Beamion LUNG-2: A phase III randomized controlled trial of zongertinib (BI 1810631) versus standard of care (SoC) in patients with locally advanced/metastatic non-squamous non-small cell lung cancer (NSCLC) harboring HER2 tyrosine kinase domain (TKD) mutations.

person Melissa Lynne Johnson Sarah Cannon Research Institute/Tennessee Oncology, Nashville, TN info_outline Melissa Lynne Johnson, Ross A. Soo, Yi-Long Wu, Navid Baktash, Daniela Maier, Sabina Eigenbrod-Giese, Tatsuya Yoshida

Authors person Melissa Lynne Johnson Sarah Cannon Research Institute/Tennessee Oncology, Nashville, TN info_outline Melissa Lynne Johnson, Ross A. Soo, Yi-Long Wu, Navid Baktash, Daniela Maier, Sabina Eigenbrod-Giese, Tatsuya Yoshida Organizations Sarah Cannon Research Institute/Tennessee Oncology, Nashville, TN, National University Cancer Institute, Singapore, Singapore, Guangdong Lung Cancer Institute, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, China, Boehringer Ingelheim (Canada) Ltd, Burlington, ON, Canada, Boehringer Ingelheim Pharma GmbH & Co. KG, Biberach an Der Riss, Germany, Boehringer Ingelheim International GmbH, Ingelheim Am Rhein, Germany, Department of Thoracic Oncology, National Cancer Center Hospital and Division of Molecular Pharmacology, National Cancer Center Research Institute, Tokyo, Japan Abstract Disclosures Research Funding Boehringer Ingelheim Background: HER2 mutations are present in 2–4% of NSCLC tumors, and ~50% occur in the TKD. First-line SoC for patients with HER2 mutation-positive (m+) NSCLC is platinum-based chemotherapy ± immunotherapy; however, no targeted first-line treatment has been approved. Zongertinib is a HER2-selective tyrosine kinase inhibitor (TKI) that binds to both wild-type and mutated HER2 but spares EGFR. In a Phase Ia trial in 53 pre-treated patients with HER2 aberration-positive solid tumors, zongertinib conferred an objective response (OR)/disease control rate (DCR) of 49/91% and an OR/DCR of 58/97% in those patients with HER2 m+ NSCLC (n=36), with manageable safety with few EGFR-associated toxicities (Beamion LUNG-1; NCT04886804). Here, we describe Beamion LUNG-2 (NCT06151574), a Phase III, randomized, active-controlled, open-label trial designed to assess the efficacy of first-line zongertinib versus SoC in patients with HER2 m+, locally advanced or metastatic non-squamous NSCLC. Methods: Approximately 270 patients from ~160 sites across 30 countries will be randomized 1:1 to receive either zongertinib or SoC and stratified by the presence of the A775_G77insYVMA HER2 mutation. In the experimental treatment arm, patients will receive 120 mg oral zongertinib once-daily in 21-day cycles. In the comparator treatment arm, patients will receive 500 mg/m 2 intravenous pemetrexed chemotherapy, plus either 75 mg/m 2 cisplatin or Area Under the Curve 5 carboplatin, plus 200 mg pembrolizumab on Day 1 once every 3 weeks (q3w) for four 21-day cycles, then maintenance with 500 mg/m 2 pemetrexed plus 200 mg pembrolizumab q3w for up to 35 cycles. Treatment in both arms will continue until progressive disease (PD; RECIST 1.1), undue toxicity, or other criteria are met. The primary endpoint is progression-free survival (RECIST 1.1), by blinded central independent review. Secondary endpoints include OR (defined as best overall response of complete or partial response, RECIST 1.1); patient-reported outcomes analysed as changes from baseline to Week 25; overall survival and occurrence of adverse events (CTCAE version 5.0). Key inclusion criteria are histologically or cytologically diagnosed advanced and/or metastatic non-squamous NSCLC; ≥1 measurable lesion (RECIST 1.1); no prior systemic treatment for locally advanced or metastatic disease; a documented HER2 TKD mutation; and eligibility to receive the selected SoC. Key exclusion criteria are tumors with targetable alterations with an available treatment; presence/history of uncontrolled/symptomatic leptomeningeal disease; and radiotherapy or major surgery ≤4 weeks prior to randomization. Clinical trial information: NCT06151574.

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