臨床研究等提出・公開システム

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)

Dato-DXd Plus Pembrolizumab vs Pembrolizumab Alone in the First-line Treatment of Subjects with Advanced or Metastatic NSCLC Without Actionable Genomic Alterations
(TROPION-Lung08)

Inoguchi Akihiro

DAIICHI SANKYO Co.,Ltd.

1-2-58, Hiromachi, Shinagawa-ku, Tokyo

dsclinicaltrial@daiichisankyo.co.jp

Contact for Clinical Trial Information

DAIICHI SANKYO Co.,Ltd.

1-2-58, Hiromachi, Shinagawa-ku, Tokyo

+81-3-6225-1111

dsclinicaltrial@daiichisankyo.co.jp

Recruiting

Feb. 28, 2022

Interventional

randomized controlled trial

open(masking not used)

active control

parallel assignment

treatment purpose

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.

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 <4 weeks of start of study intervention or more than 30 Gy (unit of ionizing radiation dose in the International System of Units) to the lung within 6 months of Cycle 1 Day 1.
5.History of another primary malignancy (beyond NSCLC) except for:
a.Malignancy treated with curative intent and with no known active disease >=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 <=T2cN0M0 without biochemical recurrence or progression and who in the opinion of the Investigator are not deemed to require active intervention.
6.Has a history of (non-infectious) interstitial lung disease (ILD)/pneumonitis including radiation pneumonitis that required steroids, has current ILD/pneumonitis, or where suspected ILD/pneumonitis cannot be ruled out by imaging at screening.
7.Clinically severe pulmonary compromise, as judged by the investigator, resulting from intercurrent pulmonary illnesses including, but not limited to, any underlying pulmonary disorder or any autoimmune, connective tissue or inflammatory disorders with pulmonary involvement or prior complete pneumonectomy.
8.Uncontrolled or significant cardiovascular disease, including:
a.Mean QT interval corrected for heart rate using Fridericia's formula (QTcF) interval >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 ECHO or MUGA scan within 28 days before randomization.
e.New York Heart Association Class 2 to 4 congestive heart failure (CHF) at screening. Participants with a history of Class 2 to 4 CHF prior to screening, must have returned to Class 1 CHF and have 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 and replication-incompetent adenoviral vaccines are not considered attenuated live vaccines) within 30 days prior to the first dose of study drug. For any subject receiving an approved severe acute respiratory syndrome coronavirus 2 (SARS-CoV2) vaccine, please follow the vaccine label and/or local guidance.
11.Active, known, or suspected autoimmune disease (has an active autoimmune disease that has required systemic treatment in the past 2 years).
12.Has a diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy (in dosage >10 mg daily of prednisone equivalent) or any other form of immunosuppressive therapy <=7 days prior to the first dose of study drug.
13.Has known human immunodeficiency virus (HIV) infection that is not well controlled.
14.Has an active hepatitis or uncontrolled hepatitis B virus (HBV) or active hepatitis C virus (HCV) infection.
15.Has an uncontrolled infection requiring IV antibiotics, antivirals, or antifungals.
16.Had an allogeneic tissue/solid organ transplant.
17.Has a history of severe hypersensitivity reactions to either the drug or inactive ingredients (including but not limited to polysorbate 81) of Dato-DXd or pembrolizumab.

Both

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

- 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 Q3W on Day 1 of each 21-day cycle (fixed pembrolizumab dose 200 mg Q3W)

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.

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 defined as the proportion of participants who achieved a best overall response (BOR) of confirmed complete response (CR) or confirmed partial response (PR), assessed by BICR and by the Investigator per RECIST Version 1.1.
6. Duration of Response by BICR and Investigator in Participants with Non-Squamous Histology, and Separately for All Randomized Participants
[Time Frame: From date of first objective response (CR or PR) to date of first radiographic disease progression or death due to any cause (whichever occurs first), up to approximately 44 months]
Duration of Response (DoR) is defined as the time from the date of the first documentation of objective response (confirmed CR or confirmed PR) to the date of the first radiographic disease progression or death due to any cause, whichever occurs first, assessed by BICR and by the Investigator per RECIST Version 1.1.
7. Time to Response by BICR and Investigator in Participants with Non-Squamous Histology, and Separately for All Randomized Participants
[Time Frame: From randomization to date of first objective response (CR or PR), up to approximately 44 months]
Time to Response (TTR) is defined as the time from randomization to the date of the first documentation of objective response (confirmed CR or confirmed PR) in responding participants, assessed by BICR and by the Investigator per RECIST Version 1.1.
8. Disease Control Rate by BICR and 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]
Disease Control Rate (DCR) is defined as the proportion of participants who achieved a BOR of confirmed CR, confirmed PR, or stable disease (SD), assessed by BICR and by the Investigator per RECIST Version 1.1.
9. Time to Deterioration 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 71 months]
Time to Deterioration (TTD) is defined as the time from randomization to first onset of a >=10-point increase in cough, chest pain, or dyspnea, confirmed by a second adjacent >=10-point increase from randomization in the same symptom, or confirmed by death within 21 days of a >=10-point increase from randomization, assessed the European Organization for Research and Treatment of Cancer Lung cancer module (EORTC-QLQ-LC13).
10. Number of Participants With Treatment-emergent Adverse Events (TEAE) with Non-Squamous Histology, and Separately for All Randomized Participants
[Time Frame: Up to 71 months]
A TEAE is defined as an AE with a start or worsening date on or after the start date of study treatment until 37 days after the end date of study treatment.
11. Proportion of Participants Who Are Anti-Drug Antibody (ADA)-Positive (Baseline and Post-Baseline) and Proportion of Participants Who Have Treatment-emergent ADA for Participants with Non-Squamous Histology, and Separately for All Randomized Participants
[Time Frame: Baseline and up to 71 months]
ADA prevalence: the proportion of subjects who are ADA-positive at any point in time (at baseline or post-baseline)
ADA incidence: the proportion of subjects having a treatment-emergent ADA
Titer and neutralizing antibodies will be determined when the ADA is positive.

+81-827-34-1000

Jan. 13, 2022

Yes

De-identified individual participant data (IPD) on completed studies and applicable supporting clinical trial documents may be available upon request at https://vivli.org/. In cases where clinical trial data and supporting documents are provided pursuant to our company policies and procedures, Daiichi Sankyo will continue to protect the privacy of our clinical trial participants. Details on data sharing criteria and the procedure for requesting access can be found at this web address: https://vivli.org/ourmember/daiichi-sankyo/ Supporting Information: - Study Protocol - Statistical Analysis Plan (SAP) - Informed Consent Form (ICF) Time Frame: Completed studies that has reached a global end or completion with all data set collected and analyzed, and for which the medicine and indication have received European Union (EU) and United States (US), and/or Japan (JP) marketing approval on or after 01 January 2014 or by the US or EU or JP Health Authorities when regulatory submissions in all regions are not planned and after the primary study results have been accepted for publication. Access Criteria: Formal request from qualified scientific and medical researchers on IPD and clinical study documents on completed clinical trials supporting products submitted and licensed in the United States, the European Union and/or Japan from 01 January 2014 and beyond for the purpose of conducting legitimate research. This must be consistent with the principle of safeguarding study participants' privacy and consistent with provision of informed consent. URL: https://vivli.org/ourmember/daiichi-sankyo/

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