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A post hoc subgroup analysis of FRESCO-2 shed light on the safety and efficacy of fruquintinib by metastatic site in metastatic colorectal cancer.
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Fruquintinib (Fruzaqla) showcased improved outcomes compared with placebo, irrespective of metastatic sites at baseline, in patients with metastatic colorectal cancer (mCRC), according to data from a post hoc subgroup analysis of the phase 3 FRESCO-2 study (NCT04322539) presented during the 2025 ESMO Gastrointestinal Cancers Congress.
In patients with liver metastases only, the median overall survival (OS) with fruquintinib plus best supportive care (BSC; n = 19) was 8.5 months vs 3.1 months with placebo plus BSC (n = 10; HR, 0.256; 95% CI, 0.079-0.824; P = .0760). The median progression-free survival (PFS) in the respective arms was 3.7 months and 1.9 months (HR, 0.157; 95% CI, 0.047-0.526; P = .0093). The objective response rates (ORRs) in the fruquintinib (n = 19) and placebo (n = 10) arms were 0%; the disease control rates (DCRs) were 63.2% and 0% (P = .001).
In patients with lung metastases only, the median OS in the fruquintinib arm (n = 25) was 14.1 months vs not evaluable in the placebo arm (n = 16; HR, 0.998; 95% CI, 0.208-4.792; P = .9561). However, OS data in this subgroup were immature because of the improved prognosis of the subset, as 13 of 16 patients who were given placebo were censored and all 13 were alive at the time of data cutoff. The median PFS with fruquintinib was 5.7 months vs 2.6 months with placebo (HR, 0.170; 95% CI, 0.056-0.516; P = .0063). The ORRs in the respective arms were 12.0% and 0%; the DCRs were 68.0% vs 50.0% (P = .255).
In patients with bone metastases with or without metastases in other sites at baseline, the median OS was 7.6 months with fruquintinib (n = 51) vs 3.4 months with placebo (n = 27; HR, 0.399; 95% CI, 0.215-0.741; P = .0065). The median PFS in the fruquintinib and placebo arms was 3.7 months and 1.8 months, respectively (HR, 0.354; 95% CI, 0.201-0.621; P = .0003). The ORRs in the respective arms were 2.0% and 0%; the respective DCRs were 54.9% and 22.2% (P = .006). In patients with peritoneal metastases with or without metastases in other sites at baseline, the median OS in the fruquintinib/BSC arm (n = 67) was 5.4 months vs 4.2 months with placebo/BSC (n = 38; HR, 0.669; 95% CI, 0.395-1.134; P = .2453). The median PFS in the respective arms was 3.4 months and 1.8 months (HR, 0.305; 95% CI, 0.180-0.518; P = .0002). The ORR in both arms was 0%; the DCRs were 52.2% and 13.2% in the respective arms (P < .0001).
“In this subgroup analysis, fruquintinib demonstrated improved outcomes vs placebo, regardless of the site of baseline metastases,” Rocio Garcia-Carbonero, MD, of Hospital Universitario 12 de Octubre, Imas12, UCM, in Madrid, Spain, and colleagues, wrote in a poster of the data. “Median OS was longer with fruquintinib vs placebo in patients with mCRC who had liver metastases only, bone metastases, or peritoneal metastases at baseline; analyses of PFS and DCR indicated improved outcomes in patients with mCRC who had lung metastases only as well.”
The study enrolled patients with mCRC from North America, Europe, Japan, and Australia (n = 691) who were randomly assigned 2:1 to placebo plus BSC (n = 230) or 5 mg of fruquintinib once daily plus BSC (n = 461) as part of 28-day cycles on a 3-weeks-on/1-week-off schedule. Treatment continued until disease progression or intolerable toxicity. The primary end point was OS, and secondary end points included PFS, ORR, DCR, and safety. A post hoc end point focused on time to ECOG performance status worsening.
For the current post hoc subgroup analysis, investigators evaluated the safety and efficacy of fruquintinib vs placebo according to the baseline presence of liver metastases only, lung metastases only, and bone or peritoneal metastases with or without metastases at other sites—all selected for clinical relevance. The Kaplan-Meier method was leveraged to examine time-to-event end points with differences tested using the log-rank test. They estimated survival hazard ratios using a Cox proportional hazards model.
In the FRESCO-2 intention-to-treat population, the median patient age in the fruquintinib and placebo arms was 64.0 years (range, 25-86). Most patients were male (fruquintinib, 53.1% vs placebo, 60.9%), had an ECOG performance status of 1 (57.5% vs 55.7%), had colon as the disease site at first diagnosis (41.6% vs 40.0%), had metastatic disease for over 18 months (92.0% vs 94.3%), received more than 3 prior lines for metastatic disease (72.9% vs 72.2%), had RAS-mutated disease (63.1% vs 63.0%) and previously received a VEGF inhibitor (96.5% vs 96.1%).
“In the fruquintinib arm, the proportion of patients who experienced grade 3 or higher treatment-emergent adverse effects [TEAEs] was numerically higher in the subgroups with peritoneal and bone metastases with or without other metastases, and lower in the subgroups with liver and lung metastases only; however, due to low patient numbers these data should be interpreted with caution,” the study authors wrote.
The most common grade 3 or higher TEAEs that were reported in at least 10% of patients who received fruquintinib per subgroup were hypertension, Palmar-plantar erythrodysesthesia, and asthenia. About 20% of patients in each subgroup experienced TEAEs that led to treatment discontinuation.
The median time to deterioration (TTD) to an ECOG performance status of 2 or higher or death within the safety follow-up was longer with fruquintinib vs placebo in those with bone metastases and peritoneal metastases. In the former subgroup, the median TTD was 5.5 months with fruquintinib vs 1.6 months with placebo (HR, 0.333; 95% CI, 0.166-0.667; P = .0015). In the latter subgroup, the median TTD was 4.2 months vs 1.8 months (HR, 0.464; 95% CI, 0.257-0.838; P = .0174).
In those with liver metastases only, the median TTD to an ECOG performance status of 2 or higher or death within the safety follow-up was 3.9 months with fruquintinib vs NE with placebo (HR, 0.320; 95% CI, 0.071-1.449; P = .2889). In those with lung metastases only, the median TTD was NE vs NE (HR, 1.040; 95% CI, 0.184-5.887; P = .8830).
Disclosures: Garcia-Carbonero disclosed serving on the advisory board for AAA, Amgen, Astellas, Bayer, BMS, Boehringer Ingelheim, Esteve, GlaxoSmithKline, HUTCHMED, Ipsen, MSD, Novartis-AAA, PharmaMar, Pierre Fabre, Sanofi, Servier, and Takeda. Institutional research grants were received from BMS, MSD, and Pfizer. He is global principal investigator of investigator-initiated clinical trials for BMS, MSD, and Pfizer. He is chair for European Neuroendocrine Tumor Society. He is past president and member of the Executive Committee for Grupo Español de Tumores Neuroendocrinos. Honoraria was received by spouse for advisory board or invited speaker roles for AbbVie, AstraZeneca, Bayer, Boehringer Ingelheim, BMS, Genomica, Lilly, MSD, Merck, Novartis, Pfizer, PharmaMar, Roche, Sanofi, Servier, and Takeda.
Garcia-Carbonero R, Dasari A, Eng C, et al. Efficacy and safety of fruquintinib vs placebo by metastatic site in metastatic colorectal cancer: A FRESCO-2 subgroup analysis. Presented at: 2025 ESMO Gastrointestinal Cancers Congress; July 2-5, 2025; Barcelona, Spain. Abstract 37P.
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