Do Early Phase Oncology Trials Predict Clinical Efficacy in Subsequent Biomarker-Enriched Phase III Randomized Trials?

Background Promising early phase trial results of biomarker-targeted therapies have occasionally led to regulatory approval. Objective We examined if early phase trials were predictive of efficacy in randomized controlled trials (RCTs) with matching treatment settings. Patients and Methods Cancer drug RCTs conducted between January 2006 and March 2021 were identified through Clinicaltrials.gov. Biomarker-enriched RCTs and associated matching early phase trials were included. Trial pairs were compared using objective response rate (ORR) and progression-free survival (PFS). We examined whether early phase trials results were associated with RCT results using logistic regression. Results The search yielded 2157 unique RCTs and 27 RCTs pairing with early phase trials were included. Based on average difference of trial pairs, ORR was similar (1.6%; 95% confidence interval (CI) − 2.5 to 5.6, p = 0.50) and median PFS was higher in early phase trials (2.0 months; 95% CI 0.9–3.0, p < 0.05). On an individual pair basis, there was large variability in difference for ORR (range − 23.9 to 20.2%) and median PFS (range − 0.8 to 7.4 months). The probability of the RCT meeting its primary endpoint is 95% (95% prediction interval (PI) 72.8–99.3%) when the early phase trial ORR is 77.7%. Conclusions Overall, in early phase trials, ORR has minimal bias and median PFS appears to be slightly overestimated. Substantial variability between trials suggests early phase trial results may be inconsistent with subsequent RCT. Early phase trial results may be associated with RCTs meeting their primary endpoint when ORR is very high; however, caution must be exercised when using early phase trials as representative of RCTs.