PROMISING new data emerged on zongertinib, an investigational oral therapy targeting HER2 mutations in advanced non-small cell lung cancer (NSCLC), was presented at the AACR Annual Meeting 2025 in Chicago. HER2 mutations occur in 2 to 4 percent of NSCLC cases and have historically lacked effective targeted treatments.
Zongertinib, a selective HER2 tyrosine kinase inhibitor, was evaluated in the phase Ia/Ib Beamion LUNG-1 trial. The therapy produced durable responses in patients with advanced, previously treated HER2-mutant NSCLC, offering a potential alternative to currently available therapies that are limited by efficacy and safety challenges.
Among the 75 patients in cohort 1, who had HER2 tyrosine kinase domain (TKD) mutations, the objective response rate was 71 percent, and disease control was achieved in 96 percent of cases. Responses were sustained with a median duration of 14.1 months and a progression-free survival of 12.4 months. Importantly, this cohort had not previously received HER2-directed antibody-drug conjugates.
In patients with less common non-TKD mutations (cohort 3), the response rate was 30 percent, with a disease control rate of 65 percent. In cohort 5, consisting of patients whose disease had progressed after treatment with HER2 antibody-drug conjugates, response and disease control rates were 48 percent and 97 percent, respectively. Median response duration in cohort 5 was 5.3 months, with a progression-free survival of 6.8 months.
Adverse events of grade 3 or higher were relatively low, observed in 17 percent of patients in cohort 1, 25 percent in cohort 3, and just 3 percent in cohort 5. No cases of interstitial lung disease were reported.
Zongertinib is currently under FDA review with Fast Track and Breakthrough Therapy designations. If approved, it would become the first oral HER2-targeted tyrosine kinase inhibitor for NSCLC, potentially reshaping treatment options for this challenging subset of lung cancer.
American Association for Cancer Research (AACR). Oral HER2-targeted Therapy Zongertinib Demonstrates Clinical Benefit in Advanced HER2-mutated Lung Cancer. 2025. Available at: https://aacr.ent.box.com/s/hhwle7pf9kajhssotgo16kfqgtxe2fwb. Last accessed: 1 May 2025.
