Zongertinib in previously treated advanced HER2-mutant non-small cell lung cancer: A single-center study.

Abstract

e20727 Background: HER2 mutations are present in 2-4% of advanced non-small cell lung cancer (NSCLC). The HER2 YVMA (A775_G776insYVMA) mutation is the most common mutation found in HER2 -mutant NSCLC and is estimated to occur in about 40-60% of cases. Zongertinib is a novel HER2-selective tyrosine kinase inhibitor which received accelerated approval by the U.S. Federal Drug Administration for the treatment of previously treated HER2-mutant NSCLC. We describe our experience treating patients with zongertinib at a large academic center in a diverse, urban U.S. population. Methods: We reviewed our electronic health records and included all patients with next generation sequencing confirmed HER2 -mutant advanced NSCLC treated with zongertinib from January 1, 2022 through January 23, 2026. Disease characteristics, treatment sequencing, outcomes, and adverse events data were collected and reported. Results: 15 patients were treated with zongertinib with a median length of follow-up of 12.6 months. The objective response rate (ORR) was 60.0%. 6- and 12-month progression-free survival rates were 66.7% and 52.5% respectively. In 6 patients previously treated with trastuzumab deruxtecan (T-Dxd), the ORR for zongertinib was 50%. In 9 patients not previously treated with T-Dxd, the ORR was 66.7%. 2 patients had sequential T-Dxd after progression on zongertinib; both had partial responses (PRs) while on T-Dxd. 1 of these patients had a durable response of 9.0 months followed by disease progression. The intracranial ORR for zongertinib in patients with baseline brain metastases was 25%. The ORR was 37.5% for 8 patients with a YVMA mutation and 85.7% for 7 patients with non-YVMA mutations. The most common mutation aside from YVMA was V777L, which was found in 3 patients (20%). Diverse mutations were identified, including in a patient with V659E (non-tyrosine kinase domain), who had a PR, and in another patient with L755P (non-exon 20), who had a PR with a durable response of 20.5 months. Treatment-related adverse events (AEs) were reported in 93.3% of patients; grade 3 or higher AEs were reported in 1 patient (increased ALT and AST). The most commonly reported AEs were diarrhea (73.3%) and rash (60%), which were predominantly grade 1. Conclusions: Our clinical experience suggests that zongertinib is safe and effective in a diverse, urban U.S. population, including patients previously treated with a HER2-targeted agent. Our findings show that in patients treated with either T-Dxd or zongertinib, subsequent treatment with another HER2-targeted agent still yielded objective responses, suggesting some distinct mechanisms of resistance against different HER2-targeted therapies. Our findings also potentially suggest that patients with HER2 non-YVMA mutations may respond to zongertinib with greater efficacy compared to those with a YVMA mutation, and further molecular analysis is underway.