FDA Extends Review Period for Zenocutuzumab in NRG1+ PDAC, NSCLC

The extended action date may allow for sufficient time to review information that developers have submitted in response to a Chemistry, Manufacturing, and Controls request from the agency. The agency has requested no additional clinical data to support the application.

The FDA has extended its review period for a biologics license application (BLA) seeking approval of zenocutuzumab in NRG1 fusion–positive cancer, according to a news release from the developers, Merus N.V.¹

The agency has extended the Prescription Drug User Fee Act date to February 4, 2025, for zenocutuzumab in this indication. The extended action date may allow for sufficient time to review information that developers have submitted in response to a Chemistry, Manufacturing, and Controls request from the agency. The agency has requested no additional clinical data to support the application.

Previously, the FDA granted priority review to zenocutuzumab as a treatment for patients with non–small cell lung cancer (NSCLC) or pancreatic ductal adenocarcinoma (PDAC) harboring NRG1 fusions in May 2024.² Supporting data for the application came from the phase 1/2 eNRGy trial (NCT02912949) evaluating the safety and antitumor activity of the agent among patients with various NRG1 fusion–positive solid tumors.

According to data presented at the 2023 European Society for Medical Oncology (ESMO) Congress, zenocutuzumab produced a confirmed objective response rate (ORR) of 44% (95% CI, 26%-65%) among 27 evaluable patients with NRG1 fusion–positive PDAC.³ These responses consisted of 1 complete response and 11 partial responses. Target lesion reduction occurred in 81% (n = 22/27) of patients.

Regarding safety in the PDAC population, grade 3 or higher adverse effects (AEs) were reported in less than 5% of patients. Data showed that no treatment-related AEs (TRAEs) resulted in discontinuation of zenocutuzumab.

Treatment with zenocutuzumab yielded an ORR of 34% (95% CI, 23%-47%) among 64 evaluable patients with NRG1 fusion–positive NSCLC.⁴ Target lesion reduction also occurred in 78% (n = 50/64) of patients.

Of 85 patients in the safety population, grade 3 or higher AEs occurred in less than 4% of patients. Additionally, no patients discontinued therapy with zenocutuzumab due to TRAEs.

“FDA acceptance of our first BLA represents an important achievement for Merus and an important potential treatment opportunity for patients with NRG1-positive cancer, a disease with poor prognosis and high unmet need. Zenocutuzumab has the potential to be the first and only targeted therapy for patients with NRG1-positive lung and pancreatic cancer, and may offer a substantial improvement over currently available therapies,” Andrew Joe, MD, chief medical officer at Merus, stated at the time of the agent’s priority review status being granted.²

In the open-label, multicenter, international, dose-escalation eNRGy trial, patients will receive zenocutuzumab intravenously at 750 mg every 2 weeks.⁵ The trial will include 3 cohorts: a PDAC harboring NRG1 fusions group, an NRG1 fusion–positive NSCLC group, and a basket cohort including various solid tumor types harboring NRG1 fusions.

The trial’s primary end points are ORR and DOR based on RECIST v1.1 criteria per local investigator assessment. Secondary end points include clinical benefit rate, time to response, progression-free survival, overall survival, safety and tolerability, and maximum plasma concentration.

Patients 18 years and older with at least 1 measurable lesion based on RECIST v1.1 guidelines, an estimated life expectancy of 12 weeks or longer, and an ECOG performance status of 0 to 2 are eligible for enrollment on the trial. Having a locally advanced unresectable or metastatic solid tumor malignancy harboring a documented NRG1 fusion was another requirement for study entry.

The FDA previously granted fast track designation to zenocutuzumab as a therapy for those with metastatic solid tumors harboring NRG1 fusions in January 2021.⁶ Additionally, zenocutuzumab earned breakthrough therapy designation from the FDA as a treatment for patients with NRG1 fusion–positive pancreatic cancer in June 2023.⁷

References

1. Merus receives FDA extension of PDUFA for zenocutuzumab. News release. Merus N.V. November 5, 2024. Accessed November 5, 2024. https://tinyurl.com/mjhn6a84
2. Merus announces U.S. FDA acceptance and priority review of biologics license application for Zeno for the treatment of NRG1+ NSCLC and PDAC. News release. Merus N.V. May 6, 2024. Accessed November 5, 2024. https://tinyurl.com/y49dppxu
3. Schram A, Macarulla T, Cleary J, et al. 1618P Durable efficacy of zenocutuzumab, a HER2 x HER3 bispecific antibody, in advanced NRG1 fusion positive (NRG1+) pancreatic ductal adenocarcinoma (PDAC). Ann Oncol. 2023;34(suppl 2):S895-S896. doi:10.1016/j.annonc.2023.09.2567
4. Schram A, Goto K, Kim D-W, et al. 1315MO Durable efficacy of zenocutuzumab, a HER2 x HER2 bispecific antibody, in advanced NRG1 fusion-positive (NRG1+) non-small cell lung cancer (NSCLC). Ann Oncol. 2023;34(suppl 2):D756-S757. doi:10.1016/j.annonc.2023.09.2349
5. A study of zenocutuzumab (MCLA-128) in patients with solid tumors harboring an NRG1 fusion (eNRGy). ClinicalTrials.gov. Accessed November 5, 2024. https://tinyurl.com/ydz8abr
6. Merus granted FDA fast track designation of zenocutuzumab for the treatment of patients with neuregulin 1 fusion cancers. News release. Merus N.V. January 7, 2021. Accessed November 5, 2024. https://tinyurl.com/yms65mue
7. Zenocutuzumab (Zeno) granted breakthrough therapy designation by the U.S. Food & Drug Administration for the treatment of NRG1+ pancreatic cancer. News release. Merus N.V. June 29, 2023. Accessed November 5, 2024. https://shorturl.at/iGRX2