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Bristol-Myers Squibb Presents Results From CheckMate -026, a Phase 3 Study of Opdivo (nivolumab) Monotherapy Versus Chemotherapy as First-Line Therapy in a Broad PD-L1 Positive Population With Advanced Lung Cancer

On October 9, 2016 Bristol-Myers Squibb Company (NYSE:BMY) reported the final primary analysis of CheckMate -026, a trial investigating the use of Opdivo (nivolumab) monotherapy as first-line therapy in patients with advanced non-small cell lung cancer (NSCLC) whose tumors expressed PD-L1 ≥1% (Press release, Bristol-Myers Squibb, OCT 9, 2016, View Source [SID:SID1234515664]). The study was powered to assess progression-free survival (PFS) for patients with ≥5% PD-L1 expression. The topline results from this study were previously disclosed and showed CheckMate -026 did not meet the primary endpoint of superior PFS compared to chemotherapy. In patients with ≥5% PD-L1 expression, the median PFS was 4.2 months with Opdivo and 5.9 months with platinum-based doublet chemotherapy (stratified hazard ratio [HR]=1.15 [95% CI: 0.91, 1.45, p=0.25]). Overall survival was 14.4 months for Opdivo versus 13.2 months for chemotherapy (HR=1.02 [95% CI: 0.80, 1.30]), and 60% of patients on the chemotherapy arm received subsequent Opdivo use after progression either through crossover or commercial access.

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The safety of Opdivo was consistent with the known safety profile of the drug in previous studies. Among all-treated patients, treatment-related adverse events (AE) of any grade and Grade 3/4 occurred in 71% and 18% of Opdivo-treated patients and 92% and 51% of chemotherapy-treated patients, respectively.

"Opdivo has replaced the standard of care in previously treated metastatic NSCLC patients regardless of PD-L1 expression, and this study aimed to answer an important clinical question of whether this PD-1 inhibitor could provide superior benefit over chemotherapy in a broad patient population in the first-line setting," said Mark Socinski, M.D., executive medical director, Florida Hospital Cancer Institute, Orlando, and lead author of the study. "These findings provide additional understanding of the role of PD-1 monotherapy in treatment-naïve patients and confirm there is still a significant opportunity for improving outcomes for the majority of these patients."

These data will be presented today, October 9, during a Presidential Symposium at the 2016 European Society for Medical Oncology (ESMO) (Free ESMO Whitepaper) Congress from 5:35 – 5:50 p.m. CEST (Abstract #LBA7_PR).

"The CheckMate -026 trial results strengthen our belief that the majority of previously untreated NSCLC patients may require combination therapy in order to experience an improved benefit versus chemotherapy," said Fouad Namouni, M.D., head of development, Oncology, Bristol-Myers Squibb. "With our broad lung cancer development program, which includes a robust Phase 3 trial evaluating the combination of Opdivo and Yervoy as first-line therapy, we will continue to aim for transformative options for the majority of lung cancer patients."

About CheckMate -026

CheckMate -026 is a Phase 3, open-label, randomized study of Opdivo as monotherapy versus investigator’s choice chemotherapy in patients with advanced non-small cell lung cancer (NSCLC). Patients enrolled in the trial had received no prior systemic treatment for advanced disease and tested positive for PD-L1 expression (≥1%). The trial randomized 541 patients to receive either Opdivo 3 mg/kg intravenously every two weeks or investigator’s choice platinum-based doublet chemotherapy in squamous patients (gemcitabine with cisplatin/gemcitabine with carboplatin/paclitaxel with carboplatin) and non-squamous patients (pemetrexed with cisplatin/pemetrexed with carboplatin, followed by optional pemetrexed maintenance) until disease progression, unacceptable toxicity or completion of six cycles. The primary endpoint is progression-free survival (PFS), as assessed by the Independent Radiology Review Committee, in patients with ≥5% PD-L1 tumor expression.

About Lung Cancer

Lung cancer is the leading cause of cancer deaths globally, resulting in more than 1.5 million deaths each year, according to the World Health Organization. Non-small cell lung cancer is one of the most common types of the disease and accounts for approximately 85% of cases. About 25% to 30% of all lung cancers are squamous cell carcinomas, and non-squamous NSCLC accounts for approximately 50% to 65% of all lung cancer cases. Survival rates vary depending on the stage and type of the cancer when it is diagnosed. Globally, the five-year survival rate for Stage I NSCLC is between 47% and 50%; for Stage IV NSCLC, the five-year survival rate drops to 2%.

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 Immuno-Oncology (I-O) medicines that will raise survival expectations in hard-to-treat cancers and will change the way patients live with cancer.

We are leading the scientific understanding of I-O through our extensive portfolio of investigational and approved agents, including the first combination of two I-O agents in metastatic melanoma, and our differentiated clinical development program, which is studying broad patient populations across more than 20 types of cancers with 11 clinical-stage molecules designed to target different immune system pathways. Our deep expertise and innovative clinical trial designs uniquely position us to advance the science of combinations across multiple tumors and potentially deliver the next wave of I-O combination regimens 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 inform which patients will benefit most from I-O therapies.

We understand making the promise of I-O 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 57 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 47 countries, including the United States and the European Union.

U.S. FDA-APPROVED INDICATIONS FOR OPDIVO

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

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 confirmatory trials.

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) is indicated for the treatment of patients with classical Hodgkin lymphoma (cHL) that has relapsed or progressed after autologous hematopoietic stem cell transplantation (HSCT) and post- transplantation brentuximab vedotin. 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.

Please refer to the end of the Important Safety Information for a brief description of the patient populations studied in the CheckMate trials.

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

Immune-mediated pneumonitis, including fatal cases, occurred with OPDIVO treatment. Across the clinical trial experience with solid tumors, fatal immune-mediated pneumonitis occurred with OPDIVO. In addition, in CheckMate 069, there were six patients who died without resolution of abnormal respiratory findings. Monitor patients for signs with radiographic imaging and symptoms of pneumonitis. Administer corticosteroids for Grade 2 or greater pneumonitis. Permanently discontinue for Grade 3 or 4 and withhold until resolution for Grade 2. In CheckMate 069 and 067, immune-mediated pneumonitis occurred in 6% (25/407) of patients receiving OPDIVO with YERVOY: Fatal (n=1), Grade 3 (n=6), Grade 2 (n=17), and Grade 1 (n=1). In CheckMate 037, 066, and 067, immune-mediated pneumonitis occurred in 1.8% (14/787) of patients receiving OPDIVO: Grade 3 (n=2) and Grade 2 (n=12). In CheckMate 057, immune- mediated pneumonitis, including interstitial lung disease, occurred in 3.4% (10/287) of patients: Grade 3 (n=5), Grade 2 (n=2), and Grade 1 (n=3). In CheckMate 025, pneumonitis, including interstitial lung disease, occurred in 5% (21/406) of patients receiving OPDIVO and 18% (73/397) of patients receiving everolimus. Immune-mediated pneumonitis occurred in 4.4% (18/406) of patients receiving OPDIVO: Grade 4 (n=1), Grade 3 (n=4), Grade 2 (n=12), and Grade 1 (n=1). In CheckMate 205 and 039, pneumonitis, including interstitial lung disease, occurred in 4.9% (13/263) of patients receiving OPDIVO. Immune-mediated pneumonitis occurred in 3.4% (9/263) of patients receiving OPDIVO: Grade 3 (n=1) and Grade 2 (n=8).

Immune-Mediated Colitis

Immune-mediated colitis can occur with OPDIVO treatment. Monitor patients for signs and symptoms of colitis. Administer corticosteroids for Grade 2 (of more than 5 days duration), 3, or 4 colitis. As a single agent, withhold OPDIVO for Grade 2 or 3 and permanently discontinue for Grade 4 or recurrent colitis upon restarting OPDIVO. When administered with YERVOY, withhold OPDIVO for Grade 2 and permanently discontinue for Grade 3 or 4 or recurrent colitis upon restarting OPDIVO. In CheckMate 069 and 067, diarrhea or colitis occurred in 56% (228/407) of patients receiving OPDIVO with YERVOY. Immune-mediated colitis occurred in 26% (107/407) of patients: Grade 4 (n=2), Grade 3 (n=60), Grade 2 (n=32), and Grade 1 (n=13). In CheckMate 037, 066, and 067, diarrhea or colitis occurred in 31% (242/787) of patients receiving OPDIVO. Immune-mediated colitis occurred in 4.1% (32/787) of patients: Grade 3 (n=20), Grade 2 (n=10), and Grade 1 (n=2). In CheckMate 057, diarrhea or colitis occurred in 17% (50/287) of patients receiving OPDIVO. Immune-mediated colitis occurred in 2.4% (7/287) of patients: Grade 3 (n=3), Grade 2 (n=2), and Grade 1 (n=2). In CheckMate 025, diarrhea or colitis occurred in 25% (100/406) of patients receiving OPDIVO and 32% (126/397) of patients receiving everolimus. Immune-mediated diarrhea or colitis occurred in 3.2% (13/406) of patients receiving OPDIVO: Grade 3 (n=5), Grade 2 (n=7), and Grade 1 (n=1). In CheckMate 205 and 039, diarrhea or colitis occurred in 30% (80/263) of patients receiving OPDIVO. Immune-mediated diarrhea (Grade 3) occurred in 1.1% (3/263) 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

Immune-mediated hepatitis can occur with OPDIVO treatment. Monitor patients for abnormal liver tests prior to and periodically during treatment. Administer corticosteroids for Grade 2 or greater transaminase elevations. Withhold for Grade 2 and permanently discontinue for Grade 3 or 4 immune- mediated hepatitis. In CheckMate 069 and 067, immune-mediated hepatitis occurred in 13% (51/407) of patients receiving OPDIVO with YERVOY: Grade 4 (n=8), Grade 3 (n=37), Grade 2 (n=5), and Grade 1 (n=1). In CheckMate 037, 066, and 067, immune-mediated hepatitis occurred in 2.3% (18/787) of patients receiving OPDIVO: Grade 4 (n=3), Grade 3 (n=11), and Grade 2 (n=4). In CheckMate 057, one patient (0.3%) developed immune-mediated hepatitis. In CheckMate 025, there was an increased incidence of liver test abnormalities compared to baseline in AST (33% vs 39%), alkaline phosphatase (32% vs 32%), ALT (22% vs 31%), and total bilirubin (9% vs 3.5%) in the OPDIVO and everolimus arms, respectively. Immune-mediated hepatitis requiring systemic immunosuppression occurred in 1.5% (6/406) of patients receiving OPDIVO: Grade 3 (n=5) and Grade 2 (n=1). In CheckMate 205 and 039, hepatitis occurred in 11% (30/263) of patients receiving OPDIVO. Immune-mediated hepatitis occurred in 3.4% (9/263): Grade 3 (n=7) and Grade 2 (n=2).

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 Dermatitis

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 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

Hypophysitis, adrenal insufficiency, thyroid disorders, and type 1 diabetes mellitus can occur with OPDIVO treatment. Monitor patients for signs and symptoms of hypophysitis, signs and symptoms of adrenal insufficiency during and after treatment, thyroid function prior to and periodically during treatment, and hyperglycemia. Administer corticosteroids for Grade 2 or greater hypophysitis. Withhold for Grade 2 or 3 and permanently discontinue for Grade 4 hypophysitis. Administer corticosteroids for Grade 3 or 4 adrenal insufficiency. Withhold for Grade 2 and permanently discontinue for Grade 3 or 4 adrenal insufficiency. Administer hormone-replacement therapy for hypothyroidism. Initiate medical management for control of hyperthyroidism. Administer insulin for type 1 diabetes. Withhold OPDIVO for Grade 3 and permanently discontinue for Grade 4 hyperglycemia.

In CheckMate 069 and 067, hypophysitis occurred in 9% (36/407) of patients receiving OPDIVO with YERVOY: Grade 3 (n=8), Grade 2 (n=25), and Grade 1 (n=3). In CheckMate 037, 066, and 067, hypophysitis occurred in 0.9% (7/787) of patients receiving OPDIVO: Grade 3 (n=2), Grade 2 (n=3), and Grade 1 (n=2). In CheckMate 025, hypophysitis occurred in 0.5% (2/406) of patients receiving OPDIVO: Grade 3 (n=1) and Grade 1 (n=1). In CheckMate 069 and 067, adrenal insufficiency occurred in 5% (21/407) of patients receiving OPDIVO with YERVOY: Grade 4 (n=1), Grade 3 (n=7), Grade 2 (n=11), and Grade 1 (n=2). In CheckMate 037, 066, and 067, adrenal insufficiency occurred in 1% (8/787) of patients receiving OPDIVO: Grade 3 (n=2), Grade 2 (n=5), and Grade 1 (n=1). In CheckMate 057, 0.3% (1/287) of OPDIVO-treated patients developed adrenal insufficiency. In CheckMate 025, adrenal insufficiency occurred in 2.0% (8/406) of patients receiving OPDIVO: Grade 3 (n=3), Grade 2 (n=4), and Grade 1 (n=1). In CheckMate 205 and 039, adrenal insufficiency (Grade 2) occurred in 0.4% (1/263) of patients receiving OPDIVO. In CheckMate 069 and 067, hypothyroidism or thyroiditis occurred in 22% (89/407) of patients receiving OPDIVO with YERVOY: Grade 3 (n=6), Grade 2 (n=47), and Grade 1 (n=36). Hyperthyroidism occurred in 8% (34/407) of patients: Grade 3 (n=4), Grade 2 (n=17), and Grade 1 (n=13). In CheckMate 037, 066, and 067, hypothyroidism or thyroiditis occurred in 9% (73/787) of patients receiving OPDIVO: Grade 3 (n=1), Grade 2 (n=37), Grade 1 (n=35). Hyperthyroidism occurred in 4.4% (35/787) of patients receiving OPDIVO: Grade 3 (n=1), Grade 2 (n=12), and Grade 1 (n=22). In CheckMate 057, Grade 1 or 2 hypothyroidism, including thyroiditis, occurred in 7% (20/287) and elevated thyroid stimulating hormone occurred in 17% of patients receiving OPDIVO. Grade 1 or 2 hyperthyroidism occurred in 1.4% (4/287) of patients. In CheckMate 025, thyroid disease occurred in 11% (43/406) of patients receiving OPDIVO, including one Grade 3 event, and in 3.0% (12/397) of patients receiving everolimus. Hypothyroidism/thyroiditis occurred in 8% (33/406) of patients receiving OPDIVO: Grade 3 (n=2), Grade 2 (n=17), and Grade 1 (n=14). Hyperthyroidism occurred in 2.5% (10/406) of patients receiving OPDIVO: Grade 2 (n=5) and Grade 1 (n=5). In CheckMate 205 and 039, hypothyroidism/thyroiditis occurred in 12% (32/263) of patients receiving OPDIVO: Grade 2 (n=18) and Grade 1: (n=14). Hyperthyroidism occurred in 1.5% (4/263) of patients receiving OPDIVO: Grade 2: (n=3) and Grade 1 (n=1). In CheckMate 069 and 067, diabetes mellitus or diabetic ketoacidosis occurred in 1.5% (6/407) of patients: Grade 4 (n=3), Grade 3 (n=1), Grade 2 (n=1), and Grade 1 (n=1). In CheckMate 037, 066, and 067, diabetes mellitus or diabetic ketoacidosis occurred in 0.8% (6/787) of patients receiving OPDIVO: Grade 3 (n=2), Grade 2 (n=3), and Grade 1 (n=1). In CheckMate 025, hyperglycemic adverse events occurred in 9% (37/406) patients. Diabetes mellitus or diabetic ketoacidosis occurred in 1.5% (6/406) of patients receiving OPDIVO: Grade 3 (n=3), Grade 2 (n=2), and Grade 1 (n=1). In CheckMate 205 and 039, diabetes mellitus occurred in 0.8% (2/263) of patients receiving OPDIVO: Grade 3 (n=1) and Grade 1 (n=1).

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

Immune-mediated nephritis can occur with OPDIVO treatment. Monitor patients for elevated serum creatinine prior to and periodically during treatment. For Grade 2 or 3 increased serum creatinine, withhold and administer corticosteroids; if worsening or no improvement occurs, permanently discontinue. Administer corticosteroids for Grade 4 serum creatinine elevation and permanently discontinue. In CheckMate 069 and 067, immune-mediated nephritis and renal dysfunction occurred in 2.2% (9/407) of patients: Grade 4 (n=4), Grade 3 (n=3), and Grade 2 (n=2). In CheckMate 037, 066, and 067, nephritis and renal dysfunction of any grade occurred in 5% (40/787) of patients receiving OPDIVO. Immune-mediated nephritis and renal dysfunction occurred in 0.8% (6/787) of patients: Grade 3 (n=4) and Grade 2 (n=2). In CheckMate 057, Grade 2 immune-mediated renal dysfunction occurred in 0.3% (1/287) of patients receiving OPDIVO. In CheckMate 025, renal injury occurred in 7% (27/406) of patients receiving OPDIVO and 3.0% (12/397) of patients receiving everolimus. Immune-mediated nephritis and renal dysfunction occurred in 3.2% (13/406) of patients receiving OPDIVO: Grade 5 (n=1), Grade 4 (n=1), Grade 3 (n=5), and Grade 2 (n=6). In CheckMate 205 and 039, nephritis and renal dysfunction occurred in 4.9% (13/263) of patients treated with OPDIVO. This included one reported case (0.3%) of Grade 3 autoimmune nephritis.

Immune-Mediated Rash

Immune-mediated rash can occur with OPDIVO treatment. Severe rash (including rare cases of fatal toxic epidermal necrolysis) occurred in the clinical program of OPDIVO. Monitor patients for rash. Administer corticosteroids for Grade 3 or 4 rash. Withhold for Grade 3 and permanently discontinue for Grade 4. In CheckMate 069 and 067, immune-mediated rash occurred in 22.6% (92/407) of patients receiving OPDIVO with YERVOY: Grade 3 (n=15), Grade 2 (n=31), and Grade 1 (n=46). In CheckMate 037, 066, and 067, immune-mediated rash occurred in 9% (72/787) of patients receiving OPDIVO: Grade 3 (n=7), Grade 2 (n=15), and Grade 1 (n=50). In CheckMate 057, immune-mediated rash occurred in 6% (17/287) of patients receiving OPDIVO including four Grade 3 cases. In CheckMate 025, rash occurred in 28% (112/406) of patients receiving OPDIVO and 36% (143/397) of patients receiving everolimus. Immune- mediated rash, defined as a rash treated with systemic or topical corticosteroids, occurred in 7% (30/406) of patients receiving OPDIVO: Grade 3 (n=4), Grade 2 (n=7), and Grade 1 (n=19). In CheckMate 205 and 039, rash occurred in 22% (58/263) of patients receiving OPDIVO. Immune-mediated rash occurred in 7% (18/263) of patients on OPDIVO: Grade 3 (n=4), Grade 2 (n=3), and Grade 1 (n=11).

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 other causes. If other etiologies are ruled out, administer corticosteroids and permanently discontinue OPDIVO for immune-mediated encephalitis. In CheckMate 067, encephalitis was identified in one patient (0.2%) receiving OPDIVO with YERVOY. In CheckMate 057, fatal limbic encephalitis occurred in one patient (0.3%) receiving OPDIVO. In CheckMate 205 and 039, encephalitis occurred in 0.8% (2/263) of patients after allogeneic HSCT after OPDIVO.

Other Immune-Mediated Adverse Reactions

Based on the severity of adverse reaction, permanently discontinue or withhold treatment, administer high-dose corticosteroids, and, if appropriate, initiate hormone-replacement therapy. In < 1.0% of patients receiving OPDIVO, the following clinically significant, immune-mediated adverse reactions occurred: uveitis, iritis, pancreatitis, facial and abducens nerve paresis, demyelination, polymyalgia rheumatica, autoimmune neuropathy, Guillain-Barré syndrome, hypopituitarism, systemic inflammatory response syndrome, gastritis, duodenitis, and sarcoidosis. Across clinical trials of OPDIVO as a single agent administered at doses of 3 mg/kg and 10 mg/kg, additional clinically significant, immune- mediated adverse reactions were identified: motor dysfunction, vasculitis, and myasthenic syndrome.

Infusion Reactions

Severe infusion reactions have been reported in <1.0% of patients in clinical trials of OPDIVO. Discontinue OPDIVO in patients with Grade 3 or 4 infusion reactions. Interrupt or slow the rate of infusion in patients with Grade 1 or 2. In CheckMate 069 and 067, infusion- related reactions occurred in 2.5% (10/407) of patients receiving OPDIVO with YERVOY: Grade 2 (n=6) and Grade 1 (n=4). In CheckMate 037, 066, and 067, Grade 2 infusion related reactions occurred in 2.7% (21/787) of patients receiving OPDIVO: Grade 3 (n=2), Grade 2 (n=8), and Grade 1 (n=11). In CheckMate 057, Grade 2 infusion reactions requiring corticosteroids occurred in 1.0% (3/287) of patients receiving OPDIVO. In CheckMate 025, hypersensitivity/infusion-related reactions occurred in 6% (25/406) of patients receiving OPDIVO and 1.0% (4/397) of patients receiving everolimus. In CheckMate 205 and 039, hypersensitivity/infusion- related reactions occurred in 16% (42/263) of patients receiving OPDIVO: Grade 3 (n=2), Grade 2 (n=24), and Grade 1 (n=16).

Complications of Allogeneic HSCT after OPDIVO

Complications, including fatal events, occurred in patients who received allogeneic HSCT after OPDIVO. Outcomes were evaluated in 17 patients from CheckMate 205 and 039, who underwent allogeneic HSCT after discontinuing OPDIVO (15 with reduced-intensity conditioning, 2 with myeloablative conditioning). Thirty-five percent (6/17) of patients died from complications of allogeneic HSCT after OPDIVO. Five deaths occurred in the setting of severe or refractory GVHD. Grade 3 or higher acute GVHD was reported in 29% (5/17) of patients. Hyperacute GVHD was reported in 20% (n=2) of patients. A steroid-requiring febrile syndrome, without an identified infectious cause, was reported in 35% (n=6) of patients. Two cases of encephalitis were reported: Grade 3 (n=1) lymphocytic encephalitis without an identified infectious cause, and Grade 3 (n=1) suspected viral encephalitis. Hepatic veno-occlusive disease (VOD) occurred in one patient, who received reduced-intensity conditioned allogeneic SCT and died of GVHD and multi-organ failure. Other cases of hepatic VOD after reduced-intensity conditioned allogeneic HSCT have also been reported in patients with lymphoma who received a PD-1 receptor blocking antibody before transplantation. Cases of fatal hyperacute GVHD have also been reported. These complications may occur despite intervening therapy between PD-1 blockade and allogeneic HSCT.

Follow patients closely for early evidence of transplant-related complications such as hyperacute GVHD, severe (Grade 3 to 4) acute GVHD, steroid-requiring febrile syndrome, hepatic VOD, and other immune- mediated adverse reactions, and intervene promptly.

Embryo-fetal Toxicity

Based on their mechanisms of action, OPDIVO and YERVOY can cause fetal harm when administered to a pregnant woman. Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with an OPDIVO- or YERVOY- containing regimen and for at least 5 months after the last dose of OPDIVO.

Lactation

It is not known whether OPDIVO or YERVOY is present in human milk. Because many drugs, including antibodies, are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from an OPDIVO-containing regimen, advise women to discontinue breastfeeding during treatment. Advise women to discontinue nursing during treatment with YERVOY and for 3 months following the final dose.

Serious Adverse Reactions

In CheckMate 067, serious adverse reactions (73% and 37%), adverse reactions leading to permanent discontinuation (43% and 14%) or to dosing delays (55% and 28%), and Grade 3 or 4 adverse reactions (72% and 44%) all occurred more frequently in the OPDIVO plus YERVOY arm relative to the OPDIVO arm. The most frequent (≥10%) serious adverse reactions in the OPDIVO plus YERVOY arm and the OPDIVO arm, respectively, were diarrhea (13% and 2.6%), colitis (10% and 1.6%), and pyrexia (10% and 0.6%). In CheckMate 037, serious adverse reactions occurred in 41% of patients receiving OPDIVO. Grade 3 and 4 adverse reactions occurred in 42% of patients receiving OPDIVO. The most frequent Grade 3 and 4 adverse drug reactions reported in 2% to <5% of patients receiving OPDIVO were abdominal pain, hyponatremia, increased aspartate aminotransferase, and increased lipase. In CheckMate 066, serious adverse reactions occurred in 36% of patients receiving OPDIVO. Grade 3 and 4 adverse reactions occurred in 41% of patients receiving OPDIVO. The most frequent Grade 3 and 4 adverse reactions reported in ≥2% of patients receiving OPDIVO were gamma-glutamyltransferase increase (3.9%) and diarrhea (3.4%). In CheckMate 057, serious adverse reactions occurred in 47% of patients receiving OPDIVO. The most frequent serious adverse reactions reported in ≥2% of patients were pneumonia, pulmonary embolism, dyspnea, pleural effusion, and respiratory failure. In CheckMate 025, serious adverse reactions occurred in 47% of patients receiving OPDIVO. The most frequent serious adverse reactions reported in ≥2% of patients were acute kidney injury, pleural effusion, pneumonia, diarrhea, and hypercalcemia. In CheckMate 205 and 039, among all patients (safety population [n=263]), adverse reactions leading to discontinuation (4.2%) or to dosing delays (23%) occurred. The most frequent serious adverse reactions reported in ≥1% of patients were infusion-related reaction, pneumonia, pleural effusion, pyrexia, rash and pneumonitis. Ten patients died from causes other than disease progression, including 6 who died from complications of allogeneic HSCT. Serious adverse reactions occurred in 21% of patients in the safety population (n=263) and 27% of patients in the subset of patients evaluated for efficacy (efficacy population [n=95]).

Common Adverse Reactions

In CheckMate 067, the most common (≥20%) adverse reactions in the OPDIVO plus YERVOY arm were fatigue (59%), rash (53%), diarrhea (52%), nausea (40%), pyrexia (37%), vomiting (28%), and dyspnea (20%). The most common (≥20%) adverse reactions in the OPDIVO arm were fatigue (53%), rash (40%), diarrhea (31%), and nausea (28%). In CheckMate 037, the most common adverse reaction (≥20%) reported with OPDIVO was rash (21%). In CheckMate 066, the most common adverse reactions (≥20%) reported with OPDIVO vs dacarbazine were fatigue (49% vs 39%), musculoskeletal pain (32% vs 25%), rash (28% vs 12%), and pruritus (23% vs 12%). In CheckMate 057, the most common adverse reactions (≥20%) reported with OPDIVO were fatigue (49%), musculoskeletal pain (36%), cough (30%), decreased appetite (29%), and constipation (23%). In CheckMate 025, the most common adverse reactions (≥20%) reported in patients receiving OPDIVO vs everolimus were asthenic conditions (56% vs 57%), cough (34% vs 38%), nausea (28% vs 29%), rash (28% vs 36%), dyspnea (27% vs 31%), diarrhea (25% vs 32%), constipation (23% vs 18%), decreased appetite (23% vs 30%), back pain (21% vs 16%), and arthralgia (20% vs 14%). In CheckMate 205 and 039, among all patients (safety population [n=263]) and the subset of patients in the efficacy population (n=95), respectively, the most common adverse reactions (reported in at least 20%) were fatigue (32% and 43%), upper respiratory tract infection (28% and 48%), pyrexia (24% and 35%), diarrhea (23% and 30%), and cough (22% and 35%). In the subset of patients in the efficacy population (n=95), the most common adverse reactions also included rash (31%), musculoskeletal pain (27%), pruritus (25%), nausea (23%), arthralgia (21%), and peripheral neuropathy (21%).

In a separate Phase 3 study of YERVOY 3 mg/kg, the most common adverse reactions (≥5%) in patients who received YERVOY at 3 mg/kg were fatigue (41%), diarrhea (32%), pruritus (31%), rash (29%), and colitis (8%).

CheckMate Trials and Patient Populations

CheckMate 069 and 067 – advanced melanoma alone or in combination with YERVOY; CheckMate 037 and 066 – advanced melanoma; CheckMate 057 – non-squamous non-small cell lung cancer (NSCLC); CheckMate 025 – renal cell carcinoma; CheckMate 205/039 – classical Hodgkin lymphoma.

Opdivo (nivolumab) Stabilized Patient-reported Outcomes in Patients With Previously Treated Recurrent or Metastatic Squamous Cell Carcinoma of the Head and Neck in Pivotal Phase 3 CheckMate -141 Study

On October 9, 2016 Bristol-Myers Squibb Company (NYSE: BMY) reported new patient-reported quality-of-life data from an exploratory endpoint in the pivotal Phase 3 CheckMate -141 trial evaluating Opdivo in patients with recurrent or metastatic squamous cell carcinoma of the head and neck after platinum therapy compared to investigator’s choice of therapy (methotrexate, docetaxel or cetuximab) (Press release, Bristol-Myers Squibb, OCT 9, 2016, View Source [SID:SID1234515663]). Outcome assessments showed Opdivo stabilized patients’ symptoms and functioning, including physical, role and social functioning across three separate instruments. Both PD-L1 expressors and non-expressors treated with investigator’s choice of therapy experienced statistically significant worsening of patient-reported outcomes from baseline to week 15 versus Opdivo. In addition, Opdivo more than doubled the time to deterioration for most functional domains measured and significantly delayed the time to worsening symptoms of fatigue, dyspnea and insomnia, compared to investigator’s choice of therapy.

These findings will be presented today, October 9, during a Presidential Symposium at the 2016 European Society for Medical Oncology Congress from 4:25-4:40 p.m. CEST (Abstract #LBA4) and will be simultaneously published in The New England Journal of Medicine.

"Patients living with this form of advanced head and neck cancer often experience debilitating physiological effects as well as emotional and social challenges brought on by the condition despite current treatment options," said Kevin Harrington, M.D., Ph.D., Professor in Biological Cancer Therapies at The Institute of Cancer Research, London, and a Consultant Clinical Oncologist at The Royal Marsden NHS Foundation Trust in London. "These patient-reported outcomes are encouraging, as they help us understand the potential for Opdivo to impact important quality-of-life measures for this patient population."

Squamous cell carcinoma of the head and neck accounts for approximately 90% of all head and neck cancers and may impact a patient’s physiological function (e.g., breathing, swallowing, eating, drinking), personal characteristics (e.g., appearance, speaking, voice), sensory function (e.g., taste, smell, hearing) as well as psychological and social functioning.

John O’Donnell, Ph.D., M.A., vice president, head, Health Economics and Outcomes Research, Bristol-Myers Squibb, commented, "At Bristol-Myers Squibb, we are committed to improving outcomes in advanced cancers and are proud to apply our Immuno-Oncology science to study the way people live with squamous cell carcinoma of the head and neck. The quality-of-life data from CheckMate -141 are important because they provide additional insights into how Opdivo may help patients with this difficult-to-treat disease."

About CheckMate -141

CheckMate -141 is a Phase 3, open-label, randomized trial that evaluated Opdivo versus investigator’s choice of therapy in patients with recurrent or metastatic squamous cell carcinoma of the head and neck (SCCHN) with tumor progression within six months of platinum therapy in the adjuvant, primary, recurrent or metastatic setting.

Patient-reported outcomes (PRO) data were collected using the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30), EORTC Head and Neck Cancer-Specific Module (EORTC QLQ-H&N35) and the 3-level EQ-5D questionnaire (EQ-5D). The questionnaires were administered at baseline (cycle 1, day 1), week 9 and at six-week intervals thereafter while patients were on treatment. Clinical relevance was assessed using an established minimally important difference (MID) of ≥10 points for EORTC subscales.

Both the EORTC QLQ-C30 and EORTC QLQ-H&N35 questionnaires showed there were significant differences in PROs between patients treated with Opdivo and those treated with investigator’s choice of therapy at 15 weeks. In the EORTC QLQ-C30, while patients treated with Opdivo had stable PROs relative to baseline, those treated with investigator’s choice of therapy had significant and clinically meaningful worsening of physical, role and social functioning (p<0.001 versus Opdivo), fatigue (p<0.001 versus Opdivo), dyspnea (p<0.001 versus Opdivo) and appetite loss (p=0.004 versus Opdivo). Opdivo more than doubled the median time to deterioration for global health status (7.7 versus 3.0 months), physical functioning (7.8 versus 3.6 months), role functioning (8.6 versus 3.8 months), cognitive functioning (7.8 versus 3.3 months) and social functioning (7.7 versus 3.0 months), compared with investigator’s choice of therapy. In emotional functioning, Opdivo demonstrated a median time to deterioration of 6.7 months versus 4.7 months for investigator’s choice of therapy. Opdivo also reduced the rate of clinically meaningful deterioration in fatigue, insomnia and dypsnea by 50% (p=0.008).

Responses to the QLQ-H&N35 questionnaire showed while patients treated with Opdivo reported stable PROs relative to baseline, those treated with investigator’s choice of therapy had significant worsening in pain (p=0.022 versus Opdivo) as well as significant and clinically meaningful worsening in sensory problems (p<0.001 versus Opdivo) and social contact problems (p=0.001 versus Opdivo). Compared with investigator’s choice of therapy, Opdivo reduced the rate of clinically meaningful deterioration in pain by 74% (p<0.001 versus investigator’s choice of therapy), sensory problems by 62% (p=0.002 versus investigator’s choice of therapy) and opening mouth problems by 51% (p=0.029 versus investigator’s choice of therapy).

Patients treated with Opdivo experienced stable health status, as measured by the EQ-5D VAS, whereas those in the investigator’s choice arm experienced worsening of health status, with a statistically significant difference at 15 weeks (p=0.037). Median time to deterioration of health status was nearly triple with 9.1 months for patients receiving Opdivo versus 3.3 months for those in the investigator’s choice arm.

About Head & Neck Cancer

Cancers that are known as head and neck cancers usually begin in the squamous cells that line the moist mucosal surfaces inside the head and neck, such as inside the mouth, nose and throat. Head and neck cancer is the seventh most common cancer globally, with an estimated 600,000 new cases per year and 223,000-300,000 deaths per year. The global incidence of squamous cell carcinoma of the head and neck (SCCHN) is expected to increase by 17% between 2012 and 2022. The five-year survival rate is reported as less than 4% for metastatic Stage IV disease. Risk factors for SCCHN include tobacco and alcohol consumption. The Human Papilloma Virus (HPV) infection also is a risk factor leading to rapid increase in oropharyngeal SCCHN in Europe and North America.

Bristol-Myers Squibb: At the Forefront of Immuno-Oncology Science & Innovation

About Opdivo

U.S. FDA-APPROVED INDICATIONS FOR OPDIVO

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

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

Please refer to the end of the Important Safety Information for a brief description of the patient populations studied in the CheckMate trials.

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.

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

Immune-Mediated Pneumonitis

Immune-mediated pneumonitis, including fatal cases, occurred with OPDIVO treatment. Across the clinical trial experience with solid tumors, fatal immune-mediated pneumonitis occurred with OPDIVO. In addition, in CheckMate 069, there were six patients who died without resolution of abnormal respiratory findings. Monitor patients for signs with radiographic imaging and symptoms of pneumonitis. Administer corticosteroids for Grade 2 or greater pneumonitis. Permanently discontinue for Grade 3 or 4 and withhold until resolution for Grade 2. In CheckMate 069 and 067, immune-mediated pneumonitis occurred in 6% (25/407) of patients receiving OPDIVO with YERVOY: Fatal (n=1), Grade 3 (n=6), Grade 2 (n=17), and Grade 1 (n=1). In CheckMate 037, 066, and 067, immune-mediated pneumonitis occurred in 1.8% (14/787) of patients receiving OPDIVO: Grade 3 (n=2) and Grade 2 (n=12). In CheckMate 057, immune-mediated pneumonitis, including interstitial lung disease, occurred in 3.4% (10/287) of patients: Grade 3 (n=5), Grade 2 (n=2), and Grade 1 (n=3). In CheckMate 025, pneumonitis, including interstitial lung disease, occurred in 5% (21/406) of patients receiving OPDIVO and 18% (73/397) of patients receiving everolimus. Immune-mediated pneumonitis occurred in 4.4% (18/406) of patients receiving OPDIVO: Grade 4 (n=1), Grade 3 (n=4), Grade 2 (n=12), and Grade 1 (n=1). In CheckMate 205 and 039, pneumonitis, including interstitial lung disease, occurred in 4.9% (13/263) of patients receiving OPDIVO. Immune-mediated pneumonitis occurred in 3.4% (9/263) of patients receiving OPDIVO: Grade 3 (n=1) and Grade 2 (n=8).

Immune-Mediated Colitis

Immune-Mediated Hepatitis

Immune-mediated hepatitis can occur with OPDIVO treatment. Monitor patients for abnormal liver tests prior to and periodically during treatment. Administer corticosteroids for Grade 2 or greater transaminase elevations. Withhold for Grade 2 and permanently discontinue for Grade 3 or 4 immune-mediated hepatitis. In CheckMate 069 and 067, immune-mediated hepatitis occurred in 13% (51/407) of patients receiving OPDIVO with YERVOY: Grade 4 (n=8), Grade 3 (n=37), Grade 2 (n=5), and Grade 1 (n=1). In CheckMate 037, 066, and 067, immune-mediated hepatitis occurred in 2.3% (18/787) of patients receiving OPDIVO: Grade 4 (n=3), Grade 3 (n=11), and Grade 2 (n=4). In CheckMate 057, one patient (0.3%) developed immune-mediated hepatitis. In CheckMate 025, there was an increased incidence of liver test abnormalities compared to baseline in AST (33% vs 39%), alkaline phosphatase (32% vs 32%), ALT (22% vs 31%), and total bilirubin (9% vs 3.5%) in the OPDIVO and everolimus arms, respectively. Immune-mediated hepatitis requiring systemic immunosuppression occurred in 1.5% (6/406) of patients receiving OPDIVO: Grade 3 (n=5) and Grade 2 (n=1). In CheckMate 205 and 039, hepatitis occurred in 11% (30/263) of patients receiving OPDIVO. Immune-mediated hepatitis occurred in 3.4% (9/263): Grade 3 (n=7) and Grade 2 (n=2).

Immune-Mediated Dermatitis

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

Immune-Mediated Nephritis and Renal Dysfunction

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 for Grade 3 or 4 rash. Withhold for Grade 3 and permanently discontinue for Grade 4. In CheckMate 069 and 067, immune-mediated rash occurred in 22.6% (92/407) of patients receiving OPDIVO with YERVOY: Grade 3 (n=15), Grade 2 (n=31), and Grade 1 (n=46). In CheckMate 037, 066, and 067, immune-mediated rash occurred in 9% (72/787) of patients receiving OPDIVO: Grade 3 (n=7), Grade 2 (n=15), and Grade 1 (n=50). In CheckMate 057, immune-mediated rash occurred in 6% (17/287) of patients receiving OPDIVO including four Grade 3 cases. In CheckMate 025, rash occurred in 28% (112/406) of patients receiving OPDIVO and 36% (143/397) of patients receiving everolimus. Immune-mediated rash, defined as a rash treated with systemic or topical corticosteroids, occurred in 7% (30/406) of patients receiving OPDIVO: Grade 3 (n=4), Grade 2 (n=7), and Grade 1 (n=19). In CheckMate 205 and 039, rash occurred in 22% (58/263) of patients receiving OPDIVO. Immune-mediated rash occurred in 7% (18/263) of patients on OPDIVO: Grade 3 (n=4), Grade 2 (n=3), and Grade 1 (n=11).

Immune-Mediated Encephalitis

Other Immune-Mediated Adverse Reactions

Infusion Reactions

Severe infusion reactions have been reported in <1.0% of patients in clinical trials of OPDIVO. Discontinue OPDIVO in patients with Grade 3 or 4 infusion reactions. Interrupt or slow the rate of infusion in patients with Grade 1 or 2. In CheckMate 069 and 067, infusion-related reactions occurred in 2.5% (10/407) of patients receiving OPDIVO with YERVOY: Grade 2 (n=6) and Grade 1 (n=4). In CheckMate 037, 066, and 067, Grade 2 infusion related reactions occurred in 2.7% (21/787) of patients receiving OPDIVO: Grade 3 (n=2), Grade 2 (n=8), and Grade 1 (n=11). In CheckMate 057, Grade 2 infusion reactions requiring corticosteroids occurred in 1.0% (3/287) of patients receiving OPDIVO. In CheckMate 025, hypersensitivity/infusion-related reactions occurred in 6% (25/406) of patients receiving OPDIVO and 1.0% (4/397) of patients receiving everolimus. In CheckMate 205 and 039, hypersensitivity/infusion- related reactions occurred in 16% (42/263) of patients receiving OPDIVO: Grade 3 (n=2), Grade 2 (n=24), and Grade 1 (n=16).

Complications of Allogeneic HSCT after OPDIVO

Embryo-fetal Toxicity

Based on their mechanisms of action, OPDIVO and YERVOY can cause fetal harm when administered to a pregnant woman. Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with an OPDIVO- or YERVOY-containing regimen and for at least 5 months after the last dose of OPDIVO.

Lactation

Serious Adverse Reactions

Common Adverse Reactions

CheckMate Trials and Patient Populations

Updated Results Presented for the Opdivo (nivolumab) and Yervoy (ipilimumab) Combination in Metastatic Renal Cell Carcinoma From Phase 1 Study

On October 9, 2016 Bristol-Myers Squibb Company (NYSE:BMY) reported updated results from the Phase 1 CheckMate -016 trial, which evaluated the safety and tolerability (primary endpoint) of Opdivo at different doses as part of a regimen with Yervoy, sunitinib or pazopanib in previously treated and treatment-naïve patients with metastatic renal cell carcinoma (mRCC) (Press release, Bristol-Myers Squibb, OCT 9, 2016, View Source [SID:SID1234515662]). These updated results include findings for the Opdivo and Yervoy combinations [Opdivo 3 mg/kg plus Yervoy 1 mg/kg arm and Opdivo 1 mg/kg plus Yervoy 3 mg/kg arm] with approximately two years of follow-up, which showed the overall response rate (ORR; secondary endpoint) was 40.4% (n=47) in both arms. Of the 38 responders in both treatment arms, 39.5% (n=15) had an ongoing response, with a median duration of response of 20.4 months (95% CI: 8.54 – NE) in the Opdivo 3 mg/kg plus Yervoy 1 mg/kg arm and 19.7 months (95% CI: 8.08 – NE) in the Opdivo 1 mg/kg plus Yervoy 3 mg/kg arm. The overall survival rate at 12 months was 81% and 85% for Opdivo 3 mg/kg plus Yervoy 1 mg/kg arm and Opdivo 1 mg/kg plus Yervoy 3 mg/kg arm, respectively, and at 24 months was 67% and 70%, respectively. There were fewer Grade 3/4 treatment-related adverse events reported in the Opdivo 3 mg/kg plus Yervoy 1 mg/kg arm (38.3%) than with Opdivo 1 mg/kg plus Yervoy 3 mg/kg arm (61.7%).

These results will be presented at the 2016 European Society for Medical Oncology (ESMO) (Free ESMO Whitepaper) Congress during a poster session on Sunday, October 9 from 1:00 – 2:00 p.m. CEST (Abstract #1062P).

"There remains a significant unmet need for treatment options that offer ongoing responses and increase survival for patients with renal cell carcinoma, the most common type of kidney cancer," said Asim Amin, M.D., Ph.D., Levine Cancer Institute, Carolinas HealthCare System. "The results from CheckMate -016 are encouraging and warrant further study, as they show with nearly two years of follow-up, patients in each Opdivo and Yervoy combination arm had a response that is ongoing in almost 40% of the patients."

Nearly a third of renal cell carcinoma (RCC) diagnoses occur once the disease has metastasized, or spread, to other parts of the body. At Stage IV, survival rates are low, with approximately 12% of advanced kidney cancer patients alive at five years.

"The findings reported at ESMO (Free ESMO Whitepaper) for CheckMate -016 validate our approach to studying the combination of our two Immuno-Oncology agents, Opdivo and Yervoy, to improve patient outcomes in metastatic renal cell carcinoma," said Vicki Goodman, M.D., development lead, Melanoma and Genitourinary Cancers, Bristol-Myers Squibb. "Our Phase 3 program for the Opdivo and Yervoy combination in the first line metastatic renal cell carcinoma is ongoing, and we hope to confirm these early findings through our continued research."

About CheckMate -016

CheckMate -016 is a multicenter, open-label, Phase 1 trial of Opdivo in combination with Yervoy, sunitinib or pazopanib in previously treated and treatment-naïve patients with metastatic renal cell carcinoma (mRCC). In the arms evaluating the combination regimen of Opdivo and Yervoy, which included 47 patients each, patients were randomized to receive Opdivo 3 mg/kg and Yervoy 1 mg/kg or Opdivo 1 mg/kg and Yervoy 3 mg/kg by intravenous infusion every three weeks for four doses, followed by Opdivo 3 mg/kg by intravenous infusion every two weeks until progression or toxicity. Prior systemic therapy was administered in 46.8% and 55.3% in the Opdivo 3 mg/kg plus Yervoy 1 mg/kg and Opdivo 1 mg/kg plus Yervoy 3 mg/kg arms, respectively. The primary endpoints were to assess the safety and tolerability, and secondary endpoints were to assess objective response rate (ORR), duration of response (DOR), overall survival (OS) and progression-free survival (PFS).

In the study, fewer patients in the Opdivo 3 mg/kg and Yervoy 1 mg/kg arm experienced Grade 3/4 treatment-related adverse events (AEs) than those in the Opdivo 1 mg/kg plus Yervoy 3 mg/kg arm (38.3% and 61.7%). Increased lipase was the most common Grade 3/4 treatment-related AE in both arms (14.9% with Opdivo 3 mg/kg and Yervoy 1 mg/kg; and 27.7% with Opdivo 1 mg/kg and Yervoy 3 mg/kg). Grade 3/4 treatment-related select AEs in the Opdivo 3 mg/kg and Yervoy 1 mg/kg and Opdivo 1 mg/kg and Yervoy 3 mg/kg arms were, respectively, gastrointestinal (4.3% and 23.4%), hepatic (6.4% and 21.3%), renal (4.3% and 4.3%), endocrinopathy (4.3% and 0.0%) and skin (0.0% and 2.1%). Discontinuations due to treatment-related AEs included five and 13 patients in the Opdivo 3 mg/kg and Yervoy 1 mg/kg and Opdivo 1 mg/kg and Yervoy 3 mg/kg arms, respectively. Treatment-related AEs leading to discontinuation in >5% of patients were increased alanine aminotransferase (ALT; 10.6%) and colitis (6.4%) in the Opdivo 1 mg/kg and Yervoy 3 mg/kg arm. No treatment-related deaths occurred in either arm. Based on these results, further development of the Opdivo 1 mg/kg and Yervoy 3 mg/kg regimen was not pursued.

Key efficacy results in previously treated and treatment-naïve mRCC patients are summarized below.

Opdivo 3 mg/kg plus
Yervoy 1 mg/kg
(n=47) Opdivo 1 mg/kg plus
Yervoy 3 mg/kg
(n=47)
Confirmed ORR, n (%); 95% CI 19 (40.4)
26.4 – 55.7
19 (40.4)
26.4 – 55.7
Best overall response,a n (%)
Complete response
Partial response
Stable disease
Disease progression
5 (10.6)
14 (29.8)
19 (40.4)
8 (17.0)
0 (0.0)
19 (40.4)
17 (36.2)
8 (17.0)
Median DOR, mos. (range) 20.4
(95% CI: 8.54 – NE)
19.7
(95% CI: 8.08 – NE)
12-month OS rate (%) 81 85
24-month OS rate 67 70
Median OS, mos. (range); 95% CI Not reached 32.6 (25.99–NE)
Median PFS, mos. (range) 6.6 (3.55 – 14.9) 9.1 (5.62 – 15.67)
a Best overall response was indeterminate in one patient (2.1%) in the Opdivo 3 mg/kg plus Yervoy 1 mg/kg arm and in two patients (4.3%) in the Opdivo 1 mg/kg plus Yervoy 3 mg/kg arm.

About Renal Cell Carcinoma

Renal cell carcinoma (RCC) is the most common type of kidney cancer in adults, accounting for more than 100,000 deaths worldwide each year. Clear-cell RCC is the most prevalent type of RCC and constitutes 80% to 90% of all cases. Renal cell carcinoma is approximately twice as common in men as it is in women, with the highest rates of the disease found in North America and Europe. Globally, the five-year survival rate for those diagnosed with advanced kidney cancer is 12%.

Bristol-Myers Squibb: At the Forefront of Immuno-Oncology Science & Innovation

About Opdivo

U.S. FDA-APPROVED INDICATIONS FOR OPDIVO

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

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

Please refer to the end of the Important Safety Information for a brief description of the patient populations studied in the CheckMate trials.

IMPORTANT SAFETY INFORMATION

WARNING: IMMUNE-MEDIATED ADVERSE REACTIONS

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

Immune-Mediated Pneumonitis

Immune-Mediated Colitis

Immune-Mediated Hepatitis

Immune-Mediated Dermatitis

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

Immune-Mediated Nephritis and Renal Dysfunction

Immune-Mediated Rash

Immune-Mediated Encephalitis

Other Immune-Mediated Adverse Reactions

Infusion Reactions

Complications of Allogeneic HSCT after OPDIVO

Embryo-fetal Toxicity

Lactation

Serious Adverse Reactions

Common Adverse Reactions

CheckMate Trials and Patient Populations

Molecular Partners Presents Data of MP0250 in an All-Comer Phase 1-Study
in Solid Tumor Patients and Updates on Phase 2 Studies

On October 09, 2016 Molecular Partners AG (SIX: MOLN), a clinical-stage biopharmaceutical company that is developing a powerful new class of therapies known as DARPin therapies, reported additional details about its ongoing clinical oncology program MP0250. M.R. Middleton, Professor of Experimental Cancer Medicine, Department of Oncology at the University of Oxford, UK presents today the completed phase 1 dose escalation interim results of MP0250 at the poster session ‘Developmental Therapeutics’ at the Conference of the European Society of Medical Oncology (ESMO) (Free ESMO Whitepaper) (Press release, Molecular Partners, OCT 9, 2016, View Source [SID:SID1234515660]).

MP0250 is a multi-DARPin product consisting of four domains targeting vascular endothelial growth factor (VEGF) and hepatocyte growth factor (HGF) and also binds to human serum albumin (HSA) to increase the plasma half-life and potentially tissue penetration.

Prof. M.R. Middleton commented: "MP0250 used as single agent is the first DARPin drug candidate to be studied in humans as systemic treatment. The drug is generally well tolerated and the side effect profile is consistent with profound inhibition of the VEGF pathway. We have seen encouraging signs of clinical activity in these heavily pretreated patients, with two patients showing significant reduction of tumor burden and 6 patients having prolonged stable disease. MP0250 has the potential to become a new therapeutic in treating various tumor types."

These data, now based on the total enrollment of 24 patients, are an important milestone in the development of DARPin proteins as anticancer agents and expand the results that were published at the AACR (Free AACR Whitepaper)-NCI-EORTC conference in November 2015:

• MP0250 was well tolerated at the higher dose levels (up to 8 mg/kg administered every 2 weeks). This was assigned as the maximally tolerated dose (MTD). Toxicities came primarily from the inhibition of VEGF, including dose-limiting toxicities of acute left ventricular failure, nephrotic syndrome and hypertension, gastrointestinal hemorrhage and thrombotic microangiopathy.

• MP0250 had a half-life of about 12 days and shows full exposure in all patients over the whole treatment period at all doses.

2/3 Update on phase 2 strategy for MP0250

The first phase 2 study will examine MP0250 in combination with bortezomib and dexamethasone in patients with multiple myeloma who have failed proteasome and IMiD based standard therapies. The first regulatory submission for such study is planned in Q4 2016.

Based on the encouraging data from phase 1 in solid tumors, Molecular Partners decided to initiate an additional phase 2 study for a solid tumor indication. Study details will be disclosed in H1 2017.

About the DARPin technology

Molecular Partners is progressing programs in ophthalmology in partnership with Allergan and in oncology with a proprietary pipeline of DARPin drug candidates. The most advanced assets globally is abicipar, a molecule currently in phase 3 which is being advanced by Allergan. Abicipar is being followed by several DARPins for various ophthalmic indications. The most advanced systemic DARPin molecule, MP0250, is in clinical development for solid tumors and is moving to phase 2 for hematological and solid tumors. The second most advanced oncology DARPin drug candidate is MP0274, which has broad anti-HER activity, inhibiting HER1, HER2, and HER3- mediated downstream signaling via Her2 and leading to induction of apoptosis. MP0274 is currently in preclinical development. There is a growing pipeline of immune-oncological treatments following the two proprietary lead assets.

Dynavax Presents Early Clinical Data From Lead Cancer Immunotherapy Candidate, SD-101, at ESMO Annual Congress

On October 9, 2016 Dynavax Technologies Corporation (NASDAQ: DVAX) reported the first presentation of findings from an ongoing Phase 1/2 study evaluating SD-101, Dynavax’s intratumoral TLR9 agonist, in combination with Keytruda (pembrolizumab), Merck’s anti-PD-1 treatment (Press release, Dynavax Technologies, OCT 9, 2016, View Source [SID:SID1234515674]). Early results evaluating five patients with metastatic melanoma for efficacy and 16 patients for safety were reported. In patients naïve to anti-PD-1 treatment objective responses were observed in three out of four (75%) including one complete response (CR) and two partial responses (PR’s). One patient with progressive disease while receiving anti-PD-1 therapy was observed to have stable disease (SD). These data were presented in a poster session on Sunday at the European Society of Medical Oncology (ESMO) (Free ESMO Whitepaper) Annual Congress 2016 in Copenhagen, Denmark.

SD-101 in combination with pembrolizumab was well-tolerated. No dose-limiting toxicities of the combination were observed in any dose cohort, and a maximum tolerated dose (MTD) was not identified. No immune-related adverse events were reported, and the most common treatment-emergent adverse events were grade 1-2 flu-like symptoms, including fever, chills and myalgia consistent with the engagement of TLR9 and production of interferon alpha. The study also included biomarker assessments suggesting that treatment with SD-101 and pembrolizumab resulted in elevation of gene signatures consistent with an increase in immune cell types and multiple immune functions.

About MEL-01 (KEYNOTE-184)

The ongoing dose-escalation and expansion study of SD-101 in combination with pembrolizumab includes patients with histologically or cytologically confirmed unresectable Stage IIIc/IV melanoma. The primary endpoints of the trial are MTD and evaluation of the safety of intratumoral SD-101 in combination with pembrolizumab. In addition, the trial is evaluating response as assessed by the investigator according to RECIST v1.1, biomarker assessments and duration of response. Patients previously treated with anti-PD-1 and other immunotherapies are included.

About SD-101

SD-101 is Dynavax’s proprietary, second-generation, Toll-like Receptor 9 (TLR9) agonist CpG-C class oligodeoxynucleotide. SD-101 activates multiple anti-tumor activities of innate immune cells and activates plasmacytoid dendritic cells to stimulate T cells specific for antigens released from dying tumor cells. TLR9 agonists such as SD-101 enhance T and B cell responses and provide potent Type 1 interferon induction and maturation of plasmacytoid dendritic cells to antigen-presenting cells. SD-101 is being evaluated in several Phase 1/2 oncology studies to assess its preliminary safety and activity.