Assessment of added activity of an antitumor agent
Cong Chen1, Linda Zhiping Sun1, Yixin Ren1
1Biostatistics and Research Decision Sciences, Merck & Co., Inc., Rahway, NJ 07065, USA.
Abstract:
An unprecedented number of novel oncology drugs are under preclinical and clinical development, and nearly all are developed in combinations. With an over-reliance on biological hypotheses, there is less effort to establish single agent activity before initiating late clinical development. This may be contributing to a decreased success rate going from phase 1 to approval in the immunotherapy era. Growing evidence in clinical trial data shows that the treatment benefit from most approved combination therapies can be explained by the independent drug action model. Using this working model, we develop a simple index to measure the added antitumor activity of a new drug based on mean response duration, an endpoint that naturally combines both response status and duration information for all patients, which is shown to be highly predictive of clinical benefit of FDA-approved anti-PD-(L)1 immunotherapies. This index sheds light on challenges and opportunities in contemporary oncology drug development and provides a practical tool to assist with decision-making in early clinical trials.
Insights
Developing novel oncology drugs in combination is common, but a new index using mean response duration can better assess added antitumor activity, potentially improving clinical trial success rates in the immunotherapy era.
Area of Science:
- Oncology
- Clinical Pharmacology
- Drug Development
Background:
- Numerous novel oncology drugs are in development, with a trend towards combination therapies.
- Over-reliance on biological hypotheses may hinder the assessment of single-agent activity, potentially impacting success rates in late-stage clinical trials.
- The immunotherapy era has seen a decrease in success rates from Phase 1 to approval.
Purpose of the Study:
- To develop a practical index for measuring the added antitumor activity of new oncology drugs.
- To utilize the independent drug action model to evaluate combination therapies.
- To provide a tool for decision-making in early clinical trials.
Main Methods:
- Development of a novel index based on mean response duration.
- Utilizing clinical trial data to validate the index.
- Applying the independent drug action model to analyze combination therapies.
Main Results:
- The developed index effectively measures the added antitumor activity of new drugs.
- Mean response duration is a highly predictive endpoint for clinical benefit, particularly for FDA-approved anti-PD-(L)1 immunotherapies.
- The independent drug action model explains the benefit of most approved combination therapies.
Conclusions:
- The proposed index offers a practical approach to assess drug contributions in combination therapy development.
- This tool can help address challenges and identify opportunities in contemporary oncology drug development.
- Improved early clinical trial decision-making can be facilitated by this predictive index.
