Study of Pembrolizumab Given With Ipilimumab or Placebo in Participants With Untreated Metastatic Non-Small Cell Lung Cancer (NSCLC) (MK-3475-598/KEYNOTE-598)

Study Overview
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Brief Summary
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The purpose of this study is to determine the efficacy of pembrolizumab given in combination with either ipilimumab or placebo as first-line treatment in participants with metastatic non-small cell lung cancer (NSCLC). The primary hypothesis of this study is that overall survival (OS) and/or progression-free survival (PFS) is prolonged in participants who receive pembrolizumab and ipilimumab compared to those who receive pembrolizumab and placebo. With Amendment 6 (effective date: 11-Dec-2020), active participants, investigator, and sponsor personnel or delegate(s) involved in the treatment administration or clinical evaluation of the participants will be unblinded. Participants will discontinue ipilimumab and placebo and participants who remain on treatment will receive open-label pembrolizumab only.

Official Title
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A Phase 3, Randomized, Double-Blind Study of Pembrolizumab Plus Ipilimumab vs Pembrolizumab Plus Placebo in Previously Untreated, Stage IV, Metastatic Non-small Cell Lung Cancer Subjects Whose Tumors Are PD-L1 Positive (TPS ≥ 50%) (KEYNOTE-598)

Conditions
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Carcinoma, Non-Small-Cell Lung

Intervention / Treatment
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* Biological: Pembrolizumab
* Biological: Ipilimumab
* Other: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Has a histologically or cytologically confirmed diagnosis of Stage IV metastatic non-small cell lung cancer (NSCLC) (American Joint Committee on Cancer version 8) Has measurable disease per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) as determined by investigator Has Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 Has a life expectancy of at least 3 months Has provided archival tumor tissue sample or newly obtained core or excisional biopsy of a tumor lesion not previously irradiated Female participants of childbearing potential must have a negative serum pregnancy test within 72 hours prior to receiving the first dose of study therapy Female participants of reproductive potential must agree to use contraception starting from the first dose of study medication, throughout the study period, and for up to 120 days after the last dose of study medication Exclusion Criteria: Has received prior systemic chemotherapy/other targeted or biological antineoplastic therapy treatment for their Stage IV metastatic NSCLC Has a tumor that harbors an epidermal growth factor receptor (EGFR)-sensitizing (activating) mutation or an anaplastic lymphoma kinase (ALK) translocation Is currently participating in or has participated in a trial of an investigational agent or has used an investigational device within 4 weeks prior to the first dose of study therapy Has received prior therapy with an anti-Programmed Cell Death Receptor 1 (PD-1), anti-Programmed Cell Death Receptor Ligand 1 (anti-PD-L1), or anti- Programmed Cell Death Receptor Ligand 2 (PD-L2) agent or with an agent directed to another stimulatory or co-inhibitory T-cell receptor (eg, cytotoxic T-lymphocyte-associated protein 4 [CTLA-4], OX-40, CD137) Has received prior radiotherapy within 2 weeks of start of study therapy or received lung radiation therapy of >30 Gray (Gy) within 6 months of the first dose of study therapy Has recovered from all radiation-related toxicities, does not require corticosteroids, and has not had radiation pneumonitis Is receiving systemic steroid therapy ≤7 days prior to the first dose of study therapy or receiving any other form of immunosuppressive medication Has a known additional malignancy that is progressing or has required active treatment within the past 3 years with the exception of curatively treated basal cell carcinoma of the skin, squamous cell carcinoma of the skin and/or curatively resected in situ cancers Has known untreated central nervous system (CNS) metastases and/or carcinomatous meningitis Has an active autoimmune disease that has required systemic treatment in past 2 years (i.e., with use of disease-modifying agents, corticosteroids, or immunosuppressive drugs) Has a diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy (i.e., doses exceeding 10 mg daily of prednisone equivalent) or any other form of immunosuppressive therapy within 7 days prior the first dose of study therapy Has a history of (non-infectious) pneumonitis that required systemic steroids or current pneumonitis/interstitial lung disease Has had an allogeneic tissue/solid organ transplant Has received a live vaccine within 30 days prior to the first dose of study therapy Has an active infection requiring systemic therapy Has a known history of human immunodeficiency virus (HIV) infection Has a known history of hepatitis B or known active hepatitis C virus infection Has a known history of active tuberculosis Has known psychiatric or substance abuse disorders that would interfere with cooperating with the requirements of the trial Is a regular user of any illicit drugs or had a recent history of substance abuse Is pregnant or breast feeding or expecting to conceive starting from the first dose of study medication, throughout the study period, and for up to 120 days after the last dose of study medication Has severe hypersensitivity to pembrolizumab and/or any of its excipients and/or to ipilimumab and/or any of its excipients Has a c-ros oncogene 1 (ROS1) mutation

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: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Pembrolizumab + Ipilimumab<br>Participants receive 200 mg of pembrolizumab by intravenous (IV) infusion on Day 1 of each 3-week cycle for up to 35 cycles of treatment plus 1 mg/kg of ipilimumab by IV infusion on Day 1 of each 6-week cycle for up to 18 cycles of treatment. | Biological: Pembrolizumab<br>* Administered as an intravenous (IV) infusion every 3 weeks (Q3W)<br>* Other names: MK-3475;Biological: Ipilimumab<br>* Administered as an IV infusion every 6 weeks (Q6W)<br>* Other names: YERVOY®;|
| Active Comparator: Pembrolizumab + Placebo<br>Participants receive 200 mg of pembrolizumab by IV infusion on Day 1 of each 3-week cycle for up to 35 cycles of treatment plus placebo by IV infusion on Day 1 of each 6-week cycle for up to 18 cycles of treatment. | Biological: Pembrolizumab<br>* Administered as an intravenous (IV) infusion every 3 weeks (Q3W)<br>* Other names: MK-3475;Other: Placebo<br>* Normal saline solution administered as an IV infusion Q6W<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Survival (OS) | OS was defined as the time from randomization to death due to any cause. Participants without documented death at the time of analysis were censored at the date of last known contact. The median survival (in months) and the associated 95% confidence intervals (CIs) were reported using Kaplan-Meier method was used. Cox regression model with Efron's method of tie handling with treatment as a covariate stratified by ECOG performance status (0 versus 1), geographic region of the enrolling site (East Asia versus non-East Asia), and predominant tumor history (squamous versus non-squamous) was used to estimate hazard ratio (HR) and 95% CIs for first course study treatment per protocol. | Up to approximately 32 months (through data cut-off date: 01 Sep 2020) | 
| Progression-free Survival (PFS) Per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) Based on Blinded Independent Central Review (BICR) | PFS was defined as the time from randomization to the first documented disease progression (PD) per RECIST 1.1 based on BICR or death due to any cause, whichever occurs first. PD is defined as ≥20% increase in sum of diameters of target lesions. In addition to relative increase of 20%, 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 has been modified to follow a maximum of 10 target lesions and a maximum of 5 target lesions per organ. The median survival (in months) and associated 95% CIs were reported using Kaplan-Meier method. Cox regression model with Efron's method of tie handling with treatment as covariate stratified by ECOG performance status (0 vs. 1), geographic region of the enrolling site (East Asia vs. non-East Asia), and predominant tumor history (squamous vs. non-squamous) was used to estimate HR and 95% CIs for first course study treatment per protocol. | Up to approximately 32 months (through data cut-off date 01 Sep 2020) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Objective Response Rate (ORR) Per RECIST 1.1 Based on BICR | ORR was defined as the percentage of participants who have 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 by BICR. In this study, RECIST 1.1 was modified to follow a maximum of 10 target lesions and a maximum of 5 target lesions per organ. Per protocol the ORR was calculated using the Miettinen & Nurminen method stratified by ECOG performance status (0 versus 1), geographic region of the enrolling site (East Asia versus non-East Asia), and predominant tumor history (squamous versus non-squamous) for the first course of study treatment. | Up to approximately 32 months (data cut-off date 01 Sep 2020) | 
| Duration of Response (DOR) Per RECIST 1.1 Based on BICR | For participants who demonstrated a confirmed CR (Disappearance of all target lesions) or confirmed PR (At least a 30% decrease in the sum of diameters of target lesions) per RECIST 1.1, DOR was defined as the time from first documented evidence of CR or PR until PD or death due to any cause, whichever occurs first. Per RECIST 1.1, PD was 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 have demonstrated an absolute increase of at least 5 mm. The appearance of one or more new lesions was also considered PD. RECIST 1.1 was modified to follow a maximum of 10 target lesions and a maximum of 5 target lesions per organ. The DOR was calculated using the product-limit (Kaplan-Meier) method for censored data. Per protocol, the DOR for all participants who experienced a CR or PR was presented for the first course of study treatment. | Up to approximately 32 months (data cut-off date 01 Sep 2020) | 
| Time to True Deterioration (TTD) in Cough, Pain in Chest, and Shortness of Breath | TTD was defined as the time to the first onset of a 10-point or greater score deterioration from baseline in any one of the 3 symptoms (cough, pain in chest or shortness of breath), confirmed by a second adjacent 10-point or greater score deterioration from baseline. Cough was based on EORTC QLQ-LC13 question 1, pain in chest was based on EORTC QLQ-LC13 question 10, and shortness of breath was based on EORTC QLQ-C30 question 8. Per protocol, TTD was reported for first course study treatment. | Up to approximately 32 months (data cut-off date 01 Sep 2020) | 
| Number of Participants Who Experienced an Adverse Event (AE) | An AE was defined as any untoward medical occurrence in a participant or clinical investigation participant administered a pharmaceutical product and which does not necessarily have to have a causal relationship with this 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 medicinal product or protocol specified procedure, whether or not considered related to the medicinal product or protocol specified procedure. Per protocol, the number of participants who experienced an AE were reported for the first course of study treatment and follow up. | Up to approximately 27 months | 
| Number of Participants Who Discontinued Study Treatment Due to an AE | An AE was defined as any untoward medical occurrence in a participant or clinical investigation participant administered a pharmaceutical product and which does not necessarily have to have a causal relationship with this 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 medicinal product or protocol specified procedure, whether or not considered related to the medicinal product or protocol specified procedure. Per protocol, the number of participants who discontinued study treatment due to an AE were reported for the first course of study treatment. | Up to approximately 24 months | 
| Change From Baseline in European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire-Core 30 (QLQ-C30) Global Health Status/Quality of Life (Items 29 and 30) Scale Score to Week 18 | The EORTC QLQ-C30 is a 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? were scored on a 7-point scale (1= Very poor to 7=Excellent). Using linear transformation, raw scores were standardized, so that scores range from 0 to 100. A higher score indicates a better overall health status. Per protocol, the change from baseline in EORTC QLQ-C30 Items 29 and 30 combined score were presented for first course study treatment. | Baseline, Week 18 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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PD1, Programmed Cell Death Receptor 1 (PD-1), Programmed Cell Death Receptor Ligand 1 (PD-L1), Cytotoxic T-lymphocyte-associated protein 4 (CTLA4), PD-1, PDL1, PD-L1, CTLA4