Treatment with the HER2 × HER3 bispecific antibody zenocutuzumab-zbco appeared to be safe and active in patients with advanced NRG1 gene fusion–positive solid tumors, according to results from the registrational phase II eNRGy study published by Schram et al in The New England Journal of Medicine. The most notable efficacy findings were in non–small cell lung cancer (NSCLC) and pancreatic cancer, which were the most represented tumor types in the study.
“NRG1 [gene] fusions are unique cancer drivers that create oncogenic chimeric ligands rather than the more widely described chimeric receptors,” the investigators commented. “This clinical study targeted cancers with this rare genomic alteration, a population enriched for cancer types with limited effective treatment options.”
Based on data from the eNRGy trial, in December 2024, the U.S. Food and Drug Administration (FDA) granted accelerated approval to zenocutuzumab for patients with NRG1 gene fusion–positive NSCLC and pancreatic adenocarcinoma. It represents the first and only approved targeted therapy in these clinical contexts.
Study Details
KEY POINTS
- In the eNRGy trial, patients with advanced NRG1 gene fusion–positive cancer had a 30% response rate (NSCLC: 29%; pancreatic cancer: 42%).
- Most zenocutuzumab-related adverse events were grade 1 or 2.
- Based on these data, the FDA granted accelerated approval to zenocutuzumab for patients with NRG1 gene fusion–positive NSCLC and pancreatic adenocarcinoma in December 2024.
A total of 204 patients with 12 different types of advanced NRG1 gene fusion–positive cancer, who had either received standard therapy or were considered ineligible for it, were enrolled and treated with 750 mg of zenocutuzumab intravenously every 2 weeks. The primary efficacy population comprised patients with 10 different tumor types, of whom 94 had NSCLC and 36 had pancreatic cancer.
Investigator-assessed overall response (complete or partial response) was evaluated as the primary endpoint. The investigators identified duration of response, progression-free survival, and safety as secondary endpoints.
Efficacy Outcomes
Among the 158 patients who had measurable disease and were enrolled at least 24 weeks before the data cutoff date, the response rate was 30% (95% confidence interval [CI] = 23%–37%). The median duration of response was 11.1 months (95% CI = 7.4–12.9 months); nearly one-fifth of responses (19%) were ongoing at the data cutoff date. Responses were observed across multiple tumor types (NSCLC: 29% [95% CI = 20%–39%]; pancreatic cancer: 42% [95% CI = 25%–59%]) and NRG1 gene fusion partners. The median duration of progression-free survival was 6.8 months (95% CI = 5.5–9.1 months).
Adverse Events
According to the investigators, most adverse events were grade 1 or 2. Diarrhea (18%), fatigue (12%), and nausea (11%) were the most frequently reported adverse events considered to be related to zenocutuzumab. Infusion-related reactions (composite term) were documented in 14% of patients. One patient discontinued treatment with zenocutuzumab because of a treatment-related adverse event.
The investigators concluded: “In this study, zenocutuzumab … showed antitumor activity in patients with advanced NRG1 [gene] fusion–positive cancer, notably NSCLC and pancreatic cancer. Responses were observed across multiple tumor types and fusion partners. This study validates NRG1 [gene] fusions as an actionable therapeutic target.”
Alison M. Schram, MD, of Memorial Sloan Kettering Cancer Center, New York, is the corresponding author of The New England Journal of Medicine article.
Disclosure: The study was funded by Merus. For full disclosures of the study authors, visit nejm.org.
