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)

NCT02039674 | Completed Phase 1 Results

• 3 other identifiers: 3475-021MK-3475-021KEYNOTE-021
• Study Type: interventional
• Target: 267
• Locations: 0 countries
• Sites: N/A

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).

Conditions

Non-small Cell Lung Carcinoma

Keywords

PD-1; PD1; Programmed Cell Death-1; Programmed Cell Death 1; Chemotherapy; Pemetrexed; Paclitaxel; Bevacizumab; Erlotinib; Gefitinib; Ipilimumab; Carboplatin

Outcome Measures

Primary Outcomes (3)

• Part 2 Cohorts G+ and G-: Objective Response Rate (ORR)

  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).

  Up to approximately 2 years

• Part 2 Cohorts D4 and H: Objective Response Rate (ORR)

  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.

  Up to approximately 2 years

• All Cohorts: Number of Participants Who Experienced a Dose-limiting Toxicity (DLT)

  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.

  Cycle 1 (Up to 21 days)

Secondary Outcomes (3)

• Part 2 Cohorts G+ and G-: Progression-Free Survival (PFS)

  Up to approximately 2 years

• Part 2 Cohorts G+ and G-: Overall Survival (OS)

  Up to approximately 2 years

• Part 2 Cohorts G+ and G-: Duration of Response (DOR)

  Up to approximately 2 years

Study Arms (14)

Part 1 Cohort A2 (Pembro2mg/kg+Paclitaxel [Pa]+Carboplatin [C])

EXPERIMENTAL

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.

Biological: Pembrolizumab; Drug: Paclitaxel; Drug: Carboplatin

Part 1 Cohort B2 (Pembro 2mg/kg+Pa+C+Bevacizumab [B])

EXPERIMENTAL

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.

Biological: Pembrolizumab; Drug: Paclitaxel; Drug: Carboplatin; Biological: Bevacizumab

Part 1 Cohort C2 (Pembro 2mg/kg+Pemetrexed [Pe]+C)

EXPERIMENTAL

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.

Biological: Pembrolizumab; Drug: Carboplatin; Drug: Pemetrexed

Part 1 Cohort D1 (Pembro 10mg/kg+Ipilimumab [I])

EXPERIMENTAL

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.

Biological: Pembrolizumab; Biological: Ipilimumab

Part 1 Cohort E (Pembro 2mg/kg+Erlotinib)

EXPERIMENTAL

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.

Biological: Pembrolizumab; Drug: Erlotinib

Part 1 Cohort F (Pembro 2mg/kg+Gefitinib)

EXPERIMENTAL

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.

Biological: Pembrolizumab; Drug: Gefitinib

Part 2 Cohort G+ (Pembro 200mg+C+Pe)

EXPERIMENTAL

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.

Biological: Pembrolizumab; Drug: Carboplatin; Drug: Pemetrexed

Part 2 Cohort H (Pembro+I)

EXPERIMENTAL

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).

Biological: Pembrolizumab; Biological: Ipilimumab

Part 1 Cohort A10 (Pembro+Paclitaxel [Pa]+Carboplatin [C])

EXPERIMENTAL

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.

Biological: Pembrolizumab; Drug: Paclitaxel; Drug: Carboplatin

Part 1 Cohort B10 (Pembro+Pa+C+Bevacizumab [B])

EXPERIMENTAL

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.

Biological: Pembrolizumab; Drug: Paclitaxel; Drug: Carboplatin; Biological: Bevacizumab

Part 1 Cohort C10 (Pembro 10mg/kg+Pemetrexed [Pe]+C)

EXPERIMENTAL

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.

Biological: Pembrolizumab; Drug: Carboplatin; Drug: Pemetrexed

Part 2 Cohort G- (Placebo+C+Pe)

EXPERIMENTAL

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.

Drug: Carboplatin; Drug: Pemetrexed

Part 1 Cohort D2 (Pembro 10mg/kg+Ipilimumab [I])

EXPERIMENTAL

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.

Biological: Pembrolizumab; Biological: Ipilimumab

Part 1 Cohort D4 (Pembro 2mg/kg+Ipilimumab [I])

EXPERIMENTAL

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.

Biological: Pembrolizumab; Biological: Ipilimumab

Interventions

Pembrolizumab BIOLOGICAL

IV on Day 1 of each 3-week cycle prior to chemo/immunotherapy

Also known as: MK-3475, KEYTRUDA®, SCH 900475

Part 1 Cohort A10 (Pembro+Paclitaxel [Pa]+Carboplatin [C]); Part 1 Cohort A2 (Pembro2mg/kg+Paclitaxel [Pa]+Carboplatin [C]); Part 1 Cohort B10 (Pembro+Pa+C+Bevacizumab [B]); Part 1 Cohort B2 (Pembro 2mg/kg+Pa+C+Bevacizumab [B]); Part 1 Cohort C10 (Pembro 10mg/kg+Pemetrexed [Pe]+C); Part 1 Cohort C2 (Pembro 2mg/kg+Pemetrexed [Pe]+C); Part 1 Cohort D1 (Pembro 10mg/kg+Ipilimumab [I]); Part 1 Cohort D2 (Pembro 10mg/kg+Ipilimumab [I]); Part 1 Cohort D4 (Pembro 2mg/kg+Ipilimumab [I]); Part 1 Cohort E (Pembro 2mg/kg+Erlotinib); Part 1 Cohort F (Pembro 2mg/kg+Gefitinib); Part 2 Cohort G+ (Pembro 200mg+C+Pe); Part 2 Cohort H (Pembro+I)

Paclitaxel DRUG

IV on Day 1 of each 3-week cycle for a maximum of 4 administrations

Also known as: ABRAXANE®

Part 1 Cohort A10 (Pembro+Paclitaxel [Pa]+Carboplatin [C]); Part 1 Cohort A2 (Pembro2mg/kg+Paclitaxel [Pa]+Carboplatin [C]); Part 1 Cohort B10 (Pembro+Pa+C+Bevacizumab [B]); Part 1 Cohort B2 (Pembro 2mg/kg+Pa+C+Bevacizumab [B])

Carboplatin DRUG

IV on Day 1 of each 3-week cycle for a maximum of 4 administrations

Also known as: PARAPLATIN®

Part 1 Cohort A10 (Pembro+Paclitaxel [Pa]+Carboplatin [C]); Part 1 Cohort A2 (Pembro2mg/kg+Paclitaxel [Pa]+Carboplatin [C]); Part 1 Cohort B10 (Pembro+Pa+C+Bevacizumab [B]); Part 1 Cohort B2 (Pembro 2mg/kg+Pa+C+Bevacizumab [B]); Part 1 Cohort C10 (Pembro 10mg/kg+Pemetrexed [Pe]+C); Part 1 Cohort C2 (Pembro 2mg/kg+Pemetrexed [Pe]+C); Part 2 Cohort G+ (Pembro 200mg+C+Pe); Part 2 Cohort G- (Placebo+C+Pe)

Bevacizumab BIOLOGICAL

IV on Day 1 of each 3-week cycle

Also known as: AVASTIN®

Part 1 Cohort B10 (Pembro+Pa+C+Bevacizumab [B]); Part 1 Cohort B2 (Pembro 2mg/kg+Pa+C+Bevacizumab [B])

Pemetrexed DRUG

IV on Day 1 of each 3-week cycle

Also known as: ALIMTA®

Part 1 Cohort C10 (Pembro 10mg/kg+Pemetrexed [Pe]+C); Part 1 Cohort C2 (Pembro 2mg/kg+Pemetrexed [Pe]+C); Part 2 Cohort G+ (Pembro 200mg+C+Pe); Part 2 Cohort G- (Placebo+C+Pe)

Ipilimumab BIOLOGICAL

IV on Day 1 of each 3-week cycle for a maximum of 4 administrations

Also known as: YERVOY®

Part 1 Cohort D1 (Pembro 10mg/kg+Ipilimumab [I]); Part 1 Cohort D2 (Pembro 10mg/kg+Ipilimumab [I]); Part 1 Cohort D4 (Pembro 2mg/kg+Ipilimumab [I]); Part 2 Cohort H (Pembro+I)

Erlotinib DRUG

Orally tablet once daily

Also known as: TARCEVA®

Part 1 Cohort E (Pembro 2mg/kg+Erlotinib)

Gefitinib DRUG

Oral tablet once daily

Also known as: IRESSA®

Part 1 Cohort F (Pembro 2mg/kg+Gefitinib)

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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

You may not qualify if:

• 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)

Sponsors & Collaborators

• Merck Sharp & Dohme LLC: lead

Related Publications (5)

• 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.

  PMID: 27745820 RESULT

• 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.

  PMID: 30138764 RESULT

• Cheng Y, Yang JC, Okamoto I, Zhang L, Hu J, Wang D, Hu C, Zhou J, Wu L, Cao L, Liu J, Zhang H, Sun H, Wang Z, Gao H, Yan Y, Xiao S, Lin J, Pietanza MC, Kurata T. Pembrolizumab plus chemotherapy for advanced non-small-cell lung cancer without tumor PD-L1 expression in Asia. Immunotherapy. 2023 Sep;15(13):1029-1044. doi: 10.2217/imt-2023-0043. Epub 2023 Jul 19.

  PMID: 37465924 DERIVED

• 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.

  PMID: 30529597 DERIVED

• 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.

  PMID: 30429032 DERIVED

Related Links

• Merck Oncology Clinical Trials Information

MeSH Terms

Conditions

Carcinoma, Non-Small-Cell Lung

Interventions

pembrolizumab; Paclitaxel; Albumin-Bound Paclitaxel; Carboplatin; Bevacizumab; Pemetrexed; Ipilimumab; Erlotinib Hydrochloride; Gefitinib

Condition Hierarchy (Ancestors)

Carcinoma, Bronchogenic; Bronchial Neoplasms; Lung Neoplasms; Respiratory Tract Neoplasms; Thoracic Neoplasms; Neoplasms by Site; Neoplasms; Lung Diseases; Respiratory Tract Diseases

Intervention Hierarchy (Ancestors)

Taxoids; Cyclodecanes; Cycloparaffins; Hydrocarbons, Alicyclic; Hydrocarbons, Cyclic; Hydrocarbons; Organic Chemicals; Diterpenes; Terpenes; Albumins; Proteins; Amino Acids, Peptides, and Proteins; Coordination Complexes; Antibodies, Monoclonal, Humanized; Antibodies, Monoclonal; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Serum Globulins; Globulins; Guanine; Hypoxanthines; Purinones; Purines; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds; Glutamates; Amino Acids, Acidic; Amino Acids; Amino Acids, Dicarboxylic; Quinazolines

Results Point of Contact

• Title: Senior Vice President, Global Clinical Development
• Organization: Merck Sharp & Dohme LLC

ClinicalTrialsDisclosure@merck.com

1-800-672-6372

Study Officials

• Medical Director

  Merck Sharp & Dohme LLC

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: January 16, 2014
• First Posted: January 17, 2014
• Study Start: February 21, 2014
• Primary Completion: November 7, 2016
• Study Completion: October 18, 2021
• Last Updated: November 8, 2022
• Results First Posted: December 2, 2017

Record last verified: 2022-10

Data Sharing

• IPD Sharing: Will share