Response Rate as a Regulatory End Point in Single-Arm Studies of Advanced Solid Tumors

IMPORTANCE Objective response rate (ORR) is an increasingly important end point for accelerated development of highly active anticancer therapies, yet its relationship to regulatory approval is not well characterized. OBJECTIVE To identify circumstances in which a high ORR is associated with regulatory approval, and therefore might be an appropriate end point for definitive single-arm studies of anticancer therapies. DATA SOURCE A database of all oncology clinical trials registered at clinicaltrials. gov between October 1, 2007, and September 30, 2010. STUDY SELECTION Trials of palliative systemic therapies for 4 measurable solid tumor types, limited to those with trial arms of at least 20 patients reporting ORR per Response Evaluation Criteria in Solid Tumors (RECIST). DATA EXTRACTION AND SYNTHESIS A systematic search was used to identify the reported ORR for each eligible treatment arm that had been presented publicly. MAIN OUTCOMES AND MEASURES For each treatment regimen, defined as a single-agent or unique combination of agents for 1 cancer type, the mean ORR and the maximum ORR statistically exceeded were calculated, and their association with regulatory approval was studied. A regimen was considered approved for a specific cancer type if it had received regulatory approval in any country for treatment of advanced cancer of that type. RESULTS From 1800 trials, 874 eligible trial arms in 578 eligible trials were identified; 542 arms had ORR data available for 294 regimens. Maximum ORR and mean ORR were significantly associated with regulatory approval (tau = 0.27, P <.001; tau = 0.12, P = .01); this relationship was stronger for single-agent therapies (tau = 0.49; tau = 0.41) than for combination regimens (tau = 0.28; tau = 0.17). Evaluation of ORR thresholds between 20% and 60% as potential trial end points demonstrated that ORR statistically exceeding 30% with a single agent had 98% specificity and 89% positive predictive value for identifying regimens achieving regulatory approval. CONCLUSIONS AND RELEVANCE For single-agent regimens, high ORR was associated with regulatory approval; this relationship was less strong for combination regimens. Our data suggest that high ORR (eg, statistically exceeding an ORR of 30%) is an appropriate end point for single-arm trials aiming to demonstrate breakthrough activity of a single-agent anticancer therapy.