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

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.

For safety information, please click here

* 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.