First Randomized Study Evaluating Opdivo (nivolumab)+Yervoy (ipilimumab) Regimen Demonstrates Superior Efficacy Versus Yervoy Alone in Patients with Previously Untreated Advanced Melanoma April 20, 2015 08:30 AM Eastern Daylight Time PRINCETON, N.J.--(BUSINESS WIRE)--Bristol-Myers Squibb Company (NYSE:BMY) today announced positive results from a Phase II trial (CheckMate -069), evaluating the Opdivo (nivolumab)+Yervoy (ipilimumab) regimen versus Yervoy alone in patients with previously untreated advanced melanoma. Patients with BRAF wild-type mutation status treated with the Opdivo+Yervoy regimen experienced a higher objective response rate (ORR) of 61% (n=44/72) – the primary study endpoint – compared to 11% (n=4/37) for patients administered Yervoy monotherapy (P<0.001). Complete responses were also reported in 22% (n=16) of patients with BRAF wild-type mutation status administered the Opdivo+Yervoy regimen and in no patients who received Yervoy monotherapy. Similar results were also observed in BRAF mutation-positive patients. The safety profile was consistent with previously-reported studies evaluating the Opdivo+Yervoy regimen and included grade 3-4 colitis (17%), diarrhea (11%), and increased alanine aminotransferase (11%)."With the Opdivo+Yervoy regimen, we observed much higher response rates which were sustained, as well as significant reduction in tumor burden than with Yervoy. These responses seen in CheckMate -069 demonstrate the potential of this regimen in patients with metastatic melanoma."These data will be presented today at the American Association for Cancer Research (AACR) Annual Meeting and featured during a press briefing at 8:30 AM EDT [Abstract 2860]. The results will also be published in The New England Journal of Medicine (NEJM)."These data are unprecedented in advanced melanoma, showing efficacy results that have not previously been observed with Immuno-Oncology agents," said F. Stephen Hodi, M.D., Associate Professor of Medicine, Dana-Farber Cancer Institute and an author of the NEJM manuscript. "With the Opdivo+Yervoy regimen, we observed much higher response rates which were sustained, as well as significant reduction in tumor burden than with Yervoy. These responses seen in CheckMate -069 demonstrate the potential of this regimen in patients with metastatic melanoma."Melanoma is the most serious form of skin cancer and strikes adults of all ages. While melanoma represents less than 5% of skin cancers, it results in most deaths. The CheckMate -069 trial is the first randomized study reporting outcomes in the first-line setting for advanced melanoma patients treated with a regimen of immune checkpoint inhibitors compared to Yervoy. The efficacy and safety results of CheckMate -069 are consistent with the Phase Ib dose-ranging trial (CheckMate -004), which evaluated the safety and activity of the regimen in patients with advanced melanoma."The CheckMate -069 results reinforce our belief that the future lies in the combination of Immuno-Oncology agents, including Opdivo and Yervoy, that can leverage the immune system in order to offer cancer patients options with greater efficacy beyond current treatment approaches," said Michael Giordano, senior vice president, Head of Development, Oncology. "Our strategy has always been to build upon the success achieved with Yervoy. In 2011, long-term survival for metastatic melanoma patients was unheard of, but the introduction of Yervoy has helped to make this a reality for some patients. Now we are building on this success with Opdivo, which was the first PD-1 inhibitor to demonstrate an improved survival benefit."
About CheckMate -069 CheckMate -069 is a Phase II double-blind, randomized study that evaluated the Opdivo+Yervoy regimen in patients with previously untreated unresectable Stage 3 and 4 melanoma. The study included patients with both BRAF wild-type and BRAF mutation-positive melanoma. The trial enrolled 142 patients who were randomized to receive either the Opdivo+Yervoy (n=95) regimen or Yervoy (n=47) monotherapy. Randomization was stratified by BRAF mutation status (V600 wild-type tumors versus BRAF mutation-positive tumors as assessed by an FDA-approved test). Patients in the Opdivo+Yervoy regimen group received 1 mg/kg of Opdivo plus 3 mg/kg of Yervoy every 3 weeks for 4 doses followed by 3 mg/kg of Opdivo per every 2 weeks until progression or unacceptable toxic effects. In the Yervoy monotherapy group, patients were treated with the same dosing schedule plus matching placebo.The primary endpoint was ORR in patients with BRAF wild-type tumors. Secondary endpoints included progression-free survival (PFS) in BRAF wild type patients and ORR and PFS in BRAF V600 mutation-positive patients, along with safety. Along with higher ORR and more complete responses, the regimen decreased risk of progression for BRAF mutant and wild-type patients (hazard ratios = 0.4 [95% CI: 0.23, 0.68; P<0.001] and 0.38 [95% CI: 0.15, 1.00], respectively), representing a 60-62% reduction of risk of progression or death. In BRAF wild-type patients, median PFS was not reached. In BRAF mutation-positive patients, median PFS was 8.5 months for the regimen and 2.7 months for Yervoy alone. In addition, ORR was independent of PD-L1 status: 58% among patients with PD-L1 positive tumors and 55% among those with and PD-L1 negative tumors. The minimum follow-up period after randomization was 11 months. CheckMate -069 is the first randomized study to characterize the safety profile of the Opdivo+Yervoy regimen versus Yervoy monotherapy. The safety profile was consistent with that previously reported for the Opdivo+Yervoy regimen. The treatment-related adverse event rate was similar (91% for the Opdivo+Yervoy regimen versus 93% for Yervoy monotherapy). The incidence of grade 3/4 adverse events (drug-related AEs) was higher with the Opdivo+Yervoy regimen (54%) compared to 24% of patients who received Yervoy monotherapy and managed using established safety guidelines and the majority (approximately 80%) improved or resolved with appropriate monitoring and use of corticosteroids. The most common grade 3/4 AEs with the Opdivo+Yervoy regimen were colitis (17%), diarrhea (11%), and increased alanine aminotransferase (11%). The Opdivo+Yervoy regimen was discontinued due to adverse events in 47% of patients versus 17% for Yervoy monotherapy. Of those patients who discontinued due to adverse events, 68% continued to experience a complete or partial response. There were three drug-related deaths associated with the Opdivo+Yervoy regimen.
About Opdivo and Yervoy Cancer cells may exploit "regulatory" pathways, such as checkpoint pathways, to hide from the immune system and shield the tumor from immune attack. Opdivo and Yervoy are both monoclonal antibodies and immune checkpoint inhibitors that target separate, distinct checkpoint pathways. Inhibition of these immune checkpoint pathways results in enhanced T cell function greater than the effects of either antibody alone. Opdivo became the first PD-1 immune checkpoint inhibitor to receive regulatory approval anywhere in the world on July 4, 2014 when Ono Pharmaceutical Co. announced that it received manufacturing and marketing approval in Japan for the treatment of patients with unresectable melanoma. In the U.S., the U.S. Food and Drug Administration (FDA) granted its first approval for Opdivo for the treatment of patients with unresectable or metastatic melanoma and disease progression following Yervoy (ipilimumab) and, if BRAF V600 mutation positive, a BRAF inhibitor. Recently, on March 5, 2015, Opdivo received its second FDA approval for the treatment of patients with metastatic squamous non-small cell lung cancer (NSCLC) with progression on or after platinum-based chemotherapy.In the European Union, the European Medicines Agency (EMA) has validated for review the Marketing Authorization Application for Opdivo in advanced melanoma. The application has also been granted accelerated assessment by the EMA's Committee for Medicinal Products for Human Use (CHMP). The EMA also validated for review the MAA for Opdivo in NSCLC.On March 25, 2011, the FDA approved Yervoy 3 mg/kg monotherapy for patients with unresectable or metastatic melanoma. Yervoy is now approved in more than 40 countries. Bristol-Myers Squibb has a broad, global development program to study Opdivo in multiple tumor types consisting of more than 50 trials – as monotherapy or in combination with other therapies – in which more than 7,000 patients have been enrolled worldwide.
OPDIVO (nivolumab) IMPORTANT SAFETY INFORMATION
Immune-Mediated Pneumonitis Severe pneumonitis or interstitial lung disease, including fatal cases, occurred with OPDIVO treatment. Across the clinical trial experience in 691 patients with solid tumors, fatal immune-mediated pneumonitis occurred in 0.7% (5/691) of patients receiving OPDIVO; no cases occurred in Trial 3. In Trial 3, immune-mediated pneumonitis occurred in 6% (7/117) of patients receiving OPDIVO including five Grade 3 and two Grade 2 cases. Monitor patients for signs and symptoms of pneumonitis. Administer corticosteroids for Grade 2 or greater pneumonitis. Permanently discontinue OPDIVO for Grade 3 or 4 and withhold OPDIVO until resolution for Grade 2. Immune-Mediated ColitisIn Trial 3, diarrhea occurred in 21% (24/117) of patients receiving OPDIVO. Grade 3 immune-mediated colitis occurred in 0.9% (1/117) of patients. Monitor patients for immune-mediated colitis. Administer corticosteroids for Grade 2 (of more than 5 days duration), 3, or 4 colitis. Withhold OPDIVO for Grade 2 or 3. Permanently discontinue OPDIVO for Grade 4 colitis or recurrent colitis upon restarting OPDIVO. Immune-Mediated HepatitisIn Trial 3, the incidences of increased liver test values were AST (16%), alkaline phosphatase (14%), ALT (12%), and total bilirubin (2.7%). Monitor patients for abnormal liver tests prior to and periodically during treatment. Administer corticosteroids for Grade 2 or greater transaminase elevations. Withhold OPDIVO for Grade 2 and permanently discontinue OPDIVO for Grade 3 or 4 immune-mediated hepatitis. Immune-Mediated Nephritis and Renal DysfunctionIn Trial 3, the incidence of elevated creatinine was 22%. Immune-mediated renal dysfunction (Grade 2) occurred in 0.9% (1/117) of patients. Monitor patients for elevated serum creatinine prior to and periodically during treatment. For Grade 2 or 3 serum creatinine elevation, withhold OPDIVO and administer corticosteroids; if worsening or no improvement occurs, permanently discontinue OPDIVO. Administer corticosteroids for Grade 4 serum creatinine elevation and permanently discontinue OPDIVO.
Immune-Mediated Hypothyroidism and Hyperthyroidism In Trial 3, hypothyroidism occurred in 4.3% (5/117) of patients receiving OPDIVO. Hyperthyroidism occurred in 1.7% (2/117) of patients including one Grade 2 case. Monitor thyroid function prior to and periodically during treatment. Administer hormone replacement therapy for hypothyroidism. Initiate medical management for control of hyperthyroidism.
Other Immune-Mediated Adverse Reactions The following clinically significant immune-mediated adverse reactions occurred in <2% of OPDIVO-treated patients: adrenal insufficiency, uveitis, pancreatitis, facial and abducens nerve paresis, demyeliniation, autoimmune neuropathy, motor dysfunction and vasculitis. Across clinical trials of OPDIVO administered at doses 3 mg/kg and 10 mg/kg, additional clinically significant, immune-mediated adverse reactions were identified: hypophysitis, diabetic ketoacidosis, hypopituitarism, Guillain-Barré syndrome, and myasthenic syndrome. Based on the severity of adverse reaction, withhold OPDIVO, administer high-dose corticosteroids, and, if appropriate, initiate hormone- replacement therapy.
Embryofetal Toxicity Based on its mechanism of action, OPDIVO 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 OPDIVO and for at least 5 months after the last dose of OPDIVO. LactationIt is not known whether OPDIVO is present in human milk. Because many drugs, including antibodies, are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from OPDIVO, advise women to discontinue breastfeeding during treatment.
Serious Adverse Reactions In Trial 3, serious adverse reactions occurred in 59% of patients receiving OPDIVO. The most frequent serious adverse drug reactions reported in ≥2% of patients were dyspnea, pneumonia, chronic obstructive pulmonary disease exacerbation, pneumonitis, hypercalcemia, pleural effusion, hemoptysis, and pain. Common Adverse ReactionsThe most common adverse reactions (≥20%) reported with OPDIVO in Trial 3 were fatigue (50%), dyspnea (38%), musculoskeletal pain (36%), decreased appetite (35%), cough (32%), nausea (29%), and constipation (24%). Please see U.S. Full Prescribing Information for OPDIVO here.
YERVOY® (ipilimumab) INDICATION & IMPORTANT SAFETY INFORMATION
YERVOY (ipilimumab) is indicated for the treatment of unresectable or metastatic melanoma.
Important Safety InformationWARNING: IMMUNE-MEDIATED ADVERSE REACTIONS YERVOY can result in severe and fatal immune-mediated adverse reactions due to T-cell activation and proliferation. 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) and thyroid function tests at baseline and before each dose.Permanently discontinue YERVOY and initiate systemic high-dose corticosteroids for severe immune-mediated reactions.
Recommended Dose Modifications Withhold dose for any moderate immune-mediated adverse reactions or for symptomatic endocrinopathy until return to baseline, improvement to mild severity, or complete resolution, and patient is receiving <7.5 mg prednisone or equivalent per day.
Permanently discontinue YERVOY for any of the following: Persistent moderate adverse reactions or inability to reduce corticosteroid dose to 7.5 mg prednisone or equivalent per day Failure to complete full treatment course within 16 weeks from administration of first dose Severe or life-threatening adverse reactions, including any of the following: Colitis with abdominal pain, fever, ileus, or peritoneal signs; increase in stool frequency (≥7 over baseline), stool incontinence, need for intravenous hydration for >24 hours, gastrointestinal hemorrhage, and gastrointestinal perforation AST or ALT >5 × the upper limit of normal (ULN) or total bilirubin >3 × the ULN Stevens-Johnson syndrome, toxic epidermal necrolysis, or rash complicated by full-thickness dermal ulceration or necrotic, bullous, or hemorrhagic manifestations Severe motor or sensory neuropathy, Guillain-Barré syndrome, or myasthenia gravis Severe immune-mediated reactions involving any organ system Immune-mediated ocular disease which is unresponsive to topical immunosuppressive therapy
Immune-mediated Enterocolitis: In the pivotal Phase 3 study in YERVOY-treated patients, 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%) and moderate (diarrhea with up to 6 stools above baseline, abdominal pain, mucus or blood in stool; Grade 2) enterocolitis occurred in 28 (5%) patients Across all YERVOY-treated patients (n=511), 5 (1%) developed intestinal perforation, 4 (0.8%) died as a result of complications, and 26 (5%) were hospitalized for severe enterocolitis Infliximab was administered to 5 of 62 (8%) patients with moderate, severe, or life-threatening immune-mediated enterocolitis following inadequate response to corticosteroids Monitor patients for signs and symptoms of enterocolitis (such as diarrhea, abdominal pain, mucus or blood in stool, with or without fever) and of bowel perforation (such as peritoneal signs and ileus). In symptomatic patients, rule out infectious etiologies and consider endoscopic evaluation for persistent or severe symptoms Permanently discontinue YERVOY in patients with severe enterocolitis and initiate systemic corticosteroids (1-2 mg/kg/day of prednisone or equivalent). Upon improvement to ≤Grade 1, initiate corticosteroid taper and continue over at least 1 month. In clinical trials, rapid corticosteroid tapering resulted in recurrence or worsening symptoms of enterocolitis in some patients Withhold YERVOY for moderate enterocolitis; administer anti-diarrheal treatment and, if persistent for >1 week, initiate systemic corticosteroids (0.5 mg/kg/day prednisone or equivalent)
Immune-mediated Hepatitis: In the pivotal Phase 3 study in YERVOY-treated patients, 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% 13 (2.5%) additional YERVOY-treated patients experienced moderate hepatotoxicity manifested by LFT abnormalities (AST or ALT elevations >2.5x but ≤5x the ULN or total bilirubin elevation >1.5x but ≤3x the ULN; Grade 2) Monitor LFTs (hepatic transaminase and bilirubin levels) and assess patients for signs and symptoms of hepatotoxicity before each dose of YERVOY. In patients with hepatotoxicity, rule out infectious or malignant causes and increase frequency of LFT monitoring until resolution Permanently discontinue YERVOY in patients with Grade 3-5 hepatotoxicity and administer systemic corticosteroids (1-2 mg/kg/day of prednisone or equivalent). When LFTs show sustained improvement or return to baseline, initiate corticosteroid tapering and continue over 1 month. Across the clinical development program for YERVOY, mycophenolate treatment has been administered in patients with persistent severe hepatitis despite high-dose corticosteroids Withhold YERVOY in patients with Grade 2 hepatotoxicity In a dose-finding trial, Grade 3 increases in transaminases with or without concomitant increases in total bilirubin occurred in 6 of 10 patients who received concurrent YERVOY (3 mg/kg) and vemurafenib (960 mg BID or 720 mg BID) Immune-mediated Dermatitis:In the pivotal Phase 3 study in YERVOY-treated patients, severe, life-threatening, or fatal immune-mediated dermatitis (e.g., 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 There were 63 (12%) YERVOY-treated patients with moderate (Grade 2) dermatitis Monitor patients for signs and symptoms of dermatitis such as rash and pruritus. Unless an alternate etiology has been identified, signs or symptoms of dermatitis should be considered immune-mediated Permanently discontinue YERVOY in patients with severe, life-threatening, or fatal immune-mediated dermatitis (Grade 3-5). Administer systemic corticosteroids (1-2 mg/kg/day of prednisone or equivalent). When dermatitis is controlled, corticosteroid tapering should occur over a period of at least 1 month. Withhold YERVOY in patients with moderate to severe signs and symptoms Treat mild to moderate dermatitis (e.g., localized rash and pruritus) symptomatically. Administer topical or systemic corticosteroids if there is no improvement within 1 week
Immune-mediated Neuropathies: In the pivotal Phase 3 study in YERVOY-treated patients, 1 case of fatal Guillain-Barré syndrome and 1 case of severe (Grade 3) peripheral motor neuropathy were reported Across the clinical development program of YERVOY, myasthenia gravis and additional cases of Guillain-Barré syndrome have been reported Monitor for symptoms of motor or sensory neuropathy such as unilateral or bilateral weakness, sensory alterations, or paresthesia. Permanently discontinue YERVOY in patients with severe neuropathy (interfering with daily activities) such as Guillain-Barré–like syndromes Institute medical intervention as appropriate for management of severe neuropathy. Consider initiation of systemic corticosteroids (1-2 mg/kg/day of prednisone or equivalent) for severe neuropathies. Withhold YERVOY in patients with moderate neuropathy (not interfering with daily activities) Immune-mediated Endocrinopathies:In the pivotal Phase 3 study in YERVOY- treated patients, 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 Moderate endocrinopathy (requiring hormone replacement or medical intervention; Grade 2) occurred in 12 (2.3%) YERVOY-treated patients and consisted of hypothyroidism, adrenal insufficiency, hypopituitarism, and 1 case each of hyperthyroidism and Cushing's syndrome Median time to onset of moderate to severe immune-mediated endocrinopathy was 11 weeks and ranged up to 19.3 weeks after the initiation of YERVOY Monitor patients for clinical signs and symptoms of hypophysitis, adrenal insufficiency (including adrenal crisis), and hyper- or hypothyroidism Patients may present with fatigue, headache, mental status changes, abdominal pain, unusual bowel habits, and hypotension, or nonspecific symptoms which may resemble other causes such as brain metastasis or underlying disease. Unless an alternate etiology has been identified, signs or symptoms should be considered immune-mediated Monitor thyroid function tests and clinical chemistries at the start of treatment, before each dose, and as clinically indicated based on symptoms. In a limited number of patients, hypophysitis was diagnosed by imaging studies through enlargement of the pituitary gland Withhold YERVOY in symptomatic patients. Initiate systemic corticosteroids (1-2 mg/kg/day of prednisone or equivalent) and initiate appropriate hormone replacement therapy. Long-term hormone replacement therapy may be necessary Other Immune-mediated Adverse Reactions, Including Ocular Manifestations:In the pivotal Phase 3 study in YERVOY-treated patients, clinically significant immune-mediated adverse reactions seen in <1% were: nephritis, pneumonitis, meningitis, pericarditis, uveitis, iritis, and hemolytic anemia Across the clinical development program for YERVOY, likely immune-mediated adverse reactions also reported with <1% incidence were: myocarditis, angiopathy, temporal arteritis, vasculitis, polymyalgia rheumatica, conjunctivitis, blepharitis, episcleritis, scleritis, leukocytoclastic vasculitis, erythema multiforme, psoriasis, pancreatitis, arthritis, autoimmune thyroiditis, sarcoidosis, neurosensory hypoacusis, autoimmune central neuropathy (encephalitis), myositis, polymyositis, and ocular myositis Permanently discontinue YERVOY for clinically significant or severe immune-mediated adverse reactions. Initiate systemic corticosteroids (1-2 mg/kg/day of prednisone or equivalent) for severe immune-mediated adverse reactions Administer corticosteroid eye drops for uveitis, iritis, or episcleritis. Permanently discontinue YERVOY for immune-mediated ocular disease unresponsive to local immunosuppressive therapy
Pregnancy & Nursing: YERVOY is classified as pregnancy category C. There are no adequate and well-controlled studies of YERVOY in pregnant women. Use YERVOY during pregnancy only if the potential benefit justifies the potential risk to the fetus Human IgG1 is known to cross the placental barrier and YERVOY is an IgG1; therefore, YERVOY has the potential to be transmitted from the mother to the developing fetus It is not known whether YERVOY is secreted in human milk. Because many drugs are secreted in human milk and because of the potential for serious adverse reactions in nursing infants from YERVOY, a decision should be made whether to discontinue nursing or to discontinue YERVOY
Common Adverse Reactions: 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%) Please see Full Prescribing Information, including Boxed WARNING regarding immune-mediated adverse reactions, available at www.bms.com.Yervoy is a registered trademark of Bristol-Myers Squibb Company.
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