Fruquintinib plus FOLFIRI or mFOLFOX6 as second-line therapy for patients with <i>RAS</i> -mutant metastatic colorectal cancer (mCRC): A phase II, multicenter, open-label study.

Abstract

3528 Background: Nearly half of metastatic colorectal cancer (mCRC) patients harbor RAS mutations, and the standard second-line regimen for this substantial subgroup of patients is combination chemotherapy (FOLFIRI/FOLFOX) with bevacizumab, which offers limited efficacy. Fruquintinib, an oral VEGFR-1, -2, and -3 inhibitor, has shown efficacy in refractory mCRC. This study evaluated the efficacy and safety of fruquintinib in combination with FOLFIRI or FOLFOX as second-line therapy for patients with RAS-mutant mCRC. Methods: This multicenter, open-label, single-arm phase II trial enrolled patients with RAS mutant mCRC who had failed first-line standard therapy. Participants received fruquintinib (4 mg once daily, days 1-21) plus FOLFIRI or mFOLFOX every 28 days. The primary endpoint was progression-free survival (PFS). Secondary endpoints included objective response rate (ORR), disease control rate (DCR), overall survival (OS), and safety. Results: As of Nov 11, 2025, 42 eligible pts were enrolled and received at least one cycle of treatment. Baseline characteristics included median age (63.0 [range: 35-74]), male (59.5%), ECOG PS 1 (66.7%), left-sided (73.8%), liver metastasis (59.5%), prior anti-VEGF therapies (73.8%). The median PFS was 8.1 months (95% CI: 6.18, 9.46) and median OS was not reached yet. The Kaplan-Meier estimates for PFS rates at 3, 6, 9, and 12 months were 85.3%, 73.5%, 35.9%, and 15.4%, respectively. In the subgroup analysis, median PFS were longer in pts without liver metastases (8.4mo vs 6.4mo, HR: 1.65, 95%CI: 0.65-4.18), those with left-sided lesion (8.1mo vs 4.8mo, HR: 2.14, 95%CI: 0.79-5.77) and pts without prior anti-VEGF therapies (8.4mo vs 6.5mo, HR: 1.79, 95%CI: 0.59-5.36). The ORR was 52.5% (21/40) which consisted of CR 5% and PR 47.5%. The DCR was 97.5% (39/40). Additionally, the most common any grade treatment-emergent adverse events (TEAEs) were hypertension (23.8%), diarrhea (19.1%), and mucositis (19.1%). Grade ≥3 TEAEs was 14.3% including diarrhea (4.8%), intestinal obstruction (2.4%) and leukopenia (2.4%). Conclusions: Fruquintinib combined with either FOLFIRI or mFOLFOX6 as second-line therapy for patients with RAS-mutant metastatic colorectal cancer (mCRC) demonstrated promising efficacy and a manageable safety profile. Clinical trial information: NCT05634590 .