Background: HER2mutations are present in 2–4% of NSCLC tumors, and ~50% occur in the TKD. First-line SoC for patients with HER2mutation-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 HER2aberration-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 HER2m+ 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 HER2m+, 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/m² intravenous pemetrexed chemotherapy, plus either 75 mg/m² 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/m² 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.