Clinical trial NCT02494583: Study of Pembrolizumab (MK-3475) as First-Line Monotherapy and Combination Therapy for Treatment of Advanced Gastric or Gastroesophageal Junction Adenocarcinoma (MK-3475-062/KEYNOTE-062)
Official title: A Randomized, Active-Controlled, Partially Blinded, Biomarker Select, Phase III Clinical Trial of Pembrolizumab as Monotherapy and in Combination With Cisplatin+5-Fluorouracil Versus Placebo+Cisplatin+5-Fluorouracil as First-Line Treatment in Subjects With Advanced Gastric or Gastroesophageal Junction (GEJ) Adenocarcinoma
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Gastric Adenocarcinoma
Keywords: Gastric carcinoma
Gastric cancer
Gastroesophageal junction cancer
Gastroesophageal junction carcinoma
Programmed Cell Death-1 (PD1, PD-1),
Programmed Death-Ligand 1 (PDL1, PD-L1)
Programmed Cell Death Receptor Ligand 2 (PDL2, PD-L2)
Lead sponsor: Merck Sharp & Dohme LLC
Sponsor class: INDUSTRY
First posted: 2015-07-10
Enrollment: 763
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: This is a study of pembrolizumab (MK-3475) as first-line treatment for participants with advanced gastric or gastroesophageal junction (GEJ) adenocarcinoma. Participants whose tumors express programmed death-ligand 1 (PD-L1) will be randomly assigned to one of the three treatment arms of the study: pembrolizumab as monotherapy \[pembro mono\], pembrolizumab plus standard of care (SOC) chemotherapy with cisplatin plus 5-fluorouracil (5-FU) or capecitabine \[pembro combo\], or placebo plus SOC chemotherapy with cisplatin plus 5-fluorouracil (5-FU) or capecitabine \[SOC\].

The primary study hypotheses are that pembrolizumab in combination with SOC chemotherapy is superior to SOC chemotherapy alone in terms of Progression-free Survival (PFS) and Overall Survival (OS) in participants with PD-L1 Combined Positive Score (CPS) ≥1, pembrolizumab in combination with SOC chemotherapy is superior to SOC chemotherapy alone in terms of OS in participants with PD-L1 CPS ≥10, pembrolizumab monotherapy is non-inferior to SOC chemotherapy alone in terms of OS in participants with PD-L1 CPS ≥1, and pembrolizumab monotherapy is superior to SOC chemotherapy alone in terms of OS in participants with PD-L1 CPS ≥1 and in participants with PD-L1 CPS ≥10.

Detailed description: As specified by the protocol, primary and secondary efficacy analyses will be evaluated in gastric cancer participants with PD-L1 CPS ≥1 (all participants) and PD-L1 CPS ≥10 (OS) by comparing the pembro mono arm or pembro combo arm separately to the SOC arm.

Eligibility criteria: Inclusion Criteria:

* Performance status of 0 or 1 on the Eastern Cooperative Oncology Group (ECOG) Performance Scale within 3 days prior to first dose of study medication
* Has histologically- or cytologically-confirmed diagnosis of locally advanced unresectable or metastatic gastric or GEJ adenocarcinoma
* Human epidermal growth factor receptor 2- (HER2/neu-) negative and programmed cell death ligand 1 (PD-L1)-positive
* Has measurable disease
* Female participants of childbearing potential must be willing to use adequate contraception or be surgically sterile, or abstain from heterosexual activity for the course of the study through 120 days after the last dose of study medication
* Male participants of childbearing potential should agree to use an adequate method of contraception starting with the first dose of study medication through 120 days after the last dose of study medication
* Adequate organ function

Exclusion Criteria:

* Squamous cell or undifferentiated gastric cancer
* Previous therapy for locally advanced, unresectable or metastatic gastric/GEJ cancer. Participant may have received prior neoadjuvant or adjuvant therapy as long as it was completed at least 6 months prior to randomization
* 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.
* Radiotherapy within 14 days of randomization
* Known additional malignancy that is progressing or requires active treatment with the exception of basal cell carcinoma of the skin, 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
* Active autoimmune disease that has required systemic treatment in past 2 years
* Diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy (in dosing exceeding 10 mg daily of prednisone equivalent) or any other form of immunosuppressive therapy within 7 days prior the first dose of study medication
* History of non-infectious pneumonitis that required steroids or current pneumonitis
* Active infection requiring systemic therapy
* Pregnant, breastfeeding, or expecting to conceive or father children within the projected duration of the trial, starting with the screening visit through 120 days after the last dose of study medication
* Prior therapy with an anti-programmed cell death (PD)-1, anti-PD-L1, or anti-PD-L2 agent
* Known history of human immunodeficiency virus (HIV)
* Known active Hepatitis B or C
* Currently participating in and receiving study therapy or has participated in a study of an investigational agent or has used an investigational device within 4 weeks prior to the first dose of study medication
* Received a live vaccine within 30 days prior to the first dose of study medication

Primary outcomes:
measure: Pembro Combo vs SOC: Progression Free Survival (PFS) Per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) by Blinded Independent Central Review (BICR) in Participants With PD-L1 CPS ≥1 (All Participants)
timeFrame: Up to approximately 36 months
measure: Pembro Combo vs SOC: Overall Survival (OS) in Participants With PD-L1 CPS ≥1 (All Participants)
timeFrame: Up to approximately 42 months
measure: Pembro Combo vs SOC: OS in Participants With PD-L1 CPS ≥10
timeFrame: Up to approximately 42 months
measure: Pembro Mono vs SOC: OS in Participants With PD-L1 CPS ≥1 (All Participants)
timeFrame: Up to approximately 42 months
measure: Pembro Mono vs SOC: OS in Participants With PD-L1 CPS ≥10
timeFrame: Up to approximately 42 months
Secondary outcomes:
measure: Pembro Combo vs SOC: Objective Response Rate (ORR) Per RECIST 1.1 by BICR in Participants With PD-L1 CPS ≥1 (All Participants)
timeFrame: Up to approximately 42 months
measure: Pembro Combo vs SOC: Duration of Response (DOR) Per RECIST 1.1 by BICR in Participants With PD-L1 CPS ≥1 (All Participants)
timeFrame: Up to approximately 42 months
measure: Pembro Mono vs SOC: ORR Per RECIST 1.1 by BICR in Participants With PD-L1 CPS ≥1 (All Participants)
timeFrame: Up to approximately 42 months
measure: Pembro Mono vs SOC: DOR Per RECIST 1.1 by BICR in Participants With PD-L1 CPS ≥1 (All Participants)
timeFrame: Up to approximately 42 months
measure: Pembro Mono vs SOC: PFS Per RECIST 1.1 by BICR in Participants With PD-L1 CPS ≥1 (All Participants)
timeFrame: Up to approximately 42 months
measure: Pembro Mono vs SOC: Change From Baseline to Week 18 in the European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire-Core 30 (QLQ-C30) Global Health Status/Quality of Life (Items 29 and 30) Combined Score
timeFrame: Baseline, Week 18
measure: Pembro Combo vs SOC: Change From Baseline to Week 18 in the EORTC QLQ-C30 Global Health Status/Quality of Life (Items 29 and 30) Combined Score
timeFrame: Baseline, Week 18
measure: Pembro Mono vs. SOC: Change From Baseline to Week 18 in EORTC QLQ-Module for Gastric Cancer (STO22) Pain Symptom Subscale Score
timeFrame: Baseline, Week 18
measure: Pembro Combo vs. SOC: Change From Baseline to Week 18 in EORTC QLQ-STO22 Pain Symptom Subscale Score
timeFrame: Baseline, Week 18
measure: Number of Participants Experiencing an Adverse Event (AE)
timeFrame: Up to approximately 33 months
measure: Number of Participants Discontinuing Study Treatment Due to an AE
timeFrame: Up to approximately 30 months
Other outcomes:
Locations:
Study officials:
affiliation: Merck Sharp & Dohme LLC
name: Medical Director
role: STUDY_DIRECTOR
References:
citation: Lee KW, Van Cutsem E, Bang YJ, Fuchs CS, Kudaba I, Garrido M, Chung HC, Lee J, Castro HR, Chao J, Wainberg ZA, Cao ZA, Aurora-Garg D, Kobie J, Cristescu R, Bhagia P, Shah S, Tabernero J, Shitara K, Wyrwicz L. Association of Tumor Mutational Burden with Efficacy of Pembrolizumab+/-Chemotherapy as First-Line Therapy for Gastric Cancer in the Phase III KEYNOTE-062 Study. Clin Cancer Res. 2022 Aug 15;28(16):3489-3498. doi: 10.1158/1078-0432.CCR-22-0121.
citation: Chao J, Fuchs CS, Shitara K, Tabernero J, Muro K, Van Cutsem E, Bang YJ, De Vita F, Landers G, Yen CJ, Chau I, Elme A, Lee J, Ozguroglu M, Catenacci D, Yoon HH, Chen E, Adelberg D, Shih CS, Shah S, Bhagia P, Wainberg ZA. 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. JAMA Oncol. 2021 Jun 1;7(6):895-902. doi: 10.1001/jamaoncol.2021.0275.
citation: Shitara K, Van Cutsem E, Bang YJ, Fuchs C, Wyrwicz L, Lee KW, Kudaba I, Garrido M, Chung HC, Lee J, Castro HR, Mansoor W, Braghiroli MI, Karaseva N, Caglevic C, Villanueva L, Goekkurt E, Satake H, Enzinger P, Alsina M, Benson A, Chao J, Ko AH, Wainberg ZA, Kher U, Shah S, Kang SP, Tabernero J. Efficacy and Safety of Pembrolizumab or Pembrolizumab Plus Chemotherapy vs Chemotherapy Alone for Patients With First-line, Advanced Gastric Cancer: The KEYNOTE-062 Phase 3 Randomized Clinical Trial. JAMA Oncol. 2020 Oct 1;6(10):1571-1580. doi: 10.1001/jamaoncol.2020.3370.