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Tumor shrinkage and objective response rates: gold standard for oncology efficacy screening trials, or an outdated
Penelope Bradbury1, Lesley Seymour
1From the NCIC Clinical Trials Group, Queen's University, Kingston, Ontario, Canada.
Abstract:
Phase II clinical trials have long been used to screen new cancer therapeutics for antitumor activity ("efficacy") worthy of further evaluation. Traditionally, the primary end point used in these screening trials has been objective response rate (RR), with the desired rate being arbitrarily set by the researchers before initiation of the trial. For cytotoxic agents, especially in common tumor types, response has been a reasonably robust and validated surrogate of benefit. Phase II trials with response as an end point have a modest sample size (15-40 patients) and are completed rapidly allowing early decisions regarding future development of a given agent. More recently, a number of new agents have proven successful in pivotal phase III studies, despite a low or very modest RR demonstrated in early clinical trials. Researchers have postulated that these novel agents, as a class, may not induce significant regression of tumors, and that the use of RR as an end point for phase II studies will result in false negative results, and point out that not all available data is used in making the decision. Others have pointed out that even novel agents have proven unsuccessful in pivotal trials if objective responses are not demonstrated in early clinical trials. We review here the historical and current information regarding objective tumor response.
Insights
Objective response rate (RR) is a traditional endpoint for Phase II cancer trials. However, novel therapeutics may show benefit despite low RR, necessitating a re-evaluation of this screening method.
Area of Science:
- Oncology
- Clinical Trials
- Drug Development
Background:
- Phase II clinical trials traditionally use objective response rate (RR) to assess cancer therapeutic efficacy.
- Cytotoxic agents in common tumor types have historically shown RR as a validated surrogate of clinical benefit.
- The modest sample size and rapid completion of Phase II trials facilitate early decisions on drug development.
Purpose of the Study:
- To review the historical and current use of objective tumor response as a primary endpoint in Phase II cancer clinical trials.
- To evaluate the suitability of objective response rate (RR) for novel therapeutic agents.
- To discuss the potential for false-negative results with RR in early-phase screening of new cancer drugs.
Main Methods:
- Review of historical data and current literature on Phase II clinical trial endpoints.
- Analysis of the role of objective response rate (RR) in cancer drug development.
- Examination of the impact of novel therapeutic agents on traditional Phase II endpoints.
Main Results:
- Objective response rate (RR) has been a standard endpoint for Phase II cancer trials.
- Novel agents may demonstrate clinical benefit independent of significant tumor regression (low RR).
- Relying solely on RR may lead to premature termination of promising drug candidates.
- Some novel agents have failed in later-stage trials without early objective responses.
Conclusions:
- The utility of objective response rate (RR) as a sole endpoint in Phase II trials for novel cancer therapeutics is increasingly questioned.
- Alternative or supplementary endpoints may be necessary to accurately assess the efficacy of new drug classes.
- Careful consideration of all available data is crucial for informed decision-making in early-phase cancer drug development.
