In a phase IA to IB trial reported in The New England Journal of Medicine, Heymach et al found that first-line zongertinib was active in patients with advanced or metastatic HER2-mutant non–small cell lung cancer (NSCLC).
As noted by the investigators, zongertinib is an oral, irreversible tyrosine kinase inhibitor that selectively inhibits HER2 while sparing wild-type EGFR, potentially minimizing associated toxicity.
Study Details
The current report involved a cohort (cohort 2; n = 74) of the international multicohort trial with no previous treatment for advanced disease who initiated zongertinib at 120 mg once daily between November 2023 and August 2025. The primary endpoint was objective response assessed by blinded independent central review. Zongertinib at 120 mg once daily was also evaluated in 30 patients with active brain metastases in an exploratory cohort (cohort 4).
Key Findings
The confirmed objective response rate in cohort 2 was 76% (95% confidence interval [CI] = 65%–84%), with complete response in eight patients (11%). Median duration of response was 15.2 months (95% CI = 9.8 months to not evaluable). Median progression-free survival was 14.4 months (95% CI = 11.1 months to not evaluable). Treatment-related adverse events of any grade occurred in 67 patients (91%), including events of grade 3 or higher in 14 (19%).
In cohort 4, the confirmed intracranial objective response rate was 47% (95% CI = 30%–64%). Median duration of intracranial response was 6.9 months (95% CI = 2.9 months to not evaluable). Median intracranial progression-free survival was 8.2 months (95% CI = 4.1–11.3 months). Treatment-related adverse events of grade 3 or higher occurred in five patients (17%).
The investigators concluded: “Zongertinib showed sustained efficacy in previously untreated patients with advanced or metastatic HER2-mutant NSCLC. Treatment-related adverse events were predominantly low-grade.”
John V. Heymach, MD, PhD, of the Department of Thoracic/Head and Neck Medical Oncology, University of Texas MD Anderson Cancer Center, Houston, is the corresponding author for the New England Journal of Medicine article.
DISCLOSURE: The study was funded by Boehringer Ingelheim. For full disclosures of the study authors, visit nejm.org.
