Beamion LUNG-3: Zongertinib in resectable <i>HER2</i> -mutant NSCLC.

Abstract

TPS8129 Background: Zongertinib is an irreversible tyrosine kinase inhibitor that selectively inhibits HER2 while sparing wild-type EGFR, thereby minimizing associated toxicities. Based on recent data from the Phase Ib Beamion LUNG-1 trial (NCT04886804), zongertinib was approved in the USA (accelerated), China (conditional), and Japan for previously treated patients with advanced/metastatic HER2 -mutant NSCLC. Clinically meaningful efficacy has also been seen with zongertinib as first-line therapy in treatment-naïve patients with advanced HER2 -mutant NSCLC. Beamion LUNG-3 (NCT07195695) is an ongoing, global Phase III trial investigating zongertinib as adjuvant monotherapy compared with SoC (immunotherapy [IO] or observation) in patients with early-stage, resectable HER2 -mutant NSCLC. Methods: Patients with histologically confirmed, resectable, Stage II–IIIB (post-operative, AJCC 9 th edition) HER2 -mutant NSCLC will be enrolled. Patients must be aged ≥18 years, have an ECOG PS of 0 or 1, have tumors that harbor a HER2 mutation within the tyrosine kinase domain, and have completed 3–4 cycles of neoadjuvant platinum-based chemotherapy + IO or 4 cycles of adjuvant platinum-based chemotherapy (≥2 cycles permitted if discontinued due to toxicity), followed by complete surgical resection. Patients must have a full recovery from surgical procedures and the ability to be randomized within 2–8 weeks of the last treatment for patients who underwent adjuvant chemotherapy, or within 4–10 weeks of surgery for patients who underwent neoadjuvant therapy. Approximately 400 patients will be randomized 1:1 to receive zongertinib 120 mg once daily or physician’s choice SoC (observation or IO with nivolumab, pembrolizumab, atezolizumab, or durvalumab). Stratification will be based on tumor stage (II, IIIA, IIIB), pretreatment (neoadjuvant/adjuvant), and physician’s choice of SoC (IO/observation). Patients will remain on treatment for up to 3 years (if receiving zongertinib) or up to 1 year (if receiving SoC), or until tumor recurrence, undue toxicity, or any other protocol-defined stopping criterion. The primary endpoint is disease-free survival (DFS) by investigator assessment, defined as the time from randomization until tumor recurrence or death from any cause. Secondary endpoints include overall survival (OS, defined as the time from randomization until death from any cause) and occurrence of grade ≥3 adverse events from first treatment administration (or from randomization for patients in the observation arm) until the earliest of tumor recurrence or 3 years since treatment started. The trial will be conducted at ~200 sites in 32 countries; enrollment is ongoing. Results will inform whether HER2-targeted adjuvant therapy improves DFS and OS in patients with early-stage HER2 -mutant NSCLC. Clinical trial information: NCT07195695 .