Overall survival with fruquintinib versus placebo after adjusting for subsequent anticancer therapy in patients with refractory metastatic colorectal cancer in the FRESCO-2 study.
Authors: Sara Lonardi, Arvind Dasari, Josep Tabernero, Rocio Garcia-Carbonero, Elena Elez, Takayuki Yoshino, Alberto F. Sobrero, James C. Yao, Pilar Garcia-Alfonso, Judit Kocsis, Antonio Cubillo Gracian, Andrea Sartore-Bianchi, Taroh Satoh, Violaine Randrian, Jiri Tomasek, Geoff Chong, Andrew Scott Paulson, Liwen Wu, Lucy F. Chen, Cathy Eng
Journal: Journal of Clinical Oncology (2025)

171 Background: Fruquintinib is a highly selective, oral inhibitor of all 3 vascular endothelial growth factor receptors (VEGFRs -1, -2, and -3) that is approved by the US FDA and in the EU, UK, and Japan for previously treated metastatic colorectal cancer (mCRC), regardless of biomarker status. The phase 3 FRESCO-2 study (NCT04322539) met its primary endpoint demonstrating significantly improved overall survival with fruquintinib + best supportive care (BSC) vs placebo + BSC. As patients may have received subsequent anticancer therapy after progression, understanding the impact on overall survival is important. This analysis examined overall survival data from FRESCO-2 after adjusting for subsequent anticancer therapy. Methods: In FRESCO-2, patients were randomized 2:1 to receive fruquintinib (5 mg) or matching placebo by mouth, once daily, 3 weeks on, 1 week off, + BSC. Eligible patients had received prior chemotherapy, anti-VEGF therapy, anti-EGFR therapies (if indicated), and TAS-102 and/or regorafenib. We assessed the impact of subsequent anticancer therapy on overall survival by excluding patients who received subsequent therapies, censoring these patients, and determining the causal hazard ratio using inverse probability of censoring weights (IPCW) and marginal structural models (MSM) to adjust for the potential bias introduced by subsequent treatments. Results: In FRESCO-2, a lower proportion of patients in the fruquintinib vs placebo arm received subsequent anticancer therapy (29.4% vs 34.3%). Among these patients, the most common subsequent anticancer therapies in the fruquintinib vs placebo arms were fluorouracil (7.7% vs 9.6%) and regorafenib (7.5% vs 7.8%). The overall survival benefit seen with fruquintinib vs placebo in the intent-to-treat population (hazard ratio [HR]: 0.66; 95% confidence intervals [CI]: 0.55–0.80) was improved when patients who had received subsequent anticancer therapy were excluded (HR: 0.45; 95% CI: 0.36–0.57) or censored (HR: 0.63; 95% CI: 0.50–0.79). In addition, the overall survival benefit seen with fruquintinib vs placebo was improved after adjusting for subsequent anticancer therapy using IPCW (HR: 0.43; 95% CI: 0.33–0.55) and MSM (HR: 0.48; 95% CI: 0.38–0.60). Patients receiving fruquintinib had similar rates of grade ≥3 adverse events, whether or not they received subsequent anticancer therapy (51.5% and 67.4%, respectively). Conclusions: Consistent with the primary analysis of the FRESCO-2 intent-to-treat population, fruquintinib improved overall survival vs placebo after adjusting for the impact of subsequent anticancer therapy. Furthermore, these analyses are robust with consistent results reported using IPCW and MSM. These findings support fruquintinib as a new treatment option for patients with previously treated mCRC. Clinical trial information: NCT04322539 .