Stomach Neoplasms
Conditions
Keywords
programmed cell death 1 (PD-1, PD1), programmed cell death ligand 1 (PD-L1, PDL1), programmed cell death ligand 2 (PD-L2, PDL2)
Brief summary
The purpose of this study is to evaluate the efficacy of pembrolizumab (MK-3745) in combination with chemotherapy (Cisplatin combined with 5-Fluorouracil \[FP regimen\] or oxaliplatin combined with capecitabine \[CAPOX regimen\]) versus placebo in combination with chemotherapy (FP or CAPOX regimens) in the treatment of human epidermal growth factor receptor 2 (HER2) negative advanced gastric or GEJ adenocarcinoma in adult participants. The primary hypotheses of this study are that pembrolizumab plus chemotherapy is superior to placebo plus chemotherapy in terms of overall survival (OS). Once a participant has achieved the study objective or the study has ended, the participant will be discontinued from this study and enrolled in an extension study (Keynote 587; NCT03486873) to continue protocol-defined assessments and treatment.
Interventions
BIOLOGICALPembrolizumab
Administered as an IV infusion on Day 1 Q3W
DRUGCisplatin
Administered as an IV infusion on Day 1 Q3W
DRUG5-fluorouracil
Administered as a continuous IV infusion on Days 1-5 Q3W
DRUGoxaliplatin
Administered as an IV infusion on Day 1 Q3W
DRUGcapecitabine
Administered orally BID on Days 1 to 14 Q3W
Administered as an IV infusion on Day 1 Q3W
Sponsors
Merck Sharp & Dohme LLC
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Has histologically or cytologically confirmed diagnosis of locally advanced unresectable or metastatic gastric or gastroesophageal junction (GEJ) adenocarcinoma with known programmed cell death ligand 1 (PD-L1) expression status * Has human epidermal growth factor receptor 2 (HER2) negative cancer * Male participants must agree to use contraception during the treatment period and through 95 days after the last dose of chemotherapy, refrain from donating sperm, and be abstinent from heterosexual intercourse, as their preferred and usual lifestyle, and agree to remain abstinent or must agree to use contraception per study protocol unless confirmed to be azoospermic during this period * Female participants who are not pregnant, not breastfeeding, and at least one of the following conditions applies: not a woman of childbearing potential (WOCBP) OR is a WOCBP who agrees to use contraception or be abstinent from heterosexual intercourse, as their preferred and usual lifestyle, during the treatment period and through 180 days after the last dose of chemotherapy or through 120 days after the last dose of pembrolizumab, whichever is last, and agrees not to donate eggs to others or freeze/store for her own use for the purpose of reproduction during this period * Has measurable disease per Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST 1.1) as assessed by investigator assessment * Has provided archival tumor tissue sample or newly obtained core or excisional biopsy of a tumor lesion not previously irradiated * Has provided tumor tissue sample deemed adequate for PD-L1 biomarker analysis * Has provided tumor tissue sample for microsatellite instability (MSI) biomarker analysis * Has an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 within 3 days prior to the start of study intervention * Has adequate organ function as demonstrated by laboratory testing within 10 days prior to the start of study treatment
Exclusion criteria
* Has squamous cell or undifferentiated gastric cancer * Has had major surgery, open biopsy, or significant traumatic injury within 28 days prior to randomization, anticipation of the need for major surgery during the course of study intervention, or has not recovered adequately from the toxicity and/or complications from previous surgery * Has preexisting peripheral neuropathy \>Grade 1 * Is a WOCBP who has a positive urine pregnancy test within 24 hours for urine or within 72 hours for serum prior to randomization or treatment allocation * Has had previous therapy for locally advanced, unresectable or metastatic gastric/GEJ cancer. Participants may have received prior neoadjuvant and/or adjuvant therapy as long as it was completed ≥6 months prior to randomization * Has received prior therapy with an anti-programmed cell death (PD)-1, anti-PD-L1 or anti-programmed cell death ligand 2 (PD-L2) agent or with an agent directed to another stimulatory or co-inhibitory T-cell receptor (e.g., cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), OX- 40, CD137) * Has received prior systemic anticancer therapy including investigational agents within 4 weeks prior to randomization or has not recovered from all adverse events (AEs) due to any previous therapies to ≤Grade 1 or baseline * Has received prior radiotherapy within 2 weeks prior to study start or has not recovered from all previous radiation-related toxicities, required corticosteroids, and have not had radiation pneumonitis. A 1-week washout is permitted for palliative radiation (≤2 weeks of radiotherapy) to non-central nervous system (CNS) disease * Has received a live or live-attenuated vaccine within 30 days prior to the first dose of study treatment * Is currently participating in 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 treatment * Has a diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy or any other form of immunosuppressive therapy within 7 days prior to the first dose of study treatment * Has a known additional malignancy that is progressing or has required active treatment within the past 5 years with the exception of basal cell carcinoma of the skin, squamous cell carcinoma of the skin, or carcinoma in situ (eg, breast carcinoma, cervical cancer in situ) that have undergone potentially curative therapy * Has known active CNS metastases and/or carcinomatous meningitis * Has severe hypersensitivity (≥Grade 3) to pembrolizumab and/or any of its excipients * Has an active autoimmune disease that has required systemic treatment in past 2 years * Has a history of (non-infectious) pneumonitis that required steroids or has current pneumonitis * Has an active infection requiring systemic therapy * Has a known history of human immunodeficiency virus (HIV) infection * Has a known history of Hepatitis B (defined as Hepatitis B surface antigen \[HBsAg\] reactive) or known active Hepatitis C virus (defined as Hepatitis C virus \[HCV\] ribonucleic acid \[RNA\] detected qualitatively) infection * Has a known history of active tuberculosis * Has hypokalemia (serum potassium less than the lower limit of normal) * Has hypomagnesemia (serum magnesium less than the lower limit of normal) * Has hypocalcemia (serum calcium less than the lower limit of normal) * Has a history or current evidence of any condition (eg, known deficiency of the enzyme dihydropyrimidine dehydrogenase), therapy, or laboratory abnormality that might confound the results of the study, interfere with the participant's participation for the full duration of the study, or is not in the best interest of the participant to participate, in the opinion of the treating investigator * Has a known psychiatric or substance abuse disorder that would interfere with the participant's ability to cooperate with the requirements of the study * Is pregnant or breastfeeding or expecting to conceive or father children within the projected duration of the study, starting with the screening visit through 180 days after the last dose of chemotherapy or through 120 days after the last dose of pembrolizumab, whichever is last * Has had an allogenic tissue/solid organ transplant * Has a known severe hypersensitivity (≥ Grade 3) to any of the study chemotherapy agents (including, but not limited to, infusional 5-fluorouracil or oral capecitabine) and/or to any of their excipients * For participants taking cisplatin: has Grade ≥2 audiometric hearing loss
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Overall Survival (OS) in All Participants | Up to 45.9 months | OS was defined as the time from randomization to death due to any cause. Participants without documented death at the time of the analysis were censored at the date of the last follow-up. OS was estimated using the product-limit (Kaplan-Meier) method for censored data. |
| Overall Survival (OS) In Participants With Programmed Cell Death Ligand 1 (PD-L1) Combined Positive Score (CPS) ≥1 | Up to 45.9 months | OS was defined as the time from randomization to death due to any cause. Participants without documented death at the time of the analysis were censored at the date of the last follow-up. OS was estimated using the product-limit (Kaplan-Meier) method for censored data. |
| Overall Survival (OS) In Participants With Programmed Cell Death Ligand 1 (PD-L1) Combined Positive Score (CPS) ≥10 | Up to 45.9 months | OS was defined as the time from randomization to death due to any cause. Participants without documented death at the time of the analysis were censored at the date of the last follow-up. OS was estimated using the product-limit (Kaplan-Meier) method for censored data. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Progression Free Survival (PFS) Per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) Assessed by Blinded Independent Central Review (BICR) in All Participants | Up to 49.5 months | PFS was defined as the time from randomization to the first documented progressive disease (PD) or death due to any cause, whichever occurred first. Per RECIST 1.1 as assessed by BICR, PD was defined as ≥20% increase in the sum of diameters of target lesions. In addition to the relative increase of 20%, the sum must also have demonstrated an absolute increase of ≥5 mm. The appearance of ≥1 new lesions was also considered PD. PFS was estimated using the product-limit (Kaplan-Meier) method for censored data. |
| Progression Free Survival (PFS) Per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) Assessed by Blinded Independent Central Review (BICR) in Participants With Programmed Cell Death Ligand 1 (PD-L1) Combined Positive Score (CPS) ≥1 | Up to 49.5 months | PFS was defined as the time from randomization to the first documented progressive disease (PD) or death due to any cause, whichever occurred first. Per RECIST 1.1 as assessed by BICR, PD was defined as ≥20% increase in the sum of diameters of target lesions. In addition to the relative increase of 20%, the sum must also have demonstrated an absolute increase of ≥5 mm. The appearance of ≥1 new lesions was also considered PD. PFS was estimated using the product-limit (Kaplan-Meier) method for censored data. |
| Progression Free Survival (PFS) Per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) Assessed by Blinded Independent Central Review (BICR) in Participants With Programmed Cell Death Ligand 1 (PD-L1) Combined Positive Score (CPS) ≥10 | Up to 49.5 months | PFS was defined as the time from randomization to the first documented progressive disease (PD) or death due to any cause, whichever occurred first. Per RECIST 1.1 as assessed by BICR, PD was defined as ≥20% increase in the sum of diameters of target lesions. In addition to the relative increase of 20%, the sum must also have demonstrated an absolute increase of ≥5 mm. The appearance of ≥1 new lesions was also considered PD. PFS was estimated using the product-limit (Kaplan-Meier) method for censored data. |
| Objective Response Rate (ORR) Per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) Assessed by Blinded Independent Central Review (BICR) in All Participants | Up to 49.5 months | ORR was defined as the percentage of the participants who had a confirmed Complete Response (CR: disappearance of all target lesions) or Partial Response (PR: ≥30% decrease in the sum of diameters (SOD) of target lesions, taking as reference the baseline SOD) according to RECIST 1.1 as assessed by BICR. |
| Objective Response Rate (ORR) Per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) Assessed by Blinded Independent Central Review (BICR) in Participants With Programmed Cell Death Ligand 1 (PD-L1) Combined Positive Score (CPS) ≥1 | Up to 49.5 months | ORR was defined as the percentage of the participants who had a confirmed Complete Response (CR: disappearance of all target lesions) or Partial Response (PR: ≥30% decrease in the sum of diameters (SOD) of target lesions, taking as reference the baseline SOD) according to RECIST 1.1 as assessed by BICR. |
| Objective Response Rate (ORR) Per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) Assessed by Blinded Independent Central Review (BICR) in Participants With Programmed Cell Death Ligand 1 (PD-L1) Combined Positive Score (CPS) ≥10 | Up to 49.5 months | ORR was defined as the percentage of the participants who had a confirmed Complete Response (CR: disappearance of all target lesions) or Partial Response (PR: ≥30% decrease in the sum of diameters (SOD) of target lesions, taking as reference the baseline SOD) according to RECIST 1.1 as assessed by BICR. |
| Duration of Response (DOR) Per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) Assessed by Blinded Independent Central Review (BICR) in All Participants | Up to 49.5 months | DOR was defined as the time from first documented evidence of a confirmed Complete Response (CR) or Partial Response (PR) until progressive disease (PD) or death, whichever occurred first. Per RECIST 1.1 as assessed by BICR, CR was the disappearance of all target lesions and PR was ≥30% decrease in the sum of diameters (SOD) of target lesions, taking as reference the baseline SOD. PD was defined as ≥20% increase in the SOD of target lesions according to RECIST 1.1. In addition to the relative increase of 20%, the SOD must also have demonstrated an absolute increase of ≥5 mm. The appearance of ≥1 new lesions was also considered PD. DOR for participants who had not progressed or died at the time of analysis was censored at the date of the last tumor assessment. DOR was estimated using the product-limit (Kaplan-Meier) method for censored data. |
| Duration of Response (DOR) Per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) Assessed by Blinded Independent Central Review (BICR) in Participants With Programmed Cell Death Ligand 1 (PD-L1) Combined Positive Score (CPS) ≥1 | Up to 49.5 months | DOR was defined as the time from first documented evidence of a confirmed Complete Response (CR) or Partial Response (PR) until progressive disease (PD) or death, whichever occurred first. Per RECIST 1.1 as assessed by BICR, CR was the disappearance of all target lesions and PR was ≥30% decrease in the sum of diameters (SOD) of target lesions, taking as reference the baseline SOD. PD was defined as ≥20% increase in the SOD of target lesions according to RECIST 1.1. In addition to the relative increase of 20%, the SOD must also have demonstrated an absolute increase of ≥5 mm. The appearance of ≥1 new lesions was also considered PD. DOR for participants who had not progressed or died at the time of analysis was censored at the date of the last tumor assessment. DOR was estimated using the product-limit (Kaplan-Meier) method for censored data. |
| Duration of Response (DOR) Per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) Assessed by Blinded Independent Central Review (BICR) in Participants With Programmed Cell Death Ligand 1 (PD-L1) Combined Positive Score (CPS) ≥10 | Up to 49.5 months | DOR was defined as the time from first documented evidence of a confirmed Complete Response (CR) or Partial Response (PR) until progressive disease (PD) or death, whichever occurred first. Per RECIST 1.1 as assessed by BICR, CR was the disappearance of all target lesions and PR was ≥30% decrease in the sum of diameters (SOD) of target lesions, taking as reference the baseline SOD. PD was defined as ≥20% increase in the SOD of target lesions according to RECIST 1.1. In addition to the relative increase of 20%, the SOD must also have demonstrated an absolute increase of ≥5 mm. The appearance of ≥1 new lesions was also considered PD. DOR for participants who had not progressed or died at the time of analysis was censored at the date of the last tumor assessment. DOR was estimated using the product-limit (Kaplan-Meier) method for censored data. |
| Number of Participants Who Experienced an Adverse Event (AE) | Up to approximately 49.3 months | An AE was defined as any untoward medical occurrence, in a clinical study participant, temporally associated with the use of study intervention, whether or not considered related to the study intervention. An AE could therefore have been any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the use of a study intervention. The number of participants with at least one AE is presented. |
| Number of Participants Who Discontinued Study Treatment Due To an Adverse Event (AE) | Up to approximately 46.3 months | An AE was defined as any untoward medical occurrence in a clinical study participant, temporally associated with the use of study intervention, whether or not considered related to the study intervention. An AE could therefore have been any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the use of a study intervention. The number of participants who discontinued study treatment due to an AE is presented. |
Countries
Argentina, Australia, Brazil, Canada, Chile, China, Colombia, Costa Rica, Czechia, Denmark, France, Germany, Guatemala, Hong Kong, Hungary, Ireland, Israel, Italy, Japan, Mexico, New Zealand, Peru, Poland, Russia, South Africa, South Korea, Spain, Switzerland, Taiwan, Turkey (Türkiye), Ukraine, United Kingdom, United States
Contacts
STUDY_DIRECTORMedical Director
Merck Sharp & Dohme LLC
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Pembrolizumab + Chemotherapy (FP or CAPOX Regimen) Participants received pembrolizumab 200 mg intravenously (IV) on Day 1 of each 21-day cycle (Q3W) for up to 35 cycles (approximately 2 years) + physicians' choice of either cisplatin 80 mg/m\^2 IV on Day 1 Q3W and 5-fluorouracil (5FU) 800 mg/m\^2/day via continuous IV infusion on Days 1 to 5 Q3W (FP regimen) OR oxaliplatin 130 mg/m\^2 IV on Day 1 Q3W + capecitabine 1000 mg/m\^2 orally twice a day (BID) on Days 1 to 14 Q3W (CAPOX regimen).
Participants who completed up to 35 administrations of pembrolizumab (approximately 2 years) or achieved a complete response (CR) but experienced progression of disease (PD), could have initiated a second course of pembrolizumab for up to 17 cycles (approximately 1 additional year). | 790 |
| Placebo + Chemotherapy (FP or CAPOX Regimen) Participants received placebo on Day 1 Q3W for up to 35 cycles (approximately 2 years) + physicians' choice of either cisplatin 80 mg/m\^2 IV on Day 1 Q3W and 5FU 800 mg/m\^2/day via continuous IV infusion on Days 1 to 5 Q3W (FP regimen) OR oxaliplatin 130 mg/m\^2 IV on Day 1 Q3W + capecitabine 1000 mg/m\^2 orally BID on Days 1 to 14 Q3W (CAPOX regimen). | 789 |
| Total | 1,579 |
Baseline characteristics
| Characteristic | Pembrolizumab + Chemotherapy (FP or CAPOX Regimen) | Placebo + Chemotherapy (FP or CAPOX Regimen) | Total |
|---|---|---|---|
| Age, Continuous | 59.3 Years STANDARD_DEVIATION 11.9 | 60.0 Years STANDARD_DEVIATION 11.8 | 59.6 Years STANDARD_DEVIATION 11.8 |
| Chemotherapy Regimen CAPOX Regimen | 682 Participants | 681 Participants | 1363 Participants |
| Chemotherapy Regimen FP Regimen | 108 Participants | 108 Participants | 216 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 175 Participants | 157 Participants | 332 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 590 Participants | 615 Participants | 1205 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 25 Participants | 17 Participants | 42 Participants |
| Geographic Region Asia | 263 Participants | 262 Participants | 525 Participants |
| Geographic Region Rest of World | 326 Participants | 325 Participants | 651 Participants |
| Geographic Region Western Europe/Israel/North America/Australia | 201 Participants | 202 Participants | 403 Participants |
| Programmed Cell Death Ligand 1 (PD-L1) Combined Positive Score (CPS) ≥10 Status CPS <10 | 508 Participants | 516 Participants | 1024 Participants |
| Programmed Cell Death Ligand 1 (PD-L1) Combined Positive Score (CPS) ≥10 Status CPS ≥10 | 280 Participants | 273 Participants | 553 Participants |
| Programmed Cell Death Ligand 1 (PD-L1) Combined Positive Score (CPS) ≥10 Status Unknown | 2 Participants | 0 Participants | 2 Participants |
| Programmed Cell Death Ligand 1 (PD-L1) Combined Positive Score (CPS) <1 and CPS ≥1 Status CPS <1 | 172 Participants | 172 Participants | 344 Participants |
| Programmed Cell Death Ligand 1 (PD-L1) Combined Positive Score (CPS) <1 and CPS ≥1 Status CPS ≥1 | 618 Participants | 617 Participants | 1235 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 31 Participants | 36 Participants | 67 Participants |
| Race (NIH/OMB) Asian | 270 Participants | 269 Participants | 539 Participants |
| Race (NIH/OMB) Black or African American | 12 Participants | 9 Participants | 21 Participants |
| Race (NIH/OMB) More than one race | 43 Participants | 30 Participants | 73 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 1 Participants | 2 Participants | 3 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 7 Participants | 8 Participants | 15 Participants |
| Race (NIH/OMB) White | 426 Participants | 435 Participants | 861 Participants |
| Sex: Female, Male Female | 263 Participants | 245 Participants | 508 Participants |
| Sex: Female, Male Male | 527 Participants | 544 Participants | 1071 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 689 / 790 | 733 / 789 | 8 / 12 |
| other Total, other adverse events | 755 / 785 | 751 / 787 | 10 / 12 |
| serious Total, serious adverse events | 358 / 785 | 317 / 787 | 1 / 12 |
Outcome results
Primary
Overall Survival (OS) in All Participants
OS was defined as the time from randomization to death due to any cause. Participants without documented death at the time of the analysis were censored at the date of the last follow-up. OS was estimated using the product-limit (Kaplan-Meier) method for censored data.
Time frame: Up to 45.9 months
Population: The analysis population included all randomized participants.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Pembrolizumab + Chemotherapy (FP or CAPOX Regimen) | Overall Survival (OS) in All Participants | 12.9 Months |
| Placebo + Chemotherapy (FP or CAPOX Regimen) | Overall Survival (OS) in All Participants | 11.5 Months |
p-value: <0.000195% CI: [0.7, 0.87]Log Rank
Primary
Overall Survival (OS) In Participants With Programmed Cell Death Ligand 1 (PD-L1) Combined Positive Score (CPS) ≥1
OS was defined as the time from randomization to death due to any cause. Participants without documented death at the time of the analysis were censored at the date of the last follow-up. OS was estimated using the product-limit (Kaplan-Meier) method for censored data.
Time frame: Up to 45.9 months
Population: The analysis population included randomized participants with a PD-L1 CPS of ≥1.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Pembrolizumab + Chemotherapy (FP or CAPOX Regimen) | Overall Survival (OS) In Participants With Programmed Cell Death Ligand 1 (PD-L1) Combined Positive Score (CPS) ≥1 | 13.0 Months |
| Placebo + Chemotherapy (FP or CAPOX Regimen) | Overall Survival (OS) In Participants With Programmed Cell Death Ligand 1 (PD-L1) Combined Positive Score (CPS) ≥1 | 11.4 Months |
p-value: <0.000195% CI: [0.65, 0.84]Log Rank
Primary
Overall Survival (OS) In Participants With Programmed Cell Death Ligand 1 (PD-L1) Combined Positive Score (CPS) ≥10
OS was defined as the time from randomization to death due to any cause. Participants without documented death at the time of the analysis were censored at the date of the last follow-up. OS was estimated using the product-limit (Kaplan-Meier) method for censored data.
Time frame: Up to 45.9 months
Population: The analysis population included randomized participants with a PD-L1 CPS of ≥10.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Pembrolizumab + Chemotherapy (FP or CAPOX Regimen) | Overall Survival (OS) In Participants With Programmed Cell Death Ligand 1 (PD-L1) Combined Positive Score (CPS) ≥10 | 15.7 Months |
| Placebo + Chemotherapy (FP or CAPOX Regimen) | Overall Survival (OS) In Participants With Programmed Cell Death Ligand 1 (PD-L1) Combined Positive Score (CPS) ≥10 | 11.8 Months |
p-value: <0.000195% CI: [0.53, 0.79]Log Rank
Secondary
Duration of Response (DOR) Per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) Assessed by Blinded Independent Central Review (BICR) in All Participants
DOR was defined as the time from first documented evidence of a confirmed Complete Response (CR) or Partial Response (PR) until progressive disease (PD) or death, whichever occurred first. Per RECIST 1.1 as assessed by BICR, CR was the disappearance of all target lesions and PR was ≥30% decrease in the sum of diameters (SOD) of target lesions, taking as reference the baseline SOD. PD was defined as ≥20% increase in the SOD of target lesions according to RECIST 1.1. In addition to the relative increase of 20%, the SOD must also have demonstrated an absolute increase of ≥5 mm. The appearance of ≥1 new lesions was also considered PD. DOR for participants who had not progressed or died at the time of analysis was censored at the date of the last tumor assessment. DOR was estimated using the product-limit (Kaplan-Meier) method for censored data.
Time frame: Up to 49.5 months
Population: The analysis population included all randomized participants who experienced a confirmed CR or PR.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Pembrolizumab + Chemotherapy (FP or CAPOX Regimen) | Duration of Response (DOR) Per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) Assessed by Blinded Independent Central Review (BICR) in All Participants | 8.0 Months |
| Placebo + Chemotherapy (FP or CAPOX Regimen) | Duration of Response (DOR) Per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) Assessed by Blinded Independent Central Review (BICR) in All Participants | 5.7 Months |
Secondary
Duration of Response (DOR) Per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) Assessed by Blinded Independent Central Review (BICR) in Participants With Programmed Cell Death Ligand 1 (PD-L1) Combined Positive Score (CPS) ≥1
DOR was defined as the time from first documented evidence of a confirmed Complete Response (CR) or Partial Response (PR) until progressive disease (PD) or death, whichever occurred first. Per RECIST 1.1 as assessed by BICR, CR was the disappearance of all target lesions and PR was ≥30% decrease in the sum of diameters (SOD) of target lesions, taking as reference the baseline SOD. PD was defined as ≥20% increase in the SOD of target lesions according to RECIST 1.1. In addition to the relative increase of 20%, the SOD must also have demonstrated an absolute increase of ≥5 mm. The appearance of ≥1 new lesions was also considered PD. DOR for participants who had not progressed or died at the time of analysis was censored at the date of the last tumor assessment. DOR was estimated using the product-limit (Kaplan-Meier) method for censored data.
Time frame: Up to 49.5 months
Population: The analysis population included randomized participants, with a PD-L1 CPS ≥1, who experienced a confirmed CR or PR.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Pembrolizumab + Chemotherapy (FP or CAPOX Regimen) | Duration of Response (DOR) Per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) Assessed by Blinded Independent Central Review (BICR) in Participants With Programmed Cell Death Ligand 1 (PD-L1) Combined Positive Score (CPS) ≥1 | 8.3 Months |
| Placebo + Chemotherapy (FP or CAPOX Regimen) | Duration of Response (DOR) Per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) Assessed by Blinded Independent Central Review (BICR) in Participants With Programmed Cell Death Ligand 1 (PD-L1) Combined Positive Score (CPS) ≥1 | 5.6 Months |
Secondary
Duration of Response (DOR) Per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) Assessed by Blinded Independent Central Review (BICR) in Participants With Programmed Cell Death Ligand 1 (PD-L1) Combined Positive Score (CPS) ≥10
DOR was defined as the time from first documented evidence of a confirmed Complete Response (CR) or Partial Response (PR) until progressive disease (PD) or death, whichever occurred first. Per RECIST 1.1 as assessed by BICR, CR was the disappearance of all target lesions and PR was ≥30% decrease in the sum of diameters (SOD) of target lesions, taking as reference the baseline SOD. PD was defined as ≥20% increase in the SOD of target lesions according to RECIST 1.1. In addition to the relative increase of 20%, the SOD must also have demonstrated an absolute increase of ≥5 mm. The appearance of ≥1 new lesions was also considered PD. DOR for participants who had not progressed or died at the time of analysis was censored at the date of the last tumor assessment. DOR was estimated using the product-limit (Kaplan-Meier) method for censored data.
Time frame: Up to 49.5 months
Population: The analysis population included randomized participants, with a PD-L1 CPS ≥10, who experienced a confirmed CR or PR.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Pembrolizumab + Chemotherapy (FP or CAPOX Regimen) | Duration of Response (DOR) Per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) Assessed by Blinded Independent Central Review (BICR) in Participants With Programmed Cell Death Ligand 1 (PD-L1) Combined Positive Score (CPS) ≥10 | 10.9 Months |
| Placebo + Chemotherapy (FP or CAPOX Regimen) | Duration of Response (DOR) Per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) Assessed by Blinded Independent Central Review (BICR) in Participants With Programmed Cell Death Ligand 1 (PD-L1) Combined Positive Score (CPS) ≥10 | 5.8 Months |
Secondary
Number of Participants Who Discontinued Study Treatment Due To an Adverse Event (AE)
An AE was defined as any untoward medical occurrence in a clinical study participant, temporally associated with the use of study intervention, whether or not considered related to the study intervention. An AE could therefore have been any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the use of a study intervention. The number of participants who discontinued study treatment due to an AE is presented.
Time frame: Up to 33.7 months
Population: The analysis population included all participants who received at least one dose of study treatment.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Pembrolizumab + Chemotherapy (FP or CAPOX Regimen) | Number of Participants Who Discontinued Study Treatment Due To an Adverse Event (AE) | 257 Participants |
| Placebo + Chemotherapy (FP or CAPOX Regimen) | Number of Participants Who Discontinued Study Treatment Due To an Adverse Event (AE) | 204 Participants |
Secondary
Number of Participants Who Experienced an Adverse Event (AE)
An AE was defined as any untoward medical occurrence, in a clinical study participant, temporally associated with the use of study intervention, whether or not considered related to the study intervention. An AE could therefore have been any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the use of a study intervention. The number of participants with at least one AE is presented.
Time frame: Up to 36.7 months
Population: The analysis population included all participants who received at least one dose of study treatment.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Pembrolizumab + Chemotherapy (FP or CAPOX Regimen) | Number of Participants Who Experienced an Adverse Event (AE) | 776 Participants |
| Placebo + Chemotherapy (FP or CAPOX Regimen) | Number of Participants Who Experienced an Adverse Event (AE) | 771 Participants |
Secondary
Objective Response Rate (ORR) Per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) Assessed by Blinded Independent Central Review (BICR) in All Participants
ORR was defined as the percentage of the participants who had a confirmed Complete Response (CR: disappearance of all target lesions) or Partial Response (PR: ≥30% decrease in the sum of diameters (SOD) of target lesions, taking as reference the baseline SOD) according to RECIST 1.1 as assessed by BICR.
Time frame: Up to 49.5 months
Population: The analysis population included all randomized participants.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Pembrolizumab + Chemotherapy (FP or CAPOX Regimen) | Objective Response Rate (ORR) Per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) Assessed by Blinded Independent Central Review (BICR) in All Participants | 51.3 Percentage of Participants |
| Placebo + Chemotherapy (FP or CAPOX Regimen) | Objective Response Rate (ORR) Per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) Assessed by Blinded Independent Central Review (BICR) in All Participants | 42.0 Percentage of Participants |
p-value: 0.0000995% CI: [4.4, 14.1]Miettinen & Nurminen method
Secondary
Objective Response Rate (ORR) Per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) Assessed by Blinded Independent Central Review (BICR) in Participants With Programmed Cell Death Ligand 1 (PD-L1) Combined Positive Score (CPS) ≥1
ORR was defined as the percentage of the participants who had a confirmed Complete Response (CR: disappearance of all target lesions) or Partial Response (PR: ≥30% decrease in the sum of diameters (SOD) of target lesions, taking as reference the baseline SOD) according to RECIST 1.1 as assessed by BICR.
Time frame: Up to 49.5 months
Population: The analysis population included randomized participants with a PD-L1 CPS ≥1.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Pembrolizumab + Chemotherapy (FP or CAPOX Regimen) | Objective Response Rate (ORR) Per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) Assessed by Blinded Independent Central Review (BICR) in Participants With Programmed Cell Death Ligand 1 (PD-L1) Combined Positive Score (CPS) ≥1 | 52.1 Percentage of Participants |
| Placebo + Chemotherapy (FP or CAPOX Regimen) | Objective Response Rate (ORR) Per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) Assessed by Blinded Independent Central Review (BICR) in Participants With Programmed Cell Death Ligand 1 (PD-L1) Combined Positive Score (CPS) ≥1 | 42.6 Percentage of Participants |
p-value: 0.0004195% CI: [3.9, 15]Miettinen & Nurminen method
Secondary
Objective Response Rate (ORR) Per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) Assessed by Blinded Independent Central Review (BICR) in Participants With Programmed Cell Death Ligand 1 (PD-L1) Combined Positive Score (CPS) ≥10
ORR was defined as the percentage of the participants who had a confirmed Complete Response (CR: disappearance of all target lesions) or Partial Response (PR: ≥30% decrease in the sum of diameters (SOD) of target lesions, taking as reference the baseline SOD) according to RECIST 1.1 as assessed by BICR.
Time frame: Up to 49.5 months
Population: The analysis population included randomized participants with a PD-L1 CPS ≥10.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Pembrolizumab + Chemotherapy (FP or CAPOX Regimen) | Objective Response Rate (ORR) Per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) Assessed by Blinded Independent Central Review (BICR) in Participants With Programmed Cell Death Ligand 1 (PD-L1) Combined Positive Score (CPS) ≥10 | 60.6 Percentage of Participants |
| Placebo + Chemotherapy (FP or CAPOX Regimen) | Objective Response Rate (ORR) Per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) Assessed by Blinded Independent Central Review (BICR) in Participants With Programmed Cell Death Ligand 1 (PD-L1) Combined Positive Score (CPS) ≥10 | 43.0 Percentage of Participants |
p-value: 0.0000295% CI: [9.3, 25.5]Miettinen & Nurminen method
Secondary
Progression Free Survival (PFS) Per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) Assessed by Blinded Independent Central Review (BICR) in All Participants
PFS was defined as the time from randomization to the first documented progressive disease (PD) or death due to any cause, whichever occurred first. Per RECIST 1.1 as assessed by BICR, PD was defined as ≥20% increase in the sum of diameters of target lesions. In addition to the relative increase of 20%, the sum must also have demonstrated an absolute increase of ≥5 mm. The appearance of ≥1 new lesions was also considered PD. PFS was estimated using the product-limit (Kaplan-Meier) method for censored data.
Time frame: Up to 49.5 months
Population: The analysis population included all randomized participants.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Pembrolizumab + Chemotherapy (FP or CAPOX Regimen) | Progression Free Survival (PFS) Per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) Assessed by Blinded Independent Central Review (BICR) in All Participants | 6.9 Months |
| Placebo + Chemotherapy (FP or CAPOX Regimen) | Progression Free Survival (PFS) Per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) Assessed by Blinded Independent Central Review (BICR) in All Participants | 5.6 Months |
p-value: <0.000195% CI: [0.67, 0.85]Log Rank
Secondary
Progression Free Survival (PFS) Per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) Assessed by Blinded Independent Central Review (BICR) in Participants With Programmed Cell Death Ligand 1 (PD-L1) Combined Positive Score (CPS) ≥1
PFS was defined as the time from randomization to the first documented progressive disease (PD) or death due to any cause, whichever occurred first. Per RECIST 1.1 as assessed by BICR, PD was defined as ≥20% increase in the sum of diameters of target lesions. In addition to the relative increase of 20%, the sum must also have demonstrated an absolute increase of ≥5 mm. The appearance of ≥1 new lesions was also considered PD. PFS was estimated using the product-limit (Kaplan-Meier) method for censored data.
Time frame: Up to 49.5 months
Population: The analysis population included randomized participants with a PD-L1 CPS ≥1.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Pembrolizumab + Chemotherapy (FP or CAPOX Regimen) | Progression Free Survival (PFS) Per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) Assessed by Blinded Independent Central Review (BICR) in Participants With Programmed Cell Death Ligand 1 (PD-L1) Combined Positive Score (CPS) ≥1 | 6.9 Months |
| Placebo + Chemotherapy (FP or CAPOX Regimen) | Progression Free Survival (PFS) Per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) Assessed by Blinded Independent Central Review (BICR) in Participants With Programmed Cell Death Ligand 1 (PD-L1) Combined Positive Score (CPS) ≥1 | 5.6 Months |
p-value: <0.000195% CI: [0.63, 0.82]Log Rank
Secondary
Progression Free Survival (PFS) Per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) Assessed by Blinded Independent Central Review (BICR) in Participants With Programmed Cell Death Ligand 1 (PD-L1) Combined Positive Score (CPS) ≥10
PFS was defined as the time from randomization to the first documented progressive disease (PD) or death due to any cause, whichever occurred first. Per RECIST 1.1 as assessed by BICR, PD was defined as ≥20% increase in the sum of diameters of target lesions. In addition to the relative increase of 20%, the sum must also have demonstrated an absolute increase of ≥5 mm. The appearance of ≥1 new lesions was also considered PD. PFS was estimated using the product-limit (Kaplan-Meier) method for censored data.
Time frame: Up to 49.5 months
Population: The analysis population included randomized participants with a PD-L1 CPS ≥10.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Pembrolizumab + Chemotherapy (FP or CAPOX Regimen) | Progression Free Survival (PFS) Per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) Assessed by Blinded Independent Central Review (BICR) in Participants With Programmed Cell Death Ligand 1 (PD-L1) Combined Positive Score (CPS) ≥10 | 8.1 Months |
| Placebo + Chemotherapy (FP or CAPOX Regimen) | Progression Free Survival (PFS) Per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) Assessed by Blinded Independent Central Review (BICR) in Participants With Programmed Cell Death Ligand 1 (PD-L1) Combined Positive Score (CPS) ≥10 | 5.6 Months |
p-value: <0.000195% CI: [0.51, 0.76]Log Rank