Study of Pembrolizumab (MK-3475) Monotherapy Versus Sacituzumab Govitecan in Combination With Pembrolizumab for Participants With Metastatic Non-small Cell Lung Cancer (NSCLC) With Programmed Cell Death Ligand 1 (PD-L1) Tumor Proportion Score (TPS) ≥50% (MK-3475-D46)

Study Overview
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Brief Summary
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The purpose of this study is to compare pembrolizumab (MK-3475) in combination with sacituzumab govitecan with pembrolizumab alone with respect to progression-free survival (PFS) and overall survival (OS) per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) as assessed by blinded independent central review (BICR) among adults with metastatic non-small cell lung cancer (NSCLC) with programmed cell death ligand 1 (PD-L1) tumor proportion score (TPS) ≥50%).

Official Title
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An Open-label, Multicenter, Phase 3 Randomized, Active-Comparator-Controlled Clinical Study of Pembrolizumab (MK-3475) in Combination With Sacituzumab Govitecan Versus MK-3475 Monotherapy as First-line Treatment in Participants With PD L1 TPS Greater Than or Equal to 50% Metastatic Non-small Cell Lung Cancer (KEYNOTE D46/EVOKE-03)

Conditions
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Carcinoma, Non-Small-Cell Lung

Intervention / Treatment
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* Biological: Sacituzumab Govitecan
* Biological: Pembrolizumab


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: The main inclusion criteria include but are not limited to the following: Has a histologically or cytologically confirmed diagnosis of metastatic non-small cell lung cancer (NSCLC) Has confirmation that epidermal growth factor receptor (EGFR), anaplastic lymphoma kinase 1 (ALK-1), or ROS proto-oncogene 1 (ROS-1)-directed therapy is not indicated as primary therapy Has provided tumor tissue that demonstrates PD-L1 tumor proportion score (TPS) ≥50% of tumor cells as assessed by immunohistochemistry (IHC) at a central laboratory Has a life expectancy of at least 3 months Exclusion Criteria: The main exclusion criteria include but are not limited to the following: Has history of a second malignancy, unless potentially curative treatment has been completed with no evidence of malignancy for 3 years Has received prior systemic chemotherapy or other targeted or biological antineoplastic therapy for their metastatic NSCLC Has previously received treatment with Topoisomerase 1 inhibitors or Trop-2 targeted therapy Has received prior therapy with an anti-programmed cell death 1 protein (anti-PD-1), anti-programmed cell death ligand 1 (anti-PD-L1), or anti anti- programmed cell death ligand 2 (PD-L2) agent or with an agent directed to another stimulatory or coinhibitory T-cell receptor Has received prior radiotherapy within 2 weeks of start of study intervention or has radiation-related toxicities requiring corticosteroids Has received radiation therapy to the lung that is >30 Gray (Gy) within 6 months of the first dose of study intervention Has received a live or live-attenuated vaccine within 30 days before the first dose of study intervention Has received an investigational agent or has used an investigational device within 4 weeks before study intervention administration Has cardiac disease Myocardial infarction or unstable angina pectoris within 6 months of enrollment History of serious ventricular arrhythmia, high-grade atrioventricular block, or other cardiac arrhythmias requiring antiarrhythmic medications; history of QT interval prolongation New York Heart Association (NYHA) Class III or greater congestive heart failure or left ventricular ejection fraction of <40% Has active chronic inflammatory bowel disease Has diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy or any other form of immunosuppressive therapy within 7 days prior the first dose of study medication Has known active central nervous system (CNS) metastases and/or carcinomatous meningitis Has severe hypersensitivity (≥Grade 3) to pembrolizumab or sacituzumab govitecan and/or any of their excipients Has active autoimmune disease that has required systemic treatment in past 2 years except replacement therapy History of (noninfectious) pneumonitis/interstitial lung disease that required steroids or has current pneumonitis/interstitial lung disease Has active infection requiring systemic therapy Has history of human immunodeficiency virus (HIV) infection History of hepatitis B or known active hepatitis C virus infection Has history or current evidence of any condition, therapy, laboratory abnormality, or other circumstance that might confound the results of the study or interfere with the participant's participation for the full duration of the study, such that it is not in the best interest of the participant to participate, in the opinion of the treating investigator Have not adequately recovered from major surgery or have ongoing surgical complications

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Pembrolizumab + Sacituzumab Govitecan<br>Participants receive sacituzumab govitecan 10mg/kg intravenous (IV) infusion once weekly on Day 1 and Day 8 of a continuous 21-day cycle until progressive disease (PD) requiring discontinuation, unacceptable toxicity, withdrawal of consent, or death. Participants receive pembrolizumab 200mg IV infusion on Day 1 every 3 weeks (Q3W) for up to 35 cycles (each cycle length = 21 days). | Biological: Sacituzumab Govitecan<br>* IV infusion<br>* Other names: Trodelvy®;Biological: Pembrolizumab<br>* IV infusion<br>* Other names: Keytruda®;|
| Experimental: Pembrolizumab<br>Participants receive pembrolizumab 200mg IV infusion on Day 1 Q3W for up to 35 cycles (each cycle length = 21 days). | Biological: Pembrolizumab<br>* IV infusion<br>* Other names: Keytruda®;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression-Free Survival (PFS) | PFS is defined as the time from randomization to the first documented progressive disease (PD) or death due to any cause, whichever occurs first as per the Response Criteria in Solid Tumors Version 1.1 (RECIST 1.1). PD is defined as ≥20% increase in the sum of diameters of target lesions. In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of ≥5 mm. The appearance of one or more new lesions is also considered PD. RECIST 1.1 is modified to follow a maximum of 10 target lesions and a maximum of 5 target lesions per organ. PFS as assessed by blinded independent central review (BICR) will be presented. | Up to approximately 34 months | 
| Overall Survival (OS) | OS is defined as the time from randomization to death due to any cause. | Up to approximately 48 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Objective Response (OR) | OR is defined as the confirmed Complete Response (CR: Disappearance of all target lesions) or a Partial Response (PR: At least a 30% decrease in the sum of diameters of target lesions) per RECIST 1.1 by BICR. | Up to approximately 34 months | 
| Duration of Response (DOR) | DOR is defined as the time from the first documented evidence of a Complete Response (CR: Disappearance of all target lesions) or a Partial Response (PR: At least a 30% decrease in the sum of diameters of target lesions) per RECIST 1.1 until Progressive Disease (PD) or death due to any cause, whichever occurs first, in participants demonstrating a CR or PR. Per RECIST 1.1, PD is defined as at least a 20% increase in the sum of diameters of target lesions. In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. The appearance of one or more new lesions is also considered PD. | Up to approximately 48 months | 
| TTD in Cough Score (Item 31) on the EORTC QLQ-LC13 | The EORTC QLQ-LC13 is a lung cancer-specific supplemental questionnaire used in combination with the EORTC QLQ-C30. Participant responses to the question How much did you cough? will be scored on a 4-point scale (1=Not at All to 4=Very Much). Using linear transformation, raw scores are standardized, so that scores range from 0 to 100. Higher scores indicate more frequent coughing and a worse outcome. TTD is defined as the time to first onset of 10 or more (out of 100) deterioration from baseline and confirmed by a second adjacent 10 or more deterioration from baseline. TTD in the score of EORTC QLQ-LC13 Item 31 will be presented. | Up to approximately 48 months | 
| TTD in Chest Pain Score (Item 40) on the EORTC QLQ-LC13 | The EORTC QLQ-LC13 is a lung cancer-specific supplemental questionnaire used in combination with the EORTC QLQ-C30. Participant responses to the question Have you had pain in your chest? are scored on a 4-point scale (1=Not at All to 4=Very Much). Using linear transformation, raw scores are standardized, so that scores range from 0 to 100. Higher scores indicate worse level of chest pain. TTD is defined as the time to first onset of 10 or more (out of 100) deterioration from baseline and confirmed by a second adjacent 10 or more deterioration from baseline. TTD in the score of EORTC QLQ-LC13 Item 40 will be presented. | Up to approximately 48 months | 
| Number of Participants Who Experience an Adverse Event (AE) | An AE is any untoward medical occurrence in a participant, temporally associated with the use of study treatment, whether or not considered related to the study treatment. An AE can therefore be any unfavourable and unintended sign (including an abnormal laboratory finding, for example), symptom, or disease temporally associated with the use of a study intervention. Per protocol, the number of participants who experience an AE will be reported. | Up to approximately 48 months | 
| Number of Participants Who Discontinue Study Treatment Due To an AE | An AE is any untoward medical occurrence in a participant, temporally associated with the use of study treatment, whether or not considered related to the study treatment. An AE can therefore be any unfavourable and unintended sign (including an abnormal laboratory finding, for example), symptom, or disease temporally associated with the use of a study intervention. Per protocol, the number of participants who discontinue study treatment due to an AE will be reported. | Up to approximately 48 months | 
| Change from Baseline in the Global Health Status/Quality of Life (Items 29 and 30) Combined Score on the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire - Core 30 (EORTC QLQ-C30) | The EORTC QLQ-C30 is a 30-item questionnaire to assess the overall quality of life of cancer patients. Participant responses to the questions How would you rate your overall health during the past week? and How would you rate your overall quality of life during the past week? will be scored on a 7-point scale (1= Very poor to 7=Excellent). Using linear transformation, raw scores will be standardized, so that scores range from 0 to 100. Higher scores indicate a better overall health status. Per protocol, the change from baseline in EORTC QLQ-C30 Items 29 and 30 combined score will be presented. | Baseline and up to approximately 48 months | 
| Change from Baseline in Physical Functioning (Items 1-5) Combined Score on the EORTC QLQ-C30 | The EORTC QLQ-C30 is a 30-item questionnaire to assess the overall quality of life of cancer patients. Participant responses to 5 questions about their physical functioning will be scored on a 4-point scale (1=Not at All to 4=Very Much). Using linear transformation, raw scores will be standardized, so that scores range from 0 to 100. Higher scores indicate a better level of physical functioning. The change from baseline in Physical Functioning (EORTC QLQ-C30 Items 1-5) combined score will be presented. | Baseline and up to approximately 48 months | 
| Change from Baseline in Role Functioning (Items 6-7) Combined Score on the EORTC QLQ-C30 | The EORTC QLQ-C30 is a 30-item questionnaire to assess the overall quality of life of cancer patients. Participant responses to the questions Were you limited in doing either your work or other daily activities during the past week? and  Were you limited in pursuing your hobbies or other leisure time activities during the past week? will be scored on a 4-point scale (1=Not at All to 4=Very Much). Higher scores indicate a better level of role functioning. Change from baseline in the role functioning (EORTC QLQ-C30 Items 6-7) combined score will be presented. | Baseline and up to approximately 48 months | 
| Change from Baseline in Dyspnea Score (Item 8) on the EORTC QLQ-C30 | The EORTC QLQ-C30 is a 30-item questionnaire to assess the overall quality of life of cancer patients. Participant responses to the question Were you short of breath? will be scored on a 4-point scale (1=Not at All to 4=Very Much). Using linear transformation, raw scores will be standardized, so that scores range from 0 to 100. Higher scores indicates a worse level of dyspnea. The change from baseline in dyspnea (EORTC QLQ-C30 Item 8) score will be presented. | Baseline and up to approximately 48 months | 
| Change from Baseline in Cough Score (Item 31) on the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire - Lung Cancer 13 (EORTC QLQ-LC13) | The EORTC QLQ-LC13 is a lung cancer-specific supplemental questionnaire used in combination with the EORTC QLQ-C30. Participant responses to the question How much did you cough? will be scored on a 4-point scale (1=Not at All to 4=Very Much). Using linear transformation, raw scores are standardized, so that scores range from 0 to 100. Higher scores indicate more frequent coughing and a worse outcome. The change from baseline in cough (EORTC QLQ-LC13 Item 31) score will be presented. | Baseline and up to approximately 48 months | 
| Change from Baseline in Chest Pain Score (Item 40) on the EORTC QLQ-LC13 | The EORTC QLQ-LC13 is a lung cancer-specific supplemental questionnaire used in combination with the EORTC QLQ-C30. Participant responses to the question Have you had pain in your chest? are scored on a 4-point scale (1=Not at All to 4=Very Much). Using linear transformation, raw scores are standardized, so that scores range from 0 to 100. Higher scores indicate worse level of chest pain. The change from baseline in chest pain (EORTC QLQ-LC13 Item 40) score will be presented. | Baseline and up to approximately 48 months | 
| Time to Deterioration (TTD) in the Global Health Status/Quality of Life (Items 29 and 30) Combined Score on the EORTC QLQ-C30 | The EORTC-QLQ-C30 is a 30-item questionnaire developed to assess the quality of life of cancer patients. Participant responses to Items 29 and 30 (How would you rate your overall health during the past week? and How would you rate your overall quality of life during the past week?) will be scored on a 7-point scale (1=Very Poor to 7=Excellent). Higher scores indicate a better overall outcome. TTD is defined as the time to first onset of 10 or more (out of 100) deterioration from baseline and confirmed by a second adjacent 10 or more deterioration from baseline. TTD in the score of EORTC QLQ-C30 Items 29 and 30 will be presented. | Up to approximately 48 months | 
| TTD in Physical Functioning (Items 1-5) Combined Score on the EORTC QLQ-C30 | The EORTC QLQ-C30 is a 30-item questionnaire to assess the overall quality of life of cancer patients. Participant responses to 5 questions about their physical functioning will be scored on a 4-point scale (1=Not at All to 4=Very Much). Using linear transformation, raw scores will be standardized, so that scores range from 0 to 100. Higher scores indicate a better level of physical functioning. TTD is defined as the time to first onset of 10 or more (out of 100) deterioration from baseline and confirmed by a second adjacent 10 or more deterioration from baseline. TTD in the score of EORTC QLQ-C30 Items 1-5 will be presented. | Up to approximately 48 months | 
| TTD in Role Functioning (Items 6-7) Combined Score on the EORTC QLQ-C30 | The EORTC QLQ-C30 is a 30-item questionnaire to assess the overall quality of life of cancer patients. Participant responses to the questions Were you limited in doing either your work or other daily activities during the past week? and  Were you limited in pursuing your hobbies or other leisure time activities during the past week? will be scored on a 4-point scale (1=Not at All to 4=Very Much). Higher scores indicate a better level of role functioning. TTD is defined as the time to first onset of 10 or more (out of 100) deterioration from baseline and confirmed by a second adjacent 10 or more deterioration from baseline. TTD in the score of EORTC QLQ-C30 Items 6-7 will be presented. | Up to approximately 48 months | 
| TTD in Dyspnea Score (Item 8) on the EORTC QLQ-C30 11 | The EORTC QLQ-C30 is a 30-item questionnaire to assess the overall quality of life of cancer patients. Participant responses to the question Were you short of breath? will be scored on a 4-point scale (1=Not at All to 4=Very Much). Using linear transformation, raw scores will be standardized, so that scores range from 0 to 100. Higher scores indicates a worse level of dyspnea. TTD is defined as the time to first onset of 10 or more (out of 100) deterioration from baseline and confirmed by a second adjacent 10 or more deterioration from baseline. TTD in the score of EORTC QLQ-C30 Item 8 will be presented. | Up to approximately 48 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Programmed Cell Death-1 (PD1, PD-1), Programmed Death-Ligand 1 (PDL1, PD-L1), Programmed Cell Death-2 (PD2, PD-2), Programmed Death-Ligand 2 (PDL2, PD-L2), Trophoblast Cell Surface Antigen-2 (TROP-2), Antibody-Drug Conjugate (ADC)