In a registrational, multinational, phase II eNRGy study, zenocutuzumab, a bispecific antibody against HER2 and HER3, showed durable antitumour activity in patients with NRG1 fusion-positive cancers, notably non-small cell lung cancer (NSCLC) and pancreatic cancer. Responses were observed across multiple fusion partners.
This study targeted cancers with this rare genomic alteration, a population enriched for cancer types with limited effective treatment options. The findings validate NRG1 fusions as an actionable therapeutic target according to Dr. Alison M. Schram of the Memorial Sloan Kettering Cancer Center in New York, NY, US and colleagues who published the findings on 5 February 2025 in The New England Journal of Medicine.
The authors wrote in the background that NRG1 fusions occur in less than 1% of solid tumours, are enriched in invasive mucinous adenocarcinoma of the lung and KRAS wild-type pancreatic cancer, and are oncogenic in vitro and in vivo. Chimeric NRG1 fusion proteins bind to HER3 through an EGF-like binding domain, triggering HER2–HER3 heterodimerisation and activation of downstream growth and proliferation signalling pathways. Targeting HER2 and HER3 represents a potential therapeutic approach for patients with NRG1 fusion-positive cancer, regardless of tumour type.
Zenocutuzumab is a first-in-class, humanised, full-length IgG1 bispecific antibody that blocks HER2-HER3 dimerisation and NRG1 fusion protein interactions with HER3, which results in suppression of tumour cell proliferation and survival through the PI3K-AKT-mTOR oncogenic signalling pathway. In vitro, zenocutuzumab also mediates antibody-dependent cellular cytotoxicity. Preclinical investigations have shown the anticancer activity of zenocutuzumab in multiple tumour types.
Clinical efficacy of zenocutuzumab was evaluated in a phase II eNRGy study. The study investigators reported in their article the efficacy and safety analyses of consecutively enrolled patients with advanced solid tumours harbouring an NRG1 fusion treated with zenocutuzumab monotherapy.
Patients with advanced NRG1 fusion-positive cancer involving any tumour type were assigned to receive zenocutuzumab at a dose of 750 mg intravenously every 2 weeks. The primary endpoint was overall response (complete or partial response) according to investigator assessment. Secondary endpoints included duration of response (DoR), progression-free survival (PFS), and safety.
A total of 204 patients with 12 tumour types were enrolled and treated. Among 158 patients who had measurable disease and were enrolled at least 24 weeks before the data cut-off date, a response occurred in 30% (95% confidence interval [CI] 23 to 37).
The median DoR was 11.1 months (95% CI 7.4 to 12.9); 19% of responses were ongoing at the data cut-off date. Responses were observed in multiple tumour types including in 27 of 93 patients (29%) with NSCLC and 15 of 36 patients (42%) with pancreatic cancer and across multiple NRG1 fusion partners. The median PFS was 6.8 months (95% CI 5.5 to 9.1).
Adverse events were primarily grade 1 or 2. The most common adverse events that were considered by the investigator to be related to zenocutuzumab were diarrhoea that occurred in 18% of the patients, fatigue in 12%, and nausea in 11%. Infusion-related reactions were observed in 14% of the patients. One patient discontinued zenocutuzumab owing to a treatment-related adverse event.
The authors commented that NRG1 rearrangements are often not detected by DNA-based sequencing techniques because the large introns in NRG1 are not typically included in targeted next-generation sequencing panels or whole-exome sequencing. RNA-based sequencing, which was predominantly used in the eNRGy study, is a superior method for identifying these alterations.
In line with published data, a low incidence of concurrent driver alterations was reported in patients in the eNRGy study, which supports the use of RNA-based sequencing in patients with driver-negative tumours, including those with NSCLC and KRAS wild-type pancreatic cancer, to test more comprehensively for gene fusions.
The antitumour activity observed in the Early Access Program was consistent with that in the eNRGy study.
The study was funded by Merus.
Reference
Schram AM, Goto K, Kim D-W, et al. for the eNRGy Investigators. Efficacy of Zenocutuzumab in NRG1 Fusion–Positive Cancer. N Engl J Med 2025;392:566-576.