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Bristol-Myers Squibb Highlights Breadth of Immuno-Oncology–Based Combination Research and Commitment to Advancing Precision Medicine at ASCO 2018

May 16, 2018

PRINCETON, N.J.--(BUSINESS WIRE)--May 16, 2018--Bristol-Myers Squibb Company (NYSE:BMY) today announced that data from over 70 Company-sponsored studies and collaborations evaluating its oncology compounds across more than 20 types of cancer will be featured at the American Society of Clinical Oncology (ASCO) Annual Meeting 2018 in Chicago from June 1-5. Presentations will report data from clinical trials highlighting the potential role of Immuno-Oncology (I-O)–based combinations, including translational research to help identify patient populations that may have the potential to benefit from I-O therapy. Additional findings include patient-reported outcomes and real-world data.

Key data from Company-sponsored studies and supported research include:

Bristol-Myers Squibb Oral Abstracts

Nivolumab plus platinum-doublet chemotherapy vs chemo as first-line treatment for advanced non-small cell lung cancer with <1% tumor PD-L1 expression: results from CheckMate -227 Author: H. Borghaei Abstract #9001 Oral Abstract Session: Lung Cancer—Non-Small Cell Metastatic Monday, June 4, 3:12-3:24 PM CDT, Hall B1 NKTR-214 (CD122-biased agonist) plus nivolumab in patients with advanced solid tumors: Preliminary Phase 1/2 results of PIVOT Author: A. Diab Abstract #3006 Oral Abstract Session: Developmental Therapeutics—Immunotherapy Saturday, June 2, 5-5:12 PM CDT, Hall B1 Adjuvant therapy with nivolumab vs ipilimumab after complete resection of stage III/IV melanoma: Updated results from a Phase 3 trial (CheckMate -238) Author: J. Weber Abstract #9502 Oral Abstract Session: Melanoma/Skin Cancers Monday, June 4, 8:24-8:36 AM CDT, Arie Crown Theater Nivolumab as neoadjuvant therapy in patients with resectable Merkel cell carcinoma in CheckMate -358 Author: S. Topalian Abstract #9505 Oral Abstract Session: Melanoma/Skin Cancers Monday, June 4, 9:48-10 AM CDT, Arie Crown Theater Adaptive Phase 2 randomized trial of nivolumab after induction treatment in triple negative breast cancer (TONIC trial): Final response data stage I and first translational data Author: M. Kok Abstract #1012 Clinical Science Symposium Session: Breast Cancer Immunotherapy: Can we Crack the Code? Monday June 4, 3:48-4 PM CDT, Hall D2

New / Early Assets and Translational Medicine

BMS-986205, an indoleamine 2,3-dioxygenase 1 inhibitor (IDO1i), in combination with nivolumab: Updated safety across all tumor cohorts and efficacy in patients with advanced bladder cancer Author: J. Tabernero Abstract #4512 Poster Discussion Session: Genitourinary (Nonprostate) Cancer Saturday, June 2, 8-11:30 AM CDT, Hall A, Poster Board #338 Discussed at the Poster Discussion Session on Saturday, June 2, 1:15-2:30 PM CDT, Hall D2 Phase 1 trial of BMS-986253, an anti-IL-8 monoclonal antibody in patients with metastatic or unresectable solid tumors Author: J. Collins Abstract #3091 Poster Session: Developmental Therapeutics—Immunotherapy Monday, June 4, 8-11:30 AM CDT, Hall A, Poster Board #305 Serum interleukin 8 (IL-8) may serve as a biomarker of response to Immuno-Oncology therapy Author: M. Carleton Abstract #3025 Poster Session: Developmental Therapeutics—Immunotherapy Monday, June 4, 8-11:30 AM CDT, Hall A, Poster Board #239 Phase 1, open-label, adaptive biomarker trial that informs the evolution of combination Immuno-Oncology therapies (ADVISE), a precision I-O approach to personalized medicine Author: J. Luke Abstract #TPS3101 Poster Session: Developmental Therapeutics—Immunotherapy Monday, June 4, 8-11:30 AM CDT, Hall A, Poster Board #351a Phase 1b/2 study of nivolumab in combination with an anti–IL-8 monoclonal antibody, BMS-986253, in a biomarker-enriched population of patients with advanced cancer Author: I. Melero Abstract #TPS3109 Poster Session: Developmental Therapeutics—Immunotherapy Monday, June 4, 8-11:30 AM CDT, Hall A, Poster Board #319a Pharmacodynamics and genomic profiling of patients treated with cabiralizumab plus nivolumab provide evidence of on-target tumor immune modulations and support future clinical applications Author: M. Carleton Abstract #3020 Poster Discussion Session: Developmental Therapeutics—Immunotherapy Monday, June 4, 8-11:30 AM CDT, Hall A, Poster Board #234 Discussed at the Poster Discussion Session on Monday, June 4, 11:30 AM-12:45 PM CDT, Hall B1

Head and Neck

Nivolumab vs investigator’s choice in patients with recurrent or metastatic squamous cell carcinoma of the head and neck: Analysis of CheckMate -141 by age Author: N. Saba Abstract #6028 Poster Session: Head and Neck Cancer Saturday, June 2, 1:15-4:45 PM CDT, Hall A, Poster Board #16

Hematology

Extended 5-y follow-up of Phase 3 ELOQUENT-2 study of elotuzumab plus lenalidomide/dexamethasone (ELd) vs Ld in relapsed/refractory multiple myeloma Author: S. Lonial Abstract #8040 Poster Session: Hematologic Malignancies—Plasma Cell Dyscrasia Monday, June 4, 8-11:30 AM CDT, Hall A, Poster Board #49

Genitourinary

A Phase 3, randomized, open-label study of nivolumab combined with cabozantinib vs sunitinib in patients with previously untreated advanced or metastatic renal cell carcinoma (CheckMate -9ER) Author: T. Choueiri Abstract #TPS4598 Poster Session: Genitourinary (Nonprostate) Cancer Saturday, June 2, 8-11:30 AM CDT, Hall A, Poster Board #418a A Phase 3, open-label, randomized study of nivolumab plus ipilimumab or standard of care vs SoC alone in patients with previously untreated unresectable or metastatic urothelial carcinoma (CheckMate -901) Author: M. Galsky Abstract #TPS4588 Poster Session: Genitourinary (Nonprostate) Cancer Saturday, June 2, 8-11:30 AM CDT, Hall A, Poster Board #413a Quality of life in patients with advanced renal cell carcinoma in the randomized, open-label CheckMate -214 trial Author: D. Cella Abstract #3073 Poster Session: Developmental Therapeutics—Immunotherapy Monday, June 4, 8-11:30 AM CDT, Hall A, Poster Board #287 An open-label, Phase 2 study of nivolumab in combination with either rucaparib, docetaxel, or enzalutamide in men with castration-resistant metastatic prostate cancer (CheckMate -9KD) Author: K. Fizazi Abstract #TPS3126 Poster Session: Developmental Therapeutics—Immunotherapy Monday, June 4, 8-11:30 AM CDT, Hall A, Poster Board #327b Efficacy and safety of nivolumab in patients with advanced or recurrent uterine cervical or corpus cancers Author: K. Hasegawa Abstract #5594 Poster Session: Gynecologic Cancer Monday, June 4, 1:15-4:45 PM CDT, Hall A, Poster Board #321

Lung Cancer

Nivolumab plus ipilimumab vs platinum-doublet chemotherapy as first-line treatment for advanced non-small cell lung cancer: Safety analysis and patient-reported outcomes from CheckMate -227 Author: M. Reck Abstract #9020 Poster Discussion Session: Lung Cancer—Non-Small Cell Metastatic Sunday, June 3, 8-11:30 AM CDT, Hall A, Poster Board #343 Discussed at the Poster Discussion Session on Sunday, June 3, 11:30 AM-12:45 PM CDT, Arie Crown Theater Immuno-oncology biomarker study in a large cohort of LC-SCRUM-Japan: Assessment of PD-L1 expression and tumor mutation burden in non-small cell lung cancer patients treated with immune checkpoint inhibitors Author: K. Yoh Abstract #9070 Poster Session: Lung Cancer—Non-Small Cell Metastatic Sunday, June 3, 8-11:30 AM CDT, Hall A, Poster Board #393 Phase 1b trial of nivolumab combined with metformin for refractory/recurrent solid tumors Author: T. Kubo Abstract #TPS3119 Poster Session: Developmental Therapeutics—Immunotherapy Monday, June 4, 8-11:30 AM CDT, Hall A, Poster Board #324a

Melanoma

Treatment-free survival, a novel outcome applied to Immuno-Oncology agents in advanced melanoma Author: M. Regan Abstract #9531 Poster Session: Melanoma/Skin Cancers Monday, June 4, 1:15-4:15 PM CDT, Hall A, Poster Board #358 Clinical and economic outcomes associated with sequential treatment in BRAF mutant advanced melanoma patients Author: A. Tarhini Abstract #9538 Poster Session: Melanoma/Skin Cancers Monday, June 4, 1:15-4:15 PM CDT, Hall A, Poster Board #365 Indirect treatment comparison of nivolumab vs placebo as an adjuvant therapy for resected melanoma Author: A. Shoushtari Abstract #9593 Poster Session: Melanoma/Skin Cancers Monday, June 4, 1:15-4:15 PM CDT, Hall A, Poster Board #420 Assessing the value of nivolumab vs placebo and ipilimumab as adjuvant therapy for resected melanoma Author: M. Freeman Abstract #9594 Poster Session: Melanoma/Skin Cancers Monday, June 4, 1:15-4:15 PM CDT, Hall A, Poster Board #421

Clinical Collaborations

Anti-CD27 Agonist antibody varlilumab with nivolumab for colorectal and ovarian cancer: Phase 1/2 clinical trial results Author: R. Sanborn Abstract #3001 Oral Abstract Session: Developmental Therapeutics—Immunotherapy Saturday, June 2, 3:12-3:24 PM CDT, Hall B1 Correlation of degree of tumor immune infiltration and insertion-and-deletion burden with outcome on PD-1 therapy in advanced renal cell cancer Author: M. Voss Abstract #4518 Poster Discussion Session: Genitourinary (Nonprostate) Cancer Saturday, June 2, 1:15-2:30 PM CDT, Hall D2 Discussed at the Poster Discussion Session on Saturday, June 2, 1:15-2:30 PM CDT, Hall D2 Profiling the immune checkpoint pathway in acute myeloid leukemia Author: P. Dama Abstract #7015 Poster Discussion Session: Hematologic Malignancies—Leukemia, Myelodysplastic Syndromes, and Allotransplant Monday, June 4, 8-11:30 AM CDT, Hall A, Poster Board #75 Discussed at the Poster Discussion Session on Monday, June 4, 11:30 AM-12:45 PM CDT, E450 Initial results from first-in-human study of IPI-549, a tumor macrophage targeting agent, combined with nivolumab in advanced solid tumors Author: R. Sullivan Abstract #3013 Poster Session: Developmental Therapeutics—Immunotherapy Monday, June 4, 8-11:30 AM CDT, Hall A Discussed at the Poster Discussion Session on Monday, June 4, 11:30 AM-12:45 PM CDT, Hall B1 Veliparib in combination with nivolumab and platinum doublet chemotherapy in metastatic/advanced NSCLC Author: J. Clarke Abstract #3061 Poster Session: Developmental Therapeutics—Immunotherapy Monday, June 4, 8-11:30 AM CDT, Hall A, Poster Board #275 Epacadostat plus nivolumab for advanced melanoma: Updated phase 2 results of the ECHO-204 study Author: A. Daud Abstract #9511 Poster Session: Melanoma/Skin Cancers Monday, June 4, 1:15-4:15 PM CDT, Hall A, Poster Board #338 Discussed at the Poster Discussion Session on Monday, June 4, 2018, 4:45-6 PM CDT, E451 A Phase 1 study of concomitant galinpepimut-s in combination with nivolumab in patients with WT1+ ovarian cancer in second or third remission Author: R. O’Cearbhaill Abstract #5553 Poster Session: Gynecologic Cancer Monday, June 4, 1:15-4:45 PM CDT, Hall A, Poster Board #280

Bristol-Myers Squibb & Immuno-Oncology: Advancing Oncology Research

At Bristol-Myers Squibb, patients are at the center of everything we do. Our vision for the future of cancer care is focused on researching and developing transformational medicines, including Immuno-Oncology (I-O) therapeutic approaches, for hard-to-treat cancers that could potentially improve outcomes for these patients.

We are leading the integrated scientific understanding of both tumor cell and immune system pathways, through our extensive portfolio of investigational compounds and approved agents. Our differentiated clinical development program is studying broad patient populations across more than 50 types of cancers with 24 clinical-stage molecules designed to target different immune system pathways. Our deep expertise and innovative clinical trial designs position us to advance the I-O/I-O, I-O/chemotherapy, I-O/targeted therapies and I-O radiation therapies across multiple tumors and potentially deliver the next wave of therapies with a sense of urgency. We also continue to pioneer research that will help facilitate a deeper understanding of the role of immune biomarkers and how a patient’s tumor biology can be used as a guide for treatment decisions throughout their journey.

We understand making the promise of transformational medicines like I-O therapies a reality for the many patients who may benefit from these therapies requires not only innovation on our part but also close collaboration with leading experts in the field. Our partnerships with academia, government, advocacy and biotech companies support our collective goal of providing new treatment options to advance the standards of clinical practice.

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 enrolled more than 25,000 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 60 countries, including the United States, the European Union and Japan. 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.

INDICATIONS

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

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

OPDIVO® (nivolumab), in combination with YERVOY® (ipilimumab), is indicated for the treatment of patients with unresectable or metastatic melanoma. This indication is approved under accelerated approval based on progression-free survival. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials.

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

OPDIVO® (nivolumab) is indicated for the treatment of patients with advanced renal cell carcinoma (RCC) who have received prior anti-angiogenic therapy.

OPDIVO® (nivolumab), in combination with YERVOY® (ipilimumab), is indicated for the treatment of patients with intermediate or poor-risk, previously untreated advanced renal cell carcinoma (RCC).

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) 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) 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 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.

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® (10 mg/mL) is an injection for intravenous (IV) use.

IMPORTANT SAFETY INFORMATION

WARNING: IMMUNE-MEDIATED ADVERSE REACTIONS

YERVOY can result in severe and fatal immune-mediated adverse reactions. These immune-mediated reactions may involve any organ system; however, the most common severe immune-mediated adverse reactions are enterocolitis, hepatitis, dermatitis (including toxic epidermal necrolysis), neuropathy, and endocrinopathy. The majority of these immune-mediated reactions initially manifested during treatment; however, a minority occurred weeks to months after discontinuation of YERVOY.

Assess patients for signs and symptoms of enterocolitis, dermatitis, neuropathy, and endocrinopathy and evaluate clinical chemistries including liver function tests (LFTs), adrenocorticotropic hormone (ACTH) level, and thyroid function tests at baseline and before each dose.

Permanently discontinue YERVOY and initiate systemic high-dose corticosteroid therapy for severe immune-mediated reactions.

Immune-Mediated Pneumonitis

OPDIVO can cause immune-mediated pneumonitis. Fatal cases have been reported. Monitor patients for signs with radiographic imaging and for symptoms of pneumonitis. Administer corticosteroids for Grade 2 or more severe pneumonitis. Permanently discontinue for Grade 3 or 4 and withhold until resolution for Grade 2. In patients receiving OPDIVO monotherapy, fatal cases of immune-mediated pneumonitis have occurred. Immune-mediated pneumonitis occurred in 3.1% (61/1994) of patients. In patients receiving OPDIVO 1 mg/kg with YERVOY 3 mg/kg, immune-mediated pneumonitis occurred in 6% (25/407) of patients. In patients receiving OPDIVO 3 mg/kg with YERVOY 1 mg/kg, immune-mediated pneumonitis occurred in 4.4% (24/547) of patients.

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: Grade 3 (n=1) and Grade 2 (n=12).

Immune-Mediated Colitis

OPDIVO can cause immune-mediated colitis. Monitor patients for signs and symptoms of colitis. Administer corticosteroids for Grade 2 (of more than 5 days duration), 3, or 4 colitis. Withhold OPDIVO monotherapy for Grade 2 or 3 and permanently discontinue for Grade 4 or recurrent colitis upon re-initiation of OPDIVO. When administered with YERVOY, withhold OPDIVO and YERVOY for Grade 2 and permanently discontinue for Grade 3 or 4 or recurrent colitis. In patients receiving OPDIVO monotherapy, immune-mediated colitis occurred in 2.9% (58/1994) of patients. In patients receiving OPDIVO 1 mg/kg with YERVOY 3 mg/kg, immune-mediated colitis occurred in 26% (107/407) of patients including three fatal cases. In patients receiving OPDIVO 3 mg/kg with YERVOY 1 mg/kg, immune-mediated colitis occurred in 10% (52/547) of patients.

In a separate Phase 3 study of YERVOY 3 mg/kg, severe, life-threatening, or fatal (diarrhea of ≥7 stools above baseline, fever, ileus, peritoneal signs; Grade 3-5) immune-mediated enterocolitis occurred in 34 (7%) patients. Across all YERVOY-treated patients in that study (n=511), 5 (1%) developed intestinal perforation, 4 (0.8%) died as a result of complications, and 26 (5%) were hospitalized for severe enterocolitis.

Immune-Mediated Hepatitis

OPDIVO can cause immune-mediated hepatitis. Monitor patients for abnormal liver tests prior to and periodically during treatment. Administer corticosteroids for Grade 2 or greater transaminase elevations. For patients without HCC, withhold OPDIVO for Grade 2 and permanently discontinue OPDIVO for Grade 3 or 4. For patients with HCC, withhold OPDIVO and administer corticosteroids if AST/ALT is within normal limits at baseline and increases to >3 and up to 5 times the upper limit of normal (ULN), if AST/ALT is >1 and up to 3 times ULN at baseline and increases to >5 and up to 10 times the ULN, and if AST/ALT is >3 and up to 5 times ULN at baseline and increases to >8 and up to 10 times the ULN. Permanently discontinue OPDIVO and administer corticosteroids if AST or ALT increases to >10 times the ULN or total bilirubin increases >3 times the ULN. In patients receiving OPDIVO monotherapy, immune-mediated hepatitis occurred in 1.8% (35/1994) of patients. In patients receiving OPDIVO 1 mg/kg with YERVOY 3 mg/kg, immune-mediated hepatitis occurred in 13% (51/407) of patients. In patients receiving OPDIVO 3 mg/kg with YERVOY 1 mg/kg, immune-mediated hepatitis occurred in 7% (38/547) of patients.

In Checkmate 040, immune-mediated hepatitis requiring systemic corticosteroids occurred in 5% (8/154) of patients receiving OPDIVO.

In a separate Phase 3 study of YERVOY 3 mg/kg, severe, life-threatening, or fatal hepatotoxicity (AST or ALT elevations >5x the ULN or total bilirubin elevations >3x the ULN; Grade 3-5) occurred in 8 (2%) patients , with fatal hepatic failure in 0.2% and hospitalization in 0.4%.

Immune-Mediated Neuropathies

In a separate Phase 3 study of YERVOY 3 mg/kg, 1 case of fatal Guillain-Barré syndrome and 1 case of severe (Grade 3) peripheral motor neuropathy were reported.

Immune-Mediated Endocrinopathies

OPDIVO can cause immune-mediated hypophysitis, immune-mediated adrenal insufficiency, autoimmune thyroid disorders, and Type 1 diabetes mellitus. Monitor patients for signs and symptoms of hypophysitis, signs and symptoms of adrenal insufficiency, thyroid function prior to and periodically during treatment, and hyperglycemia. Administer hormone replacement as clinically indicated and corticosteroids for Grade 2 or greater hypophysitis. Withhold for Grade 2 or 3 and permanently discontinue for Grade 4 hypophysitis. Administer corticosteroids for Grade 3 or 4 adrenal insufficiency. Withhold for Grade 2 and permanently discontinue for Grade 3 or 4 adrenal insufficiency. Administer hormone-replacement therapy for hypothyroidism. Initiate medical management for control of hyperthyroidism. Withhold OPDIVO for Grade 3 and permanently discontinue for Grade 4 hyperglycemia.

In patients receiving OPDIVO monotherapy, hypophysitis occurred in 0.6% (12/1994) of patients. In patients receiving OPDIVO 1 mg/kg with YERVOY 3 mg/kg, hypophysitis occurred in 9% (36/407) of patients. In patients receiving OPDIVO 3 mg/kg with YERVOY 1 mg/kg, hypophysitis occurred in 4.6% (25/547) of patients In patients receiving OPDIVO monotherapy, adrenal insufficiency occurred in 1% (20/1994) of patients. In patients receiving OPDIVO 1 mg/kg with YERVOY 3 mg/kg, adrenal insufficiency occurred in 5% (21/407) of patients. In patients receiving OPDIVO 3 mg/kg with YERVOY 1 mg/kg, adrenal insufficiency occurred in 7% (41/547) of patients. In patients receiving OPDIVO monotherapy, hypothyroidism or thyroiditis resulting in hypothyroidism occurred in 9% (171/1994) of patients. Hyperthyroidism occurred in 2.7% (54/1994) of patients receiving OPDIVO monotherapy. In patients receiving OPDIVO 1 mg/kg with YERVOY 3 mg/kg, hypothyroidism or thyroiditis resulting in hypothyroidism occurred in 22% (89/407) of patients. Hyperthyroidism occurred in 8% (34/407) of patients receiving this dose of OPDIVO with YERVOY. In patients receiving OPDIVO 3 mg/kg with YERVOY 1 mg/kg, hypothyroidism or thyroiditis resulting in hypothyroidism occurred in 22% (119/547) of patients. Hyperthyroidism occurred in 12% (66/547) of patients receiving this dose of OPDIVO with YERVOY. In patients receiving OPDIVO monotherapy, diabetes occurred in 0.9% (17/1994) of patients. In patients receiving OPDIVO 1 mg/kg with YERVOY 3 mg/kg, diabetes occurred in 1.5% (6/407) of patients. In patients receiving OPDIVO 3 mg/kg with YERVOY 1 mg/kg, diabetes occurred in 2.7% (15/547) of patients.

In a separate Phase 3 study of YERVOY 3 mg/kg, severe to life-threatening immune-mediated endocrinopathies (requiring hospitalization, urgent medical intervention, or interfering with activities of daily living; Grade 3-4) occurred in 9 (1.8%) patients. All 9 patients had hypopituitarism, and some had additional concomitant endocrinopathies such as adrenal insufficiency, hypogonadism, and hypothyroidism. 6 of the 9 patients were hospitalized for severe endocrinopathies.

Immune-Mediated Nephritis and Renal Dysfunction

OPDIVO can cause immune-mediated nephritis. Monitor patients for elevated serum creatinine prior to and periodically during treatment. Administer corticosteroids for Grades 2-4 increased serum creatinine. Withhold OPDIVO for Grade 2 or 3 and permanently discontinue for Grade 4 increased serum creatinine. In patients receiving OPDIVO monotherapy, immune-mediated nephritis and renal dysfunction occurred in 1.2% (23/1994) of patients. In patients receiving OPDIVO 1 mg/kg with YERVOY 3 mg/kg, immune-mediated nephritis and renal dysfunction occurred in 2.2% (9/407) of patients. In patients receiving OPDIVO 3 mg/kg with YERVOY 1 mg/kg, immune-mediated nephritis and renal dysfunction occurred in 4.6% (25/547) of patients.

Immune-Mediated Skin Adverse Reactions and Dermatitis

OPDIVO can cause immune-mediated rash, including Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN), some cases with fatal outcome. Administer corticosteroids for Grade 3 or 4 rash. Withhold for Grade 3 and permanently discontinue for Grade 4 rash. For symptoms or signs of SJS or TEN, withhold OPDIVO and refer the patient for specialized care for assessment and treatment; if confirmed, permanently discontinue. In patients receiving OPDIVO monotherapy, immune-mediated rash occurred in 9% (171/1994) of patients. In patients receiving OPDIVO 1 mg/kg with YERVOY 3 mg/kg, immune-mediated rash occurred in 22.6% (92/407) of patients. In patients receiving OPDIVO 3 mg/kg with YERVOY 1 mg/kg, immune-mediated rash occurred in 16.6% (91/547) of patients.

In a separate Phase 3 study of YERVOY 3 mg/kg, severe, life-threatening, or fatal immune-mediated dermatitis (eg, Stevens-Johnson syndrome, toxic epidermal necrolysis, or rash complicated by full thickness dermal ulceration, or necrotic, bullous, or hemorrhagic manifestations; Grade 3-5) occurred in 13 (2.5%) patients. 1 (0.2%) patient died as a result of toxic epidermal necrolysis. 1 additional patient required hospitalization for severe dermatitis.

Immune-Mediated Encephalitis

OPDIVO can cause immune-mediated encephalitis. Evaluation of patients with neurologic symptoms may include, but not be limited to, consultation with a neurologist, brain MRI, and lumbar puncture. Withhold OPDIVO in patients with new-onset moderate to severe neurologic signs or symptoms and evaluate to rule out other causes. If other etiologies are ruled out, administer corticosteroids and permanently discontinue OPDIVO for immune-mediated encephalitis. In patients receiving OPDIVO monotherapy, encephalitis occurred in 0.2% (3/1994) of patients. Fatal limbic encephalitis occurred in one patient after 7.2 months of exposure despite discontinuation of OPDIVO and administration of corticosteroids. Encephalitis occurred in one patient receiving OPDIVO 1 mg/kg with YERVOY 3 mg/kg (0.2%) after 1.7 months of exposure. Encephalitis occurred in one patient receiving OPDIVO 3 mg/kg with YERVOY 1 mg/kg (0.2%) after approximately 4 months of exposure.

Other Immune-Mediated Adverse Reactions

Based on the severity of the adverse reaction, permanently discontinue or withhold OPDIVO, administer high-dose corticosteroids, and, if appropriate, initiate hormone-replacement therapy. Across clinical trials of OPDIVO monotherapy or in combination with YERVOY, the following clinically significant immune-mediated adverse reactions, some with fatal outcome, occurred in <1.0% of patients receiving OPDIVO: myocarditis, rhabdomyolysis, myositis, uveitis, iritis, pancreatitis, facial and abducens nerve paresis, demyelination, polymyalgia rheumatica, autoimmune neuropathy, Guillain-Barré syndrome, hypopituitarism, systemic inflammatory response syndrome, gastritis, duodenitis, sarcoidosis, histiocytic necrotizing lymphadenitis (Kikuchi lymphadenitis), motor dysfunction, vasculitis, aplastic anemia, pericarditis, and myasthenic syndrome.

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 may require treatment with systemic steroids to reduce the risk of permanent vision loss.

Infusion Reactions

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