Background
International phase 3, double-blind, placebo-controlled (14 countries). N=691 refractory metastatic colorectal adenocarcinoma. All standard cytotoxic/targeted therapy exhausted; progressed on or intolerant to trifluridine-tipiracil and/or regorafenib. Median 4 prior lines; 73% >3 lines. Fruquintinib: oral selective VEGFR-1/2/3 inhibitor.
Interventions and follow up
Arm A: fruquintinib 5 mg PO daily, days 1–21 of 28-day cycles (n=461) + best supportive care.
Arm B: matched placebo, same schedule (n=230) + best supportive care.
Randomization: 2:1 favoring fruquintinib.
Primary endpoint: overall survival; final analysis at 480 OS events.
mFollow up: NR.
Arm B: matched placebo, same schedule (n=230) + best supportive care.
Randomization: 2:1 favoring fruquintinib.
Primary endpoint: overall survival; final analysis at 480 OS events.
mFollow up: NR.
Results
OS: 7.4 vs 4.8 mo, HR 0.66, 95% CI 0.55–0.80, P<.001.
PFS: 3.7 vs 1.8 mo, HR ~0.32.
Subgroups: benefit consistent across prior-therapy and RAS strata.
PFS: 3.7 vs 1.8 mo, HR ~0.32.
Subgroups: benefit consistent across prior-therapy and RAS strata.
Adverse events
Overall: G3+ AEs 63% vs 50%.
Most common G3+: hypertension 14%, asthenia 8%, hand-foot syndrome 6%.
Deaths: one treatment-related death per arm (intestinal perforation; cardiac arrest).
Most common G3+: hypertension 14%, asthenia 8%, hand-foot syndrome 6%.
Deaths: one treatment-related death per arm (intestinal perforation; cardiac arrest).
Conclusions
Fruquintinib significantly improved OS and PFS in heavily pretreated refractory mCRC with manageable VEGFR-class toxicity, establishing a new oral late-line option.
Key Limitations
Absolute OS gain modest (2.6 mo) with no confirmed objective responses, so benefit is largely disease stabilization. Placebo comparator reflects absence of an active standard in this heavily pretreated population. No biomarkers to select responders.
Clinical Context
Global FRESCO-2, complementing the China-based FRESCO study, supported FDA approval (Nov 2023) and EMA approval of fruquintinib for previously treated mCRC. ESMO recognizes fruquintinib as a refractory-setting option alongside trifluridine-tipiracil (± bevacizumab) and regorafenib, with sequencing individualized by tolerance and prior exposure.