Abstract 1151: NRG1 fusion-positive solid tumors: clinical detection, genomic landscape, and real-world data in PDAC
Authors: Alison M. Schram, Soo-Ryum Yang, Matteo Repetto, Rogelio Velasco, Genessa Kahn, Richard Do, Sara Dinapoli, Purvil Sukhadia, Megan Troxel, Zeynep Tarcan, Kerem Ozcan, Marc Ladanyi, James Harding, Alexander Drilon, Olca Basturk, Eileen O'Reilly
Journal: Cancer Research (2025)

Background: Gene fusions in NRG1 are unique oncogenic drivers that occur in approximately 0.2% of solid tumors and are enriched in KRAS wild-type pancreatic cancer (PDAC). NRG1 fusions activate the HER3/HER2/PI3K pathway and can be targeted with HER2 and/or HER3-directed therapy. Recently, the FDA granted Breakthrough Therapy Designation to a HER2/HER3 bispecific antibody for treatment of NRG1+ cancer. Despite emerging evidence that NRG1 fusions are clinically meaningful biomarkers, the clinicopathologic features of patients with NRG1+ cancer remain poorly understood. We describe patients with NRG1+ solid tumors at Memorial Sloan Kettering Cancer Center (MSK) with a focus on real-world outcomes in PDAC. Methods: This retrospective study included patients with NRG1+ solid tumors detected using tumor next-generation sequencing (NGS) at MSK from July 2014 to July 2024 using MSK-IMPACT (DNA-based NGS) and MSK-Fusion (RNA-based NGS). NRG1 fusions were considered oncogenic if they were predicted to be in-frame and retain the EGF-like domain. Clinicopathologic data including sex, smoking status, age at diagnosis, cancer type, fusion partner, microsatellite instability (MSI) status, tumor mutational burden (TMB), and genomic co-mutations were manually extracted from the medical record. When available, raw sequencing data was reviewed. NRG1+ PDAC cases underwent central radiology and pathology review, in addition to extraction of treatment data and real-world progression free survival. Results: Out of 76,531 patients, pathogenic NRG1 fusions were detected in 48 patients. The majority were female (56%), White (69%), non-smokers (58%), with a median age of 61 years-old at diagnosis (range: 9 to 83). The most common tumor types were lung (60%), PDAC (21%), and breast (10%). Approximately half (46%) had been treated with HER2 and/or HER3-directed therapy. Patients were identified by RNA (n= 34), DNA (n= 11), or both (n=3). Of 32 co-tested cases, 29 were identified on RNA alone. 21 distinct fusion partners were identified, most commonly CD74 (40%) and ATP1B1 (10%). No tumor had a high TMB or MSI. All lung cancers were otherwise driver-negative and all PDAC were KRAS wild-type. Patients with NRG1+ PDAC exhibited distinct histopathologic and clinical features compared to KRAS-mutated PDAC. Pathology demonstrated smaller tubular structures lined by cuboidal cells with minimal intracytoplasmic mucin. In the PDAC NRG1+ cohort (n=10), median age of diagnosis was 48.5 years old (range: 25 to 66) and median PFS on 1st-line chemotherapy for advanced disease was 8.3 months (n=7; 95% CI 2.9 to NR; range 0.2+ to 25.2 months). Conclusion: NRG1 fusions are a newly described clinically actionable target in solid tumors. We report the landscape of NRG1+ cancers in solid tumors and demonstrate the importance of RNA testing to identify this targetable alteration. We show NRG1+ PDAC has a unique histology and natural history. Citation Format: Alison M. Schram, Soo-Ryum Yang, Matteo Repetto, Rogelio Velasco, Genessa Kahn, Richard Do, Sara Dinapoli, Purvil Sukhadia, Megan Troxel, Zeynep Tarcan, Kerem Ozcan, Marc Ladanyi, James Harding, Alexander Drilon, Olca Basturk, Eileen O'Reilly. NRG1 fusion-positive solid tumors: clinical detection, genomic landscape, and real-world data in PDAC [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 1151.