Josh Friedman , 2025-04-29 16:08:00
April 29, 2025
3 min read
Key takeaways:
- Most patients who received zongertinib achieved an objective response in a phase 1 trial.
- Nearly all participants achieved disease control.
Zongertinib conferred benefit in certain patients with previously treated HER2-mutant advanced non-small cell lung cancer in a phase 1 trial, according to findings presented at American Association for Cancer Research Annual Meeting.
The results, also published in The New England Journal of Medicine, showed more than 70% of participants with tyrosine kinase domain (TKD) mutations achieved an objective response.
John V. Heymach
“Zongertinib (Boehringer Ingelheim) provided clinically meaningful benefit in previously treated patients with advanced NSCLC with HER2 mutations within and outside the TKD, including in patients with brain metastases,” John V. Heymach, MD, PhD, chair of Thoracic and Head and Neck Medical Oncology at The University of Texas MD Anderson Cancer Center, said during his presentation.
Background, methods
Between 2% and 4% of patients with NSCLC have HER2 mutations, according to study background.
Historically, these individuals have worse prognosis and higher incidence of brain metastases compared with other patients with NSCLC.
Researchers have had difficulty targeting TKI-inhibiting HER2 mutations for patients with NSCLC because drugs used to inhibit those mutations also inhibited EGFR, which can cause adverse events such as rash and diarrhea.
“Zongertinib was designed to be highly selective for mutant HER2 and spare wild-type EGFR, therefore potentially limiting those EGFR-related toxicities,” Heymach said.
Heymach and colleagues evaluated zongertinib in patients with previously treated HER2-mutant advanced NSCLC in the Beamion LUNG-1 study.
Researchers investigated 120 mg and 240 mg doses in five cohorts during phase 1B of the study. They moved forward with the 120 mg dose at the interim analysis.
Heymach reported data from cohorts 1, 3 and 5 during his presentation.
Cohort 1 included 75 participants (median age, 62 years; range, 30-80; 68% women; 53% Asian) with previously treated HER2-mutant advanced NSCLC with TKD mutations.
Cohort 5 included 31 patients (median age, 61 years; range, 31-85; 68% women; 35% Asian) with TKD mutations who had previous HER2-directed treatment.
Cohort 3 included 20 patients (median age, 65 years; range, 27-77; 55% men; 45% Asian) with non-TKD mutations.
Objective response served as the primary endpoint. Blinded independent central review assessed ORR for cohorts 1 and 5. Investigators conducted the assessment for cohort 3.
Duration of response, disease control rate and PFS served as secondary endpoints.
Results, next steps
At median follow-up of 11.3 months, patients in cohort 1 had an ORR of 71% (95% CI, 60%-80%), including 7% who had a complete response.
Patients had a median time to response of 1.4 months (range, 1.1-6.9) and median duration of response of 14.1 months (95% CI, 6.9 months-not reached).
The cohort also had a disease control rate of 96% (95% CI, 89%-99%) and median PFS of 12.4 months (95% CI, 8.2-not reached).
Patients with brain metastases had an intracranial response rate of 41% (95% CI, 25%-59%) and disease control rate of 81% (95% CI, 63%-92%).
Of participants in cohort 1, 44% remained on treatment at data cutoff.
Drug-related adverse events occurred in 97% of patients, with 17% experiencing grade 3 or worse toxicities.
The most common adverse events included diarrhea (56%), rash (33%) and increased aspartate aminotransferase (AST; 24%).
The most common grade 3 or worse adverse events included increased alanine aminotransferase (8%) and AST (5%). One patient experienced grade 3 or worse diarrhea.
In all, adverse events caused 7% of participants to reduce their dose and 3% to discontinue treatment.
No patients developed drug-related interstitial lung disease.
Heymach described the safety profile as “mild and manageable.”
Patients in cohort 5 had an ORR of 48% (95% CI, 32%-65%), a complete response rate of 3% and a disease control rate of 97% (95% CI, 84%-99%).
Those in cohort 3 had an ORR of 30% (95% CI, 15%-52%) and disease control rate of 65% (95% CI, 43%-82%).
“Zongertinib demonstrated meaningful clinical activity … in the largest known dataset in this patient population,” Heymach said of cohort 3.
Researchers are still evaluating patients with TKD mutations who have not received previous treatments (cohort 2) and those with TKD mutations and active brain metastases (cohort 4).
The randomized, phase 3 Beamion LUNG-2 study, in which patients with advanced or metastatic HER-2 mutant NSCLC will receive first-line zongertinib or standard of care, is currently enrolling.
Future research into combination therapies is warranted, as well.
“I’m excited about looking at combinations with HER2 [antibody-drug conjugates],” Heymach said. “There we have two different types of active drugs that hopefully can be combined. Chemotherapy combinations … I think make sense, and there are other types of drugs also that could potentially be combined with a good safety profile.
“We’re excited to see the performance of monotherapy, but moving forward I anticipate that combinations are going to play an important role.”
Reference:
Sources/Disclosures
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Heymach JV, et al. Abstract CT050. Presented at: American Association for Cancer Research Annual Meeting; April 25-30, 2025; Chicago.
Disclosures:
Boehringer Ingelheim funded the study. Heymach reports serving on advisory committees for AbbVie, Anheart, AstraZeneca, Bayer, BioAtla, BioNTech, Boehringer Ingelheim, Bristol Myers Squibb, Dizal, Eli Lilly & Co., Ellipsis, EMD Serono, Genentech, GSK, Hengrui Therapeutics, Janssen Global Services, Leads Biolabs, ModeX Therapeutics, Novartis, Pfizer, Regeneron, Remunity, Sanofi, Spectrum and Takeda; research support from AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, Spectrum, Taiho and Takeda; and royalties and licensing fees from Spectrum. Please see the study for all other authors’ relevant financial disclosures.
