Efficacy of zenocutuzumab in NRG1 fusion-positive cancer Journal Article
| Authors: | Schram, A. M.; Goto, K.; Kim, D. W.; Macarulla, T.; Hollebecque, A.; O'Reilly, E. M.; Ou, S. H. I.; Rodon, J.; Rha, S. Y.; Nishino, K.; Duruisseaux, M.; Park, J. O.; Neuzillet, C.; Liu, S. V.; Weinberg, B. A.; Cleary, J. M.; Calvo, E.; Umemoto, K.; Nagasaka, M.; Springfeld, C.; Bekaii-Saab, T.; O'Kane, G. M.; Opdam, F.; Reiss, K. A.; Joe, A. K.; Wasserman, E.; Stalbovskaya, V.; Ford, J.; Adeyemi, S.; Jain, L.; Jauhari, S.; Drilon, A.; for the eNRGy Investigators |
| Article Title: | Efficacy of zenocutuzumab in NRG1 fusion-positive cancer |
| Abstract: | BACKGROUND: Neuregulin 1 (NRG1) fusions are recurrent oncogenic drivers found in multiple solid tumors. NRG1 binds to human epidermal growth factor receptor 3 (HER3), leading to heterodimerization with HER2 and activation of downstream growth and proliferation pathways. The efficacy and safety of zenocutuzumab, a bispecific antibody against HER2 and HER3, in patients with NRG1 fusion-positive solid tumors are unclear. METHODS: In this registrational, phase 2 clinical study, we assigned patients with advanced NRG1 fusion-positive cancer involving any tumor type to receive zenocutuzumab at a dose of 750 mg intravenously every 2 weeks. The primary end point was overall response (complete or partial response) according to investigator assessment. Secondary end points included duration of response, progression-free survival, and safety. RESULTS: A total of 204 patients with 12 tumor types were enrolled and treated. Among 158 patients who had measurable disease and were enrolled at least 24 weeks before the data-cutoff date, a response occurred in 30% (95% confidence interval [CI], 23 to 37). The median duration of response was 11.1 months (95% CI, 7.4 to 12.9); 19% of responses were ongoing at the data-cutoff date. Responses were observed in multiple tumor types - including in 27 of 93 patients (29%; 95% CI, 20 to 39) with non-small-cell lung cancer (NSCLC) and 15 of 36 patients (42%; 95% CI, 25 to 59) with pancreatic cancer - and across multiple NRG1 fusion partners. The median progression-free survival 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 diarrhea (in 18% of the patients), fatigue (in 12%), and nausea (in 11%). Infusion-related reactions (composite term) were observed in 14% of the patients. One patient discontinued zenocutuzumab owing to a treatment-related adverse event. CONCLUSIONS: Zenocutuzumab showed efficacy in patients with advanced NRG1 fusion-positive cancer, notably NSCLC and pancreatic cancer, with mainly low-grade adverse events. (Funded by Merus; eNRGy ClinicalTrials.gov number, NCT02912949.). Copyright © 2025 Massachusetts Medical Society. |
| Keywords: | adult; aged; aged, 80 and over; middle aged; genetics; clinical trial; neoplasm; neoplasms; progression free survival; phase 2 clinical trial; epidermal growth factor receptor 2; monoclonal antibody; multicenter study; oncogene proteins, fusion; receptor, erbb-2; drug therapy; epidermal growth factor receptor 3; progression-free survival; neu differentiation factor; neuregulin-1; receptor, erbb-3; antibodies, monoclonal, humanized; very elderly; humans; human; male; female; immunological antineoplastic agent; antineoplastic agents, immunological; nrg1 protein, human; oncogene fusion protein |
| Journal Title: | New England Journal of Medicine |
| Volume: | 392 |
| Issue: | 6 |
| ISSN: | 0028-4793 |
| Publisher: | Massachusetts Medical Society |
| Date Published: | 2025-02-06 |
| Start Page: | 566 |
| End Page: | 576 |
| Language: | English |
| DOI: | 10.1056/NEJMoa2405008 |
| PUBMED: | 39908431 |
| PROVIDER: | scopus |
| PMCID: | PMC11878197 |
| DOI/URL: | |
| Notes: | Source: Scopus |
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