Abstract Background NRG1 fusions are unique oncogenic drivers that activate the HER3/HER2/PI3K pathway. The FDA granted Accelerated Approval to a HER2/HER3 antibody, zenocutuzumab, for treatment of NRG1 fusion-positive (NRG1+) non-small-cell lung and pancreatic cancer (PDAC). The optimal detection methods and clinicopathologic features of patients with NRG1+ cancer have not been systematically studied. We review NRG1+ cancer and focus on outcomes in PDAC. Methods NRG1+ patients at Memorial Sloan Kettering were identified using institutional databases. Clinicopathologic data were extracted from the medical record. NRG1+ PDAC cases underwent review of radiology, pathology, treatment data, and assessment of progression-free and overall survival. Results Out of 76,531 patients, 48 NRG1+ cases were identified. The most common tumor types were lung (60%), PDAC (21%), and breast (10%). Approximately half (46%) received HER2 and/or HER3-directed therapy. Patients were identified by RNA (n = 34), DNA (n = 11), or both (n = 3). RNA was superior to DNA for fusion identification. Twenty-one fusion partners were detected, most commonly CD74 (40%) and ATP1B1 (10%). Lung cancers were otherwise driver-negative and PDAC were KRAS wild-type. NRG1+ PDAC exhibited distinct histopathologic and clinical features. Median age was 48.5 years, median PFS on 1st-line chemotherapy was 12.6 months (n = 7; 95% CI 2.9-NR), and median OS from diagnosis was 39.6 months (n = 9; 95% CI 23.2-NR). Conclusions NRG1 fusions are a newly described clinically actionable target in solid tumors. We report the landscape of NRG1+ cancers and highlight the importance of RNA testing. NRG1+ PDAC is enriched in younger patients with KRAS wild-type disease and has a unique biology.
Schram et al. (2025) studied this question.