Use of progression-free survival (PFS) to predict overall survival (OS) in patients with metastatic renal cell carcinoma (mRCC).

Abstract

4525 Background: PFS has been used as a clinical trial endpoint evaluating the efficacy of novel agents in mRCC, and has led to the approval by the FDA of VEGF targeted therapeutics. This approach is attractive as a major challenge in designing trials in mRCC has been the attenuation of potential impact on survival by second line and beyond therapies with emerging active agents. A data set from a prospective randomized phase III trial was analyzed to assess whether progression-free survival (PFS) can be used as a predictor of overall survival (OS) and to investigate the dependence between PFS and OS in patients with mRCC. Methods: Data from CALGB 90206, which enrolled 732 patients in a randomized phase III trial of interferon alpha vs. interferon alpha/bevacizumab, were analyzed. Patients were eligible if they had metastatic RCC, a clear cell histologic component, no prior systemic therapy for RCC, Karnofsky performance status of ≥ 70%, adequate bone marrow, hepatic, cardiac and renal function, blood pressure controlled to < 160/90 mmHg and lack of central nervous system metastases. Landmark analyses of PFS at 3 and 6 months from randomization were performed to minimize lead time bias. The log rank test and the proportional hazards model were used to assess the significance effect of PFS at 3 and at 6 months in predicting OS. The association between OS and PFS was investigated using Kendall's tau. Results: The median survival time among patients who experienced progression at 3 months was 6.0 months (95% CI = 5.3-6.9) compared to 25.2 months in patients who did not progress at 3-months (95% CI=22.2 – 28.5), log-rank p-value <0.0001). Compared to patients who did not progress at 3 and at 6 months, the adjusted hazard ratios for death were 2.6 (95% CI=2.1 – 3.1, p-value <0.001) and 2.9 (95% CI=2.4 – 3.5, p-value<0.001) for men who progressed at 3 and 6-months, respectively. The association between PFS and OS was 0.52 (95% confidence limits=0.48-0.55). Conclusions: Although PFS at 3 and at 6 months predict OS in patients with mRCC, the association was modest. PFS is not an optimal intermediate endpoint. These observations require prospective validation. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Genentech Genentech