Dr Heymach on the Efficacy of Zongertinib in Previously Treated HER2-Mutant NSCLC

"In cohort 1, which was the primary cohort, the ORR was 71%, and the [median] progression-free survival was 12.4 months. That's longer than other targeted agents that have been tested in this stage."

John V. Heymach, MD, PhD, chair of Thoracic/Head and Neck Medical Oncology, and the David Bruton Endowed Chair in Cancer Research at The University of Texas MD Anderson Cancer Center, discussed key results from the phase 1b Beamion LUNG-1 trial (NCT04886804) evaluating zongertinib (BI 1810631) in patients with previously treated advanced non–small cell lung cancer (NSCLC) harboring HER2 mutations.

Findings presented at the 2025 AACR Annual Meeting demonstrated that treatment with zongertinib generated responses and exhibited activity in patients with HER2 mutations both within and outside the tyrosine kinase domain (TKD). In cohort 1 (n = 75), patients harboring TKD HER2 mutations achieved an overall response rate (ORR) of 71% (95% CI, 60%-80%), which included a complete response (CR) rate of 7% and a partial response (PR) rate of 64%, Heymach reported. Rates of stable disease (SD) and progressive disease (PD) in this cohort were 25% and 4%, respectively, and the disease control rate (DCR) was 96% (95% CI, 89%-99%). The median best change from baseline in target lesions for cohort 1 was –43% (range, –100% to 22%).

The median progression-free survival (PFS) in cohort 1 was 12.4 months (95% CI, 8.2-not evaluable), which is longer than what has been observed with other HER2-targeted TKIs tested in this setting, Heymach commented.

In cohort 3, patients with non-TKD HER2 mutations (n = 20) experienced an ORR of 30% (95% CI, 15%-52%), with all responses being PRs. In this group, the rates of SD and PD were 35% and 30%, respectively, and 1 patient (5%) was not evaluable (NE), resulting in a DCR of 65% (95% CI, 43%-82%), Heymach stated.

In cohort 5, which included patients with advanced NSCLC and TKD HER2 mutations who had received prior platinum-based chemotherapy with or without immunotherapy and a prior HER2-directed antibody-drug conjugate (n = 31), the ORR was 48% (95% CI, 32%-65%). This included a CR rate of 3% and a PR rate of 45%. The DCR in this cohort was 97% (95% CI, 84%-99%), with no patients experiencing PD as their best response, 48% achieving SD, and 3% classified as NE. Among patients who previously received fam-trastuzumab deruxtecan-nxki (Enhertu; n = 22), the ORR was 41% (95% CI, 23%-61%).