Correcting overall survival (OS) effect for the impact of cross-over via rank preserving structural failure time (RPSFT) model: Case of mRCC RECORD-1 trial of everolimus (EVE).

Abstract

4690 Background: The pivotal RECORD-1 trial examined the impact of EVE on PFS (Progression Free Survival) and OS in mRCC patients after failure on a VEGFr-TKI therapy. The study design allowed for crossover to open label EVE following progression on placebo. The ITT analysis of OS indicated a positive effect of EVE (HR=0.87, 95%CI: 0.65- 1.15, p=0.162). The conventional ITT approach is likely to underestimate the true treatment effect due to the crossover. Methods: The RPSFT model is based on a structural accelerated failure time model: each day spent on EVE (whether in the EVE randomization group or after cross-over from placebo) is assumed to prolong survival time compared to a day spent on placebo (Treatment Free Survival Time, TFST), by a multiplicative factor. The method reconstructs each patient's underlying TFST for a range of values of the multiplicative factor until the TFST curves between EVE and placebo cannot be distinguished on the basis of a linear rank test statistic (LRST). This estimation method provides a randomization based estimate of treatment effect corrected for the bias due to crossover. The robustness of the treatment effect estimate was assessed using a family of LRTS for the distance between TSFT curves (Harrington-Fleming family). Results: Using the traditional log-rank test statistic, the RPSFT estimated survival time was 1.9-fold longer (95% CI: 0.5–8.5) with EVE versus placebo. The treatment effect estimate was fairly robust against the distance measure used in the estimation. Conclusions: The treatment effect estimate was fairly robust to the choice of the test and the OS benefit for VEGFr-TKI refractory mRCC patients treated with everolimus was confirmed. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Novartis Novartis Novartis, sanofi-aventis