NRG1 fusion-positive solid tumors: clinical detection, genomic landscape, and real-world data in pancreatic cancer.

BACKGROUND

NRG1 fusions are unique oncogenic drivers that activate the HER3/HER2/PI3K pathway. The US Food and Drug Administration granted accelerated approval to a HER2/HER3 antibody, zenocutuzumab, for treatment of NRG1 fusion-positive non-small cell lung cancer and pancreatic ductal adenocarcinoma (PDAC). The optimal detection methods and clinicopathological features of patients with NRG1 fusion-positive cancer have not been systematically studied. Here, we review NRG1 fusion-positive cancer and focus on outcomes in PDAC.

METHODS

Patients with NRG1 fusion-positive disease at Memorial Sloan Kettering Cancer Center were identified using institutional databases. Clinicopathological data were extracted from medical records. NRG1 fusion-positive PDAC cases underwent review of radiology, pathology, treatment data, and assessment of progression-free and overall survival.

RESULTS

Of 76 531 patients, 48 NRG1 fusion-positive cases were identified. The most common tumor types were lung (60%), PDAC (21%), and breast (10%). Approximately half (46%) of these patients 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 cases were KRAS wild type. NRG1 fusion-positive PDAC exhibited distinct histopathological and clinical features. Median patient age was 48.5 years, median progression-free survival on first-line chemotherapy was 12.6 months (n = 7; 95% confidence interval [CI] = 2.9 to not reached), and median overall survival from diagnosis was 39.6 months (n = 9; 95% CI = 23.2 to not reached).

CONCLUSIONS

NRG1 fusions are a newly described, clinically actionable target in solid tumors. We report the landscape of NRG1 fusion-positive cancers and highlight the importance of RNA testing. NRG1 fusion-positive PDAC is enriched in younger patients with KRAS wild-type disease and has unique biology.