NCT02039674

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)

Completed Phase 1, PHASE2 Results posted Last updated 8 November 2022

What this trial tests

Phase 1, PHASE2 trial testing Pembrolizumab in Non-small Cell Lung Carcinoma in 267 participants. Completed in 18 October 2021.

Timeline

21 February 2014

Primary endpoint
7 November 2016

18 October 2021

Quick facts

Lead sponsor	Merck Sharp & Dohme LLC
Phase	Phase 1, PHASE2
Status	Completed
Study type	INTERVENTIONAL
Allocation	randomized
Design	parallel
Masking	none
Primary purpose	treatment
Enrollment	267
Start date	21 February 2014
Primary completion	7 November 2016
Estimated completion	18 October 2021

Drugs / interventions tested

• Pembrolizumab (pembrolizumab) — full drug profile →
• Paclitaxel — full drug profile →
• Carboplatin
• Bevacizumab
• Pemetrexed — full drug profile →
• Ipilimumab — full drug profile →
• Erlotinib
• Gefitinib

Conditions studied

• Non-small Cell Lung Carcinoma — all drugs for Non-small Cell Lung Carcinoma →

Sponsor

Merck Sharp & Dohme LLC — full company profile →

Who can join

18 and older, any sex, with Non-small Cell Lung Carcinoma. Patients with the condition only — healthy volunteers not accepted.

Results — posted to ClinicalTrials.gov

Per-arm endpoint measurements with 95% confidence intervals where reported. Source: trial results section.

Part 2 Cohorts G+ and G-: Objective Response Rate (ORR) Primary · 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).

Group	Value	95% CI
Part 2 Cohort G+ (Pembro 200 mg+Pe+C)	55.0	41.6 – 67.9
Part 2 Cohort G- (Placebo+Pe+C)	28.6	17.9 – 41.3

Part 2 Cohorts D4 and H: Objective Response Rate (ORR) Primary · 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.

Group	Value	95% CI
Part 2 Cohorts D4 & H (Pembro 2mg/kg+I)	29.5	16.8 – 45.2

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

Group	Value	95% CI
Part1 Cohort A2 (Pembro 2 mg/kg+Paclitaxel [Pa]+Carboplatin [C])	0
Part1 Cohort A10 (Pembro10mg/kg+Pa+C)	0
Part 1 Cohort B2 (Pembro 2mg/kg+Pa+C+Bevacizumab [B])	0
Part 1 Cohort B10 (Pembro 10 mg/kg+Pa+C+B)	0
Part 1 Cohort C2 (Pembro 2 mg/kg+Pemetrexed [Pe]+C)	0
Part 1 Cohort C10 (Pembro 10 mg/kg+Pe+C)	0
Part 1 Cohort D1 (Pembro 10mg/kg+Ipilimumab [I])	0
Part 1 Cohort D2 (Pembro 10 mg/kg+I)	0
Part 1 Cohort D4 (Pembro 2 mg/kg+I)	0
Part 1 Cohort E (Pembro 2 mg/kg+Erlotinib)	0
Part 1 Cohort F (Pembro 2 mg/kg+Gefitinib)	0
Part 2 Cohort G+ (Pembro 200 mg+Pe+C)	0

Part 2 Cohorts G+ and G-: Progression-Free Survival (PFS) Secondary · 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.

Group	Value	95% CI
Part 2 Cohort G+ (Pembro 200 mg+Pe+C)	24.5	9.7 – 36.3
Part 2 Cohort G- (Placebo+Pe+C)	9.9	6.2 – 15.2

Part 2 Cohorts G+ and G-: Overall Survival (OS) Secondary · Up to approximately 2 years

OS was defined as the time from randomization to death due to any cause.

Group	Value	95% CI
Part 2 Cohort G+ (Pembro 200 mg+Pe+C)	34.5	24.0 – NA
Part 2 Cohort G- (Placebo+Pe+C)	21.1	14.9 – 35.6

Part 2 Cohorts G+ and G-: Duration of Response (DOR) Secondary · 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.

Group	Value	95% CI
Part 2 Cohort G+ (Pembro 200 mg+Pe+C)	NA	NA – NA
Part 2 Cohort G- (Placebo+Pe+C)	NA	NA – NA

Adverse events — posted to ClinicalTrials.gov

Time frame: Up to approximately 92 months (Up to 90 days after last dose of study treatment). Reporting threshold: 5%. Adverse-event reports describe events observed during the trial — not all are caused by the drug.

Part 1 Cohort A10 (Pembro10mg/kg+Pa+C)

Serious: 5/12 (42%)

Deaths: 10/12

Part 1 Cohort A2 (Pembro 2 mg/kg+Paclitaxel [Pa]+Carboplatin [C])

Serious: 7/13 (54%)

Deaths: 10/13

Cohort A Second Course (Pembro 2 mg/kg Monotherapy)

Serious: 0/2 (0%)

Deaths: 2/2

Part 1 Cohort B10 (Pembro 10 mg/kg+Pa+C+B)

Serious: 8/13 (62%)

Deaths: 11/13

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

Serious: 8/11 (73%)

Deaths: 9/12

Cohort B Second Course (Pembro 2 mg/kg Monotherapy)

Serious: 0/1 (0%)

Deaths: 1/1

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

Serious: 7/12 (58%)

Deaths: 11/12

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

Serious: 6/12 (50%)

Deaths: 8/12

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

Serious: 1/3 (33%)

Deaths: 3/3

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

Serious: 1/3 (33%)

Deaths: 3/3

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

Serious: 5/12 (42%)

Deaths: 11/12

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

Serious: 8/12 (67%)

Deaths: 5/12

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

Serious: 5/7 (71%)

Deaths: 7/7

Cohort E Second Course (Pembro 2 mg/kg Monotherapy)

Serious: 0/1 (0%)

Deaths: 0/1

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

Serious: 30/59 (51%)

Deaths: 42/60

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

Serious: 21/62 (34%)

Deaths: 47/63

Cohort G+ Second Course (Pembro 200 mg Monotherapy)

Serious: 0/2 (0%)

Deaths: 1/2

Cohort G Crossover (Pembro 200 mg Monotherapy)

Serious: 7/28 (25%)

Deaths: 24/28

Part 2 Cohort H (Pembro 2mg/kg+I)

Serious: 12/33 (36%)

Deaths: 31/33

Serious adverse events (116 terms)

Reaction	System	Part 1 Cohort A10 (Pembro1…	Part 1 Cohort A2 (Pembro 2…	Cohort A Second Course (Pe…	Part 1 Cohort B10 (Pembro …	Part 1 Cohort B2 (Pembro 2…	Cohort B Second Course (Pe…	Part 1 Cohort C10 (Pembro …	Part 1 Cohort C2 (Pembro 2…	Part 1 Cohort D1 (Pembro 1…	Part 1 Cohort D2 (Pembro 1…	Part 1 Cohort D4 (Pembro 2…	Part 1 Cohort E (Pembro 2 …	Part 1 Cohort F (Pembro 2 …	Cohort E Second Course (Pe…	Part 2 Cohort G+ (Pembro 2…	Part 2 Cohort G- (Placebo+…	Cohort G+ Second Course (P…	Cohort G Crossover (Pembro…	Part 2 Cohort H (Pembro 2m…
Cellulitis	Infections and infestations	—	—	—	—	—	—	—	—	—	—	—	—	—	—	—	—	—	—	—
Alanine aminotransferase increased	Investigations	—	—	—	—	—	—	—	—	—	—	—	—	—	—	—	—	—	—	—
Aspartate aminotransferase increased	Investigations	—	—	—	—	—	—	—	—	—	—	—	—	—	—	—	—	—	—	—
Acute kidney injury	Renal and urinary disorders	—	—	—	—	—	—	—	—	—	—	—	—	—	—	—	—	—	—	—
Pyrexia	General disorders	—	—	—	—	—	—	—	—	—	—	—	—	—	—	—	—	—	—	—
Pneumonia	Infections and infestations	—	—	—	—	—	—	—	—	—	—	—	—	—	—	—	—	—	—	—
Pleural effusion	Respiratory, thoracic and mediastinal disorders	—	—	—	—	—	—	—	—	—	—	—	—	—	—	—	—	—	—	—
Anaemia	Blood and lymphatic system disorders	—	—	—	—	—	—	—	—	—	—	—	—	—	—	—	—	—	—	—
Febrile neutropenia	Blood and lymphatic system disorders	—	—	—	—	—	—	—	—	—	—	—	—	—	—	—	—	—	—	—
Pancytopenia	Blood and lymphatic system disorders	—	—	—	—	—	—	—	—	—	—	—	—	—	—	—	—	—	—	—
Abdominal pain	Gastrointestinal disorders	—	—	—	—	—	—	—	—	—	—	—	—	—	—	—	—	—	—	—
Small intestinal obstruction	Gastrointestinal disorders	—	—	—	—	—	—	—	—	—	—	—	—	—	—	—	—	—	—	—
Death	General disorders	—	—	—	—	—	—	—	—	—	—	—	—	—	—	—	—	—	—	—
Fatigue	General disorders	—	—	—	—	—	—	—	—	—	—	—	—	—	—	—	—	—	—	—
Sepsis	Infections and infestations	—	—	—	—	—	—	—	—	—	—	—	—	—	—	—	—	—	—	—
Cerebrovascular accident	Nervous system disorders	—	—	—	—	—	—	—	—	—	—	—	—	—	—	—	—	—	—	—
Encephalopathy	Nervous system disorders	—	—	—	—	—	—	—	—	—	—	—	—	—	—	—	—	—	—	—
Chronic obstructive pulmonary disease	Respiratory, thoracic and mediastinal disorders	—	—	—	—	—	—	—	—	—	—	—	—	—	—	—	—	—	—	—
Dyspnoea	Respiratory, thoracic and mediastinal disorders	—	—	—	—	—	—	—	—	—	—	—	—	—	—	—	—	—	—	—
Pneumonitis	Respiratory, thoracic and mediastinal disorders	—	—	—	—	—	—	—	—	—	—	—	—	—	—	—	—	—	—	—
Neutropenia	Blood and lymphatic system disorders	—	—	—	—	—	—	—	—	—	—	—	—	—	—	—	—	—	—	—
Thrombocytopenia	Blood and lymphatic system disorders	—	—	—	—	—	—	—	—	—	—	—	—	—	—	—	—	—	—	—
Aortic valve disease	Cardiac disorders	—	—	—	—	—	—	—	—	—	—	—	—	—	—	—	—	—	—	—
Arteriosclerosis coronary artery	Cardiac disorders	—	—	—	—	—	—	—	—	—	—	—	—	—	—	—	—	—	—	—
Atrial fibrillation	Cardiac disorders	—	—	—	—	—	—	—	—	—	—	—	—	—	—	—	—	—	—	—

Other adverse events (393 terms — click to expand)

Reaction	System	Part 1 Cohort A10 (Pembro1…	Part 1 Cohort A2 (Pembro 2…	Cohort A Second Course (Pe…	Part 1 Cohort B10 (Pembro …	Part 1 Cohort B2 (Pembro 2…	Cohort B Second Course (Pe…	Part 1 Cohort C10 (Pembro …	Part 1 Cohort C2 (Pembro 2…	Part 1 Cohort D1 (Pembro 1…	Part 1 Cohort D2 (Pembro 1…	Part 1 Cohort D4 (Pembro 2…	Part 1 Cohort E (Pembro 2 …	Part 1 Cohort F (Pembro 2 …	Cohort E Second Course (Pe…	Part 2 Cohort G+ (Pembro 2…	Part 2 Cohort G- (Placebo+…	Cohort G+ Second Course (P…	Cohort G Crossover (Pembro…	Part 2 Cohort H (Pembro 2m…
Nausea	Gastrointestinal disorders	—	—	—	—	—	—	—	—	—	—	—	—	—	—	—	—	—	—	—
Fatigue	General disorders	—	—	—	—	—	—	—	—	—	—	—	—	—	—	—	—	—	—	—
Anaemia	Blood and lymphatic system disorders	—	—	—	—	—	—	—	—	—	—	—	—	—	—	—	—	—	—	—
Constipation	Gastrointestinal disorders	—	—	—	—	—	—	—	—	—	—	—	—	—	—	—	—	—	—	—
Vomiting	Gastrointestinal disorders	—	—	—	—	—	—	—	—	—	—	—	—	—	—	—	—	—	—	—
Diarrhoea	Gastrointestinal disorders	—	—	—	—	—	—	—	—	—	—	—	—	—	—	—	—	—	—	—
Dyspnoea	Respiratory, thoracic and mediastinal disorders	—	—	—	—	—	—	—	—	—	—	—	—	—	—	—	—	—	—	—
Decreased appetite	Metabolism and nutrition disorders	—	—	—	—	—	—	—	—	—	—	—	—	—	—	—	—	—	—	—
Arthralgia	Musculoskeletal and connective tissue disorders	—	—	—	—	—	—	—	—	—	—	—	—	—	—	—	—	—	—	—
Headache	Nervous system disorders	—	—	—	—	—	—	—	—	—	—	—	—	—	—	—	—	—	—	—
Rash	Skin and subcutaneous tissue disorders	—	—	—	—	—	—	—	—	—	—	—	—	—	—	—	—	—	—	—
Cough	Respiratory, thoracic and mediastinal disorders	—	—	—	—	—	—	—	—	—	—	—	—	—	—	—	—	—	—	—
Oedema peripheral	General disorders	—	—	—	—	—	—	—	—	—	—	—	—	—	—	—	—	—	—	—
Aspartate aminotransferase increased	Investigations	—	—	—	—	—	—	—	—	—	—	—	—	—	—	—	—	—	—	—
Blood creatinine increased	Investigations	—	—	—	—	—	—	—	—	—	—	—	—	—	—	—	—	—	—	—
Dizziness	Nervous system disorders	—	—	—	—	—	—	—	—	—	—	—	—	—	—	—	—	—	—	—
Insomnia	Psychiatric disorders	—	—	—	—	—	—	—	—	—	—	—	—	—	—	—	—	—	—	—
Pruritus	Skin and subcutaneous tissue disorders	—	—	—	—	—	—	—	—	—	—	—	—	—	—	—	—	—	—	—
Upper respiratory tract infection	Infections and infestations	—	—	—	—	—	—	—	—	—	—	—	—	—	—	—	—	—	—	—
Urinary tract infection	Infections and infestations	—	—	—	—	—	—	—	—	—	—	—	—	—	—	—	—	—	—	—
Alanine aminotransferase increased	Investigations	—	—	—	—	—	—	—	—	—	—	—	—	—	—	—	—	—	—	—
Hyperglycaemia	Metabolism and nutrition disorders	—	—	—	—	—	—	—	—	—	—	—	—	—	—	—	—	—	—	—
Hypokalaemia	Metabolism and nutrition disorders	—	—	—	—	—	—	—	—	—	—	—	—	—	—	—	—	—	—	—
Back pain	Musculoskeletal and connective tissue disorders	—	—	—	—	—	—	—	—	—	—	—	—	—	—	—	—	—	—	—
Alopecia	Skin and subcutaneous tissue disorders	—	—	—	—	—	—	—	—	—	—	—	—	—	—	—	—	—	—	—
Neutrophil count decreased	Investigations	—	—	—	—	—	—	—	—	—	—	—	—	—	—	—	—	—	—	—
Dry eye	Eye disorders	—	—	—	—	—	—	—	—	—	—	—	—	—	—	—	—	—	—	—
Lacrimation increased	Eye disorders	—	—	—	—	—	—	—	—	—	—	—	—	—	—	—	—	—	—	—
Fall	Injury, poisoning and procedural complications	—	—	—	—	—	—	—	—	—	—	—	—	—	—	—	—	—	—	—
Hypothyroidism	Endocrine disorders	—	—	—	—	—	—	—	—	—	—	—	—	—	—	—	—	—	—	—
Weight decreased	Investigations	—	—	—	—	—	—	—	—	—	—	—	—	—	—	—	—	—	—	—
Pain in extremity	Musculoskeletal and connective tissue disorders	—	—	—	—	—	—	—	—	—	—	—	—	—	—	—	—	—	—	—
Dysgeusia	Nervous system disorders	—	—	—	—	—	—	—	—	—	—	—	—	—	—	—	—	—	—	—
Depression	Psychiatric disorders	—	—	—	—	—	—	—	—	—	—	—	—	—	—	—	—	—	—	—
Abdominal pain	Gastrointestinal disorders	—	—	—	—	—	—	—	—	—	—	—	—	—	—	—	—	—	—	—
Dyspepsia	Gastrointestinal disorders	—	—	—	—	—	—	—	—	—	—	—	—	—	—	—	—	—	—	—
Sinusitis	Infections and infestations	—	—	—	—	—	—	—	—	—	—	—	—	—	—	—	—	—	—	—
Platelet count decreased	Investigations	—	—	—	—	—	—	—	—	—	—	—	—	—	—	—	—	—	—	—
White blood cell count decreased	Investigations	—	—	—	—	—	—	—	—	—	—	—	—	—	—	—	—	—	—	—
Neuropathy peripheral	Nervous system disorders	—	—	—	—	—	—	—	—	—	—	—	—	—	—	—	—	—	—	—

Most-reported serious reactions: Cellulitis, Alanine aminotransferase increased, Aspartate aminotransferase increased, Acute kidney injury, Pyrexia, Pneumonia, Pleural effusion, Anaemia.

Data from ClinicalTrials.gov NCT02039674 adverse events section.

Sponsor's own description

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).

Publications & conference data

8 peer-reviewed publications reference this trial (live from Europe PMC):

1. Hallmarks of response, resistance, and toxicity to immune checkpoint blockade.
   Morad G, Helmink BA, Sharma P, Wargo JA. · · 2021 · cited 1197× · PMID 34624224 · DOI 10.1016/j.cell.2021.09.020
2. 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.
   Langer CJ, Gadgeel SM, Borghaei H, Papadimitrakopoulou VA, et al · · 2016 · cited 1120× · PMID 27745820 · DOI 10.1016/s1470-2045(16)30498-3
3. Combination strategies with PD-1/PD-L1 blockade: current advances and future directions.
   Yi M, Zheng X, Niu M, Zhu S, et al · · 2022 · cited 1018× · PMID 35062949 · DOI 10.1186/s12943-021-01489-2
4. Toxicities of the anti-PD-1 and anti-PD-L1 immune checkpoint antibodies.
   Naidoo J, Page DB, Li BT, Connell LC, et al · · 2015 · cited 1005× · PMID 26371282 · DOI 10.1093/annonc/mdv383
5. The Challenges of Tumor Mutational Burden as an Immunotherapy Biomarker.
   Jardim DL, Goodman A, de Melo Gagliato D, Kurzrock R. · · 2021 · cited 935× · PMID 33125859 · DOI 10.1016/j.ccell.2020.10.001
6. Management of acquired resistance to EGFR TKI-targeted therapy in advanced non-small cell lung cancer.
   Wu SG, Shih JY. · · 2018 · cited 577× · PMID 29455650 · DOI 10.1186/s12943-018-0777-1
7. Combination of anti-angiogenic therapy and immune checkpoint blockade normalizes vascular-immune crosstalk to potentiate cancer immunity.
   Lee WS, Yang H, Chon HJ, Kim C. · · 2020 · cited 534× · PMID 32913278 · DOI 10.1038/s12276-020-00500-y
8. Improvement of the anticancer efficacy of PD-1/PD-L1 blockade via combination therapy and PD-L1 regulation.
   Wu M, Huang Q, Xie Y, Wu X, et al · · 2022 · cited 336× · PMID 35279217 · DOI 10.1186/s13045-022-01242-2