Tumor genome and microenvironment alteration by trastuzumab deruxtecan as neoadjuvant therapy for HER2-mutant NSCLC.

Non-small cell lung cancer (NSCLC) patients carrying HER2 exon 20 insertion (HER2 20ins) are respond poorly to conventional therapies and pan HER inhibitors. Trastuzumab Deruxtecan (T-DXd) has been approved in second line treatment in advanced NSCLC, but its efficacy in operable patients remains unclear. Here, we report a case of a patient with operable, HER2 20ins NSCLC who received neoadjuvant T-DXd, along with a second HER2 20ins patient who received conventional chemotherapy as a clinical reference. We utilized whole-genome sequencing (WGS) and immune microenvironment analysis to investigate the treatment's impact. WGS analysis revealed marked reduction in tumor clones with genome instability and extrachromosomal DNA (ecDNA) following T-DXd treatment. Meanwhile, immune profiling demonstrated substantially increased CD8 + T cell infiltration in tumor cores with elevated PD-1 expression. In contrast, such changes in CD8 + T cell infiltration and PD-1 expression were not evident in another HER2 20ins patient who received conventional chemotherapy. These findings suggest that neoadjuvant T-DXd may represent a promising therapeutic option for locally advanced HER2-mutant NSCLC, warranting further investigation in larger cohorts.