NRG1 fusions in non-small cell lung cancer: biology, diagnostics, and emerging HER2/HER3 therapies—a narrative review

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Background and Objective: NRG1 gene fusions are rare but clinically relevant oncogenic drivers in non-small cell lung cancer (NSCLC) and drive tumorigenesis through ligand-dependent activation of HER2/HER3 signaling. In contrast to kinase-driven oncogenic fusions, NRG1 alterations preserve the EGF-like domain that can drive HER3 dimerization and activation of downstream PI3K/AKT and MAPK signaling pathways. NRG1 fusions were first detected in invasive mucinous adenocarcinoma but have since been identified across multiple cancers and are increasingly recognized as actionable alterations in NSCLC. Herein, we provide a narrative review summarizing current evidence on the biological basis of NRG1 fusion-positive NSCLC, diagnostic considerations, and emerging therapeutic strategies. Methods: Structured literature searches were conducted in PubMed and key oncology conference databases to identify relevant publications between January 1, 2014 and May 15, 2026. English-language studies focusing on biological mechanisms, clinicopathological features, diagnostic strategies, and therapeutic approaches in NRG1 fusion-positive NSCLC were eligible for inclusion. Key Content and Findings: NRG1 fusion-positive NSCLC represents a distinct molecular subtype characterized by mucinous histology, low tumor mutational burden (TMB), and dependence on HER2/HER3 signaling. Detection remains technically challenging due to limitations of DNA-based sequencing approaches, underscoring the importance of RNA-based assays and integrated molecular profiling. Early clinical experience with pan-ErbB tyrosine kinase inhibitors demonstrated heterogeneous and often limited activity. Other HER2/HER3-targeted strategies, including the bispecific antibody zenocutuzumab and HER3-directed monoclonal antibodies, have shown clinically meaningful antitumor activity. The accelerated approval of zenocutuzumab in 2024 represented a pivotal milestone in the clinical management of this rare molecular subgroup. Conclusions: NRG1 fusion-positive NSCLC represents an emerging actionable lung cancer subtype with distinct biological and clinical features. The therapeutic landscape has evolved substantially with the introduction of molecular diagnostics and HER2/HER3-targeted therapies. Continued investigation of resistance mechanisms and optimal treatment sequencing will be crucial to improve outcomes for patients with this rare but clinically impactful disease.

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