Introduction

Colorectal cancer (CRC) is the third most common cause of cancer and the second most common cause of cancer-related death worldwide. Despite increasing survival rates, metastatic CRC (mCRC) remains a lethal disease with a 5-year survival rate of around 14%.¹ Currently, first-line treatment relies on a chemotherapy combination including conventional fluorouracil-based chemotherapy, and more recently, targeted therapies have been developed for specific molecular subtypes and primary tumor sidedness.² Later-line nonselective treatments include the oral agents trifluridine-tipiracil and regorafenib; however, there is still an unmet need for safe and effective treatments for patients with mCRC.³

On November 8, 2023, the FDA approved fruquintinib (Fruzaqla, Takeda Pharmaceuticals, Inc) for adult patients with mCRC who had received prior fluoropyrimidine-, oxaliplatin-, and irinotecan-based chemotherapy; an anti–vascular endothelial growth factor (VEGF) therapy; and, if RAS wild type and medically appropriate, an anti–epidermal growth factor receptor (EGFR) therapy.⁴ Fruquintinib is the first chemotherapy-free targeted oral therapy approved for mCRC regardless of biomarker status or prior types of therapies in more than 10 years.⁵ The recommended fruquintinib dose is 5 mg orally once daily, with or without food, for the first 21 days of each 28-day cycle until disease progression or unacceptable toxicity.⁶

Mechanism of Action

The VEGF pathway is vital to the neoangiogenesis associated with tumor proliferation. Antiangiogenic agents that target the VEGF pathway can inhibit either the ligand (VEGF inhibitors) or its receptor (VEGF receptor [VEGFR] inhibitors). These agents play a role in inhibiting the growth of new blood vessels, leading to vascular regression, tumor vessel normalization, and constriction. Fruquintinib is a VEGFR inhibitor that blocks new blood vessel growth associated with tumor proliferation. Fruquintinib is a potent, highly selective small-molecule inhibitor of VEGFR-1, -2, and -3.^7-9

Clinical Trials

Efficacy and FDA approval were based on 2 phase III trials, FRESCO (NCT02314819) and FRESCO-2 (NCT04322539).

FRESCO (NCT02314819), a multicenter, placebo-controlled trial conducted in China, evaluated 416 patients with mCRC who had disease progression during or after prior fluoropyrimidine-, oxaliplatin, and irinotecan-based chemotherapy. Most patients had multiple metastases, with liver metastases present in 185 of 278 (66.5%) in the fruquintinib group and 102 of 138 (73.9%) in the placebo group.¹⁰ FRESCO-2 (NCT04322539), an international, multicenter, randomized, double-blind, placebo-controlled trial, evaluated 691 patients with mCRC who had disease progression during or after prior fluoropyrimidine-, oxaliplatin-, and irinotecan-based chemotherapy; an anti-VEGF biological therapy; an anti-EGFR biological therapy if RAS wild type; and at least one of trifluridine-tipiracil or regorafenib. In the overall population, 436 of 691 patients (63%) had a tumor with a RAS mutation, and 495 (72%) had liver metastases.¹¹

In both trials, patients were randomly allocated (2:1) to either fruquintinib 5 mg orally once daily or placebo for the first 21 days of each 28-day cycle plus best supportive care. Patients received therapy until disease progression or unacceptable toxicity. Overall survival (OS) was the major efficacy outcome in both trials.

Table 1. Primary Outcomes in FRESCO and FRESCO-2

Figure 1. Kaplan-Meier Estimates for Overall Survival in Patients with Metastatic Colorectal Cancer Receiving Fruquintinib vs Placebo (intent-to-treat population) in FRESCO

Figure 2. Kaplan-Meier Estimates of Overall Survival in the Intent-to-Treat Population in FRESCO-2

Adverse Effects

The most common adverse reactions (reported in 20% or more of patients) were hypertension, asthenia, hand-foot syndrome, proteinuria, dysphonia, abdominal pain, and diarrhea. In FRESCO, grade 3 or higher toxicity was higher for fruquintinib than for placebo (61% vs 19%).⁹ In FRESCO-2, the grade 3 or higher toxicity rate was higher for fruquintinib than for placebo (63% vs 50%). Common grade 3 or higher toxicities for fruquintinib included hypertension (14%), asthenia (8%), and hand-foot syndrome (6%).¹⁰

Table 1. Adverse Events in FRESCO

Table 2. Adverse Events in FRESCO-2

Conclusion

Fruquintinib, a novel chemotherapy-free oral targeted therapy, has gained approval for mCRC without consideration of biomarker status or prior treatment types. In 2 phase III clinical trials, the combination of fruquintinib with best supportive care showed significant enhancements in OS and corresponding improvements in progression-free survival compared with placebo plus best supportive care. These findings provide substantial support for considering fruquintinib as a viable global treatment for patients dealing with refractory mCRC. Further analysis of quality-of-life data will contribute to solidifying the clinical benefits of fruquintinib within this specific patient population. Additional comparative studies against other later-line treatments would also be beneficial in determining the optimal place in therapy for this novel medication.

References

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