STUDY PROTOCOL article
Front. Oncol.
Sec. Thoracic Oncology
This article is part of the Research TopicPrecision Immuno-Oncology: Harnessing Novel Drug Development, Biomarkers, and Nanoparticle-Based Therapeutic Platforms to Overcome Cancer ResistanceView all 4 articles
TROPION-Lung10: a phase 3 study of datopotamab deruxtecan and rilvegostomig in patients with treatment-naïve locally advanced or metastatic nonsquamous non-small cell lung cancer with high PD-L1 expression and without actionable genomic alterations
Provisionally accepted
Tom Newsom-Davis1*
Barbara Melosky2
Rebecca S Heist3
Shun Lu4
Giulia Pasello5Xiwei Chen6Marta Stachowiak7Pavlo Lyfar8Alessandra Forcina9Suresh S Ramalingam10- 1Chelsea and Westminster Hospital, London, United Kingdom
- 2BC Cancer-Vancouver Centre, Vancouver, BC, Canada
- 3Massachusetts General Hospital, Boston, United States
- 4Shanghai Lung Center, Shanghai, China
- 5Veneto Institute of Oncology, Padova, Italy
- 6Biostatistics, AstraZeneca, Wilmington, DE, United States
- 7Clinical Development, AstraZeneca, Warsaw, Poland
- 8Global Development, AstraZeneca, Mississauga, ON, Canada
- 9Oncology R&D, AstraZeneca, Cambridge, United Kingdom
- 10Winship Cancer Institute of Emory University Atlanta, Atlanta, GA, United States
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Background: Immunotherapy targeting the programmed cell death (ligand)-1 (PD-[L]1) pathway has improved outcomes for patients with advanced/metastatic non-small cell lung cancer (NSCLC) without actionable genomic alterations (AGAs), especially those with high PD-L1 expression (on ≥50% of tumor cells [TC]); however, some patients have primary or acquired resistance to treatment and new therapeutic strategies are needed. Datopotamab deruxtecan (Dato-DXd), a trophoblast cell surface antigen 2 (TROP2)-directed antibody-drug conjugate, and rilvegostomig, a bispecific anti-PD-1/anti-TIGIT antibody, have shown promising efficacy and manageable safety profiles in patients with advanced/metastatic NSCLC. Methods and design: TROPION-Lung10 (NCT06357533) is a phase 3, open-label, multicenter, randomized study evaluating the efficacy and safety of first-line Dato-DXd plus rilvegostomig versus standard-of-care pembrolizumab in patients with advanced/metastatic nonsquamous NSCLC with PD-L1 TC expression ≥50% and without AGAs. Approximately 675 adults with nonsquamous stage IIIB/C or IV NSCLC not amenable to curative surgery or definitive chemoradiation, PD-L1 TC ≥50%, and no AGAs will be enrolled. Patients will be randomized (2:1:2) to receive Dato-DXd (6 mg/kg intravenously [IV] every 3 weeks [Q3W]) plus rilvegostomig (750 mg IV Q3W), rilvegostomig alone (750 mg IV Q3W), or pembrolizumab (200 mg IV Q3W for up to 35 cycles/24 months). The dual primary endpoints are progression-free survival (PFS) by blinded independent central review (BICR) per Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v1.1) and overall survival (OS) in the TROP2 normalized membrane ratio (NMR) biomarker-positive population for Dato-DXd plus rilvegostomig versus pembrolizumab. Key secondary endpoints are PFS by BICR per RECIST v1.1 and OS in the full analysis set (FAS). Other secondary endpoints include: objective response rate and duration of response by BICR per RECIST v1.1; PFS2; patient-reported outcomes in the TROP2 NMR-positive population and FAS; and safety.
Keywords: Antibody-drug conjugate, Datopotamab deruxtecan, Non-small cell lung cancer, Programmed cell death ligand-1, rilvegostomig, TIGIT, topoisomerase I, TROPION-Lung10
Received: 15 Oct 2025; Accepted: 15 Dec 2025.
Copyright: © 2025 Newsom-Davis, Melosky, Heist, Lu, Pasello, Chen, Stachowiak, Lyfar, Forcina and Ramalingam. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
* Correspondence: Tom Newsom-Davis
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