Zenocutuzumab Shows Durable Efficacy in NRG1 Fusion-Positive Cancers in Phase II eNRGy Trial

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Results of the multinational Phase II eNRGy trial (NCT02912949) show that zenocutuzumab (Bizengri) produced durable antitumor activity across multiple tumor types in patients with advanced neuregulin 1 (NRG1) fusion–positive cancer, particularly those with non-small cell lung cancer (NSCLC) and pancreatic cancer. The study authors noted that the findings support NRG1 fusions as a viable treatment target for this type of cancer.^1,2

“In the eNRGy study, efficacy was observed in multiple cancer types, which supports the potential of zenocutuzumab as a therapy for NRG1 fusion–positive cancer involving any tumor type,” the study authors wrote. “Patient enrollment was substantially higher for NSCLC and pancreatic cancer than for other tumor types, and additional data could clarify the effect of histologic type on efficacy.”¹

Zenocutuzumab is a bispecific antibody that targets and attaches to HER2 and HER3 on the surface of malignant cells and tumor cells, which stops NRG1 from attaching to HER3. In preclinical mammalian studies, zenocutuzumab was found to lower cell proliferation and signaling through the phosphoinositide 3-kinase-AKT-mammalian targeted rapamycin pathway. Further, testing in mouse models with NRG1-positive disease showed antitumor activity in both lung and pancreatic cancers, along with mediation of antibody-dependent cellular cytotoxicity.³

In December 2024, the FDA granted zenocutuzumab with accelerated approval for adults with unresectable or metastatic NSCLC harboring NRG1 gene fusion with disease progression on or after prior systemic therapy, or advanced, unresectable, or metastatic pancreatic ductal adenocarcinoma harboring an NRG1 gene fusion with disease progression on or after prior systemic therapy.⁴

Trial Design

The registrational, open-label eNRGy trial enrolled 204 patients with 12 different tumor types with advanced NRG1 fusion–positive cancer across 49 centers in 12 countries. Patients were administered zenocutuzumab at a dose of 750 mg intravenously every two weeks until occurrence of disease progression, death, unacceptable toxic effects, or withdrawal of consent. The trial’s primary endpoint was overall response (complete or partial response) as per investigator assessment, with secondary endpoints that included duration of response (DOR), progression-free survival (PFS), and safety.

Investigators observed a response in 30% (95% confidence interval [CI], 23 to 37) of 158 patients with measurable disease who were enrolled at least 24 weeks prior to the data-cutoff date. Median DOR was 11.1 months (95% CI, 7.4 to 12.9), with 19% of responses ongoing at the data-cutoff date.

Responses were observed in 27 of 93 patients (29%; 95% CI, 20 to 39) with NSCLC and in 15 of 36 patients (42%; 95% CI, 25 to 59) with pancreatic cancer, as well as across multiple NRG1 fusion partners. Median PFS was 6.8 months (95% CI, 5.5 to 9.1).

In terms of safety, adverse events (AEs) were primarily grade 1 or 2, with the most common AEs associated with zenocutuzumab being diarrhea (18%), fatigue (12%), and nausea (11%). One patient discontinued zenocutuzumab as a result of treatment-related AEs.

“In the multinational eNRGy study, zenocutuzumab, a bispecific antibody against HER2 and HER3, showed durable antitumor activity in patients with NRG1 fusion–positive cancer,” the study authors concluded. “NRG1 fusions are unique cancer drivers that create oncogenic chimeric ligands rather than the more widely described chimeric receptors (NTRK, RET, ROS1, ALK, and FGFR fusions). No targeted therapy for NRG1 fusion–positive cancer is approved. This clinical study targeted cancers with this rare genomic alteration, a population enriched for cancer types with limited effective treatment options.”¹

References

1. Schram A., et al. Efficacy of Zenocutuzumab in NRG1 Fusion–Positive Cancer. N Engl J Med 2025;392:566-576. DOI: 10.1056/NEJMoa2405008. Vol. 392 No. 6.

2. A Study of Zenocutuzumab (MCLA-128) in Patients With Solid Tumors Harboring an NRG1 Fusion (eNRGy). ClinicalTrials.gov. Updated February 3, 2025. Accessed February 13, 2025. https://clinicaltrials.gov/study/NCT02912949

3. Merus announces fda approval of bizengri® (zenocutuzumab-zbco) for nrg1+ pancreatic adenocarcinoma and nrg1+ non–small cell lung cancer (nsclc) based on safety and efficacy data from the enrgy study. Merus. December 4, 2024. Accessed February 13, 2025. https://ir.merus.nl/news-releases/news-release-details/merus-announces-fda-approval-bizengrir-zenocutuzumab-zbco-nrg1

4. FDA grants accelerated approval to zenocutuzumab-zbco for non-small cell lung cancer and pancreatic adenocarcinoma. FDA. December 4, 2024. Accessed February 13, 2025. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-accelerated-approval-zenocutuzumab-zbco-non-small-cell-lung-cancer-and-pancreatic