Gastric Neoplasms, Gastroesophageal Junction Adenocarcinoma
Conditions
Keywords
programmed cell death receptor 1 (PD-1), programmed cell death ligand 1 (PD-L1), anti-PD-1, anti PD-1, GEJ, Gastric Cancer
Brief summary
The study will compare the efficacy and safety of pembrolizumab plus trastuzumab in combination with standard of care (SOC) chemotherapy versus trastuzumab in combination with SOC chemotherapy in participants with HER2-positive gastric cancer. The primary hypotheses of the study are that pembrolizumab plus trastuzumab in combination with chemotherapy is superior to trastuzumab plus chemotherapy in terms of 1) progression free survival (PFS) per Response Evaluation Criteria in Solid Tumors 1.1 (RECIST 1.1) as assessed by blinded independent central review (BICR), and 2) overall survival (OS).
Detailed description
Pembrolizumab (200 mg) or placebo will be administered intravenously \[IV\] on day 1 of each 3-week cycle. Trastuzumab (8 mg/kg loading dose, 6 mg/kg maintenance dose) will be administered IV on day 1 of each 3-week cycle. SOC chemotherapy for the global cohort will either be FP (80 mg/m\^2 cisplatin administered IV on Day 1 of each 3-week cycle and 800 mg/m\^2 5-fluorouracil \[5-FU\] administered IV on Days 1-5 of each 3-week cycle) or CAPOX (1000 mg/m\^2 capecitabine administered orally twice daily \[BID\] on days 1-14 of each 3-week cycle and 130 mg/m\^2 oxaliplatin administered IV on Day 1 of each 3-week cycle). A Japan cohort will receive SOX chemotherapy consisting of S-1 (tegafur, 5-chloro-2,4-dihydroxypyridine \[CDHP\], and potassium oxonate \[Oxo\]) administered orally BID according to Body Surface Area (BSA) on Days 1-14 of each 3-week cycle and oxaliplatin (130 mg/m\^2) administered IV on Day 1 each 3-week cycle.
Interventions
BIOLOGICALPembrolizumab
200 mg on Day 1 of each 3-week cycle as an IV infusion.
BIOLOGICALPlacebo
Solution for IV infusion on Day 1 of each 3-week cycle.
DRUGCisplatin
80 mg/m\^2 on Day 1 of each 3-week cycle as an IV infusion, administered as part of FP chemotherapy regimen.
DRUG5-FU
800 mg/m\^2/day continuous on Days 1-5 of each 3-week cycle (120 hours or per local standard), administered as part of FP chemotherapy regimen.
DRUGOxaliplatin
130 mg/m\^2 on Day 1 of each 3-week cycle over 2 hours as an IV infusion, administered as part of CAPOX chemotherapy regimen and as part of SOX chemotherapy regimen.
DRUGCapecitabine
1000 mg/m\^2 as oral capsules BID on Days 1-14 of each 3-week cycle, administered as part of CAPOX chemotherapy regimen.
DRUGS-1
Combination product of tegafur, CDHP, and Oxo. Oral capsules BID on Days 1-14 of each 3-week cycle based on body surface area (BSA): \<1.25 m\^2 BSA =40 mg, 1.25 to \<1.5 m\^2 BSA=50 mg, ≥1.5 m\^2 BSA=60 mg. Administered as part of SOX chemotherapy regimen.
BIOLOGICALTrastuzumab
8 mg/kg loading dose and then 6 mg/kg maintenance dose administered IV on day 1 of each 3-week cycle.
Sponsors
Merck Sharp & Dohme LLC
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
Inclusion criteria include, but are not limited to: * Histologically or cytologically confirmed diagnosis of previously untreated, locally advanced unresectable or metastatic human epidermal growth factor receptor 2 (HER2) positive gastric or gastroesophageal junction (GEJ) adenocarcinoma * HER2-positive defined as either immunohistochemistry (IHC) 3+ or IHC 2+ in combination with in-situ hybridization positive (ISH+) or fluorescent in-situ hybridization (FISH), as assessed by central review on primary or metastatic tumor * Has measurable disease as defined by Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST 1.1) as determined by the site investigator * Male participants must agree to use approved contraception * Female participants who are not pregnant or breastfeeding, and who are either not a woman of childbearing potential (WOCBP), or are a WOCBP who agrees to use approved contraception * Has a performance status of 0 or 1 on the Eastern Cooperative Oncology Group (ECOG) Performance Scale within 3 days prior to the first dose of trial treatment * Has a life expectancy of greater than 6 months * Has adequate organ function
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Progression Free Survival (PFS) Per RECIST 1.1 Assessed by BICR | Up to 46 months | PFS is defined as the time from randomization to the first documented disease progression per RECIST 1.1 as assessed by BICR or death due to any cause, whichever occurs first. Per RECIST 1.1, progressive disease (PD) is 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 is also considered progression. PFS was determined for first course pembrolizumab in the Global Cohort. Per statistical analysis plan, participants in the Japan-specific SOX Cohort were not included in the efficacy analysis. |
| Overall Survival (OS) | Up to 63 months | OS is defined as the time from randomization to death due to any cause. OS was determined for first course pembrolizumab in the Global Cohort. Per statistical analysis plan, participants in the Japan-specific SOX Cohort were not included in the efficacy analysis. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Objective Response Rate (ORR) Per RECIST 1.1 Assessed by BICR | Up to 63 months | ORR is defined as the percentage of participants who have a Complete Response (\[CR\], disappearance of all evidence of disease) or Partial Response (\[PR\], regression of measurable disease and no new sites) per RECIST 1.1 as assessed by blinded independent central review (BICR). ORR was determined for first course pembrolizumab in the Global Cohort. Per statistical analysis plan, participants in the Japan-specific SOX Cohort were not included in the efficacy analysis. |
| Duration of Response (DOR) Per RECIST 1.1 Assessed by BICR | Up to 63 months | For participants who demonstrate CR or PR, DOR is defined as the time from first response (CR or PR) to subsequent disease progression or death from any cause, whichever occurs first. DOR was determined for first course pembrolizumab in the Global Cohort. Per statistical analysis plan, participants in the Japan-specific SOX Cohort were not included in the efficacy analysis. |
| Number of Participants Who Experienced an Adverse Event (AE) | Up to 63 months | An AE is any untoward medical occurrence in a participant that is temporally associated with the use of study treatment, whether or not considered related to the study treatment. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the use of a study treatment. The number of participants who experienced an AE is reported for each treatment arm. Per statistical analysis plan, data from the second course of pembrolizumab was not included in the safety analysis. |
| Number of Participants Who Discontinued Study Treatment Due to AEs | Up to 63 months | An AE is any untoward medical occurrence in a participant that is temporally associated with the use of study treatment, whether or not considered related to the study treatment. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the use of a study treatment. The number of participants who discontinued study treatment due to an AE is reported for each treatment arm. Per statistical analysis plan, data from the second course of pembrolizumab was not included in the safety analysis. |
Countries
Australia, Brazil, Chile, China, France, Germany, Guatemala, Ireland, Israel, Italy, Japan, New Zealand, Poland, Russia, South Korea, Spain, Turkey (Türkiye), Ukraine, United Kingdom, United States
Contacts
STUDY_DIRECTORMedical Director
Merck Sharp & Dohme LLC
Participant flow
Pre-assignment details
Per protocol, response or progression for participants in the Japan-specific SOX (S-1 plus oxaliplatin) Cohort and for participants in the second course of pembrolizumab were not counted towards efficacy analysis, and adverse events for participants during the second course of pembrolizumab were not counted towards safety analysis.
Participants by arm
| Arm | Count |
|---|---|
| Global Pembrolizumab + Standard of Care First Course Participants received 200 mg pembrolizumab IV every 3 weeks (Q3W) plus trastuzumab (8 mg/kg loading dose, 6 mg/kg maintenance thereafter) IV Q3W in combination with FP or CAPOX chemotherapy. Eligible participants from the Global Cohort Pembrolizumab + Standard of Care who stopped initial course of pembrolizumab due to complete response (CR) or who had stable disease (SD), PR, or CR after completion of 35 cycles of pembrolizumab but progressed after discontinuation, initiated a second course of pembrolizumab at the investigator's discretion. Participants received 200 mg pembrolizumab IV every 3 weeks (Q3W) for up to 17 additional cycles (approximately 1 year additional treatment). | 350 |
| Global Standard of Care Participants received matched placebo to pembrolizumab IV Q3W plus trastuzumab (8mg/kg loading dose, 6mg/kg maintenance thereafter) IV Q3W in combination with FP or CAPOX chemotherapy. | 348 |
| Japan Pembrolizumab + Trastuzumab + S-1 Plus Oxaliplatin Participants received 200 mg pembrolizumab IV every 3 weeks (Q3W) plus trastuzumab (8 mg/kg loading dose, 6 mg/kg maintenance thereafter) IV Q3W in combination with SOX chemotherapy. | 20 |
| Japan Trastuzumab + S-1 Plus Oxaliplatin Participants received matched placebo to pembrolizumab IV Q3W plus trastuzumab (8mg/kg loading dose, 6mg/kg maintenance thereafter) IV Q3W in combination with SOX chemotherapy. | 20 |
| Total | 738 |
Baseline characteristics
| Characteristic | Global Pembrolizumab + Standard of Care First Course | Global Standard of Care | Japan Trastuzumab + S-1 Plus Oxaliplatin | Total | Japan Pembrolizumab + Trastuzumab + S-1 Plus Oxaliplatin |
|---|---|---|---|---|---|
| Age, Continuous | 60.4 Years STANDARD_DEVIATION 11.8 | 61.7 Years STANDARD_DEVIATION 10.8 | 64.1 Years STANDARD_DEVIATION 6.8 | 61.2 Years STANDARD_DEVIATION 11.3 | 66.1 Years STANDARD_DEVIATION 12.8 |
| Chemotherapy Regimen CAPOX (capecitabine and oxaliplatin) | 297 Participants | 299 Participants | 0 Participants | 596 Participants | 0 Participants |
| Chemotherapy Regimen FP (cisplatin plus 5 fluorouracil) | 53 Participants | 49 Participants | 0 Participants | 102 Participants | 0 Participants |
| Chemotherapy Regimen SOX (S-1 plus oxaliplatin) | 0 Participants | 0 Participants | 20 Participants | 40 Participants | 20 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 38 Participants | 45 Participants | 1 Participants | 85 Participants | 1 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 309 Participants | 293 Participants | 19 Participants | 640 Participants | 19 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 3 Participants | 10 Participants | 0 Participants | 13 Participants | 0 Participants |
| Geographic Region Asia | 118 Participants | 119 Participants | 0 Participants | 237 Participants | 0 Participants |
| Geographic Region Japan | 0 Participants | 0 Participants | 20 Participants | 40 Participants | 20 Participants |
| Geographic Region Rest of the World | 119 Participants | 118 Participants | 0 Participants | 237 Participants | 0 Participants |
| Geographic Region Western Europe/Israel/North America/Australia | 113 Participants | 111 Participants | 0 Participants | 224 Participants | 0 Participants |
| Programmed Cell Death Ligand 1 (PD-L1) Combined Positive Score (CPS) Status at Baseline CPS<1 | 52 Participants | 52 Participants | 3 Participants | 111 Participants | 4 Participants |
| Programmed Cell Death Ligand 1 (PD-L1) Combined Positive Score (CPS) Status at Baseline CPS≥1 | 298 Participants | 296 Participants | 17 Participants | 627 Participants | 16 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 5 Participants | 6 Participants | 0 Participants | 11 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 119 Participants | 121 Participants | 20 Participants | 280 Participants | 20 Participants |
| Race (NIH/OMB) Black or African American | 2 Participants | 2 Participants | 0 Participants | 4 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 6 Participants | 5 Participants | 0 Participants | 11 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 2 Participants | 0 Participants | 2 Participants | 0 Participants |
| Race (NIH/OMB) White | 218 Participants | 212 Participants | 0 Participants | 430 Participants | 0 Participants |
| Sex: Female, Male Female | 66 Participants | 68 Participants | 5 Participants | 142 Participants | 3 Participants |
| Sex: Female, Male Male | 284 Participants | 280 Participants | 15 Participants | 596 Participants | 17 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 |
|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 264 / 350 | 288 / 348 | 14 / 20 | 17 / 20 | 3 / 11 |
| other Total, other adverse events | 345 / 350 | 338 / 346 | 20 / 20 | 20 / 20 | 9 / 11 |
| serious Total, serious adverse events | 163 / 350 | 159 / 346 | 10 / 20 | 9 / 20 | 0 / 11 |
Outcome results
Primary
Overall Survival (OS)
OS is defined as the time from randomization to death due to any cause. OS was determined for first course pembrolizumab in the Global Cohort. Per statistical analysis plan, participants in the Japan-specific SOX Cohort were not included in the efficacy analysis.
Time frame: Up to 63 months
Population: All randomized Global Cohort participants in the Pembrolizumab First Course arm and SOC arm were included in this analysis. Per statistical analysis plan, participants in the Japan-specific SOX Cohort were not included in the efficacy analysis.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Global Pembrolizumab + Standard of Care First Course | Overall Survival (OS) | 20.0 Months |
| Global Standard of Care | Overall Survival (OS) | 16.8 Months |
Comparison: OS in all participants of the Global Pembrolizumab + SOC First Course was compared to PFS in all participants of the Global Standard of Care to address the hypothesis (pembrolizumab in combination with trastuzumab plus chemotherapy is superior to trastuzumab plus chemotherapy alone).p-value: 0.00495% CI: [0.67, 0.94]Log Rank
Primary
Progression Free Survival (PFS) Per RECIST 1.1 Assessed by BICR
PFS is defined as the time from randomization to the first documented disease progression per RECIST 1.1 as assessed by BICR or death due to any cause, whichever occurs first. Per RECIST 1.1, progressive disease (PD) is 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 is also considered progression. PFS was determined for first course pembrolizumab in the Global Cohort. Per statistical analysis plan, participants in the Japan-specific SOX Cohort were not included in the efficacy analysis.
Time frame: Up to 46 months
Population: All randomized Global Cohort participants in the Pembrolizumab First Course arm and SOC arm were included in this analysis. Per statistical analysis plan, participants in the Japan-specific SOX Cohort were not included in the efficacy analysis.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Global Pembrolizumab + Standard of Care First Course | Progression Free Survival (PFS) Per RECIST 1.1 Assessed by BICR | 10.0 Months |
| Global Standard of Care | Progression Free Survival (PFS) Per RECIST 1.1 Assessed by BICR | 8.1 Months |
Comparison: PFS in all participants of the Global Pembrolizumab + SOC First Course was compared to PFS in all participants of the Global Standard of Care to address the hypothesis (pembrolizumab in combination with trastuzumab plus chemotherapy is superior to trastuzumab plus chemotherapy alone).p-value: 0.000295% CI: [0.61, 0.87]Log Rank
Secondary
Duration of Response (DOR) Per RECIST 1.1 Assessed by BICR
For participants who demonstrate CR or PR, DOR is defined as the time from first response (CR or PR) to subsequent disease progression or death from any cause, whichever occurs first. DOR was determined for first course pembrolizumab in the Global Cohort. Per statistical analysis plan, participants in the Japan-specific SOX Cohort were not included in the efficacy analysis.
Time frame: Up to 63 months
Population: All randomized Global Cohort participants in the Pembrolizumab First Course arm and SOC arm and who had CR or PR per RECIST 1.1 as assessed by BICR were included in this analysis. Per statistical analysis plan, participants in the Japan-specific SOX Cohort were not included in the efficacy analysis.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Global Pembrolizumab + Standard of Care First Course | Duration of Response (DOR) Per RECIST 1.1 Assessed by BICR | 11.13 Months |
| Global Standard of Care | Duration of Response (DOR) Per RECIST 1.1 Assessed by BICR | 9.5 Months |
Secondary
Number of Participants Who Discontinued Study Treatment Due to AEs
An AE is any untoward medical occurrence in a participant that is temporally associated with the use of study treatment, whether or not considered related to the study treatment. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the use of a study treatment. The number of participants who discontinued study treatment due to an AE is reported for each treatment arm. Per statistical analysis plan, data from the second course of pembrolizumab was not included in the safety analysis.
Time frame: Up to 63 months
Population: All randomized participants in the Global Cohort Pembrolizumab and SOC arms who received at least 1 dose of treatment, and all participants in the Japan-specific SOX Cohort who received at least 1 dose of treatment were included in this analysis. Per statistical analysis plan, data from the second course of pembrolizumab was not included in the safety analysis.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Global Pembrolizumab + Standard of Care First Course | Number of Participants Who Discontinued Study Treatment Due to AEs | 150 Participants |
| Global Standard of Care | Number of Participants Who Discontinued Study Treatment Due to AEs | 136 Participants |
| Japan Pembrolizumab + Trastuzumab + S-1 Plus Oxaliplatin | Number of Participants Who Discontinued Study Treatment Due to AEs | 11 Participants |
| Japan Trastuzumab + S-1 Plus Oxaliplatin | Number of Participants Who Discontinued Study Treatment Due to AEs | 11 Participants |
Secondary
Number of Participants Who Experienced an Adverse Event (AE)
An AE is any untoward medical occurrence in a participant that is temporally associated with the use of study treatment, whether or not considered related to the study treatment. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the use of a study treatment. The number of participants who experienced an AE is reported for each treatment arm. Per statistical analysis plan, data from the second course of pembrolizumab was not included in the safety analysis.
Time frame: Up to 63 months
Population: All randomized participants in the Global Cohort Pembrolizumab and SOC arms who received at least 1 dose of treatment, and all participants in the Japan-specific SOX Cohort who received at least 1 dose of treatment were included in this analysis. Per statistical analysis plan, data from the second course of pembrolizumab was not included in the safety analysis.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Global Pembrolizumab + Standard of Care First Course | Number of Participants Who Experienced an Adverse Event (AE) | 348 Participants |
| Global Standard of Care | Number of Participants Who Experienced an Adverse Event (AE) | 346 Participants |
| Japan Pembrolizumab + Trastuzumab + S-1 Plus Oxaliplatin | Number of Participants Who Experienced an Adverse Event (AE) | 20 Participants |
| Japan Trastuzumab + S-1 Plus Oxaliplatin | Number of Participants Who Experienced an Adverse Event (AE) | 20 Participants |
Secondary
Objective Response Rate (ORR) Per RECIST 1.1 Assessed by BICR
ORR is defined as the percentage of participants who have a Complete Response (\[CR\], disappearance of all evidence of disease) or Partial Response (\[PR\], regression of measurable disease and no new sites) per RECIST 1.1 as assessed by blinded independent central review (BICR). ORR was determined for first course pembrolizumab in the Global Cohort. Per statistical analysis plan, participants in the Japan-specific SOX Cohort were not included in the efficacy analysis.
Time frame: Up to 63 months
Population: All randomized Global Cohort participants in the Pembrolizumab First Course arm and SOC arm were included in this analysis. Per statistical analysis plan, participants in the Japan-specific SOX Cohort were not included in the efficacy analysis.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Global Pembrolizumab + Standard of Care First Course | Objective Response Rate (ORR) Per RECIST 1.1 Assessed by BICR | 72.6 Percentage of Participants |
| Global Standard of Care | Objective Response Rate (ORR) Per RECIST 1.1 Assessed by BICR | 60.1 Percentage of Participants |
Comparison: ORR in all participants of the Global Pembrolizumab + SOC First Course was compared to PFS in all participants of the Global Standard of Care to address the hypothesis (pembrolizumab in combination with trastuzumab plus chemotherapy is superior to trastuzumab plus chemotherapy alone).p-value: 0.000295% CI: [5.6, 19.4]Stratified Miettinen and Nurminen Method