Approximately 2-4% of non-small cell lung cancer harbor an oncogenic HER2-mutation, though oncogene-targeted therapy in this context has far lagged successes with analogous EGFR- and ALK-driven non-small cell lung cancer (NSCLC). At the same time, like breast cancer, HER2-mutated NSCLC has an aggressive natural history with high likelihood of brain metastases. Enter zongertinib, an oral selective HER2-TKI. An early-phase single-arm trial assessed daily zongertinib as first-line monotherapy for 74 patients with metastatic HER2-mutant non-squamous NSCLC achieving a median progression-free survival of 14 months, which compares favorably to historical controls receiving chemo-immunotherapy. What’s more, of the 30 patients with brain metastases at enrollment, half achieved an intracranial response. | Heymach, N Engl J Med 2026
