Beamion LUNG-1: Examining the Efficacy and Safety of Zongertinib in 2L Treatment of mNSCLC With HER2 Mutations

Beamion LUNG-1: Examining Zongertinib Efficacy and Safety in Second-Line mNSCLC With HER2 Mutations

Zongertinib represents the first FDA-approved HER2-specific tyrosine kinase inhibitor (TKI) for HER2 mutations, offering a unique focus on the ERBB family of alterations while sparing EGFR. The Beamion LUNG-1 study, presented at the American Association for Cancer Research Annual Meeting 2025 and published in the New England Journal of Medicine with John Heymach as first author, established zongertinib’s efficacy in the second-line setting through a comprehensive phase 1 escalation followed by expansion study design. Cohort 1 specifically evaluated patients with HER2 mutations who had received prior carboplatin, pemetrexed, with or without pembrolizumab, demonstrating impressive efficacy with a 75% response rate, median progression-free survival of 14 months, and median duration of response of 14.1 months.

The safety profile of zongertinib distinguishes it significantly from chemotherapy-based approaches like trastuzumab deruxtecan, demonstrating true targeted therapy characteristics without chemotherapy-like toxicity. Approximately 50% of patients experienced diarrhea, primarily low grade (grade 1-2), with only 1% experiencing grade 3 diarrhea. Additional toxicities included mild cutaneous reactions and rash, but notably less severe than older- generation HER2 TKIs, plus mild aspartate aminotransferase-alanine aminotransferase elevations with sub-10% grade 3 rates. Critically, no interstitial lung disease was observed, along with absence of significant nausea, vomiting, or major hematologic toxicity, clearly separating zongertinib as a well-tolerated targeted therapy option.

Additional cohorts provided valuable insights into zongertinib’s broader clinical utility. Cohort 3 examined patients with prior HER2-directed therapy, including those who had received trastuzumab deruxtecan, showing an approximately 50% response rate with durable efficacy and no increased toxicity rates, particularly no increased interstitial lung disease risk. Patients with non–tyrosine kinase domain mutations (outside exons 18-24) showed a 30% response rate, while central nervous system (CNS) activity demonstrated 43% intracranial response rate (60% per FDA label). Ongoing cohorts include first-line untreated patients (cohort 2) and active untreated CNS metastases (cohort 4), addressing critical unmet needs. The August 8, 2025, approval established zongertinib as standard second-line care, with ongoing frontline trials (Beamion LUNG-2) comparing it to chemotherapy plus immunotherapy.