Multinational phase 1a-1b trial of first-line zongertinib in advanced HER2-mutant non-small cell lung cancer

Zongertinib is an oral, irreversible tyrosine kinase inhibitor that selectively inhibits HER2 while sparing wild-type EGFR, thereby minimizing associated toxic effects. Cohort 2 of the multinational phase 1a-1b Beamion LUNG-1 trial evaluated zongertinib 120 mg once daily for patients with advanced or metastatic nonsquamous HER2-mutant non-small cell lung cancer (NSCLC) who had not previously received treatment. The primary endpoint was objective response as assessed by blinded independent central review. Among 74 patients, the percentage with a confirmed objective response was 76% (95% CI 65-84), with a median duration of response 15.2 months (9.8-NE) and median progression-free survival 14.4 months (11.1-NE). Adverse events of any grade occurred in 99% of patients and of grade 3 or higher in 45%. Treatment-related adverse events of any grade occurred in 91% and of grade 3 or higher in 19%. In cohort 4 of Beamion LUNG-1, a total of 30 patients with active brain metastases received zongertinib 120 mg once daily; of these, 47% (95% CI 30-64) had a confirmed intracranial objective response (RANO criteria), and 17% had treatment-related adverse events of grade 3 or higher. The authors conclude that zongertinib showed sustained efficacy in previously untreated patients with advanced or metastatic HER2-mutant NSCLC; treatment-related adverse events were predominantly low-grade.