Expansion cohorts in phase 1 oncology trials: a systematic review of their design, implementation and outcomes

The urgent need for drug development for cancer patients and the complexity of novel therapies have led to the increasing importance of expansion cohorts (EC) within phase 1 trial design. We conducted a systematic review of oncology phase 1 trials with EC published from 2019 to 2023. The objective was to assess the characteristics, purpose and outcomes of EC. A mixed-effects meta-regression model was conducted to analyse response rates. 479 published phase 1 trials with EC were included (median number of EC patients per trial: 27). The EC objective was stated in 55.7% of studies (76.8% safety, 16.5% dosing, 25.8% pharmacokinetics, 22.1% pharmacodynamics, 77.5% preliminary efficacy). 117 trials (24.4%) included a statistical justification plan. The mean Overall Response Rate (ORR) was 20.2% in solid tumours and 46.8% in haematological malignancies. Among drug classes, Antibody-drug conjugates showed the highest ORR (32.1%). Higher ORR was significantly associated with combination therapies, haematological trials, trials with statistical justification for EC sample size and trials not containing Immunotherapy. EC have evolved to become large dynamic studies assessing both preliminary efficacy and safety. This study highlights the importance of clearly stated EC objectives and sample size justification to enhance the rigour and interpretability of early-phase evidence.