KEYMAKER-U01 Substudy 1: Efficacy and Safety Study of Pembrolizumab (MK-3475) Plus Chemotherapy When Used With Investigational Agents in Treatment-naïve Participants With Advanced Non-small Cell Lung Cancer (NSCLC) (MK-3475-01A/KEYMAKER-U01A)

Study Overview
=================
Brief Summary
-----------------
The purpose of this study is to assess the efficacy and safety of pembrolizumab (MK-3475) PLUS chemotherapy in combination with vibostolimab (MK-7684), boserolimab (MK-5890), MK-4830, or MK-0482 in treatment-naïve participants with advanced squamous or non-squamous NSCLC. This study is one of three pembrolizumab substudies being conducted under one pembrolizumab umbrella master protocol (MK-3475-U01/KEYMAKER-U01).

Detailed Description
-----------------
The master screening protocol is MK-3475-U01 (KEYMAKER-U01) - NCT04165798

Official Title
-----------------
KEYMAKER-U01 Substudy 1: A Phase 2, Umbrella Study With Rolling Arms of Investigational Agents With Pembrolizumab in Combination With Chemotherapy in Treatment-Naive Patients With Advanced Non-small Cell Lung Cancer (NSCLC)

Conditions
-----------------
Carcinoma, Non-Small-Cell Lung

Intervention / Treatment
-----------------
* Biological: Pembrolizumab
* Drug: Carboplatin
* Drug: Paclitaxel
* Drug: Pemetrexed
* Biological: Vibostolimab
* Biological: Boserolimab
* Biological: MK-4830
* Biological: MK-0482


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Has histologically- or cytologically-confirmed diagnosis of Stage IV squamous or nonsquamous NSCLC Participants with nonsquamous NSCLC who are not eligible for an approved targeted therapy Is able to provide archival tumor tissue sample collected either within 5 years or within the interval from completion of last treatment but before entering the screening period or newly obtained core or excisional biopsy of a tumor lesion not previously irradiated obtained within 90 days of treatment initiation Has not received prior systemic treatment for their metastatic NSCLC Is able to complete all screening procedures within the 35-day screening window Has adequate organ function within 10 days of initiation of study treatment Male participants must agree to use contraception and should refrain from donating sperm during the treatment period and for at least 120 days after the last dose of pembrolizumab and for at least 180 days after the last dose of chemotherapy Female participants must not be pregnant or breastfeeding, and at least one of the following conditions apply: Not a woman of childbearing potential (WOCBP), OR A WOCBP who agrees to use contraception during the treatment period and for at least 120 days after the last dose of pembrolizumab and for at least 180 days after the last dose of chemotherapy Exclusion Criteria: Has a diagnosis of small cell lung cancer Has a diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy (in dosing exceeding 10 mg daily of prednisone equivalent) or any other form of immunosuppressive therapy within 7 days before the first dose of study treatment Has a known additional malignancy that is progressing or has required active treatment within the past 2 years Has known active central nervous system (CNS) metastases and/or carcinomatous meningitis Has an active autoimmune disease that has required systemic treatment in the past 2 years Has a history of (noninfectious) pneumonitis that required steroids or has current pneumonitis Has an active infection requiring systemic therapy Has clinically significant cardiac disease, including unstable angina, acute myocardial infarction within 6 months from Day 1 of study treatment administration, or New York Heart Association Class III or IV congestive heart failure Has a known history of HIV infection Has a known history of Hepatitis B or known active Hepatitis C virus infection Has had major surgery <3 weeks before the first dose of study treatment Is expected to require any other form of antineoplastic therapy while on study Has symptomatic ascites or pleural effusion (if receiving pemetrexed; Alimta®, Eli Lilly) Has a history or current evidence of a gastrointestinal (GI) condition (e.g. inflammatory bowel disease, Crohn's disease, ulcerative colitis) or impaired liver function or diseases that in the opinion of the investigator may significantly alter the absorption or metabolism of oral medications Is getting chemotherapy and has clinically active diverticulitis, intra-abdominal abscess, GI obstruction, or peritoneal carcinomatosis Has preexisting neuropathy that is moderate in intensity Has received prior systemic cytotoxic chemotherapy or other targeted or biological antineoplastic therapy for metastatic disease Has received prior therapy with an anti-programmed cell death-1 (PD-1), anti-programmed cell death-ligand 1 (PD-L1), or anti-PD-L2 agent or prior therapy targeting other immunoregulatory receptors or mechanisms Is currently receiving either strong or moderate inhibitors of cytochrome P450 3A4 (CYP3A4) or cytochrome P450 2C8 (CYP2C8) that cannot be discontinued for the duration of the study Is currently receiving strong or moderate inducers of CYP3A4 or CYP2C8 that cannot be discontinued for the duration of the study Is unable to interrupt aspirin or other non-steroidal anti-inflammatory drugs (NSAIDs), other than aspirin dose less than or equal to 1.3 gm/day for a 5-day period (8-day period for long acting agents such as peroxicam), for participants who will receive pemetrexed Is unable or unwilling to take folic acid or vitamin B12 supplementation, for participants who will receive pemetrexed Has a known sensitivity to any component of carboplatin, paclitaxel, pemetrexed or any of their excipients Has received prior radiation therapy to the lung that is >30 Gray (Gy) within 6 months of the first dose of study treatment Has received a live vaccine within 30 days before the first dose of study treatment. Any licensed COVID-19 vaccine (including for Emergency Use) in a particular country is allowed as long as they are messenger ribonucleic acid (mRNA) vaccines, adenoviral vaccines, or inactivated vaccines. Investigational vaccines (ie, those not licensed or approved for Emergency Use) are not allowed Has received any prior immunotherapy and was discontinued from that treatment due to a severe or worse immune-related adverse event (irAE) Has had chemotherapy or biological cancer therapy within 4 weeks before the first dose of study treatment or has not recovered to Common Terminology Criteria for Adverse Events (CTCAE) Grade 1 or better from the AEs due to cancer therapeutics administered more than 4 weeks before the first dose of study treatment (including participants who had previous immunomodulatory therapy with residual irAEs) Is currently participating in or has participated in a study of an investigational agent or has used an investigational device within 4 weeks before the first dose of study treatment Previously had a severe hypersensitivity reaction to treatment with monoclonal antibodies (including pembrolizumab) and/or any of their excipients Is pregnant or breastfeeding or expecting to conceive or father children within the projected duration of the study, starting with the screening visit through 120 days after the last dose of study treatment Has had an allogenic tissue/solid organ transplant

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Pembrolizumab+Vibostolimab+Carboplatin + Paclitaxel<br>On Day 1 of each 3-week cycle, participants with squamous NSCLC receive pembrolizumab 200 mg intravenously (IV) PLUS vibostolimab IV PLUS carboplatin Area Under the Concentration-Time Curve (AUC) 6 IV PLUS paclitaxel 200 mg/m^2 IV in Cycles 1-4, followed by maintenance treatment of pembrolizumab 200 mg IV PLUS vibostolimab IV in Cycles 5-35 (total treatment duration: up to approximately 2 years). | Biological: Pembrolizumab<br>* IV infusion<br>* Other names: KEYTRUDA®;Drug: Carboplatin<br>* IV infusion<br>* Other names: PARAPLATIN®;Drug: Paclitaxel<br>* IV infusion<br>* Other names: ABRAXANE®;Biological: Vibostolimab<br>* IV infusion<br>* Other names: MK-7684;|
| Experimental: Pembrolizumab+Vibostolimab+Carboplatin + Pemetrexed<br>On Day 1 of each 3-week cycle, participants with nonsquamous NSCLC receive pembrolizumab 200 mg IV PLUS vibostolimab IV PLUS carboplatin AUC 5 IV PLUS pemetrexed 500 mg/m^2 IV in Cycles 1-4, followed by maintenance treatment of pembrolizumab 200 mg IV PLUS vibostolimab IV PLUS pemetrexed 500 mg/m^2 IV in Cycles 5-35 (total treatment duration: up to approximately 2 years). | Biological: Pembrolizumab<br>* IV infusion<br>* Other names: KEYTRUDA®;Drug: Carboplatin<br>* IV infusion<br>* Other names: PARAPLATIN®;Drug: Pemetrexed<br>* IV infusion<br>* Other names: ALIMTA®;Biological: Vibostolimab<br>* IV infusion<br>* Other names: MK-7684;|
| Experimental: Pembrolizumab+Boserolimab+Carboplatin+Paclitaxel<br>On Day 1 of each 3-week cycle, participants with squamous NSCLC receive pembrolizumab 200 mg IV PLUS carboplatin AUC 6 IV PLUS paclitaxel 200 mg/m^2 IV PLUS boserolimab IV on Day 1 every 6 weeks (every other 3-week cycle) (Q6W) in Cycles 1-4, followed by maintenance treatment of pembrolizumab 200 mg IV Q3W PLUS boserolimab IV Q6W from Cycles 5 up to Cycle 35 (total treatment duration: up to approximately 2 years). | Biological: Pembrolizumab<br>* IV infusion<br>* Other names: KEYTRUDA®;Drug: Carboplatin<br>* IV infusion<br>* Other names: PARAPLATIN®;Drug: Paclitaxel<br>* IV infusion<br>* Other names: ABRAXANE®;Biological: Boserolimab<br>* IV infusion<br>* Other names: MK-5890;|
| Experimental: Pembrolizumab+Boserolimab+Carboplatin+Pemetrexed<br>On Day 1 of each 3-week cycle, participants with nonsquamous NSCLC receive pembrolizumab 200 mg IV PLUS carboplatin AUC 5 IV PLUS pemetrexed 500 mg/m^2 IV PLUS boserolimab IV on Day 1 every 6 weeks (every other 3-week cycle) (Q6W) in Cycles 1-4, followed by maintenance treatment of pembrolizumab 200 mg IV Q3W PLUS pemetrexed 500 mg/m^2 IV Q3W PLUS boserolimab IV Q6W from Cycles 5 up to Cycle 35 (total treatment duration: up to approximately 2 years). | Biological: Pembrolizumab<br>* IV infusion<br>* Other names: KEYTRUDA®;Drug: Carboplatin<br>* IV infusion<br>* Other names: PARAPLATIN®;Drug: Pemetrexed<br>* IV infusion<br>* Other names: ALIMTA®;Biological: Boserolimab<br>* IV infusion<br>* Other names: MK-5890;|
| Experimental: Pembrolizumab+MK-4830+Carboplatin+Paclitaxel<br>On Day 1 of each 3-week cycle, participants with squamous NSCLC receive pembrolizumab 200 mg IV PLUS MK-4830 IV PLUS carboplatin AUC 6 IV PLUS paclitaxel 200 mg/m^2 IV in Cycles 1-4, followed by maintenance treatment of pembrolizumab 200 mg IV PLUS MK-4830 IV in Cycles 5-35 (total treatment duration: up to approximately 2 years). | Biological: Pembrolizumab<br>* IV infusion<br>* Other names: KEYTRUDA®;Drug: Carboplatin<br>* IV infusion<br>* Other names: PARAPLATIN®;Drug: Paclitaxel<br>* IV infusion<br>* Other names: ABRAXANE®;Biological: MK-4830<br>* IV infusion<br>|
| Experimental: Pembrolizumab+MK-4830+Carboplatin+Pemetrexed<br>On Day 1 of each 3-week cycle, participants with nonsquamous NSCLC receive pembrolizumab 200 mg IV PLUS MK-4830 IV PLUS carboplatin AUC 5 IV PLUS pemetrexed 500 mg/m^2 IV in Cycles 1-4, followed by maintenance treatment of pembrolizumab 200 mg IV PLUS MK-4830 IV PLUS pemetrexed 500 mg/m^2 IV in Cycles 5-35 (total treatment duration: up to approximately 2 years). | Biological: Pembrolizumab<br>* IV infusion<br>* Other names: KEYTRUDA®;Drug: Carboplatin<br>* IV infusion<br>* Other names: PARAPLATIN®;Drug: Pemetrexed<br>* IV infusion<br>* Other names: ALIMTA®;Biological: MK-4830<br>* IV infusion<br>|
| Experimental: Pembrolizumab+MK-0482+Carboplatin+Paclitaxel<br>On Day 1 of each 3-week cycle, participants with squamous NSCLC receive pembrolizumab 200 mg IV PLUS MK-0482 IV PLUS carboplatin AUC 6 IV PLUS paclitaxel 200 mg/m^2 IV in Cycles 1-4, followed by maintenance treatment of pembrolizumab 200 mg IV PLUS MK-0482 IV in Cycles 5-35 (total treatment duration: up to approximately 2 years). | Biological: MK-0482<br>* IV Infusion<br>|
| Experimental: Pembrolizumab+MK-0482+Carboplatin+Pemetrexed<br>On Day 1 of each 3-week cycle, participants with nonsquamous NSCLC receive pembrolizumab 200 mg IV PLUS MK-0482 IV PLUS carboplatin AUC 5 IV PLUS pemetrexed 500 mg/m^2 IV in Cycles 1-4, followed by maintenance treatment of pembrolizumab 200 mg IV PLUS MK-0482 IV PLUS pemetrexed 500 mg/m^2 IV in Cycles 5-35 (total treatment duration: up to approximately 2 years). | Biological: MK-0482<br>* IV Infusion<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Objective Response Rate (ORR) According to Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) | ORR was defined as the percentage of participants in the analysis population who had a Complete Response (CR: Disappearance of all target lesions) or a Partial Response (PR: ≥30% decrease in the sum of diameters of target lesions) per RECIST 1.1. | Up to approximately 24 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression-Free Survival (PFS) According to Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) | PFS is defined as the time from first dose of study treatment until either the earliest date of documented progressive disease (PD) or death due to any cause, whichever occurs first. Per 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. | Up to approximately 24 months | 
| Number of Participants Who Experience One or More Adverse Events (AEs) | An AE is defined as any unfavorable and unintended sign, symptom, disease, or worsening of preexisting condition temporally associated with study treatment and irrespective of causality to study treatment. | Up to approximately 27 months | 
| Number of Participants Who Discontinue Study Treatment Due to an Adverse Event (AE) | An AE is defined as any unfavorable and unintended sign, symptom, disease, or worsening of preexisting condition temporally associated with study treatment and irrespective of causality to study treatment. | Up to approximately 24 months | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Programmed Cell Death-1 (PD1, PD-1), Programmed Death-Ligand 1 (PDL1, PD-L1)