The FDA granted breakthrough therapy designation to the oral HER2 TKI zongertinib (Hernexeos) for the first-line treatment of adult patients with unresectable or metastatic nonsquamous non-small cell lung cancer (NSCLC) harboring HER2 tyrosine kinase domain (TKD) activating mutations, based on phase 1b Beamion LUNG-1 data. In cohort 1 at 120 mg daily (n=75), the confirmed objective response rate was 71% (complete response rate 7%, partial response 64%) at a median follow-up of 11.3 months; 40% of responders had ongoing responses at cutoff. Median duration of response was 14.1 months and median progression-free survival was 12.4 months. Zongertinib previously received FDA accelerated approval for the post-systemic-therapy setting in the same biomarker-defined population.
Beamion LUNG-1 is an open-label, multi-cohort study enrolling adults with advanced solid tumors, including HER2-mutant NSCLC, with RECIST-measurable disease and ECOG performance status of 0 to 2. Following an early randomization to 120 mg vs 240 mg, the protocol selected 120 mg daily for subsequent patients. Additional efficacy signals included a confirmed objective response rate of 48% in cohort 5 (antibody-drug conjugate-pretreated HER2 TKD NSCLC; n=31) and 30% in exploratory cohort 3 (non-TKD HER2 mutations; n=20). Safety at 120 mg showed adverse events (AEs) in all patients; treatment-related AEs in 97% (17% grade ≥3), with low rates of dose reduction (7%) and discontinuation (3%); and no treatment-related interstitial lung disease was reported.
Reference: Flaherty C. Zongertinib Receives FDA Breakthrough Therapy Designation in Nonsquamous NSCLC With HER2 TKD Mutations. OncLive. Published September 4, 2025. Accessed September 16, 2025. https://www.onclive.com/view/zongertinib-receives-fda-breakthrough-therapy-designation-in-nonsquamous-nsclc-with-her2-tkd-mutations
