Open Access
REVIEW
Toxicities of Fruquintinib in Gastrointestinal Malignancies: A Systematic Review and Meta-Analysis
Daniel Thomas Jones1,*, Tajveer Sangha1, Arman Manjikian1, Micheal Ghobrial1, Qasim Shawesh1, Emaan Tiwana1, Emi Hearn1, Arash Latif1, Elaine Tupas1, Aishwarya Hanspal1, Rishi Kumar Nanda2, Ramaditya Srinivasmurthy3, Jason Ta4, Meghana Pandit3, Charles Abraham Joseph Larson5, Kyaw Zin Thein6
1 Department of Internal Medicine, Sunrise Health GME Consortium, Las Vegas, NV, USA
2 College of Osteopathic Medicine, Touro University Nevada, Las Vegas, NV, USA
3 Department of Internal Medicine, Mount Sinai Morningside/West, New York, NY, USA
4 Department of Internal Medicine, HCA Healthcare/USF Morsani College of Medicine GME Consortium, HCA Florida Citrus Hospital, Inverness, FL, USA
5 Trinity School of Medicine, Warner Robins, GA, USA
6 Division of Hematology and Medical Oncology, Comprehensive Cancer Centers of Nevada, Central Valley, Las Vegas, NV, USA
* Corresponding Author: Daniel Thomas Jones. Email: 
Oncology Research https://doi.org/10.32604/or.2026.078524
Received 02 January 2026; Accepted 22 May 2026; Published online 15 June 2026
Abstract
Backgrounds: Fruquintinib is a selective vascular endothelial growth factor receptor (VEGFR)-1/2/3 inhibitor approved for previously treated metastatic colorectal cancer. As its use expands across gastrointestinal (GI) malignancies and combination regimens, randomized evidence is needed to define the toxicity profile most relevant to clinical monitoring, particularly hypertension, dermatologic toxicity, renal toxicity, bleeding, and thrombotic events. The objective of this study was to synthesize randomized controlled trial evidence to quantify the incidence and relative risk of key toxicities associated with fruquintinib in gastrointestinal malignancies. Methods: MEDLINE, EMBASE, and Cochrane CENTRAL were searched from inception through 1 January 2026 for phase II–III randomized controlled trials of fruquintinib in GI cancers reporting hypertension, proteinuria, hemorrhage, venous thromboembolism (VTE), and hand-foot skin reaction or palmar-plantar erythrodysesthesia (HFSR/PPE). Trial-reported CTCAE adverse events were pooled as risk ratios (RRs) with 95% confidence intervals (CIs) using Mantel-Haenszel random-effects models. Exploratory subgroup analyses were performed in metastatic colorectal cancer (mCRC). Results: Four randomized trials (n = 1872) were included. Fruquintinib significantly increased grade ≥3 hypertension (RR 9.01, 95% CI 4.67–17.40) and grade ≥3 HFSR/PPE (RR 26.00, 95% CI 6.42–105.29). Any-grade proteinuria was also increased (RR 1.89, 95% CI 1.30–2.74). Grade ≥3 hemorrhage occurred at low absolute rates and was numerically higher with fruquintinib, but the pooled estimate did not reach statistical significance (RR 1.82, 95% CI 0.92–3.61). VTE estimates were imprecise because of sparse events (any-grade VTE: RR 1.23, 95% CI 0.53–2.88; grade ≥3 VTE: RR 1.96, 95% CI 0.52–7.36). Conclusions: In randomized evidence across GI malignancies, the principal safety signals associated with fruquintinib are grade ≥3 hypertension and grade ≥3 HFSR/PPE, together with increased any-grade proteinuria. Grade ≥3 hemorrhage was uncommon and numerically higher, whereas VTE estimates remained imprecise. These findings support early blood pressure optimization, proactive dermatologic management, routine urinalysis monitoring, and individualized assessment of bleeding and thrombotic risk when initiating therapy.
Keywords
Fruquintinib; gastrointestinal malignancies; metastatic colorectal cancer; vascular endothelial growth factor receptor; tyrosine kinase inhibitors; meta-analysis
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