First Randomized Study Evaluating Opdivo™ (nivolumab)+Yervoy® (ipilimumab) Regimen Demonstrates Superior Efficacy Versus Yervoy® Alone in Patients with Previously Untreated Advanced Melanoma
• Opdivo™ +Yervoy® regimen achieves objective response rate of 61%, including a 22% complete response rate, in previously untreated, advanced melanoma patients with BRAF wild-type mutation status • Opdivo™ +Yervoy® regimen decreased risk of melanoma progression or death compared to Yervoy® alone by 60%, based upon hazard ratio of 0.4; median progression-free survival for the regimen not reached with a minimum follow-up of 11 months • Safety profile of the Opdivo™ +Yervoy® regimen from this trial (CheckMate -069) was consistent with previously-reported studies
Bristol-Myers Squibb Company (NYSE: BMY) announced positive results from a Phase 2 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%).
These data were presented on April 20 at the American Associaton for Cancer Research (AACR) Annual Meeting. The results were also 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 1b 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 2 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™ received regulatory approval on July 4, 2014 byOno Pharmaceutical Co. 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.
Market authorization for Opdivo has not yet been obtained in Canada.
Yervoy®is now approved in more than 40 countries, including Canada.On February 1, 2012 Health Canada approved Yervoy®3 mg/kg for the treatment of unresectable or metastatic melanoma in patients who have failed or do not tolerate other systemic therapy for advanced disease. On September 10, 2014, Health Canada approved Yervoy® (ipilimumab) as a first-line therapy in adults with unresectable or metastatic melanoma,
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.
YERVOY® (ipilimumab) INDICATION & IMPORTANT SAFETY INFORMATION
YERVOY® (ipilimumab) is indicated for the treatment of unresectable or metastatic melanoma.
Important Safety Information
WARNING: IMMUNE-MEDIATED ADVERSE REACTIONS
YERVOY®should be administered under the supervision of physicians experienced in the treatment of cancer.
YERVOY®can cause severe and fatal immune-mediated adverse reactions, including enterocolitis, intestinal perforation, hepatitis, dermatitis (including toxic epidermal necrolysis), neuropathy, endocrinopathy, as well as toxicities in other organ systems. While most of these reactions occurred during the induction period, onset months after the last dose has been reported [see WARNINGS AND PRECAUTIONS].
Early diagnosis and appropriate management are essential to minimize life-threatening complications. Patients should be monitored for signs and symptoms suggestive of immune-mediated adverse reactions; clinical chemistries (e.g., electrolytes, liver and thyroid functions) should be evaluated at baseline and before each dose. Diarrhea, increased stool frequency, bloody stool, liver function test elevations, rash, and endocrinopathies must be considered immune-mediated and YERVOY®-related, unless an alternate etiology has been identified.
For severe immune-mediated adverse reactions, YERVOY®should be permanently discontinued; systemic high-dose corticosteroid with or without additional immunosuppressive therapy may be required for treatment
Recommended Dose Modifications
Withhold scheduled dose of YERVOY®for any moderate immune-mediated adverse reactions (including elevations in AST or ALT in the range of >2.5 - ≤5 times the upper limit of normal or bilirubin >1.5-≤3 times the upper limit of normal) or for symptomatic endocrinopathy. For patients with complete or partial resolution of adverse reactions (Grade 0–1), and who are receiving less than 7.5 mg prednisone or equivalent per day, resume YERVOY®at a dose of 3 mg/kg every 3 weeks until administration of all 4 planned doses or 16 weeks from first dose, whichever occurs earlier.
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 (e.g. nephritis, pneumonitis, pancreatitis, non-infectuous myocardiatis)
- Immune-mediated ocular disease which is unresponsive to topical immunosuppressive therapy
- In the pivotal Phase 3 study in YERVOY®-treated patients, severe, life-threatening, or fatal immune-mediated enterocolitis (diarrhea of ≥7 stools above baseline, fever, ileus, peritoneal signs; Grade 3-5) 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 6 of 62 (10%) 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)
- 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)
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 Stevens-Johnson syndrome, toxic epidermal necrolysis, or rash complicated by full thickness dermal ulceration, or necrotic, bullous, or hemorrhagic manifestations.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
- 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)
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
- 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:
- Animal reproduction studies have shown reproductive toxicityHuman 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 ipilimumab is secreted in human milk. However, because human IgG1 is known to be secreted in human breast milk, there is potential for ipilimumab to be passed from mother to nursing child. Women who are taking YERVOY®should not breast-feed.
Common Adverse Reactions:
· YERVOY®is most commonly associated with adverse reactions resulting from increased or excessive immune activity In the pivotal Phase 3 study in patients who received 3 mg/kg YERVOY®the most frequently reported adverse reactions (occurring at ≥10%) were diarrhea, rash, pruritus, fatigue, nausea, vomiting, decreased appetite, and abdominal pain. Please see Product Monograph, including Boxed WARNING regarding immune-mediated adverse reactions, available at www.bms.ca.
Yervoy® is a registered trademark of Bristol-Myers Squibb Company.
About Advanced Melanoma
Melanoma is a form of skin cancer characterized by the uncontrolled growth of pigment-producing cells (melanocytes) located in the skin. Metastatic melanoma is the deadliest form of the disease, and occurs when cancer spreads beyond the surface of the skin to the other organs, such as the lymph nodes, lungs, brain or other areas of the body. The incidence of melanoma has been increasing for at least 30 years. In 2015, an estimated 73,870 melanoma cases will be diagnosed in the U.S. Melanoma is mostly curable when treated in its early stages. However, in its late stages, the average survival rate is just 6 months with a 1-year survival of 25.5%, making it one of the most aggressive forms of cancer.
Melanoma is the deadliest form of skin cancer, accounting for 8% of cases of skin cancer in Canada but 70% of the deaths from the disease. Melanoma accounts for about 3% of all new cancer cases, placing it among the top 10 cancers diagnosed in Canada. In Canada, in 2014, it was estimated that 6,500 Canadians would be diagnosed with melanoma, and that 1,050 Canadians would die from it.
Melanoma is characterized by the uncontrolled growth of pigment-producing cells (melanocytes) located in the skin. Metastatic melanoma occurs when cancer spreads beyond the surface of the skin to other organs, such as the lymph nodes, lungs, brain or other areas of the body. Unresectable melanoma is a melanoma that cannot be removed or resected by surgery. The survival rate for melanoma is high if it is detected early but the advanced form, metastatic melanoma, is an aggressive disease which, until recently, was characterized by high mortality.
Immuno-Oncology at Bristol-Myers Squibb
Surgery, radiation, cytotoxic or targeted therapies have represented the mainstay of cancer treatment over the last several decades, but long-term survival and a positive quality of life have remained elusive for many patients with advanced disease.
To address this unmet medical need, Bristol-Myers Squibb is leading research in an innovative field of cancer research and treatment known as immuno-oncology, which involves agents whose primary mechanism is to work directly with the body’s immune system to fight cancer. The company is exploring a variety of compounds and immunotherapeutic approaches for patients with different types of cancer, including researching the potential of combining immuno-oncology agents that target different pathways in the treatment of cancer.
Bristol-Myers Squibb is committed to advancing the science of immuno-oncology, with the goal of changing survival expectations and the way patients live with cancer.
About Bristol-Myers Squibb
Bristol-Myers Squibb is a global pharmaceutical company whose mission is to discover, develop and deliver innovative medicines that help patients prevail over serious diseases. For more information about Bristol-Myers Squibb, visit www.bms.com, or follow us on Twitter at http://twitter.com/bmsnews.
About BMS Canada
Bristol-Myers Squibb Canada has been delivering innovative medicines for serious diseases to Canadian patients in the areas of cardiovascular health, oncology, neuroscience, immunoscience and virology for over 80 years. Bristol-Myers Squibb Canada employs over 300 employees across the country. For more information, please visit www.bmscanada.ca.
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 regarding 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 change any of them, and could cause actual outcomes and results to differ materially from current expectations. No forward-looking statement can be guaranteed. Among other risks, there can be no guarantee that the combination treatment of Opdivo™and Yervoy® will receive regulatory approval or, if approved, that it will become a commercially successful regimen. Forward-looking statements in this press release should be evaluated together with the many 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, 2014 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 forward-looking statement, whether as a result of new information, future events or otherwise.
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