Abstract
The vascular endothelial growth factor pathway plays a key role in the pathogenesis of gastric cancer. In the multicenter, double-blind phase 3 FRUTIGA trial, 703 patients with advanced gastric or gastroesophageal junction adenocarcinoma who progressed on fluorouracil- and platinum-containing chemotherapy were randomized (1:1) to receive fruquintinib (an inhibitor of vascular endothelial growth factor receptor-1/2/3; 4 mg orally, once daily) or placebo for 3 weeks, followed by 1 week off, plus paclitaxel (80 mg/m2 intravenously on days 1/8/15 per cycle). The study results were positive as one of the dual primary endpoints, progression-free survival (PFS), was met (median PFS, 5.6 months in the fruquintinib arm versus 2.7 months in the placebo arm; hazard ratio 0.57; 95% confidence interval 0.48–0.68; P < 0.0001). The other dual primary endpoint, overall survival (OS), was not met (median OS, 9.6 months versus 8.4 months; hazard ratio 0.96, 95% confidence interval 0.81–1.13; P = 0.6064). The most common grade ≥3 adverse events were neutropenia, leukopenia and anemia. Fruquintinib plus paclitaxel as a second-line treatment significantly improved PFS, but not OS, in Chinese patients with advanced gastric or gastroesophageal junction adenocarcinoma and could potentially be another treatment option for these patients. ClinicalTrials.gov registration: NCT03223376.
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Data availability
The study protocol and statistical analysis plan are available in the Supplementary Information. De-identified participant data that underlie the results reported in this article can be made available to investigators for research purposes on a case-by-case basis after the time of this publication. Requests for access to data should be addressed to P.T. (panfengt@hutch-med.com) for consideration. The response to data access requests will be made within 4 weeks of receipt.
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Acknowledgements
This study was funded by the National Science and Technology Major Project (project no. 2019ZX09301012), the Science and Technology Commission of Shanghai Municipality (Science, Technology and Innovation Action Plan, project no. 17431900100) and HUTCHMED Limited. We appreciate all participants in this trial, including patients, their families and caregivers and the staff and investigators at all the study sites. We also thank the members of the IDMC. Medical writing and editorial support were provided by J. Y. Lee of Parexel, which was funded by HUTCHMED Limited.
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Contributions
P.T., S.F., W.S. and R.-H.X. provided substantial contributions to the conception and design of the study. The funder and R.-H.X. had the responsibility of study oversight. F.W., L.S., W.G., T.L., J.L., S.Q., Y.B., Z.C., J.W., Y.P., Y.S., F. Zhao, Y.C., F.Y., K.G., T.Z., H.P., H.Z., F. Zhou, Y.Q., L.Y., W.M., Q.L., W.D., W.L., S.W., Y.T., D.M., X.Y., Y.D., Y.Y., M.L., W.H., D.C., G.L., P.T. and R.-H.X. contributed to the data collection. Q.L., P.T. and S.F. contributed to the analysis and interpretation of the data. Q.L., P.T., S.F., M.S. and W.S. provided administrative support. P.T. and R.-H.X. had full access to all the data in the study and contributed to the verification of the data. F.W., Q.L., P.T., S.F., M.S., W.S. and R.-H.X. participated in writing the manuscript draft. All authors participated in reviewing the manuscript and provided final approval for the decision to submit the paper for publication.
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Q.L., P.T., S.F., M.S. and W.S. are employees of HUTCHMED Limited. All other authors declare no competing interests.
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Nature Medicine thanks Aurélien Latouche, Florian Lordick and the other, anonymous, reviewer(s) for their contribution to the peer review of this work. Primary Handling Editor: Saheli Sadanand, in collaboration with the Nature Medicine team.
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Extended data
Extended Data Fig. 1 The graphical approach used to control the type I error at a two-sided level of 0.049a for the analyses of the dual primary endpoints progression-free survival and overall survival.
aThe stopping boundaries for interim (50% information) and final analyses were computed with Lan-DeMets approximation to the O’Brien-Fleming boundary.
Extended Data Fig. 2 Kaplan-Meier estimates.
Kaplan-Meier estimates of (A) progression-free survival and (B) overall survival in the non-diffuse G/GEJ adenocarcinoma patients with lymph node metastases (intention-to-treat set).
Supplementary information
Supplementary Information
Supplementary Tables 1 and 2, Study protocol, Statistical analysis plan, IDMC charter and List of investigators and participating sites.
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Wang, F., Shen, L., Guo, W. et al. Fruquintinib plus paclitaxel versus placebo plus paclitaxel for gastric or gastroesophageal junction adenocarcinoma: the randomized phase 3 FRUTIGA trial. Nat Med (2024). https://doi.org/10.1038/s41591-024-02989-6
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DOI: https://doi.org/10.1038/s41591-024-02989-6
