Fruquintinib in refractory metastatic colorectal cancer: separating randomized trial evidence from observational data

We read with interest the systematic review and meta-analysis by Udaikumar et al. evaluating fruquintinib in refractory metastatic colorectal cancer (mCRC) (1). The review addresses a clinically important question, and the inclusion of both randomized and real-world studies reflects current clinical practice. However, several methodological and interpretative issues require clarification.

First, the randomized evidence for fruquintinib monotherapy is clear and should be kept separate from observational data. The two phase III placebo-controlled trials, FRESCO and FRESCO-2 (2,3) demonstrate highly consistent overall survival (OS) and progression-free survival (PFS) benefits despite being conducted in markedly different treatment eras and populations. These trials should therefore be presented as confirmatory evidence, rather than folded into broader pooled estimates. Second, pooling single-arm observational studies for objective response, disease control, and adverse events warrants caution (4). These cohorts differ substantially in prior therapy, treatment line, and patient selection, and the substantial heterogeneity and small-study effects acknowledged by the authors limit the interpretability of pooled single-arm estimates (5). Such results are best viewed descriptively rather than as precise summary measures (6). Third, the comparisons between fruquintinib monotherapy and fruquintinib combined with programmed death-1 (PD-1) inhibitors are derived predominantly from retrospective, non-randomized cohorts and cross-study comparisons (5). Even in recent meta-analyses specifically evaluating combination strategies (7), the underlying evidence base remains heterogeneous with respect to prior therapies, treatment line, and patient selection, and randomized data constitute only a minority of included studies. While pooled analyses report numerically higher response rates and PFS with combination therapy, no consistent OS advantage has been demonstrated. These findings remain hypothesis-generating and should not be read as comparative or causal evidence. Finally, clarification would be helpful regarding discrepancies between stated inclusion criteria and the inclusion of retrospective observational studies, as well as inconsistencies between reported quality assessments in the text and accompanying tables.

In summary, the randomized trials convincingly establish the efficacy of fruquintinib monotherapy in refractory mCRC. A stricter distinction between confirmatory trial evidence and observational data would make the conclusions more proportionate to the data.

Acknowledgments

None.

Footnote

Provenance and Peer Review: This article was a standard submission to the journal. The article did not undergo external peer review.

Funding: None.

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://jgo.amegroups.com/article/view/10.21037/jgo-2026-1-0004/coif). A.K. is co-founder shareholder of AJM Med-i-caps Ltd. and consultant for Jinshan Science & Technology Ltd. He has also been co-founder and director of iCERV Ltd. A.K. received research support in the form of grants from Given Imaging Ltd under the auspices of the European Society of Gastrointestinal Endoscopy (ESGE), and from IntroMedic (also noted as SynMed/Intromedic), and has served as a consultant for Jinshan Ltd., with consultancy fees from Jinshan and lecture honoraria from Covidien/Medtronic. Additionally, he has benefited from lecture honoraria and educational travel support from a range of entities including Jinshan, Dr Falk Pharma UK, Ferring, Aquilant, and Almirall, and has participated in advisory board activities for companies such as Tillots, Ankon, and Dr Falk Pharma UK. W.M. is shareholder and co-founder of Sanprobi sp. z o.o. and Endoklinika sp. z o.o. He has received speakers honoraria from Ferring, Alfasigma, Novonordisk, and Polpharma. He is Co-Editor-in-Chief of Przeglad Gastroenterologiczny/Gastroenterology Review, President of the Polish Society of Gastroenterology, Chair of Train the Trainers and Governing Council WGO, Country Representative (Poland) - European Lifestyle Medicine Organization, and Country Coordinator (Poland) - HpEuReg Registry. The other author has no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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