Zongertinib Granted Accelerated Approval in Nonsquamous NSCLC for HER2 TKD-Activating Mutations

FDA today granted accelerated approval to zongertinib (Hernexeos; Boehringer Ingelheim), an HER2-selective tyrosine kinase inhibitor, to treat adults with unresectable or metastatic nonsquamous non–small cell lung cancer (NSCLC). Patients can receive zongertinib when an FDA-approved test shows their tumors have HER2 (ERBB2) tyrosine kinase domain (TKD)–activating mutations, and they previously have received systemic therapy.

The announcement was made in a statement from the FDA, which had previously granted zongertinib priority review and breakthrough designation.1

In addition, the FDA approved the Oncomine Dx Target Test (Life Technologies Corporation) as a companion diagnostic device to determine which patients with NSCLC have HER2 (ERBB2) TKD-activating mutations and may be eligible for treatment with zongertinib.1

John Heymach, MD, PhD | Image: MD Anderson

Zongertinib was evaluated in patients with unresectable or metastatic nonsquamous NSCLC with HER2 TKD mutations who had received prior systemic therapy and received zongertinib in Beamion LUNG-1 (NCT04886804).2 In that trial, investigators evaluated the objective response rate (ORR) and the duration of response (DOR) as determined by blinded independent central review. Initial results were presented in September 2024 at the World Conference on Lung Cancer,3 and zongertinib took center stage in April at the American Association of Cancer Research (AACR).4 Results reported by the FDA were as follows:1

• Among 71 patients who previously received platinum-based chemotherapy but had not been previously treated with a HER2-targeted tyrosine kinase inhibitor or antibody-drug conjugate (ADC), results showed an ORR of 75% (95% CI, 63-83), with 58% having a DOR of ≥ 6 months.1
• Among 34 patients who previously received platinum-based chemotherapy and a HER2-targeted ADC, ORR was 44% (95% CI, 29-61), with 27% having a DOR ≥ 6 months.1

In its statement, the FDA said prescribing information will include warnings and precautions for hepatotoxicity, left ventricular dysfunction, interstitial lung disease (ILD)/pneumonitis, and embryo-fetal toxicity.

The FDA said that zongertinib dosing is based on body weight. The agency spelled out the following dosing schedule: for patients who weigh less than 90 kg, the dose is 120 mg by mouth once daily. For those who weigh 90 kg or more, the dose is 180 mg by mouth once daily. The drug may be taken with or without food. Treatment continues until disease progression or unacceptable toxicity.

John Heymach, MD, PhD, chair of the Department of Thoracic/Head and Neck Medical Oncology at The University of Texas MD Anderson Cancer Center and lead investigator of the phase 1A/1B Beamion LUNG-1 trial, explained during his AACR presentation that existing oral small-molecule inhibitors of HER2 are less effective against HER2-mutated cancers and can cause side effects due to cross-targeting effects with EGFR.3

In an interview with The American Journal of Managed Care® (AJMC®)during the AACR meeting,5 he said the patients eligible for zongertinib have historically had limited treatment options. And while the label does warn about ILD, the data presented at AACR showed no cases of ILD.

“Antibody-drug conjugates like trastuzumab deruxtecan often have ILD, or interstitial lung disease, as a side effect. For this reason, I think, in the earlier clinical studies, they're very careful about what patients were put on to make sure they didn't have any preexisting lung issues that could compound that,” Heymach said during the April interview with AJMC.5

“Patients with lung cancer have a lot of preexisting lung issues, so having an option that has no appreciable risk that we've seen so far of interstitial lung disease is an important thing for these patients.”

References

1. FDA grants accelerated approval to zongertinib for non-squamous NSCLC with HER2 TKD activating mutations. News release. 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. Heymach JV, Ruiter G, Ahn MJ. Zongertinib in previously treated HER2-mutant non–small cell lung cancer. N Engl J Med. 2025;392(23):2321-2333. doi:10.1056/NEJMoa2503704
3. Zongertinib demonstrates promising efficacy in patients with HER2 mutant NSCLC. News release. International Association for the Study of Lung Cancer. September 9, 2024. Accessed August 8, 2025. https://www.iaslc.org/iaslc-news/press-release/zongertinib-demonstrates-promising-efficacy-patients-her2-mutant-nsclc
4. Caffrey M, McCormick B. Zongertinib shows durable responses with no interstitial lung disease in HER2-mutated advanced NSCLC. AJMC.com. August 28, 2025. Accessed August 8, 2025. https://www.ajmc.com/view/zongertinib-shows-durable-responses-with-no-interstitial-lung-disease-in-her2-mutated-advanced-nsclc
5. Zongertinib shows durable responses in previously treated HER2-mutated NSCLC: John Heymach, MD, PhD. AJMC.com. April 28, 2025. Accessed August 8, 2025. https://www.ajmc.com/view/zongertinib-shows-durable-responses-in-previously-treated-her2-mutated-nsclc-john-heymach-md-phd