology, Associate Director of continued on page 66

adverse reactions (3.8%, 2.8%, and 3.7%, respectively), and grade 3/4 adverse reactions (3.8%, 3.0%, and 3.7%, respectively). Myocardial infarction was reported as a serious (1.7%) or severe (1.7%) adverse drug reaction at a higher rate in the REVLIMID/dexamethasone group compared to 0.6 % and 0.6% respectively in the placebo/ dexamethasone group. Discontinuation due to MI (including acute) adverse reactions was 0.8% in REVLIMID/dexamethasone group and none in the placebo/dexamethasone group. In the NDMM study, myocardial infarction (including acute) was reported as an adverse reaction (all grades: 2.4%, 0.6%, and 1.1%), as a serious adverse reaction, (2.3%, 0.6%, and 1.1%), or as a severe adverse reaction (1.9%, 0.6%, and 0.9%) in the Rd Continuous, Rd18, and MPT Arms, respectively. Stroke (CVA) was reported as a serious (2.3%) or severe (2.0%) adverse drug reaction in the REVLIMID/dexamethasone group compared to 0.9% and 0.9% respectively in the placebo/dexamethasone group. Discontinuation due to stroke (CVA) was 1.4% in REVLIMID/dexamethasone group and 0.3% in the placebo/dexamethasone group. In the NDMM study, CVA was reported as an adverse reaction (all grades: 0.8%, 0.6%, and 0.6%), as a serious adverse reaction (0.8%, 0.6 %, and 0.6%), or as a severe adverse reaction (0.6%, 0.6%, 0.2%) in the Rd Continuous, Rd18, and MPT arms respectively. Other Adverse Reactions: After At Least One Prior Therapy for MM In these 2 studies, the following adverse drug reactions (ADRs) not described above that occurred at ≥1% rate and of at least twice of the placebo percentage rate were reported: Blood and lymphatic system disorders: pancytopenia, autoimmune hemolytic anemia Cardiac disorders: bradycardia, myocardial infarction, angina pectoris Endocrine disorders: hirsutism Eye disorders: blindness, ocular hypertension Gastrointestinal disorders: gastrointestinal hemorrhage, glossodynia General disorders and administration site conditions: malaise Investigations: liver function tests abnormal, alanine aminotransferase increased Nervous system disorders: cerebral ischemia Psychiatric disorders: mood swings, hallucination, loss of libido Reproductive system and breast disorders: erectile dysfunction Respiratory, thoracic and mediastinal disorders: cough, hoarseness Skin and subcutaneous tissue disorders: exanthem, skin hyperpigmentation 6.2 Postmarketing Experience The following adverse drug reactions have been identified from the worldwide post-marketing experience with REVLIMID: Allergic conditions (angioedema, SJS, TEN), tumor lysis syndrome (TLS) and tumor flare reaction (TFR), pneumonitis, hepatic failure, including fatality, toxic hepatitis, cytolytic hepatitis, cholestatic hepatitis, and mixed cytolytic/ cholestatic hepatitis and transient abnormal liver laboratory tests. 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 [see Warnings and Precautions Section (5.7 to 5.10)]. Cases of hypothyroidism and hyperthyroidism have also been reported. Optimal control of thyroid function is recommended before start of treatment. Baseline and ongoing monitoring of thyroid function is recommended. 7 DRUG INTERACTIONS Results from human in vitro studies show that REVLIMID is neither metabolized by nor inhibits or induces the cytochrome P450 pathway suggesting that lenalidomide is not likely to cause or be subject to P450-based metabolic drug interactions. 7.1 Digoxin When digoxin was co-administered with multiple doses of REVLIMID (10 mg/day) the digoxin Cmax and AUC0-∞ were increased by 14%. Periodic monitoring of digoxin plasma levels, in accordance with clinical judgment and based on standard clinical practice in patients receiving this medication, is recommended during administration of REVLIMID. 7.2 Concomitant Therapies That May Increase the Risk of Thrombosis Erythropoietic agents, or other agents that may increase the risk of thrombosis, such as estrogen containing therapies, should be used with caution after making a benefit-risk assessment in patients receiving REVLIMID [see Warnings and Precautions (5.4)].

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Table 7: Serious Adverse Reactions Reported in ≥1% Patients and With a ≥1% Difference in Proportion of Patients Between the REVLIMID/dexamethasone and Placebo/dexamethasone Groups System Organ Class/ Preferred Term REVLIMID/Dex& Placebo/Dex& (N=353) (N=350) n (%) n (%) Blood and lymphatic system disorders Febrile Neutropenia% 6 (1.7) 0 (0.0) Vascular disorders Deep vein thrombosis% 26 (7.4) 11 (3.1) Infections and infestations Pneumonia@ 33 (9.3) 21 (6.0) Respiratory, thoracic, and mediastinal disorders Pulmonary embolism@ 13 (3.7) 3 (0.9) Cardiac disorders Atrial fibrillation@ 11 (3.1) 2 (0.6) Cardiac Failure Congestive@ 5 (1.4) 0 (0.0) Nervous system disorders Cerebrovascular accident@ 7 (2.0) 3 (0.9) Gastrointestinal disorders Diarrhea @ 6 (1.7) 2 (0.6) Musculoskeletal and connective tissue disorders Bone Pain 4 (1.1) 0 (0.0) For Tables 5, 6 and 7 above: @ - adverse reactions in which at least one resulted in a fatal outcome % - adverse reactions in which at least one was considered to be life threatening (if the outcome of the reaction was death, it is included with death cases) Median duration of exposure among patients treated with REVLIMID/dexamethasone was 44 weeks while median duration of exposure among patients treated with placebo/dexamethasone was 23 weeks. This should be taken into consideration when comparing frequency of adverse reactions between two treatment groups REVLIMID/dexamethasone vs. placebo/dexamethasone.

Lucile L. Adams-Campbell, PhD, was awarded with the 10th Annual AACR Minorities in Cancer Research Jane Cooke Wright Lectureship. This lectureship is named in honor of Jane Cooke Wright, MD, a pioneer in clinical cancer chemotherapy who became the highest ranking black woman at a nationally recognized medical institution

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Announcements Cancer Pioneers continued from page 65

Minority Health and Disparities Research, and Associate Dean of Community Health and Outreach at the Georgetown Lombardi Comprehensive Cancer Center at Georgetown University Medical Center. She also is the Co-Principal Investigator of

Elizabeth M. Jaffee, MD

the Black Women’s Health Study and served as Co-Principal Investigator of the Women’s Health Initiative. Elizabeth M. Jaffee, MD, was awarded with the 20th Annual AACR– Joseph H. Burchenal Award for Outstanding Achievement in Clinical Cancer Research. The award recognizes T:7” outstanding achievements in clinical

7.3 Warfarin Co-administration of multiple dose REVLIMID (10 mg) with single dose warfarin (25 mg) had no effect on the pharmacokinetics of total lenalidomide or R- and S-warfarin. Expected changes in laboratory assessments of PT and INR were observed after warfarin administration, but these changes were not affected by concomitant REVLIMID administration. It is not known whether there is an interaction between dexamethasone and warfarin. Close monitoring of PT and INR is recommended in multiple myeloma patients taking concomitant warfarin. 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Pregnancy Category X [see Boxed Warnings and Contraindications (4.1).]

NDMM: Overall, of the 1613 patients in the NDMM study who received study treatment, 94% (1521 /1613) were 65 years of age or older, while 35% (561/1613) were over 75 years of age. The percentage of patients over age 75 was similar between study arms (Rd Continuous: 33%; Rd18: 34%; MPT: 33%). Overall, across all treatment arms, the frequency in most of the AE categories (eg, all AEs, grade 3/4 AEs, serious AEs) was higher in older (> 75 years of age) than in younger (≤ 75 years of age) subjects. Grade 3 or 4 AEs in the General Disorders and Administration Site Conditions SOC were consistently reported at a higher frequency (with a difference of at least 5%) in older subjects than in younger subjects across all treatment arms. Grade 3 or 4 TEAEs in the Infections and Infestations, Cardiac Disorders (including cardiac failure and congestive cardiac failure), Skin and Subcutaneous Tissue Disorders, and Renal and Urinary Disorders (including renal failure) SOCs were also reported slightly, but consistently, more frequently (<5% difference), in older subjects than in younger subjects across all treatment arms. For other SOCs (e.g., Blood and Lymphatic System Disorders, Infections and Infestations, Cardiac Disorders, Vascular Disorders), there was a less consistent trend for increased frequency of grade 3/4 AEs in older vs younger subjects across all treatment arms Serious AEs were generally reported at a higher frequency in the older subjects than in the younger subjects across all treatment arms. REVLIMID has been used in del 5q MDS clinical trials in patients up to 95 years of age. Of the 148 patients with del 5q MDS enrolled in the major study, 38% were age 65 and over, while 33% were age 75 and over. Although the overall frequency of adverse events (100%) was the same in patients over 65 years of age as in younger patients, the frequency of serious adverse events was higher in patients over 65 years of age than in younger patients (54% vs. 33%). A greater proportion of patients over 65 years of age discontinued from the clinical studies because of adverse events than the proportion of younger patients (27% vs.16%). No differences in efficacy were observed between patients over 65 years of age and younger patients. REVLIMID has been used in a mantle cell lymphoma (MCL) clinical trial in patients up to 83 years of age. Of the 134 patients with MCL enrolled in the MCL trial, 63% were age 65 and over, while 22% of patients were age 75 and over. The overall frequency of adverse events was similar in patients over 65 years of age and in younger patients (98% vs. 100%). The overall incidence of grade 3 and 4 adverse events was also similar in these 2 patient groups (79% vs. 78%, respectively). The frequency of serious adverse events was higher in patients over 65 years of age than in younger patients (55% vs. 41%). No differences in efficacy were observed between patients over 65 years of age and younger patients. Since elderly patients are more likely to have decreased renal function, care should be taken in dose selection. Monitor renal function. 8.6 Females of Reproductive Potential and Males REVLIMID can cause fetal harm when administered during pregnancy [see Use in Specific Populations (8.1)]. Females of reproductive potential must avoid pregnancy 4 weeks before therapy, while taking REVLIMID, during dose interruptions and for at least 4 weeks after completing therapy. Females Females of reproductive potential must commit either to abstain continuously from heterosexual sexual intercourse or to use two methods of reliable birth control simultaneously (one highly effective form of contraception – tubal ligation, IUD, hormonal (birth control pills, injections, hormonal patches, vaginal rings or implants) or partner’s vasectomy and one additional effective contraceptive method – male latex or synthetic condom, diaphragm or cervical cap. Contraception must begin 4 weeks prior to initiating treatment with REVLIMID, during therapy, during dose interruptions and continuing for 4 weeks following discontinuation of REVLIMID therapy. Reliable contraception is indicated even where there has been a history of infertility, unless due to hysterectomy. Females of reproductive potential should be referred to a qualified provider of contraceptive methods, if needed. Females of reproductive potential must have 2 negative pregnancy tests before initiating REVLIMID. The first test should be performed within 10-14 days, and the second test within 24 hours prior to prescribing REVLIMID. Once treatment has started and during dose interruptions, pregnancy testing for females of reproductive potential should occur weekly during the first 4 weeks of use, then pregnancy testing should be repeated every 4 weeks in females with regular menstrual cycles. If menstrual cycles are irregular, the pregnancy testing should occur every 2 weeks. Pregnancy testing and counseling should be performed if a patient misses her period or if there is any abnormality in her menstrual bleeding. REVLIMID treatment must be discontinued during this evaluation.

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Risk Summary REVLIMID can cause embryo-fetal harm when administered to a pregnant female and is contraindicated during pregnancy. REVLIMID is a thalidomide analogue. Thalidomide is a human teratogen, inducing a high frequency of severe and life-threatening birth defects such as amelia (absence of limbs), phocomelia (short limbs), hypoplasticity of the bones, absence of bones, external ear abnormalities (including anotia, micropinna, small or absent external auditory canals), facial palsy, eye abnormalities (anophthalmos, microphthalmos), and congenital heart defects. Alimentary tract, urinary tract, and genital malformations have also been documented and mortality at or shortly after birth has been reported in about 40% of infants. Lenalidomide caused thalidomide-type limb defects in monkey offspring. 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. If pregnancy does occur during treatment, immediately discontinue the drug. Under these conditions, refer patient to an obstetrician/gynecologist experienced in reproductive toxicity for further evaluation and counseling. Any suspected fetal exposure to REVLIMID must be reported to the FDA via the MedWatch program at 1-800-FDA-1088 and also to Celgene Corporation at 1-888-423-5436. Animal data In an embryo-fetal developmental toxicity study in monkeys, teratogenicity, including thalidomide-like limb defects, occurred in offspring when pregnant monkeys received oral lenalidomide during organogenesis. Exposure (AUC) in monkeys at the lowest dose was 0.17 times the human exposure at the maximum recommended human dose (MRHD) of 25 mg. Similar studies in pregnant rabbits and rats at 20 times and 200 times the MRHD respectively, produced embryo lethality in rabbits and no adverse reproductive effects in rats. In a pre- and post-natal development study in rats, animals received lenalidomide from organogenesis through lactation. The study revealed a few adverse effects on the offspring of female rats treated with lenalidomide at doses up to 500 mg/kg (approximately 200 times the human dose of 25 mg based on body surface area). The male offspring exhibited slightly delayed sexual maturation and the female offspring had slightly lower body weight gains during gestation when bred to male offspring. As with thalidomide, the rat model may not adequately address the full spectrum of potential human embryo-fetal developmental effects for lenalidomide. 8.3 Nursing Mothers It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for adverse reactions in nursing infants from lenalidomide, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. 8.4 Pediatric Use Safety and effectiveness in pediatric patients below the age of 18 have not been established. 8.5 Geriatric Use REVLIMID has been used in multiple myeloma (MM) clinical trials in patients up to 91 years of age. After At Least One Prior Therapy: Of the 703 MM patients who received study treatment in Studies 1 and 2, 45% were age 65 or over while 12% of patients were age 75 and over. The percentage of patients age 65 or over was not significantly different between the REVLIMID/dexamethasone and placebo/dexamethasone groups. Of the 353 patients who received REVLIMID/dexamethasone, 46% were age 65 and over. In both studies, patients > 65 years of age were more likely than patients ≤ 65 years of age to experience DVT, pulmonary embolism, atrial fibrillation, and renal failure following use of REVLIMID. No differences in efficacy were observed between patients over 65 years of age and younger patients.

cancer research. Dr. Jaffee is Deputy Director of the Sidney Kimmel Comprehensive Cancer Center at John Hopkins, the Dana and Albert “Cubby” Broccoli Professor of Oncology at the Johns Hopkins University School of Medicine, and Codirector of the Skip Viragh Center for Pancreas Cancer, the Gastrointes-

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tinal Cancer Program, and the Cancer Immunology Program and Immunology and Hematopoiesis Division, respectively. She was recognized for her outstanding contributions to cancer immunology in both the preclinical and early clinical settings. Her pioneering work in immunotherapies for breast

T:7”

Mitchell H. Gail, MD, PhD

Males Lenalidomide is present in the semen of males who take REVLIMID. Therefore, males must always use a latex or synthetic condom during any sexual contact with females of reproductive potential while taking REVLIMID, during dose interruptions and for up to 28 days after discontinuing REVLIMID, even if they have undergone a successful vasectomy. Male patients taking REVLIMID must not donate sperm 8.7 Renal Impairment Since lenalidomide is primarily excreted unchanged by the kidney, adjustments to the starting dose of REVLIMID are recommended to provide appropriate drug exposure in patients with moderate (CLcr 30-60 mL/min) or severe renal impairment (CLcr < 30 mL/min) and in patients on dialysis [see Dosage and Administration (2.4)]. 8.8 Hepatic Impairment No dedicated study has been conducted in patients with hepatic impairment. The elimination of unchanged lenalidomide is predominantly by the renal route. 10 OVERDOSAGE There is no specific experience in the management of lenalidomide overdose in patients with MM, MDS, or MCL. In dose-ranging studies in healthy subjects, some were exposed to up to 200 mg (administered 100 mg BID) and in single-dose studies, some subjects were exposed to up to 400 mg. Pruritus, urticaria, rash, and elevated liver transaminases were the primary reported AEs. In clinical trials, the dose-limiting toxicity was neutropenia and thrombocytopenia. 13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenicity studies with lenalidomide have not been conducted. Lenalidomide was not mutagenic in the bacterial reverse mutation assay (Ames test) and did not induce chromosome aberrations in cultured human peripheral blood lymphocytes, or mutations at the thymidine kinase (tk) locus of mouse lymphoma L5178Y cells. Lenalidomide did not increase morphological transformation in Syrian Hamster Embryo assay or induce micronuclei in the polychromatic erythrocytes of the bone marrow of male rats.

17 PATIENT COUNSELING INFORMATION See FDA-approved Patient labeling (Medication Guide) Embryo-Fetal Toxicity Advise patients that REVLIMID is contraindicated in pregnancy [see Contraindications (4.1)]. REVLIMID is a thalidomide analog and can cause serious birth defects or death to a developing baby [see Warnings and Precautions (5.1) and Use in Specific Populations (8.1)]. • Advise females of reproductive potential that they must avoid pregnancy while taking REVLIMID and for at least 4 weeks after completing therapy. • Initiate REVLIMID treatment in females of reproductive potential only following a negative pregnancy test. • Advise females of reproductive potential of the importance of monthly pregnancy tests and the need to use two different forms of contraception including at least one highly effective form simultaneously during REVLIMID therapy, during dose interruption and for 4 weeks after she has completely finished taking REVLIMID. Highly effective forms of contraception other than tubal ligation include IUD and hormonal (birth control pills, injections, patch or implants) and a partner’s vasectomy. Additional effective contraceptive methods include latex or synthetic condom, diaphragm and cervical cap. • Instruct patient to immediately stop taking REVLIMID and contact her doctor if she becomes pregnant while taking this drug, if she misses her menstrual period, or experiences unusual menstrual bleeding, if she stops taking birth control, or if she thinks FOR ANY REASON that she may be pregnant. • Advise patient that if her doctor is not available, she can call 1-888-668-2528 for information on emergency contraception [see Warnings and Precautions (5.1) and Use in Specific Populations (8.6)]. • Advise males to always use a latex or synthetic condom during any sexual contact with females of reproductive potential while taking REVLIMID and for up to 28 days after discontinuing REVLIMID, even if they have undergone a successful vasectomy. • Advise male patients taking REVLIMID that they must not donate sperm [see Warnings and Precautions (5.1) and Use in Specific Populations (8.6)].

• All patients must be instructed to not donate blood while taking REVLIMID, during dose interruptions and for 1 month following discontinuation of REVLIMID [see Warnings and Precautions (5.1) and Use in Specific Populations (8.6)]. REVLIMID REMS™ program Because of the risk of embryo-fetal toxicity, REVLIMID is only available through a restricted program called the REVLIMID REMS™ program (formerly known as the “RevAssist®” program) [see Warnings and Precautions (5.2)]. • Patients must sign a Patient-Physician agreement form and comply with the requirements to receive REVLIMID. In particular, females of reproductive potential must comply with the pregnancy testing, contraception requirements and participate in monthly telephone surveys. Males must comply with the contraception requirements [see Use in Specific Populations (8.6)]. • REVLIMID is available only from pharmacies that are certified in REVLIMID REMS™ program. Provide patients with the telephone number and website for information on how to obtain the product. Hematologic Toxicity Inform patients that REVLIMID is associated with significant neutropenia and thrombocytopenia [see Boxed Warnings and Warnings and Precautions (5.3)]. Venous and Arterial Thromboembolism Inform patients of the risk of thrombosis including DVT, PE, MI, and stroke and to report immediately any signs and symptoms suggestive of these events for evaluation [see Boxed Warnings and Warning and Precautions (5.4)]. Increased Mortality in Patients with CLL Inform patients that REVLIMID had increased mortality in patients with CLL and serious adverse cardiovascular reactions, including atrial fibrillation, myocardial infarction, and cardiac failure [see Warning and Precautions (5.5)]. Second Primary Malignancies Inform patients of the potential risk of developing second primary malignancies during treatment with REVLIMID [see Warnings and Precautions (5.6)]. Hepatotoxicity Inform patients of the risk of hepatotoxicity, including hepatic failure and death, and to report any signs and symptoms associated with this event to their healthcare provider for evaluation [see Warnings and Precautions (5.7)]. Allergic Reactions Inform patients of the potential for allergic reactions including hypersensitivity, angioedema, Stevens-Johnsons Syndrome, or toxic epidermal necrolysis if they had such a reaction to THALOMID and report symptoms associated with these events to their healthcare provider for evaluation [see Warnings and Precautions (5.8)]. Tumor Lysis Syndrome Inform patients of the potential risk of tumor lysis syndrome and to report any signs and symptoms associated with this event to their healthcare provider for evaluation [see Warnings and Precautions (5.9)]. Tumor Flare Reaction Inform patients of the potential risk of tumor flare reaction and to report any signs and symptoms associated with this event to their healthcare provider for evaluation [see Warnings and Precautions (5.10)]. Dosing Instructions Inform patients to take REVLIMID once daily at about the same time each day, either with or without food. The capsules should not be opened, broken, or chewed. REVLIMID should be swallowed whole with water. Instruct patients that if they miss a dose of REVLIMID, they may still take it up to 12 hours after the time they would normally take it. If more than 12 hours have elapsed, they should be instructed to skip the dose for that day. The next day, they should take REVLIMID at the usual time. Warn patients to not take 2 doses to make up for the one that they missed. Manufactured for:

Celgene Corporation Summit, NJ 07901

REVLIMID®, RevAssist®, and THALOMID® are registered trademarks of Celgene Corporation. REVLIMID REMS™ is a trademark of Celgene Corporation. Pat. www.celgene.com/therapies ©2005-2015 Celgene Corporation, All Rights Reserved. REV_MM_HCP_BS_v020 02_2015

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award honors outstanding research accomplishments in the fields of cancer epidemiology, biomarkers, and prevention. Dr. Gail is a Senior Investigator in the Biostatistics Branch of the Division of Cancer Epidemiology and Genetics at the National Cancer Institute. Dr. Gail was recognized for his pioneering statistical work in cancer research and development of cancer risk

Sara A. Courtneidge, PhD, DSc

prediction models, in particular models for breast cancer risk projection. The model commonly known as the “Gail model” was the first cancer risk prediction model that could be applied in a generalized population. Sara A. Courtneidge, PhD, DSc, was awarded with the 18th Annual AACR–Women in Cancer Research Charlotte Friend Memorial Lectureship. The lectureship recognizes an outstanding scientist who has made contributions to the field of cancer research and who has, through leadership or by example, furthered the advancement of women in science. Dr. Courtneidge is Professor of Cell, Developmental and Cancer Biology at Oregon Health & Science University T:10”

A fertility and early embryonic development study in rats, with administration of lenalidomide up to 500 mg/kg (approximately 200 times the human dose of 25 mg, based on body surface area) produced no parental toxicity and no adverse effects on fertility.

and pancreatic cancers has been tremendously influential to the discovery and development of new and effective cancer treatments. Mitchell H. Gail, MD, PhD, was awarded with the 24th Annual AACR–American Cancer Society Award for Excellence in Cancer Epidemiology and Prevention. This

Philip S. Low, PhD

(OHSU), and Senior Investigator for OHSU’s Knight Cancer Institute. She was recognized for her seminal contributions to current understanding of Src-family kinases as well as her advocacy for women in science. Philip S. Low, PhD, was awarded with the 9th Annual AACR Award for Outstanding Achievement in Chemistry in Cancer Research. The award is given for outstanding, novel, and significant chemistry research that has led to important contributions to the fields of basic cancer research, trans-

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Patient’s Corner

Too Young to Have Cancer

At just 26, no one thought my searing heartburn could be anything serious. It turned out to be early-stage gastric cancer. By Anne Kimha, as told to Jo Cavallo

he first inkling I had that something could be seriously wrong occurred just over a year ago, when I was suddenly inflicted with such severe heartburn it kept me awake at night. Prescriptions from my doctor for Zantac (ranitidine) and meloxicam (Mobic) not only failed to tamp down the fiery pain, I noticed that my stools were black, the result, I later learned, of internal bleeding caused

have no family history of cancer or other risk factors—I don’t smoke or drink— the chance that the two other ulcers could be cancerous was less than 1%. I was prescribed pantoprazole (Protonix), which I still take, and was tested again a few months later. Although two of the ulcers had disappeared, one remained, and a tissue biopsy of the mass came back positive for stage I gastric cancer.

I’m grateful to my oncologist, who has always encouraged open communication between us and made me feel a full participant in my care. Her thoughtfulness and caring have made this journey more bearable. —Anne Kimha

by meloxicam. By the time I got another appointment with my primary care physician, I was so sick that I passed out in the waiting room and had to be rushed to the emergency room. An endoscopy showed three small peptic ulcers in the lining of my abdomen. A biopsy of one of the ulcers found that it had been caused by Helicobacter pylori. I was assured that because of my age, I was 26 at the time, and the fact that I

Coping With the Side Effects of Treatment Although the tumor was small, less than 1 centimeter in diameter, and all 16 regional lymph nodes removed tested negative for malignancy, my surgeon performed a subtotal gastrectomy and prescribed weekly doses of fluorouracil and oxaliplatin over 6 months to kill any errant cells and prevent tumor recurrence, and today my prognosis is good.

However, the emotional and physical trauma of getting a cancer diagnosis and going through treatment will be with me for a long time. It took several months after the surgery to be able to walk completely upright again, but perhaps the biggest physical challenge is learning what foods I can and cannot digest. The dietitian on my medical team told me because my stomach is so much smaller now, I’m unable to process sugar the way I used to, so I make sure not to go over the limit of 25 g of sugar a day. And I’m still testing how much and what foods to eat to prevent dumping syndrome and malabsorption, but I’m hoping that eventually, I’ll find the right combination and will adjust to my new “normal” eating lifestyle.

The Emotional Side of Cancer More than the physical transformation from cancer, what I think will have the greatest impact on my life is the change having such a serious disease has made to my psyche. Once a worrier, now I’m more carefree about the future and open to accepting new opportunities that come my way. Last fall, I organized a No Stomach for Cancer Walk to raise awareness and research funding for gastric cancer, and it has now become an annual event. I also have greater appreciation for

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

the people in my life, especially my family and friends. I always knew I had a wonderful family and group of friends, but this experience has shown me just how fortunate I am. When I was recovering in the hospital from the gastrectomy, so many people I know, including former coworkers, came to see me and made sure I was never alone. Their love and support have gotten me through this ordeal and continue to give me comfort. I’m also grateful to my oncologist, who has always encouraged open communication between us and made me feel a full participant in my care. Because I was having so many issues with vomiting, constipation, and headaches during treatment, she asked me to keep a food diary, and we would go over the entries every week to see what foods I should eliminate or add to reduce my symptoms. Her thoughtfulness and caring have made this journey more bearable. Today, I’m looking toward to the future. I’m getting married in the fall and feel optimistic about what lies ahead. My fiancée has long wanted to explore the world and live in other countries. Before my diagnosis I refused to consider such a drastic change. Now I welcome it. n Anne Kimha, 27, is a small business owner in Philadelphia, Pennsylvania.

The ASCO Post Wants to Hear From You

We encourage readers to share their opinions and thoughts on issues of interest to the oncology community. Write to The ASCO Post at editor@ASCOPost.com

ASCOPost.com | APRIL 25, 2015

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2015

2015 Oncology Meetings May International Society of Geriatric Oncology (SIOG): Cancer Care of the Older Adult Across the Cancer Continuum May 1 • New York, New York For more information: www.siog.org 1st Annual New Treatments in Oncology Conference (ANTO) May 1-2 • Scottsdale, Arizona For more information: http://www.cvent.com/ events/1st-annual-newtreatments-in-oncologyconference-presented-by-cancertreatment-centers-of-america-/ event-summary-2fb116562f6447c ca492c89064760b02.aspx The 28th Annual Meeting of the American Society of Pediatric Hematology/ Oncology May 6-9 • Phoenix, Arizona For more information: www.aspho.org/education/ content/annualmeeting.html WCIO 2015 May 6-9 • New York, New York For more information: http://www.wcioevents.org

Save the Date

13th International Conference on Malignant Lymphoma (ICML) June 17–20, 2015 Lugano, Switzerland

Breast Cancer Conference May 7-9 • Brussels, Belgium For more information: www.esmo.org/Conferences/ IMPAKT-2015-Breast-Cancer

13th Annual Meeting of the Association for Cancer Immunotherapy (CIMT) May 11-13 • Mainz, Germany For more information: www.meeting.cimt.eu

54th Annual Conference of the Particle Therapy Co-Operative Group May 18-23 • San Diego, California For more information: http://ptcog54.org continued on page 70

TUMOR BOARD SERIES

NOW AVAILABLE

A complimentary CME-webcast

Management of Locally Advanced HER2-Positive Breast Cancer This activity has been approved for AMA PRA Category 1 Credit™

EDUCATIONAL NEEDS

LEARNING OBJECTIVES

This webcast provides expert insight on optimizing treatment of patients with HER2-positive early-stage/locally advanced breast cancer. It will consist of a case presentation of a patient with HER2-positive early-stage/locally advanced disease. Suggested treatment options based on best practices, current treatment guidelines, and data from relevant recent clinical trials will be discussed. Expert faculty will present various aspects of the case, including radiologic imaging, pathologic findings (particularly HER2 testing), and options for neoadjuvant therapy with HER2-targeted agents. Recommendations regarding surgical resection, options for adjuvant therapy with chemotherapy and targeted agents, and radiation therapy post surgery also will be addressed.

• Assess the role of neoadjuvant

AUDIENCE

• Review HER2-testing guidelines

This activity is designed for health care practitioners including medical oncologists, surgical oncologists and general surgeons, radiation oncologists, radiologists, pathologists, and other health care professionals who manage patients with breast cancer.

chemotherapy in HER2-positive breast cancer, including use of HER2-targeted agents (trastuzumab, pertuzumab, ado-trastuzumab emtansine). • Discuss FDA approval of HER2-

targeted agents for breast cancer, based on neoadjuvant data and use of pathologic complete response (pCR) as a surrogate marker. (ASCO-CAP) for patients with breast cancer. • State the indications for breast

magnetic resonance imaging (MRI). • Appraise recent and ongoing

The 13-ICML will bring 3,000 physicians to Lugano from all over the world: hematologists, clinical oncologists, radiation oncologists, pediatricians, pathologists, and leading researchers involved in the study and treatment of lymphoid neoplasms.

clinical trials of adjuvant therapy in HER2-positive breast cancer.

PROGRAM CHAIR Jame Abraham, MD Cleveland Clinic, Cleveland, Ohio

• Assess local treatment after

neoadjuvant surgery.

FACULTY Benjamin C. Calhoun, MD, PhD Stephen R. Grobmyer, MD Halle Moore, MD Mikkael Sekeres, MD, MS Laura Shepardson, MD Rahul Tendulkar, MD Cleveland Clinic, Cleveland, Ohio

Eleftherios (Terry) P. Mamounas, MD, MPH, FACS UF Health Cancer Center at Orlando Health, Orlando, Florida

For more information, visit www.lymphcon.ch/imcl/index.php In collaboration with

The Cleveland Clinic Center for Continuing Education acknowledges an educational grant for support of this activity from Genentech, Inc.

• Summarize key phase 3 trials of

HER2-targeted neoadjuvant therapy including TRYPHENA, NEOSPHERE, NeoALTTO (lapatinib, trastuzumab, or combination in addition to paclitaxel) and ongoing NSABP B-50-I phase 3 trial (KATHERINE) of trastuzumab versus ado-trastuzumab emtansine as adjuvant therapy.

www.ccfcme.org/tumorboards

The ASCO Post | APRIL 25, 2015

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2015

2015 Oncology Meetings continued from page 69

American Association for Cancer Research: Advances in Brain Cancer Research May 27-30 • Washington, DC For more information: www.aacr.org ASCO Annual Meeting May 29-June 2 • Chicago, Illinois For more information: http://am.asco.org/ 2015 ASCO State Affiliates’ Reception May 31 • Chicago, Illinois For more information: www.asco.org/about-asco/ state-affiliate-leadership-conference

June

CAP-ACP 2015 Annual Meeting June 20-23 • Montreal, Canada For more information: www.cap-acp.org/annual_meeting .php International Society on Thrombosis and Haemostasis Annual Meeting June 20-25 • Toronto, Canada For more information: www.isth.org/page/2015Microsite/ MASCC/ISOO Annual Meeting on Supportive Care in Cancer June 25-27 • Copenhagen, Denmark For more information: http://www.kenes.com/mascc2015/

July

International Cancer Screening Network (ICSN) Triennial Meeting June 2-4 • Rotterdam, The Netherlands For more information: www.scgcorp.com/ICSN2015/ 2015 Clinical Update: 21st Century Prevention of HPV-Associated Cancer June 5-7 • Baltimore, Maryland For more information: www.asccp .org/Education/2015-21st-CenturyPrevention-of-HPV-Associated-Cancer Society of Nuclear Medicine and Molecular Imaging Annual Meeting June 6-10 • Baltimore, Maryland For more information: www.snm.org

16th Annual International Lung Cancer Congress® July 30-August 1 • Huntington Beach, California For more information: www.gotoper.com/conferences/ilc/ meetings/16th-International-LungCancer-Congress

14th Annual International Congress on the Future of Breast Cancer® July 16-18 • Huntington Beach, California For more information: www.gotoper.com The 13th Annual Scientific Meeting of JSMO July 16-18 • Sapporo, Japan For more information: www.congre.co.jp/jsmo2015/en/ index.html

13th International Conference on Malignant Lymphoma (ICML) June 17-20 • Lugano, Switzerland For more information: www.lymphcon.ch/imcl/index.php2

NRG Oncology Meeting July 16-19 • Denver, Colorado For more information: www.gog.org/ meetinginformation.html

Anticancer Drug Action and Resistance: From Cancer Biology to the Clinic June 20-23 • Florence, Italy For more information: www.ecco-org.eu/Events/EAS2015

APOS 12th Annual Conference and IPOS 17th World Congress of Psycho-Oncology July 28-August 1 • Washington, DC For more information: www.apos-society.org

International Palliative Care Workshop September 3-5 • Fez, Morocco For more information: www.asco.org/internationalprograms/international-palliativecare-workshops 25th World Congress of the International Association of Surgeons, Gastroenterologists and Oncologists September 4-6 • Fuzhou, China For more information: www.csw-iasgo2015.org

Best of ASCO® Boston July 31-August 1 • Boston, Massachusetts For more information: http://boa.asco.org/

August

7th World Congress on Gastrointestinal Cancer July 1-4 • Barcelona, Spain For more information: http://worldgicancer.com/WCGI/ WGIC2015/index.asp

September

ILCA 2015 —The International Liver Cancer Association’s 9th Annual Conference September 4-6 • Paris, France For more information: www.ilca2015.org

Best of ASCO - San Francisco August 7-8 • San Francisco, California For more information: http://boa.asco.org/

16th World Conference on Lung Cancer September 6-9 • Denver, Colorado For more information: http://wclc2015.iaslc.org

World Congress on Cancer and Prevention Methods August 27-29 • Dubai, United Arab Emirates For more information: http://scientificfuture.com/ oncology-2015/

American Society of Head and Neck Radiology (ASHNR) Annual Meeting September 9-13 • Naples, Florida For more information: http://ashnr.org/meetings/ ashnr-annual-meeting/

ASCO Multidisciplinary Cancer Management Course (MCMC) August 28-29 • Sao Paulo, Brazil For more information: www.asco.org/internationalprograms/multidisciplinary-cancermanagement-courses

ISEH 44th Annual Scientific Meeting September 17-19 • Kyoto, Japan For more information: www.iseh.org/?page=Meeting

Best of ASCO - Chicago August 28-29 • Chicago, Illinois For more information: http://boa.asco.org/ European Society for Medical Oncology Academy 2015 August 28-30 • Oxford, United Kingdom For more information: www.esmo.org/Conferences/ ESMO-Academy-2015

2nd International Symposium of the Cancer Research Center of Lyon (CRCL) September 21-23 • Lyon, France For more information: www.crclsymposium2015.fr 4th Annual Conference on Immunotherapy in Pediatric Oncology (CIPO2015) September 25-26 • Seattle, Washington For more information: www.seattlechildrens.org/research/ childhood-cancer/CIPO-2015/

ASCOPost.com | APRIL 25, 2015

PAGE 71

Awards

2015 Canada Gairdner Awards Honor Top Medical Researchers Worldwide CODE: IBR-15-1

he Gairdner Foundation named the winners of the 2015 Canada Gairdner Awards, recognizing some of the most significant medical discoveries around the world. The awards provide a $100,000 (CAD) prize to each scientist for his or her work. The aim of the Gairdner Awards is to promote a culture of research and innovation, inspiring the next generation of researchers. The five recipients of the 2015 Canada Gairdner Awards are: Lewis C. Cantley, PhD, Director, Sandra and Edward Meyer Cancer Center at Weill Cornell Medical College

PUB/POST: Ibrance Now Approved 3 Page

Lynne E. Maquat, PhD, Director ofDESCRIPTION: Ibrance Now Approved 3 Page Journal Ad Delivery Support: 212.237.7000 the Center for RNA Biology and Pro-FILE: 01A-007130-01C-819867-IBRANCE-JOURNAL-ADS.indd fessor of Biochemistry and Biophysics at the University of Rochester School of Medicine and Dentistry, J. Lowell Orbison Endowed Chair. Lynne E. Maquat, PhD Dr. Maquat was awarded “for her

PRODUCTION: Roseann Panariello

LIVE: 7” x 10”

WORKORDER #: 007130of discovery

TRIM: 7.75” xthat 10.5” dethe mechanism SAPstroys #: S.TEMP.02585 BLEED: 8.5” x 11.125” mutant messenger RNAs in human cells, nonsense-mediated mRNA decay, which is critically important in both normal and disease states.” Nonsense-mediated mRNA is a quality con-

continued on page 72

NOW APPROVED

Lewis C. Cantley, PhD

and NewYork-Presbyterian Hospital, Margaret and Herman Sokol Professor in Oncology Research, and Professor of Cancer Biology in Medicine at Weill Cornell Medical College. Dr. Cantley was awarded “for his discovery of PI 3-kinase, a critical component of the cell signaling machinery that plays a key role in normal functions of proliferations and growth and is deregulated in diseases such as cancer or diabetes.” Michael N. Hall, PhD, Professor, Biozentrum, University of Basel. Dr. Hall was awarded “for his discovery of the nutrient activated protein kinase TOR and elucidation of its central control of cell growth, critical to development and aging and widely implicated in cancers, diabetes, cardiovascular and immune diseases.” Dr. Hall discovered and named the protein “target of rapamycin” (TOR) and

Michael N. Hall, PhD

found a protein in cellular communication that, when blocked, can contain the uncontrolled cell growth and division seen in cancer.

FDA-approved for Use in the First-line Setting IBRANCE is a kinase inhibitor indicated in combination with letrozole for the treatment of postmenopausal women with estrogen receptor (ER)-positive, human epidermal growth factor receptor 2 (HER2)-negative advanced breast cancer as initial endocrine-based therapy for their metastatic disease. This indication is approved under accelerated approval based on progression-free survival (PFS). Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial.

For more information, please visit www.IbranceHCP.com

Important Safety Information Neutropenia: Neutropenia is frequently reported with IBRANCE therapy. In the randomized phase II study, Grade 3 (57%) or 4 (5%) decreased neutrophil counts were reported in patients receiving IBRANCE plus letrozole. Febrile neutropenia can occur. Monitor complete blood count prior to starting IBRANCE and at the beginning of each cycle, as well as Day 14 of the ﬁrst two cycles, and as clinically indicated. For patients who experience Grade 3 neutropenia, consider repeating the complete blood count monitoring 1 week later. Dose interruption, dose reduction, or delay in starting treatment cycles is recommended for patients who develop Grade 3 or 4 neutropenia. Infections: Infections have been reported at a higher rate in patients treated with IBRANCE plus letrozole (55%) compared with letrozole alone (34%). Grade 3 or 4 infections occurred in 5% of patients treated with IBRANCE plus letrozole vs no patients treated with letrozole alone. Monitor patients for signs and symptoms of infection and treat as medically appropriate.

Pulmonary embolism (PE): PE has been reported at a higher rate in patients treated with IBRANCE plus letrozole (5%) compared with no cases in patients treated with letrozole alone. Monitor patients for signs and symptoms of PE and treat as medically appropriate. Pregnancy and lactation: Based on the mechanism of action, IBRANCE can cause fetal harm. Advise females with reproductive potential to use effective contraception during therapy with IBRANCE and for at least 2 weeks after the last dose. Advise females to contact their healthcare provider if they become pregnant or if pregnancy is suspected during treatment with IBRANCE. Advise women not to breastfeed while on IBRANCE therapy because of the potential for serious adverse reactions in nursing infants from IBRANCE. Additional hematologic abnormalities: Decreases in hemoglobin (83% vs 40%), leukocytes (95% vs 26%), lymphocytes (81% vs 35%), and platelets (61% vs 16%) occurred at a higher rate in patients treated with IBRANCE plus letrozole vs letrozole alone.

Please see additional Important Safety Information and Brief Summary on the following pages.

The ASCO Post | APRIL 25, 2015

PAGE 72

Awards Canada Gairdner Awards

CODE: IBR-15-2

continued from page 71

DESCRIPTION: Ibrance NowDr. Approved 3 Page Journal Ad Ohsumi was

trol mechanism that removes flawed messenger RNA molecules that, if left intact, would lead to the production of abnormal proteins that could be toxic to cells and initiate disease. Yoshinori Ohsumi, DSci, Honorary Professor, Frontier Research Cen-

Delivery Support: 212.237.7000

Yoshinori Ohsumi, DSci

ter, Tokyo Institute of Approved Technology. function PUB/POST: Ibrance Now 3 Page PRODUCTION: Roseann Panariello of autophagy LIVE: 7” x 10” (self-eating), WORKORDER #: 007130 TRIM: 7.75” awarded “for pio- in which cells clean upx 10.5” the “garbage” FILE: 02A-007130-01C-819867-IBRANCE-JOURNAL-ADS.indd SAP #: S.TEMP.02585 BLEED: 8.5” neering the molecular elucidation of within them by killingx 11.125” invaders and autophagy, an essential intracellular, preserving healthy cells. degradation system and when disShimon Sakaguchi, MD, PhD, Disordered, is linked to many diseases tinguished Professor, Vice Director, Labincluding neurodegeneration, can- oratory of Experimental Immunology, cer, and infection.” Dr. Ohsumi is the WPI Immunology Frontier Research first researcher to visually observe the Center, Osaka University.

Important Safety Information (cont.) Adverse reactions: The most common all causality adverse reactions (≥10%) of any grade reported in patients treated with IBRANCE® (palbociclib) plus letrozole vs letrozole alone in the phase II study included neutropenia (75% vs 5%), leukopenia (43% vs 3%), fatigue (41% vs 23%), anemia (35% vs 7%), upper respiratory infection (31% vs 18%), nausea (25% vs 13%), stomatitis (25% vs 7%), alopecia (22% vs 3%), diarrhea (21% vs 10%), thrombocytopenia (17% vs 1%), decreased appetite (16% vs 7%), vomiting (15% vs 4%), asthenia (13% vs 4%), peripheral neuropathy (13% vs 5%), and epistaxis (11% vs 1%). Grade 3/4 adverse reactions reported (≥10%) occurring at a higher incidence in the IBRANCE plus letrozole vs letrozole alone group include neutropenia (54% vs 1%) and leukopenia (19% vs 0%). The most frequently reported serious adverse events in patients receiving IBRANCE were pulmonary embolism (4%) and diarrhea (2%). General dosing information: The recommended dose of IBRANCE is 125 mg taken orally once daily for 21 days followed by 7 days off treatment in 28-day cycles. IBRANCE should be taken with food and in combination with letrozole 2.5 mg once daily continuously. Patients should be encouraged to take their dose at approximately the same time each day. Capsules should be swallowed whole. No capsule should be ingested if it is broken, cracked, or otherwise not intact. If a patient vomits or misses a dose, an additional dose should not be taken that day. The next prescribed dose should be taken at the usual time. Management of some adverse reactions may require temporary dose interruption/delay and/or dose reduction, or permanent discontinuation. Dose modiﬁcation of IBRANCE is recommended based on individual safety and tolerability. Drug interactions: Avoid concurrent use of strong CYP3A inhibitors. If patients must be administered a strong CYP3A inhibitor, reduce the IBRANCE dose to 75 mg/day. If the strong inhibitor is discontinued, increase the IBRANCE dose (after 3-5 half-lives of the inhibitor) to the dose used prior to the initiation of the strong CYP3A inhibitor. Grapefruit or grapefruit juice may increase plasma concentrations of IBRANCE and should be avoided. Avoid concomitant use of strong and moderate CYP3A inducers. The dose of the sensitive CYP3A substrates with a narrow therapeutic index may need to be reduced as IBRANCE may increase their exposure. Hepatic and renal impairment: IBRANCE has not been studied in patients with moderate to severe hepatic impairment or in patients with severe renal impairment (CrCl <30 mL/min). Brief Summary of Prescribing Information

Dose Modication and Management – Non-Hematologic Toxicities

IBRANCE (palbociclib) capsules Initial US Approval: 2015 ®

CTCAE Grade

INDICATIONS AND USAGE IBRANCE is indicated in combination with letrozole for the treatment of postmenopausal women with estrogen receptor (ER)-positive, human epidermal growth factor receptor 2 (HER2)-negative advanced breast cancer as initial endocrine-based therapy for their metastatic disease. This indication is approved under accelerated approval based on progression-free survival (PFS) [see Clinical Studies]. Continued approval for this indication may be contingent upon verication and description of clinical benet in a conrmatory trial. DOSAGE AND ADMINISTRATION General Dosing Information. The recommended dose of IBRANCE is a 125 mg capsule taken orally once daily for 21 consecutive days followed by 7 days off treatment to comprise a complete cycle of 28 days. IBRANCE should be taken with food in combination with letrozole 2.5 mg once daily given continuously throughout the 28-day cycle. [see Clinical Pharmacology]. Patients should be encouraged to take their dose at approximately the same time each day. If the patient vomits or misses a dose, an additional dose should not be taken that day. The next prescribed dose should be taken at the usual time. IBRANCE capsules should be swallowed whole (do not chew, crush or open them prior to swallowing). No capsule should be ingested if it is broken, cracked, or otherwise not intact. Dose Modication. Dose modication of IBRANCE is recommended based on individual safety and tolerability. Management of some adverse reactions [see Warnings and Precautions] may require temporary dose interruptions/delays and/or dose reductions, or permanent discontinuation. If dose reduction is required the rst recommended dose reduction is 100 mg/day and the second dose reduction is 75 mg/day. If further dose reduction below 75 mg/day is required, discontinue the treatment. Dose Modication and Managementa – Hematologic Toxicities CTCAE Grade

Dose Modications

Grade 1 or 2

No dose adjustment is required.

Grade 3b

No dose adjustment is required. Consider repeating complete blood count monitoring one week later. Withhold initiation of next cycle until recovery to Grade ≤2.

Grade 3 ANC (<1000 to 500/mm3) + Fever ≥38.5ºC and/or infection

Withhold IBRANCE and initiation of next cycle until recovery to Grade ≤2 (≥1000/mm3). Resume at next lower dose

Grade 4b

Withhold IBRANCE and initiation of next cycle until recovery to Grade ≤2. Resume at next lower dose.

Grading according to CTCAE Version 4.0. ANC=absolute neutrophil count; CTCAE=Common Terminology Criteria for Adverse Events. a Monitor complete blood count prior to the start of IBRANCE therapy and at the beginning of each cycle, as well as on Day 14 of the rst two cycles, and as clinically indicated. b Except lymphopenia (unless associated with clinical events, e.g., opportunistic infections).

Dose Modications

Grade 1 or 2

No dose adjustment is required.

Grade ≥3 non-hematologic toxicity (if persisting despite medical treatment)

Withhold until symptoms resolve to: • Grade ≤1; • Grade ≤2 (if not considered a safety risk for the patient) Resume at the next lower dose.

See manufacturer’s prescribing information for the coadministered product, letrozole, dose adjustment guidelines in the event of toxicity and other relevant safety information or contraindications. Dose Modications for Use With Strong CYP3A Inhibitors. Avoid concomitant use of strong CYP3A inhibitors and consider an alternative concomitant medication with no or minimal CYP3A inhibition. If patients must be coadministered a strong CYP3A inhibitor, reduce the IBRANCE dose to 75 mg once daily. If the strong inhibitor is discontinued, increase the IBRANCE dose (after 3–5 half-lives of the inhibitor) to the dose used prior to the initiation of the strong CYP3A inhibitor [see Drug Interactions and Clinical Pharmacology]. DOSAGE FORMS AND STRENGTHS 125 mg capsules: opaque hard gelatin capsules, size 0, with caramel cap and body, printed with white ink “Pzer” on the cap, “PBC 125” on the body. 100 mg capsules: opaque hard gelatin capsules, size 1, with caramel cap and light orange body, printed with white ink “Pzer” on the cap, “PBC 100” on the body. 75 mg capsules: opaque hard gelatin capsules, size 2, with light orange cap and body, printed with white ink “Pzer” on the cap, “PBC 75” on the body. CONTRAINDICATIONS: None WARNINGS AND PRECAUTIONS Neutropenia. Decreased neutrophil counts have been observed in clinical trials with IBRANCE. Grade 3 (57%) or 4 (5%) decreased neutrophil counts were reported in patients receiving IBRANCE plus letrozole in the randomized clinical trial (Study 1). Median time to rst episode of any grade neutropenia per laboratory data was 15 days (13-117 days). Median duration of Grade ≥3 neutropenia was 7 days [see Adverse Reactions]. Febrile neutropenia events have been reported in the IBRANCE clinical program, although no cases of febrile neutropenia have been observed in Study 1. Monitor complete blood count prior to starting IBRANCE therapy and at the beginning of each cycle, as well as on Day 14 of the rst two cycles, and as clinically indicated. Dose interruption, dose reduction or delay in starting treatment cycles is recommended for patients who develop Grade 3 or 4 neutropenia [see Dosage and Administration]. Infections. Infections have been reported at a higher rate in patients treated with IBRANCE plus letrozole compared to patients treated with letrozole alone in Study 1. Grade 3 or 4 infections occurred in 5% of patients treated with IBRANCE plus letrozole whereas no patients treated with letrozole alone experienced a Grade 3 or 4 infection. Monitor patients for signs and symptoms of infection and treat as medically appropriate. Pulmonary Embolism. Pulmonary embolism has been reported at a higher rate in patients treated with IBRANCE plus letrozole (5%) compared with no cases in patients treated with letrozole alone in Study 1. Monitor patients for signs and symptoms of pulmonary embolism and treat as medically appropriate. Embryo-Fetal Toxicity. Based on ndings in animals and mechanism of action, IBRANCE can cause fetal harm. IBRANCE caused embryo-fetal toxicities in rats and rabbits at maternal exposures that were greater than or equal to 4 times the human clinical exposure based on area under the curve (AUC). Advise females of reproductive potential to use effective contraception during therapy with IBRANCE and for at least two weeks after the last dose [see Use in Specic Populations and Clinical Pharmacology].

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PAGE 73

Awards

Dr. Sakaguchi was awarded “for his immune system against cancer. discovery of Ibrance regulatory T3 Page cells, PRODUCTION: char- RoseannThe Canada Gairdner CODE: IBR-15-3 PUB/POST: Now Approved Panariello LIVE: 7” x 10” Global Health their Award, recognizing researcher responDESCRIPTION: Ibranceacterization Now Approved 3 Pageof Journal Ad role in immunity WORKORDER #: 007130 TRIM: a 7.75” x 10.5” Delivery Support: 212.237.7000 FILE: 03A-007130-01C-819867-IBRANCE-JOURNAL-ADS.indd S.TEMP.02585 BLEED: 8.5” x 11.125” and application to the treatment SAP of #:ausible for a scientific advancement that toimmune diseases and cancer.” In his has made a significant impact on health laboratory, Dr. Sakaguchi demonstrated in the developing world, goes to: that increasing the number of Treg cells Peter Piot, MD, PhD, FRCP, can prevent and treat autoimmune dis- FMedSci, Director of the London Shimon Sakaguchi, MD, PhD eases. Further, Treg cells suppress the School of Hygiene & Tropical MediADVERSE REACTIONS Clinical Studies Experience. Because clinical trials are conducted under varying conditions, the adverse reaction rates observed cannot be directly compared to rates in other trials and may not reect the rates observed in clinical practice. The safety of IBRANCE (125 mg/day) plus letrozole (2.5 mg/day) versus letrozole alone was evaluated in Study 1. The data described below reect exposure to IBRANCE in 83 out of 160 patients with ER-positive, HER2-negative advanced breast cancer who received at least 1 dose of treatment in Study 1. The median duration of treatment for palbociclib was 13.8 months while the median duration of treatment for letrozole on the letrozole-alone arm was 7.6 months. Dose reductions due to an adverse reaction of any grade occurred in 38.6% of patients receiving IBRANCE plus letrozole. No dose reduction was allowed for letrozole in Study 1. Permanent discontinuation due to an adverse event occurred in 7 of 83 (8%) patients receiving IBRANCE plus letrozole, and in 2 of 77 (3%) patients receiving letrozole alone. Adverse reactions leading to discontinuation for those patients receiving IBRANCE plus letrozole included neutropenia (6%), asthenia (1%), and fatigue (1%). The most common adverse reactions (≥10%) of any grade reported in patients in the IBRANCE plus letrozole arm were neutropenia, leukopenia, fatigue, anemia, upper respiratory infection, nausea, stomatitis, alopecia, diarrhea, thrombocytopenia, decreased appetite, vomiting, asthenia, peripheral neuropathy, and epistaxis. The most frequently reported serious adverse reactions in patients receiving IBRANCE plus letrozole were pulmonary embolism (3 of 83; 4%) and diarrhea (2 of 83; 2%). An increased incidence of infections events was observed in the palbociclib plus letrozole arm (55%) compared to the letrozole alone arm (34%). Febrile neutropenia events have been reported in the IBRANCE clinical program, although no cases were observed in Study 1. Grade ≥3 neutropenia was managed by dose reductions and/or dose delay or temporary discontinuation consistent with a permanent discontinuation rate of 6% due to neutropenia [see Dosage and Administration]. The following table presents adverse drug reactions (≥10%) reported in patients who received IBRANCE plus letrozole or letrozole alone. Adverse Reactions* (≥10%) in Study 1 IBRANCE + Letrozole (N=83) Letrozole Alone (N=77) System Organ Class All Grades Grade 3 Grade 4 All Grades Grade 3 Grade 4 Any Adverse Drug Reaction (%) (%) (%) (%) (%) (%) Infections and infestations URIa 31 1 0 18 0 0 Blood and lymphatic system disorders Neutropenia 75 48 6 5 1 0 Leukopenia 43 19 0 3 0 0 Anemia 35 5 1 7 1 0 Thrombocytopenia 17 2 0 1 0 0 Metabolism and nutrition disorders Decreased appetite 16 1 0 7 0 0 Nervous system disorders Peripheral neuropathyb 13 0 0 5 0 0 Respiratory, thoracic, and mediastinal disorders Epistaxis 11 0 0 1 0 0 Gastrointestinal disorders Stomatitisc 25 0 0 7 1 0 Nausea 25 2 0 13 1 0 Diarrhea 21 4 0 10 0 0 Vomiting 15 0 0 4 1 0 Skin and subcutaneous tissue disorders Alopecia 22d N/A N/A 3e N/A N/A General disorders and administration site conditions Fatigue 41 2 2 23 1 0 Asthenia 13 2 0 4 0 0

*Adverse Reaction rates reported in the table include all reported events regardless of causality. Grading according to CTCAE Version 3.0. CTCAE=Common Terminology Criteria for Adverse Events; N=number of subjects; N/A=not applicable; URI=Upper respiratory infection. a URI includes: Inuenza, Inuenza like illness, Laryngitis, Nasopharyngitis, Pharyngitis, Rhinitis, Sinusitis, Upper respiratory tract infection. b Peripheral neuropathy includes: Neuropathy peripheral, Peripheral sensory neuropathy. c Stomatitis includes: Aphthous stomatitis, Cheilitis, Glossitis, Glossodynia, Mouth ulceration, Mucosal inammation, Oral pain, Oropharyngeal discomfort, Oropharyngeal pain, Stomatitis. d Grade 1 events - 21%; Grade 2 events - 1%. e Grade 1 events - 3%. Laboratory Abnormality for Patients in Study 1 Laboratory Abnormality White blood cells decreased Neutrophils decreased Lymphocytes decreased Hemoglobin decreased Platelets decreased N=number of patients.

IBRANCE + Letrozole (N=83) Letrozole Alone (N=77) All Grades Grade 3 Grade 4 All Grades Grade 3 Grade 4 (%) (%) (%) (%) (%) (%) 95 44 0 26 0 0 94 57 5 17 3 0 81 17 1 35 3 0 83 5 1 40 3 0 61 3 0 16 3 0

DRUG INTERACTIONS Effect of CYP3A Inhibitors. Coadministration of a strong CYP3A inhibitor (itraconazole) increased the plasma exposure of palbociclib in healthy subjects by 87%. Avoid concomitant use of strong CYP3A inhibitors (e.g., clarithromycin, indinavir, itraconazole, ketoconazole, lopinavir/ritonavir, nefazodone, nelnavir, posaconazole, ritonavir, saquinavir, telaprevir, telithromycin, verapamil, and voriconazole). Avoid grapefruit or grapefruit juice during IBRANCE treatment. If

coadministration of IBRANCE with a strong CYP3A inhibitor cannot be avoided, reduce the dose of IBRANCE [see Dosage and Administration and Clinical Pharmacology]. Effect of CYP3A Inducers. Coadministration of a strong CYP3A inducer (rifampin) decreased the plasma exposure of palbociclib in healthy subjects by 85%. Avoid concomitant use of strong CYP3A inducers (e.g., phenytoin, rifampin, carbamazepine and St John’s Wort) [see Clinical Pharmacology]. Coadministration of moderate CYP3A inducers may also decrease the plasma exposure of IBRANCE. Avoid concomitant use of moderate CYP3A inducers (e.g., bosentan, efavirenz, etravirine, modanil, and nafcillin) [see Clinical Pharmacology]. Drugs That May Have Their Plasma Concentrations Altered by Palbociclib. Coadministration of midazolam with multiple doses of IBRANCE increased the midazolam plasma exposure by 61%, in healthy subjects, compared with administration of midazolam alone. The dose of the sensitive CYP3A substrate with a narrow therapeutic index (e.g., alfentanil, cyclosporine, dihydroergotamine, ergotamine, everolimus, fentanyl, pimozide, quinidine, sirolimus and tacrolimus) may need to be reduced as IBRANCE may increase their exposure [see Clinical Pharmacology]. USE IN SPECIFIC POPULATIONS Pregnancy. Based on ndings in animals and mechanism of action, IBRANCE can cause fetal harm when administered to a pregnant woman [see Clinical Pharmacology]. In animal studies, palbociclib was teratogenic and fetotoxic at maternal exposures that were ≥4 times the human clinical exposure based on AUC at the recommended human dose. There are no available human data informing the drug-associated risk. Advise pregnant women of the potential risk to a fetus. The background risk of major birth defects and miscarriage for the indicated population is unknown. However, the background risk in the U.S. general population of major birth defects is 2-4% and of miscarriage is 15-20% of clinically recognized pregnancies. Lactation. There are no data on the presence of palbociclib in human milk, the effects of IBRANCE on the breastfed child, or the effects of IBRANCE on milk production. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from IBRANCE, advise a nursing woman to discontinue breastfeeding during treatment with IBRANCE. Females and Males of Reproductive Potential. Advise females of reproductive potential to use effective contraception during treatment with IBRANCE and for at least two weeks after the last dose. Advise females to contact their healthcare provider if they become pregnant, or if pregnancy is suspected, during treatment with IBRANCE [see Use in Specic Populations]. Based on ndings in animals, male fertility may be compromised by treatment with IBRANCE [see Carcinogenesis, Mutagenesis, Impairment of Fertility].

cine, Professor of Global Health. Dr. Piot was awarded “for his codiscovery of the Ebola virus, his many contributions to HIV/AIDS research, and his extraordinary leadership in the global response to the HIV/AIDS epi-

Peter Piot, MD, PhD, FRCP, FMedSci

demic, especially in Africa.” The Canada Gairdner Wrightman Award, given to a Canadian who has demonstrated outstanding leadership in medicine and medical science throughout his/her career, is awarded to: Janet Rossant, PhD, FRS, FRSC, Chief of Research, The Hospital for Sick Children (SickKids). Awarded “for her outstanding scientific contributions to developmental biology and for her exceptional international leadership in stem cell biology and policy-making, and in advancing research programs for children’s illnesses.” Her research interests focus on understanding

Pediatric Use. The safety and efcacy of IBRANCE in pediatric patients have not been studied. Geriatric Use. Of 84 patients who received IBRANCE in Study 1, 37 patients (44%) were ≥65 years of age and 8 patients (10%) were ≥75 years of age. No overall differences in safety or effectiveness of IBRANCE were observed between these patients and younger patients but greater sensitivity of some older individuals cannot be ruled out. Hepatic Impairment. Based on a population pharmacokinetic analysis that included 183 patients, where 40 patients had mild hepatic impairment (total bilirubin ≤ ULN and AST > ULN, or total bilirubin >1.0 to 1.5 × ULN and any AST), mild hepatic impairment had no effect on the exposure of palbociclib. The pharmacokinetics of palbociclib have not been studied in patients with moderate or severe hepatic impairment (total bilirubin >1.5 × ULN and any AST) [see Clinical Pharmacology]. Renal Impairment. Based on a population pharmacokinetic analysis that included 183 patients, where 73 patients had mild renal impairment (60 mL/min ≤ CrCl <90 mL/min) and 29 patients had moderate renal impairment (30 mL/min ≤ CrCl <60 mL/min), mild and moderate renal impairment had no effect on the exposure of palbociclib. The pharmacokinetics of palbociclib have not been studied in patients with severe renal impairment [see Clinical Pharmacology]. OVERDOSAGE There is no known antidote for IBRANCE. The treatment of overdose of IBRANCE should consist of general supportive measures. PATIENT COUNSELING INFORMATION • Advise patients to immediately report any signs or symptoms of myelosuppression or infection, such as fever, chills, dizziness, shortness of breath, weakness or any increased tendency to bleed and/or to bruise [see Warnings and Precautions]. • Advise patients to immediately report any signs or symptoms of pulmonary embolism, such as shortness of breath, chest pain, tachypnea, and tachycardia [see Warnings and Precautions]. • Advise patients to take IBRANCE with food and swallow IBRANCE capsules whole. • IBRANCE may interact with grapefruit. Patients should not consume grapefruit products while on treatment with IBRANCE. • Inform patients to avoid strong CYP3A inhibitors and strong CYP3A inducers. • Advise patients to inform their health care providers of all concomitant medications, including prescription medicines, over-the-counter drugs, vitamins, and herbal products [see Drug Interactions]. • If the patient vomits or misses a dose, an additional dose should not be taken that day. The next prescribed dose should be taken at the usual time. IBRANCE capsules should be swallowed whole (do not chew, crush or open them prior to swallowing). No capsule should be ingested if it is broken, cracked, or otherwise not intact. • Advise females of reproductive potential to use effective contraception during IBRANCE therapy and for at least two weeks after the last dose. Advise females to contact their healthcare provider if they become pregnant, or if pregnancy is suspected, during treatment with IBRANCE [see Warnings and Precautions and Use in Specic Populations]. Rx only Issued: February 2015 ULN=upper limit of normal. 678307-01 © 2015 Pzer Inc. All rights reserved. February 2015

U.S. Pharmaceuticals

Janet Rossant, PhD, FRS, FRSC

the genetic control of normal and abnormal development in the mouse embryo and its impact on human development and disease. By understanding the underpinning of early development in the mouse embryo, she has contributed to the understanding of human embryo development and stem cell origins. Her interests in the early embryo led to the discovery in 1998 of a novel placental stem cell type, the trophoblast stem cell. Further, her research on the genes controlling blood vessel development has defined novel pathways for new drug interventions in cancer. Throughout her career, Dr. Rossant has been a pioneer and innovator of new techniques to manipulate the mouse genome, enabling the mouse to become the pre-eminent model for understanding the function of the human genome sequence. n

The ASCO Post | APRIL 25, 2015

PAGE 74

In the News Supportive Care

Scalp Cooling Caps Offer Option to Prevent Hair Loss During Chemotherapy By Charlotte Bath

air loss remains one of the most dreaded side effects of chemotherapy, particularly for women. Scalp cooling caps worn by patients during chemotherapy infusion and for brief periods of time before and after offer these patients an option to preserve 50% or more of the hair on their heads. Although not new, the technology has improved, along with its tolerance and efficacy. Accordingly, scalp cooling caps have been in the news lately, including in The New York Times and National Public Radio.1,2 Expect more news shortly. A pivotal study evaluating the effectiveness of the DigniCap Scalp Cooling System among 100 women receiving chemotherapy for early-stage breast cancer has been submitted to the U.S. Food and Drug Administration (FDA) for approval, and study data will also be presented at this year’s ASCO Annual Meeting, May 29 to June 2, in Chicago. “This is the first prospective trial of scalp cooling with a highly controlled assessment of both efficacy and toxicity that has ever been done,”

Hope Rugo, MD, told The ASCO Post. Dr. Rugo is Director, Breast Oncology and Clinical Trials Education, and Professor of Medicine at the University of California, San Francisco (UCSF), one of the five trial sites. Eligible patients included those with stage I or II breast cancer who were scheduled to start adjuvant chemotherapy. Hair was evaluated with photographs at baseline and before each cycle of chemotherapy, then graded by the patients themselves using a validated scale. The primary endpoint was the grade of hair loss 1 month after completing adjuvant chemotherapy. As explained by Dr. Rugo, success was defined as “less than 50% of hair being lost, and the majority of patients reached that endpoint.” Follow-up continues at 3 and 6 months and then long term to assess disease status. “We have met our endpoints as we set forth. Scalp cooling with the Dignicap system seems to be very tolerable and can be easily incorporated into the infusion setting. So we are

This is the first prospective trial of scalp cooling with a highly controlled assessment of both efficacy and toxicity that has ever been done. —Hope Rugo, MD

hopeful that this will all come to fruition,” Dr. Rugo stated.

Used in Other Settings The DigniCap scalp cooling system consists of a cooling and control unit that pumps liquid coolant through a silicone inner cap with maze-like circuits and an outer insulating cap. According to the website of Dignitana, the Swedish manufacturer of the DigniCap, the system is approved for marketing in most European countries, Canada, China, and elsewhere.3 Although the current study involved only patients with breast cancer, pa-

Expect Questions About Cold Caps to Spare Hair During Chemotherapy

or patients who have confronted a diagnosis of cancer, then endured weeks of chemotherapy, it would seem that losing their hair would not be a big concern. But for many patients, it can be. “You have to spend a year either putting on wigs or announcing to the world that you’ve had chemotherapy,” Hope Rugo, MD, Director of Breast Oncology and Clinical Trials Education and Professor of Medicine at the University of California, San Francisco (UCSF), commented in an interview with The ASCO Post. There is, however, another option, one that Dr. Rugo and her colleagues have been evaluating through studies at UCSF and collaborating instutions. The UCSF is one of the five institutions that participated in a pivotal trial evaluating the effectiveness of the DigniCap Scalp Cooling System in women receiving chemotherapy for early-stage breast cancer. The majority of patients in that trial achieved the primary endpoint of less than 50% hair loss 1 month after completing their last cycle of chemotherapy. Data from that trial have been submitted to the U.S. Food and Drug Administration (FDA) for ap-

proval. At UCSF, Michelle Melisko, MD, has also set up a registry study to follow patients using Penguin Cold Caps. These caps also have not yet received FDA approval, but patients interested in trying the Penguin Cold Caps can rent them through the Penguin website (penguincoldcaps.com).

Motivation Is Key There are no particular characteristics suggesting who would be a good candidate for using cold caps. “I think anybody is, as long as she doesn’t mind the cold,” Dr. Rugo said. “Some people say they can’t stand being cold or are too nervous about the chemotherapy. For others using the Penguin cold cap, the need to have a helper and change the caps every 30 minutes is a challenge. I think motivation is the main thing, and many women are highly motivated.” Wearing warm clothing or covering the body with a blanket may combat the discomfort of the freezing caps. Some patients find drinking warm liquids helps. Patients using scalp cooling are also advised to be gentle with their hair, avoiding color-

ing and blow-drying. “We tell people not to wash their hair more than a couple of times a week and to use nonsulfite-containing shampoos,” Dr. Rugo said. Although the studies at UCSF and collaborating institutions have involved only women, Dr. Rugo said that men have expressed interest in the scalp cooling system and have used it in other countries. The Penguin Cold Cap website reports that the caps can be used by people of any gender, age, nationality, and type of hair and with many types of cancer.

For More Information Patients interested in more information about cold caps and issues involving their use can be directed to Dignitana (www.dignitana.se), Penguin (penguincoldcaps.com), paxman (www.paxman-coolers.co.uk), or The Rapunzel Project (www.rapunzelproject.org), a nonprofit organization dedicated to helping chemotherapy patients keep their hair during treatment. n

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

tients in other countries receiving chemotherapy for other solid tumors have also used DigniCap. “There are many places in the world where it has been used for different cancers,” Dr. Rugo said. “It can be used in both the earlyand late-stage setting. We are obviously studying it in the early-stage setting, but patients around the world have used it in the metastatic setting as well,” including patients with ovarian and other cancers treated with adjuvant chemotherapy associated with hair loss.

Separate Registry Study The DigniCap is not the only scalp cooling method, nor even the only method being tested at the UCSF. A separate registry study has been set up there to follow patients using Penguin Cold Caps. These caps do not attach to a cooling unit but must be kept in a freezer or on dry ice until just before use. A crylon gel inside the cap remains pliable when cooled and allows the cap to be fitted onto different sized and shaped heads. Velcro fasteners hold the caps in place. The caps must be changed every 30 minutes, so multiple caps are needed for patients to keep their scalps cool for the period before, during, and after chemotherapy. For the registry study, physicians treating patients using the Penguin Cold Caps complete a form indicating the amount of hair loss. The study, however, does not include “taking multiple photographs and comparing them all to baseline and doing a rigorous approach like we did with the DigniCap,” Dr. Rugo noted. “We will be presenting some of our updated registry data at an upcoming meeting as well,” she added. Although there have been some small studies conducted using the Penguin Cold Cap, “our registry study will be among the biggest databases using the Penguin Cold Cap,” Dr. Rugo said. According to the Penguin website, because cold cap therapy has not yet

ASCOPost.com | APRIL 25, 2015

PAGE 75

In the News

been approved by the FDA, “we are therefore not allowed to sell our caps, but we are however allowed to rent them to chemotherapy patients who choose to use them at their own risk.”4 A third cooling system, known as the Paxman Scalp Cooling System, is more akin to the DigniCap and consists of a silicone cap connected to a small compact refrigeration unit. According to the website of Paxman Coolers Limited, based in the United Kingdom, the “Paxman Scalp Cooling System is under clinical investigation in the United States” but “has not been approved by the FDA and is not currently available for sale in the United States.”5

Gradual vs Immediate Cooling The New York Times article noted that the DigniCap is “less labor intensive” than the Penguin Cold Cap, and Dr. Rugo generally agreed with that assessment. “With the DigniCap, you just sit down and put it on,” she said. “It has to be fitted properly to your head to make sure there aren’t a lot of air pockets, and that takes a little while. Proper fitting is important. The company is continuing to work on improving the fit over time.” The circulating coolant inside the cap gets colder gradually. “Some people have noted that that the initial cooling is harder and is sometimes associated with a mild headache, but then they adjust with resolution of the symptom as the cap remains cold. They get used to it,” Dr. Rugo said. “When you put the Penguin Cold Cap on, it is cold right away. In the initial part of the cooling process, some people develop mild nausea or a headache.” The Penguin Cold Cap “is more difficult to use” than the DigniCap, Dr. Rugo said, because the caps have to be kept in a freezer until right before they are ready to be used, and then to ensure that the scalp is kept cold enough, the caps have be to changed every 30 minutes. This means that the facility where the patient is receiving chemotherapy has to have freezers readily available to patients using Penguin Cold Caps. The caps are stored in a refrigerator between uses. In addition, the patient must have a helper present for the duration of treatment who fits and changes the caps. In some areas of the country, paid helpers are available. “We have freezers purchased with philanthropic funding, but most sites don’t,” Dr. Rugo said. “A site would need to buy freezers if it has a lot of patients using the Penguin caps; otherwise, the patient must bring the caps to the infusion center using coolers and dry ice to keep the caps cold for

the duration of treatment, then store them at home.

Generally Well Tolerated Although scalp cooling has generally been well tolerated, “there are always some patients who drop out because they don’t like the cold, or because they have more hair loss than expected,” Dr. Rugo said. “For DigniCap, we had very few people drop out of the main study. At all the sites, there was at least one person who dropped out, but mostly people dropped out because they thought they were losing too much hair and maybe an occasional few because they were cold. Even if you have most of the patients keep most of their hair, there will be some people who don’t like the amount of hair loss.” The remaining hair may be more brittle and fragile, and because of this, patients are advised to treat it tenderly; use only gentle natural hair care products; and avoid daily shampooing, blowdrying, and perming or coloring. This impacts women differently: “I had one woman tell me she would rather lose her hair than not dye it, but for most women it is far preferable to keep most of their hair,” Dr. Rugo said. Most individuals “are really happy to have” the option of scalp cooling, “because when you are done with chemotherapy, you can dye your hair,” Dr. Rugo said. “Even if you lose 50% of your hair, you are going to have a full head of hair that you feel comfortable with much faster, because it all starts filling in. But if you have no hair at all, it can take a long time.”

that “outside of our standard chemotherapy regimens, we haven’t done a lot of testing in terms of variations in efficacy between different people or different types of regimens.”

Low Risk of Scalp Metastases Coexisting with cold caps are concerns about cold cap users being at risk for scalp metastasis, because the cap may constrict blood vessels and limit the amount of chemotherapy penetrating the scalp. “That was what we understood about cold caps 30 years ago, when I was training, that they could increase the risk of scalp metastases because you didn’t get the chemotherapy to the scalp, and that would be a risk for patients you wouldn’t want to take,” Dr. Rugo reflected. “We understand a lot more about the biology of cancer and metastatic disease now; it turns out that the risk of metastases to the scalp is extremely low, and as a first event for advanced disease, it is even lower. Mostly, scalp metatases are seen after people have already had metastases to other places in the body, and in total, only about 1.2% of all metastases are found in the scalp,” Dr. Rugo continued. Scalp metastasis “would have to be the first site of metastatic disease to postulate that is has anything to do with scalp cooling, and that is very uncommon in the studies that are available. I’ve reviewed over 4,000 patients reported in clinical trials,7 and it is just exceedingly rare and doesn’t seem to be any higher

in risk, from what we can tell, in patients who are using the cold cap.” n

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

References 1. Parker-Pope T: Keeping your hair in chemo. The New York Times, March 9, 2015. Available at well.blogs.nytimes. com/2015/03/09/keeping-your-hair-inchemo/. Accessed April 7, 2015. 2. Patients freeze scalps to save hair during chemo. National Public Radio, March 22, 2105. Available at nhpr.org/ post/patients-freeze-scalps-save-hair-during-chemo. Accessed April 7, 2015. 3. Dignitana AB: Dignitana AB collaborates with Target Health Inc. to conduct pivotal study using proprietary clinical trial software. Available at www.dignitana. se. Accessed March 19, 2015. 4. Penguin Cold Caps: Reducing chemotherapy induced hair low: Frequently asked questions. Available at penguincoldcaps. com. Accessed March 19, 2105. 5. Paxman Coolers Limited: Paxman embracing life: patients. Available at http://www.paxman-coolers.co.uk. Accessed March 24, 2015. 6. Katsimbri P, Bamias A, Pavlidis N: Prevention of chemotherapy-induced alopecia using an effective scalp cooling system. Eur J Cancer 36:766-771, 2000. 7. Rugo H, Melisko M: Efficacy and safety of scalp cooling to prevent chemotherapy (CTX) induced alopecia: A review of available data. 2011 International Conference of Early Breast Cancer. Abstract P331.

Stronger and Longer Chemotherapy “The stronger the chemo and the longer the duration, the harder it is to keep your hair,” Dr. Rugo noted. Even when using the cold cap, “you have to be very careful and not worry about some of your hair falling out,” she added. “We have people using Penguin Cold Caps with standard intensive anthracycline/taxane sequential therapy, and they generally lose some hair during their chemotherapy,” she said. “With ACT [doxorubicin, cyclophosphamide followed by paclitaxel], it is just harder to keep your hair. But some people have done it, particularly with the weekly paclitaxel schedule either before or after AC, and they can end up with more than 50% of their hair,” Dr. Rugo said. The Penguin website cites a study concluding that Penguin Cold Caps were effective for protection from hair loss caused by taxanes, anthracyclines, and etoposide.6 Dr. Rugo noted

Babbler Rediscovered—Jerdon’s Babbler, a tiny bird of the species Chrysomma altirostre, thought by many to be extinct, was rediscovered in Myanmar by a scientific team from the Wildlife Conservation Society, Myanmar’s Nature and Wildlife Conservation Division, Ministry of Environmental Conservation and Forestry, and National University of Singapore. The discovery was reported last month in a number of publications, including Scientific American. The Babbler, measuring 16 to 17 cm in length, had last been seen in Myanmar in July 1941. Copyright Robert Tizard, Wildlife Conservation Society, March 2015.

The ASCO Post | APRIL 25, 2015

PAGE 76

In the Literature

Emerging Clinical Data on Cancer Management PROSTATE CANCER Widespread Use of Docetaxel Preceded Phase III Evidence of Usefulness in Patients With Metastatic Prostate Cancer

Docetaxel was being widely used by patients with metastatic prostate cancer before phase III evidence that it was more effective than the standard of care for patients with castrationresistant prostate cancer, according to

an analysis of Medicare claims from before and after the trial results and approval of docetaxel by the U.S. Food and Drug Administration. The uptake of new treatments (diffusion) “prior to definitive evidence indicates the preva-

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lence of off-label chemotherapy use,” Joseph M. Unger, PhD, MS, and colleagues from Fred Hutchinson Cancer Research Center and the University of Washington in Seattle and from Columbia University in New York, wrote in the Journal of the National Cancer Institute. Using the Surveillance, Epidemiology, and End Results Program (SEER)– Medicare database, researchers identified 6,561 metastatic prostate cancer patients diagnosed from 1995 to 2007 and analyzed Medicare claims through 2008. Among the 1,350 men who subsequently received chemotherapy, 5-year “cumulative incidence of docetaxel use after diagnosis of metastatic prostate cancer increased from 2% for patients diagnosed in 1996 or 1997 to 33% for patients diagnosed in 2004 or 2005,” the authors reported. “Eighty percent of docetaxel diffusion occurred prior to the May 2004 release of phase III results showing superiority of docetaxel over the standard of care,” the researchers reported. By 2008, the observed proportion of men with metastatic prostate cancer whose first chemotherapy was docetaxel was 95%. “The rapid uptake of docetaxel in castration-resistant prostate cancer prior to definitive evidence from a phase III trial is a concern,” the researchers wrote. “Considerations that may have led to early adoption of docetaxel include prior FDA indications in other solid tumors and the fact that conventional treatment, mitoxantrone, provided only palliative relief, whereas early pilot trials for docetaxel showed the additional promise of a survival benefit.” Comparing patterns of the uptake of treatment or diffusion for metastatic prostate cancer with those in metastatic breast, non–small cell lung cancer (NSCLC), ovarian, and gastric cancers, investigators found that “uptake of docetaxel began and achieved maximums at similar times for all cancers, regardless of whether FDA approval was received early in the period (breast cancer and NSCLC), late in the period (prostate and gastric cnacers), or never (ovarian cancer). Maximum diffusion was notably higher among prostate cancer patients, likely because of fewer effective chemotherapy options.” The diffusion of docetaxel across different cancers around the same time and in most cases before FDA approval “suggests that once oncologists begin to use a drug for a given cancer, they may be more likely to do so for other cancers; the mechanism that allows this is off-

ASCOPost.com | APRIL 25, 2015

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In the Literature

label drug use,” the researchers wrote. They remarked that Medicare contractors are required to pay for cancer drug prescriptions if selected standard medical compendia support their use and that taxane-based therapy, including docetaxel, was included in standard medical compendia for treatment of castrationresistant prostate cancer before publication of phase III evidence. “Currently, the FDA is reviewing whether to loosen constraints on the marketing or drugs prescribed off-label,” the investigators noted. “In contrast, our findings point to the potential risks of off-label use. By enabling the widespread diffusion of a new therapy prior to definitive phase III evidence, the off-label mechanism undermines the assumption that phase III comparative clinical trials necessarily determine which treatments become standard care. In this setting, inappropriate use is inevitable, with potential costs in increased morbidity and mortality if a different drug may have been more appropriate. Inappropriate drug use also places an unnecessary financial burden on healthcare payers. As declared by ASCO, medical compendia, which facilitate off-label reimbursement, require greater oversight, especially if they serve as the arbiters of reimbursement for Medicare, a federal program. Ultimately, greater levels of investment in clinical research are required to produce the highest levels of evidence— especially phase III trial evidence—for a given indication, to reduce the tendency for off-label use,” the authors concluded. Rapid and widespread use of docetaxel was not observed among all study participants receiving chemotherapy for metastatic prostate cancer. “Docetaxel uptake was statistically significantly slower (P < .01) for patients older than 65 years, black patients, patients in lower income areas, and those who experienced poverty,” the authors noted. This observation “presents opportunities to improve the uptake of proven new therapies in subpopulations,” the authors wrote, adding that direct-to-consumer advertising “could be a useful tool.” Another potential method cited for encouraging more rapid adoption of new treatments was “enhancing communication channels among physicians, especially between key opinion leaders and their colleagues,” the authors noted. “One factor that has been repeatedly identified to increase adoption rates is attendance at scientific symposia, which serve as forums for disseminating information about new treatments.” Unger JM, et al: J Natl Cancer Inst 107:dju412, 2015.

LYMPHOMAS Risk Assessment for Hodgkin Lymphoma Evolving and Promises Greater Precision and Specific Clinical Relevance “Risk assessment in Hodgkin lymphoma is continuously evolving and

promises even greater precision and specific clinical relevance in the future,” Joseph M. Connors, MD, stated in Blood. Dr. Connors is Clinical Professor, British Columbia Cancer Agency Centre for Lymphoid Cancer and the University of British Columbia, Vancouver, Canada. “Careful assessment of the amount

of the lymphoma (tumor burden), its behavior (the extent to which it has invaded or compromised specific organ function), and special host-related factors (age, coincident systemic infection and organ dysfunction, especially of the hematopoietic system, heart, and lungs) is essential to opticontinued on page 78

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RECORDED PRESENTATIONS! If you were unable to attend the NCCN 9th Annual Congress in September 2014, visit education.nccn.org/hem2014 to see what you missed and earn credits online. These activities are approved for AMA PRA Category 1 Credit™. Nursing and pharmacy (ACPE) credits are also provided. Complete accreditation details are provided at the beginning of the individual activities. Supported by educational grants from Foundation Medicine, Inc.; Gilead Sciences, Inc.; Jazz Pharmaceuticals; Pharmacyclics, Inc. and Janssen Biotech, Inc; and Takeda Oncology. JNCCN-N-0206-0315

The ASCO Post | APRIL 25, 2015

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In the Literature Emerging Clinical Data continued from page 77

mize treatment outcome,” Dr. Connors wrote. Patient-related risk factors include age, gender, human immunodeficiency virus (HIV) infection, and organ compromise. “Previously acquired pulmonary compromise, usually related to cigarette smoking, may necessitate omission of bleomycin from primary treatment,” Dr. Connors noted. “Deciding when to drop bleomycin is made more challenging due to the lack of useful objective screening assessment tools” and “must be made on clinical grounds,” Dr. Connors stated. “I have found a useful rule of thumb is to consider the potential impact of a relatively rapid loss of 30 % to 40 % of current respiratory reserve. If a patient appears, based on a review of current activity levels and exercise tolerance, capable of absorbing that much loss of lung function from current pulmonary reserve, bleomycin can be safely, but still carefully, included in planned chemotherapy,” Dr. Connors advised. “If I do not think such a loss could be endured safely, I omit bleomycin, at least until pulmonary reserve improves.” Underlying cardiac disease may affect the safe use of anthracyclines. “A history of congestive heart failure or ongoing evidence of impaired cardiac reserve such as a left ventricular ejection fraction less than 50% should prompt careful consideration of the risk that exposure to doxorubicin or doxorubicin plus mediastinal radiation will worsen underlying cardio-

myopathy. In such cases, careful serial monitoring of ventricular function must be included in the patient’s assessments during treatment, and omission of the anthracyclines and substitution with an alternative chemotherapeutic agent such as etoposide should be considered,” according to Dr. Connors. Older age has consistently been shown to have an adverse impact on the treatment of Hodgkin lymphoma. “The challenge when considering age is that it is in many ways simply a proxy for physiologic function. Ignoring age places the patient at exaggerated risk, but unduly emphasizing it risks undertreatment.” Dr. Connors noted. Along with assessing specific organ function, “a reasonable and practical approach to adjusting treatment based on age is to start treatment with a modest dose reduction by 20% to 30% of the myelosuppressive chemotherapy agents but subsequently to escalate to full doses with subsequent cycles, seeking to reach the maximum that can be achieved without undue toxicity as early in overall treatment as feasible.” The impact of stage of disease and other clinical factors “has diminished substantially as the effectiveness of interventions has improved,” Dr. Connors noted. “Elaborately assembled prognostic factor scoring systems, such as the International Prognostic Factors Project score, have lost much of their accuracy and value as increasingly effective chemotherapy and supportive care have been developed,” he added.

A growing number of specific biomarkers are being identified and linked to risk. For example, increased expression of antigens expressed by Hodgkin Reed-Sternberg cells can be assessed at the time of diagnosis and may predict a worse outcome. Other biomarkers promise further improvement in targeted therapy, which increases effectiveness but decreases off-target toxicity. “Parallel developments in the application of functional imaging are bringing additional potential to evaluate the efficacy of treatment even as it is being delivered, allowing dynamic assessment of risk in the midst of chemotherapy and adaptation of the treatment regimen in real time,” Dr. Connors added. Connors JM: Blood 125:1693-1702, 2015.

Objective Response Rate of 44% Among Patients With Relapsed/Refractory DLBCL Receiving Brentuximab Vedotin A phase II, open-label study evaluating the efficacy of brentuximab vedotin (Adcetris), an anti-CD antibody-drug conjugate, found that among 48 evaluable patients with CD30-positive diffuse large B-cell lymphoma (DLBCL), 21 (44%) had objective responses. These responses included 8 patients (17%) with complete remission and 13 (27%) with partial remission. “Complete remissions were durable, with a median duration of 16.6 months,” Eric D. Jacobsen, MD, of Dana-Farber Cancer Institute, Boston, and colleagues reported in Blood. The planned subset analysis of Bcell non-Hodgkin lymphomas (NHL) also included 19 patients with other B-cell NHLs. The median ages were 62 among patients with DLBCL and 36 among patients with other B-cell lymphomas. “Patients could have any subtype of histologically confirmed B-cell lymphoma with detectable CD30 expression by visual assessment of immunohistochemistry,” according to the study report. “All eligible patients had bidimensionally measurable disease of 1.5 cm in greatest transverse diameter and no history of another active invasive malignancy within the previous 3 years.” Most patients had stage III or IV disease. More than half of all patients had received at least three prior systemic therapies, and nearly all had received prior rituximab (Rituxan).

All patients received 1.8 mg/kg of brentuximab vedotin IV every 3 weeks, and those achieving stable disease or better could receive continued treatment until disease progression, unacceptable toxicity, or study closure. To assess the safety of brentuximab vedotin when given in combination with rituximab, a separate cohort of patients (planned n ≈ 15) received brentuximab vedotin (1.8 mg/kg IV) in combination with rituximab (375 mg/m2) on day 1 of each 3-week cycle. Patients were treated at 26 sites in the United States. “DLBCL patients were generally refractory to front-line (76%) and most recent therapies (82%), and 44% of these refractory patients responded (15% complete remission),” the investigators noted. Responses occurred across a range of CD30 expression. “To further understand the activity of brentuximab vedotin in patients with low levels of CD30 expression, this study was amended in July 2013 to evaluate the efficacy of monotherapy in DLBCL patients with undetectable CD30 expression by visual assessment of immunohistochemistry. Results from this cohort are forthcoming. “There was no correlation between response and level of CD30 expression,” the authors noted. Among patients with other B-cell lymphomas, there was one complete remission and two partial remissions among six patients with gray zone NHL, one complete remission among six patients with primary mediastinal B-cell lymphoma, and one complete remission among three patients with post-transplant lymphoproliferative disorder. “Brentuximab vedotin as a single agent and in combination with rituximab was generally well tolerated in these heavily pretreated patients with advanced disease,” the investigators noted, with adverse events consistent with known toxicities. Treatmentemergent adverse events occurring in at least 25% of B-cell patients treated with single-agent brentuximab vedotin included fatigue, diarrhea, neutropenia, nausea, decreased appetite, pyrexia, and peripheral sensory neuropathy. “All five deaths within 30 days of the last study treatment were disease related,” the authors stated. n Jacobsen ED, et al: Blood 125:13941402, 2015. In the Literature is compiled and written for The ASCO Post by Charlotte Bath.

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Perspective Chandrakanth Are, MBBS, MBA, FRCS, FACS continued from page 1

the enormous burden of the diagnosis. They were well informed of the nature of pancreatic cancer, its lethality, and the likely treatment options. After performing the appropriate preoperative clearances, the patient was taken to the operating room for a pancreaticoduodenectomy, which she tolerated well. After an undulating but nonetheless uncomplicated postoperative course bereft of major events, she was discharged to a skilled nursing facility. Over the next few months, she returned to the clinic for follow-up and was in good spirits.

A Diligent Family Caregiver While this course of events may appear similar to that of any other patient with pancreatic cancer, the reality was and continues to be far from it. At our very first meeting, I noticed that the husband, an electrical engineering professor, was very involved and methodical. In the postoperative period, I was impressed by his diligence and involvement in his wife’s care. Every morning, by the time I got to his wife’s room, he was already there ready to give me a very inclusive progress report along with appropriate documentation of drains, ambulation, and so forth. Although he continued working at his daytime job in another city about

A Continuing Friendship The first time we met after Mrs. X’s demise, her husband reminisced about her last few months in this world—how she remained so graceful even while living under such a blanket of physical and mental suffering; how she had always looked forward to visiting us in the clinic and she made an extra effort to look good for the trip; how it was difficult in the final few days of her life; how he feels that she is better off now, as death is the ultimate relief from suffering in this world. Our discussions were always based on frankness when his wife was alive, and they continued in that manner even afterward. There were many times he wondered in my presence whether she should have had the operation, considering the comorbidities his wife had prior to the operation and her need for several months of postoperative care at a skilled nursing facility. Acknowledging that hindsight is a luxury, we have agreed that the best decisions were made at the time, with the information on hand. As our friendship continued, the husband decided to dedicate a part of his life to join the fight against pancreatic cancer on multiple levels. He got involved in advocacy groups that lobby for funding for pancreatic cancer research and treatment in Washington, DC. This has required multiple trips to the capital, which he undertook with

The ability to touch lives and build relationships with patients and families may be the most gratifying of [a physician’s privileges]. Let us not let anyone—or any system—deprive physicians of that privilege. —Chandrakanth Are, MBBS, MBA, FRCS, FACS

50 miles away, he was at the hospital everyday without fail until the day she was discharged. I even commented that maybe I could put him to work with other patients, considering the comprehensive care he provided for his wife. All of these interactions led to the development of a very strong physician– patient/family member relationship. After her discharge, we met each other during his wife’s clinic visits. He was always the same—very informed, methodical but professional, and courteous to a fault. As is the case with many patients with this lethal disease, the patient passed away the next year.

the utmost enthusiasm. To make himself even more useful in this endeavor, he stays remarkably up to date on statistics and advances relating to pancreatic cancer.

Heartwarming Stories Our friendship continues at regular lunches or the occasional dinner meeting. On these occasions, it is heartwarming to hear the stories he recalls about his wife of 50 years. Although his wife departed this world nearly 4 years ago, anyone listening to him would think that she might walk around the continued on page 81

Family Perspective By Jerald Varner, PhD

r. Are extended to me the opportunity to make additional comments about his article. I am the husband of the most wonderful Mrs. X he discusses. As always, Dr. Are’s comments are very kind and generous.

Three Roles Based on my experience and observations, I would like to mention three roles a family member or friend may play in the care of a patient. The first is in the role of helping a patient make decisions about the course of treatment. Because of medications

tients’ anxieties and help them focus on the processes needed for their recovery. Very simply stated, this role is to be there for the patient.

Relationship and Trust As Dr. Are has already indicated that the diagnosis of pancreatic cancer leaves the patient with very little if any hope. The 5-year survival rate for patients with pancreatic cancer is 6%, and from what my wife and I had heard, we were painfully aware that it was really only a question of how long. After the diagnosis, we were re-

The relationship and trust that we developed with Dr. Are made it easier and, at times, at all possible to carry the burden.… He is a great example of the kind of relationship that can and should exist between a doctor and patient. —Jerald Varner, PhD

or surgery, patients who need to make treatment decisions may not be at the top of their game, so to speak. To have another person listen to and evaluate information about treatment options can be helpful and reassuring to the patient. The old adage “two heads are better than one” comes to mind. The second key role is to be involved in the logistics of actually caring for the patient. Little things such as making sure the water pitcher is full, getting snacks, running errands, and walking with the patient when indicated can make him or her more comfortable. Small kindnesses such as these, always done while being careful not to get in the way of the trained professional caregivers, can help the patient maintain a positive outlook and speed recovery. The third role, and maybe the most important, is to be physically present with the patient. The hospital or caregiving setting can be unfamiliar, frightening, and intimidating to the patient. A familiar face and trusted companion can help allay paDr. Varner is an Associate Professor of Electrical Engineering at the University of Nebraska, Lincoln.

ferred to Dr. Are, who made it apparent at our first meeting and throughout the treatment course that he was genuinely concerned and cared about us. Yes, I did all the things mentioned with loving care for my wife, but it was Dr. Are who made me feel that I was part of the team. He made it very clear that the role I played and the things I did were very important in the care and treatment of my wife. The relationship and trust that we developed with Dr. Are made it easier and, at times, at all possible to carry the burden. I still recall that after a grueling 9-hour surgery, Dr. Are took the time to sit down and talk with us. In the end, we could not change the outcome, but the journey to that end would have been much more difficult without our relationship with Dr. Are. He is a great example of the kind of relationship that can and should exist between a doctor and patient. That relationship continued after my wife died—not as a relationship between doctor and patient, but as a relationship between friends. I am thankful that Dr. Are was present with us on our journey and is still a presence in my life. I also wish to thank him for allowing me to share in the writing of this article. n

ASCOPost.com | APRIL 25, 2015

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Perspective Chandrakanth Are, MBBS, MBA, FRCS, FACS continued from page 80

corner at any minute. His love and affection for her are undiminished from the time of their courtship, when he was a shoe salesman and his wife was the attractive woman who worked as the boss’s bookkeeper. He recounts how a young man funding his own university education thought that stealing a kiss from the boss’s bookkeeper might translate to a pay raise. He tells of how, in a long-ago era devoid of pretense, they worked in the morning and drove in the afternoon to a local church to get married, and he remembers the happy life they shared for the next 50 years before fate separated them. For the occasional dinner meeting, my wife and I have had the pleasure of visiting their home. We were served a nice home-cooked meal, something I

am sure was much like meals the couple had shared. We talked about their European ancestry while reviewing some black-and-white and sepia-toned photographs. We were shown around the house, with every sentence during the tour including his wife’s name or a reference to her. As we departed after dinner, I could not help but remark that the house is a shrine to his wife. He is blessed to have his family in the same town and is kept extremely busy with his teaching commitments. Nonetheless, the loneliness he feels in the absence of his life partner of 50 years is painfully obvious. Our meetings likely rekindle his memories, giving him the opportunity to think of his life partner with fondness.

The Human Touch I have gained immensely—both personally and professionally—from this relationship with Mrs. X’s hus-

band. This is what we should be inculcating into the education of today’s physician trainees. In this era of artificiality, consisting of electronic medical records, cookie-cutter measures, metrics on patient satisfaction, tick-the-box curricula, and inordinate emphasis on controlling costs at the expense of everything else, it is very easy to forget the human side of medicine. All of these modern concerns have the potential to drive us away from the basic tenet of medicine— not only to cure the disease but also to build a relationship with the patient and family. Our relationship with the sick does not stop when a soul departs. It continues to provide comfort to the rest of the family as needed. While this may not equate to any direct medical intervention with its essential “relative value unit” generation, this postcrisis relationship should be consid-

ered just as crucial a part of treatment. The medical profession is based on the “human touch.” Our patients provide a unique privilege for us to touch their lives and, in turn, be touched by them. They provide us the honor of becoming a part of their lives at their happiest and saddest moments. They open the door to their most private and intimate moments. They invite us into their past, present, and future life journeys, with all the attendant emotions. There is no other profession that offers this rare privilege. For all the rigors, trials, and tribulations, as well as the sacrifices made over the years of training, we physicians are granted many privileges. The ability to touch lives and build relationships with patients and families may be the most gratifying of those privileges. Let us not let anyone—or any system—deprive physicians of that privilege. n

Letters to the Editor

Nivolumab in Lung Cancer

find The ASCO Post to be a good way to hear about new ideas that I might otherwise have missed. I read an article recently about the approval of nivolumab (Opdivo) for treating metastatic squamous non-small cell lung cancer (The ASCO Post, April 10, 2015, page 25). I thought it would have been much more useful if a reference to the published trial data or presentation was

provided, but then learned that no such data had yet been published in a peerreviewed journal or presented at a major oncology conference, like ASCO or ESMO (European Society of Medical Oncology). It is my hope that no oncologist would prescribe a new drug without seeing the published literature. n —Philip Champion MD, FRCPC Charlottetown, PE, C1A 8T5, Canada

The ASCO Post Replies

ivolumab (Opdivo) was approved by the U.S. Food and Drug Administration (FDA) for the treatment of lung cancer on March 4, 2015, before clinical data from the pivotal trials (CheckMate 017 and CheckMate 063) were presented at a major oncology conference or published in a peer-reviewed journal. Data from CheckMate 063 have since been published.1 Data from CheckMate 017 were shared with health authorities in December 2014, according to the manufacturer, Bristol-Myers Squibb, and the company plans to work with investigators toward future presentation and publication of the results from CheckMate 017.

CheckMate 017: Survival Benefit CheckMate 017 was an open-label, randomized phase III study evaluating

nivolumab (3 mg/kg intravenously over 60 minutes every 2 weeks) (n = 135) vs docetaxel (75 mg/m2 intravenously administered every 3 weeks), in previously treated patients (n = 137) with advanced, squamous cell non–small cell lung cancer (NSCLC). This trial included patients regardless of their tumor’s programmed death ligand 1 (PD-L1) status. The primary endpoint of this trial was overall survival. The trial was stopped early because an assessment conducted by the independent data monitoring committee concluded that the study met its endpoint, demonstrating superior overall survival in patients receiving nivolumab. In patients receiving nivolumab, the median overall survival was 9.2 months (95% confidence interval [CI] = 7.3– 13.3 months) vs 6 months in patients receiving docetaxel (95% CI = 5.1–7.3

months). The hazard ratio was 0.59 (95% = 0.44–0.79; P = .00).

CheckMate 063: Safety and Efficacy The safety profile of nivolumab in squamous NSCLC was established in CheckMate 063, a phase II single-arm, open-label, multinational, multicenter trial of nivolumab, administered as a single agent in patients with metastatic squamous NSCLC with disease progression after receiving a platinum-based therapy and at least one additional systemic treatment regimen (n = 117). Patients received 3 mg/kg of nivolumab administered intravenously over 60 minutes every 2 weeks. This trial included patients regardless of the PD-L1 status of their tumor. The most common adverse reactions were fatigue (50%), dyspnea (38%), musculoskeletal pain (36%), decreased appetite (35%), cough (32%), nausea (29%), and constipation (24%). Serious adverse reactions occurred in 59% of patients receiving nivolumab. The most frequent serious adverse reactions reported in ≥ 2% of patients were dyspnea, pneumonia, chronic obstructive pulmonary disease exacerbation, pneumonitis, hypercalcemia, pleural effusion, hemoptysis, and pain. Adverse reactions resulted in drug discontinuation in 27% and drug delay in 29% of patients.

Accelerated Drug Approval In a related news release, Richard Pazdur, MD, Director of the Office of Hematology and Oncology Products in the FDA’s Center for Drug Evaluation and Research, said, “The FDA worked proactively with [Bristol-Myers Squibb] to facilitate the early submission and review of this important clinical trial when results first became available in late December 2014.”

Richard Pazdur, MD

Dr. Pazdur told The ASCO Post that the FDA believes prescribing should be based on a product’s label. The product label for nivolumab is available at http://packageinserts.bms.com/pi/pi_ opdivo.pdf n Reference 1. Rizvi NA, Mazieres J, Planchard D, et al: Activity and safety of nivolumab, an anti-PD-1 immune checkpoint inhibitor, for patients with advanced refractory squamous non-small-cell lung cancer (CheckMate 063): A phase 2, single-arm trial. Lancet Oncol 16:257-265, 2015.

T:7"

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 3.2%. 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 occur 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).]

AVASTIN® (bevacizumab) chemotherapeutic agents. Examples include palmar‑plantar erythrodysaesthesia syndrome with pegylated liposomal doxorubicin or capecitabine peripheral sensory neuropathy with paclitaxel or oxaliplatin, and nail disorders or alopecia with paclitaxel. 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 4996 patients with CRC, non‑squamous NSCLC, glioblastoma, mRCC, or cervical cancer or platinum‑ resistant recurrent epithelial ovarian, fallopian tube or primary peritoneal cancer including controlled (Studies 1, 2, 4, 5, 8 9 and 10) or uncontrolled, single arm trials (Study 6) treated at the recommended dose and schedule for a median of 6 to 23 doses of Avastin. [See Clinical Studies (14).] The population was aged 18‑89 years (median 60 years), 42% male and 86% 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 9 doses of Avastin, 337 mRCC patients who received a median of 16 doses of Avastin, 218 cervical cancer patients who received a median of 6 doses of Avastin and 179 platinum‑resistant recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer patients who received a median of 6 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, 1338 adjuvant CRC patients, including 669 female patients, who received a median of 23 doses of Avastin, and 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 (5.3).] 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 (5.4).] 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%). From a clinical trial in patients with persistent, recurrent, or metastatic cervical cancer (Study 9), Grade 3 or 4 VTE have been reported in 10.6% of patients treated with chemotherapy and Avastin compared with 5.4% in patients receiving chemotherapy alone. There were no patients with Grade 5 VTE. [See Dosage and Administration (2.4), Warnings and Precautions (5.6).] 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%. Proteinuria Grade 3–4 proteinuria ranged from 0.7 to 7.4% in Studies 1, 2, 4, 5, 8 and 10. 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 (5.9).] 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,

T:13"

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. 1.5 Persistent, Recurrent, or Metastatic Carcinoma of the Cervix Avastin in combination with paclitaxel and cisplatin or paclitaxel and topotecan is indicated for the treatment of persistent, recurrent, or metastatic carcinoma of the cervix. [See Clinical Studies (14.6).] 1.6 Platinum‑Resistant Recurrent Epithelial Ovarian, Fallopian Tube, or Primary Peritoneal Cancer Avastin in combination with paclitaxel, pegylated liposomal doxorubicin or topotecan is indicated for the treatment of patients with platinum‑ resistant recurrent epithelial ovarian, fallopian tube or primary peritoneal cancer who received no more than 2 prior chemotherapy regimens. 4 CONTRAINDICATIONS None. 5 WARNINGS AND PRECAUTIONS 5.1 Gastrointestinal Perforations and Fistulae 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 3.2% across clinical studies. [See Adverse Reactions (6.1).] From a clinical trial in patients with persistent, recurrent, or metastatic cervical cancer (Study 9), gastrointestinal perforations were reported in 3.2% of Avastin treated patients, all of whom had a history of prior pelvic radiation. Fatal outcome was reported in <1% of Avastin‑treated patients. In a platinum‑resistant ovarian cancer trial (Study 10), the incidence of GI perforation was 1.7% (3/179). In this trial, patients with evidence of recto‑sigmoid involvement by pelvic examination or bowel involvement on CT scan or clinical symptoms of bowel obstruction were excluded. The typical presentation may include abdominal pain, nausea, emesis, constipation, and fever. Perforation can be complicated by intra‑abdominal abscess, fistula formation, and the need for diverting ostomies. The majority of cases occurred within the first 50 days of initiation of Avastin. Avoid use of Avastin in patients with ovarian cancer who have evidence of recto‑sigmoid involvement by pelvic examination or bowel involvement on CT scan or clinical symptoms of bowel obstruction. Permanently discontinue Avastin in patients with gastrointestinal perforation. In Avastin clinical trials, gastrointestinal fistulae have been reported with an incidence of up to 2% in patients with metastatic colorectal cancer and ovarian cancer. In a cervical cancer trial (Study 9), the incidence of gastrointestinal‑vaginal fistulae was 8.3% in Avastin‑treated patients and 0.9% in control patients, all of whom had a history of prior pelvic radiation. Patients who develop GI vaginal fistulas may also have bowel obstructions and require surgical intervention as well as diverting ostomies. [See Boxed Warning, Dosage and Administration (2.4).] 5.2 Non‑Gastrointestinal Fistulae Serious and sometimes fatal fistula formation involving tracheo‑ esophageal, bronchopleural, biliary, vaginal, renal and bladder sites occurs at a higher incidence in Avastin‑treated patients compared to controls. Uncommon (<1%) reports of fistulae that involve areas of the body other than the gastrointestinal tract were observed in clinical trials across various indications and have also been reported in post‑ marketing experience. Most events occurred within the first 6 months of Avastin therapy. From a clinical trial in patients with persistent, recurrent, or metastatic cervical cancer (Study 9), 1.8% of Avastin‑treated patients and 1.4% of control patients were reported to have had non‑gastrointestinal vaginal, vesical, or female genital tract fistulae. Permanently discontinue Avastin in patients with tracheoesophageal (TE) fistula or any Grade 4 fistula. Discontinue Avastin in patients with fistula formation involving an internal organ. [See Dosage and Administration (2.4).] 5.3 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).]

AVASTIN® (bevacizumab) 5.4 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 0.4 to 6.9 %. [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).] 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 Venous Thromboembolic Events Patients treated for persistent, recurrent, or metastatic cervical cancer with Avastin may be at increased risk of venous thromboembolic events (VTE). From a clinical trial in patients with persistent, recurrent, or metastatic cervical cancer (Study 9), Grade ≥ 3 VTE were reported in 10.6% of patients treated with chemotherapy and Avastin compared with 5.4% in patients receiving chemotherapy alone. Permanently discontinue Avastin in patients with life‑threatening (Grade 4) VTE, including pulmonary embolism. [See Dosage and Administration (2.4), Adverse Reactions (6.1).] 5.7 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).] 5.8 Posterior Reversible Encephalopathy Syndrome (PRES) PRES has been reported with an incidence of < 0.5% in clinical studies. The onset of symptoms occurred from 16 hours to 1 year after initiation of Avastin. PRES 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 PRES. Discontinue Avastin in patients developing PRES. 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 PRES is not known. [See Dosage and Administration (2.4).] 5.9 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).] 5.10 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).] 5.11 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 and Fistulae[See Boxed Warning, Dosage and Administration (2.4), Warnings and Precautions (5.1).] • Non‑Gastrointestinal Fistulae [See Dosage and Administration (2.4), Warnings and Precautions (5.2).] • Surgery and Wound Healing Complications [See Boxed Warning, Dosage and Administration (2.4), Warnings and Precautions (5.3).] • Hemorrhage [See Boxed Warning, Dosage and Administration (2.4), Warnings and Precautions (5.4).] • Arterial Thromboembolic Events [See Dosage and Administration (2.4), Warnings and Precautions (5.5).] • Venous Thromboembolic Events [See Dosage and Administration (2.4), Warnings and Precautions (5.6).] • Hypertensive Crisis [See Dosage and Administration (2.4), Warnings and Precautions (5.7).] • Posterior Reversible Encephalopathy Syndrome [See Dosage and Administration (2.4), Warnings and Precautions (5.8).] • Proteinuria [See Dosage and Administration (2.4), Warnings and Precautions (5.9).] • Infusion Reactions [See Dosage and Administration (2.4), Warnings and Precautions (5.10)] • Ovarian Failure [See Warnings and Precautions (5.11), 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 Some of the adverse reactions are commonly seen with chemotherapy; however, Avastin may exacerbate these reactions when combined with

T:10.25" S:9.5"

AVASTIN® (bevacizumab) 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. 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 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 (5.11), Use in Specific Populations (8.6).] Post-Treatment Vascular Events In an open‑label, randomized, controlled trial of Avastin in adjuvant colorectal cancer, an indication for which Avastin is not approved, the overall incidence rate of post‑treatment Grade ≥ 3 vascular events was 3.1% (41 of 1338) among patients receiving mFOLFOX6 plus Avastin, compared to 1.6% (21 of 1349) among patients receiving mFOLFOX6 alone. Post‑treatment vascular events included arterial and venous thromboembolic events, ischemic events, and vascular aneurysms. 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) Arm 1 IFL+ Placebo (n = 396)

System Organ Class/ IFN‑α + Placebo IFN‑α + Avastin Preferred terma (n = 304) (n = 337) Gastrointestinal disorders Diarrhea 16% 21% General disorders and administration site conditions Fatigue 27% 33% Investigations Weight decreased 15% 20% Metabolism and nutrition disorders Anorexia 31% 36% Musculoskeletal and connective tissue disorders Myalgia 14% 19% Back pain 6% 12% Nervous system disorders Headache 16% 24% Renal and urinary disorders Proteinuria 3% 20% Respiratory, thoracic and mediastinal disorders Epistaxis 4% 27% Dysphonia 0% 5% Vascular disorders Hypertension 9% 28%

Arm 2 IFL+ Avastin (n = 392)

74%

87%

7% 5% 5%

10% 8% 8%

2% 5% 1% 1%

12% 9% 3% 3%

25% 2%

34% 4%

31% 14%

37% 21%

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%

20%

26%

19%

39% 10% 15% 2%

47% 35% 26% 9%

40% 32% 25% 6%

26% 1%

32% 6%

6% 6%

14%

21%

24%

36%

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 FluoropyrimidineOxaliplatin 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

Adverse events were encoded using MedDRA, Version 10.1.

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). Persistent, Recurrent, or Metastatic Carcinoma of the Cervix All grade adverse reactions were collected in Study 9. Grade 1‑4 adverse reactions occurring where the incidence difference is ≥ 5% in patients receiving Avastin plus chemotherapy compared to chemotherapy alone are presented in Table 4. Table 4 NCI‑CTC Grades 1‑4 and 3‑4 Adverse Reactions in Study 9 (Incidence Difference of ≥ 5% Between Treatment Arms in Chemo + Avastin vs. Chemo Alone) Grade 1‑4 Grade 3‑4 reactions reactions Chemo Chemo+ Chemo Chemo+ Alone Avastin Alone Avastin (n=222) (n=218) (n=222) (n=218) Metabolism and Nutrition Disorders Decreased Appetite 26% 34% Hyperglycemia 19% 26% Hypomagnesemia 15% 24% Hyponatremia 10% 19% Hypoalbuminemia 11% 16% General Disorders and Administration Site Conditions Fatigue 75% 80% Edema Peripheral 22% 15% Investigations Weight Decreased 7% 21% Blood Creatinine Increased 10% 16% Infections and Infestations Urinary Tract Infection 14% 22% Infection 5% 10% Vascular Disorders Hypertension 6% 29% 0.5% 11.5% Thrombosis 3% 10% 2.7% 8.3% Nervous System Disorders Headache 13% 22% Dysarthria 1% 8% Gastrointestinal Disorders Stomatitis 10% 15% Proctalgia 1% 6% Anal Fistula — 6% Blood and Lymphatic System Disorders Neutropenia 6% 12% Lymphopenia 5% 12% Psychiatric Disorders Anxiety 10% 17% Reproductive System and Breast Disorders Pelvic Pain 8% 14% Respiratory, Thoracic and Mediastinal Disorders Epistaxis 1% 17% Renal and Urinary Disorders Proteinuria 3% 10%

AVASTIN® (bevacizumab)

Grade 3 or 4 adverse reactions occurring at a higher incidence ( ≥2%) in 218 patients receiving chemotherapy plus Avastin compared to 222 patients receiving chemotherapy alone were abdominal pain (11.9% vs. 9.9%), diarrhea (5.5% vs. 2.7%), anal fistula (3.7% vs. 0%), proctalgia (2.8% vs. 0%), urinary tract infection (8.3% vs. 6.3%), cellulitis (3.2% vs. 0.5%), fatigue (14.2% vs. 9.9%), hypokalemia (7.3% vs. 4.5%), hyponatremia (3.7% vs. 1.4%), dehydration (4.1% vs. 0.5%), neutropenia (7.8% vs. 4.1%), lymphopenia (6.0% vs. 3.2%), back pain (5.5% vs. 3.2%), and pelvic pain (5.5% vs. 1.4%). There were no Grade 5 adverse reactions occurring at a higher incidence (≥2%) in patients receiving chemotherapy plus Avastin compared to patients receiving chemotherapy alone. Platinum-Resistant Recurrent Epithelia Ovarian, Fallopian Tube, or Primary Peritoneal Cancer Patients with evidence of recto‑sigmoid involvement by pelvic examination or bowel involvement on CT scan or clinical symptoms of bowel obstruction were excluded in this study. Grade 2‑4 adverse events occurring at a higher incidence ( ≥5%) in patients receiving Avastin plus chemotherapy compared to patients receiving chemotherapy alone are presented in Table 5. Table 5 Grade 2−4 Adverse Events Occurring at Higher Incidence [ ≥ 5%] in Chemo + Avastin vs. Chemo Safety−Evaluable Patients

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 (5.9).] 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 (5.11), 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.

System Organ Class Preferred Term Blood And Lymphatic System Disorders Neutropenia General Disorders And Administration Site Conditions Mucosal Inflammation Infections And Infestations Infection Nervous System Disorders Peripheral Sensory Neuropathy Renal And Urinary Disorders Proteinuria Respiratory, Thoracic and Mediastinal Disorders Epistaxis Skin And Subcutaneous Tissue Disorders Palmar−Plantar Erythrodysaesthesia Syndrome Vascular Disorders Hypertension

Chemo Chemo+Avastin (n = 181) (n = 179) 25.4%

30.7%

5.5%

12.8%

4.4%

10.6%

7.2%

17.9%

0.6%

12.3%

0.0%

5.0%

10.6%

5.5%

19.0%

Grade 3−4 adverse events occurring at a higher incidence ( ≥ 2%) in 179 patients receiving Avastin plus chemotherapy compared to 181 patients receiving chemotherapy alone were hypertension (6.7% vs. 1.1%) and palmar‑plantar erythrodysaesthesia syndrome (4.5% vs. 1.7%). There were no Grade 5 events occurring at a higher incidence ( ≥ 2%) in patients receiving Avastin plus chemotherapy compared to patients receiving chemotherapy alone. 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, PRES, 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. 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

S:12.5"

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

AVASTIN® (bevacizumab) 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. 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 PRES (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)

Avastin® (bevacizumab) Manufactured by: Genentech, Inc. A Member of the Roche Group 1 DNA Way South San Francisco, CA 94080‑4990

Now FDA Approved in PlatinumResistant Ovarian Cancer The first biologic regimen to demonstrate a significant increase in median PFS vs chemotherapy alone1 AURELIA ITT

Exploratory efficacy analysis by chemotherapy cohort Avastin + paclitaxel cohort

Primary endpoint

Avastin + topotecan cohort

Avastin + PLD cohort

6.8

Avastin + chemotherapy Chemotherapy alone

9.6 6.2

(n=179)

(n=55)

HR=0.47 (95% Cl, 0.31–0.72)

(n=182)

HR=0.38 (95% Cl, 0.30–0.49), P<0.0001

(n=60)

Months

3.9

5.1 2.1

(n=57)

(n=63)

HR=0.24 (95% Cl, 0.15–0.38)

Months

3.4

(n=62)

3.5 (n=64)

HR=0.47 (95% Cl, 0.32–0.71)

Cohort analysis based on prespecified endpoint (PFS). Analysis not designed to evaluate statistical significance between treatment arms or compare among the 3 chemotherapy cohorts.

Statistically significant improvement in ITT investigator-assessed PFS was supported by a retrospective independent review analysis PFS=progression-free survival; ITT=intent-to-treat; HR=hazard ratio; CI=confidence interval; PLD=pegylated liposomal doxorubicin.

Indication Avastin in combination with paclitaxel, pegylated liposomal doxorubicin or topotecan is indicated for the treatment of patients with platinum-resistant recurrent epithelial ovarian, fallopian tube or primary peritoneal cancer who received no more than 2 prior chemotherapy regimens.

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 3.2% 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 0.4% to 6.9% — 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 — GI fistulae (up to 2% in metastatic colorectal cancer patients; less commonly in other cancer types) — Non-GI fistulae (<1% in trials across various indications; 1.8% in a cervical cancer trial) — Arterial thromboembolic events (grade ≥3, 2.6%) — Proteinuria (nephrotic syndrome, <1%) Additional serious adverse events with increased incidence in the Avastintreated arm vs control included — GI-vaginal fistulae occurred in 8.3% of patients in a cervical cancer trial

AVY/110514/0041

Printed in USA.

(11/14)

— Hypertension (grade 3–4, 5%–18%) — Posterior reversible encephalopathy syndrome (PRES) (<0.5%) 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 Avoid use in patients with ovarian cancer who have evidence of recto-sigmoid involvement by pelvic examination or bowel involvement on CT scan or clinical symptoms of bowel obstruction

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 — Proteinuria — Lacrimation disorder — Headache — Taste alteration — Back pain — Hypertension — Dry skin — Exfoliative dermatitis — Rhinitis — Rectal hemorrhage Across all studies, Avastin was discontinued in 8.4% to 21% of patients because of adverse reactions

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 prOC, grade 3–4 adverse events occurring at a higher incidence (≥2%) in 179 patients receiving Avastin plus chemotherapy compared to 181 patients receiving chemotherapy alone were hypertension (6.7% vs 1.1%) and palmar-plantar erythrodysaesthesia syndrome (4.5% vs 1.7%). There were no grade 5 events occurring at a higher incidence (≥2%) in patients receiving Avastin plus chemotherapy compared to patients receiving chemotherapy alone 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. prOC=platinum-resistant recurrent epithelial ovarian, fallopian tube or primary peritoneal cancer. Reference: 1. Avastin Prescribing Information. Genentech, Inc. November 2014.