Background: Pts with mCRC have limited treatment options following progression on standard therapies. Current standard of care (SOC) after pts progress on trifluridine/tipiracil (TAS-102) or regorafenib is re-challenge with previous systemic treatments, enrollment in a clinical trial, or best supportive care (BSC). Fruquintinib (Elunate) is a novel, highly selective, vascular endothelial growth factor (VEGF) receptor (VEGFR)-1, -2, and -3 tyrosine kinase inhibitor (TKI) (Cancer Biol Ther 2014;15:1635-1645). Fruquintinib is approved in China to treat pts with mCRC who received or are intolerant to fluoropyrimidine-, oxaliplatin-, and irinotecan-based chemotherapy, anti-VEGF therapy, and, if RAS wild type, anti-epidermal growth factor receptor (EGFR) therapy. Approval was based on results of the phase 3 FRESCO study (2013-013-00CH1; NCT02314819; JAMA 2018;319:2486-2496), in which fruquintinib 5 mg daily (QD), 3 weeks on, 1 week off (3 on/1 off), significantly improved overall survival (OS) in pts with mCRC in the 3rd-line+ setting when compared to placebo (median OS 9.3 months [mo] versus 6.6 mo; hazard ratio [HR] 0.65; p < .001). Progression-free survival (PFS) was also superior (median PFS 3.7 mo versus 1.8 mo; HR 0.26; p < .001). The toxicities of fruquintinib were consistent with those of other VEGF TKIs and were manageable. At the time FRESCO was conducted in China, SOC for pts with mCRC differed from that in the US, EU, and Japan. We describe here a global phase 3 study (FRESCO-2; 2019-013-GLOB1; NCT04322539) being conducted to investigate fruquintinib’s efficacy and safety in pts with refractory mCRC and a treatment profile representative of the global SOC. Methods: FRESCO-2 is a randomized, double-blind, placebo-controlled study to compare fruquintinib + BSC to placebo + BSC. Key inclusion criteria are progression on or intolerance to treatment with TAS-102 and/or regorafenib; previous treatment with standard approved therapies including chemotherapy, anti-VEGF therapy, and, if RAS wild type, anti-EGFR therapy. Prior therapy with immune checkpoint or BRAF inhibitors is required for pts with corresponding tumor alterations. Pts (~522) will be randomized 2:1 to receive either fruquintinib 5 mg orally (PO) QD + BSC or placebo 5 mg PO QD + BSC, with a 3 on/1 off schedule. Randomization will be stratified by prior therapy, RAS status, and duration of metastatic disease. The primary endpoint is OS; secondary endpoints include PFS, disease control rate, objective response rate, duration of response, and safety. Final OS analyses will be performed when 364 OS events are observed; futility analysis will be conducted with 1/3 (121) OS events. If enrichment of post-regorafenib pts occurs, enrollment to that strata will be capped at approximately 262. FRESCO-2 will be activated in the US, EU, and Japan; global enrollment is anticipated over 13 mo. Clinical trial information: NCT04322539