Study of Pembrolizumab (MK-3475) Subcutaneous (SC) Versus Pembrolizumab Intravenous (IV) Administered With Platinum Doublet Chemotherapy in Participants With Metastatic Squamous or Nonsquamous Non-Small Cell Lung Cancer (NSCLC) (MK-3475-A86)

Study Overview
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Brief Summary
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The purpose of this study is to evaluate pembrolizumab (MK-3475) subcutaneous (SC) administration as the first-line therapy in the treatment of metastatic squamous and nonsquamous NSCLC by assessing the pharmacokinetics (PK), safety, and efficacy of pembrolizumab SC injection in combination with standard-of-care chemotherapy. The primary hypothesis of the study is Pembrolizumab SC is noninferior to pembrolizumab intravenous (IV) for Cycle 1 Area Under Curve (AUC) and Cycle 6 minimal concentration (Ctrough) at steady state. Participants who discontinue study treatment after receiving the first course of 35 administrations of pembrolizumab (approximately up to 2 years) for reasons other than disease progression or intolerability, may be eligible for a second course of pembrolizumab for up to approximately 1 additional year if they have experienced radiographic disease progression per RECIST 1.1 as assessed by BICR after stopping first course treatment.

Official Title
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A Randomized, Phase 3, Open-label Study to Investigate the Pharmacokinetics and Safety of Subcutaneous Pembrolizumab Versus Intravenous Pembrolizumab, Administered With Platinum Doublet Chemotherapy, in the First-Line Treatment of Participants With Metastatic Squamous or Nonsquamous Non-Small-Cell Lung Cancer

Conditions
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Non-Small Cell Lung Cancer

Intervention / Treatment
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* Biological: Pembrolizumab SC
* Biological: Pembrolizumab IV
* Drug: Paclitaxel
* Drug: Nab-Paclitaxel
* Drug: Carboplatin
* Drug: Cisplatin
* Drug: Pemetrexed


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Has pathologically (histologically or cytologically) confirmed diagnosis of squamous or nonsquamous non-small cell lung cancer (NSCLC) Has Stage IV (T any, N any, M1a, M1b, or M1c - American Joint Committee on Cancer 8th Edition) squamous or nonsquamous NSCLC Has confirmation that epidermal growth factor receptor (EGFR), Anaplastic lymphoma kinase (ALK), or ROS Proto-Oncogene 1, Receptor Tyrosine Kinase (ROS1)-directed therapy is not indicated in nonsquamous NSCLC as well as mixed nonsquamous/squamous NSCLC. Participants with purely squamous NSCLC do not require testing Has not received prior systemic treatment for their metastatic NSCLC. Participants who received adjuvant or neoadjuvant therapy are eligible if the adjuvant/neoadjuvant therapy was completed at least 12 months prior to the development of metastatic disease Has an Eastern Cooperative Oncology Group (ECOG) performance score (PS) of 0 or 1 Male participants are eligible to participate if they agree to use contraception as per protocol unless confirmed to be azoospermic A female participant is eligible to participate if she is not pregnant or breastfeeding, and at least one of the following conditions applies: is not a woman of childbearing potential (WOCBP) or is a WOCBP who agrees of using a contraceptive method per protocol Has measurable disease per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) as assessed by the local site investigator/radiology Submit an archival tumor tissue sample or newly obtained core or incisional biopsy of a tumor lesion not previously irradiated for PD-L1 status determination prior to randomization Has adequate organ function Exclusion Criteria: Has a known additional malignancy that is progressing or has required active treatment within the past 3 years Has known central nervous system (ie, brain and/or spinal cord) metastases and/or carcinomatous meningitis. Participants with treated brain metastases may participate only if they satisfy all of the following: a) Have no evidence of new or enlarging brain metastases confirmed by post-treatment repeat brain imaging performed at least 4 weeks after pretreatment brain imaging, and b) Are neurologically stable without the need for steroids for at least 14 days before first dose of trial treatment as per local site assessment Has severe hypersensitivity to study intervention and/or any of its excipients Has an active autoimmune disease that has required systemic treatment in past 2 years Has a history of (noninfectious) pneumonitis/interstitial lung disease that required steroids or has current pneumonitis/interstitial lung disease Has an active infection requiring systemic therapy Has a known history of human immunodeficiency virus (HIV) infection and/or Hepatitis B infection or known active Hepatitis C infection Has a known psychiatric or substance abuse disorder that would interfere with the participant's ability to cooperate with the requirements of the study Has symptomatic ascites or pleural effusion. A participant who is clinically stable after treatment for these conditions is eligible Before the first dose of study intervention: a) Has received prior systemic cytotoxic chemotherapy for metastatic NSCLC b) Has received antineoplastic biological therapy for metastatic NSCLC c) Has had major surgery (<3 weeks prior to first dose) d) Has received prior therapy with an anti-programmed cell death 1 (anti-PD-1), anti-programmed cell death ligand 1 (anti-PD-L1), or anti-programmed cell death ligand 2 (anti-PD-L2) agent or with an agent directed to another stimulatory or coinhibitory T-cell receptor Received radiation therapy to the lung that is >30 Gray within 6 months of the first dose of study intervention Is expected to require any other form of antineoplastic therapy while on study For participants with nonsquamous histology: Is unable to interrupt aspirin or other Non-steroidal anti-inflammatory drugs (NSAIDs), other than an aspirin dose ≤1.3 g/day, for a 5-day period For participants with nonsquamous histology: Is unable or unwilling to take folic acid or vitamin B12 supplementation Has received prior radiotherapy within 2 weeks of start of study intervention or have had a history of radiation pneumonitis. Participants must have recovered from all radiation-related toxicities and not require corticosteroids. A 1-week washout is permitted for palliative radiation (≤2 weeks of radiotherapy) to non-CNS disease Has received a live or live attenuated vaccine within 30 days prior to the first dose of study intervention Is currently participating in or has participated in a study of an investigational agent or has used an investigational device within 4 weeks prior to the first dose of study intervention Has a 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 intervention Has had an allogenic tissue/solid organ transplant

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: Arm A: Pembrolizumab SC + Platinum Doublet Chemotherapy<br>Participants receive pembrolizumab subcutaneous (SC) administration on Day 1 of each cycle (cycle length = 3 weeks) for up to 35 cycles (up to  2 years) PLUS paclitaxel IV (on Day 1 of each cycle) OR nab-paclitaxel IV (on Days 1, 8, and 15 of each cycle) and carboplatin IV (on Day 1 of each cycle) for 4 cycles for Squamous NSCLC; PLUS carboplatin IV (on Day 1 of each cycle) Or cisplatin IV (on Day 1 of each cycle) for 4 cycles and pemetrexed IV (on Day 1 of each cycle) until progression, intolerable adverse events, or participant/physician decision for Non-squamous NSCLC. | Biological: Pembrolizumab SC<br>* SC injection<br>Drug: Paclitaxel<br>* IV injection<br>* Other names: Taxol;Drug: Nab-Paclitaxel<br>* IV infusion<br>* Other names: Nanoparticle albumin-bound paclitaxel;Drug: Carboplatin<br>* IV infusion<br>* Other names: Paraplatin NovaPlus;Drug: Cisplatin<br>* IV infusion<br>* Other names: Platinol-AQ;Drug: Pemetrexed<br>* IV infusion<br>* Other names: Pemetrexed Disodium;|
| Active Comparator: Arm B: Pembrolizumab IV + Platinum Doublet Chemotherapy<br>Participants receive pembrolizumab intravenous (IV) administration on Day 1 of each cycle (cycle length = 3 weeks) for up to 35 cycles (up to  2 years) PLUS paclitaxel IV (on Day 1 of each cycle) OR nab-paclitaxel IV (on Days 1, 8, and 15 of each cycle) and carboplatin IV (on Day 1 of each cycle) for 4 cycles for Squamous NSCLC; PLUS carboplatin IV (on Day 1 of each cycle) Or cisplatin IV (on Day 1 of each cycle) for 4 cycles and pemetrexed IV (on Day 1 of each cycle) until progression, intolerable adverse events, or participant/physician decision for Non-squamous NSCLC. | Biological: Pembrolizumab IV<br>* IV injection<br>* Other names: SCH 900475;Drug: Paclitaxel<br>* IV injection<br>* Other names: Taxol;Drug: Nab-Paclitaxel<br>* IV infusion<br>* Other names: Nanoparticle albumin-bound paclitaxel;Drug: Carboplatin<br>* IV infusion<br>* Other names: Paraplatin NovaPlus;Drug: Cisplatin<br>* IV infusion<br>* Other names: Platinol-AQ;Drug: Pemetrexed<br>* IV infusion<br>* Other names: Pemetrexed Disodium;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Area Under The Curve From 0-3 Weeks (AUC 0-3wks) of Pembrolizumab at Cycle 1 | AUC0-3wks at Cycle 1 is defined as the area under curve exposure parameter over a 3-week dosing interval in Cycle 1. | Pharmacokinetic (PK) collection at designated timepoints in Cycle 1 (Up to approximately 3 weeks; cycle length = 3 weeks) | 
| Cycle 6 Model-Based Minimal Concentration (Ctrough) of Pembrolizumab | Cycle 6 model-based Ctrough is defined as the trough concentration predicted by the PK model at the end of the dosing interval in Cycle 6. | PK collection at end of Cycle 6 (approximately at end of Week 18; cycle length = 3 weeks) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Objective Response (OR) per Response Evaluation Criteria In Solid Tumors Version 1.1 (RECIST 1.1) as Assessed by Blinded Independent Central Review (BICR) | The OR rate is defined as the percentage of participants who achieve a confirmed complete response (CR: disappearance of all target lesions) or Partial Response (PR: at least a 30% decrease in the sum of diameters of target lesions) per RECIST 1.1 as assessed by BICR. | Up to approximately 5 years | 
| Observed Ctrough of Pembrolizumab at the End of Cycle 1 | Ctrough of Cycle 1 is defined as the observed trough concentration at the end of the dosing interval in Cycle 1. | PK collection at end of Cycle 1 (approximately at end of Week 3; cycle length = 3 weeks) | 
| Maximum Concentration (Cmax) of Pembrolizumab at Cycle 1 | Cmax at Cycle 1 is defined as the observed peak concentration over the dosing interval in Cycle 1. | PK collection at designated timepoints in Cycle 1 (Up to approximately 3 weeks; cycle length = 3 weeks) | 
| AUC 0-3wks of Pembrolizumab at Cycle 6 | AUC0-3wks at Cycle 6 is defined as the area under curve exposure parameter over a 3-week dosing interval in Cycle 6. | PK collection at designated timepoints in Cycle 6 (Up to approximately 3 weeks; cycle length = 3 weeks) | 
| Cmax of Pembrolizumab at Cycle 6 | Cmax at Cycle 6 is defined as the observed peak concentration over the dosing interval in Cycle 6. | PK collection at designated timepoints in Cycle 6 (Up to approximately 3 weeks; cycle length = 3 weeks) | 
| Observed Ctrough of Pembrolizumab at the End of Cycle 6 | Ctrough of Cycle 6 is defined as the observed trough concentration measured at the end of the dosing interval in Cycle 6. | PK collection at end of Cycle 6 (approximately at end of Week 18; cycle length = 3 weeks) | 
| Number of Participants Who Experienced an Adverse Event (AE) | An AE is any untoward medical occurrence in a clinical study participant, temporally associated with the use of study intervention, whether or not considered related to the study intervention. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the use of a study intervention. The number of participants who experience an AE will be reported. | Up to approximately 28 months | 
| Number of Participants Who Discontinued Study Treatment Due to an AE | An AE is any untoward medical occurrence in a clinical study participant, temporally associated with the use of study intervention, whether or not considered related to the study intervention. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the use of study intervention. The number of participants who discontinue study treatment due to an AE will be presented. | Up to approximately 25 months | 
| Progression-Free Survival (PFS) per RECIST 1.1 as Assessed by BICR | PFS is defined as the time from randomization to the first documented PD per RECIST 1.1 by BICR or death due to any cause, whichever occurs first. 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 5 years | 
| Overall Survival (OS) | OS is defined as the time from randomization to death due to any cause. | Up to approximately 5 years | 
| Duration of Response (DOR) per RECIST 1.1 as Assessed by BICR | For participants who show confirmed CR (disappearance of all target lesions) or PR (at least a 30% decrease in the sum of diameters of target lesions) per RECIST 1.1, duration of response is defined as the time from the first documented evidence of CR or PR until disease progression (PD) per RECIST 1.1 by BICR or death due to any cause, whichever occurs first. 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 5 years | 
| Anti-Drug Antibodies (ADAs) Incidence After Administration of Pembrolizumab | ADA incidence will be assessed by analyzing the development of ADAs following administration of pembrolizumab SC and pembrolizumab IV. | Up to approximately 26 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 Cell Death-Ligand 1 (PDL1, PD-L1), Programmed Cell Death-Ligand 2 (PDL2, PD-L2)