The novel HER2-targeted tyrosine kinase inhibitor zongertinib elicited durable responses in patients with advanced, previously treated non–small cell lung cancer (NSCLC) that harbored a HER2 mutation, according to the preliminary results of the early-phase Beamion LUNG-1 trial. These findings were presented by John V. Heymach, MD, PhD, Chair of Thoracic/Head and Neck Medical Oncology and the Ruth Legett Jones Distinguished Chair at The University of Texas MD Anderson Cancer Center, at the 2025 American Association for Cancer Research (AACR) Annual Meeting (Abstract CT050) and were simultaneously published in The New England Journal of Medicine.
Between 2% and 4% of NSCLC tumors have an activating mutation in HER2. To date, the only HER2-targeted therapy approved by the U.S. Food and Drug Administration (FDA) for NSCLC is fam-trastuzumab deruxtecan-nxki (T-DXd), an antibody-drug conjugate that delivers a cytotoxic drug directly to cells expressing HER2. However, T-DXd is not effective in all patients and is accompanied by the risk of significant side effects, including interstitial lung disease, explained Dr. Heymach. In addition, T-DXd must be given intravenously in a clinic.
“There remains a clear unmet need for an effective, easily tolerable, and convenient targeted therapy for patients with HER2-mutated NSCLC,” he added.
This potentially practice-changing approval of zongertinib would provide access to a highly efficacious treatment option with a manageable safety profile and would be the first oral therapy and only tyrosine kinase inhibitor approved for patients with HER2-mutated NSCLC.— John V. Heymach, MD, PhD
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Oral small-molecule inhibitors of HER2, such as lapatinib and neratinib, have been approved by the FDA for HER2-overexpressing breast cancer, but these inhibitors are not as effective against HER2-mutated cancers and may also cause side effects related to cross-targeting of EGFR, Dr. Heymach said. Zongertinib selectively inhibits HER2 without targeting EGFR, and preclinical studies have showed it may prove to be more active than other HER2 inhibitors, with fewer toxicities.
Study Details and Results
In cohort 1 (primary analysis cohort) of the first-in-human Beamion LUNG-1 clinical trial, 75 patients with previously treated NSCLC whose tumors harbored mutations in the tyrosine kinase domain (TKD) of HER2 were treated with the recommended dose of 120 mg of zongertinib once a day. The researchers also assessed the outcomes of patients treated at the recommended dose in exploratory cohorts, including 20 previously treated patients whose tumors had HER2 mutations outside the TKD (cohort 3) and 31 patients whose tumors had HER2 mutations within the TKD and had previously received a HER2-targeted antibody-drug conjugate (cohort 5).
Overall, 71%, 30%, and 48% of patients in cohorts 1, 3, and 5, respectively, experienced an objective response to zongertinib. The disease control rate was 96% in cohort 1, 65% in cohort 3, and 97% in cohort 5.
Responses were also durable, noted Dr. Heymach, lasting for a median of 14.1 months in cohort 1 and 5.3 months in cohort 5. Similarly, the median progression-free survival was 12.4 months in cohort 1 and 6.8 months in cohort 5. Neither duration of response nor progression-free survival were mature in cohort 3 at the time of this analysis.
In addition to the efficacy observed in patients with traditional mutations in the HER2 TKD, Dr. Heymach emphasized that the results from cohort 3 suggest zongertinib may also target less common HER2 mutations that lie outside the TKD. Further, the results from cohort 5 suggest that zongertinib may benefit patients whose cancers did not respond to or relapsed after treatment with a HER2-targeted antibody-drug conjugate such as T-DXd.
Safety Profile
The rates of grade 3 or higher adverse events were 17%, 25%, and 3% in cohorts 1, 3, and 5, respectively, and no cases of interstitial lung disease were reported. Dr. Heymach stressed that the lower rate of severe side effects as compared with other therapies may stem from the drug’s selectivity to HER2.
“Zongertinib demonstrated a very favorable safety profile, with little or no significant rash, diarrhea, or pneumonitis—toxicities that were observed [with] prior therapies,” he said. “These initial studies suggest that it may be more effective and less toxic than other available therapies for these patients.”
Zongertinib is currently being reviewed by the FDA under Fast Track and Breakthrough Therapy designations for the indication evaluated in this study.
“Until recently, there were no effective targeted therapies for HER2-mutated NSCLC,” Dr. Heymach said. “This potentially practice-changing approval of zongertinib would provide access to a highly efficacious treatment option with a manageable safety profile and would be the first oral therapy and only tyrosine kinase inhibitor approved for patients with HER2-mutated NSCLC.”
Disclosure: Funding for this study was provided by Boehringer Ingelheim. Dr. Heymach has served on the advisory committees for AstraZeneca, Boehringer Ingelheim, Catalyst Pharmaceuticals, Genentech, GSK, Guardant Health, Foundation Medicine, Hengrui Therapeutics, Eli Lilly and Company, Novartis, Spectrum Pharmaceuticals, EMD Serono, Sanofi, Takeda Pharmaceuticals, Mirati Therapeutics, Bristol Myers Squibb, BrightPath Biotherapeutics, Janssen Global Services, Nexus Health Systems, Pneuma Respiratory, Kairos Ventures, Roche, and Leads Biolabs; has received research support from AstraZeneca, GSK, and Spectrum Pharmaceuticals; and has received royalties and licensing fees from Spectrum Pharmaceuticals.
