Zongertinib Yields Clinical Benefit in Previously Treated, HER2-Mutated, Advanced NSCLC

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Treatment with zongertinib (BI 1810631) generated responses in patients with previously treated advanced non–small cell lung cancer (NSCLC) harboring HER2 mutations, according to data from the phase 1a/b Beamion LUNG-1 trial (NCT04886804) presented at the 2025 AACR Annual Meeting.1

Activity with zongertinib was observed in patients with HER2 mutations within or outside the tyrosine kinase domain (TKD). Findings showed that patients harboring TKD HER2 mutations treated in cohort 1 (n = 75) achieved an overall response rate (ORR) of 71% (95% CI, 60%-80%), comprising a complete response (CR) rate of 7% and a partial response (PR) rate of 64%. The rates of stable disease (SD) and progressive disease (PD) were 25% and 4%, respectively, and the disease control rate (DCR) was 96% (95% CI, 89%-99%). The median best change in baseline target lesions for this cohort was –43% (range, –100% to 22%).

In cohort 3, patients harboring non-TKD HER2 mutations (n = 20) experienced an ORR of 30% (95% CI, 15%-52%). All responders had a PR, and the rates of SD and PD were 35% and 30%, respectively. One patient was not evaluable (NE), and the DCR was 65% (95% CI, 43%-82%).

In cohort 5, patients with advanced NSCLC with TKD HER2 mutations who received prior treatment with a HER2-directed antibody-drug conjugate (ADC; n = 31) achieved an ORR of 48% (95% CI, 32%-65%), including a CR rate of 3% and a PR rate of 45%. The DCR was 97% (95% CI, 84%-99%). No patients in this cohort had a best response of PD, 48% had SD, and 3% were NE. Notably, patients who previously received fam-trastuzumab deruxtecan-nxki (Enhertu; n = 22) had an ORR of 41% (95% CI, 23%-61%).

“Zongertinib provided clinically meaningful benefit in previously treated patients with advanced NSCLC with HER2 mutations both within and outside the TKD, including in patients with brain metastases,” lead study author John V. Heymach, MD, PhD, said in a press conference ahead of the presentation of the data. Heymach is a professor, chair, and the David Bruton, Jr Chair in Cancer Research in the Department of Thoracic/Head and Neck Medical Oncology of the Division of Cancer Medicine at The University of Texas MD Anderson Cancer Center in Houston.

In February 2025, the FDA granted priority review to the new drug application (NDA) seeking the approval of zongertinib for the treatment of adult patients with unresectable or metastatic NSCLC harboring HER2 mutations who have received prior systemic therapy.2 The NDA was supported by data from Beamion LUNG-1.

Beamion LUNG-1 Background

The phase 1a portion of the study evaluated zongertinib—a potent, covalent TKI that is highly selective for HER2 and spares EGFR wild-type—in patients with HER2-altered solid tumors, including NSCLC.1 Dose expansion included cohorts specifically for patients with NSCLC.

During phase 1a, patients received escalating doses of zongertinib either once per day or twice per day in 3-week cycles. The maximum tolerated dose was not reached during this portion, and 2 doses were initially selected for use in expansion. However, after an interim futility analysis during dose expansion, 120 mg once per day was picked as the dose for that portion.

Dose expansion included 5 cohorts for patients with NSCLC: those with previously treated, advanced NSCLC with TKD HER2 mutations (cohort 1); patients with treatment-naive disease harboring TKD HER2 mutations (cohort 2); those with previously treated NSCLC with non-TKD HER2 mutations (cohort 3); patients with NSCLC with brain metastases and TKD HER2 mutations (cohort 4); and those with previously treated NSCLC harboring TKD HER2 mutations who received a prior HER2-directed ADC (cohort 5). Notably, data from cohorts 2 and 4 are not yet available.

Blinded independent central review–assessed ORR per RECIST 1.1 criteria served as the primary end point for cohorts 1 and 3. Investigator-assessed ORR was the primary end point for cohort 5. Secondary end points included duration of response (DOR), DCR, progression-free survival (PFS), and DCR in patients with central nervous system lesions at baseline.

Additional Efficacy and Safety Data from Cohort 1

Findings also showed that 44% of patients treated in cohort 1 remained on treatment at data cutoff. The median time to response in this cohort was 1.4 months (range, 1.1-6.9).

The median DOR was 14.1 months (95% CI, 6.9-not evaluable [NE]), and the median PFS was 12.4 months (95% CI, 8.2-NE).

Heymach reported that the safety profile of zongertinib was consistent across cohorts 1, 3, and 5, including no instances of interstitial lung disease. “In patients with TKD [HER2] mutations [in cohort 1], the vast majority of adverse [effects (AEs)] were mild and manageable,” he said.

In cohort 1, treatment-related grade 3 diarrhea was reported in 1 patient. AEs led to dose reductions in 7% of patients in this cohort, and AEs led to treatment discontinuation in 3% of patients.

The rates of any-grade and grade 3 or higher TRAEs in cohort 1 were 95% and 17%, respectively. The most common TRAEs included diarrhea (any-grade, 56%; grade ≥3, 1%), rash (33%; 0%), increased aspartate aminotransferase levels (24%; 5%), increased alanine aminotransferase levels (21%; 8%), nausea (15%; 0%), dry skin (15%; 0%), pruritus (13%; 0%), decreased white blood cell count (13%; 0%), anemia (12%; 0%), decreased neutrophil count (12%; 1%), and nail disorder (11%; 0%).

Disclosures: Heymach reported serving on advisory committees for AstraZeneca, Boehringer Ingelheim, Genentech, GlaxoSmithKline, Hengrui Therapeutics, Eli Lilly, Novartis, Spectrum, EMD Serono, Sanofi, Takeda, Bristol Myers Squibb, Janssen Global Services, EMD Serono, Pfizer, and Leads Biolabs; receiving research support from AstraZeneca, GlaxoSmithKline, Spectrum, Boehringer Ingelheim, Taiho, Bristol Myers Squibb, and Takeda; and receiving royalties and licensing fees from Spectrum.

References

1. Heymach JV, Ruiter G, Ahn M-J, et al. Zongertinib in patients with pretreated HER2-mutant advanced NSCLC: Beamion LUNG-1. Presented at: 2025 AACR Annual Meeting; April 25-30, 2025; Chicago, IL. Abstract CT050.
2. Boehringer’s zongertinib receives Priority Review from U.S. FDA for the treatment of HER2 (ERBB2)-mutant advanced non-small cell lung cancer. Boehringer. February 19, 2025. Accessed April 28, 2025. https://www.boehringer-ingelheim.com/us/zongertinib-granted-priority-review-us-fda