Image Credit: Adobe Stock Images/Nanthiwan

The FDA has granted accelerated approval to Boehringer Ingelheim’s Hernexeos (zongertinib tablets) as the first orally administered targeted therapy for adults with unresectable or metastatic non-squamous non-small cell lung cancer (NSCLC) harboring HER2 (ERBB2) tyrosine kinase domain activating mutations, following prior systemic therapy. According to the company, accelerated approval was based on results from the Phase Ib Beamion-LUNG 1 trial (NCT04886804).¹

What Does the Approval of Hernexeos Mean for Patients with HER2-Mutant NSCLC?

“With the approval of zongertinib, we have an effective, targeted, orally administered treatment option for patients with HER2 (ERBB2)-mutant non-small cell lung cancer in the US that not only elicits a durable response but, importantly, has a manageable safety profile,” Beamion-LUNG 1 trial coordinating investigator John Heymach, MD, PhD, chair, thoracic/head and neck medical oncology, The University of Texas MD Anderson Cancer Center, said in a press release. “In a patient population where there are currently limited treatment options, this approval represents a significant advancement in cancer care.”

Beamion-LUNG 1 Trial Design and Enrollment

• The open-label, dose-escalation Beamion-LUNG 1 trial is currently evaluating Hernexeos in 554 patients with unresectable or metastatic NSCLC harboring HER2 tyrosine kinase domain activating mutations.
• Patients were divided into three cohorts. Patients in cohort 1 received either Hernexeos 120 mg or 240 mg once daily, patients in cohort 5 started at 240 mg daily, and patients in cohort 3 received 240 mg once daily and had non-tyrosine kinase domain HER2 mutations.
• The primary endpoint of the trial was objective response rate (ORR) as assessed by blinded independent central review for cohorts 1 and 5, and by investigator review for cohort 3.
• Secondary endpoints included duration of response (DoR) and progression-free survival (PFS).^2,3

Efficacy Results

• Results showed a 75% ORR in 71 patients from cohort 1, with 58% achieving a DOR of at least six months.¹
• The median DOR in cohort 1 was 14.1 months, while median PFS was 12.4 months.
• In cohort 5, ORR was 48%, whereas in cohort 3, ORR was 30%.³

Safety Profile

• The safety profile of Hernexeos was reported to be manageable, with a 2.9% discontinuation rate.
• The most common adverse events (AEs) reported from a pooled safety population included diarrhea, rash, hepatotoxicity, fatigue, and nausea.¹
• In cohort 1, drug-related AEs were reported in 17% of patients; in cohort 5, the rate was 3%, and in cohort 3, it was 25%.

Disease Context

According to Boehringer Ingelheim, HER2 occurs in approximately 2% to 4% of all cases of NSCLC. Lung cancer remains the leading cause of cancer-related death, with global cases projected to surpass three million by 2040.

Historically, the five-year survival rate for metastatic NSCLC has been under 10%. It is also the most common form of lung cancer, and because early symptoms are often absent or mistaken for other conditions, many patients are diagnosed at advanced stages when the cancer has already spread.¹

“The advocacy community is thrilled about the approval of zongertinib, as it is another testament to the importance of personalized options for lung cancer that allow for a much more targeted approach for a subgroup of patients who have been waiting many years for innovative treatments,” said Marcia Horn, president, CEO, International Cancer Advocacy Network, executive director, Exon 20 Group/HER2 Warriors, in the press release. “Understanding your cancer’s unique biomarkers, including HER2, through comprehensive testing is critical for all patients with NSCLC, as it can unlock targeted treatment options.”

References

1. U.S. FDA grants accelerated approval to Boehringer’s HERNEXEOS® as first orally administered targeted therapy for previously treated patients with HER2-mutant advanced NSCLC. Boehringer Ingelheim. August 8, 2025. Accessed August 11, 2025. https://www.boehringer-ingelheim.com/human-health/cancer/lung-cancer/fda-approval-hernexeos-first-oral-treatment-her2-mutant-advanced-nsclc
2. 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. Accessed August 11, 2025. https://clinicaltrials.gov/study/NCT04886804?term=Beamion-LUNG%201&rank=2
3. Zongertinib in Previously Treated HER2-Mutant Non–Small-Cell Lung Cancer. The New England Journal of Medicine. April 28, 2025. Accessed August 11, 2025. https://www.nejm.org/doi/full/10.1056/NEJMoa2503704?logout=true