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Clinical Trial
. 2025 Oct;30(10):2043-2052.
doi: 10.1007/s10147-025-02852-9. Epub 2025 Sep 1.

Efficacy and safety of fruquintinib in patients with refractory metastatic colorectal cancer: a FRESCO-2 subgroup analysis of patients enrolled in Japan

Daisuke Kotani  1 , Takayuki Yoshino  2 , Toshiki Masuishi  3 , Yu Sunakawa  4 , Atsuo Takashima  5 , Kentaro Yamazaki  6 , Hisato Kawakami  7   8 , Tomohiro Nishina  9 , Yoshito Komatsu  10 , Taito Esaki  11 , Cathy Eng  12 , Stacey Ukrainskyj  13 , Rajash Pallai  14 , Shivani Nanda  13 , Zhao Yang  13 , William Schelman  13 , Marek Kania  13 , Taroh Satoh  15
Affiliations
Clinical Trial

Efficacy and safety of fruquintinib in patients with refractory metastatic colorectal cancer: a FRESCO-2 subgroup analysis of patients enrolled in Japan

Daisuke Kotani et al. Int J Clin Oncol. 2025 Oct.

Abstract

Background: In the phase 3 FRESCO-2 study, fruquintinib plus best supportive care (BSC) significantly improved overall survival (OS) versus placebo plus BSC in patients with refractory metastatic colorectal cancer (mCRC). We present the results of a FRESCO-2 post hoc subgroup analysis evaluating outcomes of patients enrolled in Japan.

Methods: In FRESCO-2, patients had previously received all standard chemotherapies, anti-VEGF and anti-EGFR therapies if indicated, and had progressed on, or were intolerant to trifluridine-tipiracil and/or regorafenib. Patients were randomized 2:1 to receive fruquintinib 5 mg or matching placebo by mouth once daily on days 1-21 in 28-day cycles, plus BSC. The primary endpoint was OS; secondary endpoints included progression-free survival (PFS) and safety.

Results: Of the 56 patients enrolled in Japan, 40 (71.4%) and 16 (28.6%) were randomized to fruquintinib and placebo, respectively. OS was improved with fruquintinib versus placebo (median 6.9 vs. 5.6 months; hazard ratio [HR], 0.42; 95% confidence interval [CI] 0.19 - 0.92). PFS was also improved with fruquintinib versus placebo (median 3.6 vs. 1.8 months; HR, 0.27; 95% CI 0.13 - 0.56). The incidence of grade ≥ 3 treatment-emergent adverse events (TEAEs) with fruquintinib versus placebo was 71.8% versus 29.4%; the most common grade ≥ 3 TEAEs with fruquintinib were hypertension (23.1%) and palmar-plantar erythrodysesthesia (17.9%).

Conclusions: Fruquintinib improved OS and PFS versus placebo in FRESCO-2 patients enrolled in Japan and demonstrated a manageable safety profile. Results from the Japan subgroup were consistent with the global FRESCO-2 population, thus supporting fruquintinib as a novel treatment option for patients in Japan with refractory mCRC.

Clinical trial details: ClinicalTrials.gov; NCT04322539.

Keywords: Fruquintinib; Japan subgroup analysis; Metastatic colorectal cancer; VEGFR inhibitor.

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Conflict of interest statement

Declarations. Competing interests: DK has received honoraria from Takeda, Chugai, Eli Lilly, Merck Sharp & Dohme (MSD), Ono Pharmaceutical, Seagen, Guardant Health, Eisai, Taiho, Bristol Myers Squibb, Daiichi Sankyo, Pfizer, Merck Biopharma, and Sysmex; and reports grants or funds from Ono Pharmaceutical, MSD, Novartis, Servier, Janssen, IQVIA, Syneos Health, CIMIC, and CMIC Shift Zero. TY has received honoraria from Chugai, Takeda, Merck Biopharma, Bayer Yakuhin, Ono Pharmaceutical, and MSD; consulting fees from Sumitomo Corp; and reports grants or funds from Amgen, Bristol Myers Squibb, Chugai, Daiichi Sankyo, Eisai, FALCO Biosystems, Genomedia, Medical & Biological Laboratories, Merus N.V., Molecular Health GmbH, MSD, Nippon Boehringer Ingelheim, Ono Pharmaceutical, Pfizer Japan, Roche Diagnostics, Sanofi, Sysmex, Taiho, and Takeda. TM has received honoraria from Bayer Yakuhin, Bristol Myers Squibb, Chugai, Daiichi Sankyo, Eli Lilly, Merck Serono, Ono Pharmaceutical, Sanofi, Taiho, Takeda, Yakult Honsha, MSD, Takata, Astellas, and Nippon Kayaku; and reports grants or funds from Amgen, Boehringer Ingelheim, CMIC, Daiichi Sankyo, Eli Lilly Japan, MSD, Novartis, Ono Pharmaceutical, Pfizer, and Syneos Health. YS has received honoraria and grants or funds from Takeda. KY reports honoraria from Chugai, Daiichi Sankyo, Yakult Honsha, Takeda, Merck Serono, Taiho, Eli Lilly, Ono Pharmaceutical, MSD, and Bristol Myers Squibb; and grants or funds from Taiho. HK reports honoraria from Bristol Myers Squibb, Bayer Yakuhin, Eli Lilly Japan K.K., MSD, Ono Pharmaceutical, Chugai, Daiichi Sankyo, Merck Biopharma, Takeda, Yakult Pharmaceutical Industry, Teijin Pharma, Taiho, Otsuka Pharmaceutical, Nippon Kayaku, GlaxoSmithKline, Amgen, Novartis, and Astellas; consulting fees from Daiichi Sankyo, Astellas, and AbbVie; grants or funds from Eisai, Bristol Myers Squibb, Kobayashi Pharmaceutical, Astellas, Taiho; and other potential financial relationship with Medical & Biological Laboratories. TN reports honoraria from Astellas, and Ono Pharmaceutical. YK has received honoraria from Ono Pharmaceutical, Taiho, Chugai, Eli Lilly, Bayer, MSD, Astellas, Yakult, Daiichi Sankyo, and Incyte; and reports grants or funds from Ono Pharmaceutical, Taiho, Chugai, Eli Lilly, Bayer, MSD, Astellas, Yakult, Daiichi Sankyo, Incyte, Eisai, NCCH, Syneos Health, CMIC, and Parexel. TE has received honoraria from Chugai, Taiho, Ono Pharmaceutical, Hisamitsu, Roche Diagnostics, Zeria, MSD, Eli Lilly, and Daiichi Sankyo; and grants or funds from Ono Pharmaceutical, Seagen, Taiho, Jazz Pharmaceuticals, Ignyta, Quintiles, Bristol Myers Squibb, Asahi Kasei Pharma, ALX Oncology, MSD, Nihon Kayaku, Astellas, Amgen, IQVIA, Daiichi Sankyo, Chugai, Syneos Health Clinical, Pfizer, and Amgen. CE reports consulting fees from Amgen, Elevation, GlaxoSmithKline, GE HealthCare, IGM, Merck Biopharma, Natera, Pfizer, Seagen, Taiho, AbbVie, and Takeda; and potential financial relationships paid to Vanderbilt from Janssen, Merck Biopharma, Gritstone, and Hutchinson. SN is employed by and holds stocks/shares with HUTCHMED International Corporation. WS is an employee of and holds stocks/shares with HUTCHMED International Corporation. MK was a previous HUTCHMED International Corporation employee during study conduct and analysis. TS has received honoraria from MSD, AstraZeneca, Ono Pharmaceutical, Bristol Myers Squibb, and Daiichi Sankyo; and reports grants or funds from MSD, AstraZeneca, Ono Pharmaceutical, Bristol Myers Squib, Daiichi Sankyo, Shionogi Pharmaceutical, and Janssen. AT, SU, RP, and ZY have no conflicts to report. Ethics approval: FRESCO-2 was conducted in accordance with the Declaration of Helsinki and Good Clinical Practice guidelines, including the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use, and all applicable laws and regulations. The protocol was approved by the institutional review boards and independent ethics committees at each site. All participating patients provided written informed consent.

Figures

Fig. 1
Fig. 1
Patient disposition. *One patient randomized to the fruquintinib arm received placebo instead. †Patients with missing end-of-study information were considered to be remaining on study. ‡Patients who received study drug but had missing end-of-treatment information were considered to be remaining on treatment. BSC, best supportive care; ITT, intention-to-treat
Fig. 2
Fig. 2
OS from the date of randomization (ITT population). BSC, best supportive care; CI, confidence interval; HR, hazard ratio; ITT, intention-to-treat; OS, overall survival
Fig. 3
Fig. 3
PFS from the date of randomization (ITT population). BSC, best supportive care; CI, confidence interval; HR, hazard ratio; ITT, intention-to-treat; PFS, progression-free survival
See this image and copyright information in PMC

References

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