PRINCETON, N.J., & ALAMEDA, Calif.--(BUSINESS WIRE)--?Bristol Myers Squibb?(NYSE: BMY) and?Exelixis, Inc.?(NASDAQ: EXEL) today announced results from new analyses from the pivotal Phase 3 CheckMate -9ER trial, demonstrating clinically meaningful, sustained efficacy benefits as well as quality of life improvements with the combination of?OPDIVO^??(nivolumab) and?CABOMETYX^??(cabozantinib) compared to sunitinib in the first-line treatment of advanced renal cell carcinoma (RCC). These data will be presented in two posters at the virtual American Society of Clinical Oncology (ASCO) 2021 Genitourinary Cancers Symposium from February 11 to 13, 2021 and featured in the Poster Highlights Session on February 13, 2021 from 9:00 a.m. ? 9:45 a.m. EST. Abstract #308: Nivolumab + cabozantinib (NIVO+CABO) vs. sunitinib (SUN) for advanced renal cell carcinoma (aRCC): outcomes by sarcomatoid histology and updated trial results with extended follow-up of CheckMate -9ER (Motzer, et. al.) With a median follow-up of two years (23.5 months),?OPDIVO?in combination with?CABOMETYX?continued to show superior progression-free survival (PFS), objective response rate (ORR) and overall survival (OS) versus sunitinib, with a low rate of treatment-related adverse events (TRAEs) leading to discontinuation. No new safety signals were identified with extended follow-up. Across the full study population:

• PFS: The combination doubled median PFS (17.0 months vs. 8.3 months, respectively; HR 0.52; 95% CI: 0.43 to 0.64), the trial?s primary endpoint, compared to sunitinib.
• ORR: Nearly twice as many patients responded to?OPDIVO?in combination with?CABOMETYX?vs. sunitinib (54.8% vs. 28.4%).
• OS:?OPDIVO?in combination with?CABOMETYX?maintained improvements in OS, demonstrating a 34% reduction in the risk of death compared to sunitinib (HR: 0.66; 95% CI: 0.50 to 0.87).
• Disease control rate: In an exploratory analysis, the combination was associated with a disease control rate (including complete response, partial response and stable disease) of 88.2% vs. 69.9% with sunitinib.
• Complete response (CR): The CR rate, also exploratory, for?OPDIVO?in combination with?CABOMETYX?was 9.3% compared to 4.3% with sunitinib.
• TRAE discontinuations: Among patients treated with?OPDIVO?and?CABOMETYX, 6.6% discontinued both agents due to TRAEs, 9.7% discontinued?OPDIVO?only and 7.2% discontinued?CABOMETYX?only.

In an exploratory subgroup analysis of 75 patients with sarcomatoid features, the combination of?OPDIVO?and?CABOMETYX?showed benefit in this population typically associated with a poor prognosis, reducing the risk of death by 64% vs. sunitinib (HR 0.36; 95% CI: 0.17 to 0.79) and demonstrating both superior PFS (10.3 months vs. 4.2 months) and ORR (55.9% vs. 22.0%). Abstract #285: Patient-reported outcomes of patients with advanced renal cell carcinoma (aRCC) treated with first-line nivolumab plus cabozantinib versus sunitinib: the CheckMate -9ER trial (Cella, et. al.) In a separate analysis from the CheckMate -9ER trial conducted with 18.1 months of median follow-up, patients treated with the combination of?OPDIVO?and?CABOMETYX?reported statistically significant health-related quality of life benefits. Treatment with?OPDIVO?in combination with?CABOMETYX?was associated with a lower treatment burden, decreased risk of deterioration and a reduction of disease-related symptoms compared to sunitinib. These exploratory outcomes were measured using Functional Assessment of Cancer Therapy Kidney Symptom Index-19 (FKSI-19), a quality of life tool specific to kidney cancer, and EQ-5D-3L instruments. ?There is a continued need for new therapies that show benefit across subgroups of patients with advanced renal cell carcinoma,? said Robert Motzer, M.D., Kidney Cancer Section Head, Genitourinary Oncology Service, and Jack and Dorothy Byrne Chair in Clinical Oncology, Memorial Sloan Kettering Cancer Center. ?In CheckMate -9ER, nivolumab in combination with cabozantinib doubled progression-free survival, increased overall survival and response rate and, in an exploratory analysis, showed impressive disease control, and these promising efficacy results were sustained with extended follow-up. Also of note, patients in this study reported significant quality of life improvements, which are important for patients undergoing treatment for this challenging disease.? ?These additional data from CheckMate -9ER provide strong evidence that?OPDIVO?in combination with?CABOMETYX?may help patients achieve and maintain control of their disease,? said Dana Walker, M.D., M.S.C.E., vice president, development program lead, genitourinary cancers, Bristol Myers Squibb. ?This regimen brings together two proven agents in advanced renal cell carcinoma, and we believe it will play an important role alongside other first-line treatment options. We look forward to the potential to build on our heritage of transforming patient outcomes with?OPDIVO-based combinations across a wide range of tumor types.? ?The overall survival benefit and quality-of-life measures reported in these findings continue to show improvement with the combination of?CABOMETYX?and?OPDIVO?after an extended follow-up of two years,? said Gisela Schwab, M.D., President, Product Development and Medical Affairs and Chief Medical Officer, Exelixis. ?These new findings from CheckMate -9ER and the recent FDA approval of the combination regimen are extremely encouraging as we further explore the potential of?CABOMETYX?in combination with immunotherapies to help more patients with difficult-to-treat tumor types.? OPDIVO?in combination with?CABOMETYX?was approved for the first-line treatment of advanced RCC by the U.S. Food and Drug Administration (FDA) in January 2021, and further applications are under review with health authorities globally. Bristol Myers Squibb and Exelixis thank the patients and investigators involved in the CheckMate -9ER clinical trial. About CheckMate -9ER CheckMate -9ER is an open-label, randomized, multi-national Phase 3 trial evaluating patients with previously untreated advanced or metastatic renal cell carcinoma (RCC). A total of 651 patients (23% favorable risk, 58% intermediate risk, 20% poor risk; 25% PD-L1=1%) were randomized to receive?OPDIVO?plus?CABOMETYX?(n=323) vs. sunitinib (n=328). The primary endpoint is progression-free survival (PFS). Secondary endpoints include overall survival (OS) and objective response rate (ORR). The primary efficacy analysis is comparing the doublet combination vs. sunitinib in all randomized patients. The trial is sponsored by Bristol Myers Squibb and Ono Pharmaceutical Co and co-funded by Exelixis, Ipsen and Takeda Pharmaceutical Company Limited. About Renal Cell Carcinoma Renal cell carcinoma (RCC) is the most common type of kidney cancer in adults, accounting for more than 179,000 deaths worldwide each year. RCC is approximately twice as common in men as in women, with the highest rates of the disease in North America and Europe. The five-year survival rate for those diagnosed with metastatic, or advanced, kidney cancer is 13%. Bristol Myers Squibb: Creating a Better Future for People with Cancer Bristol Myers Squibb is inspired by a single vision ? transforming patients? lives through science. The goal of the company?s cancer research is to deliver medicines that offer each patient a better, healthier life and to make cure a possibility. Building on a legacy across a broad range of cancers that have changed survival expectations for many, Bristol Myers Squibb researchers are exploring new frontiers in personalized medicine, and through innovative digital platforms, are turning data into insights that sharpen their focus. Deep scientific expertise, cutting-edge capabilities and discovery platforms enable the company to look at cancer from every angle. Cancer can have a relentless grasp on many parts of a patient?s life, and Bristol Myers Squibb is committed to taking actions to address all aspects of care, from diagnosis to survivorship. Because as a leader in cancer care, Bristol Myers Squibb is working to empower all people with cancer to have a better future. About?OPDIVO^? Opdivo?is a programmed death-1 (PD-1) immune checkpoint inhibitor that is designed to uniquely harness the body?s own immune system to help restore anti-tumor immune response. By harnessing the body?s own immune system to fight cancer,?Opdivo?has become an important treatment option across multiple cancers. Opdivo?s?leading global development program is based on Bristol Myers Squibb?s scientific expertise in the field of Immuno-Oncology and includes a broad range of clinical trials across all phases, including Phase 3, in a variety of tumor types. To date, the?Opdivo?clinical development program has treated more than 35,000 patients. The?Opdivo?trials have contributed to gaining a deeper understanding of the potential role of biomarkers in patient care, particularly regarding how patients may benefit from?Opdivo?across the continuum of PD-L1 expression. In July 2014,?Opdivo?was the first PD-1 immune checkpoint inhibitor to receive regulatory approval anywhere in the world.?Opdivo?is currently approved in more than 65 countries, including the United States, the European Union, Japan and China. In October 2015, the Company?s?Opdivo?and Yervoy combination regimen was the first Immuno-Oncology combination to receive regulatory approval for the treatment of metastatic melanoma and is currently approved in more than 50 countries, including the United States and the European Union. About?CABOMETYX^??(cabozantinib) In the U.S.,?CABOMETYX?tablets are approved for the treatment of patients with advanced RCC; for the treatment of patients with HCC who have been previously treated with sorafenib; and for patients with advanced RCC as a first-line treatment in combination with nivolumab.?CABOMETYX?tablets have also received regulatory approvals in the European Union and additional countries and regions worldwide. In 2016, Exelixis granted Ipsen exclusive rights for the commercialization and further clinical development of cabozantinib outside of the United States and Japan. In 2017, Exelixis granted exclusive rights to Takeda Pharmaceutical Company Limited for the commercialization and further clinical development of cabozantinib for all future indications in Japan. Exelixis holds the exclusive rights to develop and commercialize cabozantinib in the United States. OPDIVO^??INDICATIONS OPDIVO^??(nivolumab), as a single agent, is indicated for the treatment of patients with unresectable or metastatic melanoma. OPDIVO^??(nivolumab), in combination with YERVOY^??(ipilimumab), is indicated for the treatment of patients with unresectable or metastatic melanoma. OPDIVO^??(nivolumab), in combination with YERVOY^??(ipilimumab), is indicated for the first-line treatment of adult patients with metastatic non-small cell lung cancer (NSCLC) whose tumors express PD-L1 (=1%) as determined by an FDA-approved test, with no EGFR or ALK genomic tumor aberrations. OPDIVO^??(nivolumab), in combination with YERVOY^??(ipilimumab) and 2 cycles of platinum-doublet chemotherapy, is indicated for the first-line treatment of adult patients with metastatic or recurrent non-small cell lung cancer (NSCLC), with no EGFR or ALK genomic tumor aberrations. 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. OPDIVO^??(nivolumab), in combination with YERVOY^??(ipilimumab), is indicated for the first-line treatment of adult patients with unresectable malignant pleural mesothelioma (MPM). OPDIVO^??(nivolumab), in combination with YERVOY^??(ipilimumab), is indicated for the first-line treatment of patients with intermediate or poor risk advanced renal cell carcinoma (RCC). OPDIVO^??(nivolumab), in combination with cabozantinib, is indicated for the first-line treatment of patients with advanced renal cell carcinoma (RCC). OPDIVO^??(nivolumab) is indicated for the treatment of patients with advanced renal cell carcinoma (RCC) who have received prior anti-angiogenic therapy. OPDIVO^??(nivolumab) is indicated for the treatment of adult patients with classical Hodgkin lymphoma (cHL) that has relapsed or progressed after autologous hematopoietic stem cell transplantation (HSCT) and brentuximab vedotin or after 3 or more lines of systemic therapy that includes autologous HSCT. This indication is approved under accelerated approval based on overall response rate. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials. OPDIVO^??(nivolumab) is indicated for the treatment of patients with recurrent or metastatic squamous cell carcinoma of the head and neck (SCCHN) with disease progression on or after platinum-based therapy. OPDIVO^??(nivolumab) is indicated for the treatment of patients with locally advanced or metastatic urothelial carcinoma who have disease progression during or following platinum-containing chemotherapy or have disease progression within 12 months of neoadjuvant or adjuvant treatment with platinum-containing chemotherapy. This indication is approved under accelerated approval based on tumor response rate and duration of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials. OPDIVO^??(nivolumab), as a single agent, is indicated for the treatment of adult and pediatric (12 years and older) patients with microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) metastatic colorectal cancer (CRC) that has progressed following treatment with a fluoropyrimidine, oxaliplatin, and irinotecan. This indication is approved under accelerated approval based on overall response rate and duration of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials. OPDIVO^??(nivolumab), in combination with YERVOY^??(ipilimumab), is indicated for the treatment of adults and pediatric patients 12 years and older with microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) metastatic colorectal cancer (CRC) that has progressed following treatment with a fluoropyrimidine, oxaliplatin, and irinotecan. This indication is approved under accelerated approval based on overall response rate and duration of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials. OPDIVO^??(nivolumab) is indicated for the treatment of patients with hepatocellular carcinoma (HCC) who have been previously treated with sorafenib. This indication is approved under accelerated approval based on overall response rate and duration of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials. OPDIVO^??(nivolumab), in combination with YERVOY^??(ipilimumab), is indicated for the treatment of patients with hepatocellular carcinoma (HCC) who have been previously treated with sorafenib. This indication is approved under accelerated approval based on overall response rate and duration of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials. OPDIVO^??(nivolumab) is indicated for the adjuvant treatment of patients with melanoma with involvement of lymph nodes or metastatic disease who have undergone complete resection. OPDIVO^??(nivolumab) is indicated for the treatment of patients with unresectable advanced, recurrent or metastatic esophageal squamous cell carcinoma (ESCC) after prior fluoropyrimidine- and platinum-based chemotherapy. OPDIVO^??IMPORTANT SAFETY INFORMATION Severe and Fatal Immune-Mediated Adverse Reactions Immune-mediated adverse reactions listed herein may not include all possible severe and fatal immune-mediated adverse reactions. Immune-mediated adverse reactions, which may be severe or fatal, can occur in any organ system or tissue. While immune-mediated adverse reactions usually manifest during treatment, they can also occur after discontinuation of OPDIVO or YERVOY. Early identification and management are essential to ensure safe use of OPDIVO and YERVOY. Monitor for signs and symptoms that may be clinical manifestations of underlying immune-mediated adverse reactions. Evaluate clinical chemistries including liver enzymes, creatinine, adrenocorticotropic hormone (ACTH) level, and thyroid function at baseline and periodically during treatment with OPDIVO and before each dose of YERVOY. In cases of suspected immune-mediated adverse reactions, initiate appropriate workup to exclude alternative etiologies, including infection. Institute medical management promptly, including specialty consultation as appropriate. Withhold or permanently discontinue OPDIVO and YERVOY depending on severity (please see section 2 Dosage and Administration in the accompanying Full Prescribing Information). In general, if OPDIVO or YERVOY interruption or discontinuation is required, administer systemic corticosteroid therapy (1 to 2 mg/kg/day prednisone or equivalent) until improvement to Grade 1 or less. Upon improvement to Grade 1 or less, initiate corticosteroid taper and continue to taper over at least 1 month. Consider administration of other systemic immunosuppressants in patients whose immune-mediated adverse reactions are not controlled with corticosteroid therapy. Toxicity management guidelines for adverse reactions that do not necessarily require systemic steroids (e.g., endocrinopathies and dermatologic reactions) are discussed below. Immune-Mediated Pneumonitis OPDIVO and YERVOY can cause immune-mediated pneumonitis. The incidence of pneumonitis is higher in patients who have received prior thoracic radiation. In patients receiving OPDIVO monotherapy, immune-mediated pneumonitis occurred in 3.1% (61/1994) of patients, including Grade 4 (<0.1%), Grade 3 (0.9%), and Grade 2 (2.1%). In HCC patients receiving OPDIVO 1 mg/kg with YERVOY 3 mg/kg every 3 weeks, immune-mediated pneumonitis occurred in 10% (5/49) of patients. In patients receiving OPDIVO 3 mg/kg with YERVOY 1 mg/kg every 3 weeks, immune-mediated pneumonitis occurred in 3.9% (26/666) of patients, including Grade 3 (1.4%) and Grade 2 (2.6%). In NSCLC patients receiving OPDIVO 3 mg/kg every 2 weeks with YERVOY 1 mg/kg every 6 weeks, immune-mediated pneumonitis occurred in 9% (50/576) of patients, including Grade 4 (0.5%), Grade 3 (3.5%), and Grade 2 (4.0%). Four patients (0.7%) died due to pneumonitis. In Checkmate 205 and 039, pneumonitis, including interstitial lung disease, occurred in 6.0% (16/266) of patients receiving OPDIVO. Immune-mediated pneumonitis occurred in 4.9% (13/266) of patients receiving OPDIVO, including Grade 3 (n=1) and Grade 2 (n=12). Immune-Mediated Colitis OPDIVO and YERVOY can cause immune-mediated colitis, which may be fatal. A common symptom included in the definition of colitis was diarrhea. Cytomegalovirus (CMV) infection/reactivation has been reported in patients with corticosteroid-refractory immune-mediated colitis. In cases of corticosteroid-refractory colitis, consider repeating infectious workup to exclude alternative etiologies. In patients receiving OPDIVO monotherapy, immune-mediated colitis occurred in 2.9% (58/1994) of patients, including Grade 3 (1.7%) and Grade 2 (1%). In patients receiving OPDIVO 1 mg/kg with YERVOY 3 mg/kg every 3 weeks, immune-mediated colitis occurred in 25% (115/456) of patients, including Grade 4 (0.4%), Grade 3 (14%) and Grade 2 (8%). In patients receiving OPDIVO 3 mg/kg with YERVOY 1 mg/kg every 3 weeks, immune-mediated colitis occurred in 9% (60/666) of patients, including Grade 3 (4.4%) and Grade 2 (3.7%). In a separate Phase 3 trial of YERVOY 3 mg/kg monotherapy, immune-mediated colitis occurred in 12% (62/511) of patients, including Grade 3-5 (7%) and Grade 2 (5%). Immune-Mediated Hepatitis and Hepatotoxicity OPDIVO and YERVOY can cause immune-mediated hepatitis. In patients receiving OPDIVO monotherapy, immune-mediated hepatitis occurred in 1.8% (35/1994) of patients, including Grade 4 (0.2%), Grade 3 (1.3%), and Grade 2 (0.4%). In patients receiving OPDIVO monotherapy in Checkmate 040, immune-mediated hepatitis requiring systemic corticosteroids occurred in 5% (8/154) of patients. In patients receiving OPDIVO 1 mg/ kg with YERVOY 3 mg/kg every 3 weeks, immune-mediated hepatitis occurred in 15% (70/456) of patients, including Grade 4 (2.4%), Grade 3 (11%), and Grade 2 (1.8%). In patients receiving OPDIVO 3 mg/kg with YERVOY 1 mg/kg every 3 weeks, immune-mediated hepatitis occurred in 7% (48/666) of patients, including Grade 4 (1.2%), Grade 3 (4.9%), and Grade 2 (0.4%). In a separate Phase 3 trial of YERVOY 3 mg/kg monotherapy, immune-mediated hepatitis occurred in 4.1% (21/511) of patients, including Grade 3-5 (1.6%) and Grade 2 (2.5%). OPDIVO in combination with cabozantinib can cause hepatic toxicity with higher frequencies of Grade 3 and 4 ALT and AST elevations compared to OPDIVO alone. Consider more frequent monitoring of liver enzymes as compared to when the drugs are administered as single agents. In patients receiving OPDIVO and cabozantinib, Grades 3 and 4 increased ALT or AST were seen in 11% of patients. Immune-Mediated Endocrinopathies OPDIVO and YERVOY can cause primary or secondary adrenal insufficiency, immune-mediated hypophysitis, immune-mediated thyroid disorders, and Type 1 diabetes mellitus, which can present with diabetic ketoacidosis. Withhold OPDIVO and YERVOY depending on severity (please see section 2 Dosage and Administration in the accompanying Full Prescribing Information). For Grade 2 or higher adrenal insufficiency, initiate symptomatic treatment, including hormone replacement as clinically indicated. Hypophysitis can present with acute symptoms associated with mass effect such as headache, photophobia, or visual field defects. Hypophysitis can cause hypopituitarism; initiate hormone replacement as clinically indicated. Thyroiditis can present with or without endocrinopathy. Hypothyroidism can follow hyperthyroidism; initiate hormone replacement or medical management as clinically indicated. Monitor patients for hyperglycemia or other signs and symptoms of diabetes; initiate treatment with insulin as clinically indicated. In patients receiving OPDIVO monotherapy, adrenal insufficiency occurred in 1% (20/1994), including Grade 3 (0.4%) and Grade 2 (0.6%). In patients receiving OPDIVO 1 mg/kg with YERVOY 3 mg/kg every 3 weeks, adrenal insufficiency occurred in 8% (35/456), including Grade 4 (0.2%), Grade 3 (2.4%), and Grade 2 (4.2%). In patients receiving OPDIVO 3 mg/kg with YERVOY 1 mg/kg every 3 weeks, adrenal insufficiency occurred in 7% (48/666) of patients, including Grade 4 (0.3%), Grade 3 (2.5%), and Grade 2 (4.1%). In patients receiving OPDIVO and cabozantinib, adrenal insufficiency occurred in 4.7% (15/320) of patients, including Grade 3 (2.2%) and Grade 2 (1.9%). In patients receiving OPDIVO monotherapy, hypophysitis occurred in 0.6% (12/1994) of patients, including Grade 3 (0.2%) and Grade 2 (0.3%). In patients receiving OPDIVO 1 mg/kg with YERVOY 3 mg/kg every 3 weeks, hypophysitis occurred in 9% (42/456), including Grade 3 (2.4%) and Grade 2 (6%). In patients receiving OPDIVO 3 mg/kg with YERVOY 1 mg/kg every 3 weeks, hypophysitis occurred in 4.4% (29/666) of patients, including Grade 4 (0.3%), Grade 3 (2.4%), and Grade 2 (0.9%). In patients receiving OPDIVO monotherapy, thyroiditis occurred in 0.6% (12/1994) of patients, including Grade 2 (0.2%). In patients receiving OPDIVO 3 mg/kg with YERVOY 1 mg/kg every 3 weeks, thyroiditis occurred in 2.7% (22/666) of patients, including Grade 3 (4.5%) and Grade 2 (2.2%). In patients receiving OPDIVO monotherapy, hyperthyroidism occurred in 2.7% (54/1994) of patients, including Grade 3 (<0.1%) and Grade 2 (1.2%). In patients receiving OPDIVO 1 mg/kg with YERVOY 3 mg/kg every 3 weeks, hyperthyroidism occurred in 9% (42/456) of patients, including Grade 3 (0.9%) and Grade 2 (4.2%). In patients receiving OPDIVO 3 mg/kg with YERVOY 1 mg/kg every 3 weeks, hyperthyroidism occurred in 12% (80/666) of patients, including Grade 3 (0.6%) and Grade 2 (4.5%). In patients receiving OPDIVO monotherapy, hypothyroidism occurred in 8% (163/1994) of patients, including Grade 3 (0.2%) and Grade 2 (4.8%). In patients receiving OPDIVO 1 mg/kg with YERVOY 3 mg/kg every 3 weeks, hypothyroidism occurred in 20% (91/456) of patients, including Grade 3 (0.4%) and Grade 2 (11%). In patients receiving OPDIVO 3 mg/kg with YERVOY 1 mg/kg every 3 weeks, hypothyroidism occurred in 18% (122/666) of patients, including Grade 3 (0.6%) and Grade 2 (11%). In patients receiving OPDIVO monotherapy, diabetes occurred in 0.9% (17/1994) of patients, including Grade 3 (0.4%) and Grade 2 (0.3%), and 2 cases of diabetic ketoacidosis. In patients receiving OPDIVO 3 mg/kg with YERVOY 1 mg/kg every 3 weeks, diabetes occurred in 2.7% (15/666) of patients, including Grade 4 (0.6%), Grade 3 (0.3%), and Grade 2 (0.9%). In a separate Phase 3 trial of YERVOY 3 mg/kg monotherapy, Grade 2-5 immune-mediated endocrinopathies occurred in 4% (21/511) of patients. Severe to life-threatening (Grade 3-4) endocrinopathies occurred in 9 (1.8%) patients. All 9 patients had hypopituitarism, and some had additional concomitant endocrinopathies such as adrenal insufficiency, hypogonadism, and hypothyroidism. Six of the 9 patients were hospitalized for severe endocrinopathies. Moderate (Grade 2) endocrinopathy occurred in 12 patients (2.3%), including hypothyroidism, adrenal insufficiency, hypopituitarism, hyperthyroidism and Cushing?s syndrome. Immune-Mediated Nephritis with Renal Dysfunction OPDIVO and YERVOY can cause immune-mediated nephritis. In patients receiving OPDIVO monotherapy, immune-mediated nephritis and renal dysfunction occurred in 1.2% (23/1994) of patients, including Grade 4 (<0.1%), Grade 3 (0.5%), and Grade 2 (0.6%). In patients receiving OPDIVO 3 mg/kg with YERVOY 1 mg/kg every 3 weeks, immune-mediated nephritis with renal dysfunction occurred in 4.1% (27/666) of patients, including Grade 4 (0.6%), Grade 3 (1.1%), and Grade 2 (2.2%). Immune-Mediated Dermatologic Adverse Reactions OPDIVO can cause immune-mediated rash or dermatitis. Exfoliative dermatitis, including Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), and drug rash with eosinophilia and systemic symptoms (DRESS) has occurred with PD-1/PD-L1 blocking antibodies. Topical emollients and/or topical corticosteroids may be adequate to treat mild to moderate nonexfoliative rashes. YERVOY can cause immune-mediated rash or dermatitis, including bullous and exfoliative dermatitis, SJS, TEN, and DRESS. Topical emollients and/or topical corticosteroids may be adequate to treat mild to moderate non-bullous/ exfoliative rashes. Withhold or permanently discontinue OPDIVO and YERVOY depending on severity (please see section 2 Dosage and Administration in the accompanying Full Prescribing Information). In patients receiving OPDIVO monotherapy, immune-mediated rash occurred in 9% (171/1994) of patients, including Grade 3 (1.1%) and Grade 2 (2.2%). In patients receiving OPDIVO 1 mg/kg with YERVOY 3 mg/kg every 3 weeks, immune-mediated rash occurred in 28% (127/456) of patients, including Grade 3 (4.8%) and Grade 2 (10%). In patients receiving OPDIVO 3 mg/kg with YERVOY 1 mg/kg every 3 weeks, immune-mediated rash occurred in 16% (108/666) of patients, including Grade 3 (3.5%) and Grade 2 (4.2%). In a separate Phase 3 trial of YERVOY 3 mg/kg monotherapy, immune-mediated rash occurred in 15% (76/511) of patients, including Grade 3-5 (2.5%) and Grade 2 (12%). Other Immune-Mediated Adverse Reactions The following clinically significant immune-mediated adverse reactions occurred at an incidence of <1% (unless otherwise noted) in patients who received OPDIVO monotherapy or OPDIVO in combination with YERVOY or were reported with the use of other PD-1/PD-L1 blocking antibodies. Severe or fatal cases have been reported for some of these adverse reactions:?cardiac/vascular:?myocarditis, pericarditis, vasculitis;?nervous system:?meningitis, encephalitis, myelitis and demyelination, myasthenic syndrome/myasthenia gravis (including exacerbation), Guillain-Barr? syndrome, nerve paresis, autoimmune neuropathy;?ocular:?uveitis, iritis, and other ocular inflammatory toxicities can occur;?gastrointestinal:?pancreatitis to include increases in serum amylase and lipase levels, gastritis, duodenitis;?musculoskeletal and connective tissue:?myositis/polymyositis, rhabdomyolysis, and associated sequelae including renal failure, arthritis, polymyalgia rheumatica;?endocrine:?hypoparathyroidism;?other (hematologic/immune):?hemolytic anemia, aplastic anemia, hemophagocytic lymphohistiocytosis (HLH), systemic inflammatory response syndrome, histiocytic necrotizing lymphadenitis (Kikuchi lymphadenitis), sarcoidosis, immune thrombocytopenic purpura, solid organ transplant rejection. In addition to the immune-mediated adverse reactions listed above, across clinical trials of YERVOY monotherapy or in combination with OPDIVO, the following clinically significant immune-mediated adverse reactions, some with fatal outcome, occurred in <1% of patients unless otherwise specified:?nervous system:?autoimmune neuropathy (2%), myasthenic syndrome/myasthenia gravis, motor dysfunction;?cardiovascular:?angiopathy, temporal arteritis;?ocular: blepharitis, episcleritis, orbital myositis, scleritis;?gastrointestinal:?pancreatitis (1.3%);?other (hematologic/immune):?conjunctivitis, cytopenias (2.5%), eosinophilia (2.1%), erythema multiforme, hypersensitivity vasculitis, neurosensory hypoacusis, psoriasis. Some ocular IMAR cases can be associated with retinal detachment. Various grades of visual impairment, including blindness, can occur. If uveitis occurs in combination with other immune-mediated adverse reactions, consider a Vogt-Koyanagi-Harada?like syndrome, which has been observed in patients receiving OPDIVO and YERVOY, as this may require treatment with systemic corticosteroids to reduce the risk of permanent vision loss. Infusion-Related Reactions OPDIVO and YERVOY can cause severe infusion-related reactions. Discontinue OPDIVO and YERVOY in patients with severe (Grade 3) or life-threatening (Grade 4) infusion-related reactions. Interrupt or slow the rate of infusion in patients with mild (Grade 1) or moderate (Grade 2) infusion-related reactions. In patients receiving OPDIVO monotherapy as a 60-minute infusion, infusion-related reactions occurred in 6.4% (127/1994) of patients. In a separate trial in which patients received OPDIVO monotherapy as a 60-minute infusion or a 30-minute infusion, infusion-related reactio