NDA Rolling Submission for Fruquintinib in Colorectal Cancer Is Complete

Rolling submission of a new drug application for fruquintinib (Elunate) in refractory, metastatic colorectal cancer (CRC) was completed, and the application was submitted to the FDA, according to a press release from HUTCHMED.¹

"This FDA submission is a significant milestone for patients in the U.S. with metastatic CRC, one of the most common and deadly cancers in the US and worldwide,” according to the manufacturers of fruquintinib.

The highly selective, potent oral VEGFR1/2/3 inhibitor was supported by data from the phase 3 FRESCO-2 study (NCT04322539), which highlighted a median overall survival (OS) of 7.4 months with fruquintinib and best supportive care compared with 4.8 months with placebo (hazard ratio [HR], 0.66; 95% CI, 0.55-0.80; P <.001).² This translated to a 35% reduction in risk of death among patients in the experimental arm.

Additionally, the median progression-free survival (PFS) was 3.7 months vs 1.8 months in each respective arm (HR, 0.32; 95% CI, 0.27-0.39; P <.001). The median duration of follow-up was 11.3 months in the fruquintinib arm compared with 11.2 months in the placebo arm. The disease control rate (DCR) was 55.5% vs 16.1% and the overall response rate (ORR) was 1.5% vs 0.0% in each respective arm.

“This FDA submission is a significant milestone for patients in the U.S. with metastatic CRC, one of the most common and deadly cancers in the US and worldwide,” Michael Shi, MD, head of Research and Development and chief medical officer at HUTCHMED, said in a press release.

The oral VEGFR inhibitor is believed to play a valuable role in interfering with tumor angiogenesis. In particular, fruquintinib was designed to enhance kinase selectivity to decrease off-target toxicity, make treatment more tolerable, and yield more consistent target coverage. Thus far, the agent appears to be tolerable and is also being assessed in combination with other anti-cancer agents.

The double-blind, placebo-controlled study randomly assigned patients 2:1 to receive either fruquintinib or placebo at a dose of 5 mg every day using a 3 weeks on, 1 week off schedule.

Patients were required to have been previously treated with chemotherapy and an anti-VEGF agent. If the patient had RAS wild-type disease, they needed to have been treated with and anti-EGFR therapy and the BRAF V600E mutant or microsatellite instability–high population needed to have previously received at least 1 targeted regimen. Prior exposure to trifluridine/tipiracil (Lonsurf) and/or regorafenib (Stivarga) was also necessary.

The study’s primary end point was OS, with key secondary end points including PFS, ORR, DCR, and safety.

Grade 3 or higher adverse effects occurred in 62.7% of those in the fruquintinib group compared with 50.4% of patients in the placebo group. In each respective arm, the most common high-grade AEs occurring in 5% or more of patients were hypertension (13.6% vs 0.9%), asthenia (7.7% vs 3.9%), and hand-food syndrome (6.4% vs 0.0%).

Applications for the agent are also anticipated to be submitted in Europe and Japan in 2023.

Fruquintinib has also demonstrated promise in combination with paclitaxel for second-line advanced gastric and gastroesophageal junction adenocarcinoma, resulting in a statistically significant and clinically meaningful PFS improvement.³ According to data from the phase 3 FRUTIGA study (NCT03223376), while significant benefit was also observed across several secondary end points, OS—the study's co-primary end point—benefit was not statistically significant despite some improvement.

References

1. HUTCHMED completes rolling submission of NDA to U.S. FDA for fruquintinib for the treatment of refractory metastatic colorectal cancer. News release. HUTCHMED. March 30, 2023. Accessed April 3, 2023. http://bit.ly/3Gcody3
2. Dasari NA, Lonardi S, Garcia-Carbonero R, et al. FRESCO-2: a global phase III multiregional clinical trial (MRCT) evaluating the efficacy and safety of fruquintinib in patients with refractory metastatic colorectal cancer. Ann Oncol. 2022;33(suppl 7):S808-S869. doi:10.1016/annonc/annonc1089
3. HUTCHMED announces positive topline result in fruquintinib phase III FRUTIGA study in second-line gastric cancer in China. News release. HUTCHMED. November 14, 2022. Accessed April 3, 2023. http://bit.ly/3hMtJyd