Updated analysis of a phase 2 study of fruquintinib plus trifluridine/tipiracil (TAS-102) as third-line treatment in patients with metastatic colorectal adenocarcinoma.

145 Background: Fruquintinib and TAS-102 are two standard therapies for patients (pts) with previous-treated mCRC worldwide. The study aimed to evaluate the efficacy and safety of fruquintinib plus TAS-102 as third-line treatment for mCRC. We previously reported that fruquintinib plus TAS-102 was well tolerated with encouraging clinical activity in pretreated mCRC. Here, we reported the updated results at the data cutoff of Sep 3, 2024. Methods: In this open-label, single-arm, multi-center, phase 2 trial (NCT05004831), pts with mCRC who had failed at least two prior standard treatment regimens were enrolled. Eligible pts received fruquintinib (4mg, qd, d1-21) and TAS-102 (35mg/m 2 , bid, d1-5, 8-12) orally every 4 weeks until disease progression or unacceptable toxicity. Primary endpoint was PFS (per RECIST v1.1). Secondary endpoints were OS, ORR, DCR and safety (per NCI-CTCAE v5.0). Results: From Mar 2022 to Aug 2023, 50 eligible pts were enrolled. Median age was 60 years (range 39-76) and 58.0% were male. 82% pts were of left-sided colon and rectal cancer, 42.0% pts were RAS mutant, 58.0% had liver metastasis and 18.0% had peritoneal metastasis. Prior treatments and proportion were standard chemotherapy 100%, anti-VEGF 88.0% and anti-EGFR 26.0%. As of Sep 3, 2024, ORR was 10.9% (95%Cl: 3.6-23.6) and DCR was 73.9% (95%Cl: 58.9-85.7). The median PFS was 6.33 months (m) (95% CI: 4.20-8.62). The 6-m, 9-m and 12-m PFS rates were 53.0% (95% CI: 40.2-70.0), 28.3% (95% CI: 17.4-45.9) and 23.1% (95% CI: 13.2-40.5), respectively. At a median follow-up of 17.6m, median OS was 18.4m (95% CI: 12.0-NA). The 6-m, 9-m and 12-m OS rates were 87.0% (95% CI: 77.8-97.3), 66.9% (95% CI: 54.0-82.9) and 64.3% (95% CI: 51.1-80.8), respectively. Median PFS was comparable in liver metastasis (LM) and non-LM pts (6.33m [95%CI: 4.13-8.62] vs. 6.46m [95%CI: 3.74-NA], P =0.54). Similar results were observed in peritoneal metastasis (PM) and non-PM pts (6.07m [95%CI: 3.74-NA] vs. 6.33m [95%CI: 4.20-8.27], P =0.95). None of RAS gene mutation, prior treatment lines ≥ 3, age ≥ 65 years, metastatic sites ≥ 2, peritoneal metastasis and right-sidedness were identified as factors significantly associated with PFS or OS (by univariable Cox proportional-hazards model). The most common treatment-related adverse events (TRAEs) of any grade and grade ≥ 3 were mainly hematological toxicities. TRAEs (any grade, grade ≥ 3) in ≥ 50% of pts including neutrophil count decreased (80.0%, 54.0%), white blood cell count decreased (70.0%, 26.0%), anemia (58.0%, 20.0%) and proteinuria (50.0%, 4%). No treatment-related deaths were observed. Conclusions: The updated analysis demonstrated encouraging survival benefits of fruquintinib plus TAS-102 as third-line treatment in patients with mCRC with acceptable toxicities. This regimen could be an alternative therapeutic approach for these patients. Clinical trial information: NCT05004831 .