A Study of Pembrolizumab (MK-3475) in Combination With Chemotherapy or Immunotherapy in Participants With Non-small Cell Lung Cancer (MK-3475-021/KEYNOTE-021)

• ClinicalTrials.gov Identifier: NCT02039674
• Recruitment Status: Completed
• First Posted: January 17, 2014
• Results First Posted: December 2, 2017
• Last Update Posted: November 8, 2022
• Sponsor: Merck Sharp & Dohme LLC
• Information provided by (Responsible Party): Merck Sharp & Dohme LLC

Tracking Information

• First Submitted Date: January 16, 2014
• First Posted Date: January 17, 2014
• Results First Submitted Date: October 27, 2017
• Results First Posted Date: December 2, 2017
• Last Update Posted Date: November 8, 2022
• Study Start Date: February 21, 2014
• Actual Primary Completion Date: November 7, 2016 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: November 27, 2019)

• Part 2 Cohorts G+ and G-: Objective Response Rate (ORR) [ Time Frame: Up to approximately 2 years ]
  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: At least a 30% decrease in the sum of diameters of target lesions) per Response Criteria in Solid Tumors version 1.1 (RECIST 1.1) as assessed by blinded independent central review (BICR).
• Part 2 Cohorts D4 and H: Objective Response Rate (ORR) [ Time Frame: Up to approximately 2 years ]
  For participants who demonstrated a confirmed response (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. Per RECIST 1.1, DOR was defined as the time from first documented evidence of CR or PR until disease progression or death. DOR was assessed by BICR.
• All Cohorts: Number of Participants Who Experienced a Dose-limiting Toxicity (DLT) [ Time Frame: Cycle 1 (Up to 21 days) ]
  DLTs were assessed using the National Cancer Institute Common Terminology Criteria for Adverse Events version 4. A DLT was defined as any of the following events: Grade 4 non-hematologic toxicity (not laboratory); Grade 4 hematologic toxicity lasting ≥7 days; Grade 3 non-hematologic toxicity (not laboratory, specifically nausea, vomiting and diarrhea) lasting >3 days despite optimal supportive care; Any Grade 3 or Grade 4 non-hematologic laboratory value requiring treatment or hospitalization, or persisting for >1 week; Febrile neutropenia Grade 3 or Grade 4; Qualifying thrombocytopenia <25,000/mm^3; Prolonged delay (>2 weeks) in initiating Cycle 2 due to treatment-related toxicity; Missing >10% of erlotinib or gefitinib doses as a result of adverse events (AEs) during the DLT window of observation; or Grade 5 toxicity.

Original Primary Outcome Measures (submitted: January 16, 2014)

• Part II, Cohort G: Progression-Free Survival (PFS) [ Time Frame: Up to 2 years ]
• Part II, Cohort G: Objective Response Rate [ Time Frame: Up to 2 years ]
• Part II, Cohort H: Overall Response Rate [ Time Frame: Up to 2 years ]
• Part I, All Cohorts: the recommended Phase II dose for MK-3475 in combination with chemotherapy or immunotherapy [ Time Frame: Up to 2 years ]

Current Secondary Outcome Measures (submitted: November 27, 2019)

• Part 2 Cohorts G+ and G-: Progression-Free Survival (PFS) [ Time Frame: Up to approximately 2 years ]
  PFS was defined as the time from randomization to the first documented disease progression, or death due to any cause, whichever occurred first. Per RECIST 1.1, progressive disease 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 demonstrate an absolute increase of at least 5 mm. The appearance of one or more new lesions was also considered progression. PFS was assessed by BICR.
• Part 2 Cohorts G+ and G-: Overall Survival (OS) [ Time Frame: Up to approximately 2 years ]
  OS was defined as the time from randomization to death due to any cause.
• Part 2 Cohorts G+ and G-: Duration of Response (DOR) [ Time Frame: Up to approximately 2 years ]
  For participants who demonstrated a confirmed response (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. Per RECIST 1.1, DOR was defined as the time from first documented evidence of CR or PR until disease progression or death. DOR was assessed by BICR.

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

Descriptive Information

• Brief Title: A Study of Pembrolizumab (MK-3475) in Combination With Chemotherapy or Immunotherapy in Participants With Non-small Cell Lung Cancer (MK-3475-021/KEYNOTE-021)
• Official Title: A Phase I/II Study of MK-3475 (SCH900475) in Combination With Chemotherapy or Immunotherapy in Patients With Locally Advanced or Metastatic Non-Small Cell Lung Carcinoma
• Brief Summary: The purpose of this study is to determine the safety, tolerability, and efficacy of pembrolizumab (MK-3475) in combination with chemotherapy or immunotherapy in participants with unresectable or metastatic non-small cell lung cancer (NSCLC).
• Detailed Description: Not Provided
• Study Type: Interventional
• Study Phase: Phase 1; Phase 2
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: None (Open Label); Primary Purpose: Treatment
• Condition: Non-small Cell Lung Carcinoma

Intervention

• Biological: Pembrolizumab
  IV on Day 1 of each 3-week cycle prior to chemo/immunotherapy
  Other Names:

  • MK-3475
  • KEYTRUDA®
  • SCH 900475
• Drug: Paclitaxel
  IV on Day 1 of each 3-week cycle for a maximum of 4 administrations
  Other Name: ABRAXANE®
• Drug: Carboplatin
  IV on Day 1 of each 3-week cycle for a maximum of 4 administrations
  Other Name: PARAPLATIN®
• Biological: Bevacizumab
  IV on Day 1 of each 3-week cycle
  Other Name: AVASTIN®
• Drug: Pemetrexed
  IV on Day 1 of each 3-week cycle
  Other Name: ALIMTA®
• Biological: Ipilimumab
  IV on Day 1 of each 3-week cycle for a maximum of 4 administrations
  Other Name: YERVOY®
• Drug: Erlotinib
  Orally tablet once daily
  Other Name: TARCEVA®
• Drug: Gefitinib
  Oral tablet once daily
  Other Name: IRESSA®

Study Arms

• Experimental: Part 1 Cohort A2 (Pembro2mg/kg+Paclitaxel [Pa]+Carboplatin [C])
  Cohort A participants receive pembrolizumab (2 mg/kg) via intravenous (IV) infusion on Day 1 of each 3-week cycle PLUS paclitaxel (200 mg/m^2) via IV infusion on Day 1 of each 3-week cycle PLUS carboplatin (Aare Under the Curve [AUC] 6 [6 mg/mL/min]) via IV infusion on Day 1 of each 3-week cycle.
  Interventions:

  • Biological: Pembrolizumab
  • Drug: Paclitaxel
  • Drug: Carboplatin
• Experimental: Part 1 Cohort B2 (Pembro 2mg/kg+Pa+C+Bevacizumab [B])
  Cohort B2 participants receive pembrolizumab (2 mg/kg) via IV infusion on Day 1 of each 3-week cycle PLUS paclitaxel (200 mg/m^2) via IV infusion on Day 1 of each 3-week cycle PLUS carboplatin (AUC 6 [6 mg/mL/min]) via IV infusion on Day 1 of each 3-week cycle PLUS bevacizumab (15 mg/kg) via IV infusion on Day 1 of each 3-week cycle.
  Interventions:

  • Biological: Pembrolizumab
  • Drug: Paclitaxel
  • Drug: Carboplatin
  • Biological: Bevacizumab
• Experimental: Part 1 Cohort C2 (Pembro 2mg/kg+Pemetrexed [Pe]+C)
  Cohort C2 participants receive pembrolizumab (2 mg/kg) via IV infusion on Day 1 of each 3-week cycle PLUS pemetrexed (500 mg/m^2) via IV infusion on Day 1 of each 3-week cycle PLUS carboplatin (AUC 5 [5 mg/mL/min]) via IV infusion on Day 1 of each 3-week cycle.
  Interventions:

  • Biological: Pembrolizumab
  • Drug: Carboplatin
  • Drug: Pemetrexed
• Experimental: Part 1 Cohort D1 (Pembro 10mg/kg+Ipilimumab [I])
  Cohort D1 participants receive pembrolizumab (10 mg/kg) via IV infusion on Day 1 of each 3-week cycle PLUS ipilimumab (1 mg/kg) via IV infusion on Day 1 of each 3-week cycle.
  Interventions:

  • Biological: Pembrolizumab
  • Biological: Ipilimumab
• Experimental: Part 1 Cohort E (Pembro 2mg/kg+Erlotinib)
  Cohort E participants receive pembrolizumab (2 mg/kg) via IV infusion on Day 1 of each 3-week cycle PLUS erlotinib (150 mg) via oral tablet once a day on every day of each 3-week cycle.
  Interventions:

  • Biological: Pembrolizumab
  • Drug: Erlotinib
• Experimental: Part 1 Cohort F (Pembro 2mg/kg+Gefitinib)
  Cohort F participants receive pembrolizumab (2 mg/kg) via IV infusion on Day 1 of each 3-week cycle PLUS gefitinib (250 mg) via oral tablet once a day on every day of each 3-week cycle.
  Interventions:

  • Biological: Pembrolizumab
  • Drug: Gefitinib
• Experimental: Part 2 Cohort G+ (Pembro 200mg+C+Pe)
  Cohort G+ participants receive pembrolizumab (200 mg) via IV infusion on Day 1 of each 3-week cycle PLUS carboplatin (AUC 5 [5 mg/mL/min]) via IV infusion on Day 1 of each 3-week cycle PLUS pemetrexed (500 mg/m^2) via IV infusion on Day 1 of each 3-week cycle.
  Interventions:

  • Biological: Pembrolizumab
  • Drug: Carboplatin
  • Drug: Pemetrexed
• Experimental: Part 2 Cohort H (Pembro+I)
  Cohort H participants receive pembrolizumab (2 mg/kg) via IV infusion on Day 1 of each 3-week cycle PLUS ipilimumab (1 mg/kg) via IV infusion on Day 1 of each 3-week cycle (at the recommended Phase II dose determined in Cohort D).
  Interventions:

  • Biological: Pembrolizumab
  • Biological: Ipilimumab
• Experimental: Part 1 Cohort A10 (Pembro+Paclitaxel [Pa]+Carboplatin [C])
  Cohort A10 participants receive pembrolizumab (10 mg/kg) via IV infusion on Day 1 of each 3-week cycle PLUS paclitaxel (200 mg/m^2) via IV infusion on Day 1 of each 3-week cycle PLUS carboplatin (AUC 6 [mg/mL/min]) via IV infusion on Day 1 of each 3-week cycle.
  Interventions:

  • Biological: Pembrolizumab
  • Drug: Paclitaxel
  • Drug: Carboplatin
• Experimental: Part 1 Cohort B10 (Pembro+Pa+C+Bevacizumab [B])
  Cohort B10 participants receive pembrolizumab (10 mg/kg) via IV infusion on Day 1 of each 3-week cycle PLUS paclitaxel (200 mg/m^2) via IV infusion on Day 1 of each 3-week cycle PLUS carboplatin (AUC 6 [6 mg/mL/min]) via IV infusion on Day 1 of each 3-week cycle PLUS bevacizumab (15 mg/kg) via IV infusion on Day 1 of each 3-week cycle.
  Interventions:

  • Biological: Pembrolizumab
  • Drug: Paclitaxel
  • Drug: Carboplatin
  • Biological: Bevacizumab
• Experimental: Part 1 Cohort C10 (Pembro 10mg/kg+Pemetrexed [Pe]+C)
  Cohort C10 participants receive pembrolizumab (10 mg/kg) via IV infusion on Day 1 of each 3-week cycle PLUS pemetrexed (500 mg/m^2) via IV infusion on Day 1 of each 3-week cycle PLUS carboplatin (AUC 5 [5 mg/mL/min]) via IV infusion on Day 1 of each 3-week cycle.
  Interventions:

  • Biological: Pembrolizumab
  • Drug: Carboplatin
  • Drug: Pemetrexed
• Experimental: Part 2 Cohort G- (Placebo+C+Pe)
  Cohort G- participants receive placebo (normal saline solution) via IV infusion on Day 1 of each 3-week cycle PLUS carboplatin (AUC 5 [5 mg/mL/min]) via IV infusion on Day 1 of each 3-week cycle PLUS pemetrexed (500 mg/m^2) via IV infusion on Day 1 of each 3-week cycle PLUS.
  Interventions:

  • Drug: Carboplatin
  • Drug: Pemetrexed
• Experimental: Part 1 Cohort D2 (Pembro 10mg/kg+Ipilimumab [I])
  Cohort D2 participants receive pembrolizumab (10 mg/kg) via IV infusion on Day 1 of each 3-week cycle PLUS ipilimumab (3 mg/kg) via IV infusion on Day 1 of each 3-week cycle.
  Interventions:

  • Biological: Pembrolizumab
  • Biological: Ipilimumab
• Experimental: Part 1 Cohort D4 (Pembro 2mg/kg+Ipilimumab [I])
  Cohort D1 participants receive pembrolizumab (2 mg/kg) via IV infusion on Day 1 of each 3-week cycle PLUS ipilimumab (1 mg/kg) via IV infusion on Day 1 of each 3-week cycle.
  Interventions:

  • Biological: Pembrolizumab
  • Biological: Ipilimumab

Publications *

• Langer CJ, Gadgeel SM, Borghaei H, Papadimitrakopoulou VA, Patnaik A, Powell SF, Gentzler RD, Martins RG, Stevenson JP, Jalal SI, Panwalkar A, Yang JC, Gubens M, Sequist LV, Awad MM, Fiore J, Ge Y, Raftopoulos H, Gandhi L; KEYNOTE-021 investigators. Carboplatin and pemetrexed with or without pembrolizumab for advanced, non-squamous non-small-cell lung cancer: a randomised, phase 2 cohort of the open-label KEYNOTE-021 study. Lancet Oncol. 2016 Nov;17(11):1497-1508. doi: 10.1016/S1470-2045(16)30498-3. Epub 2016 Oct 10.
• Borghaei H, Langer CJ, Gadgeel S, Papadimitrakopoulou VA, Patnaik A, Powell SF, Gentzler RD, Martins RG, Stevenson JP, Jalal SI, Panwalkar A, Yang JC, Gubens M, Sequist LV, Awad MM, Fiore J, Saraf S, Keller SM, Gandhi L. 24-Month Overall Survival from KEYNOTE-021 Cohort G: Pemetrexed and Carboplatin with or without Pembrolizumab as First-Line Therapy for Advanced Nonsquamous Non-Small Cell Lung Cancer. J Thorac Oncol. 2019 Jan;14(1):124-129. doi: 10.1016/j.jtho.2018.08.004. Epub 2018 Aug 21.
• Yang JC, Gadgeel SM, Sequist LV, Wu CL, Papadimitrakopoulou VA, Su WC, Fiore J, Saraf S, Raftopoulos H, Patnaik A. Pembrolizumab in Combination With Erlotinib or Gefitinib as First-Line Therapy for Advanced NSCLC With Sensitizing EGFR Mutation. J Thorac Oncol. 2019 Mar;14(3):553-559. doi: 10.1016/j.jtho.2018.11.028. Epub 2018 Dec 4.
• Gadgeel SM, Stevenson JP, Langer CJ, Gandhi L, Borghaei H, Patnaik A, Villaruz LC, Gubens M, Hauke R, Yang JC, Sequist LV, Bachman R, Saraf S, Raftopoulos H, Papadimitrakopoulou V. Pembrolizumab and platinum-based chemotherapy as first-line therapy for advanced non-small-cell lung cancer: Phase 1 cohorts from the KEYNOTE-021 study. Lung Cancer. 2018 Nov;125:273-281. doi: 10.1016/j.lungcan.2018.08.019. Epub 2018 Aug 25.

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: October 27, 2017): 267
• Original Estimated Enrollment (submitted: January 16, 2014): 320
• Actual Study Completion Date: October 18, 2021
• Actual Primary Completion Date: November 7, 2016 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion Criteria:

• Stage IIIb/IV NSCLC
• Disease progression >1 year after completing adjuvant therapy for Stage I-IIIA disease and no systemic therapy for the recurrent disease
• Resolution of any toxic effects (excepting alopecia) of the most recent therapy
• At least one radiographically measurable lesion
• Performance status of 0 or 1 on the Eastern Cooperative Oncology Group (ECOG) Performance Status scale
• Female participants of reproductive potential must not be pregnant (negative urine or serum human chorionic gonadotropin test within 72 hours of study start)
• Female and male participants of reproductive potential must agree to use adequate contraception throughout the study period and for up to 120 days after the last dose of study therapy and for up to 180 days after the last dose of chemotherapeutic agents or tyrosine kinase inhibitors

Exclusion Criteria:

• Currently participating or has participated in a study of an investigational agent or using an investigational device within 4 weeks of administration of pembrolizumab
• Expected to require any other form of antineoplastic therapy while on study
• Is on chronic systemic steroid therapy or on any other form of immunosuppressive medication
• Has received a live-virus vaccination within 30 days of planned treatment start
• Clinically active diverticulitis, intra-abdominal abscess, gastrointestinal (GI) obstruction, or abdominal carcinomatosis (known risks factors for bowel perforation)
• History of a hematologic malignancy, primary brain tumor or sarcoma, or of another primary solid tumor, unless the participant has undergone potentially curative therapy with no evidence of that disease for 5 years
• Active central nervous system (CNS) metastases and/or carcinomatous meningitis
• Severe hypersensitivity reaction to treatment with another monoclonal antibody (mAb)
• Active autoimmune disease that has required systemic treatment in the past 2 years (replacement therapies for hormone deficiencies are allowed)
• Prior treatment with any other anti-programmed cell death protein-1 (anti-PD-1), or PD Ligand-1 (PD-L1) or PD Ligand-2 (PD-L2) agent or an antibody targeting other immuno-regulatory receptors or mechanisms
• Systemic cytotoxic chemotherapy, antineoplastic biologic therapy, or major surgery within 3 weeks of the first dose of study medication
• Radiation therapy to lung >30 Gy within 6 months of first dose of study medication
• Prior tyrosine kinase inhibitor therapy or palliative radiation within 7 days of first dose of study medication
• Active infection requiring therapy
• History of Human Immunodeficiency Virus (HIV)
• Active Hepatitis B or C
• Symptomatic ascites or pleural effusion
• Interstitial lung disease or pneumonitis requiring oral or IV glucocorticoids
• Pregnant or breastfeeding, or expecting to conceive or father children within the projected duration of the study
• Psychiatric disorders and substance (drug/alcohol) abuse

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: Not Provided
• Removed Location Countries: Taiwan, United States

Administrative Information

• NCT Number: NCT02039674
• Other Study ID Numbers: 3475-021; MK-3475-021 ( Other Identifier: Merck Protocol Number ); KEYNOTE-021 ( Other Identifier: Merck )
• Has Data Monitoring Committee: No
• U.S. FDA-regulated Product: Not Provided

IPD Sharing Statement

• Plan to Share IPD: Yes
• Plan Description: http://engagezone.msd.com/doc/ProcedureAccessClinicalTrialData.pd
• 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: October 2022