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

Abstract

360 Background: Fruquintinib (FRU), a selective VEGFR 1/2/3 inhibitor, showed a significant PFS benefit in the phase 3 FRUTIGA trial (NCT03223376) for advanced gastric or gastroesophageal junction (G/GEJ) adenocarcinoma. Ramucirumab (RAM), an anti-VEGFR2 antibody, demonstrated efficacy in the RAINBOW-Asia trial (NCT02898077). This anchored MAIC compared FRU plus paclitaxel with RAM plus paclitaxel as second-line therapy in G/GEJ adenocarcinoma, addressing the absence of head-to-head trials. Methods: Individual patient data (IPD) from FRUTIGA (N = 703) and aggregated data (AgD) from RAINBOW-Asia (N = 440) were analyzed. Baseline characteristics such as age, ECOG PS, metastasis status, and prior chemotherapy were adjusted using entropy balancing. The anchored approach used placebo groups as common comparators. Primary outcome included PFS; secondary outcomes encompassed OS, ORR, and DCR. Sensitivity analyses involved restricted mean survival time (RMST) analyses and simulated treatment comparison (STC). Results: After weighting with an effective sample size of 564 for FRUTIGA, baseline covariates were well-balanced (standardized mean differences <0.1). The analysis showed that FRU plus paclitaxel had a numerical improvement in PFS compared to RAM plus paclitaxel (HR 0.78, 95% CI 0.58-1.04; p = 0.09), with a statistically significant RMST advantage of 1.18 months at 20 months (95% CI 0.08-2.27; p = 0.024). This corresponds to a 22% reduction in progression risk based on the hazard ratio. FRU treatment was associated with significantly higher objective response rates (ORR OR 1.76, 95% CI 1.16-2.68; p = 0.008) and disease control rates (DCR OR 1.94, 95% CI 1.33-2.83; p < 0.001) compared to RAM. The overall survival outcomes of the two treatments were similar (HR 1.06, 95% CI 0.79-1.42; p = 0.69). Subgroup analyses showed PFS benefits with FRU for patients with an ECOG PS of 1 (HR 0.70, P = 0.032), peritoneal metastases (HR 0.59, P = 0.043), and metastatic sites ≤2 (HR 0.65, P = 0.026). The simulated treatment comparison sensitivity analysis supported the PFS benefit (HR 0.40, 95% CI 0.32-0.50; p<0.0001). Conclusions: This MAIC demonstrated that FRU plus paclitaxel improved higher PFS and response rates compared to RAM plus paclitaxel in Asian patients with advanced G/GEJ adenocarcinoma, especially in subgroups with an ECOG PS of 1, peritoneal metastases, and metastatic sites ≤2. Although OS was similar, the response benefits and manageable safety profile make FRU a promising second-line option. Limitations include unmeasured confounders. These results should be confirmed in future prospective studies. Clinical trial information: NCT07144995 .