Zongertinib Receives FDA Breakthrough Therapy Designation in Nonsquamous NSCLC With HER2 TKD Mutations

The FDA has granted breakthrough therapy designation to the oral HER2 TKI zongertinib (Hernexeos) for the first-line treatment of adult patients with unresectable or metastatic nonsquamous non–small cell lung cancer (NSCLC) harboring HER2 tyrosine kinase domain (TKD) activating mutations.¹

This regulatory decision is supported by data from the phase 1b Beamion LUNG-1 trial (NCT04886804).

At a median follow-up of 11.3 months (95% CI, 10.2-12.3), data from the primary analysis of cohort 1, which were published in the New England Journal of Medicine, revealed that the confirmed objective response rate (cORR) with zongertinib at 120 mg daily (n = 75) was 71% (95% CI, 60%-80%; P < .001 against a ≤ 30% benchmark). This included a complete response rate of 7%, and partial response rate of 64%. Among responders (n = 53), 40% had an ongoing response at the November 29, 2024, data cutoff.

The median duration of response (DOR) 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).

Data from Beamion LUNG-1 also supported the FDA’s August 2025 decision to grant accelerated approval to zongertinib for the treatment of adult patients with unresectable or metastatic nonsquamous NSCLC harboring HER2 TKD activating mutations, as detected by an FDA-approved test, who have received prior systemic therapy.²

“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 NSCLC,” Vicky Brown, senior vice president and head of Immunology, Oncology, and Eye Health at Boehringer Ingelheim, stated in a press release.¹ “This pathway was designed to expedite the development and review of promising medicines for serious diseases and clearly highlights the potential of [zongertinib].”

Updated data for zongertinib will be presented at both the 2025 World Conference on Lung Cancer and 2025 ESMO Congress.

Beamion LUNG-1 Study Overview

This open-label study is assessing the efficacy and safety of zongertinib in patients aged 18 years or older with histologically or cytologically confirmed advanced, unresectable, and/or metastatic nonhematologic malignancies who have at least 1 measurable lesion per RECIST 1.1 criteria.^2,4 Patients are required to provide a tumor sample for confirmation of HER2 status and must be willing to undergo protocol-specified biopsies. Additional eligibility criteria include an ECOG performance status of 0 to 2, adequate organ function, and recovery from toxicities related to prior therapies.

The phase 1b portion of the trial comprises 8 cohorts, with cohorts 6 and 8 limited to sites in the US and cohort 7 limited to Japan. Cohort 1 includes patients with tumors harboring a HER2 TKD mutation, cohort 5 includes patients with TKD HER2 mutations previously treated with a HER2-directed antibody-drug conjugate, and cohort 3 includes those with tumors carrying a non-TKD HER2 mutation. Two additional global cohorts are ongoing: cohort 2, which includes patients with previously untreated nonsquamous NSCLC harboring TKD HER2 mutations and cohort 4, which consists of patients with NSCLC harboring TKD HER2 mutations and active brain metastases.

Initially, patients in cohort 1 were randomly assigned 1:1 to receive zongertinib at either 120 mg or 240 mg once daily, whereas those in cohorts 5 and 3 began treatment at 240 mg daily. Based on interim data from cohort 1, the study protocol was amended so that all subsequently enrolled patients received zongertinib at 120 mg once daily.

The primary end point of the study is ORR assessed by blinded independent central review in cohorts 1 and 5 and by investigator review in cohort 3. Secondary end points include DOR and PFS.

Additional Safety and Efficacy Data From Beamion LUNG-1

Additional data from cohort 5 (n = 31) showed that, at a median follow-up of 6.8 months (95% CI, 5.5- 8.5), the cORR was 48% (95% CI, 32%-65%) at the data cutoff. In the exploratory cohort 3 (n = 20), 30% (95% CI, 15%-52%) of patients achieved a cORR.

Regarding safety, all patients in cohort 1 who received the 120 mg dose of zongertinib experienced adverse effects (AEs). Treatment-related AEs were observed in 97% of patients, 17% of which were grade 3 or higher. However, the incidence of AEs leading to dose reductions (7%) and treatment discontinuations (3%) was low. The most common all-grade treatment-related AEs were diarrhea (56%) and rash (33%). Notably, no cases of treatment-related interstitial lung disease (ILD) or toxicities related to ILD were reported in this cohort.

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 4, 2025. https://www.boehringer-ingelheim.com/us/human-health/cancer/lung-cancer/fda-grants-boehringer-breakthrough-therapy-designation
2. Heymach JV, Ruiter G, Ahn MJ, et al. Zongertinib in previously treated HER2-mutant non–small-cell lung cancer. N Eng J Med. 2025;392(23):2321-2333. doi:10.1056/NEJMoa2503704
3. FDA grants accelerated approval to zongertinib for non-squamous NSCLC with HER2 TKD activating mutations. FDA. August 8, 2025. Accessed September 4, 2025. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-accelerated-approval-zongertinib-non-squamous-nsclc-her2-tkd-activating-mutations
4. 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 4, 2025. https://clinicaltrials.gov/study/NCT04886804