Fruquintinib Combo Shows Activity in Pretreated Metastatic CRC

"The updated analysis demonstrated encouraging survival benefits of fruquintinib plus TAS-102 as third-line treatment in patients with [metastatic] CRC with acceptable toxicities. This regimen could be an alternative therapeutic approach for these patients," according to study authors.

Clinical activity and acceptable toxicity occurred when combining fruquintinib (Fruzaqla) with trifluridine/tipiracil (TAS-102; Lonsurf) for patients with previously treated metastatic colorectal cancer (CRC), according to data from a phase 2 study (NCT05004831) presented at the 2025 ASCO Gastrointestinal Cancer Symposium.

Findings showed that the combination (n = 50) generated a median progression-free survival (PFS) of 6.33 months (95% CI, 4.20-8.62); the 6-, 9-, and 12-month PFS rates were 53.0% (95% CI, 40.2%-70.0%), 28.3% (95% CI, 17.4%-45.9%), and 23.1% (95% CI, 13.2%-40.5%), respectively.

At a median follow-up of 17.6 months, the median overall survival (OS) was 18.4 months (95% CI, 12.0-not applicable [NA]); the respective 6-, 9-, and 12-month OS rates were 87.0% (95% CI, 77.8%-97.3%), 66.9% (95% CI, 54.0%-82.9%), and 64.3% (95% CI, 51.1%-80.8%).

"The updated analysis demonstrated encouraging survival benefits of fruquintinib plus TAS-102 as third-line treatment in patients with [metastatic[ CRC with acceptable toxicities. This regimen could be an alternative therapeutic approach for these patients," lead study investigator Jianjun Peng, MD, PhD, and colleagues wrote in a poster presentation of the data. Peng is a gastrointestinal surgeon at The First Affiliated Hospital, Sun Yat-sen University in Guangzhou, China.

Phase 2 Trial Enrollment and Treatment Objectives

Eligible patients were required to be 18 to 75 years of age with metastatic or recurrent CRC who previously received at least 2 treatment regimens. An ECOG performance status of 0 or 1; measurable disease per RECIST 1.1 criteria; and no prior exposure to anti-VEGF therapy were required for enrollment.

All patients received fruquintinib at 4 mg once daily on days 1 to 21 combined with TAS-102 at 35 mg/m² twice daily on days 1 to 5 and 8 to 12 of every 4-week cycle. Treatment continued until disease progression or unacceptable toxicity.

The primary end point of the study was PFS. Secondary end points included objective response rate, disease control rate, OS, and safety/tolerability.

A total of 50 patients were enrolled between March 2022 and August 2023. The median age of the cohort was 60 years (range, 39-76), and 58.0% of the patients were male. Patients received a median of 2 prior lines of therapy (range, 1-4); 16.0% and 4.0% of patients received 3 and 4 prior lines of therapy, respectively. All patients had received prior 5-fluorouracil, and most had also received irinotecan (90.0%) and oxaliplatin (98.0%); other prior chemotherapies included raltitrexed (18.0%) and S-1 (2.0%). Prior anti-VEGF/anti-EGFR therapy included bevacizumab (Avastin; 88.0%), cetuximab (Erbitux; 26.0%), or both (20.0%).

Forty-two percent of patients had RAS mutations, 16.0% had RAS wild-type disease, and 24.0% had an unknown RAS status. Primary tumors originated in the rectum (48.0%), left side of the colon (34.0%), and right side of the colon (18.0%). Liver metastases were reported at baseline in 58.0% of patients; 60.0% had lung metastases, and 18.0% had peritoneal metastases. Seventy-six percent of patients presented with two or more metastatic sites.

As of the January 10, 2024, data cutoff, 46 patients had undergone at least 1 tumor assessment, and 7 patients remained on therapy.

Additional Efficacy Insights

PFS data were consistent across key subgroups. Patients with liver metastases achieved a median PFS of 6.33 months (95% CI, 4.13-8.62) vs 6.46 months (95% CI, 3.74-NA) in patients without liver metastases (P = .54). Similarly, patients with peritoneal metastases experienced a median PFS of 6.07 months; 95% CI, 3.74-NA) vs 6.33 months (95% CI, 4.20-8.27) for those without peritoneal metastases (P = .95).

Cox model results showed no significant impact on PFS based on primary site (HR, 1.1; 95% CI, 0.49-2.3; P = .86), number of prior treatment lines (HR, 1.0; 95% CI, 0.83-1.3; P = .68), age (HR, 1.2; 95% CI, 0.59-2.3; P = .65), number of metastatic sites (HR, 1.0; 95% CI, 0.5-2.1; P = .96), or KRAS mutation status (HR, 1.3; 95% CI, 0.6-2.7; P = .52). Similarly, no significant associations with OS were observed for these variables.

Safety Observations

Treatment-related adverse effects (TRAEs) were primarily hematologic and consistent with the known safety profile of this combination. The most common any-grade TRAEs reported in at least 10% of patients included decreased neutrophil count (any-grade, 80%; grade ≥3, 54%), decreased white blood cell count (70%; 26%), anemia (58%; 20%), proteinuria (50%; 4%), decreased platelet count (44%; 10%), decreased lymphocyte count (40%; 8%), increased thyroid stimulating hormone level (32%; 0%; hypoalbuminemia (30%; 2%), increased blood bilirubin level (26%; 12%), hypertriglyceridemia (22%; 4%), loss of appetite (22%; 0%), high cholesterol (18%; 0%), elevated aspartate or alanine aminotransferase levels (14%; 0%), fatigue (14%; 0%), abdominal pain (12%; 0%), diarrhea (12%; 0%), vomiting (10%; 0%), headache (10%; 0%), hypertension (10%; 2%), and nausea (10%; 0%).

Reference

Peng J, Long J, Huang L, et al. Updated analysis of a phase 2 study of fruquintinib plus trifluridine/tipiracil as third-line treatment in patients with metastatic colorectal adenocarcinoma. J Clin Oncol. 2025;43(suppl 4):145. doi:10.1200/JCO.2025.43.4_suppl.145