Cancer Therapy Advisor Skin Cancer Special Edition

SPECIAL EDITION:

Skin Cancer A12 FEATURE

A17 FEATURE

A19 VIEWPOINT

In the Pipeline: Melanoma Treatment Research

Molecular and Genetic Testing for Melanoma

Statin Use in Postmenopausal Women

A review of research advances that may change the treatment landscape for patients.

New tests are changing how melanoma is diagnosed and treated.

Research indicates that drug may increase the risk of non-melanoma skin cancer.

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Give MORE Patients the OPDIVO Opportunity I mmune-mediated pneumonitis, including fatal cases, occurred with OPDIVO treatment. Across the clinical trial experience with

solid tumors, fatal immune-mediated pneumonitis occurred with OPDIVO. Monitor patients for signs with radiographic imaging and symptoms of pneumonitis. Administer corticosteroids for Grade 2 or greater pneumonitis. Permanently discontinue for Grade 3 or 4 and withhold until resolution for Grade 2. In Checkmate 037, 066, and 067, immune-mediated pneumonitis occurred in 1.8% (14/787) of patients receiving OPDIVO: Grade 3 (n=2) and Grade 2 (n=12). In Checkmate 057, immune-mediated pneumonitis, including interstitial lung disease, occurred in 3.4% (10/287) of patients: Grade 3 (n=5), Grade 2 (n=2), and Grade 1 (n=3). In Checkmate 025, pneumonitis, including interstitial lung disease, occurred in 5% (21/406) of patients receiving OPDIVO and 18% (73/397) of patients receiving everolimus. Immune-mediated pneumonitis occurred in 4.4% (18/406) of patients receiving OPDIVO: Grade 4 (n=1), Grade 3 (n=4), Grade 2 (n=12), and Grade 1 (n=1).

Immune-Mediated Colitis I mmune-mediated colitis can occur with OPDIVO treatment. Monitor patients for signs and symptoms of colitis. Administer corticosteroids

for Grade 2 (of more than 5 days duration), 3, or 4 colitis. As a single agent, withhold OPDIVO for Grade 2 or 3 and permanently discontinue for Grade 4 or recurrent colitis upon restarting OPDIVO. In Checkmate 037, 066, and 067, diarrhea or colitis occurred in 31% (242/787) of patients receiving OPDIVO. Immune-mediated colitis occurred in 4.1% (32/787) of patients: Grade 3 (n=20), Grade 2 (n=10), and Grade 1 (n=2). In Checkmate 057, diarrhea or colitis occurred in 17% (50/287) of patients receiving OPDIVO. Immune-mediated colitis occurred in 2.4% (7/287) of patients: Grade 3 (n=3), Grade 2 (n=2), and Grade 1 (n=2). In Checkmate 025, diarrhea or colitis occurred in 25% (100/406) of patients receiving OPDIVO and 32% (126/397) of patients receiving everolimus. Immune-mediated diarrhea or colitis occurred in 3.2% (13/406) of patients receiving OPDIVO: Grade 3 (n=5), Grade 2 (n=7), and Grade 1 (n=1).

Immune-Mediated Hepatitis I mmune-mediated hepatitis can occur with OPDIVO treatment. Monitor patients for abnormal liver tests prior to and periodically

during treatment. Administer corticosteroids for Grade 2 or greater transaminase elevations. Withhold for Grade 2 and permanently discontinue for Grade 3 or 4 immune-mediated hepatitis. In Checkmate 037, 066, and 067, immune-mediated hepatitis occurred in 2.3% (18/787) of patients receiving OPDIVO: Grade 4 (n=3), Grade 3 (n=11), and Grade 2 (n=4). In Checkmate 057, one patient (0.3%)

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Immune-Mediated Pneumonitis

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IMPORTANT SAFETY INFORMATION

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The Only Immuno-Oncology Agent Approved In 3 Tumor Types for Appropriate Patients With Metastatic Cancer

mMelanoma

mNSCLC

aRCC

OPDIVO as a single agent is indicated for the treatment of patients with BRAF V600 mutation-positive unresectable or metastatic melanoma. This indication is approved under accelerated approval based on progression-free survival. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials.

OPDIVO is indicated for the treatment of patients with metastatic non-small cell lung cancer (NSCLC) with progression on or after platinum-based chemotherapy. Patients with EGFR or ALK genomic tumor aberrations should have disease progression on FDA-approved therapy for these aberrations prior to receiving OPDIVO. OPDIVO is indicated for the treatment of patients with advanced renal cell carcinoma (RCC) who have received prior anti-angiogenic therapy.

IMPORTANT SAFETY INFORMATION (cont’d) developed immune-mediated hepatitis. In Checkmate 025, there was an increased incidence of liver test abnormalities compared to baseline in AST (33% vs 39%), alkaline phosphatase (32% vs 32%), ALT (22% vs 31%), and total bilirubin (9% vs 3.5%) in the OPDIVO and everolimus arms, respectively. Immune-mediated hepatitis requiring systemic immunosuppression occurred in 1.5% (6/406) of patients receiving OPDIVO: Grade 3 (n=5) and Grade 2 (n=1).

For more information, please visit www.OPDIVO.com/hcp

Please see additional Important Safety Information on the following page.

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PRESCRIBED

PD-1 INHIBITOR

Based upon 2015 IMS data 1

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OPDIVO® (nivolumab) as a single agent is indicated for the treatment of patients with BRAF V600 wild-type unresectable or metastatic melanoma.

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INDICATIONS

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IMPORTANT SAFETY INFORMATION (cont’d) Immune-Mediated Endocrinopathies

H ypophysitis, adrenal insufficiency, thyroid disorders, and type 1 diabetes mellitus can occur with OPDIVO treatment. Monitor patients for signs and symptoms of hypophysitis, signs and symptoms of adrenal insufficiency during and after treatment, thyroid function prior to and periodically during treatment, and hyperglycemia. Administer corticosteroids for Grade 2 or greater hypophysitis.

Withhold for Grade 2 or 3 and permanently discontinue for Grade 4 hypophysitis. Administer corticosteroids for Grade 3 or 4 adrenal insufficiency. Withhold for Grade 2 and permanently discontinue for Grade 3 or 4 adrenal insufficiency. Administer hormone-replacement therapy for hypothyroidism. Initiate medical management for control of hyperthyroidism. Administer insulin for type 1 diabetes. Withhold OPDIVO for Grade 3 and permanently discontinue for Grade 4 hyperglycemia.

I n Checkmate 037, 066, and 067, hypophysitis occurred in 0.9% (7/787) of patients receiving OPDIVO: Grade 3 (n=2), Grade 2 (n=3), and Grade 1 (n=2). In Checkmate 025, hypophysitis occurred in 0.5% (2/406) of patients receiving OPDIVO: Grade 3 (n=1) and Grade 1 (n=1). In Checkmate 037, 066, and 067, adrenal insufficiency occurred in 1% (8/787) of patients receiving OPDIVO: Grade 3 (n=2), Grade 2 (n=5), and Grade 1 (n=1). In Checkmate 057, 0.3% (1/287) of OPDIVO-treated patients developed adrenal insufficiency. In Checkmate 025, adrenal insufficiency occurred in 2.0% (8/406) of patients receiving OPDIVO: Grade 3 (n=3), Grade 2 (n=4), and Grade 1 (n=1). In Checkmate 037, 066, and 067, hypothyroidism or thyroiditis occurred in 9% (73/787) of patients receiving OPDIVO: Grade 3 (n=1), Grade 2 (n=37), Grade 1 (n=35). Hyperthyroidism occurred in 4.4% (35/787) of patients receiving OPDIVO: Grade 3 (n=1), Grade 2 (n=12), and Grade 1 (n=22). In Checkmate 057, Grade 1 or 2 hypothyroidism, including thyroiditis, occurred in 7% (20/287) and elevated thyroid stimulating hormone occurred in 17% of patients receiving OPDIVO. Grade 1 or 2 hyperthyroidism occurred in 1.4% (4/287) of patients. In Checkmate 025, thyroid disease occurred in 11% (43/406) of patients receiving OPDIVO, including one Grade 3 event, and in 3.0% (12/397) of patients receiving everolimus. Hypothyroidism/thyroiditis occurred in 8% (33/406) of patients receiving OPDIVO: Grade 3 (n=2), Grade 2 (n=17), and Grade 1 (n=14).

Hyperthyroidism occurred in 2.5% (10/406) of patients receiving OPDIVO: Grade 2 (n=5) and Grade 1 (n=5). In Checkmate 037, 066, and 067, diabetes mellitus or diabetic ketoacidosis occurred in 0.8% (6/787) of patients receiving OPDIVO: Grade 3 (n=2), Grade 2 (n=3), and Grade 1 (n=1).

In Checkmate 025, hyperglycemic adverse events occurred in 9% (37/406) patients. Diabetes mellitus or diabetic ketoacidosis occurred in 1.5% (6/406) of patients receiving OPDIVO: Grade 3 (n=3), Grade 2 (n=2), and Grade 1 (n=1).

Other Immune-Mediated Adverse Reactions

B ased on the severity of adverse reaction, permanently discontinue or withhold treatment, administer high-dose corticosteroids, and, if appropriate, initiate hormone-replacement therapy.

In <1.0% of patients receiving OPDIVO, the following clinically significant, immune-mediated adverse reactions occurred: uveitis, pancreatitis, facial and abducens nerve paresis, demyelination, polymyalgia rheumatica, autoimmune neuropathy, Guillain-Barré syndrome, hypopituitarism, systemic inflammatory response syndrome, gastritis, duodenitis, and sarcoidosis. Across clinical trials of OPDIVO as a single agent administered at doses of 3 mg/kg and 10 mg/kg, additional clinically significant, immune-mediated adverse reactions were identified: motor dysfunction, vasculitis, and myasthenic syndrome.

Infusion Reactions

S evere infusion reactions have been reported in <1.0% of patients in clinical trials of OPDIVO. Discontinue OPDIVO in patients with Grade 3 or 4 infusion reactions. Interrupt or slow the rate of infusion in patients with Grade 1 or 2. In Checkmate 037, 066, and 067, Grade 2 infusion related reactions occurred in 2.7% (21/787) of patients receiving OPDIVO: Grade 3 (n=2), Grade 2 (n=8), and Grade 1 (n=11). In Checkmate 057, Grade 2 infusion reactions requiring corticosteroids occurred in 1.0% (3/287) of patients receiving OPDIVO. In Checkmate 025, hypersensitivity/ infusion-related reactions occurred in 6% (25/406) of patients receiving OPDIVO and 1.0% (4/397) of patients receiving everolimus.

Embryo-fetal Toxicity

B ased 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 an OPDIVO-containing regimen and for at least 5 months after the last dose of OPDIVO.

Lactation

I t 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 an OPDIVO-containing regimen, advise women to discontinue breastfeeding during treatment.

Serious Adverse Reactions

Immune-Mediated Encephalitis

I mmune-mediated encephalitis can occur with OPDIVO treatment. Withhold OPDIVO in patients with new-onset moderate to severe neurologic signs or symptoms and evaluate to rule out other causes. If other etiologies are ruled out, administer corticosteroids and permanently discontinue OPDIVO for immune-mediated encephalitis. In Checkmate 057, fatal limbic encephalitis occurred in one patient (0.3%) receiving OPDIVO.

I n Checkmate 067, the most common (≥20%) adverse reactions in the OPDIVO arm were fatigue (53%), rash (40%), diarrhea (31%), and nausea (28%). In Checkmate 037, the most common adverse reaction (≥20%) reported with OPDIVO was rash (21%). In Checkmate 066, the most common adverse reactions (≥20%) reported with OPDIVO vs dacarbazine were fatigue (49% vs 39%), musculoskeletal pain (32% vs 25%), rash (28% vs 12%), and pruritus (23% vs 12%). In Checkmate 057, the most common adverse reactions (≥20%) reported with OPDIVO were fatigue (49%), musculoskeletal pain (36%), cough (30%), decreased appetite (29%), and constipation (23%). In Checkmate 025, the most common adverse reactions (≥20%) reported in patients receiving OPDIVO vs everolimus were asthenic conditions (56% vs 57%), cough (34% vs 38%), nausea (28% vs 29%), rash (28% vs 36%), dyspnea (27% vs 31%), diarrhea (25% vs 32%), constipation (23% vs 18%), decreased appetite (23% vs 30%), back pain (21% vs 16%), and arthralgia (20% vs 14%).

Reference: 1. IMS APLD data, January 2015 – December 2015.

Please see brief summary of Full Prescribing Information on the following pages.

OPDIVO® and the related logo are trademarks of Bristol-Myers Squibb Company. ©2016 Bristol-Myers Squibb Company. All rights reserved. Printed in USA. 1506US1601666-01-01 04/16

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Common Adverse Reactions

Immune-mediated rash can occur with OPDIVO treatment. Severe rash (including rare cases of fatal toxic epidermal necrolysis) occurred in the clinical program of OPDIVO. Monitor patients for rash. Administer corticosteroids for Grade 3 or 4 rash. Withhold for Grade 3 and permanently discontinue for Grade 4. In Checkmate 037, 066, and 067, immune-mediated rash occurred in 9% (72/787) of patients receiving OPDIVO: Grade 3 (n=7), Grade 2 (n=15), and Grade 1 (n=50).

In Checkmate 057, immune-mediated rash occurred in 6% (17/287) of patients receiving OPDIVO including four Grade 3 cases. In Checkmate 025, rash occurred in 28% (112/406) of patients receiving OPDIVO and 36% (143/397) of patients receiving everolimus. Immune-mediated rash, defined as a rash treated with systemic or topical corticosteroids, occurred in 7% (30/406) of patients receiving OPDIVO: Grade 3 (n=4), Grade 2 (n=7), and Grade 1 (n=19).

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Immune-Mediated Rash

Immune-Mediated Nephritis and Renal Dysfunction

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Immune-mediated nephritis can occur with OPDIVO treatment. Monitor patients for elevated serum creatinine prior to and periodically during treatment. For Grade 2 or 3 increased serum creatinine, withhold and administer corticosteroids; if worsening or no improvement occurs, permanently discontinue. Administer corticosteroids for Grade 4 serum creatinine elevation and permanently discontinue. In Checkmate 037, 066, and 067, nephritis and renal dysfunction of any grade occurred in 5% (40/787) of patients receiving OPDIVO. Immune-mediated nephritis and renal dysfunction occurred in 0.8% (6/787) of patients: Grade 3 (n=4) and Grade 2 (n=2).

In Checkmate 057, Grade 2 immune-mediated renal dysfunction occurred in 0.3% (1/287) of patients receiving OPDIVO. In Checkmate 025, renal injury occurred in 7% (27/406) of patients receiving OPDIVO and 3.0% (12/397) of patients receiving everolimus. Immune-mediated nephritis and renal dysfunction occurred in 3.2% (13/406) of patients receiving OPDIVO: Grade 5 (n=1), Grade 4 (n=1), Grade 3 (n=5), and Grade 2 (n=6).

In Checkmate 067, serious adverse reactions (37%), adverse reactions leading to permanent discontinuation (14%) or to dosing delays (28%), and Grade 3 or 4 adverse reactions (72%) occurred in the OPDIVO arm. The most frequent (≥10%) serious adverse reactions in the OPDIVO arm were diarrhea (2.6%), colitis (1.6%), and pyrexia (0.6%). In Checkmate 037, serious adverse reactions occurred in 41% of patients receiving OPDIVO. Grade 3 and 4 adverse reactions occurred in 42% of patients receiving OPDIVO. The most frequent Grade 3 and 4 adverse drug reactions reported in 2% to <5% of patients receiving OPDIVO were abdominal pain, hyponatremia, increased aspartate aminotransferase, and increased lipase. In Checkmate 066, serious adverse reactions occurred in 36% of patients receiving OPDIVO. Grade 3 and 4 adverse reactions occurred in 41% of patients receiving OPDIVO. The most frequent Grade 3 and 4 adverse reactions reported in ≥2% of patients receiving OPDIVO were gamma-glutamyltransferase increase (3.9%) and diarrhea (3.4%). In Checkmate 057, serious adverse reactions occurred in 47% of patients receiving OPDIVO. The most frequent serious adverse reactions reported in ≥2% of patients were pneumonia, pulmonary embolism, dyspnea, pleural effusion, and respiratory failure. In Checkmate 025, serious adverse reactions occurred in 47% of patients receiving OPDIVO. The most frequent serious adverse reactions reported in ≥2% of patients were acute kidney injury, pleural effusion, pneumonia, diarrhea, and hypercalcemia.

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OPDIVO® (nivolumab) injection, for intravenous use Brief Summary of Prescribing Information. For complete prescribing information consult official package insert.

INDICATIONS AND USAGE • OPDIVO® (nivolumab) as a single agent is indicated for the treatment of patients with BRAF V600 wild-type unresectable or metastatic melanoma [see Clinical Studies (14.1) in full Prescribing Information].

• OPDIVO (nivolumab) as a single agent is indicated for the treatment of patients with BRAF V600 mutationpositive unresectable or metastatic melanoma [see Clinical Studies (14.1) in full Prescribing Information].

This indication is approved under accelerated approval based on progression-free survival. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials.

• OPDIVO (nivolumab) is indicated for the treatment of patients with metastatic non-small cell lung cancer (NSCLC) with progression on or after platinum-based chemotherapy. Patients with EGFR or ALK genomic tumor aberrations should have disease progression on FDA-approved therapy for these aberrations prior to receiving OPDIVO [see Clinical Studies (14.2) in full Prescribing Information].

• OPDIVO (nivolumab) is indicated for the treatment of patients with advanced renal cell carcinoma (RCC) who have received prior anti-angiogenic therapy [see Clinical Studies (14.3) in full Prescribing Information].

CONTRAINDICATIONS None.

WARNINGS AND PRECAUTIONS Immune-Mediated Pneumonitis Immune-mediated pneumonitis, defined as requiring use of corticosteroids and no clear alternate etiology, including fatal cases, occurred with OPDIVO treatment. Across clinical trial experience with solid tumors receiving OPDIVO, fatal immune-mediated pneumonitis occurred in 0.3% (5/1903) of patients. 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).

Monitor patients for signs with radiographic imaging and symptoms of pneumonitis. Administer corticosteroids at a dose of 1 to 2 mg/kg/day prednisone equivalents for moderate (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 (2.4) in full Prescribing Information].

Melanoma – In Trials 1, 5, and 7, diarrhea or colitis occurred in 31% (242/787) of patients. Immune-mediated colitis occurred in 4.1% (32/787) of patients: 20 patients with Grade 3, 10 patients with Grade 2, and two patients with Grade 1 colitis. The median time to onset of immune-mediated colitis was 5.6 months (range: 3 days to 13.1 months). Immune-mediated colitis led to permanent discontinuation of OPDIVO in seven patients (0.9%) and to withholding of OPDIVO in six patients (0.8%). Thirty patients received high-dose corticosteroids (at least 40 mg prednisone equivalents) for a median duration of 4.2 months (range: 3 days to 9.3 months).

Three patients with Grade 2 or 3 colitis required addition of infliximab to high-dose corticosteroids. Complete resolution (defined as improved to baseline with completion of corticosteroids) occurred in 17 patients. Among the nine patients who resumed OPDIVO after resolution, two had recurrence of immune-mediated colitis.

NSCLC – In Trial 3, diarrhea or colitis occurred in 17% (50/287) of patients receiving OPDIVO. Immune-mediated colitis occurred in 2.4% (7/287) of patients: three patients with Grade 3, two patients with Grade 2, and two patients with Grade 1. The median time to onset in these seven patients was 2.7 months (range: 4 weeks to 19 months). All seven patients received corticosteroids; six of these seven received high-dose corticosteroids for a median duration of 2.9 weeks (range: 1 week to 2.1 months). One patient with Grade 3 colitis permanently discontinued OPDIVO. All seven patients experienced complete resolution.

Five of the seven patients were retreated after complete resolution without recurrence of diarrhea or colitis.

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RCC – In Trial 6, there was an increased incidence of liver test abnormalities compared to baseline with increases in AST (33% vs. 39%), alkaline phosphatase (32% vs. 32%), ALT (22% vs. 31%), and total bilirubin (9% vs. 3.5%) in the OPDIVO and everolimus arms, respectively. Immune-mediated hepatitis requiring systemic immunosuppression occurred in 1.5% (6/406) of patients receiving OPDIVO (five with Grade 3 and one with Grade 2). None of the six patients had liver metastases. The median time to onset was 3.7 months (range: 14 days to 5.3 months). The median duration was 1.8 months (range: 0.9 to 16.3 months). OPDIVO was permanently discontinued in four patients. Dose delay occurred in all patients. Five patients had complete resolution. Among the three patients who resumed OPDIVO, two had no recurrence of liver test abnormalities.

One patient with immune-mediated nephritis developed hepatic failure on the date of death.

Immune-Mediated Endocrinopathies Hypophysitis Hypophysitis can occur with OPDIVO treatment. Monitor patients for signs and symptoms of hypophysitis.

Administer corticosteroids at a dose of 1 mg/kg/day prednisone equivalents for moderate (Grade 2) or greater hypophysitis. Withhold OPDIVO for moderate (Grade 2) or severe (Grade 3) and permanently discontinue OPDIVO for life-threatening (Grade 4) hypophysitis [see Dosage and Administration (2.4) in full Prescribing Information].

Melanoma – In Trials 1, 5, and 7, hypophysitis occurred in 0.9% (7/787) of patients: two patients with Grade 3, three patients with Grade 2, and two patients with Grade 1 hypophysitis. The median time to onset was 5.5 months (range: 1.6 to 11 months). Hypophysitis led to withholding of OPDIVO in one patient (0.1%). Three patients received high-dose corticosteroids (at least 40 mg prednisone equivalents) for a median duration of 22 days (range: 5 to 26 days).

RCC – In Trial 6, hypophysitis occurred in 0.5% (2/406) of patients receiving OPDIVO. The time to onset for the Grade 3 event was 9.2 months and for the Grade 1 event was 3.2 months. Both patients received steroid replacement doses. The Grade 3 event resulted in permanent discontinuation and the other patient with the Grade 1 event discontinued due to progressive disease. Neither patient had complete resolution or resumed treatment with OPDIVO. Adrenal Insufficiency Adrenal insufficiency can occur with OPDIVO treatment. Monitor patients for signs and symptoms of adrenal insufficiency during and after treatment. Administer corticosteroids at a dose of 1 to 2 mg/kg/day prednisone equivalents for severe (Grade 3) or life-threatening (Grade 4) adrenal insufficiency. Withhold OPDIVO for moderate (Grade 2) and permanently discontinue OPDIVO for severe (Grade 3) or life-threatening (Grade 4) adrenal insufficiency [see Dosage and Administration (2.4) in full Prescribing Information].

Melanoma – In Trials 1, 5, and 7, adrenal insufficiency occurred in 1% (8/787) of patients: two patients with Grade 3, five patients with Grade 2, and one patient with Grade 1 adrenal insufficiency. The median time to onset was 3.6 months (range: 15 days to 5.0 months). Adrenal insufficiency led to withholding of OPDIVO in four patients (0.5%). One patient received high-dose corticosteroids (at least 40 mg prednisone equivalents) for 11 days.

NSCLC – In Trial 3, 0.3% (1/287) of OPDIVO-treated patients developed adrenal insufficiency.

RCC – In Trial 6, adrenal insufficiency occurred in 2.0% (8/406) of patients receiving OPDIVO (three with Grade 3, four with Grade 2, and one with Grade 1). The median time to onset was 5.8 months (range: 22 days to 20.9 months). OPDIVO was permanently discontinued in one patient. Dose delay occurred in five patients.

Hypothyroidism and Hyperthyroidism Thyroid disorders can occur with OPDIVO treatment. 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.

Melanoma – In Trials 1, 5, and 7, hypothyroidism or thyroiditis occurred in 9% (73/787) of patients: one patient with Grade 3, 37 patients with Grade 2, and 35 patients with Grade 1 hypothyroidism. The median time to onset was 2.8 months (range: 15 days to 13.8 months). Resolution occurred in 26 patients. Management of hypothyroidism included levothyroxine in 56 patients. Hyperthyroidism occurred in 4.4% (35/787) of patients receiving OPDIVO: one patient with Grade 3, 12 patients with Grade 2, and 22 patients with Grade 1 hyperthyroidism. The median time to onset was 1.4 months (range: 1 day to 13.4 months). Resolution occurred in 27 patients. Management of hyperthyroidism included methimazole (five patients), carbimazole (four patients), and propylthiouracil (two patients).

NSCLC – In Trial 3, Grade 1 or Grade 2 hypothyroidism, including thyroiditis, occurred in 7% (20/287) of patients receiving OPDIVO and 0% (0/268) of patients receiving docetaxel, while elevated thyroid stimulating hormone (TSH) occurred in 17% of patients receiving OPDIVO and 5% of patients receiving docetaxel.

The median time to onset of hypothyroidism/thyroiditis was 2.9 months (range: 1.4 to 11.8 months). All 20 patients received levothyroxine. Two patients received corticosteroids; one of whom received high-dose

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Withhold OPDIVO for moderate or severe (Grade 2 or 3) colitis. Permanently discontinue OPDIVO for life-threatening (Grade 4) or for recurrent colitis upon restarting OPDIVO [see Dosage and Administration (2.4) in full Prescribing Information].

Melanoma – In Trials 1, 5, and 7, immune-mediated hepatitis occurred in 2.3% (18/787) of patients receiving OPDIVO: three patients with Grade 4, 11 patients with Grade 3, and four patients with Grade 2 hepatitis.

The median time to onset was 3.7 months (range: 6 days to 9 months). Immune-mediated hepatitis led to permanent discontinuation of OPDIVO in five patients (0.6%) and withholding of OPDIVO in six patients (0.8%).

All 18 patients received high-dose corticosteroids (at least 40 mg prednisone equivalents) for a median duration of 28 days (range: 5 days to 2 months). One patient with Grade 3 hepatitis required the addition of mycophenolic acid to high-dose corticosteroids. Complete resolution (defined as improved to baseline with completion of corticosteroids) occurred in 13 patients. Among the four patients who resumed OPDIVO after resolution, one had recurrence of immune-mediated hepatitis.

NSCLC – In Trial 3, one patient developed immune-mediated hepatitis (0.3%) after 7.8 months of OPDIVO exposure. The event resolved following temporary withholding of OPDIVO and high-dose corticosteroid therapy. Immune-mediated hepatitis recurred following resumption of OPDIVO, resulting in permanent discontinuation.

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Immune-mediated colitis, defined as requiring use of corticosteroids with no clear alternate etiology, can occur with OPDIVO treatment. Monitor patients for signs and symptoms of 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.

Immune-mediated hepatitis, defined as requiring use of corticosteroids and no clear alternate etiology, can occur with OPDIVO treatment. Monitor patients for abnormal liver tests prior to and periodically during treatment. Administer corticosteroids at a dose of 0.5 to 1 mg/kg/day prednisone equivalents for moderate (Grade 2) transaminase elevations, with or without concomitant elevation in total bilirubin. Administer corticosteroids at a dose of 1 to 2 mg/kg/day prednisone equivalents for severe (Grade 3) or life-threatening (Grade 4) 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 (2.4) in full Prescribing Information].

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Melanoma – In Trials 1, 5, and 7, immune-mediated pneumonitis occurred in 1.8% (14/787) of patients receiving OPDIVO: two patients with Grade 3 and 12 patients with Grade 2 pneumonitis. The median time to onset of immune-mediated pneumonitis was 2.2 months (range: 25 days to 9.7 months). Grade 3 pneumonitis led to permanent discontinuation in one patient (0.1%), and Grade 2 pneumonitis led to withholding of OPDIVO in eight patients (1.0%). All 14 patients received high-dose corticosteroids (at least 40 mg prednisone equivalents per day) for a median duration of 18 days (range: 4 days to 1.2 months). Complete resolution (defined as complete resolution of symptoms with completion of corticosteroids) occurred in 11 patients.

None of the seven patients who resumed OPDIVO after resolution had recurrence of pneumonitis.

NSCLC – In Trial 3, pneumonitis, including interstitial lung disease, occurred in 3.4% (10/287) of patients receiving OPDIVO. Of these 10 patients, there were five patients with Grade 3, two patients with Grade 2, and three patients with Grade 1 immune-mediated pneumonitis. The median time to onset was 7.2 months (range: 2.7 to 13.1 months). All five patients with Grade 3 and one of two patients with Grade 2 pneumonitis received high-dose corticosteroids and permanently discontinued OPDIVO; two of these seven were documented radiographically to have complete resolution of pneumonitis. One patient with Grade 2 pneumonitis had OPDIVO temporarily withheld, received low-dose corticosteroids, experienced complete resolution and was retreated without recurrence of pneumonitis.

RCC – In Trial 6, pneumonitis, including interstitial lung disease, occurred in 5% (21/406) of patients receiving OPDIVO and 18% (73/397) patients receiving everolimus. Immune-mediated pneumonitis occurred in 4.4% (18/406) of patients receiving OPDIVO (one with Grade 4, four with Grade 3, twelve with Grade 2, and one with Grade 1). In two of the patients, pneumonitis occurred after they had received OPDIVO followed by everolimus. One patient with ongoing pneumonitis died due to disease progression. The median time to onset was 3.82 months (range: 2 days to 22.3 months). The median duration was 1.3 months (range: 0.3 to 9.8 months). OPDIVO was permanently discontinued in six patients. Dose delay occurred in nine patients. Seven patients had complete resolution. Among the six patients who resumed OPDIVO, three did not have recurrence of pneumonitis.

Immune-Mediated Colitis

RCC – In Trial 6, diarrhea or colitis occurred in 25% (100/406) of patients receiving OPDIVO (nivolumab) and 32% (126/397) of patients receiving everolimus. Immune-mediated diarrhea or colitis occurred in 3.2% (13/406) of patients receiving OPDIVO (five patients with Grade 3, seven with Grade 2, and one with Grade 1). The median time to onset was 4.8 months (range: 2 days to 15.6 months). The median duration was 1.3 months (range: 0.2 to 3.9 months). OPDIVO was permanently discontinued in four patients. Dose delay occurred in nine patients. Twelve patients had complete resolution. Among the nine patients who resumed OPDIVO after resolution, four had no recurrence of diarrhea or colitis.

Immune-Mediated Hepatitis

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Previously Treated Metastatic Melanoma The safety of OPDIVO as a single agent was evaluated in Trial 1, a randomized, open-label trial in which 370 patients with unresectable or metastatic melanoma received OPDIVO 3 mg/kg every 2 weeks (n=268) or investigator’s choice of chemotherapy (n=102), either dacarbazine 1000 mg/m2 every 3 weeks or the combination of carboplatin AUC 6 every 3 weeks plus paclitaxel 175 mg/m2 every 3 weeks [see Clinical Studies (14.1) in full Prescribing Information]. The median duration of exposure was 5.3 months (range: 1 day to 13.8+ months) in OPDIVO-treated patients and was 2 months (range: 1 day to 9.6+ months) in chemotherapy-treated patients. In this ongoing trial, 24% of patients received OPDIVO for greater than 6 months and 3% of patients received OPDIVO for greater than 1 year.

In Trial 1, patients had documented disease progression following treatment with ipilimumab and, if BRAF V600 mutation positive, a BRAF inhibitor. The trial excluded patients with autoimmune disease, prior ipilimumab-related Grade 4 adverse reactions (except for endocrinopathies) or Grade 3 ipilimumab-related adverse reactions that had not resolved or were inadequately controlled within 12 weeks of the initiating event, patients with a condition requiring chronic systemic treatment with corticosteroids (>10 mg daily prednisone equivalent) or other immunosuppressive medications, a positive test for hepatitis B or C, and a history of HIV. The study population characteristics in the OPDIVO group and the chemotherapy group were similar: 66% male, median age 59.5 years, 98% white, baseline Eastern Cooperative Oncology Group (ECOG) performance status 0 (59%) or 1 (41%), 74% with M1c stage disease, 73% with cutaneous melanoma, 11% with mucosal melanoma, 73% received two or more prior therapies for advanced or metastatic disease, and 18% had brain metastasis. There were more patients in the OPDIVO group with elevated LDH at baseline (51% vs. 38%).

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dose of 1 to 2 mg/kg/day prednisone equivalents for patients with immune-mediated encephalitis, followed by corticosteroid taper. Permanently discontinue OPDIVO (nivolumab) for immune-mediated encephalitis [see Dosage and Administration (2.4) in full Prescribing Information].

In Trial 3, fatal limbic encephalitis occurred in one patient (0.3%) receiving OPDIVO after 7.2 months of exposure. OPDIVO was discontinued; corticosteroids were administered.

Other Immune-Mediated Adverse Reactions Other clinically significant immune-mediated adverse reactions can occur with OPDIVO. Immune-mediated adverse reactions may occur after discontinuation of OPDIVO therapy. For any suspected immune-mediated adverse reactions, exclude other causes. Based on the severity of the adverse reaction, permanently discontinue or withhold OPDIVO, administer high-dose corticosteroids, and if appropriate, initiate hormonereplacement 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 (2.4) in full Prescribing Information].

In less than 1.0% of patients receiving OPDIVO as a single agent or in combination with ipilimumab in Trials 1, 3, 4, 5, 6, and 7 (n=1887), the following clinically significant, immune-mediated adverse reactions occurred: uveitis, pancreatitis, facial and abducens nerve paresis, demyelination, polymyalgia rheumatica, autoimmune neuropathy, Guillain-Barré syndrome, hypopituitarism, systemic inflammatory response syndrome, gastritis, duodenitis, and sarcoidosis.

Across clinical trials of OPDIVO as a single agent administered at doses of 3 mg/kg and 10 mg/kg, the following additional clinically significant, immune-mediated adverse reactions were identified: motor dysfunction, vasculitis, and myasthenic syndrome.

Infusion Reactions Severe infusion reactions have been reported in less than 1.0% of patients in clinical trials of OPDIVO. Discontinue OPDIVO in patients with severe or life-threatening infusion reactions. Interrupt or slow the rate of infusion in patients with mild or moderate infusion reactions.

Melanoma – In Trials 1, 5, and 7, infusion-related reactions occurred in 2.7% (21/787) of patients receiving OPDIVO: two patients with Grade 3, eight patients with Grade 2, and 11 patients with Grade 1 infusion-related reactions.

NSCLC – In Trial 3, Grade 2 infusion reactions requiring corticosteroids occurred in 1.0% (3/287) of patients receiving OPDIVO. RCC – In Trial 6, hypersensitivity/infusion-related reactions occurred in 6% (25/406) of patients receiving OPDIVO and 1.0% (4/397) of patients receiving everolimus. The median time to onset in the OPDIVO group was 1.4 months (range: 1 day to 27.6 months). Seven patients received corticosteroids on the day of administration. Two patients discontinued OPDIVO, one for a Grade 4 reaction and one for a Grade 2 event.

No events led to dose delay. Interruption of the infusion was required in ten patients.

Embryo-fetal 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 Endocrinopathies [see Warnings and Precautions] • Immune-Mediated Nephritis and Renal Dysfunction [see Warnings and Precautions] • Immune-Mediated Rash [see Warnings and Precautions] • Immune-Mediated Encephalitis [see Warnings and Precautions] • Other Immune-Mediated Adverse Reactions [see Warnings and Precautions] • Infusion 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 practice.

The data in the Warning and Precautions section reflect exposure to OPDIVO, as a single agent, for clinically significant adverse reactions in 1903 patients enrolled in Trials 1, 3, 5, 6, 7, a single arm trial in NSCLC (n=117), or an additional dose-finding study (n=306) administering OPDIVO as a single agent at doses of 0.1 to 10 mg/kg every 2 weeks [see Warnings and Precautions].

The data described below reflect exposure to OPDIVO as a single agent in Trials 1, 5, and 7, which are randomized, active-controlled trials conducted in patients with unresectable or metastatic melanoma. Also described below are single-agent OPDIVO data from Trial 3, which is a randomized trial in patients with metastatic non-squamous NSCLC, and Trial 6, which is a randomized trial in patients with advanced RCC. Unresectable or Metastatic Melanoma

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corticosteroids. Complete resolution of hypothyroidism occurred in one patient. OPDIVO (nivolumab) was temporarily withheld due to hypothyroidism/thyroiditis in three patients; no patients discontinued OPDIVO due to hypothyroidism/thyroiditis.

Grade 1 or Grade 2 hyperthyroidism occurred in 1.4% (4/287) of patients. The median time to onset was 2 months (range: 4.1 weeks to 2.8 months). Two of four patients received methimazole and one patient also received treatment with high-dose corticosteroids. All four patients experienced complete resolution.

RCC – In Trial 6, thyroid disease occurred in 11% (43/406) of patients on OPDIVO, including one Grade 3 event, and in 12/397 (3.0%) patients on everolimus. Hypothyroidism/thyroiditis occurred in 8% (33/406) of patients receiving OPDIVO (two patients with Grade 3, 17 patients with Grade 2, and 14 patients with Grade 1).

The median time to onset was 4.6 months (range: 15 days to 13.6 months). Twenty-eight of the 33 patients received levothyroxine. No events led to permanent discontinuation. Dose delay occurred in four patients. Four patients, including three patients that never required levothyroxine, had complete resolution and three of these four patients continued OPDIVO throughout the event.

Hyperthyroidism occurred in 2.5% (10/406) of patients receiving OPDIVO (five patients with Grade 2 and five patients with Grade 1). The median time to onset was 3 months (range: 24 days to 14.2 months). No events led to permanent discontinuation. Seven patients had complete resolution. Seven were treated through the event and two had a dose delay with no recurrence of hyperthyroidism when OPDIVO was resumed. Four patients developed hyperthyroidism followed by hypothyroidism.

Type 1 Diabetes Mellitus Type 1 diabetes mellitus can occur with OPDIVO treatment. Monitor for hyperglycemia. Administer insulin for type 1 diabetes and withhold OPDIVO in cases of severe (Grade 3) hyperglycemia until metabolic control is achieved. Permanently discontinue OPDIVO for life-threatening (Grade 4) hyperglycemia.

Melanoma – In Trials 1, 5, and 7, diabetes mellitus or diabetic ketoacidosis occurred in 0.8% (6/787) of patients: two patients with Grade 3, three patients with Grade 2, and one patient with Grade 1 events. The median time to onset was 3.6 months (range: 1.4 to 12 months). Four patients initiated insulin and four patients initiated oral hypoglycemic therapy.

RCC – In Trial 6, hyperglycemic adverse events occurred in 9% (37/406) of patients. Diabetes mellitus or diabetic ketoacidosis occurred in 1.5% (6/406) of patients receiving OPDIVO (three patients with Grade 3, two patients with Grade 2, and one patient with Grade 1). The median time to onset was 7.8 months (range: 2.3 to 21.8 months). Four patients received insulin. One patient was on corticosteroids prior to the event.

No events led to permanent discontinuation. Dose delay occurred in one patient. One patient had ongoing hyperglycemia when OPDIVO was resumed.

Immune-Mediated Nephritis and Renal Dysfunction Immune-mediated nephritis, defined as renal dysfunction or ≥Grade 2 increased creatinine, requirement for corticosteroids, and no clear alternate etiology, can occur with OPDIVO treatment. Monitor patients for elevated serum creatinine prior to and periodically during treatment. Withhold OPDIVO for moderate (Grade 2) or severe (Grade 3) increased serum creatinine, 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. Permanently discontinue OPDIVO and administer corticosteroids at a dose of 1 to 2 mg/kg/day prednisone equivalents followed by corticosteroid taper for life-threatening (Grade 4) increased serum creatinine [see Dosage and Administration (2.4) in full Prescribing Information and Adverse Reactions].

Melanoma – In Trials 1, 5, and 7, nephritis and renal dysfunction of any grade occurred in 5% (40/787) of patients. Immune-mediated nephritis and renal dysfunction occurred in 0.8% (6/787) of patients: four patients with Grade 3 and two patients with Grade 2 cases. The median time to onset of immune-mediated nephritis and renal dysfunction was 4.8 months (range: 1 to 7.5 months). Immune-mediated nephritis and renal dysfunction led to withholding of OPDIVO in four patients (0.5%). Six patients received high-dose corticosteroids (at least 40 mg prednisone equivalents) for a median duration of 16 days (range: 1 day to 9.9 months). Complete resolution (defined as improved to baseline with completion of corticosteroids) occurred in three patients.

Three patients resumed OPDIVO after resolution without recurrence of nephritis or renal dysfunction.

NSCLC – In Trial 3, immune-mediated renal dysfunction (Grade 2) occurred in 0.3% (1/287) of patients.

The time to onset in this patient was 1.5 months. The patient permanently discontinued OPDIVO, received high-dose corticosteroids, and experienced complete resolution.

RCC – In Trial 6, renal injury occurred in 7% (27/406) of patients on OPDIVO and 3.0% (12/397) of patients on everolimus, rather than laboratory creatinine. Immune-mediated nephritis and renal dysfunction occurred in 3.2% (13/406) of patients receiving OPDIVO (one with Grade 5, one with Grade 4, five with Grade 3, and six with Grade 2). The median time to onset was 5.4 months (range: 1.1 to 12.3 months). Median duration was 1.4 months (range: 0.1 to 18 months). OPDIVO was permanently discontinued in five patients. Dose delay occurred in eight patients. Five patients had complete resolution. Two patients resumed OPDIVO after complete resolution and had no recurrence of nephritis.

Immune-Mediated Rash Immune-mediated rash can occur with OPDIVO treatment. Severe rash (including rare cases of fatal toxic epidermal necrolysis) occurred in the clinical program of OPDIVO. Monitor patients for rash. Administer corticosteroids at a dose of 1 to 2 mg/kg/day prednisone equivalents for severe (Grade 3) or life-threatening (Grade 4) rash. Withhold OPDIVO for severe (Grade 3) rash and permanently discontinue OPDIVO for life-threatening (Grade 4) rash [see Dosage and Administration (2.4) in full Prescribing Information].

Melanoma – In Trials 1, 5, and 7, immune-mediated rash occurred in 9% (72/787) of patients: seven patients with Grade 3, 15 patients with Grade 2, and 50 patients with Grade 1 rash. The median time to onset was 2.8 months (range: 3 days to 13.8 months). Immune-mediated rash led to permanent discontinuation of OPDIVO in one patient (0.1%) and withholding of OPDIVO in six patients (0.8%). Seven patients received high-dose corticosteroids (at least 40 mg prednisone equivalents) for a median duration of 15 days (range: 4 days to 1.0 months). Complete resolution (defined as complete resolution of symptoms with completion of corticosteroids) occurred in 32 patients (44%). Among the 35 patients who resumed OPDIVO after resolution, one had recurrence.

NSCLC – In Trial 3, immune-mediated rash occurred in 6% (17/287) of patients receiving OPDIVO. Grade 3 rash developed in four patients (1.4%), of whom one discontinued treatment.

RCC – In Trial 6, rash occurred in 28% (112/406) of patients on OPDIVO and 36% (143/397) of patients on everolimus. Immune-mediated rash, defined as a rash treated with systemic or topical corticosteroids, occurred in 7% (30/406) of patients receiving OPDIVO (four with Grade 3, seven with Grade 2, and nineteen with Grade 1). The median time to onset was 3.2 months (range: 2 days to 25.8 months). Median duration was 2.6 months (range: 0.3 to 9.4 months). Four patients received oral and 26 received topical corticosteroids.

Two patients permanently discontinued and dose delay occurred in two patients. Seventeen patients had complete resolution. Thirteen patients who continued on OPDIVO or experienced a dose delay had no recurrence of rash.

Immune-Mediated Encephalitis Immune-mediated encephalitis can occur with OPDIVO treatment. Withhold OPDIVO in patients with newonset moderate to severe neurologic signs or symptoms and evaluate to rule out infectious or other causes of moderate to severe neurologic deterioration. Evaluation may include, but not be limited to, consultation with a neurologist, brain MRI, and lumbar puncture. If other etiologies are ruled out, administer corticosteroids at a

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OPDIVO (nivolumab) was discontinued for adverse reactions in 9% of patients. Twenty-six percent of patients receiving OPDIVO had a drug delay for an adverse reaction. Serious adverse reactions occurred in 41% of patients receiving OPDIVO. Grade 3 and 4 adverse reactions occurred in 42% of patients receiving OPDIVO. The most frequent Grade 3 and 4 adverse reactions reported in 2% to less than 5% of patients receiving OPDIVO were abdominal pain, hyponatremia, increased aspartate aminotransferase, and increased lipase.

Table 1 summarizes the adverse reactions that occurred in at least 10% of OPDIVO-treated patients in Trial 1.

The most common adverse reaction (reported in at least 20% of patients) was rash.

Table 1:

Selected Adverse Reactions Occurring in ≥10% of OPDIVO-Treated Patients and at a Higher Incidence than in the Chemotherapy Arm (Between Arm Difference of ≥5% [All Grades] or ≥2% [Grades 3-4]) (Trial 1) OPDIVO (n=268)

Adverse Reaction

All Grades

Table 3:

OPDIVO (n=206)

All Grades

Grades 3-4

All Grades

Adverse Reaction

Grades 3-4

All Grades

Grades 3-4

Percentage (%) of Patients

Fatigue

49

1.9

39

3.4

Edemaa

12

1.5

4.9

0

32

2.9

25

2.4

Musculoskeletal and Connective Tissue Disorders

Percentage (%) of Patients

Musculoskeletal painb

Skin and Subcutaneous Tissue Disorders

Dacarbazine (n=205)

General Disorders and Administration Site Conditions

Chemotherapy (n=102) Grades 3-4

Selected Adverse Reactions Occurring in ≥10% of OPDIVO (nivolumab)-Treated Patients and at a Higher Incidence than in the Dacarbazine Arm (Between Arm Difference of ≥5% [All Grades] or ≥2% [Grades 3-4]) (Trial 5)

Skin and Subcutaneous Tissue Disorders

Rasha

21

0.4

7

0

Rashc

28

1.5

12

0

Pruritus

19

0

3.9

0

Pruritus

23

0.5

12

0

Erythema

10

0

2.9

0

Vitiligo

11

0

0.5

0

17

0

6

0

Respiratory, Thoracic, and Mediastinal Disorders Cough

17

0

6

0

11

0

2.0

0

10

0

5

0

Infections and Infestations Upper respiratory tract infectionb General Disorders and Administration Site Conditions Peripheral edema

Toxicity was graded per NCI CTCAE v4. a Rash is a composite term which includes maculopapular rash, rash erythematous, rash pruritic, rash follicular, rash macular, rash papular, rash pustular, rash vesicular, and dermatitis acneiform. b Upper respiratory tract infection is a composite term which includes rhinitis, pharyngitis, and nasopharyngitis.

Other clinically important adverse reactions in less than 10% of patients treated with OPDIVO in Trial 1 were ventricular arrhythmia, iridocyclitis, infusion-related reactions, increased amylase, increased lipase, dizziness, peripheral and sensory neuropathy, exfoliative dermatitis, erythema multiforme, vitiligo, and psoriasis.

Table 2:

Infections and Infestations Upper respiratory tract infectiond

Toxicity was graded per NCI CTCAE v4. a Includes periorbital edema, face edema, generalized edema, gravitational edema, localized edema, peripheral edema, pulmonary edema, and lymphedema. b Includes back pain, bone pain, musculoskeletal chest pain, musculoskeletal discomfort, myalgia, neck pain, pain in extremity, pain in jaw, and spinal pain. c Includes maculopapular rash, rash erythematous, rash pruritic, rash follicular, rash macular, rash papular, rash pustular, rash vesicular, dermatitis, dermatitis allergic, dermatitis exfoliative, dermatitis acneiform, drug eruption, and skin reaction. d Includes rhinitis, viral rhinitis, pharyngitis, and nasopharyngitis.

Other clinically important adverse reactions in less than 10% of patients treated with OPDIVO in Trial 5 were: Nervous System Disorders: peripheral neuropathy Table 4:

Test

Chemotherapy

OPDIVO

Dacarbazine

All Grades

Grades 3-4

All Grades

Grades 3-4

All Grades

Grades 3-4

All Grades

Grades 3-4

Increased ALT

25

3.0

19

0.5

Increased AST

28

2.4

12

1.0

Increased AST

24

3.6

19

0.5

Increased alkaline phosphatase

22

2.4

13

1.1

Increased alkaline phosphatase

21

2.6

14

1.6

Hyponatremia

25

5

18

1.1

Increased bilirubin

13

3.1

6

0

Increased ALT

16

1.6

5

0

Hyperkalemia

15

2.0

6

0

a

Each test incidence is based on the number of patients who had both baseline and at least one on-study laboratory measurement available: OPDIVO group (range: 252 to 256 patients) and chemotherapy group (range: 94 to 96 patients).

Previously Untreated Metastatic Melanoma Trial 5 The safety of OPDIVO was also evaluated in Trial 5, a randomized, double-blind, active-controlled trial in which 411 previously untreated patients with BRAF V600 wild-type unresectable or metastatic melanoma received OPDIVO 3 mg/kg every 2 weeks (n=206) or dacarbazine 1000 mg/m2 every 3 weeks (n=205) [see Clinical Studies (14.1) in full Prescribing Information]. The median duration of exposure was 6.5 months (range: 1 day to 16.6 months) in OPDIVO-treated patients. In this trial, 47% of patients received OPDIVO for greater than 6 months and 12% of patients received OPDIVO for greater than 1 year.

The trial excluded patients with autoimmune disease and patients requiring chronic systemic treatment with corticosteroids (>10 mg daily prednisone equivalent) or other immunosuppressive medications.

The study population characteristics in the OPDIVO group and dacarbazine group were generally similar: 59% male, median age 65 years, 99.5% white, 61% with M1c stage disease, 74% with cutaneous melanoma, 11% with mucosal melanoma, 4% with brain metastasis, and 37% with elevated LDH at baseline. There were more patients in the OPDIVO group with ECOG performance status 0 (71% vs 59%).

Adverse reactions led to permanent discontinuation of OPDIVO in 7% of patients and dose interruption in 26% of patients; no single type of adverse reaction accounted for the majority of OPDIVO discontinuations. Serious adverse reactions occurred in 36% of patients receiving OPDIVO. Grade 3 and 4 adverse reactions occurred in 41% of patients receiving OPDIVO. The most frequent Grade 3 and 4 adverse reactions reported in at least 2% of patients receiving OPDIVO were gamma-glutamyltransferase increase (3.9%) and diarrhea (3.4%).

Table 3 summarizes selected adverse reactions that occurred in at least 10% of OPDIVO-treated patients.

The most common adverse reactions (reported in at least 20% of patients and at a higher incidence than in the dacarbazine arm) were fatigue, musculoskeletal pain, rash, and pruritus.

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a

Each test incidence is based on the number of patients who had both baseline and at least one on-study laboratory measurement available: OPDIVO group (range: 194 to 197 patients) and dacarbazine group (range: 186 to 193 patients).

Trial 7 The safety of OPDIVO, administered with ipilimumab or as a single agent, was evaluated in Trial 7 [see Clinical Studies (14.1) in full Prescribing Information], a randomized (1:1:1), a double-blind trial in which 937 patients with previously untreated, unresectable or metastatic melanoma received: • OPDIVO 1 mg/kg with ipilimumab 3 mg/kg every 3 weeks for 4 doses followed by OPDIVO 3 mg/kg as a single agent every 2 weeks (OPDIVO plus ipilimumab arm; n=313), • OPDIVO 3 mg/kg every 2 weeks (OPDIVO arm; n=313), or • Ipilimumab 3 mg/kg every 3 weeks for up to 4 doses (ipilimumab arm; n=311).

The median duration of exposure to OPDIVO was 2.8 months (range: 1 day to 18.8 months) for the OPDIVO plus ipilimumab arm and 6.6 months (range: 1 day to 17.3 months) for the OPDIVO arm. In the OPDIVO plus ipilimumab arm, 39% were exposed to OPDIVO for ≥6 months and 24% exposed for >1 year. In the OPDIVO arm, 53% were exposed for ≥6 months and 32% for >1 year.

Trial 7 excluded patients with autoimmune disease, a medical condition requiring systemic treatment with corticosteroids (more than 10 mg daily prednisone equivalent) or other immunosuppressive medication within 14 days of the start of study therapy, a positive test result for hepatitis B or C, or a history of HIV. The study population characteristics were: 65% male, median age 61 years, 97% White, baseline ECOG performance status 0 (73%) or 1 (27%), 93% with AJCC Stage IV disease, 58% with M1c stage disease; 36% with elevated LDH at baseline, 4% with a history of brain metastasis, and 22% had received adjuvant therapy.

In Trial 7, serious adverse reactions (73% and 37%), adverse reactions leading to permanent discontinuation (43% and 14%) or to dosing delays (55% and 28%), and Grade 3 or 4 adverse reactions (72% and 44%) all occurred more frequently in the OPDIVO plus ipilimumab arm relative to the OPDIVO arm.

The most frequent (≥10%) serious adverse reactions in the OPDIVO plus ipilimumab arm and the OPDIVO arm, respectively, were diarrhea (13% and 2.6%), colitis (10% and 1.6%), and pyrexia (10% and 0.6%). The most frequent adverse reactions leading to discontinuation of both drugs in the OPDIVO plus ipilimumab arm and of OPDIVO in the OPDIVO arm, respectively, were diarrhea (8% and 1.9%), colitis (8% and 0.6%), increased ALT (4.8% and 1.3%), increased AST (4.5% and 0.6%), and pneumonitis (1.9% and 0.3%). The most common (≥20%) adverse reactions in the OPDIVO plus ipilimumab arm were fatigue, rash, diarrhea, nausea, pyrexia, vomiting, and dyspnea. The most common (≥20%) adverse reactions in the OPDIVO arm were fatigue, rash, diarrhea, and nausea.

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OPDIVO

Test

Percentage of Patients with Worsening Laboratory Test from Baselinea

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Percentage of Patients with Worsening Laboratory Test from Baselinea

Selected Laboratory Abnormalities Worsening from Baseline Occurring in ≥10% of OPDIVO-Treated Patients and at a Higher Incidence than in the Dacarbazine Arm (Between Arm Difference of ≥5% [All Grades] or ≥2% [Grades 3-4]) (Trial 5)

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Selected Laboratory Abnormalities Worsening from Baseline Occurring in ≥10% of OPDIVO-Treated Patients and at a Higher Incidence than in the Chemotherapy Arm (Between Arm Difference of ≥5% [All Grades] or ≥2% [Grades 3-4]) (Trial 1)

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In Trial 7, selected adverse reactions occurring in at least 10% of patients treated with OPDIVO (nivolumab) (n=313) as a single agent and at a higher incidence vs patients treated with ipilimumab (n=311) as a single agent (between-arm difference of ≥5% [All Grades] or ≥2% [Grade 3-4]) were fatiguea: 53% (All Grades), 1.9% (Grade 3-4) vs 50% (All Grades), 3.9% (Grade 3-4); pyrexia: 14% (All Grades), 0% (Grade 3-4) vs 17% (All Grades), 0.6% (Grade 3-4); rashb: 40% (All Grades), 1.6% (Grade 3-4) vs 42% (All Grades), 3.9% (Grade 3-4); diarrhea: 31% (All Grades), 3.8% (Grade 3-4) vs 46% (All Grades), 8% (Grade 3-4); nausea: 28% (All Grades), 0.6% (Grade 3-4) vs 29% (All Grades), 1.9% (Grade 3-4); vomiting: 17% (All Grades), 1.0% (Grade 3-4) vs 16% (All Grades), 1.6% (Grade 3-4); dyspnea: 12% (All Grades), 1.3% (Grade 3-4) vs 13% (All Grades), 0.6% (Grade 3-4).

Toxicity was graded per NCI CTCAE v4. a Fatigue is a composite term which includes asthenia and fatigue. b Rash is a composite term which includes rash pustular, dermatitis, dermatitis acneiform, dermatitis allergic, dermatitis atopic, dermatitis bullous, dermatitis exfoliative, dermatitis psoriasiform, drug eruption, erythema, exfoliative rash, rash erythematous, rash generalized, rash macular, rash maculopapular, rash morbilliform, rash papular, rash papulosquamous, rash pruritic, and seborrheic dermatitis.

Other clinically important adverse reactions in less than 10% of patients treated with OPDIVO as a single agent in Trial 7 were stomatitis, intestinal perforation, vitiligo; myopathy, Sjogren’s syndrome, spondyloarthropathy, neuritis, and peroneal nerve palsy.

In Trial 7, selected laboratory abnormalities worsening from baselinea in at least 20% of patients treated with OPDIVO with ipilimumab or single-agent OPDIVO and at a higher incidence vs patients treated with ipilimumab alone (between-arm difference of ≥5% [All Grades] or ≥2% [Grade 3-4]) were increased ALT: 53% (All Grades), 15% (Grade 3-4) or 23% (All Grades), 3.0% (Grade 3-4) vs 28% (All Grades), 2.7% (Grade 3-4); increased AST: 47% (All Grades), 13% (Grade 3-4) or 27% (All Grades), 3.7% (Grade 3-4) vs 27% (All Grades), 1.7% (Grade 3-4); hyponatremia: 42% (All Grades), 9% (Grade 3-4) or 20% (All Grades), 3.3% (Grade 3-4) vs 25% (All Grades), 7% (Grade 3-4); increased lipase: 41% (All Grades), 20% (Grade 3-4) or 29% (All Grades), 9% (Grade 3-4) vs 23% (All Grades), 7% (Grade 3-4); increased alkaline phosphatase: 40% (All Grades), 6% (Grade 3-4) or 24% (All Grades), 2.0% (Grade 3-4) vs 22% (All Grades), 2.0% (Grade 3-4); hypocalcemia: 29% (All Grades), 1.1% (Grade 3-4) or 13% (All Grades), 0.7% (Grade 3-4) vs 21% (All Grades), 0.7% (Grade 3-4); increased amylase: 25% (All Grades), 9.1% (Grade 3-4) or 15% (All Grades), 1.9% (Grade 3-4) vs 14% (All Grades), 1.6% (Grade 3-4); increased creatinine: 23% (All Grades), 2.7% (Grade 3-4) or 16% (All Grades), 0.3% (Grade 3-4) vs 16% (All Grades), 1.3% (Grade 3-4); anemia: 50% (All Grades), 2.7% (Grade 3-4) or 39% (All Grades), 2.6% (Grade 3-4) vs 40% (All Grades), 6% (Grade 3-4); lymphopenia: 35% (All Grades), 4.8% (Grade 3-4) or 39% (All Grades), 4.3% (Grade 3-4) vs 27% (All Grades), 3.4% (Grade 3-4). a Each test incidence is based on the number of patients who had both baseline and at least one on-study laboratory measurement available: OPDIVO plus ipilimumab (range: 241 to 297 patients); OPDIVO (range: 260 to 306); ipilimumab (range: 253 to 304 patients).

Docetaxel (n=268)

OPDIVO (n=287) Adverse Reaction

All Grades

Grades 3-4

All Grades

Grades 3-4

Percentage (%) of Patients Respiratory, Thoracic, and Mediastinal Disorders Cough

30

0.3

25

0

Metabolism and Nutrition Disorders Decreased appetite

29

1.7

22

1.5

23

0.7

17

0.7

Gastrointestinal Disorders Constipation Skin and Subcutaneous Tissue Disorders Pruritus

11

0

1.9

0

Toxicity was graded per NCI CTCAE v4.

Other clinically important adverse reactions observed in patients treated with OPDIVO and which occurred at a similar incidence in docetaxel-treated patients and not listed elsewhere in section 6 include: fatigue/asthenia (49% Grade 1-4, 6% Grade 3-4), musculoskeletal pain (36%), pleural effusion (5.6%), pulmonary embolism (4.2%), urticaria (1.4%), and polymyalgia rheumatica (0.3%).

172004996.indd 7

OPDIVO

Test All Grades

Docetaxel Grades 3-4

All Grades

Grades 3-4

Chemistry

a

b

Hyponatremia

35

6

32

2.7

Increased AST

28

2.8

14

0.4

Increased alkaline phosphatase

27

1.1

18

0.4

Increased ALT

23

2.4

15

0.4

Increased creatinine

18

0

13

0.4

Increased TSHb

17

N/A

5

N/A

Each test incidence is based on the number of patients who had both baseline and at least one on-study laboratory measurement available: OPDIVO group (range: 280 to 287 patients) and docetaxel group (range: 252 to 262 patients); TSH: OPDIVO group n=209 and docetaxel group n=207.

Not graded per NCI CTCAE v4.0.

Renal Cell Carcinoma The safety of OPDIVO was evaluated in Trial 6, a randomized open-label trial in which 803 patients with advanced RCC who had experienced disease progression during or after at least one anti-angiogenic treatment regimens received OPDIVO 3 mg/kg every 2 weeks (n=406) or everolimus 10 mg daily (n=397) [see Clinical Studies (14.3) in Full Prescribing Information]. The median duration of treatment was 5.5 months (range: 1 day to 29.6+ months) in OPDIVO-treated patients and 3.7 months (range: 6 days to 25.7+ months) in everolimus-treated patients.

Study therapy was discontinued for adverse reactions in 16% of OPDIVO patients and 19% of everolimus patients. Forty-four percent (44%) of patients receiving OPDIVO had a drug delay for an adverse reaction.

Serious adverse reactions occurred in 47% of patients receiving OPDIVO. The most frequent serious adverse reactions reported in at least 2% of patients were acute kidney injury, pleural effusion, pneumonia, diarrhea, and hypercalcemia.

Rate of death on treatment or within 30 days of the last dose of study drug was 4.7% on the OPDIVO arm versus 8.6% on the everolimus arm.

The most common adverse reactions (reported in at least 20% of patients) were asthenic conditions, cough, nausea, rash, dyspnea, diarrhea, constipation, decreased appetite, back pain, and arthralgia. Table 7 summarizes adverse reactions that occurred in greater than 15% of OPDIVO treated patients.

Table 7:

Grade 1-4 Adverse Reactions in >15% of Patients Receiving OPDIVO (Trial 6) OPDIVO (n=406)

Everolimus (n=397)

Percentage (%) of Patients

Any Adverse Reactions

Grades 1-4

Grades 3-4

Grades 1-4

Grades 3-4

98

56

96

62

General Disorders and Administration Site Conditions Asthenic conditionsa

56

6

57

7

Pyrexia

17

0.7

20

0.8

Respiratory, Thoracic and Mediastinal Disorders Cough/productive cough

34

0

38

0.5

Dyspnea/exertional dyspnea

27

3.0

31

2.0

Upper respiratory infectionb

18

0

11

0

Gastrointestinal Disorders Nausea

28

0.5

29

1

Diarrheac

25

2.2

32

1.8

Constipation

23

0.5

18

0.5

Vomiting

16

0.5

16

0.5

Rashd

28

1.5

36

1.0

Pruritus/generalized pruritus

19

0

14

0

23

1.2

30

1.5

Arthralgia

20

1.0

14

0.5

Back pain

21

3.4

16

2.8

Skin and Subcutaneous Tissue Disorders

Metabolism and Nutrition Disorders Decreased appetite Musculoskeletal and Connective Tissue Disorders

Toxicity was graded per NCI CTCAE v4. a Asthenic conditions covering PTs asthenia, decreased activity, fatigue, and malaise. b Includes nasopharyngitis, pharyngitis, rhinitis, and viral URI. c Includes colitis, enterocolitis, and gastroenteritis. d Includes dermatitis, dermatitis acneiform, rash erythematous, rash generalized, rash macular, rash maculopapular, rash papular, rash pruritic, erythema multiforme, and erythema.

Other clinically important adverse reactions in Trial 6 were: General Disorders and Administration Site Conditions: peripheral edema/edema

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Selected Adverse Reactions Occurring in ≥10% of OPDIVO-Treated Patients and at a Higher Incidence than Docetaxel (Between Arm Difference of ≥5% [All Grades] or ≥2% [Grades 3-4]) (Trial 3)

Percentage of Patients with Worsening Laboratory Test from Baselinea

B:10.75”

Table 5:

Selected Laboratory Abnormalities Worsening from Baseline Occurring in ≥10% of OPDIVO (nivolumab)-Treated Patients for all NCI CTCAE Grades and at a Higher Incidence than Docetaxel (Between Arm Difference of ≥5% [All Grades] or ≥2% [Grades 3-4]) (Trial 3)

S:10”

Metastatic Non-Squamous Non-Small Cell Lung Cancer The safety of OPDIVO was evaluated in Trial 3, a randomized, open-label, multicenter trial in patients with metastatic non-squamous NSCLC and progression on or after one prior platinum doublet-based chemotherapy regimen [see Clinical Studies (14.2) in full Prescribing Information]. Patients received 3 mg/kg of OPDIVO (n=287) administered intravenously over 60 minutes every 2 weeks or docetaxel (n=268) administered intravenously at 75 mg/m2 every 3 weeks. The median duration of therapy was 2.6 months (range: 0 to 24.0+ months) in OPDIVO-treated patients and was 2.3 months (range: 0 to 15.9 months) in docetaxel-treated patients. In this trial, 30% of patients received OPDIVO for greater than 6 months and 20% of patients received OPDIVO for greater than 1 year.

Trial 3 excluded patients with active autoimmune disease, medical conditions requiring systemic immunosuppression, or with symptomatic interstitial lung disease.

The median age of all randomized patients was 62 years (range: 21 to 85); 37% of patients in the OPDIVO group were ≥65 years of age and 47% of patients in the docetaxel group were ≥65 years of age, 55% were male, and 92% were white. Twelve percent of patients had brain metastases and ECOG performance status was 0 (31%) or 1 (69%).

OPDIVO was discontinued in 13% of patients, and was delayed in 29% of patients for an adverse reaction.

Serious adverse reactions occurred in 47% of patients receiving OPDIVO. The most frequent serious adverse reactions reported in at least 2% of patients receiving OPDIVO were pneumonia, pulmonary embolism, dyspnea, pleural effusion, and respiratory failure. In the OPDIVO arm, seven deaths were due to infection including one case of Pneumocystis jirovecii pneumonia, four were due to pulmonary embolism, and one death was due to limbic encephalitis.

The most common adverse reactions (reported in at least 20% of patients) were fatigue, musculoskeletal pain, cough, decreased appetite, and constipation. Table 5 summarizes selected adverse reactions occurring more frequently in at least 10% of OPDIVO-treated patients.

Table 6:

B:8” T:7.75” S:7.25”

Gastrointestinal Disorders: abdominal pain/discomfort Musculoskeletal and Connective Tissue Disorders: extremity pain, musculoskeletal pain Nervous System Disorders: headache/migraine, peripheral neuropathy Investigations: weight decreased Skin Disorders: Palmar-plantar erythrodysesthesia The most common laboratory abnormalities which have worsened compared to baseline in ≥30% of patients include increased creatinine, lymphopenia, anemia, increased AST, increased alkaline phosphatase, hyponatremia, elevated triglycerides, and hyperkalemia. Table 8 summarizes the laboratory abnormalities that occurred in greater than 15% of OPDIVO (nivolumab)-treated patients.

Table 8:

Grade 1-4 Laboratory Values Worsening from Baseline Occurring in >15% of Patients on OPDIVO (Trial 6) Percentage of Patients with Worsening Laboratory Test from Baselinea OPDIVO

Test

Everolimus

Grades 1-4

Grades 3-4

Grades 1-4

Grades 3-4

Lymphopenia

42

6

53

11

Anemia

39

8

69

16

Increased creatinine

42

2.0

45

1.6

Increased AST

33

2.8

39

1.6

Increased alkaline phosphatase

32

2.3

32

0.8

Hyponatremia

32

7

26

6

Hyperkalemia

30

4.0

20

2.1

Hypocalcemia

23

0.9

26

1.3

Increased ALT

22

3.2

31

0.8

Hypercalcemia

19

3.2

6

0.3

Increased triglycerides

32

1.5

67

11

Increased cholesterol

21

0.3

55

1.4

Hematology

Chemistry

Lipids

a

Each test incidence is based on the number of patients who had both baseline and at least one on-study laboratory measurement available: OPDIVO group (range: 259 to 401 patients) and everolimus group (range: 257 to 376 patients).

Of 1037 patients who were treated with OPDIVO as a single agent 3 mg/kg every 2 weeks and evaluable for the presence of anti-nivolumab antibodies, 128 patients (12.3%) tested positive for treatment-emergent antinivolumab antibodies by an electrochemiluminescent (ECL) assay and nine patients (0.9%) had neutralizing antibodies against nivolumab. There was no evidence of altered pharmacokinetic profile or increased incidence of infusion reactions with anti-nivolumab antibody development.

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 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 Pregnancy 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. 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.

PATIENT COUNSELING INFORMATION 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 withholding 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].

• Endocrinopathies: Advise patients to contact their healthcare provider immediately for signs or symptoms of hypophysitis, adrenal insufficiency, hypothyroidism, hyperthyroidism, and diabetes mellitus [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].

• Rash: Advise patients to contact their healthcare provider immediately for rash [see Warnings and Precautions].

• Encephalitis: Advise patients to contact their healthcare provider immediately for neurological signs or symptoms of encephalitis [see Warnings and Precautions].

• Infusion Reactions: Advise patients of the potential risk of infusion reaction [see Warnings and Precautions].

• Females of Reproductive Potential: 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].

• Lactation: Advise women not to breastfeed while taking OPDIVO [see Use in Specific Populations].

Manufactured by: Bristol-Myers Squibb Company Princeton, NJ 08543 USA U.S. License No. 1713 1363787A0

Revised: January 2016 1506US1600098-14-01

Data 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.

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T:10.5”

As with all therapeutic proteins, there is a potential for immunogenicity.

OVERDOSAGE There is no information on overdosage with OPDIVO.

B:10.75”

Immunogenicity

Lactation Risk Summary It is not known whether OPDIVO (nivolumab) 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 Of the 272 patients randomized to OPDIVO in Trial 1, 35% were 65 years or older and 15% were 75 years or older. Of the 292 patients randomized to OPDIVO in Trial 3, 37% were 65 years or older and 7% were 75 years or older. Of the 210 patients randomized to OPDIVO in Trial 5, 50% were 65 years or older and 13% were 75 years or older. Of the 406 patients treated with OPDIVO in Trial 6, 37% of patients were 65 years or older and 8% were 75 years or older. Of the 316 patients randomized to OPDIVO in Trial 7, 37% were 65 years or older and 12% were 75 years or older. No overall differences in safety or efficacy were reported between elderly patients and younger patients.

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].

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

S:10”

In addition, among patients with TSH less than ULN at baseline, a greater proportion of patients experienced a treatment-emergent elevation of TSH greater than ULN in the OPDIVO group compared to the everolimus group (26% and 14%, respectively).

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.

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Stereotactic radiosurgery (SRS) with concurrent immunotherapy appears to be effective for the treatment of melanoma brain metastases, according to a study published in Cancer.

Researchers enrolled 75 patients with 566 lesions, 55% (313) of which were treated with concurrent immunotherapy, defined as within 4 weeks of radiotherapy; 45% (253) were not treated with concurrent therapy. Treatment effect was determined with the Wilcoxon rank-sum test at 1.5, 3, and 6 months post-SRS treatment.

Median percent reduction in lesion volume was significantly improved for patients treated with RSS and immunotherapy concurrently. At 1.5 months, lesions of patients in the “concurrent” cohort were reduced a median of 63.1%, versus 43.2% in the “nonconcurrent” cohort (P < .0001.) At 3 and 6 months, concurrent versus nonconcurrent reductions were 83.0% versus 52.8% (P < .0001) and 94.9% versus 66.2% (P < .0001), respectively.

Results were similarly significant for patients who received anti–programmed cell death protein 1 (anti-PD-1) therapy rather than anti–cytotoxic T-lymphocyte-associated protein 4 (anti–CTLA-4); at 1.5, 3, and 6 months, the anti-PD-1 versus anti-CTLA-4-related reductions were 71.1% versus 48.2%, (P < .0001), 89.3% versus 66.2% (P < .0001), and 95.1% versus 75.9% (P = .0004), respectively.

The authors concluded both that immunotherapy within 4 weeks of SRS promotes better lesion reduction for patients with melanoma brain metastases, and that anti-PD-1 therapy is superior to anti-CTLA-4 after SRS.

Nivolumab Followed by Ipilimumab Sequence Beneficial in Melanoma Treatment Nivolumab followed by ipilimumab may be more clinically beneficial in contrast with the reverse sequence for treatment in patients with advanced melanoma, according to a study published in The Lancet Oncology.

Researchers led by Jeffrey Weber, MD, of the New York University Langone Medical Center, conducted a randomized, open-label, phase 2 study of 140 patients who were

randomly assigned to induction with intravenous nivolumab, followed by a planned switch to intravenous ipilimumab or the reverse sequence.

Primary endpoint was treatment-related grade 3 to 5 adverse events until week 25; secondary endpoints were “the proportion of patients who achieved a response at week 25 and disease progression at weeks 13 and 25.”

The researchers found that the proportion of patients with a response at week 25 was higher with nivolumab followed by ipilimumab than with the reverse sequence. Progression was found in 26 patients in the nivolumab followed by ipilimumab group, in contrast with 43 in the reverse sequence group at week 13; at week 25, progression was found in 26 patients in the former group and 42 in the latter.

The frequencies of treatment-related grade 3 to 5 adverse events up to week 25 were similar between the nivolumab followed by ipilimumab group and the reverse sequence group.

With a median follow-up of 19.8 months, median overall survival was not reached in the nivolumab followed by ipilimumab group. Median overall survival was found to be 16.9 months in the ipilimumab followed by nivolumab group, with a median follow-up of 14.7 months.

It was found that a higher proportion of patients in the nivolumab followed by ipilumumab group achieved 12-month overall survival.

Disease-Free Status Is Achieved by Combining Immunotherapy Treatments in Patient With Metastatic Melanoma A patient with refractory metastatic melanoma was successfully treated with a novel combination of 2 different types of immunotherapy.

Melanoma is the most deadly form of skin cancer, accounting for the overwhelming majority of deaths from skin cancer once it metastasizes to other tissues in the body. Frequently, treatment of metastatic melanoma involves enhancing the immune system’s ability to destroy the tumor.

Isolation of a pure population of the patient’s own T cells, a type of immune system cell, followed by administration of that population back to the patient can allow the T cells to target the disease. Another immunotherapy option is treatment with ipilimumab, an antibody that can activate the patient’s existing T cells by inhibiting the function of a protein called CTLA4.

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Immunotherapy Timing and Variety Important Following Radiotherapy for Patients With Melanoma Brain Metastases

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Psychosocial, Demographic Factors Related to Worry in Patients With Melanoma Identified Researchers have identified a number of psychosocial, clinical, and demographic factors that may contribute to the experience of worry in patients with melanoma.

The factors included age and occupation, according to results recently published in Melanoma Research.

Researchers led by Zoe Rogers, MSc, of the University of Leeds in the United Kingdom, conducted the questionnaire-based Leeds Melanoma Cohort study of a population-ascertained cohort of 2184 patients who had been

diagnosed with cutaneous melanoma in the 3 to 6 months prior to initiation.

They used Pearson x2-tests and odds ratios as well as 95% confidence intervals in order to test pairwise association between categorical variables and assess the effects of predictor variables on the outcome measure of melanoma-related worry.

The study found that a total of 520 patients felt worried about their future with respect to melanoma while 1568 felt confident. Worry was found to be less likely in men with partners compared to women with partners, and increasing age was protective against worry.

Worry was found to be more likely for patients with stage 3/4 melanoma, patients with melanoma arising in sun-protected sites or no occupation, those who reported insufficient emotional support from health care providers, those who had perceived financial hardship, and those with over 3 previous negative life events.

“The study supports the view that individuals with melanoma who worry most about the future may do so because of the cumulative effects of stress (both disease and non-cancer related) and a perceived lack of support from health care teams and within their lives generally,” the authors concluded.

Study Evaluates Lymphodepletion Intensity Before Adoptive Cell Transfer in Melanoma The addition and intensification of total body irradiation to the lymphodepleting chemotherapy regimen in patients undergoing adoptive cell transfer of tumor-infiltrating lymphocytes for metastatic melanoma did not improve outcomes, according to research that was recently published in the Journal of Clinical Oncology.

Because previous research has demonstrated that the addition and intensification of total body irradiation to the preparative chemotherapy regimen improved objective complete and partial response rates, investigators sought to assess the importance of adding total body irradiation in a randomized trial.

For the study, researchers enrolled 101 patients with metastatic melanoma. Seventy-six of those enrolled had M1c disease. Participants were randomly assigned to receive nonmyeloablative chemotherapy with or without 1200 cGy total body irradiation prior to the transfer of tumor-infiltrating lymphocytes.

Results showed that 24% of patients in both treatment arms achieved a complete response. Median overall survival was

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Both treatments can slow the progression of metastatic melanoma, but usually neither therapy can result in complete remission. Researchers wondered if combining the treatments could yield better results.

This study, which was recently published in the Journal of Experimental Medicine, tested the combination of immunotherapies on a patient with multiple metastases who had previously experienced little response to either T cell transfers or ipilimumab therapy.

The male patient was 53 years old and received an infusion of his own T cells followed immediately with a dose of ipilimumab. The T cell infusion was treated with interleukin-21, an immune system protein that promotes T cell survival.

The patient’s tumors began to shrink within weeks.

Eventually, the tumors disappeared completely. More than 5 years later, the patient remains completely disease-free.

This combined approach increased the amount of antitumor T cells circulating in the patient’s bloodstream in both the short and long term. In addition, the heightened immune response stimulated by this treatment resulted in the development of new types of T cells that attacked the tumors in other ways. This phenomenon is known as epitope spreading.

“Combining CTLA4 blockade with the transfer of well-characterized, robust antitumor T cells represents an encouraging strategy to enhance the activity of the adoptively transferred T cells and induce antitumor responses,” said senior author Cassian Yee, MD, who executed this research when he was in the Program in Immunology at Fred Hutchinson Cancer Research Center in Seattle, Washington.

“This strategy may hold broad promise for ipilimumabresistant melanomas.”

A10 SKIN CANCER ADVISOR | JULY/AUGUST 2016 | CancerTherapyAdvisor.com

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LATEST NEWS

Outcomes Are Not Improved With Pegylated Interferon Alpha-2a vs Interferon Alpha-2a Pegylated interferon-alpha-2a (PEG-IFN) did not improve improve outcomes for patients with melanoma compared with interferon-alpha-2a (IFN). Furthermore, patients receiving PEG-IFN were more likely to discontinue treatment due to toxicity, a study published in Annals of Oncology has shown.

Because disease-free survival (DFS) was improved with adjuvant treatment with IFN, and trending improved overall survival (OS) in melanoma, this trial sought to examine if PEG-IFN is superior to IFN. Primary endpoint was distant metastasis-free survival (DMFS). DFS, OS, quality of life, and tolerability were secondary end points.

For this multicenter, open-label, prospective randomized phase 3 trial, 909 patients with resected cutaneous melanoma stage 2A(T3a)-3B (AJCC 2002) were randomly assigned to receive PEG-IFN 180 mcg subcutaneously once a week for 24 months (451 patients) or IFN alpha-2a 3 MIU subcutaneously 3 times a week for 24 months (458 patients); both groups were stratified for stage, number of metastatic nodes, age, and previous interferon treatment.

No significant differences were seen between 5-year DMFS (PEG-IFN 61.0% vs IFN 67.3%; HR, 1.16; P = .21), 5-year OS (PEG-IFN 73.2% vs IFN 75.2%; HR, 1.05, P = .70), or 5-year DFS (PEG-IFN 57.3% vs IFN 60.9%; HR, 1.09, P = .40). Nor were differences found in DMFS, OS, or DFS between the treatment groups on subgroup analyses in patients ± ulcerated primaries and of different tumor stages.

Due to adverse events, 118 patients (26.2%) in the PEG-IFN group did not receive the full dosage and length of treatment; in the IFN group, 61 patients (13.3%) were affected (P < .001).

Leukopenia and elevated liver enzymes were more common in the PEG-IFN arm (56% vs 23.5% LCP; 19.1% vs 9.4 % AST; 33.0% vs 16.5% ALT). Quality of life was identical for nearly all patients.

Topical Skin Creams Are Effective in the Treatment of Superficial Basal Cell Carcinoma Topical skin creams are effective in treating superficial basal cell carcinoma, a common cancer worldwide with increasing frequency. Results from a 3-year, randomized, controlled clinical trial indicate that 2 topical creams are effective in most cases of primary, low-risk superficial basal cell carcinoma. These creams compared favorably to photodynamic therapy (PDT).

More than 80% of all skin cancers are basal cell carcinoma, which arises from the small, round cells in the lower layer of the epidermis. More than 2 million people in the United States each year develop basal cell carcinoma. Although prognosis is excellent, treatment may invade surrounding tissues causing significant disfigurement.

Most types of basal cell carcinoma require surgery; however, superficial basal cell carcinoma can be treated with noninvasive therapies such as PDT, imiquimod cream, fluorouracil cream, electrodessication, or curettage.

In this study, 601 patients with superficial basal cell carcinoma were randomly assigned to receive 1 of 3 noninvasive treatments: methylaminolevulinate-PDT (202 patients), imiquimod cream (198 patients), or fluorouracil cream (201 patients).

“The main advantages of noninvasive treatments are good cosmetic outcome, preservation of surrounding tissue, and potential for home application of either creams,” explained Marieke Roozeboom, MD, PhD, a resident in the Department of Dermatology, Maastricht University Medical Center in the Netherlands, and first author of this study.

Before this study, a lack of randomized, controlled trials with long-term follow-up comparing the effectiveness of noninvasive treatments resulted in a lack of consensus in international superficial basal cell carcinoma guidelines as to the first choice of noninvasive therapy.

Approximately 80% of patients in the imiquimod treatment arm were tumor-free. In the fluorouracil treatment arm, 68% of patients were tumor-free, and in the PDT group, 58% of patients were tumor-free.

“Based on our findings, both imiquimod and fluorouracil are effective noninvasive treatments in most primary, lowrisk superficial basal cell carcinoma, but the data provide no definite evidence for superiority of imiquimod to fluorouracil,” explained Dr Roozeboom.”

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38.2 months in patients who received total body irradiation compared with 36.6 months in those who did not (HR, 1.11; 95% CI, 0.65-1.91; P = .71).

In regard to safety, 13 of 48 evaluable patients in the total body irradiation arm reported thrombotic microangiopathy, an adverse event unique to that arm.

The study further demonstrated that only 1 of the 24 patients who achieve a complete response developed recurrent disease after a median potential follow-up of 40.9 months.

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Melanoma Pipeline: A Review of Therapies that May Change The Treatment Landscape

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he American Cancer Society estimates that approximately 76,380 new melanomas will be diagnosed in the United States in 2016 and about 10,130 patients will die from the disease. Although melanoma accounts for only 1% of skin cancer cases, the rates of melanoma have been rising for the last 30 years and melanoma causes the most skin cancer deaths.1 Immunotherapies and kinase inhibitors have drastically evolved the treatment landscape for metastatic or unresectable melanoma. In only the last 5 years, the US Food and Drug Administration has approved ipilimumab, vemurafenib, pembrolizumab, dabrafenib, trametinib, cobimetinib, and nivolumab. The National Comprehensive Cancer Net work (NCCN) guidelines for melanoma treatment recommend all of the aforementioned agents as first-line therapy, some as single-agents and others in combination with each other.2 The melanoma treatment pipeline includes additional targeted therapies and immunotherapies that have already demonstrated safety and efficacy in phase 2 and 3 trials. Cancer Therapy Advisor spoke with Ryan J. Sullivan, MD, medical oncologist at Massachusetts

With incidence rates rising each year, researchers are working hard to delevop new therapies to better treat patients with melanoma.

General Hospital in Boston to gain his insight into which therapies he believes are the most important in the future of melanoma treatment.

Binimetinib Binimetinib is a small molecule MEK inhibitor that targets key enzymes in the RAS/RAF/MEK/ERK pathway, which regulates numerous vital cellular activities including proliferation, differentiation, migration, survival, and angiogenesis.3 â&#x20AC;&#x153;Binimetinib by itself is looking like a potentially important treatment for NRAS-mutant melanoma,â&#x20AC;? said Dr Sullivan, who specializes in the treatment of melanoma and has been involved in a number of studies involving kinase inhibitors and immunotherapies.

An ongoing phase 3 clinical trial of binimetinib demonstrated that binimetinib improved median progression-free survival by 1.3 months compared with dacarbazine in patients with advanced NRAS-mutant melanoma. Further, the study demonstrated that binimetinib was generally well tolerated.3 For the international NEMO trial, researchers enrolled 402 patients with advanced NRAS-mutant melanoma and randomly assigned them 2:1 to receive binimetinib 45 mg orally twice daily or dacarbazine 1000 mg/m2 intravenously every 3 weeks.

Š BIOPHOTO ASSOCIATES / SCIENCE SOURCE

BY JASON HOFFMAN, PharmD, RPh

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Binimetinib is also being evaluated in patients with BRAF-mutant melanoma in the phase 3 COLUMBUS study, as well as in combination with ribociclib, an oral selective CDK4/6 inhibitor.

Encorafenib Encorafenib is a kinase inhibitor that inhibits BRAF activity along the RAF/ MEK/ERK pathway.

Preliminary data of a phase 2 trial evaluating encorafenib in combination with binimetinib showed that the regimen was well tolerated and had promising activity in patients with BRAF-mutant melanoma who were BRAF inhibitor treatment-naïve.4 The overall response rate and disease control rate was 74.5% and 96.4%, respectively. Furthermore, 7 of the 55 patients achieved a confirmed complete response and 34 had a confirmed partial response. Median progression-free survival was 11.3 months (95% CI, 7.4 - 14.6).

“The combination is quite active,” Dr Sullivan said. “The data that we presented at the 2015 ASCO Annual Meeting® are impressive. The response rate was at the 70+% range, which is what you see with the other combination of dabrafenib/trametinib and vemurafenib/cobimetinib.”

Of note, the response rate and progression-free survival were consistent with other BR A F inhibitor/MEK inhibitor combinations like dabrafenib and trametinib; however, encorafenib/ binimetinib was associated with lower rates of pyrexia and photosensitivity than dabrafenib/trametinib and vemurafenib/cobimetinib, respectively.4 “The toxicity profile is a little bit different than the toxicity profiles of the other 2 combinations, and that may be its distinguishing factor,” Dr Sullivan told Cancer Therapy Advisor.

“The combination of dabrafenib and trametinib is associated with a significant amount of fever syndrome, which can definitely be dose-limiting.

The combination of vemurafenib and cobimetinib has a peculiar toxicity where patients are sensitive to light.

Arthralgias are also common with vemurafenib/cobimetinib, but they are not seen with this novel combination,” he said.

However, Dr Sullivan noted that liver enzyme elevation was present in a significant minority of patients receiving

Encorafenib/ binimetinib was associated with lower rates of pyrexia and photosensitivity. encorafenib and binimetinib. These laboratory abnormalities may be the dominant toxicity if a lot of patients are treated with it.

“From a symptomatic standpoint, that combination is probably the best tolerated of the 3,” Dr Sullivan said.

The safety and efficacy of encorafenib plus binimetinib are being assessed in the multicenter, open-label, phase 3 trial, in which patients were randomly assigned 1:1:1 to receive encorafenib and binimetinib, encorafenib alone, or vemurafenib alone.4 Atezolizumab The combination of vemurafenib and atezolizumab, an investigational PD-L1 inhibitor, resulted in durable responses in patients with previously untreated BR AF V600-mutant metastatic

melanoma, according to findings of an ongoing phase 1b trial.5 “The data from the phase 1 trial of vemurafenib and atezolizumab presented at the Society for Melanoma Research 2015 Congress looked promising,” Dr Sullivan noted.

For the multicenter, open-label study, patients received the immunotherapy concurrently with the BRAF inhibitor or after a run-in period with vemurafenib alone for 56 or 28 days. Patients received atezolizumab at a dose of 20 or 15 mg/kg every 3 weeks or a fixed dose of 1200 mg and 960 mg of vemurafenib given orally twice daily during the runin period or 720 mg twice daily when used in combination.

The study demonstrated an objective response rate of 76% (95% CI, 50.1 - 93.2), which included 3 complete responses and 10 partial responses among the 17 evaluable patients. With regard to safety, no dose-limiting toxicities or unexpected adverse events were observed with the combination.

Atezolizumab plus vemurafenib is also being assessed in combination with cobimetinib for the treatment of the same patient population in a phase 1 trial.

Durvalumab Durvalumab is a human IgG1 monoclonal antibody that blocks PD-L1 binding to PD-1 and CD80 with high affinity and selectivity. A multicenter, open-label, phase 1 trial presented at the 2015 ASCO Annual Meeting showed that the immunotherapy can be combined with trametinib with or without dabrafenib for patients with BRAF-mutant and BRAF wild-type melanoma.6 For the study, 50 patients with stage 3C or 4 melanoma were assigned to receive durvalumab 3 or 10 mg/kg intravenously every 2 weeks in combination with dabrafenib 150 mg orally twice daily plus

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FEATURE trametinib 2 mg orally twice daily, or trametinib alone. Patients could also receive sequential trametinib followed by durvalumab 10 mg/kg.

Results showed that 6 of the 6 patients receiving the 3-drug combination with durvalumab at 3 mg/kg achieved a complete or partial response. Ten of the 15 patients receiving all 3 drugs with durvalumab at 10 mg/kg achieved a response. The researchers reported that most responses were ongoing.

The most common treatment-related adverse events were pyrexia, fatigue, diarrhea, rash, and vomiting.

“The data presented at the 2015 ASCO Annual Meeting were not spectacular, but long-term data are more important,” Dr Sullivan said. “Just the fact that this combination is doable is exciting.”

Eltrapuldencel-T Eltrapuldencel-T is a novel dendritic cell-based vaccine that consists of autologous dendritic cells loaded with antigens from irradiated tumor cells derived from autologous melanoma cell lines, and suspended in granulocyte macrophage colony-stimulating factor.7 A phase 2 trial evaluating the activity and tolerability of the immunotherapy in 42 patients with stage 4 and recurrent stage 3 melanoma showed a 5-year survival rate of 50% with the vaccine.

Toxicities associated with the vaccine were minimal.

Eltrapuldencel-T is being studied in the double-blind, placebo-controlled, phase 3 INTUS trial. For this study, researchers enrolled 250 patients with stage 4 or recurrent stage 3 melanoma and at least 1 lesion amenable to surgical resection. Participants were randomly assigned 2:1 to receive either eltrapuldencel-T or autologous mononuclear cells after undergoing leukapheresis to obtain mononuclear cells for each treatment arm. Patients in both arms will

receive injections weekly for 3 weeks, and then monthly for 5 months.

The primary endpoint is overall survival, and final data collection for that outcome measure is estimated to be completed in January 2017.

Seviprotimut-L Seviprotimut-L (POL-103A) is a novel melanoma vaccine designed to stimulate the body’s immune system to fight tumor cells using shed antigens from 3 proprietary melanoma cell lines. Antigens are rapidly released from the cancer cells, then purified and processed before administration to patients.8 The international, double-blind, placebo-controlled, phase 3 MAVIS trial enrolled 1059 patients to evaluate the safety and efficacy of the immunotherapy in resected stage 2b, 2c, or 3 melanoma. Patients were randomly assigned 2:1 to receive the vaccine intradermally as 4 injections or placebo. Final data collection for the primary outcome measure of recurrence-free survival is estimated to be completed in July 2016.

The MAVIS trial was initiated based on the findings of 2 randomized, placebo-controlled, phase 2 trials with a small number of patients that demonstrated favorable efficacy with regard to prolonged recurrence-free and overall survival, as well as an excellent safety profile.9

survival at 6 months was 38.6% with a median progression-free survival of 4.2 months. The overall response rate was 28.1% with 6 or more months of durable response in 19.3% of 57 evaluable patients.

The most common adverse events were grade 1 fatigue, chills, local injection site reactions, and fever. No grade 3 or 4 treatment-related adverse events were reported.

For the study, 57 patients with treated or untreated unresectable late stage melanoma received intralesional injections of CVA21 on days 1, 3, 5, 8, and 22, and then every 3 weeks for 6 additional injections.

Those who displayed immune-related progression-free survival or better at 6 months could receive 9 more injections.

“CVA21 can also be given intravenously,” Dr Sullivan noted. “This may set it apart from T-VEC (talimogene laherparepvec).”

“Vaccines in general have been a major challenge in melanoma, but a lot of these newer immunotherapies may offer something that the old vaccine could not, which is that they stimulate the immune system much better,” Dr Sullivan explained. “Whether or not they lead to more widespread antigen recognition and tumor immunity may remain to be seen.” ■ References 1. What are the key statistics about melanoma skin cancer? American Cancer Society web

Coxsackievirus A21 (CVA21) CVA21 is a novel bio-selected oncolytic and immunotherapeutic strain of Coxsackievirus A21. It is a naturally occurring, genetically unaltered virus that is being evaluated in a number of cancer types, including late-stage melanoma.10 The multicenter, open-label, phase 2 CALM study demonstrated promising activity with the immunotherapeutic agent in the treatment of stage 3C-4M1c melanoma. Results showed that immune-related progression-free

site. February 1, 2016. http://www.cancer. org/cancer/skincancer-melanoma/detailedguide/melanoma-skin-cancer-key-statistics.

Accessed March 21, 2016.

2. NCCN Clinical Practice Guidelines in Oncology™. Melanoma. Version 2.2016.

Available at: http://www.nccn.org/professionals/physician_gls/pdf/melanoma.pdf.

Accessed March 21, 2016.

3. Array BioPharma announces phase 3 binimetinib trial meets primary endpoint for NRAS-mutant melanoma [news release].

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VIEWPOINT | BY JOHN SCHIESZER

A Call for Greater Skin Cancer Surveillance Among Solid Organ Transplant Recipients Researchers found that solid organ transplant recipients may be at a very high risk of skin cancer.

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Canadian study suggested that improved strategies may be needed for cancer prevention, screening, and surveillance among solid organ transplant recipients (SOTRs).1 Researchers found that SOTRs may be at a very high risk of skin cancer. They looked at 11,061 SOTRs and found that they had a significantly higher risk of cancer death compared with the general population.

“We found that transplant recipients were almost 3 times more likely to die of cancer than the general population.

We found that for all types of cancer there was at least equivalent or excess mortality in transplant recipients.

The excess risk of cancer mortality was highest for non-melanoma skin cancer and non-Hodgkin lymphoma,” said study author Sergio Acuna, MD, of the University of Toronto in Canada.

However, he said these cancer types were not responsible for most cancer deaths. Non-melanoma skin cancer accounted only for 3.3% of the cancer deaths. Most cancer deaths in transplant recipients were related to lung cancer (20.9%), liver malignancy (17.7), non-Hodgkin lymphoma (15.9%), and colorectal cancer (7.1%).

The study suggested that cancer is a leading cause of death in SOTRs and the authors of this study said the cancer incidence rates are expected to increase

in the next 10 years as the median age of transplant recipients increases.

“We were surprised to see the magnitude of the difference in cancer mortality. Despite the increased incidence of cancer in transplant recipients and reports of worse cancer outcomes in this population, we were expecting a smaller excess in the risk of cancer mortality given the multiple competing causes of death in this population,” said study co-author Nancy Baxter, MD, PhD, a professor in the Department

Transplant recipients were almost 3 times more likely to die of cancer than the general population. of Surgery at St. Michael’s Hospital in Toronto, Canada. “It was also quite surprising to see that the risk of cancer mortality was higher than that of the general population in older transplant recipients and that the risk of cancer death was not restricted to long-term survivors, indicating that the burden of cancer mortality was substantial even early after transplantation.”

For this investigation, Dr Baxter and colleagues examined data from patients who underwent solid organ transplantation in Ontario, Canada, between 1991 and 2010. The analysis was conducted between November 2013 and February 2015. Mortality rates were examined by using data from the Canadian Organ Replacement Register, the Ontario Cancer Registry, and the Office of the Registrar General of Ontario death database.

The investigators identified 6516 kidney recipients, 2606 liver recipients, 929 heart recipients, and 705 lung transplantation recipients. The median age was 49 (37 to 58) years, and 36% were female (n = 4004). The study showed there were 3068 deaths and 20% (n = 603) were cancer-related. Cancer mortality rates for SOTRs were found to be significantly elevated compared with the Ontario population with a standardized mortality ratio (SMR) of 2.84. In addition, the study showed that the risk remained elevated when patients with pre-transplant malignant neoplasms (n = 1124) were excluded (SMR: 1.93).

Interestingly, the study showed that the increased risk was irrespective of transplanted organ.

“More research is needed to understand why these differences in cancer mortality exist between transplant and non-transplant patients. Moreover, strategies for targeted cancer screening and to improve the outcomes of transplant recipients who develop cancer, specifically related to the management of immunosuppression during cancer treatment, are also needed,” Dr Acuna told Cancer Therapy Advisor.

The study showed that SOTRs were at increased risk of non-Hodgkin lymphoma mortality. However, researchers found that cardiothoracic recipients had the highest risk and there were

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several differences in the site-specific risk of cancer mortality. The researchers found that liver transplant recipients were at increased risk of dying from post-transplant denovo liver cancers. They also found that only kidney recipients were at increased risk of mortality from leukemia, melanoma, colorectal, oral cavity/pharynx, and prostate cancer.

The investigators noted that a tailored approach to cancer screening may be required for SOTRs. Kidney recipients should be especially cautioned to take all available steps to prevent skin cancer. Dr Baxter said skin cancer is a major concern in this patient population. “Screening can really help for preventing poor outcomes of skin malignancies,” Dr Baxter told Cancer Therapy Advisor. “Oncologists should be aware that these patients are not only at increased risk of developing skin malignancies, but also at increased risk of dying of cancer.”

Dr Acuna said it is important that clinicians involved in the care of transplant recipients follow the current recommendations for cancer screenings

Feature Continued from page A14

in SOTRs. He also said clinicians should start cancer screenings early after transplantation and have a high level of suspicion to identify malig-

It is important that clinicians follow the current recommendations for cancer screenings. nancies at earlier stages. Dr Acuna said clinicians involved in the care of transplant recipients should counsel them to take every possible precaution to reduce their cancer risk, including limiting sun exposure, quitting smoking, reducing alcohol consumption, improving their diet, and increasing their physical activity.

Medical oncologist Khaled Tolba, MD, who is an assistant professor at Oregon Health & Science University, Portland, OR, said this is a very important study

in BRAF V600 metastatic melanoma. Pigment

Cell Melanoma Res. 2015;28(6):753-826.

6. Ribas A, Butler M, Lutzky J, et al. Phase I

2015. http://investor.arraybiopharma.com/

study combining anti-PD-L1 (MEDI4736) with

phoenix.zhtml?c=123810&p=irol-newsArti-

BRAF (dabrafenib) and/or MEK (trametinib)

cle&ID=2122959. Accessed March 22, 2016.

inhibitors in advanced melanoma.

4. Sullivan RJ, Weber JS, Patel SP, et al. A phase Ib/II study of BRAF inhibitor (BRAFi)

J Clin Oncol. 2015;33(suppl; abstr 3003).

7. Dillman RO, Bayer ME, Langford JA, et al.

because it demonstrated specific types of cancer that may pose a greater risk in SOTRs. He said immune suppression strategies are improving and this may also affect cancer risk among SOTRs in the coming years.

“The immune suppression will expose the patient to several viral infections and some of them might be oncogenic and lead to skin cancer or other solid tumors. In a normal person, the viral infection will get cleared but that is not the case with solid organ transplant recipients,” Dr Tolba said in an interview with Cancer Therapy Advisor. “This is definitely a concern and it is has been known for a long time. However, we are learning more about the immune suppression and we might be able to better manipulate it to prevent the problem posed by viral infections.” ■ Reference 1. Acuna SA, Fernandes KA, Daly C, et al.

Cancer mortality among recipients of solid-organ transplantation in Ontario, Canada [published online ahead of print January 7, 2016]. JAMA Oncol. doi: 10.1001/ jamaoncol.2015.5137.

8. Polynoma commences phase III melanoma vaccine clinical trial [news release].

San Diego, CA: Polynoma; June 4, 2012. http://bit.ly/1qLQUsx. Accessed March 23, 2016.

9. Bystryn JC, Zeleniuch-Jacquotte A, Oratz R, et al. Double-blind trial of a polyvalent, shed-antigen, melanoma vaccine. Clin

Cancer Res. 2001;7(7):1882-1887.

encorafenib (ENCO) plus MEK inhibitor

Phase III multicenter trial of eltrapulden-

(MEKi) binimetinib (BINI) in cutaneous mela-

cel-T: autologous dendritic cells loaded with

10. Andtbacka RHI, Curti BD, Kaufman H, et al.

noma patients naive to BRAFi treatment.

irradiated autologous tumor cells (DC-TC) in

Final data from CALM: a phase II study of

J Clin Oncol. 2015;33(suppl; abstr 9007).

granulocyte-macrophage colony stimulating

Coxsackievirus A21 (CVA21) oncolytic virus

factor (GM-CSF) in patients with metastat-

immunotherapy in patients with advanced

5. Hamid O, Patel M, Hodi S, et al. Preliminary clinical safety, tolerability and activity of atezoli-

ic melanoma (INTUS trial). J Clin Oncol.

melanoma. J Clin Oncol. 2015;33(suppl;

zumab (anti-PDL1) combined with vemurafenib

2015;33(suppl abstr TPS9082).

abstr 9030).

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BY JOHN SCHIESZER

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growing arsenal of genetic and molecular tests is changing how clinicians diagnose and treat melanoma, according to Emily Chu, MD, PhD, assistant professor of dermatology, and pathology and laboratory medicine at the University of Pennsylvania in Philadelphia.

However, she said clinicians must be careful when using many of these new testing kits.

Dr Chu, who spoke about the optimal use of new molecular tests at the American Academy of Dermatology 74th Annual Meeting, said a new generation of detection kits offer a wide variety of options.1 “I think somatic testing for the purpose of detecting actionable mutations is quite accurate, and should be used by clinicians primarily for patients with stage 4 and 3 melanomas. At our institution, there has been some discussion of doing this routinely for high-risk stage 2 patients as well but I don’t believe that the oncologists are ordering this consistently in that context,” said Dr Chu. “I think oncologists are quite savvy about BRAF testing. The targeted next-generation sequencing panels generate a lot of information about various mutations in melanomas, but typically have a longer turnaround time than simpler tests like

A growing arsenal of genetic and molecular tests is changing how clinicians diagnose and treat melanoma, however, clinicians must be careful when using them.

the polymerase chain reaction-based BRAF V600E test. That latter test can typically yield results within 48 hours.”

Dr Chu said she generally doesn’t order gene expression profiling for the purposes of prognostication because of the issue of imperfect sensitivity and specificity. She added that it is difficult to know how to change disease management for a patient if that patient gets a high-risk (class 2) result despite having an otherwise relatively low-risk melanoma.

“It has the potential to introduce unnecessary patient anxiety into an encounter,” Dr Chu told Cancer Therapy Advisor. “Gene-expression profiling for both diagnosis of melanocytic lesions and prognostication of definitive melanomas is still at a fairly early stage in my opinion. I think one important point regarding diagnosis using gene-expression profiling is that this should always be taken in the context of the pathologist’s histologic interpretation of the lesion. These tests do not have perfect sensitivity and specificity and so it is another piece of information to be used when rendering a diagnosis.”

Advances in diagnosing and treating melanoma have allowed clinicians to have more tools than ever to treat melanoma and are paving the way towards indidualized care.

According to Dr Chu, further research into specific melanoma mutations and

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Genetic and Molecular Testing Changing How Melanoma Is Diagnosed and Treated

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targeted therapies could help doctors provide more effective treatment for their patients in the future. She said clinicians must now sort out which tests are the most useful for identifying susceptibility to melanoma and the identification of the CDKN2A mutation. Clinicians must also decide which tests are the most helpful for identifying treatable mutations in patients with advanced melanomas (stages 3 to 4), and which tests are most helpful for diagnosing melanoma vs an atypical nevus.

Melanoma rates in the United States are continuing to rise and this has been a concern for many years. A report published last year by the Centers for Disease Control and Prevention suggested that incidence rates will increase for white males and females through 2019 and the death rates are projected to remain stable.2 It is estimated that about 9000 individuals will die from melanoma each year, making it the most common cause of skin cancer death. The report estimated that the annual cost of treating newly diagnosed melanomas will increase from an estimated $457 million in 2011 to $1.6 billion in 2030.

Laura Ferris, MD, PhD, an associate professor of der matolog y with the University of Pittsburg in Pennsylvania, said gene expression profiling provides patients with an alternative to more invasive procedures to better understand the biologic behavior of melanocytic skin tumors. She said it also may help provide additional information above what is available from current standard procedures of skin biopsy, histology, and sentinel node biopsy. Dr Ferris, who spoke on the current use of molecular diagnostics for melanoma at the American Academy of Dermatology 74th Annual Meeting, said clinicians now have

specific molecular assays, such as fluorescent in situ hybridization (FISH), comparative genomic hybridization, the DermTech adhesive patch test, the Myriad mRNA profiling expression test, and the Castle GEP assay, for diagnosis of melanocytic neoplasms.3 She said it is important that clinicians understand when these tests are indicated and they should be aware of the specific limitations of each.

“Oncologists should be aware of the Castle test because it can give prognostic data and help us to identify patients at increased risk of metastasis. This could be helpful in determining how

Gene expression profiling provides patients with an alternative to more invasive procedures. frequently patients should be monitored and in determining which patients may benefit from enhanced imaging surveillance to detect early metastasis,” Dr Ferris told Cancer Therapy Advisor in an interview. “In addition, as more therapeutic options for stage 3 disease become available, it may help us to better select patients who may benefit from sentinel node biopsy. In addition, the Castle test may help identify patients at high risk of metastasis despite negative sentinel node.”

She said it is important for oncologists to know the strengths and limitations of each of these individual tests.

Specifically, she noted that FISH may help distinguish indolent spitz nevi from more aggressive spitzoid melanoma.

“Ultimately, these tests may help to improve mortality and morbidity, if they can identify patients who can benefit from early therapeutic intervention, particularly with newer targeted therapies,” Dr Ferris said. “Also, if these tests can limit the number of sentinel node biopsies they can potentially limit surgical morbidity. The key is finding out how to best use these new technologies within clinical practice.”

Ali Hendi, MD, clinical assistant professor of dermatology at Georgetown University Hospital and skin cancer specialist in Washington, DC, said genetic testing is on the forefront of improving prognostication of melanomas. Although it is in its infancy, there is a great deal of promise with new molecular tests and they could affect morbidity and mortality for patients in the next couple of years with futher testing and validation.

“I think it’s a promising technology that needs to be used more to be validated,” Dr Hendi told Cancer Therapy Advisor. “The management of advanced melanoma is changing rapidly with the advent of systemic treatments that have modest improvements in survival.” ■ References 1. Chu EY. Melanoma and the genes: optimizing patient management in the age of molecular testing. Presented at the American Academy of Dermatology 74th Annual Meeting; March 7, 2016; Washington, D.C. 2. Guy GP, Thomas CC, Thompson T, Watson M, et al. Vital signs: melanoma incidence and mortality trends and projections—United States, 1982–2030. MMWR Morb Mortal Wkly Rep. 2015;64(21):591-596.

3. Ferris LK. FRM F128 - molecular diagnostics: what it means to our patients. Presented at the American Academy of Dermatology 74th Annual Meeting; March 7, 2016; Washington, D.C.

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Statin Use May Increase Risk of Non-melanoma Skin Cancer in Postmenopausal Women Lipophilic statins may be associated with an increased risk for non-melanoma skin cancer in white women.

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he use of statins, particularly lipophilic statins, may be associated with an increased risk for non-melanoma skin cancer (NMSC) in postmenopausal white women.1 However, the researchers found that there was no clear trend in duration of use. The researchers reported that women taking statins for less than 3 years had a significant increase in odds of NMSC compared with never users, but women taking statins for more than 3 years were not significantly different compared with never users.

“We felt that the relationship between NMSC and statin use is an important clinical question, as NMSC is the most common cancer in the United States and statins are a common and growing class of medications,” said study co-author Ange Wang, who is an MD candidate at Stanford University in Stanford, CA. “Some previous studies have suggested that a relationship between statin use and increased NMSC risk may exist, though most studies have been retrospective in nature. Ours is a prospective study which is subject to less recall bias.”

Wang and colleagues used data from the Women’s Health Initiative (WHI) Observational Study and WHI Clinical Trial to investigate the prospective relationship between statin use and NMSC in non-Hispanic white postmenopausal

women. The cohort included 118,357 women with no cancer history at baseline. All were between 50 and 79 years, and enrolled at 40 centers in the United States. The association of statin use and NMSC incidence was determined using random-effects logistic regression models. The investigators looked at baseline values, as well as overall statin use as a time-varying variable, statin duration, statin type, potency, and lipophilicity.

Any use of statins in the random-effects logistic regression model was associated with increased NMSC. The study showed that any use of statins in the random-effects logistic regression model was associated with significantly increased NMSC incidence (OR, 1.21) over a mean follow-up of 10.5 years. The researchers found that increased risk was associated with lovastatin (OR, 1.52) and simvastatin (OR, 1.38). In addition, lipophilic statin users had a significant increase compared with non-statin users (OR, 1.39).

“We did not find a relationship

specifically with longer duration or higher dosing/potency, but we did find that lipophilic statins in particular were associated with increased risk,” Wang told Cancer Therapy Advisor.

“Oncologists and also primary care physicians may want to consider prescribing non-lipophilic statins for patients at high risk of NMSC, based on skin type, family history, and risk factors. However, this relationship must be further evaluated in a randomized control trial format before making definitive clinical recommendations.”

Wang said the mechanisms of action are still unclear. The study showed no significant effect modification of the statin–NMSC relationship when they looked at age, body mass index, smoking, solar irradiation, vitamin D use, and skin cancer history.

K irsten Moysich, PhD, MS, of Roswell Park Cancer Institute in Buffalo, New York, said this is a well-designed study with statin use information from the time before women developed NMSC. Dr Moysich said the findings are intriguing; however, they will now need to be verified.

“While there was elevated risk among women who used lipophilic statins, there was no trend for increasing risk as a function of greater duration of use.

The authors of this paper acknowledge that this lack of a dose-response relationship might be due to the fact that other factors that could not be accounted for in the analyses might be responsible for these findings,” Dr Moysich told Cancer Therapy Advisor. ■ Reference 1. Wang A, Stefanic ML, Kapphahn K, et al.

Relation of statin use with non-melanoma skin cancer: prospective results from the Women’s Health Initiative. Br J Cancer.

2016;114(3):314–320.

CancerTherapyAdvisor.com | JULY/AUGUST 2016 | SKIN CANCER ADVISOR A19

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VIEWPOINT | BY JIM DALEY

Oncolytic Virus T-VEC Shows Therapeutic Benefit Against Melanoma A herpes simplex virus type 1-derived oncolytic immunotherapy improved overall survival.

T

a l i mogene la her pa repvec (T-V EC), a herpes simplex virus type 1–derived oncolytic immunotherapy, improved durable response rate (DRR) and overall survival (OS) in patients with advanced melanoma in a randomized, prospective phase 3 trial.1 T-VEC was derived from herpes simplex type 1 by deleting 2 viral genes and further modified by encoding the human gene for granulocyte-macrophage colony-stimulating factor (GM-CSF). GM-CSF boosts the body’s immune response while the virus selectively replicates in tumor tissue following local injection.

“Part of the importance of this data is that it is one of the first oncolytic viruses to really ever go into a randomized phase 3 study,” said Howard L. Kaufman, MD, FACS, of the Rutgers Cancer Institute of New Jersey in New Brunswick during an interview with Cancer Therapy Advisor.

Dr Kaufman said this study definitively establishes the legitimacy of oncolytic viruses in cancer therapy, which will allow research in other types of viruses and in approaches where other viral vectors can be combined. “I think we’re going to have to take it outside of melanoma and theoretically to any cancer that we can access,” he said.

The study enrolled 436 patients with

advanced melanoma. They were randomly assigned to receive intralesional T-VEC (295 patients) or subcutaneous GM-CSF (141 patients). The primary endpoint was DRR, and secondary endpoints included OS, best overall response and tumor burden, onset and duration of response, and time to treatment failure.

Study definitively establishes the legitimacy of oncolytic viruses in cancer therapy.

DRR was 16.3% for the T-VEC arm and 2.1% for the GM-CSF arm. Median OS was 23 months with T-VEC and 18.9 months with GM-CSF. “It’s very challenging to design a clinical trial for something that is basically a new class of drugs,” said Dr Kaufman.

“And there is no doubt in my mind that at the primary endpoint there is clinical activity with this agent. I also think an important point is that the toxicity profile is very tolerable.”

There were few reported grade 3 or 4 toxicities in the study, and the most

frequently occurring adverse events in the T-VEC arm were fatigue, chills, and pyrexia.

“I think T-VEC is going to be a good agent in combination because of its safety profile,” said Dr Kaufman.

He said he anticipates that this T-VEC will provide clinical oncologists with more treatment options soon. “It offers patients another option, and if they don’t respond to more established therapies, this gives them something else that is well tolerated and has been associated with very good response rates,” he said.

He noted that there will be a slight learning curve for doctors who are new to administering the treatment. “I think that for the community oncologists, it’s going to take a while to learn how to do this,” he said. “There are unique features of storing, preparing, and administering the drug, and they take a little bit of education.”

He also said that he thinks it will be important for community oncologists to educate patients about the treatment and its safety concerns. “Patients are increasingly involved in dictating their care, and most of the patients I see understand the concept [of oncolytic virus immunotherapy],” he said.

Dr Kaufman explained that although his team has not seen household transmission of the virus in the trials they have conducted, patients should be educated on how to take care of themselves and avoid accidental exposure. ■ Reference 1. Andtbacka RH et al. Talimogene laherparepvec improves durable response rate in patients with advanced melanoma.

J Clin Oncol. 2015;33(25)2780-2788.

2. FDA approves first-of-its-kind product for the treatment of melanoma [news release].

Silver Spring, MD: 1.usa.gov/1H8xe3A.

A20 SKIN CANCER ADVISOR | JULY/AUGUST 2016 | CancerTherapyAdvisor.com

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