Neuregulin 1 (NRG1) gene fusions are rare oncogenic alterations, found in less than 1% of solid tumors, that drive cancer growth in malignancies such as non-small cell lung cancer (NSCLC) and pancreatic ductal adenocarcinoma (PDAC).1 Because of their rarity and limited representation in clinical trials, patients with NRG1-positive tumors have limited targeted therapeutic options.
During the IASLC | ASCO 2025 North America Conference on Lung Cancer (NACLC), Stephen Liu, MD, Associate Professor of Medicine at Georgetown Lombardi Comprehensive Cancer Center, presented updated data supporting the targeted therapy zenocutuzumab—a novel, bispecific antibody—as a potential treatment option for patients with NRG1-positive disease.2
Dr. Liu’s presentation during the Oral Abstract Session described findings from a post-hoc analysis evaluating the safety and efficacy of zenocutuzumab for this patient population.
“Zenocutuzumab recently received accelerated US Food and Drug Administration (FDA) approval for previously treated NRG1-positive fusion NSCLC and PDAC in 2024,” Dr. Liu said. The approval marks the first systemic therapy specifically indicated for patients with NRG1 fusion-driven cancers.4 Data from the phase II eNRGy trials, as outlined in the presentation, are now being explored to assess the agent’s potential role as a first-line treatment option.
The study included 154 patients with advanced NRG1-positive NSCLC. Most patients had received prior treatment, while 21 were treatment-naïve.2 Patients in the trial were administered intravenous zenocutuzumab at a dosage of 750 mg every 2 weeks. Treatment continued until disease progression or unacceptable toxicity.
Efficacy was assessed using investigator-assessed objective response rate (ORR), measured according to RECIST v1.1, as the primary endpoint. Secondary endpoints included duration of response (DOR), time to response (TTR), clinical benefit rate (CBR), and the nature and frequency of adverse events (AEs). Clinical benefit was defined as the achievement of a complete response, partial response, or stable disease.2
“Clinically meaningful early and durable responses were demonstrated in both the treatment-naïve and previously treated patients,” Dr. Liu said. The response was 35% among those who were treatment-naïve, with a CBR of 65%. The median DOR in this cohort was 17.1 months.2
The response rate was 31% in the previously treated cohort, with a CBR of 58% and a median DOR of 7.4 months. Responses occurred quickly across both cohorts, with a median TTR of less than 2 months.2
Progression-free survival (PFS), presented on a Kaplan-Meier curve, was 7.5 months in the treatment-naïve cohort and 6.8 months in previously treated patients. Zenocutuzumab continued to demonstrate a favorable safety profile. Only one patient in each cohort discontinued treatment due to treatment-related AEs (TRAEs), and most AEs were reported as grade 1 or 2.2
Overall, the findings presented were consistent with results from the broader eNRGy trial and suggest a potential role for zenocutuzumab as a first-line treatment option in patients with NRG1-positive cancers.
Dr. Liu noted that NRG1-driven tumors often exhibit a lymphangitic mucinous growth pattern that can resemble pneumonitis on imaging, making response assessment challenging.
“These are hard to measure, and that’s why I think the response rate underestimates the benefit,” Dr. Liu said. “The clinical benefit rate in this study was defined as 6 months of stable disease. To see that clinical benefit rate closer to 70%, really reflects the value of the drug.”
References:
- 1. Kim DW, Schram AM, Hollebecque A, et al. The phase I/II eNRGy trial: Zenocutuzumab in patients with cancers harboring NRG1 gene fusions. Future Oncol. 2024;20(16):1057-1067. doi:10.2217/fon-2023-0824
- 2. Phase 2 eNRGy Trial: Zenocutuzumab Shows ‘Clinically Meaningful Early and Durable Responses’ in NRG1+ NSCLC, With Longer Responses in Treatment-naïve Group
- 3.FDA grants accelerated approval to zenocutuzumab-zbco for non-small cell lung cancer and pancreatic adenocarcinoma
