Addressing treatment switching bias in the ALTA-1L trial with g-methods: exploring the impact of model specification

Abstract Background: Treatment switching in randomized clinical trials introduces challenges in performing causal inference. Intention To Treat (ITT) analyses often fail to fully capture the causal effect of treatment in the presence of treatment switching. Consequently, decision makers may instead be interested in causal effects of hypothetical treatment strategies that do not allow for treatment switching. For example, the phase 3ALTA-1L trial showed that brigatinib may have improved Overall Survival (OS) compared to crizotinib if treatment switching had not occurred. Their sensitivity analysis using Inverse Probability of Censoring Weights(IPCW), reported a Hazard Ratio (HR) of 0.50 (95% CI, 0.28–0.87), while their initial ITT analysis estimated an HR of 0.81 (0.53–1.22). Methods: We used a directed acyclic graph to depict the clinical setting of the ALTA-1L trial in the presence of treatment switching, illustrating the concept of treatment-confounder feedback and highlighting the need for g-methods. In a re-analysis of the ALTA-1L trial data, we used IPCW and the parametric g-formula to adjust for baseline and time-varying covariates to estimate the effect of two hypothetical treatment strategies on OS: “always treat with brigatinib” versus “always treat with crizotinib”. We conducted various sensitivity analyses using different model specifications and weight truncation approaches. Results: Applying the IPCW approach in a series of sensitivity analyses yielded Cumulative HRs (cHRs)ranging between 0.38 (0.12, 0.98) and 0.73 (0.45,1.22) and Risk Ratios (RRs) ranging between 0.52 (0.32,0.98) and 0.79 (0.54,1.17). Applying the parametric g-formula resulted in cHRs ranging between 0.61(0.38,0.91) and 0.72 (0.43,1.07) and RRs ranging between 0.71 (0.48,0.94) and 0.79 (0.54,1.05). Conclusion: Our results consistently indicated that our estimated ITT effect estimate (cHR: 0.82 (0.51,1.22)may have underestimated brigatinib’s benefit by around 10-45 percentage points (using IPCW) and 10-20 percentage points (using the parametric g-formula) across a wide range of model choices. Our analyses underscore the importance of performing sensitivity analyses, as the result from a single analysis could potentially stand as an outlier in a whole range of sensitivity analyses. Trial registration: Clinicaltrials.gov Identifier: NCT02737501 on April 14, 2016