TROPION-Lung15: a randomized phase III study of osimertinib combined with datopotamab deruxtecan (Dato-DXd) or Dato-DXd alone versus platinum-doublet chemotherapy in patients with EGFR -mutated advanced non-small cell lung cancer and whose disease has progressed on prior osimertinib

Abstract

Background: Osimertinib is the preferred treatment for patients with EGFR-mutated advanced non-small cell lung cancer (NSCLC) in several settings; however, disease progression is common, and treatment options after progression are limited. Datopotamab deruxtecan (Dato-DXd), an antibody-drug conjugate comprising a humanized anti-trophoblast cell-surface antigen 2 (TROP 2) monoclonal antibody conjugated to a potent topoisomerase I inhibitor via a plasma-stable linker, has demonstrated efficacy in advanced NSCLC, including previously treated EGFR-mutated advanced NSCLC. Combining osimertinib and Dato-DXd may overcome heterogeneous osimertinib resistance mechanisms and limit tumor progression.Objectives: TROPION-Lung15 is an ongoing, phase III, open-label, sponsor-blind, multicenter, randomized trial evaluating Dato-DXd +/- osimertinib versus chemotherapy in patients with EGFR-mutated advanced NSCLC and disease progression on prior osimertinib.Methods and design: Approximately 630 patients with histologically/cytologically confirmed non-squamous NSCLC, documented epidermal growth factor receptor tyrosine kinase inhibitor-sensitive mutations, and radiologic progression on prior osimertinib monotherapy will be enrolled. Patients will be randomized 1:1:1 to Dato-DXd (6 mg/kg intravenously every 3 weeks), osimertinib (80 mg orally once daily) plus Dato-DXd, or platinum-doublet chemotherapy, stratified by the history/presence of brain metastases (yes vs no), prior osimertinib therapy (adjuvant vs post-chemoradiotherapy/first-line vs second-line), and race. Treatment will continue until radiological progression (per Response Evaluation Criteria in Solid Tumors version 1.1), unacceptable toxicity, or another discontinuation criterion is met. The dual primary endpoints are progression-free survival (PFS) by blinded independent central review (BICR) for osimertinib + Dato-DXd and PFS by BICR for Dato-DXd alone versus chemotherapy. Secondary endpoints include overall survival, central nervous system PFS by BICR, and safety/tolerability.Ethics: The study is approved by independent ethics committees/institutional review boards at each center. Patients will provide written informed consent.Discussion: TROPION-Lung15 will assess Dato-DXd +/- osimertinib in patients with EGFR-mutated advanced NSCLC and disease progression on prior osimertinib. Data from this study could lead to a new treatment option in this setting.Trial registration: ClinicalTrials.gov identifier: NCT06417814 (date of registration: May 13, 2024).