Abstract
BACKGROUND: Patients with metastatic colorectal cancer (mCRC) who have progressed on fluoropyrimidines, oxaliplatin, irinotecan, anti-angiogenic agents, and anti-epidermal growth factor receptor (EGFR) therapies have limited treatment options and poor prognosis, with a median overall survival (mOS) of ∼6 months on single-agent regorafenib or trifluridine/tipiracil. The addition of bevacizumab to trifluridine/tipiracil improved mOS to 10.8 months, and fruquintinib, a selective vascular endothelial growth factor receptor (VEGFR) 1-3 inhibitor, improved mOS to 7.4 months versus 4.8 months with placebo in refractory mCRC. However, combinations of tyrosine kinase inhibitors and immune checkpoint inhibitors have shown benefit primarily in patients without liver metastases in microsatellite stable mCRC, likely due to liver-associated immunosuppression. The QUINTIS trial evaluates whether fruquintinib plus tislelizumab can improve outcomes to the standard of care with trifluridine/tipiracil and bevacizumab in third-line and beyond mCRC. METHODS/DESIGN: QUINTIS is a prospective, randomized, open-label, multicenter, phase II trial enrolling patients with advanced or metastatic colorectal adenocarcinoma without active liver metastases who have been previously treated with fluoropyrimidines, oxaliplatin, irinotecan, bevacizumab, and, if indicated, an EGFR inhibitor. Participants are randomly assigned 1 : 1 to one of the following treatment arms: arm A (experimental): fruquintinib 5 mg orally once daily on days 1-21 of a 4-week cycle (q4w) plus tislelizumab 400 mg intravenously on day 1 every 6 weeks (q6w); or arm B (control): trifluridine/tipiracil 35 mg/m(2) orally twice daily on days 1-5 and 8-12 of a 4-week cycle (q4w) plus bevacizumab 5 mg/kg intravenously on day 1 every 2 weeks (q2w). Randomization is stratified by prior anti-angiogenic therapy (<12 versus ≥12 months ago), BRAF/RAS mutation status, and history of liver metastases (never versus treated). Tumor assessments occur every 8 weeks; follow-up continues for up to 18 months after enrolment. Optional translational research includes tumor, blood, and stool sampling to explore biomarkers of response and resistance.