Abstract CT284: A phase 3 randomized controlled trial of zongertinib (BI 1810631) compared with standard of care in patients with locally advanced or metastatic nonsquamous non-small cell lung cancer harboring HER2 tyrosine kinase domain mutations: Beamion LUNG-2

Abstract Background: First-line (1L) standard of care for patients with HER2 mutation-positive (HER2m+) non-small cell lung cancer (NSCLC) is platinum-based chemotherapy ± immunotherapy. To date, no targeted 1L treatments have been approved. Zongertinib is a HER2-selective tyrosine kinase inhibitor that binds to wild-type and mutated HER2, and spares EGFR. In Phase Ia of Beamion LUNG-1 (NCT04886804), zongertinib conferred objective response/disease control rates of 49/91% in patients with pretreated HER2 aberration-positive solid tumors, and 58/97% in those patients with HERm+ NSCLC, with manageable safety with few EGFR-associated adverse events. Purpose: Here we describe Beamion LUNG-2 (NCT06151574), a phase 3, randomized, controlled, open-label trial that will compare the efficacy and safety of 1L zongertinib with standard of care in patients with HER2m+, locally advanced/metastatic nonsquamous NSCLC. Experimental design: Approximately 270 patients will be randomized 1:1 to receive either zongertinib or standard of care. Key inclusion criteria: histologically/cytologically diagnosed advanced/metastatic nonsquamous NSCLC; no prior systemic treatment for locally advanced/metastatic disease; HER2 mutation in the tyrosine kinase domain; ≥1 measurable lesion (RECIST 1.1). Key exclusion criteria: tumors that have alterations with available therapy, and radiotherapy/major surgery ≤4 weeks prior to randomization. In the experimental arm, oral zongertinib 120 mg once daily will be given in 21-day cycles. In the comparator arm, intravenous pemetrexed 500 mg/m2 chemotherapy plus either cisplatin 75 mg/m2 or carboplatin area under the curve 5, plus pembrolizumab 200 mg will be given on day 1 every 3 weeks for 4 cycles, followed by pemetrexed 500 mg/m2 plus pembrolizumab 200 mg every 3 weeks for ≤35 cycles. In both arms, treatment will continue until progressive disease (RECIST 1.1), undue toxicity, or other criteria are met. Primary endpoint: progression-free survival (RECIST 1.1). Secondary endpoints: overall response (defined as best overall response of complete or partial response, RECIST 1.1), patient-reported outcomes (changes from baseline to Week 25), overall survival, and adverse events during the on-treatment period (CTCAE 5.0). Citation Format: Yi-Long Wu, Melissa Johnson, Ross Soo, Navid Baktash, Daniela Maier, Sabina Eigenbrod-Giese, Tatsuya Yoshida. A phase 3 randomized controlled trial of zongertinib (BI 1810631) compared with standard of care in patients with locally advanced or metastatic nonsquamous non-small cell lung cancer harboring HER2 tyrosine kinase domain mutations: Beamion LUNG-2 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr CT284.