Renal Cell Carcinoma
Conditions
Keywords
Programmed Cell Death-1 (PD1, PD-1), Programmed Death-Ligand 1 (PDL1, PD-L1), Adjuvant
Brief summary
The purpose of this study is to evaluate the safety and efficacy of pembrolizumab (MK-3475) in the adjuvant treatment of adult participants who have undergone nephrectomy and have intermediate-high risk, high risk, or M1 no evidence of disease (M1 NED) renal cell carcinoma (RCC) with clear cell component. The primary study hypothesis is that pembrolizumab is superior to placebo with respect to Disease-free Survival (DFS) as assessed by the Investigator in male and female participants with intermediate-high risk, high risk and M1 NED RCC.
Detailed description
Participants will be assigned to receive study treatment until disease recurrence, unacceptable adverse events (AEs), intercurrent illness that prevents further administration of treatment, Investigator's decision to withdraw the participant, noncompliance with study treatment or procedural requirements, administrative reasons requiring cessation of treatment, or until the participant has received 17 cycles of study treatment (approximately 1 year). Each cycle is 3 weeks long. With Protocol Amendment 02 (dated 04 Sep 2019), the secondary study objectives for the evaluation of pharmacokinetic (PK) parameters and the presence of pembrolizumab antidrug antibodies (ADA) were reclassified as tertiary study objectives.
Interventions
BIOLOGICALPembrolizumab
IV infusion
DRUGPlacebo
IV infusion
Sponsors
Merck Sharp & Dohme LLC
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Has histologically confirmed diagnosis of renal cell carcinoma (RCC) with clear cell component with or without sarcomatoid features * Female participants of childbearing potential must be willing to use an adequate method of contraception, for the course of the study through 120 days after the last dose of study treatment * Male participants of childbearing potential must agree to use an adequate method of contraception, starting with the first dose of study treatment through 120 days after the last dose of study treatment * Has intermediate-high risk, high risk, or M1 no evidence of disease (NED) RCC as defined by the following pathological tumor-node-metastasis and Fuhrman grading status: 1. Intermediate-high risk RCC: pT2, Grade 4 or sarcomatoid, N0, M0; pT3, Any Grade, N0, M0 2. High risk RCC: pT4, Any Grade N0, M0; pT Any stage, Any Grade, N+, M0 3. M1 NED RCC participants who present not only with the primary kidney tumor but also solid, isolated, soft tissue metastases that can be completely resected at one of the following: the time of nephrectomy (synchronous) or, ≤1 year from nephrectomy (metachronous) * Has received no prior systemic therapy for advanced RCC * Has undergone a partial nephroprotective or radical complete nephrectomy (and complete resection of solid, isolated, soft tissue metastatic lesion(s) in M1 NED participants) with negative surgical margins * Must have undergone a nephrectomy and/or metastasectomy ≥28 days prior to signing informed consent and ≤12 weeks prior to randomization * Must be tumor-free as assessed by the Investigator and validated by either computed tomography (CT) or magnetic resonance imaging (MRI) scan of the brain and chest, abdomen, and pelvis and a bone scan ≤28 days from randomization * Must have provided adequate tissue per the following: Nephrectomy only: tissue from nephrectomy (required); Synchronous M1 NED: tissue from nephrectomy (required) AND, metastasectomy tissue (if available); Metachronous M1 NED: tissue from metastasectomy (required) AND, nephrectomy tissue (if available) * Has an Eastern Cooperative Oncology Group Performance Status (ECOG PS) score of 0 or 1 * Has adequate organ function
Exclusion criteria
* Has had major surgery, other than nephrectomy and/or resection of pre-existing metastases for M1 NED participants, within 12 weeks prior to randomization * Has received prior radiotherapy for RCC * Has pre-existing brain or bone metastatic lesions * Has residual thrombus post nephrectomy in the vena renalis or vena cava * Has a 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 treatment * Has an active autoimmune disease that has required systemic treatment in past 2 years (i.e., with use of disease modifying agents, corticosteroids, or immunosuppressive drugs). Replacement therapy is allowed * Has a known additional malignancy that is progressing or required active treatment ≤3 years ago. Exceptions include early-stage cancers (carcinoma in situ or Stage 1) treated with curative intent, basal cell carcinoma of the skin, squamous cell carcinoma of the skin, in situ cervical cancer, in situ prostate cancer, or in situ breast cancer that has undergone potentially curative therapy * Has a history of (non-infectious) pneumonitis that required steroids or has current pneumonitis * Has an active infection requiring systemic therapy * Has a history of, or is currently on, dialysis * Has a known history of human immunodeficiency virus (HIV) infection * Has known active hepatitis B or hepatitis C virus infection * Has a known history of active tuberculosis (Bacillus tuberculosis) * Has had a prior solid organ transplant * Has severe hypersensitivity (≥ Grade 3) to pembrolizumab and/or any of its excipients * Is pregnant or breastfeeding, or expecting to conceive or father children within the projected duration of the study, starting with the Screening visit through 120 days after the last dose of study treatment * Has received prior therapy with an anti-programmed cell death protein 1 (anti-PD-1), anti-programmed cell death-ligand 1 (anti-PD-L1), or anti-programmed cell death-ligand 2 (anti-PD-L2) agent or with an agent directed to another co-inhibitory T-cell receptor (i.e., cytotoxic T-lymphocyte-associated protein 4 \[CTLA-4\], OX-40, CD137 \[tumor necrosis factor receptor superfamily member 9 (TNFRSF9)\]) or has previously participated in a Merck pembrolizumab (MK-3475) clinical trial * Has received prior anticancer therapy, monoclonal antibody, chemotherapy, or an investigational agent or device within 4 weeks or 5 half-lives (whichever is longer) before first dose of study treatment or not recovered (i.e., must be ≤ Grade 1 or at Baseline) from AEs due to previously administered agents * Has received a live 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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Disease-free Survival (DFS) as Assessed by the Investigator | Up to approximately 42 months (database cutoff date 14 Dec 2020) | DFS, as assessed by the investigator, is defined as the time from randomization to the first documented local recurrence, distant kidney cancer metastasis(es), or death due to any cause, whichever occurs first. Cox regression model with Efron's method of tie handling with treatment as a covariate stratified by metastasis status (M0 versus M1 no evidence of disease (NED) by investigator) and Eastern Cooperative Oncology Group Performance Status (ECOG PS) (0 versus 1), United States (US) participant (Yes versus No) within M0 group by investigator was used to report hazard ratio (HR) and 95% confidence intervals (CIs). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Overall Survival (OS) | Up to approximately 72 months | OS was defined as the time from randomization to death due to any cause. |
| Number of Participants Who Experienced an Adverse Event (AE) | Nonserious AEs: Up to 30 days after last dose of study treatment (Up to approximately 13 months); Serious AEs: Up to 90 days after last dose of study treatment (Up to approximately 15 months) | An AE is defined as any unfavorable and unintended change in the structure, function, or chemistry of the body temporally associated with the use of the study treatment, whether or not considered related to the use of study treatment. Participants are monitored for the occurrence of nonserious AEs for up to 30 days after last dose of study treatment and of serious AEs for up to 90 days after last dose of study treatment. The number of participants who experience an AE will be assessed. |
| Number of Participants Who Discontinued Study Drug Due to an AE | Up to approximately 12 months | An AE is defined as any unfavorable and unintended change in the structure, function, or chemistry of the body temporally associated with the use of the study treatment, whether or not considered related to the use of study treatment. The number of participants who discontinue study treatment due to an AE will be assessed. |
| First Local Disease Recurrence-specific Survival (DRSS1) as Assessed by the Investigator | Up to approximately 72 months | DRSS1 is defined as the time from randomization to the first documented local recurrence of RCC as assessed by the investigator. For DRSS1, only local recurrence is counted as an event. |
| Second Disease Recurrence-Specific Survival (DRSS2) as Assessed by the Investigator | Up to approximately 72 months | DRSS2 is defined as the time from randomization to the first documented local recurrence with visceral lesion or occurrence of distant kidney cancer metastasis(es) with visceral lesion, whichever occurs first, as assessed by the investigator. |
| Event-Free Survival (EFS) as Assessed by the Blinded Independent Central Review (BICR) | Up to approximately 72 months | EFS is defined as time from randomization to the first documented local recurrence or occurrence of distant kidney cancer metastasis(es) among participants which by BICR were considered disease-free at baseline (M0/M1 NED); or disease progression among participants which by BICR were considered to have baseline disease (M1), or death due to any cause, whichever occurs first. |
| DFS According to Participant Programmed Cell Death-Ligand 1 (PD-L1) Expression Status (Positive, Negative) as Assessed by the Investigator | Up to approximately 72 months | DFS, as assessed by the investigator, is defined as the time from randomization to the first documented local recurrence, or occurrence of distant kidney cancer metastasis(es), or death due to any cause, whichever occurs first. The PD-L1 expression status is based on combined positive score (CPS). If CPS is ≥ 1, PD-L1 expression status is positive and if the CPS is \<1, PD-L1 expression status is negative. |
| OS According to Participant PD-L1 Expression Status (Positive, Negative) | Up to approximately 72 months | OS is defined as the time from randomization to death due to any cause. The PD-L1 expression status is based on combined positive score (CPS). If CPS is ≥ 1, PD-L1 expression status is positive and if the CPS is \<1, PD-L1 expression status is negative. |
| Change From Baseline in the European Organization for the Research and Treatment of Cancer Quality of Life Questionnaire C30 (EORTC QLQ-C30) Total Score | Baseline and Week 52 | The QLQ-C30 quality of life (QOL) questionnaire contains 5 functioning scales (physical, role, cognitive, emotional, and social), 3 symptom scales (fatigue, nausea and vomiting, and pain) and single symptom items (dyspnoea, loss of appetite, insomnia, constipation and diarrhoea) and perceived financial impact of the disease. Items are scored on a 4-point scale (1=not at all, 2=a little, 3= quite a bit, 4=very much). The QLQC30 also contains 2 global health status scales that use 7-point scale scoring (1=very poor and 7=excellent). The change from baseline in the 2-item global health status/QOL life scale (range: 2-14) will be presented, with a higher score representing a higher QOL. |
| Change From Baseline in the Functional Assessment of Cancer Therapy Kidney Symptom Index-Disease Related Symptoms (FKSI-DRS) Index Score | Baseline and Week 52 | The FKSI-DRS index consists of a 9-item questionnaire that assesses the extent of participant symptoms from kidney cancer over the previous 7 days. Responses are scored on a 5-point scale (0=Not at all to 4=Very much) and summed to generate an index symptom score. These scores can range from 0 to 36, with a higher score indicating more favorable kidney cancer symptom status. The change from baseline in the FKSI-DRS index score will be presented. |
Countries
Argentina, Australia, Brazil, Canada, Chile, Colombia, Czechia, Finland, France, Germany, Ireland, Italy, Japan, Netherlands, Poland, Russia, South Korea, Spain, Taiwan, United Kingdom, United States
Contacts
STUDY_DIRECTORMedical Director
Merck Sharp & Dohme LLC
Participant flow
Pre-assignment details
Of the 994 participants randomized in the study, 984 participants received study medication and were evaluable for safety analyses (Database cutoff date 14 Dec 2020)
Participants by arm
| Arm | Count |
|---|---|
| Pembrolizumab Participants received pembrolizumab 200 mg via intravenous (IV) infusion on Day 1 of each 3-week cycle for up to 17 cycles (up to approximately 1 year). | 496 |
| Placebo Participants received placebo (saline solution) via IV infusion on Day 1 of each 3-week cycle for up to 17 cycles (up to approximately 1 year). | 498 |
| Total | 994 |
Baseline characteristics
| Characteristic | Placebo | Total | Pembrolizumab |
|---|---|---|---|
| Age, Continuous | 58.6 Years STANDARD_DEVIATION 11 | 58.4 Years STANDARD_DEVIATION 10.8 | 58.3 Years STANDARD_DEVIATION 10.6 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 62 Participants | 134 Participants | 72 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 394 Participants | 775 Participants | 381 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 42 Participants | 85 Participants | 43 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 2 Participants | 12 Participants | 10 Participants |
| Race (NIH/OMB) Asian | 75 Participants | 138 Participants | 63 Participants |
| Race (NIH/OMB) Black or African American | 5 Participants | 12 Participants | 7 Participants |
| Race (NIH/OMB) More than one race | 5 Participants | 13 Participants | 8 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 34 Participants | 70 Participants | 36 Participants |
| Race (NIH/OMB) White | 377 Participants | 749 Participants | 372 Participants |
| Sex: Female, Male Female | 139 Participants | 288 Participants | 149 Participants |
| Sex: Female, Male Male | 359 Participants | 706 Participants | 347 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 18 / 496 | 33 / 498 |
| other Total, other adverse events | 436 / 488 | 393 / 496 |
| serious Total, serious adverse events | 100 / 488 | 56 / 496 |
Outcome results
Primary
Disease-free Survival (DFS) as Assessed by the Investigator
DFS, as assessed by the investigator, is defined as the time from randomization to the first documented local recurrence, distant kidney cancer metastasis(es), or death due to any cause, whichever occurs first. Cox regression model with Efron's method of tie handling with treatment as a covariate stratified by metastasis status (M0 versus M1 no evidence of disease (NED) by investigator) and Eastern Cooperative Oncology Group Performance Status (ECOG PS) (0 versus 1), United States (US) participant (Yes versus No) within M0 group by investigator was used to report hazard ratio (HR) and 95% confidence intervals (CIs).
Time frame: Up to approximately 42 months (database cutoff date 14 Dec 2020)
Population: All randomized participants
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Pembrolizumab | Disease-free Survival (DFS) as Assessed by the Investigator | NA Months |
| Placebo | Disease-free Survival (DFS) as Assessed by the Investigator | NA Months |
p-value: 0.00195% CI: [0.53, 0.87]Log Rank
Secondary
Change From Baseline in the European Organization for the Research and Treatment of Cancer Quality of Life Questionnaire C30 (EORTC QLQ-C30) Total Score
The QLQ-C30 quality of life (QOL) questionnaire contains 5 functioning scales (physical, role, cognitive, emotional, and social), 3 symptom scales (fatigue, nausea and vomiting, and pain) and single symptom items (dyspnoea, loss of appetite, insomnia, constipation and diarrhoea) and perceived financial impact of the disease. Items are scored on a 4-point scale (1=not at all, 2=a little, 3= quite a bit, 4=very much). The QLQC30 also contains 2 global health status scales that use 7-point scale scoring (1=very poor and 7=excellent). The change from baseline in the 2-item global health status/QOL life scale (range: 2-14) will be presented, with a higher score representing a higher QOL.
Time frame: Baseline and Week 52
Secondary
Change From Baseline in the Functional Assessment of Cancer Therapy Kidney Symptom Index-Disease Related Symptoms (FKSI-DRS) Index Score
The FKSI-DRS index consists of a 9-item questionnaire that assesses the extent of participant symptoms from kidney cancer over the previous 7 days. Responses are scored on a 5-point scale (0=Not at all to 4=Very much) and summed to generate an index symptom score. These scores can range from 0 to 36, with a higher score indicating more favorable kidney cancer symptom status. The change from baseline in the FKSI-DRS index score will be presented.
Time frame: Baseline and Week 52
Secondary
DFS According to Participant Programmed Cell Death-Ligand 1 (PD-L1) Expression Status (Positive, Negative) as Assessed by the Investigator
DFS, as assessed by the investigator, is defined as the time from randomization to the first documented local recurrence, or occurrence of distant kidney cancer metastasis(es), or death due to any cause, whichever occurs first. The PD-L1 expression status is based on combined positive score (CPS). If CPS is ≥ 1, PD-L1 expression status is positive and if the CPS is \<1, PD-L1 expression status is negative.
Time frame: Up to approximately 72 months
Secondary
Event-Free Survival (EFS) as Assessed by the Blinded Independent Central Review (BICR)
EFS is defined as time from randomization to the first documented local recurrence or occurrence of distant kidney cancer metastasis(es) among participants which by BICR were considered disease-free at baseline (M0/M1 NED); or disease progression among participants which by BICR were considered to have baseline disease (M1), or death due to any cause, whichever occurs first.
Time frame: Up to approximately 72 months
Secondary
First Local Disease Recurrence-specific Survival (DRSS1) as Assessed by the Investigator
DRSS1 is defined as the time from randomization to the first documented local recurrence of RCC as assessed by the investigator. For DRSS1, only local recurrence is counted as an event.
Time frame: Up to approximately 72 months
Secondary
Number of Participants Who Discontinued Study Drug Due to an AE
An AE is defined as any unfavorable and unintended change in the structure, function, or chemistry of the body temporally associated with the use of the study treatment, whether or not considered related to the use of study treatment. The number of participants who discontinue study treatment due to an AE will be assessed.
Time frame: Up to approximately 12 months
Secondary
Number of Participants Who Experienced an Adverse Event (AE)
An AE is defined as any unfavorable and unintended change in the structure, function, or chemistry of the body temporally associated with the use of the study treatment, whether or not considered related to the use of study treatment. Participants are monitored for the occurrence of nonserious AEs for up to 30 days after last dose of study treatment and of serious AEs for up to 90 days after last dose of study treatment. The number of participants who experience an AE will be assessed.
Time frame: Nonserious AEs: Up to 30 days after last dose of study treatment (Up to approximately 13 months); Serious AEs: Up to 90 days after last dose of study treatment (Up to approximately 15 months)
Secondary
OS According to Participant PD-L1 Expression Status (Positive, Negative)
OS is defined as the time from randomization to death due to any cause. The PD-L1 expression status is based on combined positive score (CPS). If CPS is ≥ 1, PD-L1 expression status is positive and if the CPS is \<1, PD-L1 expression status is negative.
Time frame: Up to approximately 72 months
Secondary
Overall Survival (OS)
OS was defined as the time from randomization to death due to any cause.
Time frame: Up to approximately 72 months
Secondary
Second Disease Recurrence-Specific Survival (DRSS2) as Assessed by the Investigator
DRSS2 is defined as the time from randomization to the first documented local recurrence with visceral lesion or occurrence of distant kidney cancer metastasis(es) with visceral lesion, whichever occurs first, as assessed by the investigator.
Time frame: Up to approximately 72 months