HER2 Alterations in Squamous Cell Lung Cancer: Biology, Therapeutic Landscape, and Emerging Precision Approaches

Squamous cell lung cancer (SqCLC) accounts for 20-30% of non-small cell lung cancer (NSCLC) and remains associated with a poorer prognosis compared with adenocarcinoma. Despite advances in treatment, 5-year overall survival for advanced (stage IV) disease remains below 10-15%. Unlike non-squamous NSCLC, SqCLC is characterized by a high tumor mutational burden and complex genomic landscape dominated by alterations in tumor suppressor genes and lineage survival pathways including TP53, CDKN2A, PIK3CA, FGFR1, SOX2, and the NFE2L2/KEAP1 oxidative stress pathway, as well as dysregulation of the NOTCH signaling pathway, but it harbors relatively few actionable oncogenic drivers, resulting in limited treatments for targeted therapy. HER2 alterations can occur by multiple mechanisms, including activating mutations, gene amplifications, and protein overexpression. They comprise a very small percentage of NSCLC, with HER2 mutations reported in approximately 1-3% and HER2 amplifications observed roughly in 2-4%. While HER2 alterations are well characterized in lung adenocarcinoma, the prevalence, genomic context, and clinical significance of HER2 alterations in SqCLC remain incompletely defined. Advances in next-generation sequencing have led to improved ability to detect HER2 alterations and facilitated the development of HER2 targeted therapies. Available treatments for advanced/metastatic SqCLC have been historically limited to platinum-doublet chemotherapy, with immune checkpoint inhibitors such as anti-PD-1/PD-L1 newly emerging in the past decade. Selective HER2 tyrosine kinase inhibitors and HER2 antibody/drug conjugates have shown improved efficacy in HER2-altered NSCLC as shown in DESTINY-LUNG02 and BEAMION LUNG-1 trials; however, most of the enrolled patients had non-squamous histology, with minimal or no SqCLC-specific efficacy data reported. Future progress in HER2-altered SqCLC will require inclusion of SqCLC in HER2 basket trials, incorporation of comprehensive molecular profiling and standardized HER2 testing in squamous histology. This review summarizes the current state of knowledge of HER2 biology in SqCLC and highlights areas for future directions for precision oncology in SqCLC.