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 -mutated locally advanced or metastatic non-small cell lung cancer.
Journal
Therapeutic advances in medical oncology
Journal Volume
18
Start Page
Article number 17588359261430561
ISSN
1758-8340
Date Issued
2026
Author(s)
Lu, Shun
Pulla, Mariano Provencio
Mascarenhas, Eldsamira
Tanizaki, Junko
Kim, Hye Ryun
Liu, Yinglei
Feng, Shengmei
Zhang, Biao
Toms, Laurence
Goldberg, Sarah B
Abstract
Osimertinib is a first-line (1L) treatment option for patients with locally advanced/metastatic epidermal growth factor receptor ()-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 -mutated advanced NSCLC.
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 -mutated LA/M NSCLC.
The study is enrolling adults with histologically/cytologically confirmed stage IIIB/IIIC or intravenously (IV) non-squamous, -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 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.
The study is approved by independent ethics committees/institutional review boards at each center. Patients will provide informed consent.
TROPION-Lung14 will assess 1L osimertinib + Dato-DXd versus osimertinib alone in patients with -mutated LA/M NSCLC, potentially providing a new treatment option.
ClinicalTrials.gov identifier: NCT06350097 (Registration Date: April 5, 2024).
TROPION-Lung14: a clinical study comparing osimertinib in combination with datopotamab deruxtecan or osimertinib alone as the first line of treatment for patients with locally advanced or metastatic non-small-cell lung cancer (NSCLC) with a mutation in the epidermal growth factor receptor () gene Epidermal growth factor receptor () is a protein that controls cell growth and division. In some cancer cells the gene is mutated and allows cells to grow uncontrollably. Osimertinib is a medicine that blocks the activity of mutated on cancer cells, stopping their growth and is an option for treatment for people with -mutated NSCLC in various clinical situations. Most patients develop resistance to osimertinib and treatment options after the cancer gets worse are limited. Researchers are looking to see if osimertinib would be more effective when it is combined with other medicines. Datopotamab deruxtecan (Dato-DXd) is an antibody–drug conjugate that consists of an antibody (datopotamab) and an anticancer drug (DXd), joined via a plasma-stable cleavable linker. Dato-DXd has shown promising antitumor efficacy in previous studies in people with advanced or metastatic NSCLC. This study, called TROPION-Lung14, is designed to compare the combination of osimertinib and Dato-DXd with osimertinib alone as a first treatment for people with -mutated advanced NSCLC. Eligible patients will be randomly assigned to receive either osimertinib plus Dato-DXd or osimertinib alone. Patients will continue to receive treatment until their disease progresses, side effects become unacceptable, or they choose to leave the study. The main objective of the study is to see how long patients remain alive without their cancer growing or spreading (known as progression-free survival). The first results are expected to be available in early 2028, with the study expected to end in mid-2032.
Subjects
antibody–drug conjugate
datopotamab deruxtecan
epidermal growth factor receptor
non-small cell lung cancer
osimertinib
topoisomerase I
trophoblast cell-surface antigen 2
tyrosine kinase inhibitor
Type
journal article