FDA Grants Accelerated Approval to Zongertinib in HER2 NSCLC

The FDA has granted accelerated approval to zongertinib (Hernexeos) for the treatment of patients with unresectable or metastatic nonsquamous non–small cell lung cancer (NSCLC) with tumors harboring a HER2 tyrosine kinase domain (TKD) activating mutation and who have received prior systemic therapy.¹

Alongside this, the FDA approved the Oncomine Dx Target Test as a companion diagnostic to detect HER2 TKD activating mutations.

Efficacy of zongertinib was assessed in the phase 1 Beamion LUNG-1 study (NCT04886804). Here, the overall response rate (ORR) among 71 patients who received prior platinum-based chemotherapy was 75% (95% CI, 63%-83%), and 58% of patients had a duration of response (DOR) of at least 6 months. The ORR was 44% (95% CI, 29%-61%) in patients treated with platinum-based chemotherapy and a HER2-targeted antibody-drug conjugate, and 27% had a DOR of at least 6 months.

“Zongertinib provided clinically meaningful benefit in previously treated patients with advanced NSCLC with HER2 mutations both within and outside the TKD, including in patients with brain metastases,” John V. Heymach, MD, PhD, Beamion LUNG-1 investigator, said in a press conference ahead of the presentation of the data at the 2025 American Association of Cancer Research (AACR) Annual Meeting.² Heymach is a professor, chair, and the David Bruton, Jr Chair in Cancer Research in the Department of Thoracic/Head and Neck Medical Oncology of the Division of Cancer Medicine at The University of Texas MD Anderson Cancer Center in Houston.

Zongertinib is a novel TKI that selectively and irreversibly inhibits HER2 without inhibiting EGFR, which may be associated with fewer toxicities. Along with NSCLC, the agent is being investigated in other HER2 mutation-positive cancers, including colorectal and breast cancers.³

Regarding safety, findings presented at AACR showed that rates of any-grade and grade 3 or higher treatment-related adverse events in cohort 1 were 95% and 17%, respectively. The most common TRAEs included diarrhea (any grade, 56%; grade ≥3, 1%), rash (33%; 0%), increased aspartate aminotransferase levels (24%; 5%), increased alanine aminotransferase levels (21%; 8%), nausea (15%; 0%), dry skin (15%; 0%), pruritus (13%; 0%), decreased white blood cell count (13%; 0%), anemia (12%; 0%), decreased neutrophil count (12%; 1%), and nail disorder (11%; 0%).

In February 2025, the FDA granted priority review to the application of zongertinib,⁴ and in August 2024, the FDA granted breakthrough therapy designation to the agent.⁵

REFERENCES:

1. FDA grants accelerated approval to zongertinib for non-squamous NSCLC with HER2 TKD activating mutations. News release. US FDA. August 8, 2025. Accessed August 8, 2025. https://tinyurl.com/fbakh64s

2. Heymach JV, Ruiter G, Ahn M-J, et al. Zongertinib in patients with pretreated HER2-mutant advanced NSCLC: Beamion LUNG-1. Presented at: 2025 AACR Annual Meeting; April 25-30, 2025; Chicago, IL. Abstract CT050.

3. Heymach JV, Opdam F, Barve M, et al. HER2-Selective Tyrosine Kinase Inhibitor, Zongertinib (BI 1810631), in Patients With Advanced/Metastatic Solid Tumors With HER2 Alterations: A Phase Ia Dose-Escalation Study [published online ahead of print March 3, 2025. J Clin Oncol. doi: 10.1200/JCO-24-01727

4. Boehringer’s zongertinib receives Priority Review from U.S. FDA for the treatment of HER2 (ERBB2)-mutant advanced non-small cell lung cancer. News release. February 19, 2025. Accessed August 8, 2025. https://tinyurl.com/7cbv9n3a

5. Boehringer Ingelheim to unveil groundbreaking oncology research at WCLC, demonstrating strength of portfolio. News release. Boehringer Ingelheim. August 27, 2024. Accessed August 8, 2025. https://tinyurl.com/3kwxwy8p