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

Area of Science:

• Oncology
• Genomics
• Immunology

Background:

• Non-small cell lung cancer (NSCLC) with HER2 exon 20 insertions (HER2 20ins) exhibits poor response to standard treatments.
• Trastuzumab Deruxtecan (T-DXd) is approved for advanced NSCLC, but its utility in operable cases is not well-established.

Purpose of the Study:

• To evaluate the efficacy of neoadjuvant T-DXd in a patient with operable HER2 20ins NSCLC.
• To compare the molecular and immune impact of neoadjuvant T-DXd versus conventional chemotherapy in HER2 20ins NSCLC.

Main Methods:

• Case study of a patient with operable HER2 20ins NSCLC treated with neoadjuvant T-DXd.
• Comparative analysis with a second HER2 20ins NSCLC patient receiving conventional chemotherapy.
• Whole-genome sequencing (WGS) and immune microenvironment profiling were employed.

Main Results:

• T-DXd treatment led to a significant reduction in tumor clones, genome instability, and extrachromosomal DNA (ecDNA).
• Immune profiling revealed increased CD8+ T cell infiltration and elevated PD-1 expression in the T-DXd treated patient.
• Conventional chemotherapy did not induce comparable changes in immune cell infiltration or PD-1 expression.

Conclusions:

• Neoadjuvant T-DXd demonstrates potential as a therapeutic strategy for locally advanced HER2-mutant NSCLC.
• The observed molecular and immunological changes suggest T-DXd may enhance anti-tumor immunity.
• Further investigation in larger patient cohorts is warranted to confirm these findings.