Adjusting for treatment crossover in the BREAK-3 metastatic melanoma trial for dabrafenib: Preliminary analysis.

Abstract

9044 Background: In BREAK-3, dabrafenib improved PFS (hazard ratio [HR]=0.30 [95% CI 0.18–0.51; p<0.0001] as of Dec 19, 2011) vs dacarbazine (DTIC) in patients (pts) with previously untreated BRAF V600E+unresectable or metastatic melanoma. In an updated analysis (data as of June 25, 2012), PFS HR=0.37 (95% CI 0.24–0.58; p<0.0001). Overall survival (OS) results may underestimate the effect of dabrafenib as DTIC pts could cross over to dabrafenib at progression. This analysis attempts to adjust for confounding effects of crossover on OS using BREAK-3 results from June 2012 data. Methods: Randomization-based crossover adjustment methods – Rank Preserving Structural Failure Time Models (RPSFTM) and the Iterative Parameter Estimation (IPE) algorithm – were used. We conducted 2 sets of analyses testing different assumptions regarding the durability of the treatment (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: 187 and 63 pts were randomized to dabrafenib and DTIC, respectively. At the time of this analysis, 55.6% of DTIC pts crossed over to dabrafenib. Median duration of follow-up was 10.5 months and 76 (30.4%) pts died. Median OS has not yet been reached. Crossover adjustment results are presented in the Table. Conclusions: All RPSFTM and IPE analyses resulted in point estimates for the OS HR that represented a substantial increase in trt effect compared with the unadjusted HR of 0.75. Results are exploratory, as the OS data are not mature. Analyses will be updated when further data are available. [Table: see text]