FDA Grants Accelerated Approval to Zongertinib for Unresectable or Metastatic Nonsquamous NSCLC With HER2 TKD Mutations

The FDA has granted accelerated approval to zongertinib (Hernexeos) for the treatment of adult patients 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.

The approval was part of the FDA Commissioner’s National Priority Review Voucher (CNPV) pilot program, intended to accelerate the review of agents or combinations with the potential to address key national priorities.

The regulatory decision was supported by data from the single-arm, open-label, phase 1 Beamion LUNG-1 trial (NCT04886804), which demonstrated that evaluable patients who were naive to systemic therapy for advanced disease (n = 72) achieved an objective response rate (ORR) of 76% (95% CI, 65%-85%) per RECIST 1.1 criteria. Notably, the 6- and 12-month duration of response rates were 64% and 44%, respectively.

The expanded indication follows the August 2025 FDA accelerated approval of zongertinib for adult patients with unresectable or metastatic nonsquamous NSCLC whose tumors harbor HER2 TKD activating mutations, as detected by an FDA-approved test, and who have received prior systemic therapy.²

How was Beamion LUNG-1 conducted?

Beamion LUNG-1 is an ongoing, open-label, dose-escalation, -confirmation, and -expansion study evaluating zongertinib in patients with advanced solid tumors harboring HER2 aberrations, including NSCLC.³ Phase 1a includes patients with various tumor types, and phase 1b is evaluating the agent specifically in patients with HER2-mutated NSCLC.

Phase 1b of the study comprises multiple cohorts:

• Cohort 1: patients with previously treated, advanced NSCLC with TKD HER2 mutations
• Cohort 2: patients with treatment-naive disease harboring HER2 TKD mutations
• Cohort 3: patients with previously treated squamous NSCLC with non-TKD HER2 mutations
• Cohort 4: patients with NSCLC with active brain metastases and HER2 TKD mutations
• Cohort 5: patients with previously treated NSCLC harboring HER2 TKD mutations who received prior platinum-based chemotherapy with or without immunotherapy and a subsequent HER2-directed antibody-drug conjugate
• Cohorts 6/7: patients with previously treated, advanced nonsquamous NSCLC harboring HER2 TKD mutations
• Cohort 8: patients with treatment-naive, advanced NSCLC with a HER2 TKD mutation, or those with treatment-naive, advanced nonquamous NSCLC harboring a non-TKD HER2 mutation

All enrolled patients are receiving zongertinib monotherapy. Per the FDA, the recommended dose of zongertinib is 120 mg once per day for patients weighing less than 90 kg, or 180 mg once per day in patients weighing at least 90 kg.¹

ORR and DOR per RECIST 1.1 criteria were the primary objectives for the phase 1b portion of the trial.

What is the safety profile of zongertinib?

In evaluable patients (n = 177) with advanced nonsquamous NSCLC harboring HER2 TKD mutations who were treated with zongertinib in Beamion LUNG-1, irrespective of line of therapy, serious adverse effects (AEs) were reported in 36%.⁴ Serious AEs reported in at least 2% of patients comprised pulmonary embolism (4%), dyspnea (3.4%), pneumonia (2.8%), hepatotoxicity (2.3%), pleural effusion (2.3%), and pericardial effusion (2.3%). One patient (0.6%) experienced a fatal AE (pneumonia).

AEs led to permanent discontinuation of treatment in 6% of patients. The rates of dose interruptions and reductions due to AEs were 34% and 9%, respectively.

The most common any-grade AEs included diarrhea (56%), rash (32%), fatigue (26%), nausea (25%), cough (23%), musculoskeletal pain (23%), upper respiratory tract infections (23%), stomatitis (21%), nail disorders (21%), and headache (16%).

What is next for zongertinib in NSCLC?

The ongoing, randomized phase 3 Beamion LUNG-2 trial (NCT06151574) is evaluating zongertinib vs standard-of-care therapy in patients with HER2-mutant unresectable or metastatic nonsquamous NSCLC who have not received systemic therapy in the advanced or metastatic settings.⁵

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
2. FDA grants accelerated approval to zongertinib for nonsquamous NSCLC with HER2 TKD activating mutations. FDA. August 8, 2025. Accessed February 26, 2026. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-accelerated-approval-zongertinib-non-squamous-nsclc-her2-tkd-activating-mutations
3. 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
4. Hernexeos. Prescribing information. Boehringer Ingelheim Pharmaceuticals, Inc; 2026. Accessed February 26, 2026. https://patient.boehringer-ingelheim.com/us/products/hernexeos/bipdf/hernexeos-dtc-prescribing-information
5. Beamion LUNG-2: a study to test whether zongertinib (BI 1810631) helps people with advanced non-small cell lung cancer with HER2 mutations compared with standard treatment. ClinicalTrials.gov. Updated February 18, 2026. Accessed February 26, 2026. https://clinicaltrials.gov/study/NCT06151574