Characteristics and outcomes of expansion cohorts in phase 1 oncology trials: a systematic review

Phase 1 clinical trials have evolved markedly over the last decade. The urgent need for drug development for cancer patients, together with the greater complexity of novel therapies, have led to the increasing importance of expansion cohorts (ECs) within phase 1 trial design.
We conducted a systematic review of MEDLINE and EMBASE, focusing on oncology phase 1 trials with ECs involving adult participants published from 2019 to 2023. The objective was to assess the characteristics, purpose and outcomes of ECs. Descriptive analysis was performed, and a mixed-effects meta-regression model was conducted to analyse the response rates.
479 published phase 1 trials with ECs were analysed. The objective of the ECs was clearly stated in 55.7% of studies (76.8% safety, 16.5% dose refinement, 25.8% pharmacokinetics, 22.1% pharmacodynamics, 77.5% efficacy). 117 trials (24.4%) included a statistical justification plan. The mean Overall Response Rate (ORR) for studies recruiting solid tumour patients was 20.2% versus 46.8% for haematological trials. Antibody-drug conjugate trials showed the highest mean ORR (32.1%) and DCR (70.6%) among the classes of drugs. Combination trials, Trials which included a statistical justification for the expansion cohort, Haematology trials and Trials not containing Immunotherapy were significantly related with higher ORR. 59.1% of the reviewed studies progressed to later-stage trials registered in clinicaltrials.gov.
ECs have evolved to become large dynamic studies which enrol more patients, focus on efficacy as well as safety, and involve novel therapies. This study highlights the importance of statistical justification and clear statement of ECs objectives to ensure meaningful early-phase trial outcomes.