Fruquintinib, a US FDA-approved inhibitor for metastatic colorectal cancer
- Kim Petiza
- Feb 3
- 4 min read
Updated: Feb 4
Fruquintinib, a US FDA-approved inhibitor for metastatic colorectal cancer
Fruquintinib, marketed under the brand name Fruzaqla, is an oral, highly selective, and potent small-molecule inhibitor targeting vascular endothelial growth factor receptors (VEGFR) -1, -2, and -3. Developed to address the limitations of earlier anti-angiogenic therapies, fruquintinib offers a favorable efficacy and safety profile, particularly in the treatment of metastatic colorectal cancer (mCRC).
Mechanism of Action
Angiogenesis, the formation of new blood vessels, is a critical process in tumor growth and metastasis. The VEGF/VEGFR signaling pathway plays a pivotal role in this process. Fruquintinib exerts its anti-tumor effects by selectively inhibiting VEGFR-1, -2, and -3, thereby blocking VEGF-mediated endothelial cell proliferation and tubular formation. This inhibition suppresses angiogenesis, leading to restricted tumor progression.
Pharmacokinetics and Pharmacodynamics
Fruquintinib is administered orally and exhibits favorable pharmacokinetic properties:
Absorption: It achieves a steady-state maximum concentration (C_max) of approximately 300 ng/mL and an area under the concentration-time curve (AUC) of 5880 ng∙h/mL at the recommended dosage.
Metabolism: The drug is metabolized primarily in the liver, with cytochrome P450 enzymes playing a significant role.
Elimination: Fruquintinib has a half-life conducive to once-daily dosing, facilitating consistent VEGFR inhibition.
Usual Dosing
Adults: 5 mg once daily on days 1 to 21 of each 28-day cycle; continue until disease progression or unacceptable toxicity
Kidney Impairment:
Before treatment: No dosage adjustments are provided in the manufacturer's labeling.
During treatment:
Proteinuria (≥2 g in 24 hours): Withhold frսԛuintiոib until proteinuria fully resolves or is <1 g in 24 hours; resume frսquintiոib at the next lower dose level.
If nephrotic syndrome or if proteinuria does not recover to <1 g in 24 hours: Permanently discontinue frսquiոtinib.
Hepatic Impairment:
Before treatment:
Severe (total bilirubin >3 times ULN and any AST): Use is not recommended.
During treatment:
AST or ALT >3 times ULN with total bilirubin ≤2 times ULN: Withhold fruԛսintinib and monitor AST, ALT, and total bilirubin until resolution to ≤ grade 1 or baseline; resume therapy at next lower dose level.
AST or ALT >3 times ULN with total bilirubin >2 times ULN (without cholestasis or hemolysis): Permanently discontinue frսqսiոtinib.
AST or ALT >20 times ULN or total bilirubin >10 times ULN: Permanently discontinue fruԛսintinib.
Administration: Administer with or without food at approximately the same time each day. Swallow capsules whole.
Clinical Efficacy
The efficacy of fruquintinib in metastatic colorectal cancer has been demonstrated in several key clinical trials:
FRESCO Trial: This randomized, double-blind, placebo-controlled phase III trial evaluated fruquintinib in Chinese patients with mCRC who had progressed after at least two lines of chemotherapy. The study reported a median overall survival (OS) of 9.3 months for the fruquintinib group versus 6.6 months for the placebo group, indicating a significant survival benefit. There is also a benefit in progression-free survival (PFS) of 3.7 vs. 1.8 months. JAMA
FRESCO-2 Trial: An international, randomized, double-bline, placebo-controlled phase III trial assessing fruquintinib in patients with refractory mCRC. The study demonstrated a statistically significant improvement in OS (7.4 months vs. 4.8 months) and progression-free survival (PFS) (3.7 months vs. 1.8 months) compared to placebo, reinforcing the drug's efficacy in a broader population. Lancet
Safety Profile
Fruquintinib's safety profile is characterized by manageable adverse events:
Common Adverse Events: Hypertension, hand-foot syndrome, proteinuria, and diarrhea are among the most frequently reported. These events are generally mild to moderate in severity and can be managed with appropriate supportive care.
Serious Adverse Events: Severe hypertension and proteinuria have been observed but are less common. Regular monitoring of blood pressure and renal function is recommended during treatment.
Indications and Usage
Fruquintinib is indicated for the treatment of adult patients with metastatic colorectal cancer who have been previously treated with fluoropyrimidine-, oxaliplatin-, and irinotecan-based chemotherapy, an anti-VEGF therapy, and, if RAS wild-type and medically appropriate, an anti-EGFR therapy.
Patient Selection and Clinical Considerations
Fruquintinib is suitable for patients with mCRC who have exhausted standard chemotherapy options and targeted therapies. Its favorable safety profile makes it a viable option for patients who may not tolerate more aggressive treatments. However, caution is advised in patients with uncontrolled hypertension or significant proteinuria, and appropriate monitoring should be implemented.
Indications and Recommendations:
Fruquintinib is recommended as a subsequent therapy option for patients with mCRC who have progressed following standard treatments. Specifically, the NCCN guidelines include fruquintinib as a category 2A recommendation for patients who have received prior therapies, including:
Fluoropyrimidine-based chemotherapy
Oxaliplatin-based chemotherapy
Irinotecan-based chemotherapy
An anti-VEGF therapy
If RAS wild-type and medically appropriate, an anti-EGFR therapy
This recommendation is based on evidence demonstrating the efficacy of fruquintinib in improving overall survival and progression-free survival in patients with refractory mCRC.
Dosage and Administration:
The NCCN guidelines specify the dosing regimen for fruquintinib as follows:
Administer 5 mg orally once daily on days 1 through 21 of each 28-day cycle.
This schedule allows for a 7-day rest period between cycles.
Dose adjustments may be necessary based on individual patient tolerability and the occurrence of adverse events.
Safety and Monitoring:
The NCCN emphasizes the importance of monitoring for potential adverse events associated with fruquintinib, including:
Hypertension: Monitor blood pressure regularly and manage according to standard guidelines.
Proteinuria: Assess urine protein levels periodically; consider dose modifications if significant proteinuria occurs.
Hand-foot syndrome: Monitor for symptoms and provide supportive care as needed.
Hepatotoxicity: Regularly evaluate liver function tests during treatment.
These monitoring strategies are crucial to ensure patient safety and optimize therapeutic outcomes.
Clinical Considerations:
When considering fruquintinib for treatment, the NCCN guidelines suggest evaluating the following factors:
Patient performance status
Comorbid conditions
Prior treatment history
Potential drug-drug interactions
Sources:
Conclusion
Fruquintinib represents a significant advancement in the treatment of metastatic colorectal cancer, offering a targeted approach with demonstrated efficacy and a manageable safety profile. Its role in the therapeutic landscape provides oncologists with an additional option for patients who have limited treatment alternatives. Ongoing research and clinical trials continue to explore its potential in combination therapies and other tumor types, aiming to expand its applicability in oncology.
Commenti