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

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• we find that historical precedent supports statistically exceeding a high ORR as an appropriate trial end point for highly active single-agent therapies.

• Increasingly, phase 1 trials are including expansion cohorts that double as single-arm studies of efficacy: in a recent institutional analysis of 522 phase 1 trials over 3 decades, sample size was shown to have increased dramatically since 2005.13 And yet, among 60 phase 1 trials carried out in 2011, the majority of protocols had no statistical justification for planned expansion cohorts despite a mean sample size of 30 patients.13

• we found that combination therapies achieving high ORRs often do not receive regulatory approval.

• a large and unbiased analysis of the relationship between tumor response and regulatory approval. For single-agent regimens, maximum ORR statistically exceeding 30% to 45% was associated with regulatory approval, with positive predictive values in the range of 89% to 100%. This suggests that high ORR is an appropriate statistical end point for single-arm trials aiming to demonstrate breakthrough activity of a single agent.

• 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.