Comparison of efficacy discrepancy between early-phase clinical trials and phase III trials of PD-1/PD-L1 inhibitors

Background Phase III clinical trials are pivotal for evaluating therapeutics, yet a concerning failure rate has been documented, particularly impacting oncology where accelerated approvals of immunotherapies are common. These failures are predominantly attributed to a lack of therapeutic efficacy, indicating overestimation of results from phase II studies. Our research aims to systematically assess overestimation in early-phase trials involving programmed cell death-1 (PD-1)/programmed cell death-ligand 1(PD-L1) inhibitors compared with phase III trials and identify contributing factors. Methods We matched 51 pairs of early-phase and phase III clinical trials from a pool of over 9,600 PD-1/PD-L1 inhibitor trials. The matching criteria included identical treatment regimens, cancer types, treatment lines, and biomarker enrichment strategies. To assess overestimation, we compared the overall response rates (ORR) between early-phase and phase III trials. We established independent variables related to eligibility criteria, and trial design features of participants to analyze the factors influencing the observed discrepancy in efficacy between the two phases through univariable and multivariable logistic analyses. Result Early-phase trial outcomes systematically overestimated the subsequent phase III results, yielding an odds ratio (OR) comparing ORR in early-phase versus phase III: 1.66 (95% CI: 1.43 to 1.92, p<0.05). This trend of inflated ORR was consistent across trials testing PD-1/PD-L1 monotherapies and combination therapies involving PD-1/PD-L1. Among the examined factors, the exclusion of patients with autoimmune diseases was significantly associated with the disparity in efficacy between early-phase trials and phase III trials (p=0.023). We calculated a Ward statistic of 2.27 to validate the effectiveness of the model. Conclusion These findings underscore the tendency of overestimation of efficacy in early-phase trials involving immunotherapies. The observed differences could be attributed to variations in the inclusion of patients with autoimmune disorders in early-phase trials. These insights have the potential to inform stakeholders in the future development of cancer immunotherapies.