Dato-DXd Plus Pembrolizumab vs Pembrolizumab Alone in the First-line Treatment of Subjects with Advanced or Metastatic NSCLC Without Actionable Genomic Alterations

A Randomized, Open-label, Phase 3 Trial of Dato-DXd Plus Pembrolizumab vs Pembrolizumab Alone in Treatment-naive Subjects with Advanced or Metastatic PD-L1 High (TPS >=50%) Non-small Cell Lung Cancer Without Actionable Genomic Alterations - TROPION-Lung08

Status

Recruiting

Phases

Phase 3

Study type

Interventional

Source

JPRN

Registry ID

JPRN-jRCT2061210074

Enrollment

740

Registered

2022-02-05

Start date

2022-03-04

Completion date

Unknown

Last updated

2026-06-29

For informational purposes only — not medical advice. Sourced from public registries and may not reflect the latest updates. Terms

Conditions

Advanced or Metastatic PD L1 High (TPS >=50%) Non-small Cell Lung Cancer with non-squamous histology

Interventions

- Drug: Datopotamab deruxtecan Intravenous infusion every 3 weeks (Q3W) on Day 1 of each 21-day cycle (starting datopotamab deruxtecan dose of 6.0 mg/kg) - Drug: Pembrolizumab Intravenous infusion Q

Eligibility

Sex/Gender

All

Inclusion criteria

Inclusion criteria: 1.Sign and date the Tissue Screening and Main Informed Consent Forms, prior to the start of any study-specific qualification procedures. 2.Adults >=18 years or the minimum legal adult age (whichever is greater) at the time of informed consent. 3.Histologically documented non-squamous NSCLC that meets all of the following criteria (Note: Subjects with squamous histology were eligible prior to Protocol Version 5.0. After Protocol Version 5.0, subjects with squamous histology are not eligible. Subjects with mixed histology, including those with a squamous component, remain eligible the study even after Protocol Version 5.0): a.Stage IIIB or IIIC disease and not candidates for surgical resection or definitive chemoradiation, or Stage IV NSCLC disease at the time of randomization (based on the American Joint Committee on Cancer, Eighth Edition). Participants with early-stage NSCLC who have relapsed should be restaged during screening to ensure their eligibility for the study. b.Documented negative test results for epidermal growth factor receptor (EGFR), lymphoma kinase (ALK), and proto-oncogene1 (ROS1) actionable genomic alterations (AGAs) based on analysis of tumor tissue. If test results for EGFR, ALK, and ROS1 are not available, subjects are required to undergo testing performed locally for these genomic alterations. c.No known actionable genomic alterations in neurotrophic tyrosine receptor kinase (NTRK), proto-oncogene B-raf (BRAF), rearranged during transfection (RET), mesenchymal-epithelial transition factor (MET), or other actionable driver kinases with locally approved therapies. (Testing for genomic alterations besides EGFR, ALK, and ROS1 is not required prior to randomization). Subjects whose tumors harbor KRAS mutations are eligible for the study. 4.Has provided a formalin-fixed tumor tissue sample for the measurement of trophoblast cell surface protein 2 (TROP2) protein expression and for the assessment of other exploratory biomarkers. 5.Tumor has high programmed death receptor-1 (PD-L1) expression (TPS >=50%) as determined by PD-L1 immunohistochemistry (IHC) 22C3 pharmDx assay by central testing (minimum of 6 slides). 6.Has an adequate treatment washout period before Cycle 1 Day 1. 7.Measurable disease based on local imaging assessment using RECIST Version 1.1 8.Has left ventricular ejection fraction (LVEF) >=50% by either an echocardiogram (ECHO) or multigated acquisition scan (MUGA) within 28 days before randomization. 9.Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0 or 1 at screening. 10.Has a life expectancy of at least 3 months. 11.Adequate bone marrow function within 7 days before randomization.

Exclusion criteria

Exclusion criteria: 1.Has received prior systemic treatment for advanced or metastatic NSCLC. 2.Has received prior treatment for NSCLC with any of the following, including in the adjuvant/neoadjuvant setting: a.Any agent, including an antibody-drug conjugate, containing a chemotherapeutic agent targeting topoisomerase I. b.TROP2-targeted therapy. c.Any anti-programmed death receptor-1 (PD-1), anti-PD-L1, or anti-PD-ligand 2 (L2) agent or with an agent directed to another stimulatory or co-inhibitory T-cell receptor (eg, CTLA-4, OX40, CD137). d.Any other immune checkpoint inhibitors. Participants who received adjuvant or neoadjuvant therapy OTHER than those listed above, are eligible if the adjuvant/neoadjuvant therapy was completed at least 6 months prior to the diagnosis of advanced/metastatic disease. 3.Has spinal cord compression or active and untreated central nervous system (CNS) metastases and/or carcinomatous meningitis. Participants with previously treated brain metastases and who are asymptomatic may participate provided they are radiologically stable. 4.Has received prior radiotherapy =3 years before the first dose of study treatment and of low potential risk for recurrence. b.Adequately treated non-melanoma skin cancer or lentigo maligna without evidence of disease. c.Adequately treated carcinoma in situ without evidence of disease. d.Participants with a history of prostate cancer (tumor/node/metastasis stage) of Stage 470 ms regardless of sex (based on the average of the 12-lead electrocardiogram determination at screening). b.Myocardial infarction within 6 months prior to randomization. c.Uncontrolled angina pectoris within 6 months prior to randomization. d.LVEF =50% (by either an ECHO or MUGA scan within 28 days before randomization) in order to be eligible. f.Uncontrolled hypertension (resting systolic blood pressure >180 mmHg or diastolic blood pressure >110 mmHg) within 28 days before randomization. 9.Clinically significant corneal disease. 10.Has received a live vaccine or live-attenuated vaccine (messenger ribonucleic acid

Design outcomes

Primary

Measure	Time frame
1. Progression-free Survival Based on Blinded Independent Central Review in Participants With Non-Squamous Histology Who Were Administered Dato-DXd in Combination With Pembrolizumab Compared With Pembrolizumab [Time Frame: From randomization until disease progression or death (whichever occurs first), up to approximately 44 months] Progression-free Survival (PFS) is defined as the time from randomization to the first documented radiographic disease progression or death due to any cause, whichever occurs first, assessed by blinded independent central review (BICR) per Response Evaluation Criteria in Solid Tumors (RECIST), Version 1.1. 2. Overall Survival (OS) in Participants With Non-Squamous Histology Who Were Administered Dato-DXd in Combination With Pembrolizumab Compared With Pembrolizumab [Time Frame: From randomization until date of death due to any cause, up to approximately 71 months] Overall Survival (OS) is defined as the time from randomization to death due to any cause.	—

Measure

Time frame

1. Progression-free Survival Based on Blinded Independent Central Review in Participants With Non-Squamous Histology Who Were Administered Dato-DXd in Combination With Pembrolizumab Compared With Pembrolizumab [Time Frame: From randomization until disease progression or death (whichever occurs first), up to approximately 44 months] Progression-free Survival (PFS) is defined as the time from randomization to the first documented radiographic disease progression or death due to any cause, whichever occurs first, assessed by blinded independent central review (BICR) per Response Evaluation Criteria in Solid Tumors (RECIST), Version 1.1. 2. Overall Survival (OS) in Participants With Non-Squamous Histology Who Were Administered Dato-DXd in Combination With Pembrolizumab Compared With Pembrolizumab [Time Frame: From randomization until date of death due to any cause, up to approximately 71 months] Overall Survival (OS) is defined as the time from randomization to death due to any cause.

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Secondary

Measure	Time frame
1.OS in All Randomized Participants, Including Participants With Squamous and Non-Squamous Histology [Time Frame: From randomization until date of death due to any cause, up to approximately 71 months] Overall Survival (OS) is defined as the time from randomization to death due to any cause. 2.PFS Based on BICR in All Randomized Participants, Including Participants With Squamous and Non-Squamous Histology [Time Frame: From randomization until disease progression or death (whichever occurs first), up to approximately 44 months] PFS is defined as the time from randomization to the first documented radiographic disease progression or death due to any cause, whichever occurs first, assessed by BICR per Response Evaluation Criteria in Solid Tumors (RECIST), Version 1.1. 3.Progression-free Survival by Investigator in Participants with Non-Squamous Histology, and Separately for All Randomized Participants [Time Frame: From randomization until disease progression or death (whichever occurs first), up to approximately 44 months] Progression-free Survival (PFS) is defined as the time from randomization to the first documented radiographic disease progression or death due to any cause, whichever occurs first, assessed by the Investigator per RECIST Version 1.1. 4.Progression-free Survival 2 in Participants with Non-Squamous Histology, and Separately for All Randomized Participants [Time Frame: From randomization until disease progression on the next line of therapy or death (whichever occurs first), up to approximately 71 months] Progression-free Survival 2 (PFS2) is defined as the time from date of randomization to the first documented disease progression on next-line therapy or death due to any cause, whichever occurs first. 5.ORR by BICR and Investigator in Participants with Non-Squamous Histology, and Separately for All Randomized Participants [Time Frame: From randomization to first confirmed response, up to approximately 44 months] Objective Response Rate (ORR) is define	—

Measure

Time frame

1.OS in All Randomized Participants, Including Participants With Squamous and Non-Squamous Histology [Time Frame: From randomization until date of death due to any cause, up to approximately 71 months] Overall Survival (OS) is defined as the time from randomization to death due to any cause. 2.PFS Based on BICR in All Randomized Participants, Including Participants With Squamous and Non-Squamous Histology [Time Frame: From randomization until disease progression or death (whichever occurs first), up to approximately 44 months] PFS is defined as the time from randomization to the first documented radiographic disease progression or death due to any cause, whichever occurs first, assessed by BICR per Response Evaluation Criteria in Solid Tumors (RECIST), Version 1.1. 3.Progression-free Survival by Investigator in Participants with Non-Squamous Histology, and Separately for All Randomized Participants [Time Frame: From randomization until disease progression or death (whichever occurs first), up to approximately 44 months] Progression-free Survival (PFS) is defined as the time from randomization to the first documented radiographic disease progression or death due to any cause, whichever occurs first, assessed by the Investigator per RECIST Version 1.1. 4.Progression-free Survival 2 in Participants with Non-Squamous Histology, and Separately for All Randomized Participants [Time Frame: From randomization until disease progression on the next line of therapy or death (whichever occurs first), up to approximately 71 months] Progression-free Survival 2 (PFS2) is defined as the time from date of randomization to the first documented disease progression on next-line therapy or death due to any cause, whichever occurs first. 5.ORR by BICR and Investigator in Participants with Non-Squamous Histology, and Separately for All Randomized Participants [Time Frame: From randomization to first confirmed response, up to approximately 44 months] Objective Response Rate (ORR) is define

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Countries

Argentina, Australia, Belgium, Brazil, Canada, Chile, China, Czech Republic, France, Germany, Greece, Hong Kong, Hungary, Italy, Japan, Korea, Mexico, Netherlands, Poland, Portugal, Romania, Russia, Spain, Switzerland, Taiwan, Thailand, Turkey, Ukraine, United Kingdom, United States

Contacts

Public ContactContact for Clinical Trial Information

DAIICHI SANKYO Co.,Ltd.

dsclinicaltrial_jp@daiichisankyo.com+81-3-6225-1111

Outcome results

None listed

Source: JPRN (via WHO ICTRP) · Data processed: Jul 3, 2026