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Meta-Analysis of Phase II Cooperative Group Trials in Metastatic Stage IV Melanoma to Determine Progression-Free and Overall Survival Benchmarks for Future Phase II Trials

Edward L. Korn, Ping-Yu Liu, Sandra J. Lee, Judith-Anne W. Chapman, Donna Niedzwiecki, Vera J. Suman, James Moon, Vernon K. Sondak, Michael B. Atkins, Elizabeth A. Eisenhauer, Wendy Parulekar, Svetomir N. Markovic, Scott Saxman, John M. Kirkwood

From the Biometric Research Branch, Division of Cancer Treatment and Diagnosis, National Cancer Institute, Bethesda, MD; Southwest Oncology Group Statistical Office, Seattle, WA; Eastern Cooperative Oncology Group; and Department of Medicine, Beth Israel Deaconess Medical Center, Boston, MA; National Cancer Institute of Cancer Clinical Trials Group, Queen's University, Kingston, Ontario, Canada; Cancer and Leukemia Group B Statistical Center, Durham, NC; Mayo Clinic, Rochester, MN; H. Lee Moffitt Cancer Center and Research Institute, University of South Florida, Tampa, FL; Peace Corps, Washington, DC; and Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA

Corresponding author: Edward L. Korn, PhD, Biometric Research Branch, EPN-8129, Division of Cancer Treatment and Diagnosis, National Cancer Institute, Bethesda, MD 20892; e-mail: korne{at}ctep.nci.nih.gov

Purpose Objective tumor response rates observed in phase II trials for metastatic melanoma have historically not provided a reliable indicator of meaningful survival benefits. To facilitate using overall survival (OS) or progression-free survival (PFS) as an endpoint for future phase II trials, we evaluated historical data from cooperative group phase II trials to attempt to develop benchmarks for OS and PFS as reference points for future phase II trials.

Patients and Methods Individual-level and trial-level data were obtained for patients enrolled onto 42 phase II trials (70 trial arms) that completed accrual in the years 1975 through 2005 and conducted by Southwest Oncology Group, Eastern Cooperative Oncology Group, Cancer and Leukemia Group B, North Central Cancer Treatment Group, and the Clinical Trials Group of the National Cancer Institute of Canada. Univariate and multivariate analyses were performed to identify prognostic variables, and between-trial(-arm) variability in 1-year OS rates and 6-month PFS rates were examined.

Results Statistically significant individual-level and trial-level prognostic factors found in a multivariate survival analysis for OS were performance status, presence of visceral disease, sex, and whether the trial excluded patients with brain metastases. Performance status, sex, and age were statistically significant prognostic factors for PFS. Controlling for these prognostic variables essentially eliminated between-trial variability in 1-year OS rates but not in 6-month PFS rates.

Conclusion Benchmarks are provided for 1-year OS or OS curves that make use of the distribution of prognostic factors of the patients in the phase II trial. A similar benchmark for 6-month PFS is provided, but its use is more problematic because of residual between-trial variation in this endpoint.

Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.

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