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Risk-Benefit of Phase 2 Monotherapy Trials in Adult Solid Cancers: A Systematic Review and Meta-Analysis
Charlotte Ouimet1, Monica Rosu1, Jonathan Kimmelman1
1Department of Equity, Ethics and Policy, McGill University School of Population and Global Health, Montreal, Quebec, Canada.
International Journal of Cancer
|May 12, 2026
Summary
Phase 2 cancer trials show lower efficacy and shorter survival compared to phase 3, with similar risks. Drug administration in phase 2 trials should prioritize research over therapeutic benefit.
Area of Science:
- Oncology
- Clinical Trials
- Drug Development
Background:
- Phase 2 cancer trials are the initial efficacy assessments for new drugs, but their therapeutic status is ethically uncertain due to limited evidence.
- Clinical equipoise in phase 3 trials supports therapeutic drug administration, unlike in phase 2.
Purpose of the Study:
- To compare the efficacy and safety of cancer monotherapies in phase 2 trials versus phase 3 trials.
- To evaluate the risk-benefit profile of investigational cancer drugs in phase 2 compared to phase 3.
Main Methods:
- Systematic review and meta-analysis of phase 2 and phase 3 investigational monotherapy drug trials.
- Searched ClinicalTrials.gov for trials in six solid malignancies (2015-2020).
- Analyzed objective response rate (ORR), progression-free survival (PFS), overall survival (OS), and grade 3-4 adverse events.
Main Results:
- Phase 2 trials (130 arms) showed a 7% ORR versus 24% in phase 3 (52 arms).
- Median PFS was 3.23 months in phase 2 vs. 5.43 months in phase 3; median OS was 9.46 months vs. 14.44 months.
- Drug-related grade 3-4 adverse events were 30% in phase 2 vs. 25% in phase 3.
Conclusions:
- Cancer monotherapies in phase 2 trials offer a diminished risk-benefit compared to phase 3, aligning with phase 1 estimates.
- Risks in phase 2 trials should be justified by research value rather than presumed therapeutic benefit.
- Findings suggest a need to re-evaluate the ethical justification for drug administration in phase 2 cancer trials.
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