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

Conditions

Gastric Adenocarcinoma, Gastroesophageal Junction Adenocarcinoma

Keywords

Gastric cancer, Gastroesophageal junction cancer, Programmed Cell Death-1 (PD1, PD-1), Programmed Death-Ligand 1 (PDL1, PD-L1)

Brief summary

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).

Detailed description

This study will have 3 cohorts. In Cohort 1, participants who have received at least two prior therapies for their advanced disease will receive monotherapy with pembrolizumab. In Cohort 2, participants who have not received any previous therapy for their disease will receive pembrolizumab in combination with cisplatin and 5-FU or (Japan only) capecitabine. In Cohort 3, participants who have not received any previous therapy and who have programmed death ligand 1 (PD-L1)-positive tumors will receive pembrolizumab monotherapy.

Park DJ, Thura M, Chiu VK, Vicuna B, Ang KH, Sanchez B, Chia PL, Kuan KY, Li J, Zhang K, Zheng WH, Hsien Ng MC, Zeng Q.

2025-05-08

10.1016/j.xcrm.2025.102120

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Journal of Clinical Oncology2016-05-2017 citations

10.1200/jco.2016.34.15_suppl.4037

Pembrolizumab (MK-3475) plus 5-fluorouracil (5-FU) and cisplatin for first-line treatment of advanced gastric cancer: Preliminary safety data from KEYNOTE-059.

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Interventions

BIOLOGICALpembrolizumab

IV infusion

DRUGcisplatin

IV infusion

DRUG5-FU

IV infusion

DRUGcapecitabine

oral tablets

Study design

Allocation

NON_RANDOMIZED

Intervention model

PARALLEL

Primary purpose

TREATMENT

Masking

NONE

Eligibility

Sex/Gender

ALL

Age

18 Years to No maximum

Healthy volunteers

No

Inclusion criteria

- Cohort 1: * Received and progressed on ≥2 prior chemotherapy regimens for their advanced disease; prior regimen must have included a cisplatin and a fluoropyridine * Human epidermal growth factor receptor 2 (HER-2/neu) negative, or, if HER2/neu positive, must have previously received treatment with trastuzumab Inclusion Criteria - Cohort 2 or 3: * HER2/neu negative * Has not received prior systemic anti-cancer therapy for their advanced carcinoma (systemic therapy received in the neoadjuvant and adjuvant setting does not count) Inclusion Criteria - All Participants: * Histologically- or cytologically-confirmed recurrent or metastatic gastric or gastroesophageal junction adenocarcinoma that is considered incurable by local therapies * Willing to provide tissue for PD-L1 biomarker analysis from newly-obtained and/or archival tissue * Measurable disease based on Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST 1.1) * Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 within 3 days prior to first dose of study drug * Life expectancy of at least 3 months * Female participants of childbearing potential should have a negative pregnancy test and be willing to use 2 methods of birth control or be surgically sterile, or abstain from heterosexual activity for the course of the study through 120 days after the last dose of study drug (180 days for participants receiving cisplatin + 5FU) * Male participants should agree to use an adequate method of contraception starting with the first dose through 120 days after the last dose of study drug (180 days for participants receiving cisplatin + 5FU) * Adequate organ function

Exclusion criteria

- All Participants: * Currently participating and receiving study therapy or participated in a study of an investigational agent and received study therapy or used an investigation device within 4 weeks of the first dose of study drug * Active autoimmune disease that has required systemic treatment in past 2 years * Immunodeficiency or receiving systemic steroid therapy or any other form of immunosuppressive therapy within 7 days prior to the first dose of study drug * Weight loss \>10% over 2 months prior to first dose of study drug * Clinical evidence of ascites by physical exam * Prior anti-cancer monoclonal antibody (mAb) within 4 weeks prior to study Day 1 or not recovered from AEs due to agents administered more than 4 weeks earlier * Prior chemotherapy, targeted small molecule therapy, or radiation therapy within 2 weeks prior to study Day 1 or who has not recovered from AEs due to a previously administered agent * Known additional malignancy that is progressing or requires active treatment excepting basal cell carcinoma of the skin or squamous cell carcinoma of the skin that has undergone potentially curative therapy or in situ cervical cancer * Known active central nervous system (CNS) metastases and/or carcinomatous meningitis * Known history of, or any evidence of active, non-infectious pneumonitis * Active infection requiring systemic therapy * Psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the study * Pregnant or breastfeeding, or expecting to conceive or father children within the projected duration of the study, starting with the screening visit through 120 days after the last dose of study drug (180 days for participants receiving cisplatin + 5FU) * Prior therapy with an anti-programmed death-1 (PD-1), anti-PD-L1, or anti-PD-L2 agent * Human immunodeficiency virus (HIV) * Hepatitis B or C * Received live vaccine within 30 days of planned start of study drug

Design outcomes

Primary

Measure	Time frame	Description
Number of Participants Experiencing Adverse Events (AEs)	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.
Number of Participants Discontinuing Study Drug Due to AEs	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.
Objective Response Rate (ORR) For All Participants in Cohorts 1 and 3	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.
Objective Response Rate For PD-L1 Positive Participants in Cohorts 1 and 3	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.

Secondary

Measure	Time frame	Description
Progression-Free Survival (PFS) For All Participants	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 first course pembrolizumab treatment per protocol, is presented.
Progression-Free Survival For PD-L1 Positive Participants	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, is presented. Note: All participants in Cohort 3 had a PD-L1-positive tumor status.
Overall Survival (OS) For All Participants	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.
Objective Response Rate (ORR) For All Participants in Cohort 2	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.
Disease Control Rate (DCR) For All Participants	Up to approximately 75 months	Disease Control Rate (DCR) was defined as the percentage of participants in the analysis population who had a CR or a PR (CR: Disappearance of all target lesions; PR: At least a 30% decrease in the sum of diameters of target lesions) or stable disease (SD); (SD: neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for progressive disease) for ≥6 months, (for Cohort 1 ≥2 months) as assessed by central radiology review. The percentage of all participants (regardless of PD-L1 tumor status) who had a CR or PR or SD during first course pembrolizumab treatment per protocol, is presented.
Disease Control Rate For PD-L1 Positive Participants	Up to approximately 75 months	DCR was defined as the percentage of participants in the analysis population who had a CR or a PR (CR: Disappearance of all target lesions; PR: At least a 30% decrease in the sum of diameters of target lesions) or stable disease (SD); (SD: neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for progressive disease) for ≥6 months, (for Cohort 1 ≥2 months) as assessed by central radiology review. The percentage of participants with PD-L1+ tumor status who experienced a CR or PR or SD during first course pembrolizumab treatment per protocol, is presented. Note: All participants in Cohort 3 had a PD-L1-positive tumor status.
Overall Survival For PD-L1 Positive Participants	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.
Objective Response Rate For PD-L1 Positive Participants in Cohort 2	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.
Duration of Response (DOR) For All Participants	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 not progressed or died at the time of analysis were censored at the date of their last tumor assessment. The DOR for all participants (regardless of PD-L1 tumor status) during first course pembrolizumab treatment per protocol, is presented.
Duration of Response For PD-L1 Positive Participants	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 at the time of analysis were censored at the date of their last tumor assessment. The DOR 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.

Participant flow

Recruitment details

Male and female participants of at least 18 years of age with recurrent or metastatic gastric or gastro-esophageal junction (GEJ) adenocarcinoma were enrolled in this study.

Pre-assignment details

318 participants were originally allocated to the study. No study information was collected from 3 participants, who were excluded from all analyses, including disposition. Per protocol, response/progression or adverse events during the second pembrolizumab course were not counted towards efficacy outcome measures or safety outcome measures respectively.

Participants by arm

Arm	Count
Cohort 1: Pembrolizumab Monotherapy, Previously Treated Participants received pembrolizumab 200 mg intravenously (IV) on Day 1 of each 3-week cycle (Q3W) for up to 52 months. Eligible participants allocated to the pembrolizumab first course, who stopped pembrolizumab with stable disease (SD) or better, initiated a second course of pembrolizumab at the investigator's discretion at 200 mg of each 3 week cycle for up to 17 cycles up to approximately an additional year.	259
Cohort 2: Pembrolizumab Combination Therapy, Treatment Naive Participants received pembrolizumab 200 mg IV each 3-week cycle (Q3W) for up to 40 months + cisplatin 80 mg/m\^2 IV Q3W for up to 6 cycles + 5-Fluorouracil (5-FU) 800 mg/m\^2 IV on Days 1-5 every 3 weeks or (Japan only) capecitabine 1000 mg/m\^2 orally, twice per day (BID) on Days 1-14 of each 3-week cycle. Eligible participants allocated to the pembrolizumab first course, who stopped pembrolizumab with SD or better, initiated a second course of pembrolizumab at the investigator's discretion at 200 mg of each 3 week cycle for up to 17 cycles up to approximately an additional year.	25
Cohort 3: Pembrolizumab Monotherapy, Treatment Naive, PD-L1 Positive Programmed death-ligand 1 (PD-L1) positive participants received pembrolizumab 200 mg IV on Day 1 of each 3-week cycle (Q3W) for up to 52 months. Eligible participants allocated to the pembrolizumab first course, who stopped pembrolizumab with SD or better, initiated a second course of pembrolizumab at the investigator's discretion at 200 mg of each 3 week cycle for up to 17 cycles up to approximately an additional year.	31
Total	315

Withdrawals & dropouts

Period	Reason	FG000	FG001	FG002
Overall Study	Adverse Event	9	0	0
Overall Study	Death	223	22	26
Overall Study	Physician Decision	3	0	0
Overall Study	Protocol Violation	1	0	0
Overall Study	Sponsor Decision	12	3	2
Overall Study	Withdrawal by Subject	11	0	3

Baseline characteristics

Characteristic	Cohort 1: Pembrolizumab Monotherapy, Previously Treated	Cohort 2: Pembrolizumab Combination Therapy, Treatment Naive	Cohort 3: Pembrolizumab Monotherapy, Treatment Naive, PD-L1 Positive	Total
Age, Continuous	61.0 Years STANDARD_DEVIATION 11.4	58.8 Years STANDARD_DEVIATION 16.6	60.3 Years STANDARD_DEVIATION 11.2	60.7 Years STANDARD_DEVIATION 11.9
Ethnicity (NIH/OMB) Hispanic or Latino	17 Participants	1 Participants	3 Participants	21 Participants
Ethnicity (NIH/OMB) Not Hispanic or Latino	228 Participants	23 Participants	28 Participants	279 Participants
Ethnicity (NIH/OMB) Unknown or Not Reported	14 Participants	1 Participants	0 Participants	15 Participants
Race (NIH/OMB) American Indian or Alaska Native	0 Participants	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) Asian	41 Participants	17 Participants	15 Participants	73 Participants
Race (NIH/OMB) Black or African American	5 Participants	0 Participants	0 Participants	5 Participants
Race (NIH/OMB) More than one race	2 Participants	0 Participants	0 Participants	2 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) Unknown or Not Reported	11 Participants	0 Participants	0 Participants	11 Participants
Race (NIH/OMB) White	200 Participants	8 Participants	16 Participants	224 Participants
Sex: Female, Male Female	61 Participants	9 Participants	12 Participants	82 Participants
Sex: Female, Male Male	198 Participants	16 Participants	19 Participants	233 Participants

Adverse events

Event type	EG000 affected / at risk	EG001 affected / at risk	EG002 affected / at risk	EG003 affected / at risk	EG004 affected / at risk	EG005 affected / at risk
deaths Total, all-cause mortality	244 / 259	21 / 25	26 / 31	1 / 3	1 / 1	1 / 2
other Total, other adverse events	237 / 259	25 / 25	31 / 31	0 / 3	0 / 1	0 / 2
serious Total, serious adverse events	119 / 259	11 / 25	15 / 31	0 / 3	0 / 1	0 / 2

Outcome results

Primary

Number of Participants Discontinuing Study Drug Due to AEs

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.

Time frame: Up to approximately 52 months

Population: All enrolled participants who received ≥1 dose of study drug.

Arm	Measure	Value (COUNT_OF_PARTICIPANTS)
Cohort 1: Pembrolizumab Monotherapy, Previously Treated	Number of Participants Discontinuing Study Drug Due to AEs	18 Participants
Cohort 2: Pembrolizumab Combination Therapy, Treatment Naive	Number of Participants Discontinuing Study Drug Due to AEs	4 Participants
Cohort 3: Pembrolizumab Monotherapy, Treatment Naive, PD-L1 Positive	Number of Participants Discontinuing Study Drug Due to AEs	0 Participants

Primary

Number of Participants Experiencing Adverse Events (AEs)

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.

Time frame: Up to approximately 65 months

Population: All enrolled participants who received ≥1 dose of study drug.

Arm	Measure	Value (COUNT_OF_PARTICIPANTS)
Cohort 1: Pembrolizumab Monotherapy, Previously Treated	Number of Participants Experiencing Adverse Events (AEs)	248 Participants
Cohort 2: Pembrolizumab Combination Therapy, Treatment Naive	Number of Participants Experiencing Adverse Events (AEs)	25 Participants
Cohort 3: Pembrolizumab Monotherapy, Treatment Naive, PD-L1 Positive	Number of Participants Experiencing Adverse Events (AEs)	31 Participants

Primary

Objective Response Rate For PD-L1 Positive Participants in Cohorts 1 and 3

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.