Augmented two-stage estimation for treatment switching in oncology trials: Leveraging external data for improved...

Randomized controlled trials in oncology often allow control group participants to switch to experimental treatments, a practice that, while often ethically necessary, complicates the accurate estimation of long-term treatment effects. When switching rates are high or sample sizes are limited, commonly used methods for treatment switching adjustment (such as the rank-preserving structural failure time model, inverse probability of censoring weights, and two-stage estimation) may produce imprecise estimates. Real-world data can be used to develop an external control arm for the randomized controlled trial, although this approach ignores evidence from trial subjects who did not switch and ignores evidence from the data obtained prior to switching for those subjects who did. This article introduces "augmented two-stage estimation" (ATSE), a method that combines data from non-switching participants in a randomized controlled trial with an external dataset, forming a "hybrid non-switching arm". While aiming for more precise estimation, the augmented two-stage estimation requires strong assumptions. Namely, conditional on all the observed covariates: (1) a participant's decision to switch treatments must be independent of their post-progression survival, and (2) individuals from the randomized controlled trial and the external cohort must be exchangeable. With a simulation study, we evaluate the augmented two-stage estimation method's performance compared to two-stage estimation adjustment and an external control arm approach. Results indicate that performance is dependent on scenario characteristics, but when unconfounded external data are available, augmented two-stage estimation may result in less bias and improved precision compared to two-stage estimation and external control arm approaches. When external data are affected by unmeasured confounding, augmented two-stage estimation becomes prone to bias, but to a lesser extent compared to an external control arm approach.