TROPION-Lung14 study protocol: a phase III study of osimertinib in combination with datopotamab deruxtecan versus osimertinib alone as first-line treatment for patients with EGFR -mutated locally advanced or metastatic non-small cell lung cancer

Background: Osimertinib is a first-line (1L) treatment option for patients with locally advanced/metastatic epidermal growth factor receptor ( EGFR )-mutated non-small-cell lung cancer (NSCLC). Resistance to 1L osimertinib often develops and treatment options after disease progression are limited. The clinical benefit of 1L osimertinib in combination with agents which have broad antitumor activity has been demonstrated in phase III trials. Datopotamab deruxtecan (Dato-DXd), an antibody–drug conjugate composed of a humanized anti-trophoblast cell-surface antigen 2 monoclonal antibody conjugated to a potent topoisomerase I inhibitor, has demonstrated efficacy as monotherapy and in combination with osimertinib in NSCLC, including patients with EGFR -mutated advanced NSCLC. Objectives: TROPION-Lung14 (NCT06350097), an ongoing phase III, open-label, sponsor-blind, multicenter, randomized study, is evaluating the efficacy and safety of osimertinib + Dato-DXd, versus osimertinib, as 1L therapy in patients with EGFR -mutated LA/M NSCLC. Methods and design: The study is enrolling adults with histologically/cytologically confirmed stage IIIB/IIIC or intravenously (IV) non-squamous, EGFR -mutated (exon 19 deletion (Ex19del) or L858R) NSCLC, and no prior EGFR-TKI or other systemic therapy for stage IIIB/IIIC or IV disease. Prior to the randomized study period, ~20 patients will receive osimertinib + Dato-DXd in a safety run-in. Following safety run-in, ~562 patients will be randomized 1:1 to osimertinib (80 mg orally once daily (PO QD)) + Dato-DXd (6 mg/kg IV every 3 weeks) or osimertinib (80 mg PO QD). Patients will be stratified by EGFR mutation type (Ex19del vs L858R), World Health Organization performance status (0 vs 1), and central nervous system metastasis (yes vs no). Treatment will continue until Resist Evaluation Criteria in Solid Tumors version 1.1-defined progression or unacceptable toxicity. The primary endpoint is progression-free survival by blinded independent central review. Overall survival is a key secondary endpoint. Ethics: The study is approved by independent ethics committees/institutional review boards at each center. Patients will provide informed consent. Discussion: TROPION-Lung14 will assess 1L osimertinib + Dato-DXd versus osimertinib alone in patients with EGFR -mutated LA/M NSCLC, potentially providing a new treatment option. Trial registration: ClinicalTrials.gov identifier: NCT06350097 (Registration Date: April 5, 2024).