Treatment switching in evidence synthesis in oncology: A systematic review of current meta-analytical practices

The 2019 ICH E9(R1) addendum highlights the importance of estimands, including the specification of post-randomization events that may affect the interpretation of clinical trial outcomes (i.e., intercurrent events; ICEs) and strategies to handle these events. Compared to trial protocols, there is limited discussion of estimands in the context of evidence synthesis. We conducted a comprehensive review of the Cochrane Library for pairwise meta-analyses of immuno-, targeted, hormone, and other novel oncology therapies. Dates were restricted to 2021 and onwards to allow time for addendum adoption. Outcomes of interest were progression-free survival (PFS) and overall survival (OS). Information on treatment switching and analytic strategies to address treatment switching were extracted from each meta-analysis and the RCTs they included. Out of 162 oncology reviews published in the Cochrane Library since 2021, eight pairwise meta-analyses and 68 RCTs met selection criteria. Most RCTs were Phase 3 (68%; n = 46) and/or open-label (76%; n = 52). More than half of RCTs explicitly allowed switching (59%; n = 40), while more than one third (38%; n = 26) did not report on treatment switching. Among trials that allowed treatment switching, censoring mechanisms for treatment switching varied in analyses of PFS. No included RCTs censored OS at the time of treatment switching. Despite the high prevalence of treatment switching in included trials, none of the identified meta-analyses addressed treatment switching analytically. Poor reporting regarding treatment switching in the RCTs themselves hinders the utility of aggregate-level meta-analyses. To ensure accurate interpretation of meta-analytic results, improved reporting of ICEs and ICE handling strategies is needed.