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Research Article
12 August 2026

Matching-adjusted indirect comparison of fruquintinib versus ramucirumab in advanced gastric or gastroesophageal junction adenocarcinoma

Authors: Nan An https://orcid.org/0009-0001-6240-4719, Jiaying Chen, Jibin Li, Lin Shen, Weijian Guo, Tianshu Liu, Jin Li, … Show All … , Shukui Qin, Yuxian Bai, Zhendong Chen, Jufeng Wang, Yueyin Pan, Ruihua Xu, and Feng Wang [email protected]Author Info & Affiliations
Volume 15, Number 9
https://doi.org/10.57264/cer-2026-0072
PDFFormats

Abstract

Aim: Fruquintinib (Fruq), a selective VEGFR 1/2/3 inhibitor, showed a significant progression-free survival (PFS) benefit in the Phase III FRUTIGA trial for advanced gastric/gastroesophageal junction (G/GEJ) adenocarcinoma. Ramucirumab (RAM), an anti-VEGFR2 antibody, demonstrated efficacy in the RAINBOW-Asia trial. This anchored matching-adjusted indirect comparison (MAIC) evaluated Fruq plus paclitaxel versus RAM plus paclitaxel as second-line therapy for G/GEJ adenocarcinoma in the absence of head-to-head trials. Materials & methods: Data from individual patients in the FRUTIGA study (N = 703) and aggregated data from the RAINBOW-Asia study (N = 440) were analyzed. Baseline characteristics were balanced using entropy balancing. The placebo plus paclitaxel (PBO + PTX) groups served as the common comparators. The primary outcome was PFS; secondary outcomes included overall survival, objective response rate (ORR) and disease control rate (DCR). Rates of treatment-emergent adverse events (TEAEs) were also compared as an exploratory outcome using an adjusted indirect risk difference. Sensitivity analyses included restricted mean survival time and simulated treatment comparison. Results: After weighting (effective sample size = 564), baseline covariates were balanced. The anchored MAIC demonstrated that Fruq + PTX significantly improved PFS compared with RAM + PTX (HR: 0.70; 95% CI: 0.51–0.96; p = 0.0280), corresponding to a 30% reduction in progression risk, with a significant restricted mean survival time benefit of 1.18 months at 20 months (95% CI: 0.08–2.27; p = 0.024). Fruq achieved significantly higher ORR (OR: 1.76, 95% CI: 1.16–2.68; p = 0.008) and DCR (OR: 1.94, 95% CI: 1.33–2.83; p < 0.001). Overall survival was similar (0.97; 95% CI: 0.73–1.30; p = 0.8640). Subgroup analyses showed PFS benefits with Fruq in patients with ECOG PS 1, peritoneal metastases and two or fewer metastatic sites. In sensitivity analysis, the simulated treatment comparison also suggested a PFS benefit for Fruq + PTX (HR: 0.40, 95% CI: 0.32–0.50; p < 0.0001). For any-grade TEAEs, the indirect comparison showed higher adjusted relative incidences of increased bilirubin with Fruq + PTX than with RAM + PTX (RD: 12.3%; 95% CI: 2.3–22.4%, p < 0.05) and of hypokalemia (RD: 9.0%; 95% CI: 1.5–16.4%, p < 0.05). For grade ≥3 TEAEs, the adjusted relative incidence of decreased body weight was higher with Fruq + PTX than with RAM + PTX (RD: 2.9%; 95% CI: 0.6–5.2%, p < 0.05). The adjusted relative incidences of increased AST, ALT and hypocalcemia were numerically lower in the fruquintinib group than in the RAM group. Conclusion: This MAIC indicates that Fruq + PTX may be more effective than RAM + PTX in second-line advanced G/GEJ adenocarcinoma, with potentially improved PFS, ORR and DCR, and similar overall survival. Safety analyses suggested generally comparable safety profiles across the two regimens. Fruq + PTX remains a valuable treatment option, offering important comparative evidence for clinical and health technology assessment decisions.
Trial Registration: Clinicaltrials.gov identifiers: NCT07144995.

Plain language summary

Why was this study done?

Advanced gastric cancer worsens after first-line chemotherapy fails, making second-line treatment essential. Although ramucirumab (RAM) in combination with paclitaxel is an approved standard of care, and fruquintinib in combination with paclitaxel has yielded positive outcomes in a Phase III trial, no direct comparison trial has been conducted. This study aims to guide treatment choices.

What did the researchers do?

We used a matching-adjusted indirect comparison, a statistical method that adjusts for differences in patient characteristics to enable a fair comparison of treatments in the absence of a head-to-head trial. We used individual patient data from the FRUTIGA trial (fruquintinib plus paclitaxel) and published summary data from the RAINBOW-Asia trial (RAM plus paclitaxel), with the placebo groups serving as a common reference. As an exploratory analysis, we also compared the safety profiles of the two treatments.

What did the researchers find?

After matching patients' baseline characteristics:
•
Fruquintinib plus paclitaxel significantly improved progression-free survival compared with RAM plus paclitaxel, reducing the risk of cancer progression by 30%.
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Tumor response was significantly better with fruquintinib plus paclitaxel, with more patients experiencing tumor shrinkage or stabilization.
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Overall survival was similar between the two treatment groups.
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Certain patient groups – such as those with slightly reduced general health (ECOG PS 1), cancer spread to the abdominal lining (peritoneal metastases), or fewer sites of metastasis – may derive greater benefit from fruquintinib plus paclitaxel in delaying cancer progression.
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Additional sensitivity analyses consistently supported the progression-free survival benefit of fruquintinib plus paclitaxel.
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In an exploratory safety comparison, the overall safety profiles of the two treatments were generally similar and manageable.

What do the findings mean?

This analysis suggests that for patients with advanced gastric cancer requiring second-line treatment, fruquintinib combined with paclitaxel may be more effective than RAM with paclitaxel in delaying disease progression, controlling tumors and achieving similar overall survival, with a comparable safety profile. These findings provide valuable comparative evidence to inform clinical decisions but should be validated in future head-to-head trials.

Supplementary Material

File (supplementary materials.docx)

References

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