Fruquintinib in combination with tislelizumab vs trifluridine/tipiracil and bevacizumab in MSS mCRC without active liver metastases: The IKF-080/QUINTIS trial.

Abstract

TPS3684 Background: Patients with metastatic colorectal cancer (mCRC) who progress after treatment with fluoropyrimidines, oxaliplatin, irinotecan, anti-angiogenic agents, and anti-EGFR therapies have limited therapeutic options and a poor prognosis. Median overall survival (mOS) is approximately 6 months with single-agent regorafenib or trifluridine/tipiracil. The addition of bevacizumab to trifluridine/tipiracil has improved mOS to 10.8 months, while fruquintinib, a selective VEGFR-1–3 inhibitor, demonstrated a mOS of 7.4 months compared with 4.8 months for placebo in refractory mCRC. However, combinations of tyrosine kinase inhibitors and immune checkpoint inhibitors have shown clinical benefit, primarily in patients with microsatellite-stable mCRC without liver metastases, likely due to liver-associated immunosuppression. The QUINTIS trial evaluates whether fruquintinib plus the PD-1 antibody tislelizumab can improve outcomes in this clinically defined subgroup compared with the current standard of care of trifluridine/tipiracil plus bevacizumab. Methods: QUINTIS is a prospective, randomized, open-label, multicenter phase II trial enrolling 140 patients with metastatic colorectal adenocarcinoma without active liver metastases who have previously received fluoropyrimidines, oxaliplatin, irinotecan, bevacizumab, and, when indicated, an EGFR inhibitor. Participants are randomized 1:1 to Arm A (experimental): fruquintinib 5 mg orally once daily (days 1–21 of a 28-day cycle) plus tislelizumab 400 mg intravenously on day 1 every 6 weeks; or Arm B (control): trifluridine/tipiracil 35 mg/m² orally twice daily (days 1–5 and 8–12 of a 28-day cycle) plus bevacizumab 5 mg/kg intravenously every 2 weeks. No prior treatment with the study drugs is permitted. Randomization is stratified by time since prior anti-angiogenic therapy ( < 12 vs. ≥12 months), BRAF/RAS mutation status, and history of liver metastases (never vs. treated). The primary endpoint is progression-free survival; secondary endpoints include overall response, overall survival, and quality of life. Translational research includes tumor, blood, and stool sampling to explore biomarkers of response and resistance, including systemic inflammation and the diet–microbiota–immune axis. Patient enrolment started in October 2025, and enrolment will take place at 30 sites. Clinical trial information: EU CTIS No. 2024-519111-34-00.