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)

Phase 1

Completed

• Conditions: Non-small Cell Lung Carcinoma
• Interventions: Biological: Pembrolizumab; Biological: Ipilimumab; Drug: Paclitaxel; Drug: Erlotinib; Drug: Gefitinib; Drug: Carboplatin; Drug: Pemetrexed; Biological: Bevacizumab

• Registration Number: NCT02039674
• Lead Sponsor: Merck Sharp & Dohme LLC

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 available

Study Timeline

• Study First Submitted: 2014-01-16
• Study First Submitted QC: 2014-01-16
• Study First Posted: 2014-01-17
• Study Start: 2014-02-21
• Primary Completion: 2016-11-07
• Results First Submitted: 2017-10-27
• Results First Submitted QC: 2017-10-27
• Results First Posted: 2017-12-02
• Study Completion: 2021-10-18
• Status Verified: 2022-10
• Last Update Submitted: 2022-10-13
• Last Update Posted: 2022-11-08

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 267

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

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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

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Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

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

Primary Outcome Measures

Name	Time	Method
Part 2 Cohorts G+ and G-: Objective Response Rate (ORR)	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)	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)	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.

Secondary Outcome Measures

Name	Time	Method
Part 2 Cohorts G+ and G-: Progression-Free Survival (PFS)	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)	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)	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.