Genomic and immune characteristics of HER2-mutated non-small cell lung cancer and response to immune checkpoint inhibitor-based therapy.

The efficacy of immunotherapy in advanced HER2-mutated non-small cell lung cancer (NSCLC) remains incomprehensively studied. A total of 107 NSCLC patients with de novo HER2 mutations were retrospectively studied at Guangdong Lung Cancer Institute [GLCI cohort, exon 20 insertions (ex20ins): 71.0%], to compare clinical/molecular features and immune checkpoint inhibitor (ICI)-based therapy efficacy between patients with exon 20 insertion (ex20ins) and non-ex20ins. Two external cohorts (TCGA, n=21; META-ICI, n=30) were used for validation. In the GLCI cohort, 68.2% of patients displayed programmed death-ligand 1 (PD-L1) expression <1%. Compared to ex20ins patients, non-ex20ins patients had more concurrent mutations in the GLCI cohort (P<0.01) and a higher tumor mutation burden in the TCGA cohort (P=0.03). Under ICI-based therapy, advanced NSCLC patients with non-ex20ins had potentially superior progression-free survival [median: 13.0 vs 3.6 months, adjusted hazard ratio (HR): 0.31, 95% confidence interval (CI): 0.11-0.83] and overall survival (median: 27.5 vs. 8.1 months, adjusted HR: 0.39, 95% CI: 0.13-1.18) to ex20ins patients, consistent with findings in the META-ICI cohort. ICI-based therapy may serve as an option for advanced HER2-mutated NSCLC, with potentially better efficacy in non-ex20ins patients. Further investigations are warranted in clinical practice.