Zongertinib Shows Clinically Meaningful Efficacy in Advanced HER2-Mutant NSCLC

In the first-line setting, zongertinib (Hernexeos; Boehringer Ingelheim) elicited strong and clinically meaningful efficacy in treatment-naïve patients with advanced HER2-mutant non–small cell lung cancer (NSCLC), according to findings presented at the European Society for Medical Oncology 2025 Congress. The findings were from the phase 1b clinical trial, Beamion LUNG-1 (NCT04886804).^1,2

Zongertinib is an irreversible tyrosine kinase inhibitor (TKI) that selectively inhibits HER2 while sparing wild-type EGFR, therefore limiting associated toxicities. In August 2025, the FDA granted zongertinib an accelerated approval for the treatment of adults with unresectable or metastatic nonsquamous non–small cell cancer (NSCLC) with HER2 mutations.^1,3,4

Beamion LUNG-1 is an open-label, phase I dose escalation trial, with dose confirmation and expansion, of zongertinib as monotherapy in people with advanced or metastatic solid tumors and NSCLC with activating HER2 alterations. The study consisted of 2 parts: part 1, which included adults with advanced cancer (solid tumors with  HER2 gene alterations) for whom prior treatment was not successful; and part 2, which was open to people with advanced NSCLC with a specific HER2 gene mutation.^1,2,4

In the first-line setting for patients with HER2-mutant NSCLC, the standard of care remains a combination of chemotherapy and immunotherapy, with no targeted treatment approved. In this abstract, the investigators reported the first results from treatment-naïve patients with advanced HER2-mutant NSCLC enrolled in cohort 2 of the phase 1b Beamion LUNG-1 trial.^1,2

Cohort 2 included adult patients with treatment-naïve, advanced or metastatic, nonsquamous HER2-mutant NSCLC who received 120 mg of oral zongertinib once daily. Patients who had stable/asymptomatic brain metastases were also eligible. The primary end point was objective response (OR), and secondary end points included duration of objective response (DoR), disease control (DC), and progression-free survival (PFS). All end points were assessed by blinded independent central review (BICR).^1,2

As of May 8, 2025, 74 patients had received treatment with zongertinib (median age: 67 years [range: 35%–88%]). The observed OR rate was approximately 77% (95% CI 66%–85%), and 8% (n = 6) and 69% (n = 51) of patients had complete and partial responses, respectively. Additionally, 14 patients (19%) had stable disease, giving a DC rate of about 96% (95% CI 89%–99%). The 6-month DoR and PFS rates were approximately 80% (95% CI 65%–89%) and 79% (95% CI 68%–87%), respectively. The remaining 47% of responding patients remained on treatment at the time of data cut-off.¹

"NSCLC 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," presenting author Sanjay Popat, MD, PhD, professor, consultant medical oncologist, head of the Lung Unit, and lead for the Lung Cancer Research Programme at the Royal Marsden Hospital, said in a news release. "A response rate of 77% regardless of mutation subtype and a median time to response of 1.4 months indicate [sic] 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."⁴

Treatment-related adverse events (TRAEs) were reported in 91% of patients; however, only 18% of patients reported grade 3 TRAEs. There were no grade 4/5 TRAEs. The most common TRAEs were diarrhea (54%), increased ALT (18%), increased AST (16%), dysgeusia (16%), and nausea (16%).^1,2

"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 NSCLC with activating HER2 mutations," Shashank Deshpande, chairman of the Board of Managing Directors and head of Human Pharma at Boehringer Ingelheim, said in the news release.⁴

REFERENCES

1. Popat S, Yamamoto N, Girard N, et al. LBA74 – Zongertinib as first-line treatment in patients with advanced HER2-mutant NSCLC: Beamion LUNG 1. Presented at: European Society for Medical Oncology 2025 Annual Congress; Berlin, Germany. October 17–21.

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 identifier: NCT04886804. Updated October 30, 2025. Accessed November 14, 2025. https://clinicaltrials.gov/study/NCT04886804

3. US Food & Drug Administration. FDA grants accelerated approval to zongertinib for non-squamous NSCLC with HER2 TKD activating mutations. News release. August 8, 2025. Accessed November 14, 2025. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-accelerated-approval-zongertinib-non-squamous-nsclc-her2-tkd-activating-mutations

4. PR Newswire. Boehringer's HERNEXEOS® demonstrated a 77% objective response rate in treatment-naïve patients with advanced HER2 (ERBB2)-mutant NSCLC. News release. Accessed November 14, 2025. https://www.prnewswire.com/news-releases/boehringers-hernexeos-demonstrated-a-77-objective-response-rate-in-treatment-naive-patients-with-advanced-her2-erbb2-mutant-nsclc-302587594.html