Small cell transformation during acquired resistance to zongertinib in HER2-mutant non-small cell lung cancer: a case report

Background Small cell transformation (SCT) is a known acquired resistance mechanism to targeted therapies in non-small cell lung cancer (NSCLC) but has not been reported following HER2 tyrosine kinase inhibitor (TKI) therapy. We report the first case of SCT detected during acquired resistance to zongertinib, a novel selective HER2 TKI, in a patient with HER2-mutant pulmonary enteric adenocarcinoma. Case presentation A 55-year-old never-smoking male with advanced pulmonary enteric adenocarcinoma harboring HER2 exon 20 YVMA insertion (p.Y772_A775dup) and concurrent TP53/RB1 co-mutations received multiple prior lines of therapy. He obtained partial response to zongertinib. After six months, neuron-specific enolase (NSE) and pro-gastrin-releasing peptide (ProGRP) rose with disease progression. Rebiopsy of a progressing lesion revealed SCT with 80% SCLC and 20% adenocarcinoma; genomic profiling retained the original HER2 insertion and TP53/RB1 mutations. Following transformation, etoposide plus carboplatin decreased NSE and ProGRP but paradoxically increased carcinoembryonic antigen (CEA). Adding zongertinib reduced CEA, whereas the SCLC component continued to progress. The patient survived 5.6 months after SCT diagnosis. Conclusion This is the first report of SCT emerging during acquired resistance to a HER2 TKI. Baseline TP53/RB1 co-mutations may identify patients at higher risk for histologic transformation. Dynamic monitoring of neuroendocrine markers facilitates early detection, and mixed histology warrants individualized strategies targeting both tumor subclones.