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Updated: Dec 3, 2025
Evaluating the Effectiveness of Cancer Drug Sensitization In Vitro and In Vivo
Published on: February 6, 2015
Evaluation of the contribution of randomised cancer clinical trials evaluating agents without documented single-agent
Jared Foster1, Boris Freidlin1, E L Korn1
1Biometric Research Program, Division of Cancer Treatment and Diagnosis, National Cancer Institute, Bethesda, Maryland, USA.
Background:
With the development of targeted agents, the approach to combination cancer therapy has evolved to focus on identifying ways in which pathway inhibition by one agent may enhance the activity of other agents. In theory, this implies that under this new paradigm, agents are no longer required to show single-agent activity, as the pathway inhibited by the targeted agent may only have a therapeutic effect when given with other agents. This raises the question of the extent to which anticancer agents without single-agent activity can contribute to effective combination regimens.
Patients And Methods:
We reviewed outcomes of randomised phase 2 combination trials sponsored by the National Cancer Institute Cancer Therapy Evaluation Program that were activated in 2008 to 2017 and noted the single-agent activity of the experimental agents.
Results:
Fifty-three trials were identified, and 50 had available results: 7 (14%), 15 (30%) and 28 (56%) had experimental agents with single-agent activity classified as active, inactive and indeterminate, respectively. Thirteen per cent (95% CI=1.7% to 40.5%) of trials evaluating inactive agents and 11.6% (95% CI=3.9% to 25.1%) of trials evaluating agents without known single-agent activity (pooled inactive and indeterminate) were positive, compared with 42.9% (95% CI=9.9% to 81.6%) for agents with single-agent activity.
Conclusions:
Incorporating agents without documented single-agent activity into treatment regimens is unlikely to produce meaningful improvements in activity unless there is compelling biological rationale. This finding has important implications for the prioritisation of anticancer agents for combination testing, and for the allocation of clinical trial resources.
Insights
Combination cancer therapy is evolving. However, agents without proven single-agent activity rarely improve treatment effectiveness in combination regimens, suggesting careful selection is crucial for clinical trials.
Area of Science:
- Oncology
- Clinical Trials
- Drug Development
Background:
- Combination cancer therapy is shifting towards targeted agents that enhance other drugs' activity.
- This paradigm raises questions about the utility of agents lacking single-agent efficacy.
- The study investigates the role of agents without prior demonstrated activity in combination regimens.
Purpose of the Study:
- To evaluate the contribution of anticancer agents without single-agent activity in combination therapy trials.
- To inform the prioritization of agents for combination testing and clinical trial resource allocation.
Main Methods:
- Reviewed outcomes of randomized phase 2 combination trials (2008-2017) from the National Cancer Institute Cancer Therapy Evaluation Program.
- Assessed the single-agent activity of experimental agents in identified trials.
Main Results:
- Of 50 trials with results, 14% had active agents, 30% inactive, and 56% indeterminate single-agent activity.
- Trials with inactive or indeterminate agents showed significantly lower positive outcomes (11.6-13%) compared to active agents (42.9%).
Conclusions:
- Anticancer agents without documented single-agent activity are unlikely to improve combination regimen efficacy without strong biological rationale.
- Findings impact the selection of agents for combination testing and clinical trial resource allocation.
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