Dr Hirsch on the Treatment of NRG1 Fusion+ NSCLC

Fred R. Hirsch, MD, PhD, executive director, Center for Thoracic Oncology, The Tisch Cancer Institute at Mount Sinai; Joe Lowe and Louis Price Professor of Medicine (Hematology and Medical Oncology), Icahn School of Medicine at Mount Sinai, discusses the activity of HER3-directed agents in patients with non–small cell lung cancer (NSCLC) harboring NRG1 mutations.

NRG1 is implicated in the interaction and dimerization of HER2 and HER3 receptors, as well as the activation of these receptors, Hirsch begins. Thus, blocking NRG1 disrupts this interaction, he notes. Zenocutuzumab (MCLA-128), a bispecific antibody targeting HER2/HER3, has showcased encouraging results in clinical trials in patients with NRG1-positive NSCLC, according to Hirsch. For instance, in the phase 1/2 eNRGy trial (NCT04100694), the agent yielded an ORR of 37.2% (95% CI, 26.5%-48.9%). In 2023, zenocutuzumab received FDA breakthrough therapy designation for this indication, and the agent is currently under FDA priority review for this population. Another agent, afatinib (Gilotrif), has also exhibited some efficacy in this patient population and is under further clinical investigation, as are several other NRG1-targeted therapies, Hirsch notes. However, optimal treatment strategies for patients with NRG1 fusions, including the ideal line of therapy in which to use these agents, remain undetermined, Hirsch emphasizes.

Furthermore, the relationship between NRG1-targeted therapies and immunotherapy is unclear, Hirsch adds. Although anecdotal evidence varies, a global registry of patients with NRG1 fusion–positive NSCLC indicates that these tumors typically have low PD-L1 expression and low tumor mutational burden, indicating potentially limited responsiveness to immunotherapy, Hirsch says. Nonetheless, there is currently a lack of comprehensive clinical data to draw definitive conclusions, Hirsch reports. Thus, the integration of NRG1-targeted treatments with immunotherapy and the optimal sequencing of these agents in NRG1 fusion–positive disease requires further investigation, Hirsch concludes.