Clinicopathologic Features of NRG1 Fusion-Positive Non-Small Cell Lung Cancer

Data on the clinicopathological features of NRG1 fusion-positive non-small cell lung cancer (NSCLC) are limited. We conducted a retrospective, multicenter study and included patients with NRG1 fusion-positive NSCLC diagnosed between January 2018 and February 2025. Six patients were identified; five were female (83.3%), two were never-smokers (33.3%), and four were former smokers (66.7%). Adenocarcinoma was the predominant histology (n = 5), comprising mucinous (n = 2), enteric (n = 2), and not otherwise specified (n = 1) variants, while one patient had squamous cell carcinoma. All were PD-L1-negative, and CD74-NRG1 was the most common fusion (50%). Three patients received afatinib; only one achieved a partial response with a progression-free survival of 8.7 months. Median overall survival was 6.7 months. Our study demonstrates the histologic and molecular heterogeneity of NRG1 fusion-positive NSCLC, encompassing mucinous and enteric variants of adenocarcinoma. Responses to afatinib were variable, underscoring the need for more effective therapies, including zenocutuzumab and emerging agents.