First case report of transformation of adenocarcinoma to adenosquamous carcinoma with giant-cell carcinoma harboring HER2 mutation after zongertinib (BI 1810631) resistance.

[BACKGROUND] Human epidermal growth factor receptor 2 (HER2) mutations have been identified as a rare molecular subset in non-small cell lung cancer (NSCLC) with poor prognosis and limited treatment options. Zongertinib, an irreversible covalent HER2 inhibitor, demonstrated promising response rates and safety profile in the Beamion LUNG-1 trial, leading to approval for previously treated HER2-mutant NSCLC. Nevertheless, the resistance mechanisms to zongertinib remain largely unexplored despite its established efficacy.

[CASE DESCRIPTION] A 52-year-old female never-smoker was diagnosed with stage IV lung adenocarcinoma in March 2023. Next generation sequencing (NGS) of tumor tissue identified an HER2 exon 20p.Y772_A775dup mutation along with concurrent NF1, RB1, and TP53 mutations, plus increased AKT2 gene copy number. First-line platinum-based chemotherapy combined with immunotherapy was initiated with transient disease stabilization. The patient subsequently achieved a confirmed partial response to zongertinib (240 mg daily) in the Beamion LUNG-1 trial, maintaining clinical benefit for 20 months until symptomatic progression emerged. Repeat biopsy revealed histologic transformation to adenosquamous carcinoma with giant-cell features, with PD-L1 expression switch from undetectable to 80% positivity. The genomic profiling showed persistent original mutations plus newly acquired MAP3K1 mutation, HER2 amplification, and TERT amplification. In the third-line treatment, the patient was enrolled in a clinical trial evaluating BC3195, a novel CDH3-targeted antibody-drug conjugate, and achieved partial response at the time of reporting.

[CONCLUSION] This case is the first to elucidate the putative resistance mechanisms to zongertinib in HER2-mutant lung adenocarcinoma might be transformation of adenosquamous with giant-cell carcinoma and acquired HER2 amplification through integrated histological and molecular analyses. These findings highlight the necessity of post-progression biopsy and genomic profiling to characterize resistance evolution and guide subsequent therapy selection.