A Phase III, Randomized, Double-blind Trial Comparing Trastuzumab Plus Chemotherapy and Pembrolizumab With Trastuzumab Plus Chemotherapy and Placebo as First-line Treatment in Participants With HER2 Positive Advanced Gastric or Gastroesophageal Junction Adenocarcinoma (KEYNOTE 811)
Overview
- Phase
- Phase 3
- Intervention
- Pembrolizumab
- Conditions
- Gastric Neoplasms
- Sponsor
- Merck Sharp & Dohme LLC
- Enrollment
- 738
- Locations
- 192
- Primary Endpoint
- Overall Survival (OS)
- Status
- Completed
- Last Updated
- 4 months ago
Overview
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.
Investigators
Eligibility Criteria
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
Exclusion Criteria
- •Exclusion criteria include, but are not limited to:
- •Has had previous therapy for locally advanced unresectable or metastatic gastric/GEJ cancer
- •Has had major surgery, open biopsy or significant traumatic injury within 28 days prior to randomization, or anticipation of the need for major surgery during the course of study treatment
- •Has had radiotherapy within 14 days of randomization
- •Has a known additional malignancy that is progressing or has required active treatment within the past 5 years
- •Has known active central nervous system (CNS) metastases and/or carcinomatous meningitis
- •Has an active autoimmune disease that has required systemic treatment in past 2 years
- •Has a diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy
- •Has a history of (non-infectious) pneumonitis that required steroids or current pneumonitis
- •Has a known history of active tuberculosis (TB; Mycobacterium tuberculosis)
Arms & Interventions
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 investigator's choice of FP or CAPOX chemotherapy.
Intervention: Pembrolizumab
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 investigator's choice of FP or CAPOX chemotherapy.
Intervention: Cisplatin
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 investigator's choice of FP or CAPOX chemotherapy.
Intervention: 5-FU
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 investigator's choice of FP or CAPOX chemotherapy.
Intervention: Oxaliplatin
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 investigator's choice of FP or CAPOX chemotherapy.
Intervention: Capecitabine
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 investigator's choice of FP or CAPOX chemotherapy.
Intervention: Trastuzumab
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 investigator's choice of FP or CAPOX chemotherapy.
Intervention: Placebo
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 investigator's choice of FP or CAPOX chemotherapy.
Intervention: Cisplatin
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 investigator's choice of FP or CAPOX chemotherapy.
Intervention: 5-FU
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 investigator's choice of FP or CAPOX chemotherapy.
Intervention: Oxaliplatin
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 investigator's choice of FP or CAPOX chemotherapy.
Intervention: Capecitabine
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 investigator's choice of FP or CAPOX chemotherapy.
Intervention: Trastuzumab
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.
Intervention: Pembrolizumab
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.
Intervention: Oxaliplatin
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.
Intervention: S-1
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.
Intervention: Trastuzumab
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.
Intervention: Placebo
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.
Intervention: Oxaliplatin
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.
Intervention: S-1
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.
Intervention: Trastuzumab
Outcomes
Primary Outcomes
Overall Survival (OS)
Time Frame: 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.
Progression Free Survival (PFS) Per RECIST 1.1 Assessed by BICR
Time Frame: 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.
Secondary Outcomes
- Objective Response Rate (ORR) Per RECIST 1.1 Assessed by BICR(Up to 63 months)
- Duration of Response (DOR) Per RECIST 1.1 Assessed by BICR(Up to 63 months)
- Number of Participants Who Experienced an Adverse Event (AE)(Up to 63 months)
- Number of Participants Who Discontinued Study Treatment Due to AEs(Up to 63 months)