Zongertinib Receives Breakthrough Therapy Designation for Patients With HER2 Non-Small Cell Lung Cancer

Zongertinib (Hernexeos; Boehringer Ingelheim) received a breakthrough therapy designation from the FDA for the first-line treatment of adult patients with unresectable or metastatic non-squamous non-small cell lung cancer (NSCLC) whose tumors have HER2 (ERBB2) tyrosine kinase domain (TKD) activating mutations. The decision marks another step forward in the manufacturer's efforts to gain FDA approval for this indication.

3D x-ray of lung cancer | Image Credit: © catalin - stock.adobe.com

"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," Vicky Brown, senior vice president and head of Immunology, Oncology, and Eye Health, Boehringer Ingelheim, said 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]."¹

NSCLC is the most common type of lung cancer, representing roughly 80% to 85% of cases. HER2 mutations are found in about 2% of diagnoses and are associated with more aggressive, progressive disease. Zongertinib is a tyrosine kinase inhibitor (TKI) designed to irreversibly and selectively block HER2 activity while minimizing toxicity by sparing EGFR inhibition. In August 2025, it received FDA approval for adults with unresectable or metastatic nonsquamous NSCLC whose tumors have HER2 TKD activating mutations based on positive data from the Beamion LUNG-1 trial (NCT04886804).^2,3

The FDA breakthrough therapy designation and approval of zongertinib are supported by data from this trial, where zongertinib demonstrated clinically meaningful capabilities in eliciting deep, durable responses. Beamion LUNG-1 is an open-label, phase 1 dose escalation trial evaluating zongertinib as a monotherapy in patients with unresectable or metastatic, nonsquamous NSCLC with HER2 TKD mutations. The primary outcomes measured were objective response rate (ORR) and duration of response (DOR), as determined by blinded independent central review per RECIST v1.1.²

The study consists of 2 parts: part 1 is open to adults with different types of advanced cancer with HER2 alterations that include mutations, amplifications, over-expression, and fusions for whom previous treatment was not successful; and part 2 is open to people with HER2-mutant NSCLC.¹

Among patients who had received prior platinum-based chemotherapy but had not been treated with a HER2-targeted TKI or antibody-drug conjugate (ADC; n = 71), the overall response rate (ORR) was about 75% (95% CI, 63–83), with 58% experiencing a duration of response (DOR) of 6 months or longer. In comparison, for the 34 patients who had previously received both platinum-based chemotherapy and a HER2-targeted ADC, the ORR was approximately 44% (95% CI, 29–61), and 27% achieved a DOR of at least 6 months.²

Zongertinib is being further investigated in Beamion LUNG-2, a phase 3, open-label, randomized, active-controlled study comparing zongertinib with standard of care in 416 patients with unresectable or metastatic non-squamous NSCLC harboring HER2 TKD mutations.^1,4

Zongertinib dosage is weight-based: 120 mg orally once daily for patients weighing less than 90 kg and 180 mg once daily for those weighing 90 kg or more. It can be taken with or without food and should be continued until disease progression or the development of unacceptable toxicity.²

REFERENCES

1. FDA grants HERNEXEOS® breakthrough therapy designation for first line use in HER2 (ERBB2)-mutant advanced NSCLC. PR Newswire. September 3, 2025. Accessed September 4, 2025. https://www.prnewswire.com/news-releases/fda-grants-hernexeos-breakthrough-therapy-designation-for-first-line-use-in-her2-erbb2-mutant-advanced-nsclc-302545360.html

2. Gerlach A. Zongertinib approved by FDA for patients with nonsquamous NSCLC with HER2 TKD mutations. Pharmacy Times. August 8, 2025. Accessed September 4, 2025. https://www.pharmacytimes.com/view/zongertinib-approved-by-fda-for-patients-with-nonsquamous-nsclc-with-her2-tkd-mutations

3. 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). Updated July 28, 2025. Accessed August 8, 2025. https://clinicaltrials.gov/study/NCT04886804#study-overview

4. 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. Updated September 3, 2025. Accessed September 4, 2025. https://clinicaltrials.gov/study/NCT06151574?term=NCT06151574&rank=1