Later-Line Fruquintinib for Refractory Metastatic Colorectal Cancer

The benefit of vascular endothelial growth factor (VEGF)–targeted therapies — including bevacizumab, ramucirumab, aflibercept, and regorafenib — has been validated in early and later lines of therapy for patients with metastatic colorectal cancer (mCRC).

To evaluate the later-line use of the oral VEGF tyrosine kinase inhibitor fruquintinib in this setting, investigators conducted an industry-sponsored, international, randomized, double-blind, placebo-controlled, phase 3 trial (FRESCO-2) involving 691 heavily pretreated mCRC patients (most with left-sided/rectal and RAS-mutant tumors). Patients had disease progression on standard treatments, including chemotherapy, bevacizumab, EGFR-targeted therapy for RAS wild-type cancers, BRAFV600E-targeted therapy for BRAFV600E-mutant cancers, and immune checkpoint inhibitors for microsatellite instability-high cancers. Most patients (73%) had received more than 3 lines of prior therapy, and 40% had received both trifluridine-tipiracil chemotherapy and regorafenib.

At a median follow-up of 11.3 months, overall survival (the primary endpoint) was improved with fruquintinib compared with placebo (7.4 vs. 4.8 months; hazard ratio, 0.66; P<0.0001), as was progression-free survival (3.7 vs. 1.8 months; HR, 0.32; P<0.0001). The objective response rate was low with both fruquintinib and placebo (2% and 0%, respectively), but the disease control rate was higher with fruquintinib than with placebo (56% vs. 16%; P<0.0001). The rate of grade 3 or higher adverse events was 63% with fruquintinib and 50% with placebo; dose reductions of fruquintinib occurred due to hand-foot syndrome in 5% of patients, hypertension in 4%, and asthenia in 4%.