Rechallenge with zongertinib after trastuzumab deruxtecan in HER2-mutant lung cancer: A case report.

A 65-year-old man with advanced lung adenocarcinoma underwent comprehensive genomic profile testing using a blood sample after completion of standard therapy, which identified a HER2 mutation. The HER2- tyrosine kinase inhibitor (TKI); zongertinib achieved partial response; however, the tumor grew, prompting a repeat biopsy 22 months later. Repeat biopsy demonstrated HER2 protein expression and HER2 amplification, and treatment was switched to antibody-drug conjugate (ADC) trastuzumab deruxtecan (T-DXd), resulting in tumor shrinkage. After 17 months of treatment, a biopsy of the enlarged tumor revealed that HER2 protein expression decreased and HER2 amplification had disappeared, whereas the HER2 mutation remained. On this basis, zongertinib was re-administered, and the treatment was successful. This case report highlights the value of serial biopsy-based molecular reassessment and supports the potential role of TKI, ADC circulate treatment in biomarker-evolving HER2-mutant disease.