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

Sponsor

Daiichi Sankyo, Inc. (Industry)

Overall Status

Recruiting

CT.gov ID

NCT05215340

Collaborator

AstraZeneca (Industry), Merck Sharp & Dohme LLC (Industry)

740

Enrollment

Locations

Arms

50.9

Anticipated Duration (Months)

22.4

Patients Per Site

0.4

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

This study is designed to assess the efficacy and safety of datopotamab deruxtecan (Dato-DXd) in combination with pembrolizumab versus pembrolizumab alone in participants with advanced or metastatic non-small cell lung cancer (NSCLC).

Condition or Disease	Intervention/Treatment	Phase
Metastatic Non Small Cell Lung Cancer	Drug: Datopotamab Deruxtecan Drug: Pembrolizumab	Phase 3

Detailed Description

The primary objective of the study is to compare the efficacy of Dato-DXd and pembrolizumab with pembrolizumab alone in terms of either Progression Free Survival (PFS) or Overall Survival (OS) for participants with advanced or metastatic NSCLC without actionable genomic alterations whose tumor has high programmed death-ligand 1 (PD-L1) expression (TPS ≥50%) and who have not previously received systemic therapy for advanced or metastatic NSCLC.

Eligible participants will be randomized in a 1:1 ratio to the control arm (pembrolizumab alone) or the experimental arm (Dato-DXd and pembrolizumab). The study will be divided into 4 periods: Tissue Screening Period, Screening Period, Treatment Period, and Follow-up Period.

Study Design

Study Type:

Interventional

Anticipated Enrollment :

740 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

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

Actual Study Start Date :

Mar 4, 2022

Anticipated Primary Completion Date :

Jun 1, 2026

Anticipated Study Completion Date :

Jun 1, 2026

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Pembrolizumab + Datopotamab Deruxtecan (Dato-DXd) Participants will be randomized to receive 200 mg pembrolizumab followed by 6.0mg/kg Dato-DXd.	Drug: Datopotamab Deruxtecan Dato-DXd will be administered as an intravenous (IV) infusion every 3 weeks on Day 1 of each 21-day cycle. Other Names: Dato-DXd Drug: Pembrolizumab Pembrolizumab will be administered as an intravenous (IV) infusion every 3 weeks on Day 1 of each 21-day cycle.
Active Comparator: Pembrolizumb Participants will be randomized to receive 200 mg pembrolizumab.	Drug: Pembrolizumab Pembrolizumab will be administered as an intravenous (IV) infusion every 3 weeks on Day 1 of each 21-day cycle.

Arm

Intervention/Treatment

Experimental: Pembrolizumab + Datopotamab Deruxtecan (Dato-DXd)

Participants will be randomized to receive 200 mg pembrolizumab followed by 6.0mg/kg Dato-DXd.

Drug: Datopotamab Deruxtecan

Dato-DXd will be administered as an intravenous (IV) infusion every 3 weeks on Day 1 of each 21-day cycle.

Other Names:

Dato-DXd

Drug: Pembrolizumab

Pembrolizumab will be administered as an intravenous (IV) infusion every 3 weeks on Day 1 of each 21-day cycle.

Active Comparator: Pembrolizumb

Participants will be randomized to receive 200 mg pembrolizumab.

Drug: Pembrolizumab

Pembrolizumab will be administered as an intravenous (IV) infusion every 3 weeks on Day 1 of each 21-day cycle.

Outcome Measures

Primary Outcome Measures

Progression-free Survival Based on Blinded Independent Central Review in Participants Who Were Administered Dato-DXd in Combination With Pembrolizumab Compared With Pembrolizumab [From randomization until disease progression or death (whichever occurs first), up to approximately 32 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.
Overall Survival in Participants Who Were Administered Dato-DXd in Combination With Pembrolizumab Compared With Pembrolizumab [From randomization until date of death due to any cause, up to approximately 53 months]
Overall Survival (OS) is defined as the time from randomization to death due to any cause.

Secondary Outcome Measures

Objective Response Rate by Blinded Independent Central Review in Participants Who Were Administered Dato-DXd in Combination With Pembrolizumab Compared With Pembrolizumab [From randomization until disease progression or death (whichever occurs first), up to approximately 32 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 per RECIST Version 1.1.
Progression-free Survival by Investigator in Participants Who Were Administered Dato-DXd in Combination With Pembrolizumab Compared With Pembrolizumab [From randomization until disease progression or death (whichever occurs first), up to approximately 32 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.
Progression-free Survival 2 in Participants Who Were Administered Dato-DXd in Combination With Pembrolizumab Compared With Pembrolizumab [From randomization until disease progression or death (whichever occurs first), up to approximately 53 months]
Progression-free Survival 2 (PFS2) 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 local standard clinical practice.
Objective Response Rate by Investigator in Participants Who Were Administered Dato-DXd in Combination With Pembrolizumab Compared With Pembrolizumab [From randomization until disease progression or death (whichever occurs first), up to approximately 32 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 the Investigator per RECIST Version 1.1.
Duration of Response by BICR and Investigator in Participants Who Were Administered Dato-DXd in Combination With Pembrolizumab Compared With Pembrolizumab [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 32 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.
Time to Response by BICR and Investigator in Participants Who Were Administered Dato-DXd in Combination With Pembrolizumab Compared With Pembrolizumab [From randomization to date of first objective response (CR or PR), up to approximately 32 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.
Disease Control Rate by BICR and Investigator in Participants Who Were Administered Dato-DXd in Combination With Pembrolizumab Compared With Pembrolizumab [From randomization until disease progression or death (whichever occurs first), up to approximately 32 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.
Time to Deterioration in Participants Who Were Administered Dato-DXd in Combination With Pembrolizumab Compared With Pembrolizumab [From randomization until disease progression or death (whichever occurs first), up to approximately 53 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).
Number of Participants With Treatment-emergent Adverse Events (TEAE) Who Were Administered Dato-DXd in Combination With Pembrolizumab Compared With Pembrolizumab [Up to 53 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.
Proportion of Participants Who Are Anti-Drug Antibody (ADA)-Positive (Baseline and Post-Baseline) and Proportion of Participants Who Have Treatment-emergent ADA [Baseline and up to 53 months]
The immunogenicity of Dato-DXd in combination with pembrolizumab will be assessed.

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria:

Participants eligible for inclusion in the study must meet all inclusion criteria within 28 days of randomization into the study.

Sign and date the Tissue Screening and Main Informed Consent Forms, prior to the start of any study-specific qualification procedures.
Adults ≥18 years or the minimum legal adult age (whichever is greater) at the time of informed consent.
Histologically documented NSCLC that meets all of the following criteria:

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).
Documented negative test results for epidermal growth factor receptor (EGFR), lymphoma kinase (ALK), and proto-oncogene1 (ROS1) actionable genomic alterations based on analysis of tumor tissue.
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.

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.
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).
Has an adequate treatment washout period before Cycle 1 Day 1.
Measurable disease based on local imaging assessment using RECIST Version 1.1.
Has left ventricular ejection fraction (LVEF) ≥50% by either an echocardiogram (ECHO) or multigated acquisition scan (MUGA) within 28 days before randomization.
Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0 or 1 at screening.
Has a life expectancy of at least 3 months.
Adequate bone marrow function within 7 days before randomization.

Exclusion Criteria:

Has received prior systemic treatment for advanced or metastatic NSCLC.
Has received prior treatment with any of the following, including in the adjuvant/neoadjuvant setting:

Any agent, including an antibody-drug conjugate, containing a chemotherapeutic agent targeting topoisomerase I.
TROP2-targeted therapy.
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).
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.

Has spinal cord compression or active and untreated central nervous system (CNS) metastases and/or carcinomatous meningitis. Participants with previously treated brain metastases may participate provided they are radiologically stable.
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.
History of another primary malignancy (beyond NSCLC) except for:

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.
Adequately treated non-melanoma skin cancer or lentigo maligna without evidence of disease.
Adequately treated carcinoma in situ without evidence of disease.
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.

Has a history of (non-infectious) interstitial lung disease (ILD)/pneumonitis that required steroids, has current ILD/pneumonitis, or where suspected ILD/pneumonitis cannot be ruled out by imaging at screening.
Clinically severe pulmonary compromise 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.
Uncontrolled or significant cardiovascular disease, including:

Mean QT interval corrected for heart rate using Fridericia's formula (QTcF) interval >470 msec regardless of sex (based on the average of the 12-lead electrocardiogram determination at screening).
Myocardial infarction within 6 months prior to randomization.
Uncontrolled angina pectoris within 6 months prior to randomization.
LVEF <50% by ECHO or MUGA scan within 28 days before randomization.
New York Heart Association Class 2 to 4 congestive heart failure (CHF) at screening.
Uncontrolled hypertension (resting systolic blood pressure >180 mmHg or diastolic blood pressure >110 mmHg) within 28 days before randomization.

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.

Clinically significant corneal disease.
Has received a live vaccine or live-attenuated vaccine within 30 days prior to the first dose of study drug. For any participant receiving an approved severe acute respiratory syndrome coronavirus 2 (SARS-CoV2) vaccine, please follow the vaccine label and/or local guidance.
Active, known, or suspected autoimmune disease (has an active autoimmune disease that has required systemic treatment in the past 2 years).
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.
Has known human immunodeficiency virus (HIV) infection that is not well controlled.
Has an active hepatitis or uncontrolled hepatitis B or active hepatitis C infection; is positive for hepatitis B or C virus based on the evaluation of results of tests for hepatitis B (hepatitis b surface antigen, anti-HBs, anti-HBc, or hepatitis B virus [HBV] DNA) or hepatitis C virus (HCV RNA) infection.
Has an uncontrolled infection requiring IV antibiotics, antivirals, or antifungals.
Had an allogeneic tissue/solid organ transplant.
Has a history of severe hypersensitivity reactions to either the drug substances or inactive ingredients (including but not limited to polysorbate 80) of Dato-DXd or pembrolizumab.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Ironwood Cancer and Research Center	Chandler	Arizona	United States	85224
2	The Oncology Institute of Hope and Innovation	Whittier	California	United States	90603
3	American Oncology Partners of Maryland	Bethesda	Maryland	United States	20817
4	The Valley Hospital	Paramus	New Jersey	United States	07652
5	Utah Cancer Specialists	Salt Lake City	Utah	United States	84106
6	Aomori Prefectural Central Hospital	Aomori-shi	Aomori	Japan	030-8553
7	National Cancer Center Hospital East	Kashiwa-shi	Chiba	Japan	277-8577
8	NHO Shikoku Cancer Center	Matsuyama-shi	Ehime	Japan	791-0280
9	National Hospital Organization Kyushu Cancer Center	Fukuoka-shi	Fukuoka	Japan	811-1395
10	Kyushu University Hospital	Fukuoka-shi	Fukuoka	Japan	812-8582
11	Kurume University Hospital	Kurume-shi	Fukuoka	Japan	830-0011
12	Kanazawa University Hospital	Kanazawa-shi	Ishikawa	Japan	920-8641
13	Kanagawa Cancer Center	Yokohama-shi	Kanagawa	Japan	241-8515
14	Saiseikai Kumamoto Hospital	Kumamoto-shi	Kumamoto	Japan	861- 4193
15	Matsusaka Municipal Hospital	Matsusaka-shi	Mie	Japan	515-8544
16	Sendai Kousei Hospital	Sendai-shi	Miyagi	Japan	980-0873
17	Niigata Cancer Center Hospital	Niigata-shi	Niigata	Japan	961-8566
18	Kansai Medical University Hospital	Hirakata-shi	Osaka	Japan	573-1191
19	Osaka International Cancer Institute	Osaka-shi	Osaka	Japan	541-8567
20	NHO Kinki-Chuo Chest Medical Center	Sakai-shi	Osaka	Japan	591-8555
21	Saitama Cancer Center	Ina-machi	Saitama	Japan	362-0806
22	Dokkyo Medical University Hospital	Shimotsuga-gun	Tochigi	Japan	321-0293
23	Juntendo University Hospital	Bunkyo-ku	Tokyo	Japan	113-8431
24	Tokyo Metropolitan Cancer and Infectious Diseases Center Komagome Hospital	Bunkyō-Ku	Tokyo	Japan	113-8677
25	The Cancer Institute Hospital of JFCR	Koto-ku	Toyko	Japan	135-8550
26	NHO Iwakuni Clinical Center	Iwakuni-shi	Yamaguchi	Japan	740-8510
27	Yamaguchi-Ube Medical Center	Ube-shi	Yamaguchi	Japan	755-0241
28	Chungbuk National University Hospital	Cheongju-si	Chungbuk	Korea, Republic of	28644
29	Seoul National University Bundang Hospital	Seongnam	Gyeonggi-do	Korea, Republic of	13620
30	Kyungpook National University Chilgok Hospital	Daegu		Korea, Republic of	42119
31	Samsung Medical Center	Seoul		Korea, Republic of	6351
32	Chung Shan Medical University Hospital	Taichung		Taiwan	40201
33	Taipei Veterans General Hospital	Taipei City		Taiwan	11217