新一代黑色素瘤的PD-1抑制剂OPDIVO(nivolumab 纳武单抗注射液）获美国FDA推荐批准上市 2014年12月22日,美国食品和药品监管局[FDA]授权加速批准Opdivo(nivolumab)，一种对其他药物不再反应的有不能切除或转移(晚期)黑色素瘤患者的新治疗。 黑色素瘤是在美国.第五位最常见类型癌。它在黑色素瘤细胞形成，它发展皮肤色素。美国国家癌症研究所估计本年度76,100美国人将被诊断有黑色素瘤和9,710将死于此病。 Opdivo通过抑制细胞上PD-1蛋白作用，阻断机体免疫系统来自黑色素瘤肿瘤攻击。Opdivo是意向为以前曾用易普利姆玛[ipilimumab]治疗患者和，对黑色素瘤患者其肿瘤表达基因突变被称为BRAF V600，为用易普利姆玛和一种BRAF抑制剂使用后治疗。 FDA的药品评价和研究中心血液学和肿瘤学产品室主任Richard Pazdur，医学博士说：“Opdivo是自2011年被FDA批准的第七个新黑色素瘤药物。”“根据我们肿瘤免疫学和分子学通路增加了解继续发展和批准新颖治疗正在改变对严重和危及生命疾病治疗范式。” 对黑色素瘤其他FDA-批准的治疗包括易普利姆玛(2011)，聚乙二醇干扰素α-2b(2011)，威罗菲尼[vemurafenib](2011)，达拉非尼[dabrafenib](2013)，曲美替尼[trametinib](2013)和pembrolizumab (2014)。Opdivo正在比处方药用户收费目标日期2015年3月30日提前3个月被批准，这个日期是监管局计划完成其申请审评的日期。 FDA授权Opvido突破性治疗指定，优先审评和孤儿产品指定因为承办单位分别通过初步临床证据证实药物可能提供超出可得到治疗实质上改进；在申请递交时药物某种严重情况的治疗中安全性或有效性中有潜在的，显著改进；和药物是意向治疗某种罕见疾病。 Opvido正在FDA的加速批准程序下被批准，该程序允许批准某个治疗严重或危及生命疾病根据临床数据显示药物对一个替代性终点有效应可能合理地预测对患者临床获益。这个程序提供患者较早得到鼓舞人有前途新药而公司进行附加临床试验验证药物的获益。 Opdivo的疗效在120例临床试验有不能切除或转移黑色素瘤参加者中被证实。结果显示接受Opdivo参加者32%有其肿瘤皱缩(客观反应率)，在经历肿瘤皱缩参加者约三分之一这个效应持续超过6个月。 在268例用Opdivo治疗参加者和102例用化疗治疗参加者的总体试验人群中评价Opdivo的安全性。最常见药物的副作用是皮疹，瘙痒，咳嗽，山呼吸道感染，和液体潴留(水肿)。最严重副作用是严重免疫介导副作用涉及健康器官，包括肺，结肠，肝，肾和计算产生腺体。 批准日期： 2014年12月22日；公司：施贵宝公司 OPDIVO(纳武单抗[nivolumab])注射液，为静脉英文使用说明 HIGHLIGHTS OF PRESCRIBING INFORMATION These highlights do not include all the information needed to use OPDIVO safely and effectively. See full prescribing information for OPDIVO. OPDIVO (nivolumab) injection, for intravenous use Initial U.S. Approval: 2014 RECENT MAJOR CHANGES Indications and Usage (1)     11/2015 Dosage and Administration (2)     11/2015 Warnings and Precautions (5)     11/2015 INDICATIONS AND USAGE OPDIVO is a programmed death receptor-1 (PD-1) blocking antibody indicated for the treatment: • as a single agent, of patients with BRAF V600 wild-type unresectable or metastatic melanoma. (1.1) • as a single agent, of patients with unresectable or metastatic, BRAF V600 mutation-positive melanoma and disease progression following ipilimumab and a BRAF inhibitor. (1.1) This indication is approved under accelerated approval based on tumor response rate and durability of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials. • in combination with ipilimumab, of patients with BRAF V600 wild-type unresectable or metastatic melanoma (1.1). This indication is approved under accelerated approval based on tumor response rate and durability of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials. • of patients with metastatic non-small cell lung cancer in patients 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. (1.2) • of patients with advanced renal cell carcinoma who have received prior anti-angiogenic therapy. (1.3) DOSAGE AND ADMINISTRATION Administer as an intravenous infusion over 60 minutes. • Unresectable or metastatic melanoma • OPDIVO 3 mg/kg every 2 weeks. (2.1) • OPDIVO in combination with ipilimumab: OPDIVO 1 mg/kg, followed by ipilimumab on the same day, every 3 weeks for 4 doses, then OPDIVO 3 mg/kg every 2 weeks. (2.1) • Metastatic non-small cell lung cancer • OPDIVO 3 mg/kg every 2 weeks. (2.2) • Advanced renal cell carcinoma • OPDIVO 3 mg/kg every 2 weeks. (2.3) DOSAGE FORMS AND STRENGTHS Injection: 40 mg/4 mL and 100 mg/10 mL solution in a single-dose vial. (3) CONTRAINDICATIONS None. (4) WARNINGS AND PRECAUTIONS • Immune-mediated pneumonitis: Withhold for moderate and permanently discontinue for severe or life-threatening pneumonitis. (5.1) • Immune-mediated colitis: • OPDIVO as a single agent: Withhold for moderate or severe and permanently discontinue for life-threatening colitis. (5.2) • OPDIVO in combination with ipilimumab: Withhold for moderate and permanently discontinue for severe or life-threatening colitis. (5.2) • Immune-mediated hepatitis: Monitor for changes in liver function. Withhold for moderate and permanently discontinue for severe or life-threatening transaminase or total bilirubin elevation. (5.3) • Immune-mediated endocrinopathies: Withhold for moderate or severe and permanently discontinue for life-threatening hypophysitis. Withhold for moderate and permanently discontinue for severe or life-threatening adrenal insufficiency. Monitor for changes in thyroid function. Initiate thyroid hormone replacement as needed. Monitor for hyperglycemia. Withhold for severe and permanently discontinue for life-threatening hyperglycemia. (5.4) • Immune-mediated nephritis and renal dysfunction: Monitor for changes in renal function. Withhold for moderate or severe and permanently discontinue for life-threatening serum creatinine elevation. (5.5) • Immune-mediated rash: Withhold for severe and permanently discontinue for life-threatening rash. (5.6) • Immune-mediated encephalitis: Monitor for changes in neurologic function. Withhold for new-onset moderate to severe neurological signs or symptoms and permanently discontinue for immune-mediated encephalitis. (5.7) • Embryofetal toxicity: Can cause fetal harm. Advise of potential risk to a fetus and use of effective contraception. (5.10, 8.1, 8.3) ADVERSE REACTIONS Most common adverse reactions (≥20%) in patients with melanoma were: • PDIVO as a single agent: fatigue, musculoskeletal pain, rash, and pruritus. (6.1) • OPDIVO in combination with ipilimumab: rash, pruritus, headache, vomiting, and colitis. (6.1) Most common adverse reactions (≥20%) in patients with metastatic non-small cell lung cancer were fatigue, musculoskeletal pain, decreased appetite, cough, and constipation. (6.1) Most common adverse reactions (≥20%) in patients with advanced renal cell carcinoma were: asthenic conditions, cough, nausea, rash, dyspnea, diarrhea, constipation, decreased appetite, back pain, and arthralgia. (6.1) To report SUSPECTED ADVERSE REACTIONS, contact Bristol-Myers Squibb at 1-800-721-5072 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. USE IN SPECIFIC POPULATIONS Lactation: Discontinue breastfeeding. (8.2) See 17 for PATIENT COUNSELING INFORMATION and Medication Guide. Revised: 11/2015 FULL PRESCRIBING INFORMATION: CONTENTS* 1 INDICATIONS AND USAGE 1.1 Unresectable or Metastatic Melanoma • 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) ]. • OPDIVO as a single agent is indicated for the treatment of patients with unresectable or metastatic, BRAF V600 mutation-positive melanoma and disease progression following ipilimumab and a BRAF inhibitor [see Clinical Studies (14.1)]. This indication is approved under accelerated approval based on tumor response rate and durability of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials. • OPDIVO, in combination with ipilimumab, is indicated for the treatment of patients with BRAF V600 wild-type, unresectable or metastatic melanoma [see Clinical Studies (14.1)]. This indication is approved under accelerated approval based on tumor response rate and durability of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials. 1.2 Metastatic Non-Small Cell Lung Cancer 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)]. 1.3 Renal Cell Carcinoma 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)]. 2 DOSAGE AND ADMINISTRATION 2.1 Recommended Dosage for Melanoma The recommended dose of OPDIVO administered as a single agent is 3 mg/kg administered as an intravenous infusion over 60 minutes every 2 weeks until disease progression or unacceptable toxicity. • The recommended dose of OPDIVO is 1 mg/kg administered as an intravenous infusion over 60 minutes, followed by ipilimumab on the same day, every 3 weeks for 4 doses [see Clinical Studies (14.1)]. The recommended subsequent dose of OPDIVO, as a single agent, is 3 mg/kg as an intravenous infusion over 60 minutes every 2 weeks until disease progression or unacceptable toxicity. Review the Full Prescribing Information for ipilimumab prior to initiation. 2.2 Recommended Dosage for NSCLC The recommended dose of OPDIVO is 3 mg/kg administered as an intravenous infusion over 60 minutes every 2 weeks until disease progression or unacceptable toxicity. 2.3 Recommended Dosage for RCC The recommended dose of OPDIVO is 3 mg/kg administered as an intravenous infusion over 60 minutes every 2 weeks until disease progression or unacceptable toxicity. 2.4 Dose Modifications Recommendations for OPDIVO modifications are provided in Table 1. There are no recommended dose modifications for hypothyroidism or hyperthyroidism. Interrupt or slow the rate of infusion in patients with mild or moderate infusion reactions. Discontinue OPDIVO in patients with severe or life-threatening infusion reactions. Table 1: Recommended Dose Modifications for OPDIVO a  Resume treatment when adverse reaction returns to Grade 0 or 1. When OPDIVO is administered in combination with ipilimumab, if OPDIVO is withheld, ipilimumab should also be withheld. 2.5 Preparation and Administration Visually inspect drug product solution for particulate matter and discoloration prior to administration. OPDIVO is a clear to opalescent, colorless to pale-yellow solution. Discard the vial if the solution is cloudy, discolored, or contains extraneous particulate matter other than a few translucent-to-white, proteinaceous particles. Do not shake the vial. Preparation • Withdraw the required volume of OPDIVO and transfer into an intravenous container. • Dilute OPDIVO with either 0.9% Sodium Chloride Injection, USP or 5% Dextrose Injection, USP to prepare an infusion with a final concentration ranging from 1 mg/mL to 10 mg/mL. • Mix diluted solution by gentle inversion. Do not shake. • Discard partially used vials or empty vials of OPDIVO. Storage of Infusion The product does not contain a preservative. After preparation, store the OPDIVO infusion either: • at room temperature for no more than 4 hours from the time of preparation. This includes room temperature storage of the infusion in the IV container and time for administration of the infusion or • under refrigeration at 2°C to 8°C (36°F to 46°F) for no more than 24 hours from the time of infusion preparation. Do not freeze. Administration Administer the infusion over 60 minutes through an intravenous line containing a sterile, non-pyrogenic, low protein binding in-line filter (pore size of 0.2 micrometer to 1.2 micrometer). Do not coadminister other drugs through the same intravenous line. Flush the intravenous line at end of infusion. When administered in combination with ipilimumab, infuse OPDIVO first followed by ipilimumab on the same day. Use separate infusion bags and filters for each infusion. 3 DOSAGE FORMS AND STRENGTHS Injection: 40 mg/4 mL (10 mg/mL) and 100 mg/10 mL (10 mg/mL) solution in a single-dose vial. 4 CONTRAINDICATIONS None. 5 WARNINGS AND PRECAUTIONS 5.1 Immune-Mediated Pneumonitis Immune-mediated pneumonitis or interstitial lung disease, 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 as a single agent, fatal immune-mediated pneumonitis occurred in 0.3% (5/1590) 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). Across the clinical trial experience in 188 patients with melanoma who received OPDIVO in combination with ipilimumab, in Trial 4 (n=94) and an additional dose-finding study (n=94), fatal immune-mediated pneumonitis occurred in 0.5% (1/188) of patients. In Trial 4, there were six additional patients who died without resolution of abnormal respiratory findings. 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)]. Melanoma OPDIVO as a Single Agent In Trial 1, pneumonitis, including interstitial lung disease, occurred in 3.4% (9/268) of patients receiving OPDIVO and none of the 102 patients receiving chemotherapy. Immune-mediated pneumonitis occurred in 2.2% (6/268) of patients receiving OPDIVO: one with Grade 3 and five with Grade 2 pneumonitis. The median time to onset for the six cases was 2.2 months (range: 25 days to 3.5 months). In two patients, pneumonitis was diagnosed after discontinuation of OPDIVO for other reasons, and Grade 2 pneumonitis led to interruption or permanent discontinuation of OPDIVO in the remaining four patients. All six patients received high-dose corticosteroids (at least 40 mg prednisone equivalents per day); immune-mediated pneumonitis improved to Grade 0 or 1 with corticosteroids in all six patients. There were two patients with Grade 2 pneumonitis that completely resolved (defined as complete resolution of symptoms with completion of corticosteroids) and OPDIVO was restarted without recurrence of pneumonitis. In Trial 5, pneumonitis occurred in 1.4% (3/206) of patients receiving OPDIVO and in none of the 205 patients receiving dacarbazine. All cases were immune-mediated and Grade 2 in severity. The median time to onset was 2.8 months (range: 2 to 5.1 months). Pneumonitis led to interruption of OPDIVO in all three patients, all received high-dose corticosteroids, and pneumonitis completely resolved. OPDIVO was restarted in two of these patients without recurrence of pneumonitis. OPDIVO in Combination with Ipilimumab In Trial 4, pneumonitis, including interstitial lung disease, occurred in 10% (9/94) of patients receiving OPDIVO in combination with ipilimumab and 2.2% (1/46) of patients receiving ipilimumab. Immune-mediated pneumonitis occurred in 6% (6/94) of patients receiving OPDIVO in combination with ipilimumab: Grade 5 (n=1), Grade 3 (n=2), and Grade 2 (n=3) pneumonitis. The median time to onset for the six cases was 2.5 months (range: 1.3 to 4.6 months). In the patient with fatal pneumonitis, the event was diagnosed after discontinuation of OPDIVO in combination with ipilimumab for another immune-mediated adverse reaction; this patient died from pneumonitis more than 30 days after the last dose. The remaining five patients had dose interruption or permanent discontinuation of OPDIVO in combination with ipilimumab. All six patients received high-dose corticosteroids. Immune-mediated pneumonitis completely resolved in the five patients with Grade 2 or 3 pneumonitis. OPDIVO in combination with ipilimumab was restarted for one patient with Grade 2 pneumonitis after complete resolution, and pneumonitis did not recur. 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. 5.2 Immune-Mediated Colitis 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. When administered as a single agent, 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)]. When administered in combination with ipilimumab, withhold OPDIVO for moderate colitis (Grade 2). Permanently discontinue OPDIVO for severe or life-threatening (Grade 3 or 4) colitis or for recurrent colitis upon restarting OPDIVO [see Dosage and Administration (2.4)]. Melanoma OPDIVO as a Single Agent In Trial 1, diarrhea or colitis occurred in 21% (57/268) of patients receiving OPDIVO and 18% (18/102) of patients receiving chemotherapy. Immune-mediated colitis occurred in 2.2% (6/268) of patients receiving OPDIVO: five patients with Grade 3 and one patient with Grade 2 colitis. The median time to onset of immune-mediated colitis from initiation of OPDIVO was 2.5 months (range: 1 to 6 months). In three patients, colitis was diagnosed after discontinuation of OPDIVO for other reasons, and Grade 2 or 3 colitis led to interruption or permanent discontinuation of OPDIVO in the remaining three patients. Five of these six patients received high-dose corticosteroids (at least 40 mg prednisone equivalents) for a median duration of 1.4 months (range: 3 days to 2.4 months) preceding corticosteroid taper. The sixth patient continued on low-dose corticosteroids started for another immune-mediated adverse reaction. Immune-mediated colitis improved to Grade 0 with corticosteroids in five patients, including one patient with Grade 3 colitis retreated after complete resolution (defined as improved to Grade 0 with completion of corticosteroids) without additional events of colitis. Grade 2 colitis was ongoing in one patient. In Trial 5, diarrhea or colitis occurred in 28% (58/206) of patients receiving OPDIVO and 25% (52/205) of patients receiving dacarbazine. Immune-mediated colitis occurred in 4.9% (10/206) of patients receiving OPDIVO: five patients with Grade 3 and five with Grade 2. The median time to onset was 5.1 months (range: 3 days to 12.5 months). In six of ten patients, colitis was diagnosed after discontinuation of OPDIVO for other reasons, and Grade 2 or 3 colitis was followed by interruption or permanent discontinuation of OPDIVO in the remaining four patients. Nine of these ten patients received high-dose corticosteroids for a median duration of 1 month (range: 3 days to 7.4 months) preceding corticosteroid taper. Colitis improved to Grade 0 with corticosteroids in nine patients, with complete resolution occurring in six of these patients. Two patients who restarted OPDIVO after complete resolution had recurrence of colitis which again completely resolved with additional corticosteroids. In one patient, Grade 3 colitis was ongoing with corticosteroids continuing. OPDIVO in Combination with Ipilimumab In Trial 4, diarrhea or colitis occurred in 57% (54/94) of patients receiving OPDIVO in combination with ipilimumab and 46% (21/46) of patients receiving ipilimumab. Immune-mediated colitis occurred in 33% (31/94) of patients receiving OPDIVO in combination with ipilimumab: one patient with Grade 4, 16 patients with Grade 3, nine patients with Grade 2, and five patients with Grade 1 colitis. The median time to onset was 1.4 months (range: 6.1 days to 5.3 months). Immune-mediated colitis led to permanent discontinuation of OPDIVO in combination with ipilimumab in 17 patients. Thirty of the 31 patients received high-dose corticosteroids for a median duration of 1.2 months (range: 1 day to 6 months) and 11 received infliximab. Immune-mediated colitis resolved following treatment with immunosuppressive medications in 30 patients. Four patients with Grade 2 immune-mediated colitis experienced complete resolution after restarting OPDIVO in combination with ipilimumab. In Trial 4, there were three patients who died without resolution 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. RCC In Trial 6, 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 (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. 5.3 Immune-Mediated Hepatitis 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 1 to 2 mg/kg/day prednisone equivalents for moderate (Grade 2) or greater transaminase elevations, with or without concomitant elevation in total bilirubin. Withhold OPDIVO for moderate (Grade 2) and permanently discontinue OPDIVO for severe (Grade 3) or life-threatening (Grade 4) immune-mediated hepatitis [see Dosage and Administration (2.4) and Adverse Reactions (6.1)]. Melanoma OPDIVO as a Single Agent In Trial 1, there was an increased incidence of liver test abnormalities in the OPDIVO-treated group as compared to the chemotherapy-treated group, with increases in AST (28% vs. 12%), alkaline phosphatase (22% vs. 13%), ALT (16% vs. 5%), and total bilirubin (9% vs. 0). Immune-mediated hepatitis occurred in 1.1% (3/268) of patients receiving OPDIVO: two patients with Grade 3 and one patient with Grade 2 hepatitis. The time to onset was 97, 113, and 86 days after initiation of OPDIVO. In one patient, hepatitis was diagnosed after discontinuation of OPDIVO for other reasons. In two patients, OPDIVO was withheld. All three patients received high-dose corticosteroids (at least 40 mg prednisone equivalents). Liver tests improved to Grade 1 within 4 to 15 days of initiation of corticosteroids. Immune-mediated hepatitis resolved and did not recur with continuation of corticosteroids in two patients; the third patient died of disease progression with persistent hepatitis. The two patients with Grade 3 hepatitis that resolved restarted OPDIVO and, in one patient, Grade 3 immune-mediated hepatitis recurred resulting in permanent discontinuation of OPDIVO. In Trial 5, there was an increased incidence of liver test abnormalities in the OPDIVO-treated group as compared to the dacarbazine-treated group, with increases in ALT (25% vs. 19%), AST (24% vs. 19%), alkaline phosphatase (21% vs. 14%), and total bilirubin (13% vs. 6%). Immune-mediated hepatitis occurred in 0.9% (2/206) of patients receiving OPDIVO: one patient with Grade 2 and one patient with Grade 3. The time to onset was 4.1 and 4.4 months after initiation of OPDIVO. In both patients, hepatitis was diagnosed after discontinuation of OPDIVO for other reasons. Both patients received high-dose corticosteroids; one also received mycophenolic acid. Hepatitis resolved in both patients, with corticosteroids continuing in one. OPDIVO in Combination with Ipilimumab In Trial 4, immune-mediated hepatitis occurred in 15% (14/94) of patients receiving OPDIVO in combination with ipilimumab: three patients with Grade 4, nine patients with Grade 3, and two patients with Grade 2 hepatitis. The median time to onset was 2.8 months (range: 3 weeks to 5.7 months). Five patients discontinued OPDIVO in combination with ipilimumab due to hepatitis. Thirteen of the 14 patients received high-dose corticosteroids and three received mycophenolic acid. Complete resolution (defined as improved to Grade 0 with completion of corticosteroids) occurred in nine patients. Among four patients for whom OPDIVO in combination with ipilimumab was restarted, three had recurrence or worsening of hepatitis and one improved on corticosteroids. 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. 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. 5.4 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)]. Melanoma In Trial 4, hypophysitis occurred in 13% (12/94) of patients receiving OPDIVO in combination with ipilimumab: two patients with Grade 3 and 10 patients with Grade 2 hypophysitis. The median time to onset was 2.9 months (range: 1.4 to 5.5 months). Ten patients received corticosteroids, including both patients with Grade 3 hypophysitis. OPDIVO in combination with ipilimumab was restarted for eight patients without resulting in worsening of hypophysitis. Four patients were continuing with corticosteroids. 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)]. Melanoma and NSCLC In Trial 4, adrenal insufficiency occurred in 9% (8/94) of patients receiving OPDIVO in combination with ipilimumab: three patients with Grade 3, four patients with Grade 2, and one patient with Grade 1 adrenal insufficiency. The median time to onset was 3 months (range: 1.2 to 5.6 months). Grade 3 adrenal insufficiency led to discontinuation of OPDIVO in combination with ipilimumab in one patient. The remaining events each occurred after treatment discontinuation, except in two cases where OPDIVO in combination with ipilimumab was restarted and did not lead to recurrence. Three patients received high-dose corticosteroids. Six patients experienced resolution of adrenal insufficiency, three of whom remained on corticosteroids. In Trials 1, 3, and 5 (n=761), less than 1.0% 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 OPDIVO as a Single Agent In Trial 1, Grade 1 or 2 hypothyroidism occurred in 8% (21/268) of patients receiving OPDIVO and none of the 102 patients receiving chemotherapy. The median time to onset was 2.5 months (range: 24 days to 11.7 months). Seventeen of the 21 patients with hypothyroidism received levothyroxine. Fifteen of 17 patients received subsequent OPDIVO dosing while continuing to receive levothyroxine. In Trial 1, Grade 1 or 2 hyperthyroidism occurred in 3.0% (8/268) of patients receiving OPDIVO and 1.0% (1/102) of patients receiving chemotherapy. The median time to onset in OPDIVO-treated patients was 1.6 months (range: 0 to 3.3 months). Four of five patients with Grade 1 hyperthyroidism and two of three patients with Grade 2 hyperthyroidism had documented resolution of hyperthyroidism; all three patients received medical management for Grade 2 hyperthyroidism. In Trial 5, hypothyroidism occurred in 7% (14/206) of patients receiving OPDIVO (one patient with Grade 3) and 0.9% (2/205) of patients receiving dacarbazine. The median time to onset in OPDIVO patients was 4.5 months (range: 1.4 to 13.8 months). Twelve of the 14 patients received levothyroxine. In two patients, hypothyroidism was diagnosed after treatment discontinuation; ten patients received subsequent OPDIVO dosing while continuing to receive levothyroxine. In Trial 5, hyperthyroidism occurred in 4.4% (9/206) of patients receiving OPDIVO (one patient with Grade 3) and 0.9% (2/205) of patients receiving dacarbazine. The median time to onset in OPDIVO-treated patients was 1.9 months (range: 1.1 to 8.3 months). The one patient with Grade 3 hyperthyroidism received high-dose corticosteroids (at least 40 mg prednisone equivalents) and medical management, with complete resolution (defined as improved to Grade 0 with completion of corticosteroids and medical management). Six of eight patients with Grade 1 or 2 hyperthyroidism had documented resolution; four of these eight received medical management and two developed subsequent hypothyroidism. OPDIVO in Combination with Ipilimumab In Trial 4, hypothyroidism occurred in 19% (18/94) of patients receiving OPDIVO in combination with ipilimumab. All were Grade 1 or 2 in severity except for one patient who experienced Grade 3 autoimmune thyroiditis. The median time to onset was 2.1 months (range: 1 day to 4.7 months). Two patients received high-dose corticosteroids. Sixteen of the 18 patients received replacement therapy with levothyroxine. Complete resolution of hypothyroidism occurred in one patient allowing discontinuation of levothyroxine. Thirteen of 16 patients received subsequent OPDIVO in combination with ipilimumab while continuing to receive levothyroxine. In Trial 4, Grade 1 hyperthyroidism occurred in 2.1% (2/94) of patients receiving OPDIVO in combination with ipilimumab. The time to onset for both cases was 3 weeks. Both patients had a resolution of hyperthyroidism without requiring medical management and both subsequently developed hypothyroidism. 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 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 corticosteroids. Complete resolution of hypothyroidism occurred in one patient. OPDIVO 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 Trial 5, diabetes mellitus or diabetic ketoacidosis occurred in 1.0% (2/206) of patients receiving OPDIVO and none of the 205 receiving dacarbazine. One patient had Grade 3 diabetic ketoacidosis and one patient had Grade 2 diabetes mellitus. Neither patient had a prior history of diabetes. Time to onset was 2.1 and 2.8 months, respectively. In both patients, OPDIVO was withheld and management with insulin was initiated and continuing. Grade 3 diabetic ketoacidosis resolved, and OPDIVO was resumed. Grade 2 diabetes mellitus, which began while the patient was receiving corticosteroids for management of another adverse reaction, remained ongoing with continuation of OPDIVO. 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. 5.5 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) and Adverse Reactions (6.1)]. Melanoma OPDIVO as a Single Agent In Trial 1, there was an increased incidence of elevated creatinine in the OPDIVO-treated group as compared to the chemotherapy-treated group (13% vs. 9%). Grade 2 or 3 immune-mediated nephritis or renal dysfunction occurred in 0.7% (2/268) of patients at 3.5 and 6 months after OPDIVO initiation, respectively. OPDIVO was permanently discontinued in both patients; both received high-dose corticosteroids (at least 40 mg prednisone equivalents). Immune-mediated nephritis resolved and did not recur with continuation of corticosteroids in one patient. Renal dysfunction was ongoing in one patient. In Trial 5, there was an increased incidence of elevated creatinine in the OPDIVO-treated group as compared to the dacarbazine-treated group (11% vs. 10%). Grade 3 immune-mediated renal dysfunction occurred in 0.5% (1/206) of patients at 5.5 months after OPDIVO initiation. In this patient, dose interruption and initiation of high-dose corticosteroids were followed by complete resolution (defined as improved to Grade 0 with completion of corticosteroids). OPDIVO was restarted with recurrence of renal dysfunction and again resolved with corticosteroids. OPDIVO in Combination with Ipilimumab In Trial 4, Grade 2 or higher immune-mediated nephritis or renal dysfunction occurred in 2.1% (2/94) of patients. Time to onset was 1.3 weeks and 6.7 months, respectively. In one of these patients, immune-mediated renal dysfunction resolved with corticosteroids and withholding of OPDIVO, whereas the second patient died with persistent 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. 5.6 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)]. Melanoma (OPDIVO in Combination with Ipilimumab) and NSCLC In Trial 4, immune-mediated rash occurred in 37% (35/94) of patients receiving OPDIVO in combination with ipilimumab: six patients with Grade 3, 10 patients with Grade 2, and 19 patients with Grade 1 rash. The median time to onset was 2.4 weeks (range: 1 day to 6.5 months). Among the six patients with Grade 3 rash, four received systemic corticosteroids, four had OPDIVO in combination with ipilimumab withheld then restarted without resulting in recurrence of high-grade rash, and all had resolution to Grade 0 or 1 with no further requirement for systemic corticosteroids. Among the 29 patients with Grade 1 or 2 rash, six received systemic corticosteroids and two had OPDIVO in combination with ipilimumab withheld. None of the 35 patients discontinued treatment due to immune-mediated rash. 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. 5.7 Immune-Mediated Encephalitis Immune-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 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 dose of 1 to 2 mg/kg/day prednisone equivalents for patients with immune-mediated encephalitis, followed by corticosteroid taper. Permanently discontinue OPDIVO for immune-mediated encephalitis [see Dosage and Administration (2.4)]. Across clinical studies of 8490 patients receiving OPDIVO as a single agent or in combination with ipilimumab, less than 1.0% of patients were identified as having encephalitis. 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. 5.8 Other Immune-Mediated Adverse Reactions Other clinically significant immune-mediated adverse reactions can occur. Immune-mediated adverse reactions may occur after discontinuation of OPDIVO therapy. 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 hormone-replacement therapy. Upon improvement to Grade 1 or less, initiate corticosteroid taper and continue to taper over at least 1 month. Consider restarting OPDIVO after completion of corticosteroid taper based on the severity of the event [see Dosage and Administration (2.4)]. The following clinically significant, immune-mediated adverse reactions occurred in less than 1.0% of patients receiving OPDIVO as a single agent or in combination with ipilimumab in Trials 1, 3, 4, 5, and 6 (n=1261): uveitis, pancreatitis, facial and abducens nerve paresis, demyelination, polymyalgia rheumatica, autoimmune neuropathy, Guillain-Barré syndrome, hypopituitarism, and systemic inflammatory response syndrome. 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. Across clinical trials of OPDIVO in combination with ipilimumab, the following additional clinically significant, immune-mediated adverse reactions were identified: sarcoidosis, duodenitis, and gastritis. 5.9 Infusion Reactions Severe infusion reactions have been reported in less than 1.0% of patients in clinical trials of OPDIVO as a single agent. 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 and NSCLC In Trials 3 and 5, Grade 2 infusion reactions occurred in 1.0% (5/493) of patients receiving OPDIVO. In Trial 4, Grade 2 infusion reactions occurred in 3.2% (3/94) of patients receiving OPDIVO in combination with ipilimumab. 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. 5.10 Embryofetal Toxicity Based on its mechanism of action and data from animal studies, OPDIVO can cause fetal harm when administered to a pregnant woman. In animal reproduction studies, administration of nivolumab to cynomolgus monkeys from the onset of organogenesis through delivery resulted in increased abortion and premature infant death. Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with OPDIVO-containing regimen and for at least 5 months after the last dose of OPDIVO [see Use in Specific Populations (8.1, 8.3)]. 6 ADVERSE REACTIONS The following adverse reactions are discussed in greater detail in other sections of the labeling. • Immune-Mediated Pneumonitis [see Warnings and Precautions (5.1)] • Immune-Mediated Colitis [see Warnings and Precautions (5.2)] • Immune-Mediated Hepatitis [see Warnings and Precautions (5.3)] • Immune-Mediated Endocrinopathies [see Warnings and Precautions (5.4)] • Immune-Mediated Nephritis and Renal Dysfunction [see Warnings and Precautions (5.5) ] • Immune-Mediated Rash [see Warnings and Precautions (5.6) ] • Immune-Mediated Encephalitis [see Warnings and Precautions (5.7)] • Other Immune-Mediated Adverse Reactions [see Warnings and Precautions (5.8) ] • Infusion Reactions [see Warnings and Precautions (5.9)] 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The data in the Warning and Precautions section reflect exposure to OPDIVO, as a single agent, for clinically significant adverse reactions in 1590 patients enrolled in Trials 1, 3, 5, 6, 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 (5.1, 5.8)]. In addition, clinically significant adverse reactions with OPDIVO, in combination with ipilimumab, were evaluated in 188 patients with melanoma enrolled in Trial 4 (n=94) or an additional dose-finding study (n=94) administering OPDIVO in combination with ipilimumab at doses of OPDIVO ranging from 0.3 to 3 mg/kg and doses of ipilimumab ranging from 1 to 3 mg/kg, supplemented by immune-mediated adverse reaction reports in ongoing clinical trials [see Warnings and Precautions (5.1, 5.8)]. The data described below reflect exposure to OPDIVO as a single agent in Trials 1 and 5 and to OPDIVO in combination with ipilimumab in Trial 4, 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 OPDIVO as a Single Agent 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)]. The median duration of exposure was 5.3 months (range: 1 day to 13.8+ months) with a median of eight doses (range: 1 to 31) 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%). OPDIVO 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 2 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 2: 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)  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: Cardiac Disorders: ventricular arrhythmia Eye Disorders: iridocyclitis General Disorders and Administration Site Conditions: infusion-related reactions Investigations: increased amylase, increased lipase Nervous System Disorders: dizziness, peripheral and sensory neuropathy Skin and Subcutaneous Tissue Disorders: exfoliative dermatitis, erythema multiforme, vitiligo, psoriasis Table 3:  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)  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). 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)]. 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 4 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. Table 4: Selected Adverse Reactions 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)  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 5:  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)  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). OPDIVO in Combination with Ipilimumab The safety of OPDIVO, administered in combination with ipilimumab, was evaluated in Trial 4, a randomized, double-blind trial in which 140 previously untreated patients with unresectable or metastatic melanoma received OPDIVO 1 mg/kg in combination with ipilimumab 3 mg/kg every 3 weeks for four cycles, followed by OPDIVO 3 mg/kg as a single agent every 2 weeks (n=94) or single-agent ipilimumab 3 mg/kg every 3 weeks for four cycles followed by placebo every 2 weeks (n=46) [see Clinical Studies (14.1)]. The median duration of exposure to OPDIVO was 2.2 months (range: 1 day to 10 months). Among patients who received OPDIVO in combination with ipilimumab, 29% were exposed to OPDIVO for at least 6 months. Trial 4 enrolled patients who had not received systemic anticancer therapy for unresectable or metastatic melanoma and excluded patients with ocular melanoma, autoimmune disease, any condition requiring chronic systemic treatment with corticosteroids (more than 10 mg daily prednisone equivalent) or other immunosuppressive medications, a positive test for hepatitis B or C, or a history of HIV. The study population characteristics were: 67% male, median age 65 years, 98% white, baseline ECOG performance status 0 (82%) or 1 (17%), 46% with M1c stage disease; 25% with elevated LDH at baseline, 3% with a history of brain metastasis, and 23% had BRAF V600 mutation-positive melanoma. There were more patients in the OPDIVO plus ipilimumab group who had cutaneous melanoma (84% vs. 62%), while a greater proportion of patients in the ipilimumab group had acral/mucosal melanoma (8% vs. 21%). Serious adverse reactions (62% vs. 39%), adverse reactions leading to permanent discontinuation (43% vs. 11%) or dose delays (47% vs. 22%), and Grade 3 or 4 adverse reactions (69% vs. 43%) all occurred more frequently in patients receiving OPDIVO plus ipilimumab compared with those receiving single-agent ipilimumab. In the OPDIVO plus ipilimumab group, 27% (25/94) of patients did not complete all four cycles of OPDIVO in combination with ipilimumab. The first occurrence of a Grade 3 or 4 adverse reaction was during administration of OPDIVO in combination with ipilimumab in 56 patients (59%) while 9 patients (10%) experienced first occurrence of a Grade 3 or 4 adverse reaction during administration of OPDIVO as a single agent. The most common adverse reactions leading to discontinuation of OPDIVO, as compared to single-agent ipilimumab, were colitis (16% vs. 2%), diarrhea not treated with corticosteroids (4% vs. 4%), increased ALT levels (4% vs. 0), pneumonitis (3% vs. 0), and AST increase (3% vs. 0). The most frequent serious adverse events with OPDIVO in combination with ipilimumab, as compared to single-agent ipilimumab, were colitis (17% vs. 9%), diarrhea (9% vs. 7%), pyrexia (6% vs. 7%), and pneumonitis (5% vs. 0). The most common adverse reactions (reported in at least 20% of patients) in Trial 4 receiving OPDIVO in combination with ipilimumab were rash, pruritus, headache, vomiting, and colitis. Table 6 summarizes the incidence of selected adverse reactions occurring in at least 10% of patients treated with OPDIVO, in combination with ipilimumab. Table 6: Selected Adverse Reactions Occurring in ≥10% of Patients Receiving OPDIVO in Combination with Ipilimumab and at a Higher Incidence than in the Ipilimumab Arm (Between Arm Difference of ≥5% [All Grades] or ≥2% [Grades 3-4]) (Trial 4)  a  OPDIVO 1 mg/kg in combination with ipilimumab 3 mg/kg every 3 weeks for 4 doses, followed by OPDIVO 3 mg/kg as a single agent every 2 weeks until disease progression or unacceptable toxicity. b  Rash is a composite term which includes dermatitis, dermatitis acneiform, dermatitis bullous, erythema, rash erythematous, rash generalized, rash macular, rash maculopapular, rash papular, and rash pruritic. Other clinically important adverse reactions in less than 10% of patients treated with OPDIVO in combination with ipilimumab were: Nervous System Disorders: peripheral neuropathy Gastrointestinal Disorders: stomatitis, colonic perforation Table 7: Selected Laboratory Abnormalities Worsening from Baseline Occurring in ≥10% of Patients Receiving OPDIVO in Combination with Ipilimumab and at a Higher Incidence than in the Ipilimumab Arm (Between Arm Difference of ≥5% [All Grades] or ≥2% [Grades 3-4]) (Trial 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 in combination with ipilimumab group (range: 84 to 88 patients) and ipilimumab group (range: 45 to 46 patients). b  OPDIVO 1 mg/kg in combination with ipilimumab 3 mg/kg every 3 weeks for 4 doses, followed by OPDIVO 3 mg/kg as a single agent every 2 weeks until disease progression or unacceptable toxicity. 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)]. 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 8 summarizes selected adverse reactions occurring more frequently in at least 10% of OPDIVO-treated patients. Table 8: 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) 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%). Table 9: Selected Laboratory Abnormalities Worsening from Baseline Occurring in ≥10% of OPDIVO-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)  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. b  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)]. 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 10 summarizes adverse reactions that occurred in greater than 15% of OPDIVO-treated patients. Table 10:Grade 1-4 Adverse Reactions in >15% of Patients Receiving OPDIVO (Trial 6)  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 maculo-papular, 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 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 11 summarizes the laboratory abnormalities that occurred in greater than 15% of OPDIVO-treated patients. Table 11:  Grade 1-4 Laboratory Values Worsening from Baseline Occurring in >15% of Patients on OPDIVO (Trial 6)  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). 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). 6.2 Immunogenicity As with all therapeutic proteins, there is a potential for immunogenicity. Of 639 patients who were treated with OPDIVO 3 mg/kg every 2 weeks and evaluable for the presence of anti-nivolumab antibodies, 73 patients (11.4%) tested positive for treatment-emergent anti-nivolumab antibodies by an electrochemiluminescent (ECL) assay. Neutralizing antibodies against nivolumab were detected in five patients (0.8%). There was no evidence of altered pharmacokinetic profile or toxicity profile with anti-nivolumab binding antibody development. Of 105 patients who were treated with OPDIVO in combination with ipilimumab and evaluable for the presence of anti-nivolumab antibodies, 23 patients (21.9%) tested positive for treatment-emergent anti-nivolumab antibodies by an ECL assay. Neutralizing antibodies against nivolumab were detected in one patient (1%). There was no evidence of altered toxicity profile 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. 7 DRUG INTERACTIONS No formal pharmacokinetic drug-drug interaction studies have been conducted with OPDIVO. 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Risk Summary Based on its mechanism of action [see Clinical Pharmacology (12.1)] and data from animal studies, OPDIVO can cause fetal harm when administered to a pregnant woman [see Clinical Pharmacology (12.1)]. In animal reproduction studies, administration of nivolumab to cynomolgus monkeys from the onset of organogenesis through delivery resulted in increased abortion and premature infant death [see Data]. Human IgG4 is known to cross the placental barrier and nivolumab is an immunoglobulin G4 (IgG4); therefore, nivolumab has the potential to be transmitted from the mother to the developing fetus. The effects of OPDIVO are likely to be greater during the second and third trimesters of pregnancy. There are no available human data informing the drug-associated risk. Advise pregnant women of the potential risk to a fetus. The background risk of major birth defects and miscarriage for the indicated population is unknown; however, the background risk in the U.S. general population of major birth defects is 2% to 4% and of miscarriage is 15% to 20% of clinically recognized pregnancies. Data 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–dose-related increase in spontaneous abortion and increased neonatal death. Based on its mechanism of action, fetal exposure to nivolumab may increase the risk of developing immune-mediated disorders or altering the normal immune response and immune-mediated disorders have been reported in PD-1 knockout mice. In surviving infants (18 of 32 compared to 11 of 16 vehicle-exposed infants) of cynomolgus monkeys treated with nivolumab, there were no apparent malformations and no effects on neurobehavioral, immunological, or clinical pathology parameters throughout the 6-month postnatal period. 8.2 Lactation Risk Summary It is not known whether OPDIVO is present in human milk. Because many drugs, including antibodies, are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from OPDIVO, advise women to discontinue breastfeeding during treatment with OPDIVO. 8.3 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 (8.1)]. 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. 8.4 Pediatric Use The safety and effectiveness of OPDIVO have not been established in pediatric patients. 8.5 Geriatric Use Of the 272 patients randomized to OPDIVO in Trial 1, 35% of patients were 65 years or older and 15% were 75 years or older. Of the 292 patients randomized to OPDIVO in Trial 3, 37% of patients were 65 years or older and 7% were 75 years or older. Of the 210 patients randomized to OPDIVO in Trial 5, 50% of patients 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. In these trials, no overall differences in safety or efficacy were reported between elderly patients and younger patients. Trial 4, OPDIVO in combination with ipilimumab, did not include sufficient numbers of patients aged 65 years and older to determine whether they respond differently from younger patients. 8.6 Renal Impairment Based on a population pharmacokinetic analysis, no dose adjustment is recommended in patients with renal impairment [see Clinical Pharmacology (12.3)]. 8.7 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)]. 10 OVERDOSAGE There is no information on overdosage with OPDIVO. 11 DESCRIPTION Nivolumab is a human monoclonal antibody that blocks the interaction between PD-1 and its ligands, PD-L1 and PD-L2. Nivolumab is an IgG4 kappa immunoglobulin that has a calculated molecular mass of 146 kDa. OPDIVO is a sterile, preservative-free, non-pyrogenic, clear to opalescent, colorless to pale-yellow liquid that may contain light (few) particles. OPDIVO injection for intravenous infusion is supplied in single-dose vials. Each mL of OPDIVO solution contains nivolumab 10 mg, mannitol (30 mg), pentetic acid (0.008 mg), polysorbate 80 (0.2 mg), sodium chloride (2.92 mg), sodium citrate dihydrate (5.88 mg), and Water for Injection, USP. May contain hydrochloric acid and/or sodium hydroxide to adjust pH to 6. 12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action Binding of the PD-1 ligands, PD-L1 and PD-L2, to the PD-1 receptor found on T cells, inhibits T-cell proliferation and cytokine production. Upregulation of PD-1 ligands occurs in some tumors and signaling through this pathway can contribute to inhibition of active T-cell immune surveillance of tumors. Nivolumab is a human immunoglobulin G4 (IgG4) monoclonal antibody that binds to the PD-1 receptor and blocks its interaction with PD-L1 and PD-L2, releasing PD-1 pathway-mediated inhibition of the immune response, including the anti-tumor immune response. In syngeneic mouse tumor models, blocking PD-1 activity resulted in decreased tumor growth. Combined nivolumab (anti-PD-1) and ipilimumab (anti-CTLA-4) mediated inhibition results in enhanced T-cell function that is greater than the effects of either antibody alone, and results in improved anti-tumor responses in metastatic melanoma. In murine syngeneic tumor models, dual blockade of PD-1 and CTLA-4 resulted in increased anti-tumor activity. 12.3 Pharmacokinetics Nivolumab pharmacokinetics (PK) was assessed using a population PK approach for both single-agent OPDIVO and OPDIVO in combination with ipilimumab. OPDIVO as a single agent: The PK of single-agent nivolumab was studied in patients over a dose range of 0.1 to 20 mg/kg administered as a single dose or as multiple doses of OPDIVO every 2 or 3 weeks. The geometric mean (% coefficient of variation [CV%]) clearance (CL) is 9.5 mL/h (49.7%), geometric mean volume of distribution at steady state (Vss) is 8.0 L (30.4%), and geometric mean elimination half-life (t1/2) is 26.7 days (101%). Steady-state concentrations of nivolumab were reached by 12 weeks when administered at 3 mg/kg every 2 weeks, and systemic accumulation was approximately 3-fold. The exposure to nivolumab increased dose proportionally over the dose range of 0.1 to 10 mg/kg administered every 2 weeks. OPDIVO in combination with ipilimumab: The geometric mean (CV%) CL, Vss, and terminal half-life of nivolumab were 10.0 mL/h (50.3%), 7.92 L (30.1%), and 24.8 days (94.3%), respectively. When administered in combination, the CL of nivolumab was increased by 24%, whereas there was no effect on the clearance of ipilimumab. When administered in combination, the clearance of nivolumab increased by 42% in the presence of anti-nivolumab antibodies. There was no effect of anti-ipilimumab antibodies on the clearance of ipilimumab. Specific Populations: Based on a population PK analysis, the clearance of nivolumab increased with increasing body weight supporting a weight-based dose. The population PK analysis suggested that the following factors had no clinically important effect on the clearance of nivolumab: age (29 to 87 years), gender, race, baseline LDH, PD-L1 expression, tumor type, tumor size, renal impairment, and mild hepatic impairment. Renal Impairment: The effect of renal impairment on the clearance of nivolumab was evaluated by a population PK analysis in patients with mild (eGFR 60 to 89 mL/min/1.73 m2; n=313), moderate (eGFR 30 to 59 mL/min/1.73 m2; n=140), or severe (eGFR 15 to 29 mL/min/1.73 m2; n=3) renal impairment. No clinically important differences in the clearance of nivolumab were found between patients with renal impairment and patients with normal renal function [see Use in Specific Populations (8.6)]. Hepatic Impairment: The effect of hepatic impairment on the clearance of nivolumab was evaluated by population PK analyses in patients with mild hepatic impairment (total bilirubin [TB] less than or equal to the upper limit of normal [ULN] and AST greater than ULN or TB less than 1 to 1.5 times ULN and any AST; n=92). No clinically important differences in the clearance of nivolumab were found between patients with mild hepatic impairment and patients with normal hepatic function. Nivolumab has not been studied in patients with moderate (TB greater than 1.5 to 3 times ULN and any AST) or severe hepatic impairment (TB greater than 3 times ULN and any AST) [see Use in Specific Populations (8.7)]. 13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility No studies have been performed to assess the potential of nivolumab for carcinogenicity or genotoxicity. Fertility studies have not been performed with nivolumab. In 1-month and 3-month repeat-dose toxicology studies in monkeys, there were no notable effects in the male and female reproductive organs; however, most animals in these studies were not sexually mature. 13.2 Animal Toxicology and/or Pharmacology In animal models, inhibition of PD-1 signaling increased the severity of some infections and enhanced inflammatory responses. M. tuberculosis–infected PD-1 knockout mice exhibit markedly decreased survival compared with wild-type controls, which correlated with increased bacterial proliferation and inflammatory responses in these animals. PD-1 knockout mice have also shown decreased survival following infection with lymphocytic choriomeningitis virus. 14 CLINICAL STUDIES 14.1 Unresectable or Metastatic Melanoma OPDIVO as a Single Agent Trial 1 was a multicenter, open-label trial that randomized (2:1) patients with unresectable or metastatic melanoma to receive either OPDIVO administered intravenously at 3 mg/kg every 2 weeks or investigator’s choice of chemotherapy, either single-agent 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. Patients were required to have progression of disease on or following ipilimumab treatment and, if BRAF V600 mutation positive, a BRAF inhibitor. The trial excluded patients with autoimmune disease, medical conditions requiring systemic immunosuppression, ocular melanoma, active brain metastasis, or a history of Grade 4 ipilimumab-related 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. Tumor assessments were conducted 9 weeks after randomization then every 6 weeks for the first year, and every 12 weeks thereafter. Efficacy was evaluated in a single-arm, non-comparative, planned interim analysis of the first 120 patients who received OPDIVO in Trial 1 and in whom the minimum duration of follow-up was 6 months. The major efficacy outcome measures in this population were confirmed objective response rate (ORR) as measured by blinded independent central review using Response Evaluation Criteria in Solid Tumors (RECIST 1.1) and duration of response. Among the 120 patients treated with OPDIVO, the median age was 58 years (range: 25 to 88), 65% of patients were male, 98% were white, and the ECOG performance score was 0 (58%) or 1 (42%). Disease characteristics were M1c disease (76%), BRAF V600 mutation positive (22%), elevated LDH (56%), history of brain metastases (18%), and two or more prior systemic therapies for metastatic disease (68%). The ORR was 32% (95% confidence interval [CI]: 23, 41), consisting of 4 complete responses and 34 partial responses in OPDIVO-treated patients. Of 38 patients with responses, 33 patients (87%) had ongoing responses with durations ranging from 2.6+ to 10+ months, which included 13 patients with ongoing responses of 6 months or longer. There were objective responses in patients with and without BRAF V600 mutation-positive melanoma. Trial 5 was a multicenter, double-blind, randomized (1:1) trial conducted in patients with BRAF V600 wild-type unresectable or metastatic melanoma. Patients were randomized to receive either OPDIVO 3 mg/kg by intravenous infusion every 2 weeks or dacarbazine 1000 mg/m2 by intravenous infusion every 3 weeks until disease progression or unacceptable toxicity. Randomization was stratified by PD-L1 status (greater than or equal to 5% of tumor cell membrane staining by immunohistochemistry vs. less than 5% or indeterminate result) and M stage (M0/M1a/M1b versus M1c). Key eligibility criteria included histologically confirmed, unresectable or metastatic, cutaneous, mucosal, or acral melanoma; no prior therapy for metastatic disease; completion of prior adjuvant or neoadjuvant therapy at least 6 weeks prior to randomization; ECOG performance status 0 or 1; absence of autoimmune disease; and absence of active brain or leptomeningeal metastases. The trial excluded patients with ocular melanoma. Tumor assessments were conducted 9 weeks after randomization then every 6 weeks for the first year and then every 12 weeks thereafter. The major efficacy outcome measure was overall survival (OS). Additional outcome measures included investigator-assessed progression-free survival (PFS) and objective response rate (ORR) per RECIST v1.1. A total of 418 patients were randomized to OPDIVO (n=210) or dacarbazine (n=208). The median age was 65 years (range: 18 to 87), 59% were men, and 99.5% were white. Disease characteristics were M1c stage disease (61%), cutaneous melanoma (74%), mucosal melanoma (11%), elevated LDH level (37%), PD-L1 greater than or equal to 5% tumor cell membrane expression (35%), and history of brain metastasis (4%). More patients in the OPDIVO arm had an ECOG performance status of 0 (71% vs. 58%). Trial 5 demonstrated a statistically significant improvement in OS for the OPDIVO arm compared with the dacarbazine arm in an interim analysis based on 47% of the total planned events for OS. Table 12 and Figure 1 summarize the efficacy results. Table 12: Efficacy Results - Trial 5  a  p-value is compared with the allocated alpha of 0.0021 for this interim analysis. Figure 1: Kaplan-Meier Curves of Overall Survival - Trial 5 At the time of analysis, 88% (63/72) of OPDIVO-treated patients had ongoing responses, which included 43 patients with ongoing response of 6 months or longer. OPDIVO in Combination with Ipilimumab Trial 4 was a multicenter, double-blind trial that randomized (2:1) patients with previously untreated, unresectable or metastatic melanoma to receive either OPDIVO in combination with ipilimumab or single-agent ipilimumab. Key eligibility criteria were no prior systemic therapy for metastatic disease; adjuvant treatment completed at least 6 weeks prior to the first dose was permitted. Patients with ocular melanoma, active brain metastasis, autoimmune disease, or medical condition requiring systemic immunosuppression were ineligible. Patients in the combination arm received OPDIVO 1 mg/kg and ipilimumab 3 mg/kg intravenously every 3 weeks for 4 doses, then OPDIVO 3 mg/kg every 2 weeks until disease progression or unacceptable toxicity. Patients in the ipilimumab arm received ipilimumab 3 mg/kg and OPDIVO-matched placebo intravenously every 3 weeks for 4 doses followed by placebo. At the time of disease progression, patients in the ipilimumab arm were offered OPDIVO 3 mg/kg every 2 weeks. Randomization was stratified by BRAF V600 mutation status based on an FDA-approved test. Tumor assessments were conducted 12 weeks after randomization then every 6 weeks for the first year, and every 12 weeks thereafter. The major efficacy outcome measure was confirmed ORR, as determined by investigator per RECIST v1.1, in patients with BRAF V600 wild-type melanoma. Additional efficacy outcome measures were investigator-assessed duration of response and progression-free survival (PFS) in patients with BRAF V600 wild-type melanoma. Among the 109 randomized patients with BRAF V600 wild-type melanoma, the median age was 66 years (range: 27 to 87 years); 65% of patients were male; 97% were white; the ECOG performance score was 0 (84%) or 1 (15%). Forty-six percent of patients had M1c disease, 20% had elevated LDH at baseline, and 100% had no evidence of BRAF V600 mutation. Clinically important differences between arms in baseline characteristics were history of brain metastasis (6% in the combination arm and none in the ipilimumab arm), acral/mucosal melanoma (10% and 24%, respectively), and cutaneous melanoma (82% and 57%, respectively). Among patients randomized to OPDIVO in combination with ipilimumab, 59% received 4 doses of OPDIVO and ipilimumab over a median of 9.1 weeks (range: 9.0 weeks to 26.3 weeks). The study demonstrated a statistically significant increase in the confirmed ORR for patients randomized to OPDIVO in combination with ipilimumab compared with those randomized to single-agent ipilimumab (see Table 13). Table 13: Efficacy Results in BRAF V600 Wild-Type Melanoma in Trial 4 a  OPDIVO 1 mg/kg in combination with ipilimumab 3 mg/kg every 3 weeks for 4 doses, followed by OPDIVO 3 mg/kg as a single agent every 2 weeks until disease progression or unacceptable toxicity. Of 43 patients randomized to OPDIVO in combination with ipilimumab, 9 patients (21%) with response duration ranging from 3 to 7 months have progressed after response, died, or received subsequent therapy. The remaining 34 patients (79%) had ongoing responses at the time of final analysis; in 14 patients the duration of ongoing responses is at least 6 months but less than 9 months and in 20 patients the duration of ongoing responses is at least 9 months. 14.2 Metastatic Non-Small Cell Lung Cancer Second-line Treatment of Metastatic Squamous NSCLC Trial 2 was a randomized (1:1), open-label study enrolling 272 patients with metastatic squamous NSCLC who had experienced disease progression during or after one prior platinum doublet-based chemotherapy regimen. Patients received OPDIVO (n=135) administered intravenously at 3 mg/kg every 2 weeks or docetaxel (n=137) administered intravenously at 75 mg/m2 every 3 weeks. This study included patients regardless of their PD-L1 status. The trial excluded patients with autoimmune disease, symptomatic interstitial lung disease, or untreated brain metastasis. Patients with treated brain metastases were eligible if neurologically returned to baseline at least 2 weeks prior to enrollment, and either off corticosteroids, or on a stable or decreasing dose of <10 mg daily prednisone equivalents. The first tumor assessments were conducted 9 weeks after randomization and continued every 6 weeks thereafter. The majr efficacy outcome measure was overall survival (OS). In Trial 2, the median age was 63 years (range: 39 to 85) with 44% ≥65 years of age and 11% ≥75 years of age. The majority of patients were white (93%) and male (76%). Baseline ECOG performance status was 0 (24%) or 1 (76%). The trial demonstrated a statistically significant improvement in OS for patients randomized to OPDIVO as compared with docetaxel at the prespecified interim analysis when 199 events were observed (86% of the planned number of events for final analysis) (Table 14 and Figure 2). Table 14: Overall Survival in Trial 2 (Intent-to-Treat Analysis)  a  p-value is derived from a log-rank test stratified by region and prior paclitaxel use; the corresponding O’Brien-Fleming efficacy boundary significance level is 0.0315. b  Derived from a stratified proportional hazards model. Figure 2: Overall Survival - Trial 2 Second-line Treatment of Metastatic Non-Squamous NSCLC Trial 3 was a randomized (1:1), open-label study of 582 patients with metastatic non-squamous NSCLC who had experienced disease progression during or after one prior platinum doublet-based chemotherapy regimen. Appropriate prior targeted therapy in patients with known sensitizing EGFR mutation or ALK translocation was allowed. Patients received OPDIVO (n=292) administered intravenously at 3 mg/kg every 2 weeks or docetaxel (n=290) administered intravenously at 75 mg/m2 every 3 weeks. Randomization was stratified by prior maintenance therapy (yes vs. no) and number of prior therapies (1 vs. 2). The trial excluded patients with autoimmune disease, medical conditions requiring systemic immunosuppression, symptomatic interstitial lung disease, or untreated brain metastasis. Patients with treated brain metastases were eligible if neurologically stable. The first tumor assessments were conducted 9 weeks after randomization and continued every 6 weeks thereafter. The major efficacy outcome measure was overall survival (OS). Additional efficacy outcome measures were investigator-assessed objective response rate (ORR) and progression-free survival (PFS). In addition, prespecified analyses were conducted in subgroups defined by PD-L1 expression. In Trial 3, the median age was 62 years (range: 21 to 85) with 42% of patients ≥65 years and 7% of patients ≥75 years. The majority of patients were white (92%) and male (55%); the majority of patients were enrolled in Europe (46%) followed by the US/Canada (37%) and the rest of the world (17%). Baseline ECOG performance status was 0 (31%) or 1 (69%), 79% were former/current smokers, 3.6% had NSCLC with ALK rearrangement, 14% had NSCLC with EGFR mutation, and 12% had previously treated brain metastases. Prior therapy included platinum-doublet regimen (100%) and 40% received maintenance therapy as part of the first-line regimen. Histologic subtypes included adenocarcinoma (93%), large cell (2.4%), and bronchoalveolar (0.9%). Trial 3 demonstrated a statistically significant improvement in OS for patients randomized to OPDIVO as compared with docetaxel at the prespecified interim analysis when 413 events were observed (93% of the planned number of events for final analysis) (Table 15 and Figure 3). Table 15: Efficacy Results in Trial 3 a  Based on stratified log-rank test. b  p-value is compared with .0408 of the allocated alpha for this interim analysis. c  Based on a stratified proportional hazards model. d  Based on the stratified Cochran-Mantel-Haenszel test. Figure 3: Overall Survival - Trial 3 Archival tumor specimens were evaluated for PD-L1 expression following completion of the trial. Across the study population, 22% (127/582) of patients had non-quantifiable results. Of the remaining 455 patients, the proportion of patients in retrospectively determined subgroups based on PD-L1 testing using the PD-L1 IHC 28-8 pharmDx assay were: 46% (209/455) PD-L1 negative, defined as <1% of tumor cells expressing PD-L1 and 54% (246/455) had PD-L1 expression, defined as ≥1% of tumor cells expressing PD-L1. Among the 246 patients with tumors expressing PD-L1, 26% (65/246) had ≥1%, but <5% tumor cells with positive staining, 7% (16/246) had ≥5% but <10% tumor cells with positive staining, and 67% (165/246) had greater than or equal to 10% tumor cells with positive staining. Figure 4 summarizes the results of prespecified analyses of survival in subgroups determined by percentage of tumor cells expressing PD-L1. Figure 5 summarizes the results of prespecified analyses of progression-free survival in subgroups determined by percentage of tumor cells expressing PD-L1. Figure 4: Forest Plot: OS Based on PD-L1 Expression - Trial 3 Figure 5: Forest Plot: PFS Based on PD-L1 Expression - Trial 3 14.3 Renal Cell Carcinoma Trial 6 was a randomized (1:1), open-label study in patients with advanced RCC who had experienced disease progression during or after one or two prior anti-angiogenic therapy regimens. Patients had to have a Karnofsky Performance Score (KPS) ≥70% and patients were included regardless of their PD-L1 status. Trial 6 excluded patients with any history of or concurrent brain metastases, prior treatment with an mTOR inhibitor, active autoimmune disease, or medical conditions requiring systemic immunosuppression. Patients were stratified by region, Memorial Sloan Kettering Cancer Center (MSKCC) Risk Group and the number of prior anti-angiogenic therapies. Patients were randomized to OPDIVO (n=410) administered intravenously at 3 mg/kg every 2 weeks or everolimus (n=411) administered orally 10 mg daily. The median age was 62 years (range: 18 to 88) with 40% ≥65 years of age and 9% ≥75 years of age. The majority of patients were male (75%) and white (88%) and 34% and 66% of patients had a baseline KPS of 70% to 80% and 90% to 100%, respectively. The majority of patients (77%) were treated with one prior anti-angiogenic therapy. Patient distribution by MSKCC risk groups was 34% favorable, 47% intermediate, and 19% poor. The first tumor assessments were conducted 8 weeks after randomization and continued every 8 weeks thereafter for the first year and then every 12 weeks until progression or treatment discontinuation, whichever occurred later. The major efficacy outcome measure was overall survival (OS). The trial demonstrated a statistically significant improvement in OS for patients randomized to OPDIVO as compared with everolimus at the prespecified interim analysis when 398 events were observed (70% of the planned number of events for final analysis) (Table 16 and Figure 6). OS benefit was observed regardless of PD-L1 expression level. Other endpoints include confirmed objective response rates, which are also presented in Table 16. Table 16: Efficacy Results - Trial 6 a  Hazard ratio is obtained from a Cox proportional-hazards model stratified by MSKCC risk group, number of prior anti-angiogenic therapies, and region with treatment as the sole covariate. b  p-value is obtained from a two-sided log-rank test stratified by MSKCC risk group, number of prior anti-angiogenic therapies, and region. The corresponding O’Brien-Fleming efficacy boundary significance level is 0.0148. Figure 6: Overall Survival - Trial 6 16 HOW SUPPLIED/STORAGE AND HANDLING OPDIVO® (nivolumab) is available as follows: Carton Contents NDC 40 mg/4 mL single-dose vial 0003-3772-11 100 mg/10 mL single-dose vial 0003-3774-12 Store OPDIVO under refrigeration at 2°C to 8°C (36°F to 46°F). Protect OPDIVO from light by storing in the original package until time of use. Do not freeze or shake. ------------------------------------------------- Opdivo (nivolumab) Demonstrates High Overall Response Rate of 87% for Treatment of Relapsed or Refractory Hodgkin Lymphoma --Safety and tolerability results, a primary objective in the study, were consistent with other Opdivo trials --Results from another arm of this Phase 1 study show promising activity with Opdivo in non-Hodgkin Lymphoma Bristol-Myers Squibb Company (NYSE:BMY) today announced positive results from a cohort of patients in its ongoing Phase 1b trial (CheckMate -039) which evaluated PD-1 immune checkpoint inhibitor, Opdivo (nivolumab), in patients with relapsed or refractory hematological malignancies (n=23). Results showed high levels of response in patients with relapsed or refractory classical Hodgkin Lymphoma (HL), with an overall response rate of 87% (n=20) and stable disease in 13% (n=3). These findings were published today in The New England Journal of Medicine (NEJM) and highlighted in the press briefing on Saturday, December 6 during the 56th annual meeting of the American Society for Hematology . In patients with HL, initial treatment typically consists of chemotherapy and/or radiation therapy, followed by an autologous stem cell transplant (ASCT) if the disease recurs. For those who relapse within one year after receiving a standard of care like ASCT, the median survival is only 1.3 years after progression. “Despite the current treatment landscape, this patient population is still experiencing relatively short-lived responses that often result in relapse. So, there is a critical need to identify new options that can improve outcomes during the course of their care,” said Philippe Armand, M.D., Ph.D, medical oncologist, Dana-Farber Cancer Institute and Associate Professor, Department of Medicine, Harvard Medical School. “These findings with Opdivo are incredibly encouraging because they show that an immuno-oncology approach with a check point blockade has the potential to be applied to lymphomas.” CheckMate -039 results support the first Breakthrough Therapy Designation for Opdivo, granted in May 2014 by the U.S. Food and Drug Administration (FDA) for the treatment of patients with HL after failure of autologous stem cell transplant and brentuximab. “Bristol-Myers Squibb has a long standing commitment to the treatment of hematologic cancers, and we continue to advance potential treatment options for this patient population through our leadership in Immuno-Oncology,” said Michael Giordano, senior vice president, Head of Development, Oncology, Bristol-Myers Squibb. “These new data from Opdivo represent the next step towards our goal of identifying therapies that can transform the standard of care across a variety of cancer types.” On Monday, December 8, additional results from CheckMate -039 will be highlighted in a separate oral presentation (Abstract #291) that could support the potential of Opdivo to treat patients with relapsed or refractory non-Hodgkin lymphoma. This ongoing Phase 1 trial is also exploring the combination of Opdivo and Yervoy in hematologic malignancies. Data from that arm of the study will be published at a later date. Bristol-Myers Squibb has proposed the name Opdivo (pronounced op-dee-voh), which, if approved by health authorities, will serve as the trademark for nivolumab. About CheckMate -039 CheckMate -039 is an ongoing Phase 1 dose escalation study of patients with relapsed and refractory hematological malignancies, which includes a cohort evaluating Opdivo in patients with HL after failure of autologous stem cell transplant and brentuximab. The cohort includes 23 patients who were treated with Opdivo 3 mg/kg at week one, week four and every two weeks until disease progression or complete response or for a maximum of two years. The primary endpoints included evaluating the safety and tolerability of Opdivo. Secondary endpoints included determining antitumor activity, characterizing Opdivo pharmacokinetics and immunogenicity, and assessing PD-L1 and PD-L2 expression as a predictive biomarker. In the trial, 87% (n=20) achieved an overall response, with 17% (n=4) achieving complete response and 70% (n=16) a partial response. The remaining patients, 13% (n=3), experienced stable disease. Of the patients who achieved a complete and partial response, 60% (n=12) had their first response within eight weeks (range: 3-39 weeks). Data from the study also showed a progression-free survival rate of 86% at 24 weeks, meaning patients lived six months longer without their disease worsening. Safety results were reported in all patients treated in the study. Overall, drug-related adverse events of any grade were reported in 78% of patients (n=18), with the most common being rash (22%) and decreased platelet count (17%). Of these, Grade 3 adverse events occurred in 22% of patients (n=5). There were no treatment-related Grade 4 or 5 adverse events. About Opdivo Cancer cells may exploit “regulatory” pathways, such as checkpoint pathways, to hide from the immune system and shield the tumor from immune attack. Opdivo is an investigational, fully-human PD-1 immune checkpoint inhibitor that binds to the checkpoint receptor PD-1 (programmed death-1) expressed on activated T-cells. Bristol-Myers Squibb has a broad, global development program to study Opdivo in multiple tumor types consisting of more than 50 trials – as monotherapy or in combination with other therapies – in which more than 7,000 patients have been enrolled worldwide. Among these are several potentially registrational trials in non-small cell lung cancer (NSCLC), melanoma, renal cell carcinoma (RCC), head and neck cancer, glioblastoma and non-Hodgkin lymphoma. In 2012, the FDA granted Fast Track designation for Opdivo in NSCLC, melanoma and RCC. In April 2014, the company initiated a rolling submission with the FDA for Opdivo in third-line pre-treated squamous cell NSCLC and expects to complete the submission by year-end. The FDA granted Opdivo Breakthrough Therapy Designation in May 2014 for the treatment of patients with Hodgkin lymphoma after failure of autologous stem cell transplant and brentuximab. On July 4, Ono Pharmaceutical Co. announced that Opdivo received manufacturing and marketing approval in Japan for the treatment of patients with unresectable melanoma, making Opdivo the first PD-1 immune checkpoint inhibitor to receive regulatory approval anywhere in the world. On September 26, Bristol-Myers Squibb announced that the FDA accepted for priority review the Biologics License Application for previously treated advanced melanoma, and the Prescription Drug User Fee Act goal date for a decision is March 30, 2015. The FDA also granted Opdivo Breakthrough Therapy status for this indication. In the European Union, the European Medicines Agency (EMA) has validated for review the Marketing Authorization Application for Opdivo in advanced melanoma. The application has also been granted accelerated assessment by the EMA’s CHMP. The EMA also validated for review the MAA for nivolumab in NSCLC. http://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=f570b9c4-6846-4de2-abfa-4d0a4ae4e394