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)

• ClinicalTrials.gov Identifier: NCT04956692
• Recruitment Status: Active, not recruiting
• First Posted: July 9, 2021
• Results First Posted: May 20, 2024
• Last Update Posted: May 20, 2024
• Sponsor: Merck Sharp & Dohme LLC
• Information provided by (Responsible Party): Merck Sharp & Dohme LLC

Tracking Information

• First Submitted Date: July 6, 2021
• First Posted Date: July 9, 2021
• Results First Submitted Date: March 27, 2024
• Results First Posted Date: May 20, 2024
• Last Update Posted Date: May 20, 2024
• Actual Study Start Date: August 5, 2021
• Actual Primary Completion Date: April 4, 2023 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: March 27, 2024)

• Cycle 1 Area Under The Curve From 0-3 Weeks (AUC 0-3wks) of Pembrolizumab [ Time Frame: Cycle 1: predose and postdose day 1; days 2, 3, 4, 5, 6, 7, 10, and 15. Cycle 2: predose day 1. Each cycle is 21 days. ]
  Cycle 1 AUC0-3wks is defined as the area under the concentration-time curve for pembrolizumab in plasma over a 3-week dosing interval in Cycle 1. Each cycle is 21 days.
• Cycle 6 Model-Based Minimal Concentration (Ctrough) of Pembrolizumab [ Time Frame: Cycle 6: predose day 1; days 2, 3, 4, 5, 6, 7, 10, and 15. Cycle 7: predose day 1. Each cycle is 21 days. ]
  Cycle 6 model-based Ctrough is defined as the lowest concentration of pembrolizumab in plasma at the end of the dosing interval in Cycle 6, as predicted by the pharmacokinetic (PK) model based on historical intravenous pembrolizumab PK data. Each cycle is 21 days.

Original Primary Outcome Measures (submitted: July 6, 2021)

• Area Under The Curve From 0-3 Weeks (AUC 0-3wks) of Pembrolizumab at Cycle 1 [ Time Frame: Pharmacokinetic (PK) collection at designated timepoints in Cycle 1 (Up to approximately 3 weeks; cycle length = 3 weeks) ]
  AUC0-3wks at Cycle 1 is defined as the area under curve exposure parameter over a 3-week dosing interval in Cycle 1.
• Minimal Concentration (Ctrough) of Pembrolizumab at the End of Cycle 6 [ Time Frame: PK collection at end of Cycle 6 (approximately at end of Week 18; cycle length = 3 weeks) ]
  Ctrough of Cycle 6 is defined as the observed trough concentration measured at the end of the dosing interval in Cycle 6.

Current Secondary Outcome Measures (submitted: March 27, 2024)

• Objective Response (OR) Per Response Evaluation Criteria In Solid Tumors Version 1.1 (RECIST 1.1) as Assessed by Blinded Independent Central Review (BICR) [ Time Frame: Up to approximately 5 years ]
  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.
• Cycle 1 Observed Ctrough of Pembrolizumab [ Time Frame: Predose Cycle 2 day 1. Each cycle is 21 days. ]
  Cycle 1 observed Ctrough is defined as the lowest observed concentration of pembrolizumab in plasma at the end of the dosing interval in Cycle 1. Each cycle is 21 days.
• Cycle 1 Maximum Concentration (Cmax) of Pembrolizumab [ Time Frame: Cycle 1: predose day 1; days 2, 3, 4, 5, 6, 7, 10, and 15. Cycle 2: predose day 1. Each cycle is 21 days. ]
  Cycle 1 Cmax is defined as the observed peak concentration of pembrolizumab in plasma over the dosing interval in Cycle 1. Each cycle is 21 days.
• Cycle 6 AUC 0-3wks of Pembrolizumab [ Time Frame: Cycle 6: predose and postdose day 1; days 2, 3, 4, 5, 6, 7, 10, and 15. Cycle 7: predose day 1. Each cycle is 21 days. ]
  Cycle 6 AUC0-3wks is defined as the area under the concentration-time curve for pembrolizumab in plasma over a 3-week dosing interval in Cycle 6. Each cycle is 21 days.
• Cycle 6 Cmax of Pembrolizumab [ Time Frame: Cycle 6: predose and postdose day 1; days 2, 3, 4, 5, 6, 7, 10, and 15. Cycle 7: predose day 1. Each cycle is 21 days. ]
  Cmax in Cycle 6 is defined as the observed peak concentration of pembrolizumab in plasma over the dosing interval in Cycle 6. Each cycle is 21 days.
• Cycle 6 Observed Ctrough of Pembrolizumab [ Time Frame: Predose Cycle 7 day 1. Each cycle is 21 days. ]
  Cycle 6 observed Ctrough is defined as the lowest observed concentration of pembrolizumab in plasma at the end of the dosing interval in Cycle 6. Each cycle is 21 days.
• Number of Participants Who Experienced an Adverse Event (AE) [ Time Frame: Up to approximately 28 months ]
  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.
• Number of Participants Who Discontinued Study Treatment Due to an AE [ Time Frame: Up to approximately 25 months ]
  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.
• Progression-Free Survival (PFS) Per RECIST 1.1 as Assessed by BICR [ Time Frame: Up to approximately 5 years ]
  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.
• Overall Survival (OS) [ Time Frame: Up to approximately 5 years ]
  OS is defined as the time from randomization to death due to any cause.
• Duration of Response (DOR) Per RECIST 1.1 as Assessed by BICR [ Time Frame: Up to approximately 5 years ]
  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.
• Anti-Drug Antibodies (ADAs) Incidence After Administration of Pembrolizumab [ Time Frame: Up to approximately 26 months ]
  ADA incidence will be assessed by analyzing the development of ADAs following administration of pembrolizumab SC and pembrolizumab IV.

Original Secondary Outcome Measures (submitted: July 6, 2021)

• Objective Response (OR) per Response Evaluation Criteria In Solid Tumors Version 1.1 (RECIST 1.1) as Assessed by Blinded Independent Central Review (BICR) [ Time Frame: Up to approximately 5 years ]
  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.
• Ctrough of Pembrolizumab at the End of Cycle 1 [ Time Frame: PK collection at end of Cycle 1 (approximately at end of Week 3; cycle length = 3 weeks) ]
  Ctrough of Cycle 1 is defined as the observed trough concentration at the end of the dosing interval in Cycle 1.
• Maximum Concentration (Cmax) of Pembrolizumab at Cycle 1 [ Time Frame: PK collection at designated timepoints in Cycle 1 (Up to approximately 3 weeks; cycle length = 3 weeks) ]
  Cmax at Cycle 1 is defined as the observed peak concentration over the dosing interval in Cycle 1.
• AUC 0-3wks of Pembrolizumab at Cycle 6 [ Time Frame: PK collection at designated timepoints in Cycle 6 (Up to approximately 3 weeks; cycle length = 3 weeks) ]
  AUC0-3wks at Cycle 6 is defined as the area under curve exposure parameter over a 3-week dosing interval in Cycle 6.
• Cmax of Pembrolizumab at Cycle 6 [ Time Frame: PK collection at designated timepoints in Cycle 6 (Up to approximately 3 weeks; cycle length = 3 weeks) ]
  Cmax at Cycle 6 is defined as the observed peak concentration over the dosing interval in Cycle 6.
• Number of Participants Who Experienced an Adverse Event (AE) [ Time Frame: Up to approximately 28 months ]
  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.
• Number of Participants Who Discontinued Study Treatment Due to an AE [ Time Frame: Up to approximately 25 months ]
  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.
• Progression-Free Survival (PFS) per RECIST 1.1 as Assessed by BICR [ Time Frame: Up to approximately 5 years ]
  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.
• Overall Survival (OS) [ Time Frame: Up to approximately 5 years ]
  OS is defined as the time from randomization to death due to any cause.
• Duration of Response (DOR) per RECIST 1.1 as Assessed by BICR [ Time Frame: Up to approximately 5 years ]
  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.
• Anti-Drug Antibodies (ADAs) Incidence After Administration of Pembrolizumab [ Time Frame: Up to approximately 26 months ]
  ADA incidence will be assessed by analyzing the development of ADAs following administration of pembrolizumab SC and pembrolizumab IV.

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: 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)
• Official Title: 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

Brief Summary

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.

• Detailed Description: Not Provided
• Study Type: Interventional
• Study Phase: Phase 3
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: None (Open Label); Primary Purpose: Treatment
• Condition: Non-Small Cell Lung Cancer

Intervention

• Biological: Pembrolizumab SC
  SC injection
• Biological: Pembrolizumab IV
  IV injection
  Other Names:

  • MK-3475
  • KEYTRUDA®
  • SCH 900475
• Drug: Paclitaxel
  IV injection
  Other Names:

  • Nov-Onxol
  • Onxol
  • Paclitaxel Novaplus
  • Taxol
• Drug: Nab-Paclitaxel
  IV infusion
  Other Names:

  • Abraxane
  • Nanoparticle albumin-bound paclitaxel
• Drug: Carboplatin
  IV infusion
  Other Names:

  • Paraplatin
  • Paraplatin NovaPlus
• Drug: Cisplatin
  IV infusion
  Other Name: Platinol-AQ
• Drug: Pemetrexed
  IV infusion
  Other Names:

  • LY231514
  • Alimta
  • Pemetrexed Disodium

Study Arms

• Experimental: Arm A: Pembrolizumab SC + Platinum Doublet Chemotherapy
  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 non-small cell lung cancer (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.
  Interventions:

  • Biological: Pembrolizumab SC
  • Drug: Paclitaxel
  • Drug: Nab-Paclitaxel
  • Drug: Carboplatin
  • Drug: Cisplatin
  • Drug: Pemetrexed
• Active Comparator: Arm B: Pembrolizumab IV + Platinum Doublet Chemotherapy
  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 non-small cell lung cancer (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.
  Interventions:

  • Biological: Pembrolizumab IV
  • Drug: Paclitaxel
  • Drug: Nab-Paclitaxel
  • Drug: Carboplatin
  • Drug: Cisplatin
  • Drug: Pemetrexed

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Active, not recruiting
• Actual Enrollment (submitted: August 31, 2023): 531
• Original Estimated Enrollment (submitted: July 6, 2021): 450
• Estimated Study Completion Date: October 14, 2026
• Actual Primary Completion Date: April 4, 2023 (Final data collection date for primary outcome measure)

Eligibility Criteria

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

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Brazil, France, Guatemala, Hungary, Japan, Korea, Republic of, Peru, Poland, Romania, Russian Federation, South Africa, Spain, Taiwan, Turkey, Ukraine, United States

Administrative Information

• NCT Number: NCT04956692
• Other Study ID Numbers: 3475-A86; MK-3475-A86 ( Other Identifier: Merck ); jRCT2021210032 ( Registry Identifier: jRCT (Japan Registry of Clinical Trials) ); 2020-002729-27 ( EudraCT Number )
• Has Data Monitoring Committee: Yes

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

IPD Sharing Statement

• Plan to Share IPD: Yes
• Plan Description: http://engagezone.msd.com/doc/ProcedureAccessClinicalTrialData.pdf
• URL: http://engagezone.msd.com/ds_documentation.php

• Current Responsible Party: Merck Sharp & Dohme LLC
• Original Responsible Party: Same as current
• Current Study Sponsor: Merck Sharp & Dohme LLC
• Original Study Sponsor: Same as current
• Collaborators: Not Provided

Investigators

• Study Director: Medical Director; Merck Sharp & Dohme LLC

• PRS Account: Merck Sharp & Dohme LLC
• Verification Date: May 2024