FDA Grants BTD to Zongertinib, Marks New Frontier for HER2+ NSCLC

Zongertinib (Hernexeos), a highly selective oral HER2 TKI, has been granted breakthrough therapy designation (BTD) by the FDA for the first-line treatment of adult patients with unresectable or metastatic nonsquamous non–small cell lung cancer (NSCLC) harboring activating HER2 mutations.¹

This designation, which expedites the development and review of promising therapies for serious conditions, is based on a compelling body of evidence from the Beamion-LUNG 1 clinical trial (NCT04886804).

"Exploring accelerated review pathways is part of Boehringer’s strategy to have an unprecedented and generational impact on people facing cancer. We are incredibly pleased that [zongertinib] has received breakthrough therapy designation for first-line use in patients living with HER2-mutant non-small cell lung cancer,” said Vicky Brown, senior vice president and head of Immunology, Oncology, and Eye Health, Boehringer Ingelheim, in a 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].”

Last month, the FDA granted accelerated approval to zongertinib for the treatment of patients with unresectable or metastatic nonsquamous NSCLC with tumors harboring a HER2 tyrosine kinase domain (TKD) activating mutation and who have received prior systemic therapy.²

Clinical Rationale and Trial Data

Lung cancer remains the leading cause of cancer-related death globally, with NSCLC accounting for approximately 85% of all cases.¹ Within this group, HER2 mutations are a distinct, albeit rare, oncogenic driver, occurring in about 2% to 4% of NSCLC cases. These mutations, particularly in the TKD, are associated with a poor prognosis and a high incidence of brain metastases. Historically, targeted therapeutic options for HER2-mutant NSCLC have been limited, leaving a critical gap in the treatment paradigm.

The BTD was supported by primary data from the multicohort, open-label, phase 1b Beamion-LUNG 1 trial. The study evaluated the safety and efficacy of zongertinib as a monotherapy in patients with advanced solid tumors harboring HER2 aberrations. The most notable findings came from the cohort of 75 previously treated patients with HER2 TKD-mutant NSCLC, which demonstrated a robust objective response rate (ORR) of 71% (95% CI, 60%-80%). This included a 7% complete response rate and a 64% partial response rate, leading to an overall disease control rate of 96% (95% CI, 89%-99%). The median progression-free survival (PFS) was 12.4 months (95% CI, 8.2–not estimable [NE]), and the median duration of response (DOR) was 14.1 months (95% CI, 6.9–NE). These results highlight the durable and clinically meaningful antitumor activity of zongertinib in a setting with few established treatment options.

Furthermore, the trial's safety profile was manageable, with a low incidence of dose reductions (5%) and treatment discontinuations (3%). The most common all-grade treatment-related adverse events were diarrhea and rash, which are consistent with the mechanism of action of many TKIs. Notably, no new safety signals were observed, and no cases of treatment-related interstitial lung disease (ILD) were reported in this cohort, which is a significant consideration with other HER2-targeted agents.

This article was generated with assistance from Google Gemini. It was edited and reviewed by Targeted Oncology staff. If you have any questions about the use of AI, please contact us.

REFERENCES:

1. FDA grants HERNEXEOS® Breakthrough Therapy Designation for first line use in HER2 (ERBB2)-mutant advanced NSCLC. News release. Boehringer Ingelheim. September 3, 2025. Accessed September 3, 2025. https://tinyurl.com/2dsdvw44

2. FDA grants accelerated approval to zongertinib for non-squamous NSCLC with HER2 TKD activating mutations. News release. US FDA. August 8, 2025. Accessed September 3, 2025. https://tinyurl.com/fbakh64s