FDA Grants Accelerated Approval to Zongertinib for Unresectable or Metastatic NSCLC

The FDA has granted accelerated approval to zongertinib (Hernexeos; Boehringer Ingelheim Pharmaceuticals, Inc) for an expanded indication in adults with unresectable or metastatic nonsquamous non–small cell lung cancer (NSCLC) whose tumors have HER2 (ERBB2) tyrosine kinase domain (TKD)– activating mutations, as detected by an FDA-authorized test.¹

In addition to positive clinical trial results supporting zongertinib’s use in this patient population, the FDA issued this approval as part of the new Commissioner’s National Priority Voucher pilot program. This program seeks to expedite the approval of applications that address critical national health priorities and large unmet medical needs while promoting domestic manufacturing and increasing affordability.²

Zongertinib is an oral, irreversible, HER2-selective tyrosine kinase inhibitor that has previously shown efficacy in patients with advanced or solid tumors with HER2 alterations. The agent was evaluated in the single-arm, open-label, dose-escalation phase 1 clinical trial, Beamion LUNG-1 (NCT04886804).^3,4

The trial was split into 2 parts. The first part aimed to determine the highest tolerable dose of zongertinib; the second, which is ongoing, will assess whether zongertinib can cause tumors to shrink. In part 1, the following patients were enrolled: those with tumors harboring a mutation in the tyrosine kinase domain (cohort 1); those with tumors harboring a mutation in the tyrosine kinase domain previously treated with a HER2-directed antibody-drug conjugate (cohort 5); and those with tumors harboring a non–tyrosine kinase domain mutation (cohort 3).^3,4

In cohort 1, patients were initially randomly assigned to receive either 120 mg or 240 mg of zongertinib once per day. Patients in cohorts 5 and 3 initially received 240 mg daily. After an interim analysis of data from cohort 1, patients across all cohorts who were subsequently recruited received 120 mg of zongertinib. The trial’s primary end point was an objective response assessed by blinded independent central review (cohorts 1 and 5) or by investigator review (cohort 3). Secondary end points included the duration of response and progression-free survival (PFS).^3,4

Findings were published in the New England Journal of Medicine. In cohort 1, 75 patients received zongertinib at a dose of 120 mg. On November 29, 2024, at the time of data cutoff, approximately 71% of these patients (95% CI, 60%-80%; P < .001 vs a benchmark of ≤ 30%) had a confirmed objective response. The median duration of response was about 14.1 months (95% CI, 6.9-not evaluable [NE]), and the median PFS was about 12.4 months (95% CI, 8.2-NE). In cohorts 5 (n = 31) and 3 (n = 20), approximately 48% (95% CI, 32%-65%) and 30% (95% CI, 15%-52%) of patients, respectively, had a confirmed objective response.³

Grade 3 or higher drug-related adverse events (AEs) occurred in 13 (17%), 1 (3%), and 5 (25%) patients in cohorts 1, 5, and 3, respectively. Across all 3 cohorts, the investigators reported no cases of drug-related interstitial lung disease.³

According to an FDA news release, the recommended zongertinib dose is based on each patient’s body weight. For patients weighing less than 90 kg, the dose is 120 mg orally once daily; for those weighing 90 kg or more, the dose is 180 mg orally once daily. Zongertinib may be taken with or without food and is to be continued until disease progression or unacceptable toxicity.¹

REFERENCES

1. FDA grants accelerated approval to zongertinib for unresectable or metastatic non-squamous non-small cell lung cancer. FDA. February 26, 2026. Accessed February 26, 2026. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-accelerated-approval-zongertinib-unresectable-or-metastatic-non-squamous-non-small-cell?utm_medium=email&utm_source=govdelivery

2. FDA grants second approval under the National Priority Voucher Pilot Program. News release. FDA. February 26, 2026. Accessed February 26, 2026. https://www.fda.gov/news-events/press-announcements/fda-grants-second-approval-under-national-priority-voucher-pilot-program

3. Heymach JV, Ruiter G, Ahn MJ, et al; Beamion LUNG-1 Investigators. Zongertinib in previously treated HER2-mutant non–small-cell lung cancer. N Engl J Med. 2025;392(23):2321-2333. doi:10.1056/NEJMoa2503704

4. Beamion LUNG-1: a study to test different doses of zongertinib in people with different types of advanced cancer (solid tumours with changes in the HER2 gene). ClinicalTrials.gov. Updated February 19, 2026. Accessed February 26, 2026. https://clinicaltrials.gov/study/NCT04886804