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Response Rate as a Regulatory End Point in Single-Arm Studies of Advanced Solid Tumors
Geoffrey R Oxnard1, Katharine H Wilcox1, Mithat Gonen2
1Lowe Center for Thoracic Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.
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 (τ = 0.27, P < .001; τ = 0.12, P = .01); this relationship was stronger for single-agent therapies (τ = 0.49; τ = 0.41) than for combination regimens (τ = 0.28; τ = 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.
Insights
High objective response rates (ORR) in single-agent cancer therapies are linked to regulatory approval. An ORR exceeding 30% can predict approval for breakthrough single-agent anticancer treatments.
Area of Science:
- Oncology
- Clinical Trial Design
- Drug Development
Background:
- Objective response rate (ORR) is a key endpoint in accelerated anticancer drug development.
- The relationship between high ORR and regulatory approval is not well-defined.
Purpose of the Study:
- To determine the circumstances under which a high ORR correlates with regulatory approval.
- To assess if ORR can serve as an appropriate endpoint for definitive single-arm studies of anticancer therapies.
Main Methods:
- Analysis of oncology clinical trials registered between 2007-2010.
- Inclusion of trials with palliative systemic therapies for solid tumors, reporting ORR per RECIST criteria.
- Calculation of mean and maximum ORR for regimens and assessment of their association with regulatory approval.
Main Results:
- Both maximum and mean ORR were significantly associated with regulatory approval.
- The association was stronger for single-agent therapies compared to combination regimens.
- An ORR exceeding 30% for single agents demonstrated 98% specificity and 89% positive predictive value for identifying approved regimens.
Conclusions:
- High ORR is associated with regulatory approval, particularly for single-agent anticancer therapies.
- An ORR threshold exceeding 30% is a suitable endpoint for single-arm trials evaluating single-agent anticancer drugs.
- This finding supports the use of ORR in accelerating the development of promising anticancer treatments.
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