Fruquitinib Receives FDA Fast Track Designation for Metastatic Colorectal Cancer

The FDA has granted a Fast Track Designation to fruquitinib for the treatment of patients with metastatic colorectal cancer (CRC) who have received prior fluoropyrimidine-, oxaliplatin-, and irinotecan-based chemotherapy and anti-VEGF therapy, as well as anti-EGFR therapy for RAS wild-type tumors, announced Chi-Med.¹

A phase 3 registration trial, FRESCO-2 (NCT04322539) has been initiated to evaluate fruquitinib in patients with refractory metastatic CRC. The trial will be conducted in the United States, Europe, and Japan, and enrollment will begin in mid-2020.

If FRESCO-2 is positive, along with the positive phase 3 FRESCO trial results and additional completed or ongoing supportive studies, these data may support a New Drug Application (NDA) for fruquitinib for the treatment of patients with metastatic CRC in the third-line setting. Data supporting the specific indication would be reviewed during the review of the NDA.

Fruquitinib previously received approval from the China National Medical Products Administration for the same indication in 2018, based on findings from the FRESCO study. According to the results of the pivotal FRESCO trial, fruquitinib led to a statistically significant increase in overall survival (OS) compared with placebo.²

Overall, 416 patients were randomized to receive either fruquitinib (n = 278) or placebo (n = 138) plus best supportive care. The mean age of patients was 54.6 years and 38.7% were female. The disease characteristics, baseline demographics, and prior treatments appeared similar between the experimental and control arms in this study, but investigators noted there was a higher proportion of male patients in the placebo group.

The median OS was 9.30 months with the study drug (95% CI, 8.18-10.45) compared with 6.57 months (95% CI, 5.88-8.11) with placebo (HR, 0.65; 95% CI, 0.51-0.83; P <.001). The median OS was similar in the per-protocol set at 9.30 months with fruquitinib (95% CI, 8.18-10.45) versus 6.80 months (95% CI, 5.91-8.38) with placebo (HR, 0.66; 95% CI, 0.52-0.85; P = .001).

Progression-free survival appeared to be significantly improved with the study drug, inducing a median progression-free survival of 3.71 months (95% CI, 3.65-4.63) with fruquitinib versus 1.84 months (95% CI, 1.81-1.84) with placebo (HR, 0.26; 95% CI, 0.21-0.34; P <.001).

FRESCO also evaluated OS in subgroup analyses, in which similar benefit was observed among those with prior VEGF inhibitor treatment compared with the intention-to-treat population (HR, 0.68; 95% CI, 0.45-1.03). There did not appear to be a significant OS difference between fruquitinib and placebo among female patients (HR, 0.85; 95% CI, 0.57-1.29), patients who were 65 years or older (HR, 0.96; 95% CI, 0.55-1.63), and those with right-sided tumors (HR, 0.96; 95% CI, 0.53-1.75).

The objective response rate was also significantly higher with fruquitinib at 4.7% versus 0% with placebo (95% CI, 2.1-7.2; P = .01). The disease control rate with the study drug was 62.2% versus 12.3% with placebo (treatment difference, 49.9%; 95% CI, 42.0%-57.8%; P <.01).

The median exposure to treatment time was 3.7 months (range, 0.1-21.9) for fruquitinib versus 1.8 months for placebo (range, 0.1-11.1), and the mean dose intensity was 92% versus 98%, respectively. Median relative dose intensity was 100% for both fruquitinib and placebo.

Overall, 61.2% of patients in the fruquitinib arm and 19.7% in the placebo arm experienced treatment-emergent adverse events (AEs) of grade 3 severity or higher. Serious AEs were observed in 15.5% of the fruquitinib arm versus 5.8% of the placebo arm, and 14.4% of patients versus 5.1%, respectively, required hospitalization or prolongation of an existing hospital stay for the management of an AE. Fatal treatment-emergent AEs were reported in 9 patients in the experimental arm and 2 from the placebo arm. Forty-patients (15.1%) discontinued treatment with fruquitinib due to treatment-emergent AEs, most often due to proteinuria, and 8 (5.8%) discontinued placebo.

The most common grade 3/4 AEs in the fruquitinib arm included hypertension (21.2%), hand-foot skin reaction (10.8%), and proteinuria (3.2%), and grade 3 hepatic toxicities were noted in 1.5% of patients or less in both study arms.

After disease progression or study completion, 45.2% of patients received further systemic therapy, such as cytotoxic anticancer treatments, monoclonal antibodies, or kinase inhibitors, in the fruquitinib arm versus 50.7% in the placebo arm.

The purpose of the new FRESCO-2 trial is to evaluate the safety and efficacy of this agent in patients with refractory metastatic CRC, and the primary end point of the study is OS. Patients will be randomized to receive either fruquitinib plus best supportive care or placebo and best supportive care.

To be included in the study, patients must have progressed on or became intolerant to chemotherapy, biologics, and trifluridine/tipiracil (TAS-102; Lonsurf) or regorafenib (Stivarga), and must have previously received fluoropyrimidine-, oxaliplatin-, and irinotecan-based chemotherapy, an anti-VEGF biological agent, and, if RAS wild-type, an anti-EGFR therapy. For patients with tumors that are microsatellite-high or mismatch repair deficient, they must have received treatment, if eligible, with an immune checkpoint inhibitor, and patients who received oxaliplatin in the adjuvant setting must have progressed within 6 months of completing treatment. Patients must also weigh ≥40 kg, have an ECOG performance status of 0 or 1, measurable disease according to RECIST v1.1, and an expected survival of >12 weeks.

Among other criteria, patients are ineligible to enroll in the FRESCO-2 study if they have an absolute neutrophil count <1.5×109/L, a platelet count <100×109/L, or hemoglobin <9.0 g/dL, serum total bilirubin >1.5 x the upper limit of normal (ULN), and alanine aminotransferase or aspartate aminotransferase >2.5 × ULN in those without hepatic metastases.

This highly selective agent is a potent inhibitor of VEGFR1/2/3, which plays an important role in blocking tumor angiogenesis. The drug was designed to improve kinase selectivity and minimize off-target toxicities, as well as to improve tolerability and provide more consistent target coverage.¹

Based on preclinical data, fruquitinib had demonstrated good tolerability and the agent has low potential for drug-drug interactions, indicating that this agent may be appropriate for combination regimens as well.

References

Chi-Med announces fruquitinib granted US FDA fast track designation for metastatic colorectal cancer. News Release. Chi-Med. June 18, 2020. Accessed June 18, 2020. https://bit.ly/3hHNuCc

Li J, Qin S, Xu RH, et al. Effect of Fruquitinib vs Placebo on Overall Survival in Patients With Previously Treated Metastatic Colorectal Cancer: The FRESCO Randomized Clinical Trial. JAMA. 2018;319(24):2486-2496. doi:10.1001/jama.2018.7855