Quantitative Vessel Tortuosity Shows Potential as Biomarker for Antiangiogenic Activity With Fruquintinib in mCRC

Quantitative vessel tortuosity (QVT), a noninvasive, radiomics-based imaging biomarker, was able to detect the antiangiogenic mechanism of action of fruquintinib (Fruzaqla) in patients with metastatic colorectal cancer (mCRC), according to data from a retrospective analysis of the phase 3 FRESCO-2 trial (NCT04322539) presented during the 2025 ESMO Gastrointestinal Cancer Congress.

Results from the analysis demonstrated that patients in the fruquintinib group experienced a 70% decrease of vessel inflection in lung lesions from baseline to day 1 of cycle 3 (P < .0006). Additionally, patients in the fruquintinib arm experienced median reductions in vessel volume, torsion, curvature, and radius of 25% (P < .006), 15% (P < .05), 10% (P < .05), and 5% (P < .05), respectively, over the same time period. Conversely, patients in the placebo arm experienced a 30% increase in abnormal vessel branching at day 1 of cycle 3 compared with baseline (P < .05).

“Significant changes in QVT features between patients in the fruquintinib and placebo arms were observed during the first assessment, demonstrating the early antiangiogenic action of fruquintinib,” Sara Lonardi, MD, chief of the Oncology 3 Unit of Veneto Institute of Oncology in Padua, Italy, and her coauthors wrote in the poster. “The observed differences in Delta QVT radiomic features…quantify the ability of fruquintinib to prevent the formation of a twisted, heterogeneous vasculature.”

In November 2023, the FDA approved fruquintinib for the treatment of adult patients with mCRC who received previous treatment with fluoropyrimidine-, oxaliplatin-, and irinotecan-based chemotherapy, an anti-VEGF therapy, and, if RAS wild-type and medically appropriate, an anti-EGFR therapy.² The regulatory decision was partially supported by prior data from FRESCO-2, which demonstrated that patients treated with the VEGFR inhibitor experienced a 34% reduction in the risk of death compared with those who received placebo (HR, 0.66; 95% CI, 0.55-0.80; P < .001).

FRESCO-2 Study Design and Retrospective Analysis Methods

FRESCO-2 was a global, double-blind study that enrolled adult patients with metastatic CRC.³ Patients were required to have experienced disease progression on or have been intolerant to trifluridine/tipiracil (Lonsurf) or regorafenib (Stivarga). Eligible patients also needed to have a body weight of at least 40 kg, an ECOG performance status of 0 or 1, measurable disease per RECIST 1.1 criteria, and an expected survival of over 12 weeks.

Patients were randomly assigned 2:1 to receive fruquintinib (n = 461) or placebo (n = 230) at 5 mg daily, both in combination with best supportive care.¹ Treatment was administered in 28-day cycles for 3 weeks on, 1 week off. Treatment in both arms continued until disease progression or unacceptable toxicity.

The primary end point was overall survival (OS).³ Secondary end points included progression-free survival, objective response rate, disease control rate, duration of response, and safety.

This retrospective analysis included CT scans from 221 patients enrolled in FRESCO-2; 442 lesions were analyzed from 162 patients in the fruquintinib arm and 167 lesions were analyzed from 59 patients in the placebo arm.¹ For each lesion, 909 QVT features were extracted to quantify peritumoral vascularity. The longitudinal change in QVT features was calculated as the percentage change in features from screening to day 1 of cycle 3.

Following CT scan image transfer, image processing and lesion selection occurred, followed by lesion annotation and segmentation. QVT features were then extracted and selected prior to data integration and analysis.

The presence of lung metastases was the primary objective of the retrospective analysis. Notably, primary colorectal lesions were not analyzed due to the high rate of resection prior to screening.

Additional Findings From the Retrospective Analysis

Additional data from the retrospective analysis revealed that a statistically significant difference in Delta QVT with fruquintinib vs placebo was observed in 11 of the 21 preselected QVT features. Treatment with fruquintinib also showed a clear normalizing effect on tumor-associated vasculature in lung metastases. Compared with placebo, treatment with fruquintinib led to decreases in mean vessel curve intensity (P = .02095), mean branch length (P = .04677), number of branches (P = .01460), mean torsion (P = .01939), torsion length-to-distance ratio (P = .00991), number of vessel inflection points (P = .00606), mean vessel radius (P = .01282), and vessel volume (P = .00606).

“These findings establish the value of QVT as a direct measure for fruquintinib-based antiangiogenic activity and support the use of this method as a potential tool to assess treatment effect based on the mechanism of action,” Lonardi and her coauthors wrote in their conclusion. “Further analyses are planned to include liver lesions and a predictive model of OS.”

Disclosures: Lonardi reported being on the advisory boards of Amgen, Merck Serono, Lilly, Servier, AstraZeneca, MSD, Incyte, Daiichi-Sankyo, Bristol Myers Squibb, Astellas, GlaxoSmithKline, Takeda, Bayer, Rottapharm, BeiGene, Nimbus Therapeutics, and Helion. She has also been an invited speaker for Pierre Fabre, GlaxoSmithKline, Roche, Servier, Amgen, Bristol Myers Squibb, incyte, Lilly, Merck Serono, and AstraZeneca, as well as a coordinating primary investigator for Amgen, Merck Serono, Bayer, Roche, Lilly, AstraZeneca, and Bristol Myers Squibb.

References

1. Lonardi S, Yardibi O, Dasari A, et al. A novel imaging biomarker, quantitative vessel tortuosity, captures the antiangiogenic effect of fruquintinib in metastatic colorectal cancer. Presented at: ESMO Gastrointestinal Cancers Congress 2025; July 2-5, 2025; Barcelona, Spain. Abstract 32P.
2. FDA approves fruquintinib in refractory metastatic colorectal cancer. FDA. November 8, 2023. Accessed July 4, 2025. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-fruquintinib-refractory-metastatic-colorectal-cancer
3. A study of efficacy and safety of fruquintinib (HMPL-013) in participants with metastatic colorectal cancer (FRESCO-2). ClinicalTrials.gov. Updated April 4, 2025. Accessed July 4, 2025. https://clinicaltrials.gov/study/NCT04322539