Colorectal Cancer
Conditions
Keywords
Programmed Cell Death-1 (PD1, PD-1),, Programmed Cell Death Receptor Ligand 1 (PDL1, PD-L1), Programmed Cell Death Receptor Ligand 2 (PDL2, PD-L2)
Brief summary
The purpose of this China extension study is to assess the safety and efficacy of coformulated favezelimab/pembrolizumab (MK-4280A) in adult Chinese participants with metastatic colorectal cancer. The study will also compare MK-4280A with the standard of care treatment of regorafenib and TAS-102 (trifluridine and tipiracil). The primary study hypothesis is that coformulated favezelimab/pembrolizumab (MK-4280A) is superior to standard of care with respect to overall survival.
Detailed description
The China extension study will include participants previously enrolled in China in the global study for MK-4280A-007 (NCT05064059) plus those enrolled during the China extension enrollment period. A total of approximately 94 Chinese participants will be enrolled. As of Amendment 3 of the supplemental statistical analysis plan, patient reported outcomes will no longer be secondary outcome measures of the study.
Interventions
BIOLOGICALfavezelimab/pembrolizumab
Coformulated favezelimab/pembrolizumab (800 mg/200 mg), IV infusion
DRUGregorafenib
Oral
DRUGTAS-102
Oral
Sponsors
Merck Sharp & Dohme LLC
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Masking description
None (Open-label)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Has a histologically confirmed colorectal adenocarcinoma that is metastatic and unresectable. * Has measurable disease per RECIST 1.1 as assessed by the local site investigator. * Has been previously treated for the disease and radiographically progressed on or after or could not tolerate standard treatment. * Submits an archival (≤ 5 years) or newly obtained tumor tissue sample or newly obtained tumor tissue sample that has not been previously irradiated. * Has an Eastern Cooperative Oncology Group Performance Score (ECOG PS) of 0 to 1 within 10 days prior to first dose of study intervention. * Has a life expectancy of at least 3 months, based on the investigator assessment. * Has the ability to swallow and retain oral medication and not have any clinically significant gastrointestinal abnormalities that might alter absorption. * Has adequate organ function.
Exclusion criteria
* Has previously been found to have deficient mismatch repair/microsatellite instability-high (dMMR/MSI-H) tumor status. * Has known active central nervous system (CNS) metastases and/or carcinomatous meningitis or leptomeningeal disease. * Has a history of acute or chronic pancreatitis. * Has neuromuscular disorders associated with an elevated creatine kinase (eg, inflammatory myopathies, muscular dystrophy, amyotrophic lateral sclerosis, spinal muscular atrophy) * Has clinically significant cardiovascular disease within 12 months from first dose of study intervention, including New York Heart Association Class III or IV congestive heart failure, unstable angina, myocardial infarction, cerebral vascular accident, or cardiac arrhythmia associated with hemodynamic instability. * Has urine protein greater than or equal to 1g/24h. * A woman of childbearing potential who has a positive urine/serum pregnancy test within 24/72 hours prior to the first dose of study intervention. * Has received prior therapy with an anti-programmed cell death 1 (PD-1), anti-programmed death ligand 1 (PD-L1), or anti-programmed cell death ligand 2 (PD-L2), anti-lymphocyte activation gene 3 (LAG-3) antibody, with a tyrosine kinase inhibitor (TKI; eg, lenvatinib) other than rapidly accelerated fibrosarcoma (RAF) inhibitors (binimetinib is permitted if combined with a RAF inhibitor), or with an agent directed to another stimulatory or coinhibitory T-cell receptor (eg, cytotoxic T-lymphocyte-associated protein 4, OX-40, cluster of differentiation \[CD\] 137). * Has previously received regorafenib or TAS-102. * Has received prior systemic anticancer therapy including investigational agents within 28 days before randomization. * Has received prior radiotherapy within 2 weeks of start of study intervention. Participants must have recovered from all radiation-related toxicities, not require corticosteroids, and not have had radiation pneumonitis. A 1-week washout is permitted for palliative radiation (≤2 weeks of radiotherapy) to non-CNS disease. * Has received a live or live-attenuated vaccine within 30 days before the first dose of study intervention. * Has a known additional malignancy that is progressing or has required active treatment within the past 3 years. * 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 (noninfectious) pneumonitis/interstitial lung disease that required steroids or has current pneumonitis/interstitial lung disease. * Has an active infection requiring systemic therapy (eg, tuberculosis, known viral or bacterial infections, etc.). * Has a known history of human immunodeficiency virus (HIV) infection. * Has known history of Hepatitis B or known active Hepatitis C virus infection. * Has a history or current evidence of any condition, 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 had an allogenic tissue/solid organ transplant.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Overall Survival (OS) | Up to approximately 26 months | OS was defined as the time from randomization to death due to any cause. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Progression-Free Survival (PFS) According Per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) as Assessed by Blinded Independent Central Review (BICR) | Up to approximately 26 months | PFS was defined as the time from randomization to the first documented disease progression per RECIST 1.1 by BICR or death due to any cause, whichever occurred 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 must also have demonstrated an absolute increase of ≥5 mm. The appearance of one or more new lesions was also considered PD. |
| Objective Response Rate (ORR) Per RECIST 1.1 as Assessed by BICR | Up to approximately 26 months | ORR was defined as the percentage of participants who achieved a confirmed complete response (CR: Disappearance of all target lesions) or partial response (PR: At least a 30% decrease in the sum of diameters of target lesion) per RECIST 1.1 as assessed by BICR |
| Duration of Response (DOR) Per RECIST 1.1 as Assessed by BICR | Up to approximately 26 months | For participants who demonstrate confirmed CR (disappearance of all target lesions) or PR (At least a 30% decrease in the sum of diameters of target lesions), duration of response was defined as the time from the first documented evidence of CR or PR until progressive disease (PD) or death due to any cause. DOR for participants who had not progressed or died at the time of analysis was to be censored at the date of their last tumor assessment. Per RECIST 1.1, PD was defined as at least a 20% increase in the sum of diameters of target lesions as well as an absolute increase of at least a 5 mm in the sum of diameters. The appearance of one or more new lesions was also considered PD. DOR assessments were based on blinded central imaging review with confirmation. |
| Number of Participants Who Experienced at Least One Adverse Event (AE) | Up to approximately 20 months | An AE was 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. |
| Number of Participants Who Discontinued Study Treatment Due to an AE | Up to approximately 17 months | An AE was 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. The number of participants who discontinue study treatment due to an AE is presented. |
Countries
China
Participant flow
Pre-assignment details
A total of 94 Chinese participants were randomized in the China extension study. Of 94 Chinese participants, 30 participants were randomized in the global portion of the MK-4280A-007 (NCT05064059) study and 64 participants were randomized in the China extension portion.
Participants by arm
| Arm | Count |
|---|---|
| Favezelimab/Pembrolizumab Participants received coformulated favezelimab/pembrolizumab (800 mg/200 mg) intravenously (IV) on Day 1, then every 3 weeks (Q3W), for up to 35 infusions. | 50 |
| Standard of Care (Regorafenib or TAS-102) At the Investigator's choice, participants received 160 mg regorafenib orally daily on Days 1-12 of each 28-day cycle OR 35 mg/m\^2 TAS-102 orally twice daily on Days 1-5 and Days 8-12 of each 28-day cycle. | 44 |
| Total | 94 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Death | 41 | 38 |
| Overall Study | Sponsor Decision | 9 | 6 |
Baseline characteristics
| Characteristic | Standard of Care (Regorafenib or TAS-102) | Total | Favezelimab/Pembrolizumab |
|---|---|---|---|
| Age, Continuous | 57.9 Years STANDARD_DEVIATION 10.4 | 56.5 Years STANDARD_DEVIATION 10.8 | 55.3 Years STANDARD_DEVIATION 11.2 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 0 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 44 Participants | 94 Participants | 50 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 44 Participants | 94 Participants | 50 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 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 | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 0 Participants | 0 Participants | 0 Participants |
| Sex: Female, Male Female | 14 Participants | 37 Participants | 23 Participants |
| Sex: Female, Male Male | 30 Participants | 57 Participants | 27 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 41 / 50 | 38 / 44 |
| other Total, other adverse events | 46 / 49 | 44 / 44 |
| serious Total, serious adverse events | 12 / 49 | 13 / 44 |
Outcome results
Primary
Overall Survival (OS)
OS was defined as the time from randomization to death due to any cause.
Time frame: Up to approximately 26 months
Population: All randomized Chinese participants were analyzed.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Favezelimab/Pembrolizumab | Overall Survival (OS) | 9.6 Months |
| Standard of Care (Regorafenib or TAS-102) | Overall Survival (OS) | 9.2 Months |
p-value: 0.391495% CI: [0.59, 1.5]Log Rank
Secondary
Duration of Response (DOR) Per RECIST 1.1 as Assessed by BICR
For participants who demonstrate confirmed CR (disappearance of all target lesions) or PR (At least a 30% decrease in the sum of diameters of target lesions), duration of response was defined as the time from the first documented evidence of CR or PR until progressive disease (PD) or death due to any cause. DOR for participants who had not progressed or died at the time of analysis was to be censored at the date of their last tumor assessment. Per RECIST 1.1, PD was defined as at least a 20% increase in the sum of diameters of target lesions as well as an absolute increase of at least a 5 mm in the sum of diameters. The appearance of one or more new lesions was also considered PD. DOR assessments were based on blinded central imaging review with confirmation.
Time frame: Up to approximately 26 months
Population: All randomized Chinese participants who experienced CR or PR were analyzed.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Favezelimab/Pembrolizumab | Duration of Response (DOR) Per RECIST 1.1 as Assessed by BICR | NA Months |
Secondary
Number of Participants Who Discontinued Study Treatment Due to an AE
An AE was 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. The number of participants who discontinue study treatment due to an AE is presented.
Time frame: Up to approximately 17 months
Population: All randomized Chinese participants who received at least one dose of study intervention were analyzed.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Favezelimab/Pembrolizumab | Number of Participants Who Discontinued Study Treatment Due to an AE | 5 Participants |
| Standard of Care (Regorafenib or TAS-102) | Number of Participants Who Discontinued Study Treatment Due to an AE | 4 Participants |
Secondary
Number of Participants Who Experienced at Least One Adverse Event (AE)
An AE was 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.
Time frame: Up to approximately 20 months
Population: All randomized Chinese participants who received at least one dose of study intervention were analyzed.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Favezelimab/Pembrolizumab | Number of Participants Who Experienced at Least One Adverse Event (AE) | 46 Participants |
| Standard of Care (Regorafenib or TAS-102) | Number of Participants Who Experienced at Least One Adverse Event (AE) | 44 Participants |
Secondary
Objective Response Rate (ORR) Per RECIST 1.1 as Assessed by BICR
ORR was defined as the percentage of participants who achieved a confirmed complete response (CR: Disappearance of all target lesions) or partial response (PR: At least a 30% decrease in the sum of diameters of target lesion) per RECIST 1.1 as assessed by BICR
Time frame: Up to approximately 26 months
Population: All randomized Chinese participants were analyzed.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Favezelimab/Pembrolizumab | Objective Response Rate (ORR) Per RECIST 1.1 as Assessed by BICR | 6.0 Percentage of Participants |
| Standard of Care (Regorafenib or TAS-102) | Objective Response Rate (ORR) Per RECIST 1.1 as Assessed by BICR | 0.0 Percentage of Participants |
p-value: 0.050295% CI: [-2.3, 16.3]Miettinen & Nurminen Method
Secondary
Progression-Free Survival (PFS) According Per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) as Assessed by Blinded Independent Central Review (BICR)
PFS was defined as the time from randomization to the first documented disease progression per RECIST 1.1 by BICR or death due to any cause, whichever occurred 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 must also have demonstrated an absolute increase of ≥5 mm. The appearance of one or more new lesions was also considered PD.
Time frame: Up to approximately 26 months
Population: All randomized Chinese participants were analyzed.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Favezelimab/Pembrolizumab | Progression-Free Survival (PFS) According Per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) as Assessed by Blinded Independent Central Review (BICR) | 2.1 Months |
| Standard of Care (Regorafenib or TAS-102) | Progression-Free Survival (PFS) According Per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) as Assessed by Blinded Independent Central Review (BICR) | 2.1 Months |
p-value: 0.809195% CI: [0.78, 1.92]Log Rank