Results From 3 Phase 2 Studies Reported A Two-Year Survival Rate Ranging From 30 To 42 Percent In Metastatic Melanoma Patients Treated With Ipilimumab

Main Category: Melanoma / Skin Cancer
Also Included In: Clinical Trials / Drug Trials;  Cancer / Oncology
Article Date: 04 Jun 2009 - 0:00 PDT

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Bristol-Myers Squibb Company (NYSE: BMY) and Medarex, Inc. (NASDAQ: MEDX) today announced updated survival results from follow-up extensions of three Phase 2 ipilimumab studies of patients with advanced metastatic melanoma (Stage III or IV). The two-year survival rate ranged from 29.8 to 41.8 percent in patients who received ipilimumab (10 mg/kg). Results of the survival data were presented at the 45th Annual Meeting of the American Society of Clinical Oncology in Orlando, FL., May 29 - June 2, 2009. The results are based on follow-up of up to 37.5 months (median follow-up ranging from 10.1 to 16.3 months) of the patient population from studies 008, 022 and 007 treated with 10 mg/kg of ipilimumab (induction and maintenance) and, specifically, showed:

- Two-year survival rate of 32.8 percent (95% CI: 25.37%- 40.49%) in patients who had progressed while on or after receiving standard treatment (Study 008, Abstract #9033);

- Two-year survival rate of 29.8 percent (95% CI: 19.13%- 41.14%) in patients who were previously treated, relapsed or failed to respond to experimental treatment or were unable to tolerate currently approved therapies (Study 022, Abstract #9033);

- Two-year survival rate of 40.6 percent (95% CI: 27.12%- 54.37%) and 41.8 percent (95% CI: 28.30%- 55.46%) in patients receiving ipilimumab plus budesonide or ipilimumab plus placebo, respectively, which included treatment-naïve patients and patients previously treated with therapy other than ipilimumab (Study 007, Abstract #9033).

Historical melanoma survival rates from previous clinical trials have been estimated by a recent meta-analysis of 42 Phase 2 trials of over 2,100 patients with Stage III or IV metastatic melanoma indicating that, at one year, approximately 25 percent of patients were alive.1 Results from three separately published randomized Phase 3 studies using dacarbazine as the control arm reported that, at two years, approximately 8 to 12 percent of metastatic melanoma patients were alive.2,3,4 The updated survival analyses did not include additional safety data. As previously reported, safety results include follow-up of up to 16.3 months with a median follow-up ranging from 4.7 to 5.65 months. The most common immune-related adverse events were rash, diarrhea and hepatitis. Grade 3 and 4 immune-related adverse event rates were approximately 20 to 29 percent and zero to 12 percent, respectively, in patients who received 10 mg/kg of ipilimumab. Adverse events were managed with the use of supportive care and systemic steroids using established treatment guidelines in the majority of patients. Additionally, the use of systemic steroids to manage adverse events does not appear to diminish or impact the clinical effect of ipilimumab (Abstract #9037). "The ongoing survival data observed with ipilimumab are encouraging, particularly because the advanced melanoma patient population currently has limited treatment options," said Steven J. O'Day, M.D., Chief of Research and Director of the Melanoma Program at The Angeles Clinic and Research Institute, California. "The potential of ipilimumab is also underscored by the fact that we can report two-year survival results from these studies involving a significant number of metastatic melanoma patients."

Candidate Biomarkers of Ipilimumab

Researchers also presented an exploratory analysis from four Phase 2 ipilimumab studies (008, 022, 007 and 004) that looked at the association between clinical activity and multiple potential biomarkers, including the change in absolute lymphocyte count (ALC) in melanoma patients after they received ipilimumab (Abstracts #9008 and #3020). ALC is a measure of the number of immune cells in circulation.

In a combined analysis of studies 007, 008 and 022, clinical activity was associated with an increase in the rate of change in ALC. Patients with clinical activity had a higher average increase in ALC over time than did patients without clinical activity (P=0.0013) and no patient with a decrease in ALC over time had clinical activity. This association was separately confirmed in Study 004. Increases in ALC following administration of ipilimumab were also significantly associated with dose (studies 007, 008, 022: P<0.0001; study 004: P=0.0015), favoring the 10 mg/kg regimen. Based on these early biomarker findings, further research to explore the implication of ALC and other potential biomarkers of clinical activity of ipilimumab continues.

About Studies 008, 022 and 007

The three studies enrolled a total of 487 patients across North America, Europe, South America, Africa and Australia with Stage III or Stage IV metastatic melanoma treated with ipilimumab therapy (0.3 mg/kg, 3.0 mg/kg or 10 mg/kg every three weeks for up to four doses, followed by maintenance dosing every 12 weeks). Specifically, the three Phase 2 monotherapy trials include:

- A Phase 2 open-label, single-arm trial (008) evaluating overall response rate in 155 patients
who progressed while on or after receiving standard treatment;

- A Phase 2 randomized, double-blind trial (022) evaluating the efficacy of three dose levels of ipilimumab in 217 patients who were previously treated, relapsed or failed to respond to experimental treatment or were unable to tolerate currently approved therapies; and

- A Phase 2 randomized, double-blind trial (007) evaluating the rate of Grade 2+ diarrhea in 115 patients receiving ipilimumab with or without prophylactic oral budesonide. The primary endpoint of studies 008 and 022 was best overall response rate and the primary endpoint of study 007 was to compare the rate of Grade 2+ diarrhea in patients receiving ipilimumab with or without prophylactic oral budesonide. Overall survival, one-year survival rates, disease control rate, stable disease, and other measurements of anti-tumor activity and patterns of responses were secondary endpoints in studies 008, 022 and 007. The two-year survival data reported are current (through March, 2009) for all subjects followed: 93.6% from study 008, 91.7% from study 022 and 84.2% and 82.8% from the two subgroups of study 007 (placebo and budesonide, respectively).

About Study 004

Study 004 is a Phase 2 randomized, double-blind biomarker trial. The study enrolled 82 patients with advanced melanoma who were previously treated with therapy other than ipilimumab or who received no prior therapy. All patients received ipilimumab therapy (3.0 mg/kg or 10 mg/kg). Preand post-treatment (week four) tumor biopsies were performed to assess associations between tumor biomarkers and clinical activity of ipilimumab. Clinical activity was defined as complete or partial response or stable disease at ≥24 weeks using modified World Health Organization criteria.

About Ipilimumab

Ipilimumab is a fully human antibody that binds to CTLA-4 (cytotoxic T lymphocyte-associated antigen 4), a molecule on T-cells that plays a critical role in regulating natural immune responses. The absence or presence of CTLA-4 can augment or suppress the immune system's T-cell response in fighting disease.

About Advanced Melanoma

Melanoma is a form of skin cancer characterized by the uncontrolled growth of pigment-producing cells (melanocytes) located in the skin.5 As with many cancers, it is more difficult to treat once the disease has spread beyond the skin to other parts of the body by way of the bloodstream or the lymphatic system (metastatic disease).6,7 Melanoma accounts for about three percent of skin cancer cases,8 but it causes most skin cancer deaths.9 The American Cancer Society estimates that in 2009, there will be 68,720 new cases of melanoma in the U.S.9

About Bristol-Myers Squibb

Bristol-Myers Squibb is a global biopharmaceutical company whose mission is to extend and enhance human life. For more information, visit http://www.bms.com.

This press release contains "forward-looking statements" as that term is defined in the Private Securities Litigation Reform Act of 1995, regarding the research and development of ipilimumab.

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 development of ipilimumab will be successful or that the clinical studies described in this release will support the filing of a Biological License Application (BLA) with the U.S. Food and Drug Administration (FDA). Furthermore, there can be no assurances that if a BLA is filed with the FDA, that it will be filed in the timeframe developed by the parties or that such BLA will receive regulatory approval.

There can be no assurances that if approved, ipilimumab will be commercially successful. Forward-looking statements in the 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, 2008, its Quarterly Reports on Form 10-Q, and 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.

References

1. Korn, E. "Meta-analysis of Phase 2 Cooperative Group Trials in Metastatic Stage IV Melanoma to Determine Progression-Free and Overall Survival Benchmarks for Future Phase 2 Trials." Journal of Clinical Oncology.2008; 26 (4):526-534.

2. Middleton M.R., Grob J.J, Aaronson N et al. "Randomized Phase III Study of Temozolomide Versus Dacarbazine in the Treatment of Patients With Advanced Metastatic Malignant Melanoma." Journal of Clinical Oncology.2000; 18(1): 158-166.

3. Chapman P, Einhorn L, Myers M et al. "Phase III Multicenter Randomized Trial of the Dartmouth Regimen Versus Dacarbazine in Patients With Metastatic Melanoma." Journal of Clinical Oncology. 1999; 17(9): 2745-2751.

4. Bedikian AY, et al. "Bcl-2 antisense (oblimersen sodium) Plus Dacarbazine in Patients with Advanced Melanoma: The Oblimersen Melanoma Study Group." Journal of Clinical Oncology. 2006; 24(29):4738-45.

5. National Cancer Institute Web site. "Melanoma." http://www.cancer.gov/cancertopics/types/melanoma. Accessed on May 27, 2009.

6 American Cancer Society Web site. "Detailed Guide: Advanced Cancer What Is Metastatic Cancer?" See here Accessed on May 27, 2009.

7 American Cancer Society Web site. "New Treatments On Horizon For Melanoma." See here. Accessed on May 27, 2009.

8 American Cancer Society Web site. Overview: Skin Cancer - Melanoma How Many People Get Melanoma Skin Cancer? See here. Accessed on May 27 2009

9 American Cancer Society Web site. Cancer Facts & Figures 2009. http://www.cancer.org/downloads/STT/500809web.pdf. Accessed May 27, 20009.

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Bristol-Myers Squibb

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