Zenocutuzumab Demonstrates Durable Activity in NRG1 Fusion–Positive Solid Tumors

A recent phase 2 clinical trial, published in The New England Journal of Medicine, has demonstrated that zenocutuzumab, a bispecific antibody targeting HER2 and HER3, shows promising efficacy in patients with advanced NRG1 fusion–positive cancers. The study enrolled 204 patients across 12 tumor types, all treated with zenocutuzumab at a dose of 750 mg intravenously every two weeks. 

Among the 158 patients with measurable disease and sufficient follow-up, the overall response rate was 30% (95% confidence interval [CI], 23 to 37). Notably, responses were observed across multiple tumor types, including non–small-cell lung cancer (NSCLC) and pancreatic cancer. Specifically, 29% (27 of 93 patients; 95% CI, 20 to 39) with NSCLC and 42% (15 of 36 patients; 95% CI, 25 to 59) with pancreatic cancer experienced a response. The median duration of response was 11.1 months (95% CI, 7.4 to 12.9), with 19% of responses ongoing at the data-cutoff date. 

The safety profile of zenocutuzumab was favorable, with adverse events primarily being grade 1 or 2. The most common treatment-related adverse events included diarrhea (18%), fatigue (12%), and nausea (11%). Infusion-related reactions occurred in 14% of patients, and only one patient discontinued treatment due to a treatment-related adverse event. 

For practicing oncologists, these findings suggest that zenocutuzumab offers a targeted therapeutic option for patients with NRG1 fusion–positive tumors, particularly in NSCLC and pancreatic cancer. The study underscores the importance of molecular testing for NRG1 fusions in appropriate clinical contexts to identify patients who may benefit from this therapy. As the authors conclude, "Zenocutuzumab showed efficacy in patients with advanced NRG1 fusion–positive cancer, notably NSCLC and pancreatic cancer, with mainly low-grade adverse events."  

Incorporating zenocutuzumab into treatment regimens could enhance outcomes for patients harboring these specific genetic alterations. Ongoing research and longer follow-up will further elucidate the durability of responses and long-term safety profile of this promising agent.

Source:

Hong DS, Johnson ML, Meric-Bernstam F, et al. Zenocutuzumab in NRG1 Fusion–Positive Cancers. N Engl J Med. 2024;390(13):1203-1214. doi:10.1056/NEJMoa2405008