Beamion LUNG 2: A Phase III, open-label, randomized, active-controlled, multi-centre trial evaluating orally administered BI 1810631 compared with standard of care as first-line treatment in patients with unresectable, locally advanced or metastatic non-squamous non-small cell lung cancer harbouring HER2 tyrosine kinase domain mutations

INTERVENTION: Zongertinib (BI 1810631): Oral administration Pembrolizumab plus platinum‐pemetrexed chemotherapy: intravenous administration CONDITION: D002289 Unresectable, locally advanced or metastatic non‐squamous NSCLC harboring HER2 TKD mutations PRIMARY OUTCOME: PFS according to RECIST 1.1 determined by blinded central independent review. PFS is defined as the time from randomization until tumor progression according to RECIST 1.1 or death from any cause, whichever occurs earlier. INCLUSION CRITERIA: 1) Patients 18 years of age or over the legal age of consent in countries where that is greater than 18 years at the time of signature of the informed consent form (ICF). 2) Histologically or cytologically confirmed diagnosis of advanced and/or metastatic non‐squamous NSCLC. 3) Documented HER2 mutation in the TKD as per local lab results preferably by tissue NGS/PCR, but also ctDNA. 4) Availability and willingness to provide a sample of archival formalin‐fixed paraffin embedded (FFPE) tumor tissue material. 5) Patients who have not received any systemic treatment for locally advanced or metastatic disease. Prior neoadjuvant and/or adjuvant chemotherapy or immunotherapy is allowed if the treatment was completed more than 6 months prior to trial entry. 6) Presence of at least one measurable lesion according to RECIST 1.1, as determined by the local site investigator/radiology assessment. Patients with asymptomatic (i.e. no clinical [neurological] sympt SECONDARY OUTCOME: [Key secondary endpoints]; OR according to RECIST 1.1, determined by blinded central independent review, the change from baseline to Week 25 of NSCLC‐SAQ total score, and OS. OR is defined as best overall response of complete response (CR) or partial response (PR), where best overall response is determined according to RECIST 1.1 from date of randomization until the earliest of disease progression, death, or last evaluable tumor assessment before start of subsequent anti‐cancer therapy, loss to follow‐up or withdrawal of consent. OS is defined as the time from randomization until death from any cause.; ; [Secondary endpoints]; 1) Duration of response (DoR), determined by blinded central independent review. DoR is defined as the time from first documented CR or PR until the earliest of disease progression or death among patients with objective response.; 2) For patients with central nervous system (CNS) lesions at baseline: CNS PFS, determined by blinded central independent review. CNS PFS is defined as the time from randomization until tumor progression according to RANO‐BM or death from any cause, whichever occurs earlier.; 3) Bi‐compartmental PFS, determined by blinded central independent review. Bi‐compartmental PFS is defined as the time from randomization until tumor progression according to RECIST 1.1 and/or RANO‐BM or death from any cause, whichever occurs earlier.; 4) For patients with CNS lesions at baseline: CNS OR, determined by blinded central independent review. CNS OR is defined as best overall response of CR or PR, where best overall response is determined according to RANO‐BM from date of randomization until the earliest of CNS progression, death, or last evaluable tumor assessment before start of subsequent anti‐cancer therapy, loss to follow‐up or withdrawal of consent.; 5) Patient reported outcomes (PROs), analyzed as change from baseline to Week 25 of the following PRO domain scores:; ‐ NSCLC‐SAQ pain domain score; ‐ NSCLC‐SAQ dyspnoea domain score; ‐ NSCLC‐SAQ cough domain score; ‐ NSCLC‐SAQ appetite domain score; ‐ NSCLC‐SAQ fatigue domain score; ‐ EORTC QLQ‐C30 physical functioning domain score ; 6) Occurrence of adverse events (AEs) during the on‐treatment period, graded according to CTCAE version 5.0.; 7) Occurrence of serious AEs (SAEs) during the on‐treatment period, graded according to CTCAE version 5.0.