Fruquintinib

Fruquintinib is a novel small-molecule anti-VEGFR that targets VEGFR-1,-2, and -3 to inhibit angiogenesis. Tumor angiogenesis is one of the most critical biological processes for increasing oxygen and nutrient supply to cancer cells, and the VEGF/VEGFR pathway is one of the most critical pathways for this phenomenon.A262102,A262107 Indeed, oncogenic activation, loss of tumor suppressor function, and hypoxia, usually facilitated by cancer cells, are known to upregulate VEGF.^A262097

There are 2 major approaches to combatting tumor angiogenesis: neutralization of VEGF/VEGFR activity through monoclonal antibodies or blockage of VEGFR kinase activity through small-molecule inhibitors. The first approach can be exemplified by bevacizumab, a VEGF-A trap antibody. Although bevacizumab is successful in sustaining target inhibition, mandatory intravenous dosing, immunogenicity, and the potential to induce autoimmune diseases hinder its clinical application.^A262097 For the small-molecule approach, most earlier generations of VEGFR inhibitors such as sunitinib, sorafenib, regorafenib, and pazopanib have poor selectivity, thus increasing the risk of off-target toxicity. Therefore, the advent of fruquintinib, a new generation of VEGFR inhibitors with a high kinome selectivity, demonstrated the feasibility of the small-molecule inhibitor approach.^A262097

On November 8th, 2023, fruquintinib was approved by the FDA under the brand name Fruzaqla for the treatment of adult patients with metastatic colorectal cancer (mCRC) who received prior fluoropyrimidine-, oxaliplatin-, and irinotecan-based chemotherapy, an anti-VEGF therapy, and, if RAS wild-type and medically appropriate, an anti-EGFR therapy. This approval is based on favorable results obtained from the FRESCO and FRESCO-2 trials, where an increase in overall survival rate was observed in both trials.^L48791