Intermittent fruquintinib plus trifluridine/tipiracil in refractory metastatic colorectal cancer (mCRC): A single-center, single-arm phase II study.

e15560 Background: A phase II study suggested that the combination of fruquintinib (Fru) and trifluridine/tipiracil (TAS-102) could prolong progression-free survival (PFS) and overall survival (OS). However, the benefits are limited due to tolerability associated with continuous administration. This study aimed to explore the efficacy and safety of intermittent administration of Fru and TAS-102 as a 3L treatment for mCRC patients(pts). Methods: This was a single-center, single-arm, phase II study (ChiCTR2300078241). The primary endpoint was objective response rate (ORR). Secondary endpoints included PFS, OS, disease control rate (DCR), and safety. The ORR was set to ≤1% in the null hypothesis using a two-sided αof 0.05. To reject the null hypothesis and achieve an expected ORR of 10% with an 80% power, a minimum of 29 pts was required. Considering a dropout rate of 15%, the study planned to enrol 35 mCRC pts who had failed two standard treatment regimens. Eligible pts received oral Fru (3 mg, once daily, on days 1-5 and 8-12) and TAS-102 (35 mg/m², twice daily, on days 1-5) every two weeks until disease progression or unacceptable toxicity occurred. Results: A total of 35 pts were enrolled between August 2023 and March 2025. The median age was 58 years (range: 19-77). RAS mutations were present in 54.3% of pts, 62.9% had left-sided colon or rectal cancer, 54.3%, 40.0% and 45.7% had liver metastases, peritoneal metastases and multiple metastases respectively. As of December 15, 2025, 33 pts had discontinued study treatment and 2 pts were ongoing treatment. The ORR and DCR were 11.4% (4/35) and 80.0% (28/35) respectively. The median PFS (mPFS) was 7.2 (95% CI: 5.0–9.4) months(m), and median OS was 18.2 (95% CI: 10.8–25.7) m. mPFS in RAS-mutant and RAS wild-type pts were 7.2 (95% CI: 4.3-10.1) m and 6.7 (95% CI: 2.9-10.6) m, respectively (p = 0.527), with ORRs of 15.8% and 7.7% respectively. mPFS in pts with and without liver metastases were 7.0 m (95% CI: 3.0-11.0) and 7.2 m (95% CI: 6.2-8.2), respectively (p = 0.315), with ORRs of 10.5% and 12.5% respectively. Patients without peritoneal metastases or multiple metastases obtained better mPFS (7.9 m vs. 4.4 m, p = 0.041 ; 7.9 m vs. 3.7 m, p = 0.017), with ORRs of 14.3% vs. 7.1% and 15.8% vs. 6.3%. Treatment-related adverse events (TRAEs) were generally manageable and tolerable. The most common hematological TRAEs (any grade, grades 3-4) included neutropenia (80.0%, 28.6%), leukopenia (68.6%, 22.9%), and anemia (51.4%, 5.7%). Non-hematological TRAEs were mostly grades 1-2, including anorexia (37.1%), fatigue (28.6%) and nausea (14.3%). One case of grade 3 hypertension was reported. No treatment-related deaths were observed. Conclusions: An intermittent Fru+TAS-102 schedule demonstrated encouraging activity with manageable toxicity in refractory mCRC. Clinical trial information: ChiCTR2300078241.