OBJECTIVES : Treatment crossover refers to the situation in randomised controlled trials (RCTs) where patients randomised to the control group switch to the experimental treatment. This leads to biased estimates of treatment effects if crossover is not appropriately controlled for. The objective of this study was to compare the overall survival (OS) from the ALTA-1L clinical trial derived from three different treatment switching adjustments with the unadjusted data.

METHODS : The marginal structural model (MSM), the inverse probability of censoring weights (IPCW) and the rank preserving structural failure time model (RPSFTM; with and without re-censoring) were utilized to attempt to adjust for the bias introduced from 61/138 patients switching from the crizotinib arm to the brigatinib arm in the ALTA-1L clinical trial (NCT02737501).

RESULTS : The hazard ratio for brigatinib vs. crizotinib using the unadjusted OS data was 0.916 (95% CI: 0.572 – 1.466). Treatment switching methods estimated hazard ratios ranging from 0.446 to 0.939. Only RPSFTM including re-censoring increased the hazard ratio after removing the impact of subsequent brigatinib in the crizotinib arm, all other methods reduced the hazard ratio in favour of brigatinib.

CONCLUSIONS : This study demonstrates that the choice of treatment switching methodology applied can have a large impact on the estimated treatment effect of brigatinib vs. crizotinib. Limitations associated with the analyses are: (1) immature data from ALTA-1L (24.1% and 26.8% OS events had occurred in the brigatinib and crizotinib arms, respectively), (2) the difficulty in validating requirements underpinning treatment switching methodologies and (3) other subsequent ALK inhibitor use was not accounted for.