Efficacy of Zenocutuzumab in NRG1 Fusion–Positive Cancer

1. Overall objective response rate was 30%, with 1 patient having a complete response.

2. Grade 3-4 treatment-related events occurred in 7% of patients.

Evidence Rating Level: 2 (Good)

Study Rundown: Neuregulin 1 (NRG1) fusions, occur in less than 1% of solid tumours, and drive oncogenesis by activating HER2–HER3 signaling, making HER2 and HER3 promising therapeutic targets. Zenocutuzumab, a bispecific antibody targeting HER2 and HER3, was found to block HER2–HER3 dimerization and NRG1 fusion protein interactions, inhibiting tumour growth and survival. This phase 2 study explores the efficacy and safety of Zenocutuzumab in patients with advanced NRG1 fusion-positive cancers. The primary endpoint was the overall response (ORR, complete or partial) and secondary endpoints included duration of response (DoR), time to response (TtR), progression-free survival (PFS), pharmacokinetics, and safety. While some tumour reduction was seen in 72% of patients, ORR was found to be 30%, with 1 patient having complete response. Among patients with an overall response, the median DoR was 11.1 months, with a DoR at 6 and 12 months being 77% and 42%, respectively. Median TtR was 1.8 months. The most common tumour types were NSCLC (58%) and pancreatic cancer (22%). Among NSCLC, ORR was 29% with a median DoR of 12.7 months. Among pancreatic cancer, ORR was 42%, with a median DoR of 7.4 months. Median PFS was 6.8 months in the primary efficacy population as well as in NSCLC and was 9.2 months in pancreatic cancer. The pharmacokinetics of zenocutuzumab was found to be similar to other humanized monoclonal antibiotics, with a mean half-life at steady state was 8 days, and a median time to a steady state was 8 weeks. With regards to safety, grade 3-4 treatment-related events occurred in 7% of patients, with the most common being diarrhea and anemia (2% each). The strengths of this study included the breadth of outcomes investigated, and the limitations included the small sample size and methodology. Overall, this study found that zenocutuzumab showed some anti-tumour activity in patients with advanced NRG1 fusion-positive cancer.

Click to read the study in NEJM

Relevant Reading: Zenocutuzumab, a HER2xHER3 Bispecific Antibody, Is Effective Therapy for Tumors Driven by NRG1 Gene Rearrangements

In-Depth [prospective cohort]: This international, open-label, phase 2 study enrolled adults with NRG1 fusion-positive advanced or metastatic solid tumour cancer involving any tumour type and administered zenocutuzumab at a dose of 750 mg every 2 weeks until the occurrence of disease progression, death, unacceptable toxic effects, or withdrawal of consent. A total of 161 patients with 10 different tumour types received zenocutuzumab and were included in the analysis. Most patients received previous systemic treatments. While some tumour reduction was seen in 72% of patients, ORR was found to be 30% (95%CI, 23-37), with 1 patient having complete response. Among patients with an overall response, the median DoR was 11.1 months (95%CI, 7.4-12.9), with a DoR at 6 and 12 months being 77% and 42%, respectively. Median TtR was 1.8 months. The most common tumour types were NSCLC (58%) and pancreatic cancer (22%). Among NSCLC, ORR was 29% (95%CI, 20-39) with a median DoR of 12.7 months (95%CI, 7.4-20.4). Among pancreatic cancer, ORR was 42% (95%CI, 25-59), with a median DoR of 7.4 months (95%CI, 4.0-11.2). Median PFS was 6.8 months in the primary efficacy population (95%CI, 5.5-9.1) as well as in NSCLC (95%CI, 5.3-7.5) and was 9.2 months (95%CI, 5.5-11.2) in pancreatic cancer. Pharmacokinetics of zenocutuzumab was found to be similar to other humanized monoclonal antibiotics, with a mean half-life at a steady state was 8 days, and a median time to steady state was 8 weeks. With regards to safety, grade 3-4 treatment-related events occurred in 7% of patients, with the most common being diarrhea and anemia (2% each). Overall, this study found that zenocutuzumab showed some anti-tumour activity in patients with advanced NRG1 fusion-positive cancer.

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