OBJECTIVES: The ICH E9(R1) Addendum highlights the importance of specifying post-randomization events that may affect the interpretation of clinical trial outcomes (i.e., intercurrent events; ICEs) and strategies to handle these events. Here, we review current practices for handling treatment switching, a common ICE in oncology, in randomized clinical trials (RCTs) and their synthesis.

METHODS: We conducted a comprehensive review of the Cochrane Library for meta-analyses of immune-, targeted, hormone, and other novel oncology therapies. Dates were restricted to 2021 and onwards to allow time for addendum adoption. Outcomes of interest included progression-free survival (PFS) and overall survival (OS). Information on treatment switching and analytical strategies were extracted from each meta-analysis and the RCTs they included.

RESULTS: Out of 1,180 oncology reviews published in the Cochrane Library since 2021, eight meta-analyses and 66 RCTs met inclusion criteria. Most RCTs were Phase 3 (45/66, 68%) and/or open-label (50/66, 76%). Half of RCTs explicitly allowed treatment switching (37/66, 56%), while more than one third (25/66, 38%) did not report on treatment switching. Among trials that allowed treatment switching, censoring mechanisms for treatment switching varied in analyses of PFS and OS. Counter to best practice guidelines, no RCTs reported the timing of treatment switching. Despite the high prevalence of treatment switching and the variability in outcome definitions across trials, no meta-analyses addressed treatment switching analytically.

CONCLUSIONS: While treatment switching is a common and well-known ICE in oncology, no meta-analyses reviewed in this study accounted for different approaches to treatment switching in their analyses. The strategy used for this important ICE can have a major impact on the results of a study. Poor reporting in the individual RCTs themselves also hinders the utility of aggregate-level meta-analyses. To ensure accurate interpretation of meta-analytic results, a consistent strategy for this intercurrent event is needed across studies.