Subgroup analyses in randomized phase III trials of systemic treatments in patients with advanced solid tumours: a systematic review of trials published between 2017 and 2020

Background: Subgroup analyses of randomized controlled trials are very common in oncology; nevertheless, the methodological approach has not been systematically evaluated. The present analysis was conducted with the aim of describing the prevalence and methodological characteristics of the subgroup analyses in randomized controlled trials in patients with advanced cancer.Methods: A systematic literature search using PubMed was carried out to identify all phase III randomized controlled trials conducted in adult patients affected by locally advanced or metastatic solid tumours, published between 2017 and 2020.Results: Overall, 253 publications were identified. Subgroup analyses were reported in 217 (86%) publications. A statistically significant association of presence of subgroup analysis with study sponsor was observed: subgroup analyses were reported in 157 (94%) for-profit trials compared with 60 (70%) non-profit trials (P < 0.001). Description of the methodology of subgroup analysis was completely lacking in 82 trials (38%), only cited without methodological details in 100 trials (46%) and fully described in 35 trials (16%). Forest plot of subgroup analyses for the primary endpoint was available in 195 publications (77%). Among publications with reported forest plots, the median number of subgroups for primary endpoint was 19 (range 6-78). Out of the 217 publications with subgroup analyses, authors discuss the heterogeneity of treatment effect among different subgroups in 173 publications (80%), although a formal test for interaction for subgroup analysis of primary endpoint was reported for at least one variable only in 60 publications (28%). Correction for multiplicity was explicitly carried out only in nine trials (4%). Conclusions: The very high prevalence of subgroup analyses in published papers, together with their methodological weaknesses, makes advisable an adequate education about their correct presentation and correct reading. More attention about proper planning and conduction of subgroup analysis should be paid not only by readers, but also by authors, journal editors and reviewers.