Risk-Benefit of Phase 2 Monotherapy Trials in Adult Solid Cancers - A Systematic Review and Meta-Analysis

Q: What was the main objective of the systematic review and meta-analysis?

To compare efficacy and safety of cancer monotherapies in phase 2 versus phase 3 trials and assess how risk–benefit differs between these phases for ethical justification.

Q: How were phase 2 trials defined for this study?

Phase 2 included phase 2 trials and phase 1 dose-expansion cohorts, which the authors label as phase 2 for the purposes of the analysis.

Q: What did the pooled results show about efficacy in phase 2 compared with phase 3?

Phase 2 trials had a lower pooled objective response rate and shorter progression-free survival and overall survival than phase 3, with statistically significant differences reported.

Q: How did adverse event rates compare between phase 2 and phase 3 monotherapy trials?

The pooled rate of drug-related grade 3–4 adverse events was reported as higher in phase 2 than in phase 3, supporting an overall less favorable risk–benefit profile in phase 2.

Sep 22, 2026

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Phase 2 cancer trials, including phase 1 dose-expansion cohorts labeled as phase 2, serve as early direct tests of new-drug efficacy, yet lack definitive efficacy evidence for therapeutic justification during ethical review. This study systematically compared efficacy and safety of cancer monotherapies in phase 2 versus phase 3, contrasting uncertainty with clinical equipoise. Across six solid malignancies, 130 phase 2 and 52 phase 3 trial arms were analyzed.

LanguageEnglish

CategoryResearch & Report

FormatPDF

Pages10

Reading Time25 min

AccessFree to download

Introduction

Phase structure in clinical development (phase 1, phase 2, phase 3)

Rationale and ethical uncertainty in phase 2

Objectives of the systematic review

Methods

Literature search and inclusion scope

Data extraction and statistical approach

Results

Objective response and survival outcomes

Drug-related adverse events

Discussion

Risk–benefit interpretation for ethical justification in phase 2

Comparison with historical and phase 3 context

International Journal of Cancer RESEARCH ARTICLE OPEN ACCESS Cancer Therapy and Prevention Risk–Benefit of Phase 2 Monotherapy Trials in Adult Solid Cancers: A Systematic Review and Meta-Analysis Charlotte Ouimet | Monica Rosu | Jonathan Kimmelman Department of Equity, Ethics and Policy, McGill University School of Population and Global Health, Montreal, Quebec, Canada Correspondence: Jonathan Kimmelman ([jonathan.kimmelman@mcgill.ca](jonathan.kimmelman@mcgill.ca)) Received: 3 September 2025 | Revised: 25 March 2026 | Accepted: 24 April 2026 Keywords: meta-analysis | phase 2 | phase 3 | research ethics | risk and benefit ABSTRACT Phase 2 (and phase 1 dose expansion, which we label phase 2 for the purposes of this study) cancer trials are the first direct tests of a new drug's efficacy. Because efficacy evidence is lacking, the therapeutic status of drug administration during ethical review is uncertain. We compared the efficacy and safety of cancer monotherapies in phase 2 with phase 3, where clinical equipoise underwrites a therapeutic status for drug administration. In this systematic review and meta-analysis, we searched Clinicaltrials.gov for phase 2 and 3 investigational monotherapy drug trials in six solid malignancies, with primary completion dates 2015–2020, inclusive. Two independent reviewers completed data extraction. Effects were estimated using an inverse-variance weighted random-effects model meta-analysis of proportions using the R package meta. We analyzed 130 phase 2 and 52 phase 3 trial arms, enrolling 6665 and 18,694 patients. The pooled objective response rate was 7%(95% CI 5%–11%) in phase 2 versus 24% in phase 3 (95% CI 17%–31%; p < 0.0001) . The median PFS and OS were shorter in phase 2 compared to phase 3 (3.23 vs. 5.43 months, p < 0.0001; 9.46 vs. 14.44 months, p = 0.0001). The pooled rate of drug-related grade 3–4 adverse events was 30%(95% CI 23%–37%) in phase 2 and 25%(95% CI 19%–32%) in phase 3. Monotherapies delivered in phase 2 cancer trials present diminished risk–benefit compared with phase 3 and align with historic estimates for phase 1. Though there may be exceptions, risks for drug administration in phase 2 should generally be justified by appeals to research rather than therapeutic value. 1 | Introduction Clinical development typically consists of three phases. In phase 1, drugs are tested for safety, pharmacology, and to establish a dose for subsequent testing. In phase 2 (and increasingly, dose expansion cohorts within phase 1 trials), drugs are tested for potential efficacy—typically using a surrogate benefit like tumor shrinkage. In phase 3, drugs are tested against comparators, often using randomization and outcome measures of clinical benefit, such as survival. Much has been written about the risk, benefit, and ethics of phase 1 and randomized (phase 3) trials. Phase 2 trials, however, are the most common type of clinical investigation in cancer, accounting for over half of all cancer studies initiated in 2023 [1] . Unlike phase 1 dose escalation trials, they deliver biologically active doses to all patients and thus are likely to present greater prospects of benefit and harm. Like phase 1 trials, phase 2 trials typically enroll patients who have exhausted standard treatmentsand seek novel options. Investigators often present phase 2 trial participation as a therapeutic option, despite limited empirical evidence or principled arguments supporting this claim [2] . | Abbreviations: AE, adverse event; CI, confidence interval; FDA, Food and Drug Administration; NCI, National Cancer Institute; NSCLC, non-small cell lung cancer; ORR, objective response rate; OS, overall survival; OSF, Open Science Framework; PFS, progression-free survival; PRISMA, Preferred Reporting Items for Systematic Reviews and Meta-Analyses; U.S. , United States. | | --- | | This is an open access article under the terms of the Creative Commons Attribution-NonCommercial License, which

FAQs

What was the main objective of the systematic review and meta-analysis?

To compare efficacy and safety of cancer monotherapies in phase 2 versus phase 3 trials and assess how risk–benefit differs between these phases for ethical justification.

How were phase 2 trials defined for this study?

Phase 2 included phase 2 trials and phase 1 dose-expansion cohorts, which the authors label as phase 2 for the purposes of the analysis.

What did the pooled results show about efficacy in phase 2 compared with phase 3?

Phase 2 trials had a lower pooled objective response rate and shorter progression-free survival and overall survival than phase 3, with statistically significant differences reported.

How did adverse event rates compare between phase 2 and phase 3 monotherapy trials?

The pooled rate of drug-related grade 3–4 adverse events was reported as higher in phase 2 than in phase 3, supporting an overall less favorable risk–benefit profile in phase 2.

Sep 22, 2026

Upload by OmBimo