Zenocutuzumab Earns FDA Priority Review in NRG1+ NSCLC, Pancreatic Cancer

Supporting data for the BLA came from the phase 1/2 eNRGy trial (NCT02912949), in which investigators are assessing the antitumor activity and safety of zenocutuzumab in patients with various NRG1 fusion–positive solid tumors, including those with NSCLC or PDAC.

The FDA has granted priority review to a biologics license application (BLA) for zenocutuzumab as a treatment for patients with NRG1 fusion–positive non–small cell lung cancer (NSCLC) and pancreatic ductal adenocarcinoma (PDAC), according to a press release from the developers, Merus.¹

Developers noted that the investigational bispecific antibody is still under clinical development; no regulatory authority has fully evaluated the agent’s efficacy and safety.

“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,” Andrew Joe, MD, chief medical officer at Merus, said in the press release.¹ “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.”

Supporting data for the BLA came from the phase 1/2 eNRGy trial (NCT02912949), in which investigators are assessing the antitumor activity and safety of zenocutuzumab in patients with various NRG1 fusion–positive solid tumors, including those with NSCLC or PDAC. Updated findings from the trial were presented at the 2023 European Society for Medical Oncology (ESMO) Congress.

Among 64 evaluable patients with NRG1 fusion–positive NSCLC, treatment with zenocutuzumab yielded an objective response rate (ORR) of 34% (95% CI, 23%-47%), with target lesion reductions reported in 78% of patients.² Additionally, the median duration of response (DOR) was 12.9 months, with ongoing responses highlighted in 50% of patients at the time of the analysis. According to a Kaplan-Meier estimate, 79% of patients had responses lasting for 6 months.

Grade 3 or higher adverse effects (AEs) affected less than 4% of patients in the NSCLC cohort of the trial. Investigators noted that no patients discontinued study treatment due to treatment-related AEs.

In the open-label, international phase 1/2 eNRGy trial, patients with PDAC, NSCLC, or other solid tumors harboring an NRG1 fusion were assigned to receive zenocutuzumab intravenously at the recommended phase 2 dose of 750 mg every 2 weeks.³

The trial’s primary end points are ORR and DOR per investigator assessment using RECIST v1.1 guidelines. Secondary end points include ORR per central review, clinical benefit rate, time to response, safety and tolerability, and the maximum plasma concentration of zenocutuzumab.

Patients 18 years and older with 1 or more measurable lesions per RECIST v1.1 guidelines, an ECOG performance status of 0 to 2, and a minimum estimated life expectancy of 12 weeks were eligible for enrollment on the trial. Additional eligibility criteria included having adequate absolute neutrophil counts, platelet counts, and hemoglobin counts; recovery from any prior major surgery; and availability of a tumor biopsy sample.

Those with an active uncontrolled infection or unexplained fever or known hypersensitivity to any of the components of zenocutuzumab were ineligible for enrollment on the trial. Patients were also unsuitable for enrollment if they had leptomeningeal metastases, known human immunodeficiency virus or active hepatitis B or C, or a prior or concurrent malignancy apart from those that have been managed with curative intent more than 2 years before study entry.

Previously, the FDA granted fast track designation to zenocutuzumab for patients with metastatic NRG1 fusion–positive solid tumors in January 2021.⁴

Additionally, the FDA granted breakthrough therapy designation to zenocutuzumab in NRG1 fusion–positive pancreatic cancer in June 2023.⁵ Supporting data for the breakthrough therapy designation in this population came from the eNRGy trial and an Early Access Program (NCT04100694).

References

1. 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 May 7, 2024. https://tinyurl.com/y49dppxu
2. 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
3. A study of zenocutuzumab (MCLA-128) in patients with solid tumors harboring an NRG1 fusion (eNRGy). ClinicalTrials.gov. Accessed May 7, 2024. https://tinyurl.com/ydz8abrj
4. 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 May 7, 2024. https://tinyurl.com/yms65mue
5. 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 May 7, 2024. https://shorturl.at/iGRX2