Zongertinib Approved by FDA for Patients With Nonsquamous NSCLC With HER2 TKD Mutations

Zongertinib (Hernexeos, Boehringer Ingelheim Pharmaceuticals, Inc) received accelerated approval from the FDA for 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 the FDA-approved test Oncomine Dx Target Test (Life Technologies Corporation), and who have received prior systemic therapy. This marks the approval of the first oral drug for HER2-positive NSCLC.¹

X-ray 3D visualization of lungs with tumors | Image Credit: © Moon Story - stock.adobe.com

Non-small cell lung cancer (NSCLC) is the most common type of lung cancer, representing roughly 80% to 85% of cases. HER2 mutations are found in about 2% of NSCLC diagnoses and are associated with more aggressive, progressive disease. Zongertinib, a tyrosine kinase inhibitor (TKI), is designed to irreversibly and selectively block HER2 activity while minimizing toxicity by sparing EGFR inhibition. In the phase 1a/1b first-in-human Beamion LUNG-1 trial (NCT04886804), zongertinib showed promising safety and efficacy results.^1,2

The FDA approval is supported by data from this trial, where zongertinib demonstrated clinically meaningful capabilities in eliciting deep, durable responses. Beamion LUNG-1 is an open-label, phase 1 dose escalation trial evaluating zongertinib as a monotherapy in patients with advanced or metastatic small tumors; in this case, those with unresectable or metastatic, nonsquamous NSCLC with HER2 TKD mutations. The primary outcomes measured were objective response rate (ORR) and duration of response (DOR), as determined by blinded independent central review per RECIST v1.1.³

“The purpose of the first study part is to find the highest dose of a medicine called zongertinib the participants can tolerate,” the investigators wrote in their study overview on Clinicaltrials.gov. “Once this dose is found, it will be used in the second study part to test whether zongertinib can make tumors shrink.”²

In patients who had received prior platinum-based chemotherapy but had not been treated with a HER2-targeted TKI or antibody-drug conjugate (ADC; n = 71), the ORR was approximately 75% (95% CI, 63–83), with 58% of patients achieving a DOR of at least 6 months. Among 34 patients previously treated with both platinum-based chemotherapy and a HER2-targeted ADC, the ORR was approximately 44% (95% CI, 29–61), with 27% of patients maintaining a DOR of at least 6 months.³

The recommended dose of zongertinib is weight-based: 120 mg orally once daily for patients weighing less than 90 kg and 180 mg once daily for those weighing 90 kg or more. It can be taken with or without food and should be continued until disease progression or the development of unacceptable toxicity.³

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). Updated July 28, 2025. Accessed August 8, 2025. https://clinicaltrials.gov/study/NCT04886804#study-overview

3. Patient-reported outcomes show improved symptoms with zongertinib for HER2-mutated non-small cell lung cancer. Pharmacy Times. May 30, 2025. Accessed August 8, 2025. https://www.pharmacytimes.com/view/patient-reported-outcomes-show-improved-symptoms-with-zongertinib-for-her2-mutated-non-small-cell-lung-cancer