The FDA has granted zongertinib (HERNEXEOS, Boehringer Ingelheim Pharmaceuticals, Inc.) a first-line indication for adults with unresectable or metastatic non-squamous non-small cell lung cancer (NSCLC) whose tumors express HER2 (ERBB2) tyrosine kinase domain activating mutations on an FDA-authorized test.

The agency previously approved the oral tyrosine kinase inhibitor in August 2025 for the same patient population after prior systemic therapy. About 2%-4% of patients with NSCLC harbor HER2 (ERBB2) mutations, and they are associated with a poor prognosis and higher incidence of brain metastases, Boehringer said in a press release.

The accelerated approval makes zongertinib the first targeted therapy for treatment-naive patients with HER2 (ERBB2)-mutant advanced NSCLC, the company said.

The label expansion is based on a 72-patient cohort in the single-arm, open-label Beamion LUNG-1 trial who were new to systemic treatment.

The objective response rate was 76%, with 64% of responders having a response duration of at least 6 months and 44% having a response duration of at least 1 year.

Boehringer said it’s currently enrolling in Beamion LUNG-2, a confirmatory phase 3 trial for the first-line indication.

In a pooled safety analysis of 292 treatment-naive and previously treated patients, the most common adverse reactions were diarrhea (54% of patients), rash (28%), hepatotoxicity (27%), fatigue (25%), nausea (23%), musculoskeletal pain (21%), and upper respiratory tract infection (20%). Adverse events led to dose discontinuations in 6% of patients.

Labeling warnings and precautions include hepatotoxicity, left ventricular dysfunction, interstitial lung disease/pneumonitis, and embryo-fetal toxicity.

Zongertinib dosing is based on body weight: Patients weighing < 90 kg receive 120 mg once daily; for those weighing more, the dose is 180 mg once daily. Zongertinib may be taken with or without food. Treatment continues until disease progression or unacceptable toxicity.

M. Alexander Otto is a physician assistant with a master’s degree in medical science and a journalism degree from Newhouse. He is an award-winning medical journalist who worked for several major news outlets before joining Medscape. Alex is also an MIT Knight Science Journalism fellow. Email: aotto@mdedge.com