Bristol-Myers Squibb Company (BMY) announced today U.S. and European marketing applications to expand the use of Opdivo for patients along with previously treated recurrent or metastatic squamous cell carcinoma of the head and neck (SCCHN) were accepted for filing by the U.S. Meals and Drug Administration (FDA) and validated by the European Medicines Agency (EMA). In the U.S., the FDA accepted the Company’s supplemental Biologics License Application (sBLA) for Opdivo in SCCHN along with priority review, and previously granted the agent Breakthrough Therapy Designation in April 2016. The projected FDA action date is November 11, 2016. In Europe, the EMA validated a type II variation application for the same patient population. Validation of the application confirms the submission is finish and begins the EMA’s centralized review process.
Jean Viallet, M.D., Global Clinical Research Lead, Oncology, Bristol-Myers Squibb, commented, “Squamous cell carcinoma of the head and neck that progresses after platinum therapy is a devastating ailment along with a poor prognosis and has actually had fairly few treatment advancements in nearly a decade. Based on findings from CheckMate -141, Opdivo is the very first and only PD-1 inhibitor to prove to an overall survival benefit in a Phase 3 trial in these patients. These milestones are necessary steps in the regulatory processes, and we look forward to working along with authorities in the U.S. and Europe to offer Opdivo to this patient population.”
Both U.S. and European submissions were based on CheckMate -141, a pivotal Phase 3 open-label, randomized trial, that evaluated the overall survival (OS) of Opdivo in patients along with SCCHN after platinum therapy compared to investigator’s choice of therapy (methotrexate, docetaxel, or cetuximab). Based on a planned interim analysis, this trial was stopped early in January 2016 since an assessment conducted by the independent Data Monitoring Committee concluded the study met its primary endpoint of OS in patients receiving Opdivo compared to investigator’s choice of therapy. Overall survival results from CheckMate -141 were very first presented at the 2016 Annual Meeting of the American Association for Cancer Research.
Cancers that are known as head and neck cancers usually start in the squamous cells that line the moist mucosal surfaces inside the head and neck, such as inside the mouth, the nose and the throat. Head and neck cancer is the seventh most common cancer globally, along with an estimated 400,000 to 600,000 brand-new cases per year and 223,000 to 300,000 deaths per year. The five-year survival price is reported as much less compared to 4% for metastatic Stage IV disease. Squamous cell carcinoma of the head and neck (SCCHN) accounts for approximately 90% of every one of head and neck cancers along with global incidence expected to raise by 17% between 2012 and 2022. Risk factors for SCCHN include tobacco and alcohol consumption. The Human Papilloma Virus (HPV) infection is additionally a risk factor leading to rapid raise in oropharyngeal SCCHN in Europe and North America. Quality of life is regularly impacted for SCCHN patients, as physiological function (breathing, swallowing, eating, drinking), personal characteristics (appearance, speaking, voice), sensory function (taste, smell, hearing), and psychological/social function can easily be affected.
At Bristol-Myers Squibb, we have actually a vision for the future of cancer care that is focused on Immuno-Oncology, now considered a major treatment choice alongside surgery, radiation, chemotherapy and targeted therapies for certain types of cancer.
We have actually a comprehensive clinical portfolio of investigational and approved Immuno-Oncology agents, numerous of which were discovered and produced by our scientists. Our ongoing Immuno-Oncology clinical program is looking at broad patient populations, across multiple tough tumors and hematologic malignancies, and lines of therapy and histologies, along with the intent of powering our trials for overall survival and various other necessary measures enjoy durability of response. We pioneered the research leading to the very first regulatory approval for the combination of two Immuno-Oncology agents, and go on to study the role of combinations in cancer.
We are additionally investigating various other immune system pathways in the treatment of cancer including CTLA-4, CD-137, KIR, SLAMF7, PD-1, GITR, CSF1R, IDO, and LAG-3. These pathways could lead to potential brand-new treatment choices – in combination or monotherapy – to recommendations patients fight different types of cancers.
Our collaboration along with academia, as well as small and large biotech companies, to research the potential Immuno-Oncology and non-Immuno-Oncology combinations, helps achieve our objective of providing brand-new treatment choices in clinical practice.
At Bristol-Myers Squibb, we are committed to changing survival expectations in hard-to-treat cancers and the means patients live along with cancer.
About Opdivo
Cancer cells could exploit “regulatory” pathways, such as checkpoint pathways, to hide from the immune system and shield the tumor from immune attack. Opdivo is a PD-1 immune checkpoint inhibitor that binds to the checkpoint receptor PD-1 expressed on activated T-cells, and blocks the binding of PD-L1 and PD-L2, preventing the PD-1 pathway’s suppressive signaling on the immune system, including the interference along with an anti-tumor immune response.
Opdivo’s broad global development program is based on Bristol-Myers Squibb’s knowing of the biology behind Immuno-Oncology. Our company is at the forefront of researching the potential of Immuno-Oncology to extend survival in hard-to-treat cancers. This scientific expertise serves as the basis for the Opdivo development program, which involves a broad range of Phase 3 clinical trials evaluating overall survival as the primary endpoint across a variety of tumor types. The Opdivo trials have actually additionally contributed toward the clinical and scientific knowing of the role of biomarkers and exactly how patients could benefit from Opdivo across the continuum of PD-L1 expression. To date, the Opdivo clinical development program has actually enrolled much more compared to 18,000 patients.
Opdivo was the very first PD-1 immune checkpoint inhibitor to receive regulatory approval anywhere on the planet in July 2014, and currently has actually regulatory approval in 53 countries including the United States, Japan, and in the European Union.
U.S. FDA APPROVED INDICATIONS FOR OPDIVO®
OPDIVO® (nivolumab) as a single agent is indicated for the treatment of patients along with BRAF V600 wild-type unresectable or metastatic melanoma.
OPDIVO® (nivolumab) as a single agent is indicated for the treatment of patients along 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 could be contingent upon verification and description of clinical benefit in confirmatory trials.
OPDIVO® (nivolumab), in combination along with YERVOY® (ipilimumab), is indicated for the treatment of patients along with unresectable or metastatic melanoma. This indication is approved under accelerated approval based on progression-free survival. Continued approval for this indication could be contingent upon verification and description of clinical benefit in the confirmatory trials.
OPDIVO® (nivolumab) is indicated for the treatment of patients along with metastatic non-small cell lung cancer (NSCLC) along with progression on or after platinum-based chemotherapy. Patients along with EGFR or ALK genomic tumor aberrations must have actually ailment progression on FDA-approved therapy for these aberrations prior to receiving OPDIVO.
OPDIVO® (nivolumab) is indicated for the treatment of patients along with advanced renal cell carcinoma (RCC) that have actually received prior anti-angiogenic therapy.
OPDIVO® (nivolumab) is indicated for the treatment of patients along with classical Hodgkin lymphoma (cHL) that has actually 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 could be contingent upon verification and description of clinical benefit in confirmatory trials.
Please refer to the end of the necessary Safety Guide for a brief description of the patient populations studied in the CheckMate trials.
IMPORTANT SAFETY INFORMATION
WARNING: IMMUNE-MEDIATED Edge REACTIONS
YERVOY can easily result in severe and fatal immune-mediated Edge reactions. These immune- mediated reactions could involve any type of organ system; however, the most common severe immune- mediated Edge reactions are enterocolitis, hepatitis, dermatitis (including toxic epidermal necrolysis), neuropathy, and endocrinopathy. The majority of these immune-mediated reactions initially manifested throughout 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 examinations (LFTs), adrenocorticotropic hormone (ACTH) level, and thyroid function examinations at baseline and prior to 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 along with OPDIVO treatment. Across the clinical trial experience along with tough tumors, fatal immune-mediated pneumonitis occurred along with OPDIVO. In addition, in CheckMate 069, there were 6 patients that died devoid of resolution of abnormal respiratory findings. Monitor patients for signs along with radiographic imaging and symptoms of pneumonitis. Administer corticosteroids for Grade 2 or better pneumonitis. For good 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 along 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 easily occur along with OPDIVO treatment. Monitor patients for signs and symptoms of colitis. Administer corticosteroids for Grade 2 (of much more compared to 5 days duration), 3, or 4 colitis. As a single agent, withhold OPDIVO for Grade 2 or 3 and For good discontinue for Grade 4 or recurrent colitis upon restarting OPDIVO. As quickly as administered along with YERVOY, withhold OPDIVO for Grade 2 and For good 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 along 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 divide 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 every one of YERVOY-treated patients in that study (n=511), 5 (1%) produced 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 easily occur along with OPDIVO treatment. Monitor patients for abnormal liver examinations prior to and periodically throughout treatment. Administer corticosteroids for Grade 2 or better transaminase elevations. Withhold for Grade 2 and For good 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 along 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%) produced 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 divide 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, along with fatal hepatic failure in 0.2% and hospitalization in 0.4%.
Immune-Mediated Dermatitis
In a divide 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 needed hospitalization for severe dermatitis.
Immune-Mediated Neuropathies
In a divide 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 easily occur along with OPDIVO treatment. Monitor patients for signs and symptoms of hypophysitis, signs and symptoms of adrenal insufficiency throughout and after treatment, thyroid function prior to and periodically throughout treatment, and hyperglycemia. Administer corticosteroids for Grade 2 or better hypophysitis. Withhold for Grade 2 or 3 and For good discontinue for Grade 4 hypophysitis. Administer corticosteroids for Grade 3 or 4 adrenal insufficiency. Withhold for Grade 2 and For good discontinue for Grade 3 or 4 adrenal insufficiency. Administer hormone-substitute therapy for hypothyroidism. Initiate medical management for manage of hyperthyroidism. Administer insulin for type 1 diabetes. Withhold OPDIVO for Grade 3 and For good discontinue for Grade 4 hyperglycemia.
In CheckMate 069 and 067, hypophysitis occurred in 9% (36/407) of patients receiving OPDIVO along 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 along 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 produced 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 along 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 ailment 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 Edge 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 divide Phase 3 study of YERVOY 3 mg/kg, severe to life-threatening immune-mediated endocrinopathies (requiring hospitalization, urgent medical intervention, or interfering along with activities of everyday living; Grade 3-4) occurred in 9 (1.8%) patients. every one of 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 easily occur along with OPDIVO treatment. Monitor patients for elevated serum creatinine prior to and periodically throughout treatment. For Grade 2 or 3 increased serum creatinine, withhold and administer corticosteroids; if worsening or no improvement occurs, For good discontinue. Administer corticosteroids for Grade 4 serum creatinine elevation and For good 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 type of 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 along with OPDIVO. This included one reported case (0.3%) of Grade 3 autoimmune nephritis.
Immune-Mediated Rash
Immune-mediated rash can easily occur along 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 For good discontinue for Grade 4. In CheckMate 069 and 067, immune-mediated rash occurred in 22.6% (92/407) of patients receiving OPDIVO along 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 along 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 easily occur along with OPDIVO treatment. Withhold OPDIVO in patients along with new-onset moderate to severe neurologic signs or symptoms and evaluate to rule out various other causes. If various other etiologies are ruled out, administer corticosteroids and For good discontinue OPDIVO for immune-mediated encephalitis. In CheckMate 067, encephalitis was identified in one patient (0.2%) receiving OPDIVO along 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 Edge Reactions
Based on the severity of Edge reaction, For good discontinue or withhold treatment, administer high-dose corticosteroids, and, if appropriate, initiate hormone-substitute therapy. In < 1.0% of patients receiving OPDIVO, the adhering to clinically significant, immune-mediated Edge 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 Edge reactions were identified: motor dysfunction, vasculitis, and myasthenic syndrome.
Infusion Reactions
Severe infusion reactions have actually been reported in <1.0% of patients in clinical trials of OPDIVO. Discontinue OPDIVO in patients along with Grade 3 or 4 infusion reactions. Interrupt or slow the price of infusion in patients along with Grade 1 or 2. In CheckMate 069 and 067, infusion- related reactions occurred in 2.5% (10/407) of patients receiving OPDIVO along 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 that received allogeneic HSCT after OPDIVO. Outcomes were evaluated in 17 patients from CheckMate 205 and 039, that underwent allogeneic HSCT after discontinuing OPDIVO (15 along with reduced-intensity conditioning, 2 along with myeloablative conditioning). Thirty-5 percent (6/17) of patients died from complications of allogeneic HSCT after OPDIVO. 5 deaths occurred in the setting of severe or refractory GVHD. Grade 3 or better 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, devoid of an identified infectious cause, was reported in 35% (n=6) of patients. Two cases of encephalitis were reported: Grade 3 (n=1) lymphocytic encephalitis devoid of an identified infectious cause, and Grade 3 (n=1) suspected viral encephalitis. Hepatic veno-occlusive ailment (VOD) occurred in one patient, that received reduced-intensity conditioned allogeneic SCT and died of GVHD and multi-organ failure. various other cases of hepatic VOD after reduced-intensity conditioned allogeneic HSCT have actually additionally been reported in patients along with lymphoma that received a PD-1 receptor blocking antibody prior to transplantation. Cases of fatal hyperacute GVHD have actually additionally been reported. These complications could 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 various other immune- mediated Edge reactions, and intervene promptly.
Embryo-fetal Toxicity
Based on their mechanisms of action, OPDIVO and YERVOY can easily trigger fetal harm As quickly as administered to a pregnant woman. Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception throughout treatment along 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. since numerous drugs, including antibodies, are excreted in human milk and due to the potential for serious Edge reactions in nursing infants from an OPDIVO-containing regimen, advise women to discontinue breastfeeding throughout treatment. Advise women to discontinue nursing throughout treatment along with YERVOY and for 3 months adhering to the last dose.
Serious Edge Reactions
In CheckMate 067, serious Edge reactions (73% and 37%), Edge reactions leading to permanent discontinuation (43% and 14%) or to dosing delays (55% and 28%), and Grade 3 or 4 Edge reactions (72% and 44%) every one of occurred much more often in the OPDIVO plus YERVOY arm relative to the OPDIVO arm. The most frequent (≥10%) serious Edge 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 Edge reactions occurred in 41% of patients receiving OPDIVO. Grade 3 and 4 Edge reactions occurred in 42% of patients receiving OPDIVO. The most frequent Grade 3 and 4 Edge 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 Edge reactions occurred in 36% of patients receiving OPDIVO. Grade 3 and 4 Edge reactions occurred in 41% of patients receiving OPDIVO. The most frequent Grade 3 and 4 Edge reactions reported in ≥2% of patients receiving OPDIVO were gamma-glutamyltransferase raise (3.9%) and diarrhea (3.4%). In CheckMate 057, serious Edge reactions occurred in 47% of patients receiving OPDIVO. The most frequent serious Edge reactions reported in ≥2% of patients were pneumonia, pulmonary embolism, dyspnea, pleural effusion, and respiratory failure. In CheckMate 025, serious Edge reactions occurred in 47% of patients receiving OPDIVO. The most frequent serious Edge reactions reported in ≥2% of patients were acute kidney injury, pleural effusion, pneumonia, diarrhea, and hypercalcemia. In CheckMate 205 and 039, among every one of patients (safety population [n=263]), Edge reactions leading to discontinuation (4.2%) or to dosing delays (23%) occurred. The most frequent serious Edge reactions reported in 1% of patients were infusion-related reaction, pneumonia, pleural effusion, pyrexia, rash and pneumonitis. Ten patients died from induces various other compared to ailment progression, including 6 that died from complications of allogeneic HSCT. Serious Edge 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 Edge Reactions
In CheckMate 067, the most common (≥20%) Edge 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%) Edge reactions in the OPDIVO arm were fatigue (53%), rash (40%), diarrhea (31%), and nausea (28%). In CheckMate 037, the most common Edge reaction (≥20%) reported along with OPDIVO was rash (21%). In CheckMate 066, the most common Edge reactions (≥20%) reported along 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 Edge reactions (≥20%) reported along with OPDIVO were fatigue (49%), musculoskeletal pain (36%), cough (30%), decreased cravings (29%), and constipation (23%). In CheckMate 025, the most common Edge 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 cravings (23% vs 30%), spine pain (21% vs 16%), and arthralgia (20% vs 14%). In CheckMate 205 and 039, among every one of patients (safety population [n=263]) and the subset of patients in the efficacy population (n=95), respectively, the most common Edge 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 Edge reactions additionally included rash (31%), musculoskeletal pain (27%), pruritus (25%), nausea (23%), arthralgia (21%), and peripheral neuropathy (21%).
In a divide Phase 3 study of YERVOY 3 mg/kg, the most common Edge reactions (≥5%) in patients that 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 along 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
About the Bristol-Myers Squibb and Ono Pharmaceutical Co., Ltd. Collaboration
In 2011, through a collaboration agreement along with Ono Pharmaceutical Co., Ltd (Ono) Bristol-Myers Squibb expanded its territorial rights to produce and commercialize Opdivo globally except in Japan, South Korea and Taiwan, where Ono had retained every one of rights to the compound at the time. On July 23, 2014, Bristol-Myers Squibb and Ono further expanded the companies’ strategic collaboration agreement to jointly produce and commercialize multiple immunotherapies – as single agents and combination regimens – for patients along with cancer in Japan, South Korea and Taiwan.
About Bristol-Myers Squibb
Bristol-Myers Squibb is a global biopharmaceutical company whose mission is to discover, produce and deliver innovative medicines that recommendations patients prevail over serious diseases. For much more Guide Concerning Bristol-Myers Squibb, visit us at BMS.com or follow us on LinkedIn, Twitter, YouTube and Facebook.
Bristol-Myers Squibb Forward-Looking Statement
This press release contains “forward-looking statements” as that term is defined in the Private Securities Litigation Reform Act of 1995 concerning the research, development and commercialization of pharmaceutical products. Such forward-looking statements are based on current expectations and involve inherent risks and uncertainties, including factors that could delay, divert or modification any type of of them, and could trigger actual outcomes and results to differ materially from current expectations. No forward-looking statement can easily be guaranteed. Among various other risks, there can easily be no make certain that Opdivo will certainly receive regulatory approval for another indication in SCCHN. Forward-looking statements in this press release must be evaluated with each other along with the numerous uncertainties that affect Bristol-Myers Squibb’s business, particularly those identified in the cautionary factors discussion in Bristol-Myers Squibb’s Annual Report on Form 10-K for the year ended December 31, 2015 in our Quarterly Reports on Form 10-Q and our Current Reports on Form 8-K. Bristol-Myers Squibb undertakes no obligation to publicly update any type of forward-looking statement, whether as a result of brand-new information, future events or otherwise.
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