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

The FDA has granted accelerated approval to zongertinib (Hernexeos) for adult patients with unresectable or metastatic nonsquamous non–small cell lung cancer (NSCLC) whose tumors have HER2 tyrosine kinase domain (TKD) activating mutations, as detected by an FDA-approved test, and who have received prior systemic therapy.1

The regulatory decision was based on findings from the phase 1 Beamion LUNG-1 trial (NCT04886804), an open-label, dose-escalation and dose-expansion study that evaluated zongertinib monotherapy in patients with advanced NSCLC harboring HER2 alterations.

Evaluable patients who received prior platinum-based chemotherapy and had not been previously treated with a HER2-targeted tyrosine kinase inhibitor or antibody-drug conjugate (ADC; n = 71) achieved an overall response rate (ORR) of 75% (95% CI, 63%-83%). The 6-month duration of response (DOR) rate was 58%.

Those previously treated with platinum-based chemotherapy and a HER2-targeted ADC (n = 34) experienced an ORR of 44% (95% CI, 29%-61%), with a 6-month DOR rate of 27%.

Beamion LUNG-1 Overview

The Beamion LUNG-1 trial enrolled adults with histologically or cytologically confirmed unresectable or metastatic nonhematologic malignancies harboring HER2 mutations.3 Patients were required to have at least 1 measurable lesion per RECIST 1.1 criteria and an ECOG performance status of 0 or 1.

In the dose-escalation phase, patients received increasing doses of zongertinib to determine the maximum tolerated dose (MTD). The expansion phase evaluated the optimal dose for efficacy and safety in HER2-mutant nonsquamous NSCLC following prior systemic therapy.

The primary end points were the incidence of dose-limiting toxicities in phase 1a and ORR in phase 1b. Secondary end points included DOR, PFS, disease control rate, overall survival (OS), safety, and pharmacokinetics.

Regarding safety, treatment-related adverse effects (TRAEs) led to dose reductions in 5% and discontinuations in 3% of patients.2 The majority of TRAEs were grade 1 or 2, with the most common being diarrhea (51%) and rash (27%). Only 1 patient experienced a grade 3 or higher TRAE, and no cases of treatment-related interstitial lung disease were reported.

Zongertinib is also under investigation in the ongoing phase 3 Beamion LUNG-2 trial (NCT06151574), a randomized study comparing the drug with standard-of-care therapy in patients with HER2-mutant unresectable or metastatic nonsquamous NSCLC.

References

1. FDA grants accelerated approval to zongertinib for non-squamous NSCLC with HER2 TKD activating mutations. FDA. August 8, 2025. Accessed August 8, 2025. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-accelerated-approval-zongertinib-non-squamous-nsclc-her2-tkd-activating-mutations
2. 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 July 28, 2025. Accessed August 5, 2025. https://clinicaltrials.gov/study/NCT04886804