Zongertinib Yields Enduring Activity in Frontline HER2+ NSCLC Trial

Frontline treatment with zongertinib (Hernexeos) demonstrated enduring activity with low-grade toxicities among those with previously untreated HER2-mutated advanced or metastatic non–small cell lung cancer (NSCLC), according to updated findings from the phase 1a/b Beamion LUNG-1 trial (NCT04886804) published in The New England Journal of Medicine and presented at the 2026 European Lung Cancer Congress.^1,2

With a data cutoff of August 21, 2025, the confirmed objective response rate (ORR) with zongertinib at 120 mg was 76% (n = 56/74; 95% CI, 65%-84%), which included complete responses (CRs) in 11% and partial responses (PRs) in 65%. Data also showed a median time to first response of 1.4 months (95% CI, 1.1-6.9) and a median duration of response (DOR) of 15.2 months (95% CI, 9.8-not evaluable [NE]). The study treatment produced a median progression-free survival (PFS) of 14.4 months (95% CI, 11.1-NE).

Among 30 patients with active brain metastases in cohort 4, 47% (95% CI, 30%-64%) achieved a confirmed response. The ORR was 57% (95% CI, 37%-74%) among those with prior brain radiotherapy (n = 23) and 50% (95% CI, 22%-79%) among patients who received frontline zongertinib (n = 8). The median duration of intracranial response was 6.9 months (95% CI, 2.9-NE), and the median intracranial PFS was 8.2 months (95% CI, 4.1-11.3).

“[These] data show zongertinib demonstrated durable efficacy as first-line therapy in patients with treatment-naïve HER2-mutant advanced [NSCLC], a setting where there are currently limited options with durable responses,” coordinating study investigator John Heymach, MD, PhD, chair of Thoracic/Head and Neck Medical Oncology at The University of Texas MD Anderson Cancer Center, stated in a press release regarding these findings.³ “These findings, now published in The New England Journal of Medicine, may help health care providers make informed decisions on HER2 targeted treatment choices.”

In the multicohort phase 1a/b trial, 74 patients in cohort 2 were assigned to receive zongertinib at 120 mg once daily in each 21-day cycle. Study treatment continued until progressive disease, withdrawal of consent, or unacceptable toxicity. Cohort 4, an exploratory group, included those with previously treated or untreated brain metastases.

The primary end points were ORR per blinded independent central review based on RECIST v1.1 criteria in cohort 2 and intracranial responses in cohort 4. Secondary end points included DOR, PFS, and adverse effects (AEs).

Patients 18 years and older with histologically or cytologically confirmed advanced or metastatic NSCLC, HER2 mutations in the tyrosine kinase domain, and at least 1 measurable lesion outside of the central nervous system per RECIST v1.1 guidelines were eligible for study entry. Having an ECOG performance status of 0 or 1 was another requirement for enrollment.

Across cohort 2, the median age was 67 years (range, 35-88), and most patients were 18 to 64 years old (42%) and Asian (50%); an equal proportion of patients were male and female. Most of the study population had an ECOG performance status of 1 (54%), no tobacco use (64%), and metastases in the brain (30%) vs the liver (16%).

AEs of any grade and grade 3 or higher occurred in 99% and 45% of patients, respectively. The most common any-grade treatment-related toxicities included diarrhea (55%), rash (24%), increased alanine aminotransferase (18%), dysgeusia (18%), nausea (18%), and increased aspartate aminotransferase (16%). The safety profile of zongertinib among patients with brain metastases was comparable with that of the overall Beamion LUNG-1 population.

The FDA previously granted accelerated approval to zongertinib as a treatment for patients with unresectable or metastatic NSCLC harboring HER2 tyrosine kinase domain–activating mutations in February 2026 based on results from the Beamion LUNG-1 study.⁴

References

1. Heymach JV, Yamamoto N, Girard N, et al. First-line zongertinib in advanced HER2-mutant non–small-cell lung cancer. N Engl J Med. Published online April 15, 2026. doi:10.1056/NEJMoa2516969
2. Heymach JV, Yamamoto N, Girard N, et al. Zongertinib in treatment-naive patients with HER2-mutant NSCLC, including those with active brain metastases: Beamion LUNG-1. Presented at: 2026 European Lung Cancer Congress; March 25-28, 2026; Copenhagen, Denmark. Abstract 6MO.
3. Beamion LUNG-1 study results for zongertinib in treatment-naïve patients with HER2-mutant advanced NSCLC published in The New England Journal of Medicine. News release. Boehringer Ingelheim. April 16, 2026. Accessed April 17, 2026. https://tinyurl.com/y6h4hxdr
4. FDA grants second approval under the National Priority Voucher Pilot Program. News release. FDA. February 26, 2026. Accessed April 17, 2026. https://tinyurl.com/efhx9sr9