FDA Grants Breakthrough Therapy Designation to Zongertinib Tablets in NSCLC

Results from the Beamion-LUNG 1 trial showed an ORR of 75% for patients with HER2+ NSCLC treated with zongertinib.

The FDA has granted breakthrough therapy designation to zongertinib tablets (Hernexeos) as first-line treatment for patients with unresectable or metastatic non-squamous non–small cell lung cancer (NSCLC) who have tumors with HER2 (ERBB2)tyrosine kinase domain activating mutations, according to a press release from Boehringer Ingelheim.¹

Results from the phase 1 Beamion-LUNG1 trial (NCT04886804) led to this FDA designation.² Updated data is planned to be presented at the 2025 World Conference on Lung Cancer and the European Society for Medical Oncology Congress.

“We are incredibly pleased that [zongertinib tablets] has received Breakthrough Therapy Designation for first-line use in patients living with HER2-mutated NSCLC,” Vicky Brown, senior vice president and head of Immunology, Oncology, and Eye Health, Boehringer Ingelheim, said in the press release. “This pathway was designed to expedite the development and review of promising medicines for serious diseases and clearly highlights the potential of [zongertinib tablets].”

Results from the Beamion-LUNG 1 trial showed 71 patients enrolled who received prior platinum-containing chemotherapy, but no anti-HER2 tyrosine kinase inhibitors or antibody drug conjugates (ADC). For this population, the objective response rate (ORR) was 75% (95 % CI, 63%-83%), with 58% of patients having a response that lasted for at least 6 months.

The median duration of response was 14.1 months (95% CI, 6.9-not evaluable [NE]), and the median progression-free survival (PFS) was 12.4 months (95% CI, 8.2-NE). Overall, the discontinuation rate was 3%.

A total of 34 patients were given prior platinum-based chemotherapy plus a HER2-directed ADC with an ORR of 44% (95% CI, 29%-61%), and 27% had a response for at least 6 months.

The trial was created in 2 parts. The first is for patients with solid tumors with changes in the HER2 gene, and the second is for those with NSCLC who have a specific mutation in the HER2 gene.³

The primary end point in the phase 1b portion of the trial was ORR. Secondary end points included disease control rate and PFS.

Patients were eligible for treatment if they had a histologically or cytologically confirmed diagnosis of an advanced, unresectable, and/or metastatic non-hematologic malignancy; had an ECOG performance status of 0 to 2; provided a tumor sample to confirm HER2 status; and were able to comply with the protocol requirements.

Patients were excluded from treatment if they had minor surgery within 4 weeks before the first treatment, or if one was planned within 6 months after screening; previous concomitant malignancies treated in the last 2 years; had been treated with systemic anti-cancer therapy or an investigational drug in 21 days or 5 half-lives; or had previously received treatment with zongertinib.

In August 2025, the FDA approved zongertinib in this indication, with detection for mutations by an FDA-approved test.⁴ In turn, the Oncomune DX Target Test was approved as a next-generation sequencing-based companion diagnostic.⁵

In September 2025, zongertinib tablets were approved by China’s National Medical Products Administration for patients with unresectable, locally advanced, or metastatic NSCLC whose tumors have activating HER2 mutations and who have been treated with at least 1 previous line of systemic therapy.⁶

References

1. FDA grants HERNEXEOS® Breakthrough Therapy Designation for first line use in HER2 (ERBB2)-mutant advanced NSCLC. News release. September 3, 2025. Accessed September 3, 2025. https://tinyurl.com/4tty5v2b
2. Heymach JV, Ruiter G, Ahn MJ, et al. 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. Beamion LUNG-1: a study to test different doses of zongertinib in people with different types of advanced cancer (solid tumors with changes in the HER2 gene). ClinicalTrials.gov. Updated July 28, 2025. Accessed September 3, 2025. https://clinicaltrials.gov/study/NCT04886804
4. FDA grants accelerated approval to zongertinib for non-squamous NSCLC with HER2 TKD activating mutations. News release. FDA. August 8, 2025. Accessed September 3, 2025. https://tinyurl.com/bdh2d4uc
5. Thermo Fisher receives FDA approval for NGS-based companion diagnostic for new non-small cell lung cancer treatment. News release. Thermo Fisher Scientific. August 11, 2025. Accessed September 3, 2025. https://tinyurl.com/3h73v3en
6. Boehringer’s Hernexeos approved in China as first oral targeted therapy for previously treated patients with HER2-mutant advanced NSCLC. News release. Boehringer Ingelheim. September 1, 2025. Accessed September 3, 2025. https://tinyurl.com/4nw3stdp