Regulatory Decision Summary for Fruzaqla

The purpose of the New Drug Submission (NDS) for Fruzaqla was to obtain market authorization for the treatment of adult patients with metastatic colorectal cancer (mCRC) who had previously received treatment or were not considered candidates for available therapies. These therapies included fluoropyrimidine-, oxaliplatin-, and irinotecan-based chemotherapy, an anti-vascular endothelial growth factor (VEGF) agent, and an anti-epidermal growth factor receptor (EGFR) agent.

Upon review of the submitted data package, Health Canada authorized Fruzaqla for the treatment of adult patients with mCRC who had previously received treatment or were not considered candidates for available standard therapies, including fluoropyrimidine-, oxaliplatin-, and irinotecan-based chemotherapy, an anti-VEGF agent, an anti-EGFR agent (if RAS wild-type), and either trifluridine-tipiracil or regorafenib.

This submission was reviewed using the international review work-sharing model with the Access Consortium. Health Canada collaborated with the Therapeutic Goods Administration (Australia), Swissmedic (Switzerland), the Medicines and Healthcare products Regulatory Agency (United Kingdom), and the Health Sciences Authority (Singapore) via the New Chemical Entities Work Sharing Initiative (NCEWSI).

The pivotal clinical trial (FRESCO-2) was a global, randomized (2:1), double-blind, placebo-controlled, multicenter, phase 3 study designed to compare the efficacy and safety of Fruzaqla (fruquintinib) in combination with best supportive care (BSC) versus placebo in combination with BSC in adult patients with metastatic colorectal cancer (mCRC) who had progressed on or were intolerant to chemotherapy, biologics, and trifluridine/tipiracil and/or regorafenib. The study was well balanced with respect to patient demographics and disease characteristics.

A key supportive study (FRESCO), a phase 3 trial conducted in China, also evaluated Fruzaqla in mCRC patients. The primary endpoint in both studies was overall survival (OS), and the key secondary endpoint was progression-free survival (PFS).

The pivotal study met its primary endpoint, demonstrating a statistically significant improvement in OS in the Fruzaqla arm (7.4 months) compared to the placebo arm (4.8 months), corresponding to a 34% reduction in the risk of death. In this highly pretreated population with limited treatment options, the 2.6-month survival benefit was considered clinically meaningful. The study also met its key secondary endpoint, showing a statistically significant improvement in PFS in the Fruzaqla arm (3.7 months) compared to the placebo arm (1.8 months), resulting in a 68% reduction in the risk of progression or death. Consistent OS and PFS trends favouring Fruzaqla were observed across all analyzed subgroups. Results from the supportive study were consistent with those of the pivotal trial.

The safety assessment identified significant risks associated with Fruzaqla treatment in mCRC patients, including cardiovascular (hypertension), gastrointestinal (perforation), hepatic (elevated transaminases and bilirubin), infections, neurologic (posterior reversible encephalopathy syndrome), impaired wound healing, renal (proteinuria), reproductive (teratogenicity and fertility impairment), skin (palmar-plantar erythrodysesthesia syndrome), and vascular (arterial thromboembolic events, hemorrhage, aneurysms, and artery dissection). These risks are consistent with those observed with other vascular endothelial growth factor (VEGF) inhibitors. No new or unexpected safety signals were identified in the pivotal or supportive trials. All significant safety risks are clearly highlighted in the Adverse Reactions table, Warnings and Precautions, and Post Market Adverse Reactions sections of the Fruzaqla Product Monograph. These risks are considered manageable through dose modification, discontinuation, and standard medical practice, as demonstrated in the clinical trials. Risk mitigation strategies are outlined in the Product Monograph.

Clinical pharmacology and non-clinical data supported the intended use of Fruzaqla in the target population. Relevant risks and uncertainties were adequately addressed in the final Product Monograph.

The submission was considered to comply with the Quality data requirements of Section C.08.002 of the Food and Drug Regulations. The labelling documents conformed to regulatory requirements and were consistent with applicable guidance documents. A Risk Management Plan for Fruzaqla was submitted and deemed acceptable.

In conclusion, the pivotal study met its primary endpoint, supported by consistent subgroup analyses, the key secondary endpoint, and the supportive study. The safety profile was consistent with other VEGF inhibitors, and key safety concerns were sufficiently labelled and considered manageable. Fruzaqla was determined to have a positive benefit-risk profile under the proposed conditions of use.

For further details about Fruzaqla, please refer to the Product Monograph, approved by Health Canada and available through the Drug Product Database.