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Second Phase 3 Study of YERVOY (ipilimumab) in Metastatic Melanoma Meets Primary Endpoint of Overall Survival

Study 024 Evaluated Newly-Diagnosed Patients Treated with YERVOY at Investigational Dose of 10mg/kg in Combination with Dacarbazine vs. Dacarbazine Alone

Forty-Seven Percent of Patients Treated with YERVOY Plus Dacarbazine Alive at One Year, 28 Percent Alive at Two Years and 20 Percent Alive at Three Years

In Patients with an Objective Response, Median Duration was 19.3 Months in YERVOY Plus Dacarbazine Arm vs. 8.1 Months for Dacarbazine Alone Arm

Types of Safety Events Consistent with Prior Experience; Higher Incidence of Liver Enzyme Elevations and No Drug-Related Deaths in YERVOY Arm Reported

Results Published in New England Journal of Medicine and Presented at 47th Annual Meeting of the American Society of Clinical Oncology

PRINCETON, NJ--(BUSINESS WIRE)--Jun 5, 2011 - Bristol-Myers Squibb Company (NYSE: BMY) today announced results from a second Phase 3 randomized, double blind study demonstrating that YERVOY™ (ipilimumab) prolonged the lives of patients with metastatic melanoma. The data were published today in the New England Journal of Medicine and presented at the 47th Annual Meeting of the American Society of Clinical Oncology. (Abstract #5)

In study 024, patients had not received prior treatment for metastatic melanoma and were randomized to receive the investigational dose of YERVOY 10mg/kg in combination with the chemotherapy dacarbazine (850 mg/m2) or dacarbazine alone. There was a significant improvement in overall survival (HR = 0.72, P=0.0009) for patients treated with YERVOY plus dacarbazine vs. those who received dacarbazine alone. Higher estimated survival rates were observed at one year (47.3% vs. 36.3%), two years (28.5% vs. 17.9 %) and three years (20.8% vs. 12.2 %; three years was analyzed post hoc) in patients treated with YERVOY plus dacarbazine vs. those who received dacarbazine alone.

Overall, the types of adverse events (AEs) attributed to YERVOY in study 024 were generally mechanism (immune)- based and consistent with prior YERVOY studies. A higher-than-expected rate of liver enzyme elevations was reported. There were no gastrointestinal perforations in either arm of the study and no drug-related deaths in the YERVOY arm. Adverse events associated with YERVOY were managed with protocol-specific guidelines, including the administration of systemic corticosteroids, dose interruption/discontinuation and/or other immunosuppressants.

“We now have Phase 3 data demonstrating that ipilimumab improved survival in patients with metastatic melanoma in both the first and second-line settings,” said Jedd Wolchok, M.D., Ph.D., Memorial Sloan-Kettering Cancer Center, and presenter of the study results. “For physicians who treat cancer, improving overall survival is what we strive for with our patients and I believe ipilimumab is a foundational therapy for metastatic melanoma.”

“In this study, the one, two and three-year estimated survival rates demonstrate prolonged survival for patients in the YERVOY plus dacarbazine arm,” said Caroline Robert, M.D., Institute Gustave Roussy in Paris, France, and lead author on the New England Journal of Medicine paper. “Results from this study are significant in a disease as devastating at metastatic melanoma.”

The combination of dacarbazine with YERVOY is not an FDA approved-regimen. In addition, study 024 was not designed to compare the safety and efficacy of the FDA- approved monotherapy dose of 3 mg/kg for unresectable or metastatic melanoma vs. the investigational dose of 10 mg/kg. Bristol-Myers Squibb plans to conduct a head-to-head Phase 3 study comparing the safety and efficacy of these two doses given as a monotherapy in patients with unresectable or metastatic melanoma.

Detailed Study Results

In study 024, there was a significant improvement in overall survival (HR = 0.72, P=0.0009) in the YERVOY plus dacarbazine arm vs. the dacarbazine alone arm. The estimated rates of overall survival in the YERVOY plus dacarbazine arm vs. the dacarbazine alone arm were 47.3% vs. 36.3% at one year, 28.5% vs. 17.9 % at two years and 20.8% vs. 12.2 % at three years (three years was analyzed post hoc). Median overall survival in the YERVOY plus dacarbazine arm was 11.2 months (95% CI: 9.4, 13.6) compared with 9.1 months (95% CI: 7.8, 10.5) in the dacarbazine alone arm. The best objective response rate was 15.2% (38/250) in the YERVOY plus dacarbazine arm and 10.3% (26/252) in the dacarbazine alone arm. The median duration of response in those patients who achieved an objective response (CR and/or PR) was 19.3 months (95% CI: 12.1, 26.1) in the YERVOY plus dacarbazine arm (n=38) and 8.1 months (95% CI: 5.19, 19.8) in the dacarbazine alone arm (n=26).

Grade 3/4 adverse events (AEs) were observed in 56% of the YERVOY plus dacarbazine arm and 28% of the dacarbazine alone arm. Select AEs (all grades), which were reported at higher incidence in the YERVOY plus dacarbazine arm included: alanine transaminase elevation (33% versus 6%), aspartate transaminase elevation (29% versus 6%), diarrhea (36% versus 25%), pruritis (30% versus 9%), and rash (25% versus 7%). No gastrointestinal perforations were reported in either arm of the study. No drug-related deaths were reported in the YERVOY plus dacarbazine arm. One fatal gastrointestinal hemorrhage was reported in the dacarbazine arm.

The most frequent reason for discontinuation of study drug therapy was disease progression (46.2% in the YERVOY plus dacarbazine group and 77.3% in the dacarbazine group). Discontinuation due to drug-related toxicity was reported in 36% of patients in the YERVOY plus dacarbazine and 4% in the dacarbazine alone arm. A total of 37% of patients in the YERVOY plus dacarbazine arm and 66% of patients in the dacarbazine alone arm received all four doses of YERVOY or placebo.

About the Study

Study 024 is a multi-national, randomized, double-blind Phase 3 study that evaluated the safety and efficacy of YERVOY (10 mg/kg) plus dacarbzine (850 mg/m2) vs. dacarbazine alone in treatment naive patients with Stage III unresectable or Stage IV metastatic melanoma. Patients who received prior adjuvant therapy were allowed in the trial. Patients were randomly assigned in a 1:1 ratio to receive either YERVOY plus dacarbazine (n=250) or dacarbazine plus placebo (n=252) at Weeks 1, 4, 7, 10 followed by dacarbazine alone every 3 weeks through Week 22 (induction phase). If drug intolerance or progressive disease (PD) was noted during Weeks 12-24, treatment was discontinued. At Week 24, patients who had stable disease (SD) or an objective response (OR) during induction with no dose-limiting toxicity could enter a maintenance phase in which they received placebo or YERVOY every 12 weeks until PD, drug intolerance or end of study.

The primary endpoint of study 024 was overall survival. Secondary endpoints included progression-free survival, disease control rate, best overall response rate by modified WHO criteria, time to response, response duration, and safety.

About Metastatic 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 other organs, such as the lymph nodes, lungs, brain or other areas of the body. Some cancer cells can actively evade surveillance by the immune system, allowing tumors to survive. 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 mortality rate of 75%, making it one of the most aggressive forms of cancer. These rates are based on a meta-analysis of 42 Phase 2 trials of more than 2,100 previously-treated and treatment-naïve patients with Stage IV metastatic melanoma conducted by multiple cooperative groups from 1975-2005. The incidence of melanoma has been increasing for at least 30 years. The median age at diagnosis for melanoma is 57 and the median age at death is 67.

About YERVOY

In March 2011, the FDA approved YERVOY 3 mg/kg monotherapy for patients with unresectable or metastatic melanoma. YERVOY was also added to the National Comprehensive Cancer Network® (NCCN®) Clinical Practice Guidelines in Oncology (NCCN Guidelines™) for Melanoma as the only NCCN Category 1 FDA-approved agent for treatment of metastatic melanoma. A category 1 designation is based on high level evidence, such as randomized controlled trials, as well as uniform NCCN consensus. Further details can be found at www.nccn.org.*

YERVOY, which is a recombinant, human monoclonal antibody, is the first FDA-approved cancer immunotherapy that blocks the cytotoxic T- lymphocyte antigen-4 (CTLA-4). CTLA-4 is a negative regulator of T-cell activation. Ipilimumab binds to CTLA-4 and blocks the interaction of CTLA-4 with its ligands, CD80/CD86. Blockade of CTLA-4 has been shown to augment T-cell activation and proliferation. The mechanism of action of ipilimumab's effect in patients with melanoma is indirect, possibly through T-cell mediated anti-tumor immune responses.

YERVOY™ (ipilimumab) IMPORTANT SAFETY INFORMATION

WARNING: 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 corticosteroid therapy for severe immune-mediated reactions.

Recommended Dose Modifications

Withhold dose for moderate immune-mediated adverse reactions 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.

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.
  • 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.

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 upper limit of normal (ULN) or total bilirubin elevations >3X the ULN; Grade 3–5) occurred in 8 (2%), 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.

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.

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.

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%).
    • 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 of endocrinopathies 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.

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, 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, and autoimmune thyroiditis.

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.

About Bristol-Myers Squibb

Bristol-Myers Squibb is a global biopharmaceutical 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.

This press release contains "forward-looking statements" as that term is defined in the Private Securities Litigation Reform Act of 1995 regarding product development. 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 YERVOY will become a commercially successful product. 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, 2009, 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.

* Referenced with permission from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines™) for Melanoma V.4.2011. © 2011 National Comprehensive Cancer Network, Inc. All rights reserved. Accessed [Month and Day, year]. To view the most recent and complete version of the NCCN Guidelines, go online to NCCN.org. NATIONAL COMPREHENSIVE CANCER NETWORK®, NCCN®, NCCN GUIDELINES™, and all other NCCN Content are trademarks owned by the National Comprehensive Cancer Network, Inc.

 

 

 

Contact: Bristol-Myers Squibb
Media:
Sarah Koenig, 609-252-4145
sarah.koenig@bms.com
or
Investors:
John Elicker, 609-252-4611
john.elicker@bms.com

 

 

Posted: June 2011

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