Zongertinib, an investigational oral, HER2-selective, EGFR-sparing tyrosine kinase inhibitor, elicited durable responses and demonstrated clinical benefit in patients with advanced, previously treated, HER2-mutant non–small cell lung cancer (NSCLC), according to data presented by John V. Heymach, MD, PhD, Chair of Thoracic/Head and Neck Medical Oncology at The University of Texas MD Anderson Cancer Center, Houston, on behalf of his colleagues at the 2025 American Association for Cancer Research (AACR) Annual Meeting.¹ The results were simultaneously published in The New England Journal of Medicine.²

Results from the phase Ia/Ib Beamion LUNG-1 trial showed a confirmed objective response rate of 71% and a median progression-free survival of 12.4 months. Authors of the study emphasized the drug’s manageable safety profile, with low rates of wild-type EGFR-related toxicities and no reported drug-related interstitial lung disease, addressing key limitations of previous HER2-targeting agents.

“This potentially practice-changing approval of zongertinib...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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“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,” said Dr. Heymach, lead investigator of the study.

Background

As Dr. Heymach explained, there remains a clear unmet need for an effective, easily tolerable, and convenient targeted therapy for patients with HER2-mutant NSCLC. These activating mutations occur in approximately 2% to 4% of patients with NSCLC and are associated with a worse overall prognosis, including a higher incidence of brain metastases.

“Developing effective tyrosine kinase inhibitors for HER2 mutations has been challenging because of the structural complexity of the mutant kinase domain and the potential for significant toxicity resulting from off-target inhibition of wild-type EGFR, a structurally related kinase,” said Dr. Heymach. “While antibody-drug conjugates like fam-trastuzumab deruxtecan-nxki (T-DXd) have shown efficacy and gained accelerated approval, they are associated with different toxicities, including myelosuppression and interstitial lung disease, which can be particularly concerning in the NSCLC population.”

Study Methods

The Beamion LUNG-1 study is a multicenter phase Ia/Ib trial evaluating zongertinib in previously treated patients with locally advanced or metastatic HER2-mutant NSCLC. Based on phase Ia/Ib dose escalation, a dose of 120 mg daily was selected for the expansion cohorts presented. The data cutoff for this analysis was November 2024.

The results focus on three key previously treated cohorts: cohort 1 (n = 75) included patients with TKD (tyrosine kinase domain) mutations who had not received a prior HER2 antibody-drug conjugate; cohort 5 (n = 31) included patients with TKD mutations who had received a prior HER2 antibody-drug conjugate; and cohort 3 (n = 20) included patients with non-TKD mutations. The primary endpoint was objective response rate, assessed by blinded independent central review for cohorts 1 and 5 and by investigator assessment for cohort 3. Secondary endpoints included duration of response, disease control rate, and progression-free survival.

Key Results

In cohort 1, zongertinib showed efficacy, with a confirmed overall response rate of 71% and a disease control rate of 96%. “Responses were observed rapidly, with a median time to response of 1.4 months,” said Dr. Heymach. “The median duration of response was 14.1 months.” The median progression-free survival for this cohort was 12.4 months.

Zongertinib also demonstrated evidence of intracranial activity. Among 27 patients in cohort 1 with evaluable brain metastases, the intracranial overall response rate was 41%, and the disease control rate was 81%.

In cohort 5, zongertinib showed activity in a more heavily pretreated population. The overall response rate was 48%. Among the 22 patients specifically treated with prior T-DXd, the overall response rate was 41%.

According to Dr. Heymach, this finding suggests that zongertinib may prove to be effective in patients who have developed resistance to HER2-directed antibody-drug conjugates, potentially because of nonoverlapping mechanisms of resistance. The median duration of response was 5.3 months, and the median progression-free survival was 6.8 months in this cohort.

In cohort 3, zongertinib demonstrated activity, with an overall response rate of 30% and a disease control rate of 65%. Among the 17 patients with known activating non-TKD mutations, the overall response rate was 35%. This represents the largest reported data set for a tyrosine kinase inhibitor in the non-TKD, HER2-mutant NSCLC population. Duration of response and progression-free survival were not yet mature in this cohort at the time of analysis.

Safety Profile

The safety profile of zongertinib at 120 mg daily was also reported to be manageable and consistent across all cohorts. Most drug-related adverse events were grade 1 or 2. The rates of grade 3 or higher adverse events were 17% in cohort 1, 25% in cohort 3, and 3% in cohort 5. Wild-type EGFR-mediated toxicities were reported to be minimal, with low rates of significant rash or diarrhea. Of note, there were no reported cases of drug-related interstitial lung disease across any cohort.

Zongertinib is currently being reviewed by the U.S. Food and Drug Administration under Fast Track and Breakthrough Therapy designations for the indication evaluated in this study. A randomized phase III trial, Beamion LUNG-2, is currently enrolling patients to compare zongertinib with standard-of-care chemoimmunotherapy in the first-line setting for advanced HER2-mutant NSCLC.ν

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.

REFERENCES

1. Heymach JV, Ruiter G, Ahn MJ, et al: Zongertinib in patients with pretreated HER2-mutant advanced NSCLC: Beamion LUNG-1. 2025 AACR Annual Meeting. Abstract CT050. Presented April 28, 2025.

2. Heymach JV, Ruiter G, Ahn MJ, et al: Zongertinib in previously treated HER2-mutant non-small-cell lung cancer. N Engl J Med. April 28, 2025 (early release online).

EXPERT POINT OF VIEW

Invited discussant of the Beamion LUNG-1 trial, Charles Rudin, MD, PhD, called the results of this study a “significant advance for patients with HER2-mutant NSCLC.” Dr. Rudin is Deputy Director of Memorial Sloan Kettering Cancer Center, Co-Director of the Druckenmiller Center for Lung Cancer Research, and Sylvia Hassenfeld Chair in Lung Cancer Research, Memorial Sloan Kettering Cancer Center, New York.

Charles Rudin, MD, PhD

“An effective, well-tolerated, orally bioavailable therapy for patients with HER2-driven lung cancer has long been an unmet need,” said Dr. Rudin. “In my opinion, zongertinib satisfies the primary criteria we would want to see for a drug of this class.”

In Search of Effective Treatments

Dr. Rudin highlighted the historical challenges in targeting HER2 mutations, noting the complex biology, including the dimerization requirements for HER2 signaling and the difficulties in developing tyrosine kinase inhibitors that are potent against the mutant while sparing wild-type EGFR to avoid toxicities such as rash and diarrhea. Previous HER2-targeting tyrosine kinase inhibitors, such as afatinib, poziotinib, and pyrotinib, have shown limitations in terms of either modest efficacy or significant toxicity, noted Dr. Rudin.

Comparing zongertinib with the currently available antibody-drug conjugate fam-trastuzumab deruxtecan-nxki (T-DXd), Dr. Rudin acknowledged the impressive efficacy data for T-DXd from trials such as DESTINY-Lung01 and -02, demonstrating high response rates and durable benefit. However, he emphasized, antibody-drug conjugates come with distinct toxicities, including chemotherapy-like side effects, myelosuppression, and the risk of interstitial lung disease, which can lead to dose reductions or discontinuations. Conversely, zongertinib’s favorable safety profile was characterized by a low incidence of grade 3 or higher toxicities and minimal EGFR-related adverse events, addressing a key limitation of previous tyrosine kinase inhibitors.

Critical Questions Remain

“The improved tolerability is a significant advantage for zongertinib,” noted Dr. Rudin. “However, there remain critical questions about how these different modalities should be sequenced or potentially combined.”

According to Dr. Rudin, the primary question in the field now is which agent might ultimately be used in the first-line setting for HER2-mutant NSCLC, given that both approaches appear to be superior to traditional chemotherapy or chemoimmunotherapy. He noted that first-line studies are ongoing, including the phase III Beamion LUNG-2 trial evaluating zongertinib.

Although Dr. Rudin is giving an “edge” to tyrosine kinase inhibitors such as zongertinib, based on their high response rates and more favorable tolerability profile vs antibody-drug conjugates, he also highlighted brain metastases as an important challenge and potential discriminant among agents. Zongertinib showed intracranial activity, Dr. Rudin suggested, but even better brain penetration could be desirable. Other investigational tyrosine kinase inhibitors in earlier development are being specifically evaluated for their brain coverage, he added.

“The development of both next-generation tyrosine kinase inhibitors and antibody-drug conjugates represents great news for patients with HER2-mutant lung cancer, marking a significant improvement over historical outcomes,” Dr. Rudin concluded. “This is a highly competitive space with multiple active agents, ultimately benefiting patients.”

DISCLOSURE: Dr. Rudin has served as a consultant to Amgen, AstraZeneca, Daiichi Sankyo, F. Hoffmann–La Roche, Novartis, and Jazz Pharmaceuticals; has served on the scientific advisory boards of Auron Therapeutics, DISCO Pharmaceuticals, and Earli; and has received royalty payments for licensing of DLL3-directed therapeutics.