Zongertinib Yields 71% Response Rate in Early Trial for HER2-Mutant NSCLC

Zongertinib, an oral HER2-targeted therapy, demonstrated high response rates and a manageable safety profile in previously treated patients with HER2-mutant non-small cell lung cancer (NSCLC), according to results of a phase 1a/1b trial published in the New England Journal of Medicine.

The HER2 protein (human epidermal growth factor receptor 2) is best known as a biomarker in breast cancer, but it is also found in several other malignancies. HER2 mutations are found in roughly 2% to 4% of NSCLCs, most often as exon 20 insertions in the tyrosine kinase domain. These mutations are distinct from HER2 amplification or overexpression, and treatment options remain limited. Enhertu (trastuzumab deruxtecan), an intravenous antibody–drug conjugate, is currently the only FDA-approved therapy for HER2-mutant NSCLC, but it carries risks such as interstitial lung disease. Other pan-HER tyrosine kinase inhibitors have shown modest activity and are often associated with significant EGFR-related toxicities.

John Heymach, M.D., Ph.D.

Zongertinib, an oral HER2-selective tyrosine kinase inhibitor, was evaluated in three patient cohorts as part of the phase 1 Beamion LUNG-1 trial. The study was led by principal investigator John Heymach, M.D., Ph.D., who headed a team of researchers from the University of Texas MD Anderson Cancer Center. The results were published on April 28, 2025, in NEJM.

The researchers evaluated zongertinib’s efficacy and safety in three distinct cohorts of patients with previously treated HER2-mutant NSCLC. Cohort 1 included 75 patients with tumors harboring HER2 mutations in the tyrosine kinase domain, the most common mutation subtype. These patients received zongertinib at a 120 milligram (mg) dose once a day The confirmed objective response rate was 71%, with a median progression-free survival of 12.4 months and a median duration of response of 14.1 months.

A second cohort (designated “cohort 5”) included 31 patients who had been previously treated with HER2-directed antibody–drug conjugates, primarily Enhertu. In this group, the objective response rate was 48%. Meanwhile, cohort 3 consisted of 20 patients whose tumors carried HER2 mutations outside the tyrosine kinase domain. This group showed a response rate of 30%.

Across all three cohorts, treatment-related adverse events were generally low-grade. Grade 3 or higher treatment-related adverse events occurred in 17% of patients, and no cases of drug-related interstitial lung disease were reported. Side effects such as diarrhea and rash, often seen with other HER2 or EGFR-targeted therapies, were less common and generally mild.

Unlike other tyrosine kinase inhibitor drugs that affect multiple members of the HER family, zongertinib was designed to selectively inhibit HER2 while sparing EGFR. This specificity may explain the lower rate of EGFR-associated side effects observed in the trial.

“A 71% response rate is unprecedented in this cancer subtype, and not only is the data strong in showing that this treatment works, but zongertinib has the added convenience of being a once-daily oral therapy,” Heymach, who recently presented the updated results of the trial at the American Association for Cancer Research (AACR) Annual Meeting 2025, said in a news release. He described the new data as “particularly encouraging” for patients whose disease progressed after previous therapies.

In February 2025, the FDA granted Priority Review to Boehringer Ingelheim’s new drug application for zongertinib for the treatment of adults with unresectable or metastatic HER2-mutant NSCLC who have received prior systemic therapy. If approved, zongertinib would be the first orally administered, targeted treatment for this patient population.

The FDA’s decision is expected later this year. If approved, zongertinib could represent a more convenient, lower-toxicity treatment option for patients with this difficult-to-treat lung cancer subtype.

One issue with HER2-targeted therapy for NSCLC is whether the current tests are sensitive enough to detect all the tumors that might be appropriate for treatment. Yale researchers reported the results for a more sensitive test in Modern Pathology last year.