Colorectal Carcinoma
Conditions
Keywords
Programmed Cell Death Receptor 1 (PD-1), Programmed Cell Death Receptor Ligand 1 (PD-L1, PDL1)
Brief summary
In this study, participants with stage IV Microsatellite Instability-High (MSI-H) or Mismatch Repair Deficient (dMMR) colorectal carcinoma (CRC) will be randomly assigned to receive either pembrolizumab or the Investigator's choice of 1 of 6 standard of care (SOC) chemotherapy regimens for the treatment of advanced colorectal carcinoma. The primary study hypothesis is that pembrolizumab will prolong progression-free survival (PFS) or overall survival (OS) compared to current SOC chemotherapy.
Interventions
DRUGmFOLFOX6
Regimen consists of oxaliplatin 85 mg/m\^2 IV on Day 1, leucovorin 400 mg/m\^2 or levoleucovorin 200 mg/m\^2 IV on Day 1, 5-fluorouracil (5-FU) 400 mg/m\^2 IV bolus on Day 1 and then 1200 mg/m\^2/day IV over 2 days for total dose of 2400 mg/m\^2 in each 2-week cycle
DRUGFOLFIRI
Regimen consists of irinotecan 180 mg/m\^2 IV on Day 1, leucovorin 400 mg/m\^2 or levoleucovorin 200 mg/m\^2 IV on Day 1, 5-FU 400 mg/m\^2 IV bolus on Day 1 and then 1200 mg/m\^2/day IV over 2 days for total dose of 2400 mg/m\^2 in each 2-week cycle
BIOLOGICALPembrolizumab
IV infusion
BIOLOGICALBevacizumab
IV infusion
BIOLOGICALCetuximab
IV infusion
Sponsors
Merck Sharp & Dohme LLC
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Locally confirmed dMMR or MSI-H stage IV colorectal carcinoma * Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 within 10 days prior to study start * Life expectancy of at least 3 months * Measurable disease * Female participants of childbearing potential must be willing to use adequate contraception for the course of the study starting with the first dose of study medication through 180 days after the last dose of standard of care (SOC) therapy or 120 days after the last pembrolizumab dose * Male participants must agree to use adequate contraception for the course of the study starting with the first dose of study medication through 180 days after the last dose of study medication for chemotherapy arm (no contraception requirement for pembrolizumab \[MK-3475\] arm) * Adequate organ function
Exclusion criteria
* Has received prior systemic therapy for Stage IV colorectal cancer. May have received prior adjuvant chemotherapy for colorectal cancer as long as it was completed at least 6 months prior to randomization on this study * Currently participating and receiving treatment in another study, or participated in a study of an investigational agent and received treatment, or used an investigational device within 4 weeks of randomization * Active autoimmune disease that has required systemic treatment in past 2 years * Diagnosis of immunodeficiency or receiving systemic steroid therapy or any other form of immunosuppressive therapy within 7 days prior to randomization on this study * Radiation therapy within 4 weeks prior to randomization on this study and not recovered to baseline from adverse events due to radiation therapy * Known active central nervous system (CNS) metastases and/or carcinomatous meningitis * Major surgical procedure, open biopsy or significant traumatic injury within 28 days prior to randomization on this study * Has received prior therapy with an immune checkpoint inhibitor (e.g., anti-programmed cell death \[PD\]-1, anti-PD ligand 1 \[L1\], anti-PD-L2 agent, or anti-cytotoxic T-lymphocyte-associated protein 4 \[CTLA-4\] agent, etc.) * Another malignancy that is progressing or requires active treatment with the exception of non-melanomatous skin cancer that has undergone potentially curative therapy and in situ cervical carcinoma * Received a live or a live attenuated vaccine within 30 days of planned start of study medication * Known history of Human Immunodeficiency Virus (HIV), Hepatitis B or C * Known history of, or any evidence of interstitial lung disease or active, non-infectious pneumonitis * Known history of active tuberculosis (Bacillus tuberculosis \[TB\]) * Active infection requiring systemic therapy * Known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the study * Pregnant, 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 SOC (for male and female participants) or 120 days after the last dose of pembrolizumab (for female participants only)
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Progression-Free Survival (PFS) Per RECIST1.1 As Assessed by Central Imaging Vendor | Up to approximately 59 months | PFS was defined as the time from randomization to the first documented disease progression (PD) per RECIST 1.1 based on blinded central imaging vendor review or death due to any cause, whichever occurs first. Per RECIST 1.1, PD was defined as ≥20% increase in the sum of diameters of target lesions. In addition to the relative increase of 20%, the sum had to demonstrate an absolute increase of ≥5 mm. The appearance of one or more new lesions was also considered PD. Hazards ratio (HR) and associated 95% confidence intervals (CIs) from a Cox proportional hazard model with Efron's method of tie handling and with a single treatment covariate was presented for the first course study treatment per protocol. |
| Overall Survival (OS) | Up to approximately 59 months | OS was defined as the time from randomization to death due to any cause. Participants without documented death at the time of analysis were censored at the date of last known contact. HR and associated 95% CIs from a Cox proportional hazard model with Efron's method of tie handling and with a single treatment covariate was presented for the first course study treatment per protocol. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Overall Response Rate (ORR) Per RECIST1.1 as Assessed by Central Imaging Vendor | Up to approximately 59 months | ORR was defined as the percentage of the participants who experienced a Complete Response (CR; disappearance of all target lesions) or a Partial Response (PR; at least a 30% decrease in the sum of diameters of target lesions) and was assessed using RECIST 1.1 as assessed by the central imaging vendor. The percentage of participants who experienced a CR or PR was presented for the first course of study treatment per protocol. |
| Number of Participants Who Experienced an Adverse Event (AE) | Up to approximately 59 months | An AE was defined as any untoward medical occurrence in a participant or clinical investigation participant administered a study treatment and which does not necessarily have to have a causal relationship with this treatment. An AE could be any unfavourable and unintended sign (including an abnormal laboratory finding, for example), symptom, or disease temporally associated with the use of a study treatment, whether or not considered related to the study treatment. Any worsening (i.e., any clinically significant adverse change infrequency and/or intensity) of a preexisting condition that was temporally associated with the use of study treatment, was also an AE. The number of participants who experienced at least one AE was presented for the first course study treatment per protocol. |
| Number of Participants Who Discontinued Study Treatment Due to an AE | Up to approximately 59 months | An AE was defined as any untoward medical occurrence in a participant or clinical investigation participant administered a study treatment and which does not necessarily have to have a causal relationship with this treatment. An AE could be any unfavourable and unintended sign (including an abnormal laboratory finding, for example), symptom, or disease temporally associated with the use of a study treatment, whether or not considered related to the study treatment. Any worsening (i.e., any clinically significant adverse change infrequency and/or intensity) of a preexisting condition that was temporally associated with the use of study treatment, was also an AE. The number of participants who discontinued study treatment due to an AE was presented for the first course study treatment per protocol. |
Participant flow
Pre-assignment details
Of the 307 participants randomized in the study, 296 participants received study medication and were evaluable for safety analyses.
Participants by arm
| Arm | Count |
|---|---|
| Pembrolizumab Participants received pembrolizumab 200 mg intravenously (IV) on Day 1 of each 21-day cycle (Q3W) for up to 35 treatments (approximately 2 years). Eligible participants who stopped the initial course of pembrolizumab due to complete response (CR) or completed initial course of pembrolizumab and had stable disease but progressed after discontinuation, initiated a second course of pembrolizumab at the investigator's discretion for up to 17 cycles (approximately 1 year additional). | 153 |
| Standard of Care (SOC) Participants received 1 of 6 possible standard chemotherapy regimens: mFOLFOX6, or mFOLFOX6+bevacizumab 5 mg/kg IV on Day 1 of each 2-week cycle, or mFOLFOX6+cetuximab 400 mg/m\^2 IV over 2 hours then 250 mg/m\^2 over 1 hour weekly in each 2-week cycle, or FOLFIRI, or FOLFIRI+bevacizumab 5 mg/kg IV on Day 1 of each 2-week cycle, or FOLFIRI+cetuximab 400 mg/m\^2 IV over 2 hours then 250 mg/m\^2 over 1 hour weekly in each 2-week cycle. Participants with documented disease progression following chemotherapy can crossover to receive pembrolizumab for up to 35 cycles (approximately 2 years). Eligible cross over participants who stopped pembrolizumab who stopped pembrolizumab and had stable disease but progressed after discontinuation, initiated a second course of pembrolizumab at the investigator's discretion for up to 17 cycles (approximately 1 year additional). | 154 |
| Total | 307 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Death | 72 | 87 |
| Overall Study | Lost to Follow-up | 5 | 0 |
| Overall Study | Physician Decision | 0 | 2 |
| Overall Study | Sponsor decision | 74 | 55 |
| Overall Study | Withdrawal by Subject | 2 | 10 |
Baseline characteristics
| Characteristic | Standard of Care (SOC) | Total | Pembrolizumab |
|---|---|---|---|
| Age, Continuous | 60.6 Years STANDARD_DEVIATION 14.8 | 61.2 Years STANDARD_DEVIATION 14.8 | 61.9 Years STANDARD_DEVIATION 14.9 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 10 Participants | 21 Participants | 11 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 131 Participants | 259 Participants | 128 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 13 Participants | 27 Participants | 14 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 26 Participants | 50 Participants | 24 Participants |
| Race (NIH/OMB) Black or African American | 5 Participants | 14 Participants | 9 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 7 Participants | 14 Participants | 7 Participants |
| Race (NIH/OMB) White | 116 Participants | 229 Participants | 113 Participants |
| Sex: Female, Male Female | 72 Participants | 154 Participants | 82 Participants |
| Sex: Female, Male Male | 82 Participants | 153 Participants | 71 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 | 68 / 153 | 58 / 154 | 30 / 57 | 4 / 12 | 2 / 5 |
| other Total, other adverse events | 145 / 153 | 142 / 143 | 53 / 57 | 11 / 12 | 4 / 5 |
| serious Total, serious adverse events | 62 / 153 | 76 / 143 | 27 / 57 | 3 / 12 | 1 / 5 |
Outcome results
Primary
Overall Survival (OS)
OS was defined as the time from randomization to death due to any cause. Participants without documented death at the time of analysis were censored at the date of last known contact. HR and associated 95% CIs from a Cox proportional hazard model with Efron's method of tie handling and with a single treatment covariate was presented for the first course study treatment per protocol.
Time frame: Up to approximately 59 months
Population: All randomized participants
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Pembrolizumab | Overall Survival (OS) | NA Months |
| Standard of Care (SOC) | Overall Survival (OS) | 36.7 Months |
p-value: 0.035995% CI: [0.53, 1.03]Log Rank
Primary
Progression-Free Survival (PFS) Per RECIST1.1 As Assessed by Central Imaging Vendor
PFS was defined as the time from randomization to the first documented disease progression (PD) per RECIST 1.1 based on blinded central imaging vendor review or death due to any cause, whichever occurs first. Per RECIST 1.1, PD was defined as ≥20% increase in the sum of diameters of target lesions. In addition to the relative increase of 20%, the sum had to demonstrate an absolute increase of ≥5 mm. The appearance of one or more new lesions was also considered PD. Hazards ratio (HR) and associated 95% confidence intervals (CIs) from a Cox proportional hazard model with Efron's method of tie handling and with a single treatment covariate was presented for the first course study treatment per protocol.
Time frame: Up to approximately 59 months
Population: All randomized participants
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Pembrolizumab | Progression-Free Survival (PFS) Per RECIST1.1 As Assessed by Central Imaging Vendor | 16.5 Months |
| Standard of Care (SOC) | Progression-Free Survival (PFS) Per RECIST1.1 As Assessed by Central Imaging Vendor | 8.2 Months |
p-value: 0.000195% CI: [0.45, 0.79]Log Rank
Secondary
Number of Participants Who Discontinued Study Treatment Due to an AE
An AE was defined as any untoward medical occurrence in a participant or clinical investigation participant administered a study treatment and which does not necessarily have to have a causal relationship with this treatment. An AE could be any unfavourable and unintended sign (including an abnormal laboratory finding, for example), symptom, or disease temporally associated with the use of a study treatment, whether or not considered related to the study treatment. Any worsening (i.e., any clinically significant adverse change infrequency and/or intensity) of a preexisting condition that was temporally associated with the use of study treatment, was also an AE. The number of participants who discontinued study treatment due to an AE was presented for the first course study treatment per protocol.
Time frame: Up to approximately 59 months
Population: All participants who received at least 1 dose of study treatment
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Pembrolizumab | Number of Participants Who Discontinued Study Treatment Due to an AE | 21 Participants |
| Standard of Care (SOC) | Number of Participants Who Discontinued Study Treatment Due to an AE | 20 Participants |
Secondary
Number of Participants Who Experienced an Adverse Event (AE)
An AE was defined as any untoward medical occurrence in a participant or clinical investigation participant administered a study treatment and which does not necessarily have to have a causal relationship with this treatment. An AE could be any unfavourable and unintended sign (including an abnormal laboratory finding, for example), symptom, or disease temporally associated with the use of a study treatment, whether or not considered related to the study treatment. Any worsening (i.e., any clinically significant adverse change infrequency and/or intensity) of a preexisting condition that was temporally associated with the use of study treatment, was also an AE. The number of participants who experienced at least one AE was presented for the first course study treatment per protocol.
Time frame: Up to approximately 59 months
Population: All participants who received at least 1 dose of study treatment
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Pembrolizumab | Number of Participants Who Experienced an Adverse Event (AE) | 149 Participants |
| Standard of Care (SOC) | Number of Participants Who Experienced an Adverse Event (AE) | 142 Participants |
Secondary
Overall Response Rate (ORR) Per RECIST1.1 as Assessed by Central Imaging Vendor
ORR was defined as the percentage of the participants who experienced a Complete Response (CR; disappearance of all target lesions) or a Partial Response (PR; at least a 30% decrease in the sum of diameters of target lesions) and was assessed using RECIST 1.1 as assessed by the central imaging vendor. The percentage of participants who experienced a CR or PR was presented for the first course of study treatment per protocol.
Time frame: Up to approximately 59 months
Population: All randomized participants
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Pembrolizumab | Overall Response Rate (ORR) Per RECIST1.1 as Assessed by Central Imaging Vendor | 45.1 Percentage of Participants |
| Standard of Care (SOC) | Overall Response Rate (ORR) Per RECIST1.1 as Assessed by Central Imaging Vendor | 33.1 Percentage of Participants |
p-value: 0.015995% CI: [1, 22.6]Miettinen & Nurminen method