Adjusting for treatment crossover in the METRIC metastatic melanoma (MM) trial for trametinib: Preliminary analysis.

Abstract

9040 Background: In METRIC, a randomized phase III study, trametinib significantly improved PFS (hazard ratio [HR]=0.44 [95% CI 0.31–0.64; p<0.001]) vs chemotherapy (chemo) in patients (pts) with BRAF V600E+ MM and no brain metastases. Median overall survival (OS), a secondary endpoint, has not yet been reached. OS results are likely to underestimate the effect of trametinib as pts progressing on chemo could cross over to experimental treatment (trt). This analysis attempts to adjust for confounding effects of trt crossover on OS in the overall population and first line (1L) subgroup using current METRIC results. Methods: Randomization-based crossover adjustment methods – Rank Preserving Structural Failure Time Models (RPSFTM) and the Iterative Parameter Estimation (IPE) algorithm – were used. We conducted two sets of analyses testing different assumptions regarding the durability of the trt effect. “Trt group” analyses adjusted for crossover under the assumption that the trt effect is maintained until death regardless of trt duration; “On trt – observed” analyses adjusted for crossover under the assumption that the trt effect disappears upon trt discontinuation. Results are presented as HRs. Results: 178 and 95 MM pts were randomized to trametinib and chemo, respectively; 49.5% of chemo pts crossed over to trametinib as of data cut off (Oct. 2011). Median follow-up was 4.9 months and 19.8% deaths occurred across both arms. Crossover adjustment results are presented in the Table. Conclusions: RPSFTM and IPE “trt group” analyses resulted in OS HR point estimates that represented greater trt effects in the overall population and 1L subgroup compared to the unadjusted HRs. Results are exploratory because few deaths have been observed in the current dataset. Future analyses on a mature dataset should produce more robust estimates of the OS trt effect after crossover adjustment. [Table: see text]