Abstract CT330: Adjusting for confounding effects of treatment crossover in a randomized phase 2 study of dabrafenib plus trametinib in BRAF V600+ metastatic melanoma

Abstract

Abstract In a randomized phase 2 study (BRF113220), dabrafenib (150 mg twice daily) plus trametinib (2 mg once daily) improved progression-free survival (HR=0.39; 95% CI, 0.25-0.62; P<.001) vs dabrafenib alone. 54 patients were randomized to each arm. At the most recent data cut (March 2013), median duration of follow-up was 24 months and 52% of patients had died. ITT analyses of overall survival (OS) are likely to underestimate the true benefit of treatment because patients in the control arm (83%) were able to cross over to combination treatment upon progression. ITT median OS, a secondary endpoint, was 23.8 vs 20.2 months (HR=0.73; 95% CI, 0.43-1.24). We adjusted for confounding due to this crossover using randomization-based crossover adjustment methods: the rank-preserving structural failure time model (RPSFTM) and iterative parameter estimation (IPE) algorithm. Different assumptions about the durability of treatment effect were tested: “treatment group” analyses allow for a treatment effect that continues beyond treatment discontinuation, while “on treatment_observed” analyses assumed that the treatment effect disappears upon discontinuation. Results are presented in the Table. Reestimation of median OS following adjustment with both RPSFTM and IPE (possible only for the treatment group analyses) suggested an OS gain of 9.1 months with combination treatment vs dabrafenib alone (compared with a 3.6-month gain under ITT assumptions). The RPSFTM estimation method performed marginally better than the IPE analyses and may provide more robust results. After adjusting for the effect of crossover, the reduction in HRs to 0.47-0.50 suggests that the ITT analysis underestimates the effect of dabrafenib plus trametinib on OS. Results are uncertain due to the limiting assumptions associated with the RPSFTM and IPE methodology, small trial size, low number of observed deaths, and low number of control group patients who did not cross over. Crossover Adjustment MethodAssumptionOS HR (95% CI)None (ITT analysis unadjusted for crossover)0.73 (0.43-1.24)RPSFTMTreatment group0.47 (0.13-1.66)On treatment–observed analyses0.49 (0.15-1.63)IPETreatment group0.50 (0.16-1.54)On treatment–observed analyses0.47 (0.14-1.61) Citation Format: Nicholas Latimer, Mayur Amonkar, Ceilidh Stapelkamp, Peng Sun. Adjusting for confounding effects of treatment crossover in a randomized phase 2 study of dabrafenib plus trametinib in BRAF V600+ metastatic melanoma. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr CT330. doi:10.1158/1538-7445.AM2014-CT330