The FDA has extended the review period for the biologics license application (BLA) for zenocutuzumab, a drug developed by Merus N.V., for the treatment of NRG1 fusion-positive cancers. The Prescription Drug User Fee Act (PDUFA) date has been extended to February 4, 2025, to allow sufficient time for the agency to review additional information related to Chemistry, Manufacturing, and Controls (CMC) that the developers have submitted. The FDA has stated that no additional clinical data is required to support the application.
Clinical Trial Data and Efficacy
The BLA is supported by data from the phase 1/2 eNRGy trial (NCT02912949), an open-label, multicenter, international, dose-escalation study evaluating the safety and antitumor activity of zenocutuzumab in patients with various NRG1 fusion-positive solid tumors. The trial includes cohorts for pancreatic ductal adenocarcinoma (PDAC), non-small cell lung cancer (NSCLC), and a basket cohort for other solid tumors.
Data presented at the 2023 European Society for Medical Oncology (ESMO) Congress showed that zenocutuzumab achieved a confirmed objective response rate (ORR) of 44% (95% CI, 26%-65%) among 27 evaluable patients with NRG1 fusion-positive PDAC. These responses included 1 complete response and 11 partial responses, with target lesion reduction observed in 81% (n = 22/27) of patients. In 64 evaluable patients with NRG1 fusion-positive NSCLC, zenocutuzumab yielded an ORR of 34% (95% CI, 23%-47%), and target lesion reduction occurred in 78% (n = 50/64) of patients.
Safety Profile
In the PDAC population, grade 3 or higher adverse effects (AEs) were reported in less than 5% of patients, and no treatment-related AEs (TRAEs) led to discontinuation of zenocutuzumab. Among 85 patients in the safety population, grade 3 or higher AEs occurred in less than 4% of patients, and no patients discontinued therapy due to TRAEs.
Trial Design and Endpoints
The eNRGy trial involves intravenous administration of zenocutuzumab at 750 mg every 2 weeks. The primary endpoints are ORR and duration of response (DOR) based on RECIST v1.1 criteria per local investigator assessment. Secondary endpoints include clinical benefit rate, time to response, progression-free survival, overall survival, safety and tolerability, and maximum plasma concentration. Eligible patients are 18 years or older with at least one measurable lesion, an estimated life expectancy of 12 weeks or longer, and an ECOG performance status of 0 to 2, with locally advanced unresectable or metastatic solid tumors harboring a documented NRG1 fusion.
Regulatory Designations
Zenocutuzumab has received several designations from the FDA, including fast track designation in January 2021 for metastatic solid tumors harboring NRG1 fusions and breakthrough therapy designation in June 2023 for NRG1 fusion-positive pancreatic cancer. The FDA granted priority review to zenocutuzumab in May 2024 for NSCLC or PDAC harboring NRG1 fusions.
