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Background

Bevacizumab plus Interferon-alpha versus Interferon-alpha Monotherapy in Patients with Metastatic Renal Cell Carcinoma: Results of Overall Survival for CALGB 90206.

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  1. Bevacizumab plus Interferon-alpha versus Interferon-alpha Monotherapy in Patients with Metastatic Renal Cell Carcinoma: Results of Overall Survival for CALGB 90206 Brian I. Rini1, Susan Halabi 2,3, Jonathan E. Rosenberg4, Walter M. Stadler5, Daniel A.Vaena6, James N. Atkins7, Joel Picus8,Piotr Czaykowski9, Janice Dutcher10 and Eric J. Small4 1. Cleveland Clinic Taussig Cancer Institute, Cleveland, OH 2. Department of Biostatistics / Bioinformatics, Duke University Medical Center, Durham, NC 3. CALGB Statistical Center, Durham, NC 4. University of California San Francisco, San Francisco, CA 5. University of Chicago Medical Center, Chicago, IL 6. University of Iowa, Iowa City, IA 7. Southeast Cancer Control Consortium Inc. 8. Washington University, St. Louis, MO 9. University of Manitoba, Winnipeg, Manitoba; NCI Canada, Kingston, ON, Canada 10. New York Medical College, NY, NY; Eastern Cooperative Oncology Group, Boston, MA

  2. Background • Bevacizumab (BEV) plus interferon alpha (IFN) demonstrated a superior objective response rate and progression-free survival (PFS) versus IFN monotherapy in metastatic RCC patients in 2 phase III trials1,2 • The primary objective of CALGB 90206 was to compare overall survival (OS) for metastatic RCC patients receiving BEV plus IFN or IFN monotherapy 1. Escudier B et al. Lancet, 2007 2. Rini BI et al. JCO 2008

  3. Study Schema RANDOMIZE IFNA 9 MU TIW Eligibility Criteria • Confirmed metastatic RCC with a component of clear cell histology • Karnofsky PS ≥ 70% • Measurable or evaluable disease (by RECIST) • No prior systemic treatment • Adequate end-organ function • No CNS metastases • BP < 160/90 with meds • No DVT within 1 year or arterial thrombotic event within 6 months • Prior nephrectomy not required STRATIFY IFNA 9 MU TIW + Bevacizumab 10 mg/kg IV q d1 and d15 • Patients stratified for nephrectomy status (yes/no) and MSKCC risk group (0 risk factors vs. 1-2 risk factors vs. 3 or more risk factors)* * Motzer R et al., JCO 20(1), 2002

  4. Statistical Methods • The primary endpoint was OS, defined as the time from randomization to death due to any cause • The trial was designed with 86% power to detect a hazard ratio (HR) of 0.76 (assumed median OS improvement 13 to 17 months), assuming a two-sided type I error of 0.05 • The primary analysis was an intent-to-treat approach using the stratified log-rank statistic, and the present analysis was based on the target number of 588 deaths • Secondary endpoints: Progression-free survival (PFS), objective response rate (RECIST criteria), safety

  5. Patient Disposition Patients consented (n=732) IFNA monotherapy (n=363) Bevacizumab+ IFNA (n=369) Never started tx (n=13) Never started tx (n=3) Discontinued Treatment (n=346) PD / Death (n=218) Toxicity (n=66) Refused further tx (n=33) Other (n=24) Lost to follow-up (n=4) D/C after achieving CR (n=1) Discontinued Treatment (n=349) PD / Death (n=200) Toxicity (n=80) Refused further tx (n=40) Other (n=25) Lost to follow-up (n=2) D/C after achieving CR (n=2) Analyzed (n=363) Analyzed (n=369)

  6. Kaplan-Meier Overall Survival by Treatment Arm ----BEV/IFN:Median OS 18.3 months IFN: Median OS 17.4 months

  7. Overall Survival by MSKCC Risk Status* * Motzer R et al., JCO 20(1), 2002

  8. Second-line Therapy Received in Patients who Discontinued Protocol Therapy for Any Reason Other Than Death * Fifty-six percent of patients overall received at least one subsequent systemic therapy

  9. Median OS (months) according to treatment arm and subsequent therapy

  10. Baseline characteristics of patients according to subsequent therapy * There was no difference in baseline characteristics for patient who received subsequent therapy by treatment assignment

  11. Forest Plot of Overall Survival in Select Subgroups BEV/IFN better IFN better

  12. Kaplan-Meier Progression-Free Survival by Treatment Arm --Median PFS 8.4 months Median PFS 4.9 months HR= 0.71 (95% CI=0.6-0.8)

  13. Objective Response Note: patients with measurable disease only

  14. Frequency of selected grade 3 or 4 AEs

  15. Conclusions • Overall survival is greater in patients with metastatic clear cell RCC receiving bevacizumab plus interferon as initial systemic therapy compared to interferon alone, but does not meet pre-defined criteria for significance • Although the effect of bevacizumab plus IFN on OS is preserved regardless of subsequent treatment, the most robust OS is achieved in patients with favorable underlying disease biology who are able to receive subsequent therapy • The combination of bevacizumab and IFN as initial therapy in metastatic RCC patients results in a significantly greater progression-free survival and objective response rate versus IFNA monotherapy • Toxicity is greater in the combination therapy arm, including more fatigue, anorexia, hypertension and proteinuria

  16. Acknowledgements • The research for CALGB 90206 was supported, in part, by grants from the National Cancer Institute to the Cancer and Leukemia Group B (Richard L. Schilsky, MD, Chairman) and the CALGB Statistical Center (Stephen George, PhD). • Cancer Therapy Evaluation Program (CTEP) • Eastern Cooperative Oncology Group (ECOG) • National Cancer Institute Canada (NCIC) • Genentech; Schering-Plough for drug supply through CTEP • Patients, families and caregivers for the courage to participate in a randomized clinical trial

  17. Wait til next year . . .

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