ESMO 2025: Zongertinib Shows a 77% ORR in Treatment-naïve Patients with Advanced HER2 Mutant NSCLC

Results from the Beamion LUNG-1 trial (NCT04886804) evaluating zongertinib (Hernexeos®; Boehringer Ingelheim) in treatment-naïve patients (N=74) with advanced non-small cell lung cancer (NSCLC) who have HER2 (ERBB2) activating mutations in the tyrosine kinase domain (TKD), demonstrated efficacy with a confirmed objective response rate (cORR) by blinded independent central review of 77%, with 96% of patients achieving disease control.[1]

The study results were featured during the European Society for Medical Oncology (ESMO) Congress held October 17 – 21, 2025 in Berlin, Germany.

Zongertinib, is an irreversible tyrosine kinase inhibitor (TKI) that selectively inhibits HER2 (ERBB2).

HER2 (ERBB2)-mutant NSCLC
HER2 (ERBB2)-mutant non-small cell lung cancer (NSCLC) is characterized by its aggressive nature and poor prognosis. Up to 4% of lung cancers are driven by HER2 (ERBB2) mutations (or gene alterations).[2] Mutations in HER2 (ERBB2) can lead to overexpression and overactivation, which can in turn result in uncontrolled cell production, inhibition of cell death and promotion of tumor growth and spread.[3]

Today, lung cancer claims more lives than any other cancer type [4] and the incidence is set to increase to over 3 million cases worldwide by 2040.[5]

NSCLC is the most common type of lung cancer. [4] The condition is often diagnosed at a late stage,[6] and fewer than 3 in 10 patients are alive five years after diagnosis.[6] People living with advanced NSCLC can experience a detrimental physical, psychological, and emotional impact on their daily lives.[7][8][9]

There remains a high unmet medical need for additional treatment options for people living with advanced NSCLC. Up to 4% of lung cancers are driven by HER2 (ERBB2) mutations (or gene alterations).[2] Mutations in HER2 (ERBB2) can lead to overexpression and overactivation, which can in turn result in uncontrolled cell production, inhibition of cell death and promotion of tumor growth and spread.[3]

Clinical benefit
“Non-small cell lung cancer with HER2 activating mutations is a highly heterogeneous and aggressive disease which in the past has made it hard to find a targeted treatment offering significant clinical benefit,” said the presenting author, Prof. Sanjay Popat, MD, PhD, Consultant Medical Oncologist, Head of the Lung Unit, and Lead for the Lung Cancer Research Programme at the Royal Marsden Hospital.

“A response rate of 77% regardless of mutation subtype and a median time to response of 1.4 months indicate that zongertinib elicited a rapid response in treatment-naïve patients with HER2 TKD-mutant NSCLC, making it a promising future targeted treatment option in this setting,” Popat added.

Of the responders (77%), 8% of patients achieved complete response, 69% achieved partial response and 96% of patients achieved disease control. At data cut-off, median values for duration of response (DoR) and progression-free survival (PFS) were not yet mature, with 47% of patients remaining on treatment and encouraging 6-month rates for DoR of 80% and PFS of 79%.

A manageable safety profile
Data presented at ESMO demonstrated a manageable safety profile for zongertinib in treatment-naïve patients, with a similar pattern of adverse events (AEs) to that observed and reported in previously treated patients.

Adverse events led to dose reductions in 11 patients (15%) and dose discontinuations in 7 patients (9%). The most commonly reported AEs were grade 1 diarrhea and rash.

Study program
Zongertinib is included in a number of clinical studies, including the Beamion LUNG-2 (NCT06151574), a Phase 3 randomized study evaluating zongertinib as a first-line therapy versus standard of care in patients with unresectable, locally advanced or metastatic HER2-mutant NSCLC, is currently enrolling.

“We see a significant unmet need in the first-line setting for patients with HER2-mutant advanced NSCLC where there are currently no targeted treatments approved. These data are extremely encouraging and reinforce our belief in the potential of zongertinib for treatment-naïve patients with advanced non-small cell lung cancer with activating HER2 mutations,” said Shashank Deshpande, Chairman of the Board of Managing Directors and Head of Human Pharma at Boehringer Ingelheim.

“Employing our dual approach to oncology, we are advancing both cancer cell and immune cell-directed therapies to pioneer breakthroughs for patients,” Deshpande added.

Regulatory status
In the agent was recently approved by the US Food and Drug Administration as the first orally administered, targeted therapy for adult patients with unresectable or metastatic non-squamous NSCLC whose tumors have HER2 (ERBB2) tyrosine kinase domain (TKD) activating mutations, as detected by an FDA-approved test, and who have received prior systemic therapy.

This indication is approved under accelerated approval based on objective response rate and duration of response. Continued approval for these indications may be contingent upon verification and description of clinical benefit in a confirmatory trial.

The U.S. FDA also granted Breakthrough Therapy Designation for zongertinib for use in a first-line setting.

In addition to US regulatory approvals, the Center for Drug Evaluation (CDE) in China approved zongertinib for the first-line treatment of adult patients with unresectable or metastatic NSCLC whose tumors have HER2 TKD activating mutations.

Clinical trials
Beamion LUNG-1: A Study to Test Different Doses of Zongertinib in People With Different Types of Advanced Cancer (Solid Tumours With Changes in the HER2 Gene) – ClinicalTrials.gov ID NCT04886804
Beamion LUNG-2: A Study to Test Whether Zongertinib (BI 1810631) Helps People With Advanced Non-small Cell Lung Cancer With HER2 Mutations Compared With Standard Treatment – ClinicalTrials.gov ID NCT06151574
Beamion LUNG-3: A Study to Test Whether Zongertinib Helps People With Surgically Removed, Non-small Cell Lung Cancer With HER2 Mutations Compared With Standard Treatment – ClinicalTrials.gov ID NCT07195695

Highlights of prescribing Information
Zongertinib (Hernexeos®; Boehringer Ingelheim)[Prescribing Information]

References:
[1] Popat S. et al. Zongertinib as first-line treatment in patients with advanced HER2-mutant NSCLC: Beamion LUNG 1. presented at ESMO, Berlin, 17-21 October, 2025.
[2] Arcila, M. E. et al. Prevalence, clinicopathologic associations, and molecular spectrum of ERBB2 (HER2) tyrosine kinase mutations in lung adenocarcinomas. Clin. cancer Res. an Off. J. Am. Assoc. Cancer Res. 18, 4910–4918 (2012).
[3] Galogre M, et al. A review of HER2 overexpression and somatic mutations in cancers, Critical Reviews in Oncology/Hematology, Volume 186, 2023, 103997.
[4] Zeng J, Ma W, Young RB, Li T. Targeting HER2 genomic alterations in non-small cell lung cancer. J Natl Cancer Cent. 2021 May 3;1(2):58-73.
[5] International Agency for Research on Cancer – World Health Organization. Rates of trachea, bronchus and lung cancer. Available at: https://gco.iarc.fr/tomorrow/en (Accessed: October 2025).
[6] National Cancer Institute Surveillance, Epidemiology, and End Results (SEER). https://seer.cancer.gov/statfacts/html/lungb.html (Accessed: October 2025).
[7] Valentine, T. R. et al. Illness Perceptions and Psychological and Physical Symptoms in Newly Diagnosed Lung Cancer. Health Psychol. 2022 Jun; 41(6): 379–388.
[8] Andersen, B. L. et al. Newly diagnosed patients with advanced non-small cell lung cancer: A clinical description of those with moderate to severe depressive symptoms. Lung Cancer. 2020 Jul;145:195-204.
[9] Presley, C. J. et al. Functional Disability Among Older Versus Younger Adults With Advanced Non–Small-Cell Lung Cancer. JCO Oncol Pract. 2021 May 3;17(6):e848–e858.

Featured image: General images of ESMO 2019 Congress being held in Barcelona, Spain, September 27 – October 1, 2019. Courtesy European Society for Medical Oncology (ESMO). Used with Permission.

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