NCT02335411

A Study of Pembrolizumab (MK-3475) in Participants With Recurrent or Metastatic Gastric or Gastroesophageal Junction Adenocarcinoma (MK-3475-059/KEYNOTE-059)

Completed Phase 2 Results posted Last updated 8 August 2022

What this trial tests

Phase 2 trial testing pembrolizumab in Gastric Adenocarcinoma in 318 participants. Completed in 23 July 2021.

Timeline

3 February 2015

Primary endpoint
23 July 2021

23 July 2021

Quick facts

Lead sponsor	Merck Sharp & Dohme LLC
Phase	Phase 2
Status	Completed
Study type	INTERVENTIONAL
Allocation	non randomized
Design	parallel
Masking	none
Primary purpose	treatment
Enrollment	318
Start date	3 February 2015
Primary completion	23 July 2021
Estimated completion	23 July 2021

Drugs / interventions tested

• pembrolizumab (pembrolizumab) — full drug profile →
• cisplatin (cisplatin) — full drug profile →
• 5-FU (5-fu) — full drug profile →
• capecitabine (capecitabine) — full drug profile →

Conditions studied

• Gastric Adenocarcinoma — all drugs for Gastric Adenocarcinoma →
• Gastroesophageal Junction Adenocarcinoma — all drugs for Gastroesophageal Junction Adenocarcinoma →

Sponsor

Merck Sharp & Dohme LLC — full company profile →

Who can join

18 and older, any sex, with Gastric Adenocarcinoma or Gastroesophageal Junction Adenocarcinoma. 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.

Number of Participants Experiencing Adverse Events (AEs) Primary · Up to approximately 65 months

An AE is defined as any untoward medical occurrence in a participant administered study drug and which does not necessarily have to have a causal relationship with the study drug. The number of participants who experienced at least one AE is presented. Per protocol, the number of participants who experienced at least one AE during first course pembrolizumab treatment is presented.

Group	Value	95% CI
Cohort 1: Pembrolizumab Monotherapy, Previously Treated	248
Cohort 2: Pembrolizumab Combination Therapy, Treatment Naive	25
Cohort 3: Pembrolizumab Monotherapy, Treatment Naive, PD-L1 Positive	31

Number of Participants Discontinuing Study Drug Due to AEs Primary · Up to approximately 52 months

An AE was defined as any untoward medical occurrence in a participant administered study drug and which does not necessarily have to have a causal relationship with the study drug. The number of participants who discontinued study drug due to an AE is presented. Per protocol, the number of participants who discontinued drug during first course pembrolizumab treatment is presented.

Group	Value	95% CI
Cohort 1: Pembrolizumab Monotherapy, Previously Treated	18
Cohort 2: Pembrolizumab Combination Therapy, Treatment Naive	4
Cohort 3: Pembrolizumab Monotherapy, Treatment Naive, PD-L1 Positive	0

Objective Response Rate (ORR) For All Participants in Cohorts 1 and 3 Primary · Up to approximately 75 months

The Objective Response Rate (ORR) was defined as the percentage of participants in the analysis population who had a 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 Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST 1.1) as assessed by central radiology review. The percentage of all participants (regardless of programmed death-ligand 1 \[PD-L1\] tumor status) in Cohorts 1 and 3 who had a CR or PR during first course pembrolizumab treatment per protocol, is presented.

Group	Value	95% CI
Cohort 1: Pembrolizumab Monotherapy, Previously Treated	11.6	8.0 – 16.1
Cohort 3: Pembrolizumab Monotherapy, Treatment Naive, PD-L1 Positive	22.6	9.6 – 41.1

Objective Response Rate For PD-L1 Positive Participants in Cohorts 1 and 3 Primary · Up to approximately 75 months

The ORR was defined as the percentage of participants in the analysis population who had a CR or PR (CR: Disappearance of all target lesions; PR: At least a 30% decrease in the sum of diameters of target lesions) per RECIST 1.1, as assessed by central radiology review. The percentage of all participants in Cohorts 1 and 3 with PD-L1+ tumor status who experienced a CR or PR during first course pembrolizumab treatment per protocol, is presented. Note: All participants in Cohort 3 had a PD-L1-positive tumor status.

Group	Value	95% CI
Cohort 1: Pembrolizumab Monotherapy, Previously Treated	15.5	10.1 – 22.4
Cohort 3: Pembrolizumab Monotherapy, Treatment Naive, PD-L1 Positive	22.6	9.6 – 41.1

Objective Response Rate (ORR) For All Participants in Cohort 2 Secondary · Up to approximately 75 months

The Objective Response Rate (ORR) was defined as the percentage of participants in the analysis population who had a 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 Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST 1.1) as assessed by central radiology review. The percentage of all participants (regardless of PD-L1 tumor status) in Cohort 2 who had a CR or PR during first course pembrolizumab treatment per protocol, is presented.

Group	Value	95% CI
Cohort 2: Pembrolizumab Combination Therapy, Treatment Naive	60.0	38.7 – 78.9

Objective Response Rate For PD-L1 Positive Participants in Cohort 2 Secondary · Up to approximately 75 months

The ORR was defined as the percentage of participants in the analysis population who had a CR or PR (CR: Disappearance of all target lesions; PR: At least a 30% decrease in the sum of diameters of target lesions) per RECIST 1.1, as assessed by central radiology review. The percentage of participants in Cohort 2 with PD-L1+ tumor status who experienced a CR or PR during first course pembrolizumab treatment per protocol, is presented.

Group	Value	95% CI
Cohort 2: Pembrolizumab Combination Therapy, Treatment Naive	73.3	44.9 – 92.2

Duration of Response (DOR) For All Participants Secondary · Up to approximately 75 months

Duration of Response (DOR) was defined as the time from first documented evidence of CR or PR (CR: Disappearance of all target lesions; PR: At least a 30% decrease in the sum of diameters of target lesions) per RECIST 1.1, based on central imaging vendor assessment, until disease progression (PD) or death, whichever occurred 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. Participants who had

Group	Value	95% CI
Cohort 1: Pembrolizumab Monotherapy, Previously Treated	16.1	2.4 – NA
Cohort 2: Pembrolizumab Combination Therapy, Treatment Naive	4.6	2.6 – NA
Cohort 3: Pembrolizumab Monotherapy, Treatment Naive, PD-L1 Positive	38.0	2.1 – NA

Duration of Response For PD-L1 Positive Participants Secondary · Up to approximately 75 months

DOR was defined as the time from first documented evidence of CR or PR (CR: Disappearance of all target lesions; PR: At least a 30% decrease in the sum of diameters of target lesions) per RECIST 1.1, based on central imaging vendor assessment, until disease progression (PD) or death, whichever occurred 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. Participants who had not progressed or died

Group	Value	95% CI
Cohort 1: Pembrolizumab Monotherapy, Previously Treated	NA	NA – NA
Cohort 2: Pembrolizumab Combination Therapy, Treatment Naive	4.6	3.2 – NA
Cohort 3: Pembrolizumab Monotherapy, Treatment Naive, PD-L1 Positive	38.0	2.1 – NA

Progression-Free Survival (PFS) For All Participants Secondary · Up to approximately 75 months

Progression-Free Survival (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, taking as reference the smallest sum on study. 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. The PFS for all participants (regardless of PD-L1 tumor status) during fi

Group	Value	95% CI
Cohort 1: Pembrolizumab Monotherapy, Previously Treated	2.0	2.0 – 2.0
Cohort 2: Pembrolizumab Combination Therapy, Treatment Naive	6.6	5.9 – 10.6
Cohort 3: Pembrolizumab Monotherapy, Treatment Naive, PD-L1 Positive	2.9	2.0 – 6.0

Progression-Free Survival For PD-L1 Positive Participants Secondary · Up to approximately 75 months

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, taking as reference the smallest sum on study. 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. The PFS for only PD-L1 positive participants during first course pembrolizumab treatment per protocol

Group	Value	95% CI
Cohort 1: Pembrolizumab Monotherapy, Previously Treated	2.1	2.0 – 2.1
Cohort 2: Pembrolizumab Combination Therapy, Treatment Naive	6.5	4.7 – 7.9
Cohort 3: Pembrolizumab Monotherapy, Treatment Naive, PD-L1 Positive	2.9	2.0 – 6.0

Overall Survival (OS) For All Participants Secondary · Up to approximately 75 months

Overall Survival (OS) was defined as the time from randomization to death due to any cause. Participants without documented death at the time of the final analysis were censored at the date of the last follow-up. The OS for all participants (regardless of PD-L1 tumor status) during first course pembrolizumab treatment per protocol, is presented.

Group	Value	95% CI
Cohort 1: Pembrolizumab Monotherapy, Previously Treated	5.5	4.2 – 6.7
Cohort 2: Pembrolizumab Combination Therapy, Treatment Naive	13.8	8.6 – 25.6
Cohort 3: Pembrolizumab Monotherapy, Treatment Naive, PD-L1 Positive	20.7	10.0 – 29.8

Overall Survival For PD-L1 Positive Participants Secondary · Up to approximately 75 months

OS was defined as the time from randomization to death due to any cause. Participants without documented death at the time of the final analysis were censored at the date of the last follow-up. The OS for only PD-L1 positive participants during first course pembrolizumab treatment per protocol, is presented. Note: All participants in Cohort 3 had a PD-L1-positive tumor status.

Group	Value	95% CI
Cohort 1: Pembrolizumab Monotherapy, Previously Treated	5.8	4.4 – 7.8
Cohort 2: Pembrolizumab Combination Therapy, Treatment Naive	11.1	5.4 – 22.3
Cohort 3: Pembrolizumab Monotherapy, Treatment Naive, PD-L1 Positive	20.7	10.0 – 29.8

Adverse events — posted to ClinicalTrials.gov

Time frame: Up to approximately 75 months. Reporting threshold: 5%. Adverse-event reports describe events observed during the trial — not all are caused by the drug.

Cohort 1 First Course

Serious: 119/259 (46%)

Deaths: 244/259

Cohort 2 First Course

Serious: 11/25 (44%)

Deaths: 21/25

Cohort 3 First Course

Serious: 15/31 (48%)

Deaths: 26/31

Cohort 1 Second Course

Serious: 0/3 (0%)

Deaths: 1/3

Cohort 2 Second Course

Serious: 0/1 (0%)

Deaths: 1/1

Cohort 3 Second Course

Serious: 0/2 (0%)

Deaths: 1/2

Serious adverse events (146 terms)

Reaction	System	Cohort 1 First Course	Cohort 2 First Course	Cohort 3 First Course	Cohort 1 Second Course	Cohort 2 Second Course	Cohort 3 Second Course
Pleural effusion	Respiratory, thoracic and mediastinal disorders	—	—	—	—	—	—
Dysphagia	Gastrointestinal disorders	—	—	—	—	—	—
Anaemia	Blood and lymphatic system disorders	—	—	—	—	—	—
Intestinal obstruction	Gastrointestinal disorders	—	—	—	—	—	—
Acute kidney injury	Renal and urinary disorders	—	—	—	—	—	—
Pulmonary embolism	Respiratory, thoracic and mediastinal disorders	—	—	—	—	—	—
Nausea	Gastrointestinal disorders	—	—	—	—	—	—
Vomiting	Gastrointestinal disorders	—	—	—	—	—	—
Sepsis	Infections and infestations	—	—	—	—	—	—
Back pain	Musculoskeletal and connective tissue disorders	—	—	—	—	—	—
Abdominal pain	Gastrointestinal disorders	—	—	—	—	—	—
Stomatitis	Gastrointestinal disorders	—	—	—	—	—	—
Asthenia	General disorders	—	—	—	—	—	—
Pneumonia	Infections and infestations	—	—	—	—	—	—
Dehydration	Metabolism and nutrition disorders	—	—	—	—	—	—
Abdominal pain upper	Gastrointestinal disorders	—	—	—	—	—	—
Constipation	Gastrointestinal disorders	—	—	—	—	—	—
Diarrhoea	Gastrointestinal disorders	—	—	—	—	—	—
Gastrointestinal haemorrhage	Gastrointestinal disorders	—	—	—	—	—	—
Pyrexia	General disorders	—	—	—	—	—	—
Tumour pain	Neoplasms benign, malignant and unspecified (incl cysts and polyps)	—	—	—	—	—	—
Dyspnoea	Respiratory, thoracic and mediastinal disorders	—	—	—	—	—	—
Supraventricular tachycardia	Cardiac disorders	—	—	—	—	—	—
Ascites	Gastrointestinal disorders	—	—	—	—	—	—
Colitis	Gastrointestinal disorders	—	—	—	—	—	—

Other adverse events (88 terms — click to expand)

Reaction	System	Cohort 1 First Course	Cohort 2 First Course	Cohort 3 First Course	Cohort 1 Second Course	Cohort 2 Second Course	Cohort 3 Second Course
Fatigue	General disorders	—	—	—	—	—	—
Decreased appetite	Metabolism and nutrition disorders	—	—	—	—	—	—
Nausea	Gastrointestinal disorders	—	—	—	—	—	—
Anaemia	Blood and lymphatic system disorders	—	—	—	—	—	—
Constipation	Gastrointestinal disorders	—	—	—	—	—	—
Abdominal pain	Gastrointestinal disorders	—	—	—	—	—	—
Diarrhoea	Gastrointestinal disorders	—	—	—	—	—	—
Cough	Respiratory, thoracic and mediastinal disorders	—	—	—	—	—	—
Oedema peripheral	General disorders	—	—	—	—	—	—
Dyspnoea	Respiratory, thoracic and mediastinal disorders	—	—	—	—	—	—
Weight decreased	Investigations	—	—	—	—	—	—
Vomiting	Gastrointestinal disorders	—	—	—	—	—	—
Arthralgia	Musculoskeletal and connective tissue disorders	—	—	—	—	—	—
Back pain	Musculoskeletal and connective tissue disorders	—	—	—	—	—	—
Pruritus	Skin and subcutaneous tissue disorders	—	—	—	—	—	—
Dysphagia	Gastrointestinal disorders	—	—	—	—	—	—
Blood alkaline phosphatase increased	Investigations	—	—	—	—	—	—
Rash	Skin and subcutaneous tissue disorders	—	—	—	—	—	—
Aspartate aminotransferase increased	Investigations	—	—	—	—	—	—
Pyrexia	General disorders	—	—	—	—	—	—
Hypothyroidism	Endocrine disorders	—	—	—	—	—	—
Asthenia	General disorders	—	—	—	—	—	—
Hypoalbuminaemia	Metabolism and nutrition disorders	—	—	—	—	—	—
Hyperglycaemia	Metabolism and nutrition disorders	—	—	—	—	—	—
Hyponatraemia	Metabolism and nutrition disorders	—	—	—	—	—	—
Abdominal pain upper	Gastrointestinal disorders	—	—	—	—	—	—
Stomatitis	Gastrointestinal disorders	—	—	—	—	—	—
Dizziness	Nervous system disorders	—	—	—	—	—	—
Insomnia	Psychiatric disorders	—	—	—	—	—	—
Dry skin	Skin and subcutaneous tissue disorders	—	—	—	—	—	—
Ascites	Gastrointestinal disorders	—	—	—	—	—	—
Abdominal distension	Gastrointestinal disorders	—	—	—	—	—	—
Dehydration	Metabolism and nutrition disorders	—	—	—	—	—	—
Anxiety	Psychiatric disorders	—	—	—	—	—	—
Alanine aminotransferase increased	Investigations	—	—	—	—	—	—
Hypertension	Vascular disorders	—	—	—	—	—	—
Blood creatinine increased	Investigations	—	—	—	—	—	—
Neutrophil count decreased	Investigations	—	—	—	—	—	—
Hypokalaemia	Metabolism and nutrition disorders	—	—	—	—	—	—
Headache	Nervous system disorders	—	—	—	—	—	—

Most-reported serious reactions: Pleural effusion, Dysphagia, Anaemia, Intestinal obstruction, Acute kidney injury, Pulmonary embolism, Nausea, Vomiting.

Data from ClinicalTrials.gov NCT02335411 adverse events section.

Sponsor's own description

This is a study of pembrolizumab (MK-3475) for advanced gastric or gastroesophageal junction adenocarcinoma; pembrolizumab will be given as monotherapy to participants who have had previous treatment or who are treatment-naïve; pembrolizumab will also be evaluated as combination therapy with cisplatin and 5-Fluorouracil (5-FU) or (Japan only) capecitabine in treatment-naïve participants. The primary study hypothesis is that pembrolizumab will provide a clinically meaningful Overall Response Rate (ORR).

Publications & conference data

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

1. Safety and Efficacy of Pembrolizumab Monotherapy in Patients With Previously Treated Advanced Gastric and Gastroesophageal Junction Cancer: Phase 2 Clinical KEYNOTE-059 Trial.
   Fuchs CS, Doi T, Jang RW, Muro K, et al · · 2018 · cited 1439× · PMID 29543932 · DOI 10.1001/jamaoncol.2018.0013
2. 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
3. Application of PD-1 Blockade in Cancer Immunotherapy.
   Wu X, Gu Z, Chen Y, Chen B, et al · · 2019 · cited 383× · PMID 31205619 · DOI 10.1016/j.csbj.2019.03.006
4. 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
5. Assessment of Pembrolizumab Therapy for the Treatment of Microsatellite Instability-High Gastric or Gastroesophageal Junction Cancer Among Patients in the KEYNOTE-059, KEYNOTE-061, and KEYNOTE-062 Clinical Trials.
   Chao J, Fuchs CS, Shitara K, Tabernero J, et al · · 2021 · cited 319× · PMID 33792646 · DOI 10.1001/jamaoncol.2021.0275
6. Pembrolizumab alone or in combination with chemotherapy as first-line therapy for patients with advanced gastric or gastroesophageal junction adenocarcinoma: results from the phase II nonrandomized KEYNOTE-059 study.
   Bang YJ, Kang YK, Catenacci DV, Muro K, et al · · 2019 · cited 199× · PMID 30911859 · DOI 10.1007/s10120-018-00909-5
7. The Extrinsic and Intrinsic Roles of PD-L1 and Its Receptor PD-1: Implications for Immunotherapy Treatment.
   Hudson K, Cross N, Jordan-Mahy N, Leyland R. · · 2020 · cited 171× · PMID 33193345 · DOI 10.3389/fimmu.2020.568931
8. Phase III Trial of Avelumab Maintenance After First-Line Induction Chemotherapy Versus Continuation of Chemotherapy in Patients With Gastric Cancers: Results From JAVELIN Gastric 100.
   Moehler M, Dvorkin M, Boku N, Özgüroğlu M, et al · · 2021 · cited 168× · PMID 33197226 · DOI 10.1200/jco.20.00892