European Medicines Agency Validates MAA for Fruquintinib in Pretreated mCRC

The European Medicines Agency (EMA) has validated and accepted a marketing authorization application (MAA) for priority review for fruquintinib for the treatment of adult patients with pretreated metastatic colorectal cancer (mCRC).¹

Fruquintinib is a highly selective and potent VEGF1/2/3 inhibitor, which if approved, will be the first and only highly selective inhibitor of all 3 VEGF receptors approved for use in this population in the European Union.

The MAA is based on findings from the phase 3 FRESCO-2 trial (NCT04322539) conducted in the United States, Europe, Japan, and Australia, in addition to results from the phase 3 FRESCO trial (NCT02314819) conducted in China. In FRESCO-2, the addition of fruquintinib to best supportive care (BSC) led to a statistically significant and clinically meaningful improvement in overall survival (OS) and progression-free survival (PFS) vs placebo plus BSC in patients with previously treated mCRC (OS: HR, 0.662; 95% CI, 0.549-0.800; P <.001; PFS: HR, 0.321; 95% CI, 0.267-0.386; P <.001). Median PFS and OS were 3.7 months (95% CI, 3.5-3.8) and 7.4 months (95% CI, 6.7-8.2) with fruquintinib vs 1.8 months (95% CI, 1.8-1.9) and 4.8 months (95% CI, 4.0-5.8) with placebo.²

In FRESCO, treatment with fruquintinib led to an improvement in OS vs placebo as third- or later-line therapy in patients who had received at least 2 prior lines of chemotherapy, with medians of 9.3 months (95% CI, 8.2-10.5) and 6.6 months (95% CI, 5.9-8.1), respectively (HR, 0.65; 95% CI, 0.51-0.83; P < .001). Median PFS was also improved with fruquintinib, at 3.7 months (95% CI, 3.7-4.6) vs 1.8 months (95% CI, 1.8-1.8) with placebo (HR, 0.26; 95% CI, 0.21-0.34; P < .001).³

“European patients with metastatic colorectal cancer have not benefitted from a treatment advancement in over a decade,” Awny Farajallah, MD, head of Global Medical Affairs Oncology at Takeda, stated in a press release. “We are thrilled to have submitted the marketing authorization application to the EMA, bringing us one step closer to potentially offering this innovative therapy to patients with advanced disease. We believe fruquintinib has the potential to address the longstanding unmet need for patients with previously treated metastatic colorectal cancer regardless of their biomarker status, and we look forward to working with the regulators throughout the process.”

Previously, on May 25, 2023, the FDA accepted and granted priority review to a new drug application for fruquintinib, assigning a Prescription Drug User Fee Act goal date of November 30, 2023.⁴

FRESCO-2 enrolled patients with mCRC who received prior chemotherapy comprised of fluoropyrimidine, oxaliplatin, or irinotecan; a VEGF inhibitor; and an EGFR inhibitor if they had RAS wild-type disease. Eligibility criteria stipulated that patients were required to have experienced disease progression on or been intolerant to trifluridine/tipiracil (TAS-102; Lonsurf) and/or regorafenib (Stivarga).²

FRESCO was a randomized, double-blind, placebo-controlled, multicenter trial that enrolled patients with China who had histologically or cytologically confirmed mCRC that progressed after at least 2 standard chemotherapy regimens that included fluoropyrimidine, oxaliplatin, and irinotecan.³

The safety profile of fruquintinib in both trials was comparable. In FRESCO-2, the most common grade 3 or higher treatment-emergent adverse effects (TEAEs) in the investigational and control arms were hypertension (13.6% vs 0.9%), asthenia (7.7% vs 3.9%), reduced appetite (2.4% vs 1.3%), diarrhea (3.5% vs 0%), hypothyroidism (0.4% vs 0%), fatigue (3.9% vs 0.9%), hand-foot syndrome (6.4% vs 0%), abdominal pain (3.1% vs 3.0%), nausea (0.7% vs 0.9%), proteinuria (1.8% vs 0.9%), and constipation (0.4% vs 0%).

In FRESCO, the most common grade 3 or higher TEAEs in the investigational and control arms were hypertension (21.2% vs 2.2%), hand-foot skin reaction (10.8% vs 0%), proteinuria (3.2% vs 0%), decreased platelet count (2.5% vs 0%), diarrhea (2.9% vs 0%), increased bilirubin (1.4% vs 1.5%), decreased appetite (1.1% vs 0%), fatigue (1.1% vs 0%), weight loss (1.1% vs 0%), ALT level elevation (0.7% vs 1.5%), and AST level elevation (0.4% vs 0.7%).

“Based on fruquintinib’s clinical profile to date, we are optimistic about its potential as a choice for patients and physicians in the EU who find treatment options to be limited for previously treated metastatic colorectal cancer,” Dr Michael Shi, head of R&D and chief medical officer, HUTCHMED, said. “We believe the EMA validation of the marketing authorization application for fruquintinib represents an exciting initial step toward advancing treatment for patients in Europe and look forward to supporting Takeda as it pursues this goal.”

References

1. Takeda and HUTCHMED Announce Marketing Authorization Application of Fruquintinib for Previously Treated Metastatic Colorectal Cancer Validated by the European Medicines Agency. News release. June 15, 2023. Accessed June 16, 2023. https://www.takedaoncology.com/news/news-releases/takeda-and-hutchmed-announce-marketing-authorization-application-of-fruquintinib/
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):S1391-S1392. doi:10.1016/j.annonc.2022.08.021
3. Li J, Qin S, Xu RH, et al. Effect of fruquintinib 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
4. Takeda and HUTCHMED announce new drug application (NDA) for fruquintinib for treatment of previously treated metastatic colorectal cancer granted priority review. News release. Takeda. May 25, 2023. Accessed June 16, 2023. https://www.takedaoncology.com/news/news-releases/takeda-and-hutchmed-announce-new-drug-application-for-fruquintinib-for-treatment-of-previously-treated-metastatic-colorectal-cancer-granted-priority-review/