Activating HER2 mutations occur in 2% to 4% of patients with non-small cell lung cancer (NSCLC). Patients harboring such mutations often have a worse prognosis and higher incidence of brain metastases.
“There remains a clear, unmet need for a potent TKI that selectively inhibits HER2 while sparing these EGFR-related toxicities,” said John V. Heymach, MD, PhD, Chair of Thoracic, Head, and Neck Medical Oncology and a Professor at The University of Texas MD Anderson Cancer Center.
Historically, it’s been a challenge to develop TKIs for HER2 mutations because of EGFR-related toxicities and structural changes that prevent drugs from effectively targeting mutant HER2 kinase. Thus, until recently, treatment options have been limited for patients with HER2-mutant NSCLC. However, the latest results from the Beamion LUNG-1 trial suggest that research may have found a way to address current limitations with the novel TKI zongertinib.
The findings demonstrated a 71% objective response rate (ORR) in patients with tyrosine kinase domain (TKD) mutations and 48% ORR in patients who had prior HER2-directed antibody drug conjugates (ADCs).
“Compared to drugs that have previously been tested in this space such as poziotinib and afatinib, zongertinib is roughly two orders of magnitude more selective for the HER2 insertion,” Dr. Heymach said.
The results were presented during the 2025 American Association for Cancer Research (AACR) Annual Meeting. Zongertinib, a potent covalent TKI, selectively inhibits HER2 while sparing wild-type EGFR. It has already received priority review from the US Food and Drug Administration for the treatment of unresectable or metastatic NSCLC.
In the phase Ib Beamion LUNG-1 interim analysis, a 120 mg daily dose was administered following the phase Ia dose escalation. The second part of the study enrolled participants from three cohorts:
- Cohort one, the primary and largest cohort, included patients with TKD mutations in a specific HER2 region.
- Cohort five included patients with TKD mutations who had previously received a HER2-directed ADC.
- Cohort three included patients with non-TKD mutations.
The primary endpoint was ORR as assessed by a blinded independent central review for cohorts one and five or by investigator review for cohort three. The secondary endpoints included duration of response (DoR), disease control rate (DCR), and progression-free survival (PFS). Dr. Heymach presented the efficacy and safety data as of the data cutoff of November 2024.
He said responses to zongertinib were durable, with a median DoR of 14.1 months and a median time to response of 1.4 months. The median PFS for cohort one was 12.4 months. Zongertinib demonstrated intracranial activity in participants, with 81% of participants with brain metastases achieving disease control.
Additionally, zongertinib exhibited a manageable safety profile, with a low incidence of grade 3 treatment-related adverse events (TRAEs). Only 7% of participants experienced adverse events (AEs) that led to a dose reduction, and only 3% discontinued treatment due to AEs.
“Most drug related adverse events were grade 1 and 2,” Dr. Heymach said. “The most common AE was diarrhea, which was largely grade 1. Only one patient had grade 3 diarrhea.”
With a favorable safety profile and strong response rates, the Beamion LUNG-01 trial sets the stage for zongertinib as a potential first-line therapy for patients with HER2-mutant NSCLC.
The Beamion LUNG-02 trial is underway and will evaluate the efficacy and safety of zongertinib compared with pembrolizumab in combination with platinum-pemetrexed chemotherapy.
