1. In this phase 3 randomized controlled trial, fruquintinib increased median overall survival and progression-free survival compared to placebo in patients with colorectal cancer who had already undergone second line or subsequent treatment.
2. Fruquintinib was associated with an increase rate of adverse effects.
Evidence Rating Level: 1 (Excellent)
Study Rundown: Biological agents that target VEGF or EGFR are often used in conjunction with other chemotherapies to treat metastatic colorectal carcinoma (CRC). Despite these advances, the choices in these inhibitors are limited and some have significant adverse effects that limit their tolerability. The current study is a phase 3 randomized control trial that assessed the efficacy and adverse event profile of fruquintinib, a VEGF inhibitor, in patients with metastatic CRC that had progressed after second-line treatment. Median overall survival was found to be significantly prolonged with fruquintinib. Progression-free survival was also found to be significantly increased with fruquintinib. However, both treatment-emergent and serious adverse events similar to other VEGF inhibitors were found to be significantly increased in the fruquintinib-treated group.
Overall, the study shows that fruquintinib may prolong survival in patients with metastatic CRC that have progressed after second-line treatment, though numerous limitations should be noted. The study lacks of generalizability outside of China, where the study took place, highlighted by differences in prior treatments in this study population that may differ from their Western counterparts. Importantly, because other VEGF inhibitors were not available in China during the study period, it is unclear how fruquintinib compares to other VEGF inhibitors like bevacizumab and regorafenib. Future studies may evaluate the efficacy of fruquintinib in other populations.
In-Depth [randomized controlled trial]: The Fruquintinib Efficacy and Safety in 3+ Line Colorectal Cancer (FRESCO) trial is a Chinese, randomized, double-blind, placebo-controlled, multicenter, phase 3 trial in patients with metastatic CRC that had continued tumor progression despite prior treatment. Eligible patients had to have histologically or cytologically confirmed metastatic CRC that had progressed following at least 2 chemotherapy regimens. Patients with prior treatment with certain VEGF inhibitors were included while prior treatment with certain other VEGFR inhibitors were excluded. Patients were randomly assigned into a 2:1 ratio to receive either fruquintinib (5 mg/d) or matching placebo orally, once daily for 21 days. This was followed by 7 days off in 28-day cycles until disease progression, intolerable toxicity, or study withdrawal. The primary endpoint was overall survival, and secondary endpoints included progression-free survival, objective response rate, and disease control rate.
Overall, 416 patients were randomized. Median overall survival was found to be significantly prolonged with fruquintinib compared to placebo (9.3 months vs 6.6 months; hazard ratio (HR) 0.65, p < 0.001). Progression-free survival was also found to be significantly increased with fruquintinib (3.7 months vs 1.8 months; HR 0.26, p < 0.001). Both treatment-emergent (61.2% vs 19.7%) and serious adverse events 14.4% vs 5.8%) were found to be significantly increased in the fruquintinib-treated group (p < 0.05).
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