BMY receives FDA approval for YERVOY to treat metastatic melanoma

Bristol-Myers Squibb Company (NYSE: BMY) today announced that the U.S. Food and Drug Administration (FDA) approved YERVOY™ (ipilimumab) 3 mg/kg for the treatment of patients with unresectable (inoperable) or metastatic melanoma. YERVOY is the first and only therapy for unresectable or metastatic melanoma to demonstrate a significant improvement in overall survival based on results from a pivotal randomized, double-blind Phase 3 study. Median overall survival was 10 months (95% CI: 8.0-13.8) for YERVOY, 6 months (95% CI: 5.5-8.7) for gp100 and 10 months (95% CI: 8.5-11.5) for YERVOY + gp100, with p-values of 0.0026 (not adjusted for multiple comparisons) for YERVOY and 0.0004 for YERVOY + gp100 vs. gp100, respectively. As published in the New England Journal of Medicine, the Kaplan-Meier estimated survival rate at 1 year was 46% (95% CI: 37.0, 54.1) in the YERVOY arm vs. 25% (95% CI: 18.1, 32.9) in the gp100 arm. The estimated survival rate at 2 years was 24% (95% CI: 16.0, 31.5) in the YERVOY arm vs. 14%² (95% CI: 8.0, 20.0) in the gp100 arm. 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).

The full Prescribing Information for YERVOY includes a boxed warning for 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 (ipilimumab). Permanently discontinue YERVOY and initiate systemic high-dose corticosteroid therapy for severe immune-mediated reactions. Patients should be assessed for signs and symptoms of enterocolitis, dermatitis, neuropathy and endocrinopathy and clinical chemistries should be evaluated, including liver function tests and thyroid function tests, at baseline and before each dose. Please see complete Important Safety Information including Boxed WARNING regarding immune-mediated adverse reactions on pages 6-9.

"Metastatic melanoma is one of the most aggressive forms of cancer and despite the rising incidence, no new treatments have been approved in more than a decade," said Lamberto Andreotti, chief executive officer, Bristol-Myers Squibb. "Today's approval of YERVOY is an example of Bristol-Myers Squibb living its mission of developing and delivering innovative medicines that address the unmet needs of patients with serious diseases. It also represents a significant step forward in our commitment to deliver and execute against our differentiated and focused BioPharma strategy."

"For the first time, oncologists have a treatment option for patients with unresectable or metastatic melanoma that has been proven in a randomized Phase 3 clinical trial to significantly extend the lives of patients," said Steven J. O'Day, M.D., Chief of Research and Director of the Melanoma Program at The Angeles Clinic and Research Institute, California, and an investigator of the pivotal trial. "In fact, the Kaplan-Meier curve from this study suggests a prolonged survival benefit for some patients." Median overall survival was 10 months (95% CI: 8.0-13.8) for YERVOY (ipilimumab), 6 months (95% CI: 5.5-8.7) for gp100 and 10 months (95% CI: 8.5-11.5) for YERVOY + gp100, with p-values of 0.0026 (not adjusted for multiple comparisons) for YERVOY and 0.0004 for YERVOY + gp100 vs gp100, respectively.

"The FDA approval of YERVOY is the culmination of more than 14 years of research and development by our dedicated development teams and clinical trial investigators," said Elliott Sigal, M.D., Ph.D., executive vice president, chief scientific officer, and president, Research & Development, Bristol-Myers Squibb. "YERVOY is the first FDA-approved compound from our robust immuno-oncology pipeline, which comprises a variety of other compounds with the potential to harness the patient's immune system to fight cancer." The mechanism of action of ipilimumab's effect in patients with melanoma is indirect, possibly through T-cell mediated anti-tumor immune responses.

Bristol-Myers Squibb has agreed with the FDA to conduct a post-marketing study comparing the safety and efficacy of the 3 mg/kg dose vs. an investigational 10 mg/kg dose in patients with unresectable or metastatic melanoma.

The company expects to begin shipping YERVOY within weeks of today's FDA approval.

Overall Survival and Safety Profile of YERVOY in Patients with Unresectable or Metastatic Melanoma

YERVOY is the first and only therapy to demonstrate a statistically significant overall survival benefit in patients with unresectable or metastatic melanoma. The approval is based on a Phase 3, randomized (3:1:1), double-blind study that included 676 patients with unresectable or metastatic melanoma who were previously treated with one or more of the following: aldesleukin, dacarbazine, temozolomide, fotemustine, or carboplatin.

As published in the New England Journal of Medicine, the Kaplan-Meier estimated survival rate at 1 year was 46% (95% CI: 37.0, 54.1) in the YERVOY arm vs. 25% (95% CI: 18.1, 32.9) in the gp100 arm. The estimated survival rate at 2 years was 24% (95% CI: 16.0, 31.5) in the YERVOY arm vs. 14%² (95% CI: 8.0, 20.0) in the gp100 arm. Patients treated with YERVOY had a 34% reduction in the risk of death over the gp100 control arm (HR = 0.66 [95% CI: 0.51-0.87]

The best overall response rate (BORR) as assessed by the investigator was 10.9% (95% CI: 6.3, 17.4) in patients treated with YERVOY (ipilimumab)

In patients who received 3 mg/kg YERVOY alone> In patients who received 3 mg/kg of YERVOY + gp100

Results from this study were previously published in the New England Journal of Medicine and presented during a plenary session at the 46th Annual Meeting of the American Society of Clinical Oncology.

YERVOY: Risk Evaluation and Mitigation Strategy

"Bristol-Myers Squibb is committed to the safe and appropriate use of our medicines," said Annalisa Jenkins, senior vice president global medical, Bristol-Myers Squibb. "As part of the U.S. approval of YERVOY, we have collaborated with the FDA on the development of a Risk Evaluation and Mitigation Strategy to help inform patients and providers about important safety risks associated with YERVOY."

The YERVOY Risk Evaluation and Mitigation Strategy (REMS) consists of a Communication Plan to inform potential prescribers and supportive healthcare providers about serious adverse reactions associated with YERVOY. To support this communication plan, Bristol-Myers Squibb has put in place a system that will enable the company to deliver these educational materials to the appropriate healthcare professional at the time of product order.

More information and downloadable safety education materials will be available at www.YERVOY.com.

YERVOY Was Studied in a Pivotal Phase 3 Clinical Trial of Patients with Unresectable or Metastatic Melanoma

The approval is based on a Phase 3, double-blind study that randomized 676 patients with unresectable or metastatic melanoma who were previously treated with one or more of the following: aldesleukin, dacarbazine, temozolomide, fotemustine, or carboplatin. Patients were randomized in a 3:1:1 ratio to receive either YERVOY (ipilimumab) (3mg/kg) in combination with the investigational peptide vaccine gp100.

The primary endpoint of the pivotal Phase 3 study was overall survival in the YERVOY plus gp100 arm vs. the gp100 arm. Secondary efficacy endpoints included overall survival in the YERVOY plus gp100 arm vs. the YERVOY arm, overall survival in the YERVOY arm vs. the gp100 arm, BORR at week 24 and duration of response.

Patients received YERVOY (3mg/kg) as an intravenous infusion administered over 90 minutes every 3 weeks for four doses. Assessment of tumor response to YERVOY was conducted at weeks 12 and 24, and every 3 months thereafter. Patients with evidence of objective tumor response at 12 or 24 weeks had assessment for confirmation of durability of response at 16 or 28 weeks, respectively. Between 57% and 64% of patients treated in each study arm received all four planned doses.

YERVOY was studied in patients with a typically poor prognosis, including those with brain metastases, elevated LDH, and visceral disease (M1c). In the study, 71% had M1c stage, 12% had a history of previously-treated brain metastasis, 98% had ECOG performance status of 0 and 1, 23% had received aldeskeukin and 38% had elevated LDH level. Additionally, 29% of patients were 65 years or older with a median age of 57 years. The median duration of follow-up was 8.9 months. Please see complete Important Safety Information including Boxed WARNING regarding immune-mediated adverse reactions on pages 6-9.

YERVOY: Mechanism of Action

Cytotoxic T-lymphocyte antigen-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.

Source: Bristol-Myers Squibb Company