FDA approval summary
On February 26, 2026, the U.S. Food and Drug Administration (FDA) granted accelerated approval to the kinase inhibitor zongertinib (Hernexeos, Boehringer Ingelheim) for an expanded indication in adult patients with unresectable or metastatic non-squamous non-small cell lung cancer (NSCLC) whose tumors harbor HER2 (ERBB2) tyrosine kinase domain (TKD) activating mutations, as detected by an FDA-authorized test, and who have not received systemic therapy for advanced disease.
This approval expands the existing indication to the first-line setting, enabling earlier access to targeted therapy for this genomically defined NSCLC subgroup.
The application was reviewed under the FDA Commissioner’s National Priority Review Voucher (CNPV) pilot program, which aims to accelerate products addressing key national priorities.
Beamion LUNG-1 trial (NCT04886804)
Efficacy was evaluated in Beamion LUNG-1 (NCT04886804), a single-arm, open-label, multicenter, multi-cohort study.
- Design: single-arm, open-label, multicenter, multi-cohort
- Population for efficacy analysis: 72 patients with:
- unresectable or metastatic non-squamous NSCLC, and
- HER2 (ERBB2) TKD activating mutations, and
- no prior systemic therapy for advanced disease
The major efficacy outcomes were objective response rate (ORR) and duration of response (DOR), assessed by blinded independent central review (BICR) per RECIST v1.1.
Key efficacy results
- Objective response rate (ORR):
- ORR: 76% (95% CI: 65, 85)
- Duration of response (DOR):
- DOR ≥ 6 months in 64% of responders
- DOR ≥ 12 months in 44% of responders
Although Beamion LUNG-1 lacked a control arm, the high response rate and substantial proportion of patients with durable responses support a strong antitumor activity signal for zongertinib in HER2 TKD–mutated NSCLC.
Safety profile and key warnings
The prescribing information for zongertinib includes warnings and precautions for:
- Hepatotoxicity
- Left ventricular dysfunction
- Interstitial lung disease (ILD) / pneumonitis
- Embryo-fetal toxicity
As with other HER2-directed agents, cardiac and pulmonary toxicities require careful baseline assessment and ongoing monitoring. Patients with pre-existing cardiac disease or ILD warrant particularly cautious risk–benefit evaluation.
Recommended dosing
The recommended zongertinib dose is body weight–based:
- < 90 kg: 120 mg orally once daily
- ≥ 90 kg: 180 mg orally once daily
Zongertinib may be taken with or without food and should be continued until disease progression or unacceptable toxicity.
This review utilized the Real-Time Oncology Review (RTOR) pilot program to streamline data submission before the complete application was filed, and leveraged the Assessment Aid, a voluntary structured document from the applicant that facilitates the FDA’s assessment. The application received priority review, and zongertinib was granted breakthrough therapy designation, exemplifying the FDA’s expedited pathways for serious conditions.
Editorial perspective (Morningglorysciences)
HER2-mutated NSCLC represents a relatively small fraction of lung cancers, but in those patients the HER2 TKD alteration acts as a clear oncogenic driver. Historically, most HER2-targeted innovation has centered on breast and gastric cancers; only in recent years have HER2-directed antibody–drug conjugates and TKIs begun to transform the lung cancer landscape as well.
The accelerated approval of first-line zongertinib provides:
- a genomically matched TKI option in systemic therapy–naïve, HER2 TKD–mutated non-squamous NSCLC, and
- encouraging efficacy, with a 76% ORR and nearly half of responders maintaining benefit beyond 12 months.
From a practical standpoint, this raises important questions for clinicians:
- How should zongertinib be integrated relative to platinum-based chemoimmunotherapy in newly diagnosed patients?
- What are the optimal sequencing strategies with other HER2-targeted agents, such as antibody–drug conjugates, at progression?
- How do we organize testing workflows so that HER2 TKD mutations—not just HER2 protein overexpression—are reliably detected at diagnosis?
Because this is an accelerated approval based on a single-arm trial, confirmation of clinical benefit in comparative studies will be critical. Real-world data on cardiac and pulmonary toxicities, adherence in daily practice, and outcomes in patients with brain metastases or comorbidities will further refine where zongertinib fits in the treatment algorithm.
Overall, zongertinib adds a potent, biomarker-selected TKI option to the growing toolkit for HER2-driven NSCLC and underscores the continued shift toward highly personalized first-line therapy in lung cancer.
*This article is based on the AACR “FDA Approval Alert” and FDA source documents, summarized and edited by Morningglorysciences.*
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