A case for time to tumor progression (TTP) as the primary (1o) efficacy endpoint in 1st-line metastatic colorectal cancer (MCRC) therapy: Correlation of TTP and overall survival (OS)

Abstract

3503 Background: OS has been the 1o endpoint for phase III MCRC registration trials. However, increasing numbers of efficacious agents have extended OS and added therapeutic complexity. Evaluation of new drugs based on OS may be impeded by larger sample sizes, longer study durations, and crossovers. Thus, FDA, ASCO and AACR, in a review of surrogate and clinical benefit endpoints, have asked if TTP could replace OS as the 1o endpoint because it measures an early treatment effect and is not confounded by later therapies. Methods: As part of this effort, we assessed the relationship of TTP to OS in the 1o patient data from the 2 large, FDA-reviewed phase III trials (NEJM, 343:905, 2001; Lancet 355:1041, 2001) that form the basis of irinotecan/5-FU/leucovorin (IFL) approval in previously untreated MCRC. Patients (pts) were randomized to: Study 1 (bolus IFL or FL or I) and Study 2 (infusional IFL or FL) and could receive 2nd-line I or FL; 2nd-line oxaliplatin was not widely available. Results: The linear regression of OS vs TTP (mo) was OS=1.2xTTP+8.3 (r=.56), showing an ≈1:1 correlation between TTP and OS improvement and that pts lived an average of ≈8 more mo after progression. The OS:TTP relationship (slope) was not altered by treatment or prognostic factors (PS, LDH), but post-study survival (y-intercept) was affected. In a Cox regression analysis, longer OS was better explained by longer (≥6 mo) TTP (p<0.0001, hazard ratio [HR] 0.31) than by PS=0 (p<0.0001, HR 0.47) or normal LDH (p<0.0001, HR 0.51). Conclusion: An irinotecan-induced improvement in TTP translates into a similar improvement in OS, supporting the use of TTP as the 1o endpoint in phase III MCRC trials. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Pfizer Corp. Pfizer Corp. Pfizer Corp. Pfizer Corp. Aventis Pfizer Pfizer Corp.