Testing the Investigational Medication Pembrolizumab After Kidney Removal for Patients With Non-Clear Cell Renal Cell Carcinoma

Phase III Study of Adjuvant Pembrolizumab vs Active Surveillance After Nephrectomy in Patients With Non-Clear Cell Renal-Cell Carcinoma

This phase III trial compares the effect of pembrolizumab to active surveillance after a surgical procedure to completely or partially remove a kidney (nephrectomy) in improving time without disease in patients with non-clear cell renal cell cancer. Immunotherapy with monoclonal antibodies, such as pembrolizumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. Giving pembrolizumab after nephrectomy may be more effective than the usual active surveillance approach for improving time without disease in patients with non-clear cell renal cell cancer.

Study Overview

• Status: Not yet recruiting
• Conditions: Stage III Renal Cell Cancer AJCC v8; Stage IV Renal Cell Cancer AJCC v8; Non-Clear Cell Renal Cell Carcinoma
• Intervention / Treatment: Procedure: Biospecimen Collection; Procedure: Magnetic Resonance Imaging; Biological: Pembrolizumab; Other: Patient Observation; Procedure: Positron Emission Tomography; Procedure: Bone Scan; Procedure: Computed Tomography; Procedure: Echocardiography Test

Detailed Description

PRIMARY OBJECTIVE:

I. To evaluate whether adjuvant treatment of pembrolizumab will lead to better disease-free survival (DFS) compared to patients receiving no adjuvant treatment in the active surveillance arm.

SECONDARY OBJECTIVES:

I. To compare overall survival (OS) between patients receiving pembrolizumab versus (vs.) active surveillance II. To assess the safety and tolerability in each arm. III. To compare DFS between patients randomized to the pembrolizumab arm vs. the active surveillance arm in patients that are circulating tumor deoxyribonucleic acid (ctDNA) positive at baseline.

IV. To compare OS between patients randomized to the pembrolizumab arm vs. the active surveillance arm in patients that are ctDNA positive at baseline.

V. To compare the percentage of baseline ctDNA positive patients that achieve ctDNA clearance at week 12 between the pembrolizumab arm and active surveillance arm at.

VI. To compare DFS with KIM-1 status (high and low) by treatment arms. VII. To assess whether a decrease in KIM-1 after one cycle of adjuvant therapy is associated with improved DFS among patients receiving pembrolizumab.

VIII. To evaluate whether an increase in KIM 1 at predefined landmark timepoints is associated with an increased risk of subsequent DFS events.

IX. To evaluate whether persistently elevated C-reactive protein (CRP) is associated with recurrence.

EXPLORATORY OBJECTIVE:

I. To assess DFS and OS in each histology subgroups (papillary, chromophobe, unclassified, other).

OUTLINE: Patients are randomized to 1 of 2 arms.

ARM A: Patients undergo active surveillance, including computed tomography (CT) or magnetic resonance imaging (MRI), every 3 months for 1 year. Patients also undergo collection of blood samples on study and CT or MRI during follow up. Patients may undergo echocardiography (ECHO) and/or bone scan and/or positron emission tomography (PET)/CT if clinically indicated.

ARM B: Patients receive pembrolizumab intravenously (IV) over 30 minutes on day 1 of each cycle. Cycles repeat every 6 weeks for up to 9 cycles in the absence of disease progression or unacceptable toxicity. Patients also undergo CT or MRI throughout the trial and collection of blood samples on study. Patients may undergo ECHO and/or bone scan and/or PET/CT if clinically indicated.

After completion of study treatment, patients are followed up every 3 months up to year 2, every 6 months in years 2-5, and every 12 months in years 5-10.

• Study Type: Interventional
• Enrollment (Estimated): 400
• Phase: Phase 3

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Patient must be ≥ 18 years of age
• Patient must have an Eastern Cooperative Oncology Group (ECOG) performance status of 0-2
• Patient must have histologically confirmed non-clear cell renal cell carcinoma (nccRCC) with ≥ pT3Nx or pTanyN+ or pTanyNanyM1 with no evidence of disease (NED) per the American Joint Committee on Cancer (AJCC) 8th edition
• Patient must not have renal medullary carcinoma

• Patient must have had a partial or radical nephrectomy. In the case of patients with M1 NED status, a complete resection of the metastatic lesion(s) (metastasectomy) must have been completed at the time of nephrectomy or within 1 year after nephrectomy

  • Positive margins are allowed as long as no gross disease
• Patient must not have residual thrombus post nephrectomy in the vena renalis or vena cava
• Patient must be randomized ≤ 16 weeks after nephrectomy and/or < 16 weeks after metastasectomy
• Patient must have undergone imaging of chest, abdomen and pelvis with a CT or MRI after nephrectomy/metastasectomy and within 42 days prior to randomization documenting there is no evidence of liver, bone, or brain metastases
• Patient must not have received any prior anti-PD-1/PD-L1 or CTLA-4 agents
• Patient must not have received any prior radiotherapy for nccRCC
• Patient must not have received prior systemic treatment for nccRCC (except nephrectomy or metastasectomy). Patient must not have received prior immune checkpoint inhibitor agents for other cancers within 2 years prior to randomization
• Patient must not have active known or suspected autoimmune disease requiring systemic immunosuppression. The following autoimmune disorders are permitted: patients with vitiligo, type I diabetes mellitus, controlled/stable hypo or hyperthyroidism due to autoimmune or non-autoimmune conditions (hormone replacement is allowed), psoriasis not requiring systemic treatment
• Patient must not be on any immunosuppressant therapy other than inhaled steroids, intranasal steroids, topical steroids, injection steroids and systemic steroids up to 10mg prednisone equivalent
• Patient must have recovered adequately from toxicity and/or complications related to any surgery received prior to randomization
• Patient must not have a history or current evidence of uncontrolled intercurrent illness that would limit compliance with study requirement, substantially increase the risk of incurring adverse events (AEs), or compromise the ability of the patient to give written informed consent
• Patient must not have had a history of allogeneic organ transplantation

• Patient must not be pregnant or breast-feeding due to the potential harm to an unborn fetus and possible risk for adverse events in nursing infants with the treatment regimens being used

  • All patients of childbearing potential must have a blood test or urine study within 14 days prior to randomization to rule out pregnancy
  • A patient of childbearing potential is defined as anyone, regardless of whether they have undergone tubal ligation, who meets the following criteria: 1) has achieved menarche at some point, 2) has not undergone a hysterectomy or bilateral oophorectomy; or 3) has not been naturally postmenopausal (amenorrhea following cancer therapy does not rule out childbearing potential) for at least 24 consecutive months (i.e., has had menses at any time in the preceding 24 consecutive months)
• Patient must not expect to conceive or father children by using accepted and effective method(s) of contraception or by abstaining from sexual intercourse for the duration of their participation in the study. Patients of childbearing potential assigned to Arm B must continue contraception requirements for 4 months following the last dose of pembrolizumab. Patients assigned to Arm B must also not breastfeed while on protocol treatment and for 4 months after the last dose of pembrolizumab
• Patient must have the ability to understand and the willingness to sign a written informed consent document. Patients with impaired decision-making capacity (IDMC) who have a legally authorized representative (LAR) or caregiver and/or family member available will also be considered eligible
• Leukocytes ≥ 3,000/ mm^3 (must be obtained ≤ 42 days prior to protocol randomization)
• Absolute neutrophil count (ANC) ≥ 1,500/mm^3 (must be obtained ≤ 42 days prior to protocol randomization)
• Platelets ≥ 100,000/ mm^3 (must be obtained ≤ 42 days prior to protocol randomization)

• Total bilirubin ≤ 2 x institutional upper limit of normal (ULN) (must be obtained ≤ 42 days prior to protocol randomization)

  • NOTE: For patients with known Gilbert's syndrome, total bilirubin < 3 x ULN
• Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase [SGOT]) and alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) ≤ 3.0 × institutional ULN (must be obtained ≤ 42 days prior to protocol randomization)
• Estimated glomerular filtration rate (eGFR) clearance ≥ 30 mL/min/1.73 m^2 (must be obtained ≤ 42 days prior to protocol randomization)
• Human immunodeficiency virus (HIV)-infected patients on effective anti-retroviral therapy with undetectable viral load within 6 months of randomization are eligible for this trial
• For patients with evidence of chronic hepatitis B virus (HBV) infection, the HBV viral load must be undetectable on suppressive therapy, if indicated
• Patients with a history of hepatitis C virus (HCV) infection must have been treated and cured. For patients with HCV infection who are currently on treatment, they are eligible if they have an undetectable HCV viral load
• Patients with a prior or concurrent malignancy whose natural history or treatment does not have the potential to interfere with the safety or efficacy assessment of the investigational regimen are eligible for this trial
• Patients with known history or current symptoms of cardiac disease, or history of treatment with cardiotoxic agents, should have a clinical risk assessment of cardiac function using the New York Heart Association Functional Classification. To be eligible for this trial, patients must be class 2 or better

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Arm A (active surveillance); Patients undergo active surveillance, including CT or MRI, every 3 months for 1 year. Patients also undergo collection of blood samples on study and CT or MRI during follow up. Patients may undergo ECHO and/or bone scan and/or PET/CT if clinically indicated.	Procedure: Biospecimen Collection; Undergo collection of blood samples; Other Names: Biological Sample Collection; Biospecimen Collected; Specimen Collection; Sample Collection; Procedure: Magnetic Resonance Imaging; Undergo MRI; Other Names: MRI; Magnetic Resonance; Magnetic Resonance Imaging Scan; Medical Imaging, Magnetic Resonance / Nuclear Magnetic Resonance; MR; MR Imaging; MRI Scan; NMR Imaging; NMRI; Nuclear Magnetic Resonance Imaging; Magnetic Resonance Imaging (MRI); sMRI; Magnetic resonance imaging (procedure); MRIs; Structural MRI; Other: Patient Observation; Undergo active surveillance; Other Names: Observation; Active Surveillance; deferred therapy; expectant management; Watchful Waiting; Procedure: Positron Emission Tomography; Undergo PET/CT; Other Names: Medical Imaging, Positron Emission Tomography; PET; PET Scan; Positron Emission Tomography Scan; Positron-Emission Tomography; PT; Positron emission tomography (procedure); Procedure: Bone Scan; Undergo bone scan; Other Names: Bone Scintigraphy; Procedure: Computed Tomography; Undergo CT and PET/CT; Other Names: CT; CAT; CAT Scan; Computed Axial Tomography; Computerized Axial Tomography; Computerized Tomography; CT Scan; tomography; Computerized axial tomography (procedure); Computerized Tomography (CT) scan; Diagnostic CAT Scan; Diagnostic CAT Scan Service Type; Procedure: Echocardiography Test; Undergo ECHO; Other Names: Echocardiography; EC
Experimental: Arm B (pembrolizumab); Patients receive pembrolizumab IV over 30 minutes on day 1 of each cycle. Cycles repeat every 6 weeks for up to 9 cycles in the absence of disease progression or unacceptable toxicity. Patients also undergo CT or MRI throughout the trial and collection of blood samples on study. Patients may undergo ECHO and/or bone scan and/or PET/CT if clinically indicated.	Procedure: Biospecimen Collection; Undergo collection of blood samples; Other Names: Biological Sample Collection; Biospecimen Collected; Specimen Collection; Sample Collection; Procedure: Magnetic Resonance Imaging; Undergo MRI; Other Names: MRI; Magnetic Resonance; Magnetic Resonance Imaging Scan; Medical Imaging, Magnetic Resonance / Nuclear Magnetic Resonance; MR; MR Imaging; MRI Scan; NMR Imaging; NMRI; Nuclear Magnetic Resonance Imaging; Magnetic Resonance Imaging (MRI); sMRI; Magnetic resonance imaging (procedure); MRIs; Structural MRI; Biological: Pembrolizumab; Given IV; Other Names: Keytruda; MK-3475; Lambrolizumab; SCH 900475; MK3475; SCH-900475; BCD-201; Pembrolizumab Biosimilar BCD-201; Pembrolizumab Biosimilar QL2107; QL2107; GME 751; GME751; Pembrolizumab Biosimilar GME751; MK 3475; SCH900475; Pembrolizumab Biosimilar RPH-075; RPH 075; RPH-075; RPH075; Pembrolizumab Biosimilar SB27; SB 27; SB-27; SB27; Procedure: Positron Emission Tomography; Undergo PET/CT; Other Names: Medical Imaging, Positron Emission Tomography; PET; PET Scan; Positron Emission Tomography Scan; Positron-Emission Tomography; PT; Positron emission tomography (procedure); Procedure: Bone Scan; Undergo bone scan; Other Names: Bone Scintigraphy; Procedure: Computed Tomography; Undergo CT and PET/CT; Other Names: CT; CAT; CAT Scan; Computed Axial Tomography; Computerized Axial Tomography; Computerized Tomography; CT Scan; tomography; Computerized axial tomography (procedure); Computerized Tomography (CT) scan; Diagnostic CAT Scan; Diagnostic CAT Scan Service Type; Procedure: Echocardiography Test; Undergo ECHO; Other Names: Echocardiography; EC

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Disease-free survival (DFS)	A superiority test of DFS for pembrolizumab arm versus (vs.) active surveillance arm will be performed at one-sided 0.025 significance level, using a stratified log-rank test assuming exponential failure.	From randomization to first documented local recurrence, distant metastasis, secondary systemic malignancy, or death due to any cause, whichever occurs first, assessed up to 10 years

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Overall survival (OS)	OS will be assessed among all randomized patients. Kaplan-Meier estimate will characterize OS and OS comparison will be made for pembrolizumab vs. active surveillance arm using stratified log-rank test and assuming exponential failure.	From randomization to death from any cause, assessed up to 10 years
Incidence of adverse events	Adverse events will be described separately for patients treated on each arm to evaluate safety and tolerability. Toxicity will be defined using the Common Terminology Criteria for Adverse Events. All patients who receive treatment, regardless of eligibility, will be evaluated for toxicity. The 90% confidence interval for the true probability of observing a toxicity of Grade 4 or higher on a given arm will be no wider than 12.1% for each arm. The probability of observing one or more toxicities on a given arm with a true rate of 1% is 86.6% for each arm.	Up to 1 year
DFS among those that are circulating tumor deoxyribonucleic acid (ctDNA) positive	The first ctDNA analysis objective is to compare DFS between patients randomized to pembrolizumab arm vs. active surveillance arm among patients that are ctDNA positive at baseline. Among patients that are ctDNA positive at baseline, DFS will be compared between patients randomized to pembrolizumab arm vs. surveillance arm using a stratified log-rank test at 0.05 two-sided alpha level assuming exponential failure. Hazard ratios (HRs) for recurrence or death will be reported using a univariable cox proportional hazards model.	Up to 10 years
OS among those that are ctDNA positive	The second ctDNA analysis objective is to compare OS between patients randomized to pembrolizumab arm vs. active surveillance arm among patients that are ctDNA positive at baseline. Among 72 patients that are predicted to be ctDNA positive at baseline, OS will be compared between patients randomized to Pembrolizumab arm vs. surveillance arm using a stratified log-rank test at 0.05 two-sided alpha level assuming exponential failure. HRs for recurrence or death will be reported using a univariable cox proportional hazards model.	Up to 10 years
ctDNA clearance rate prediction	Will compare ctDNA clearance rate at week 12 between pembrolizumab arm and active surveillance arm. Among the 72 patients that are predicted to have ctDNA positivity at baseline, comparison of ctDNA clearance between arms will be assessed using Fisher's exact test at 0.05 two-sided alpha level.	At week 12
DFS by KIM-1 status	Will to compare DFS between the two arms among high baseline KIM-1 levels (> 86 pg/mL) and low baseline KIM-1 levels separately. Among patients that consent to biomarker study (n=360), DFS will be compared between pembrolizumab arm patients and active surveillance arm patients in each high KIM-1 level and low KIM-1 level subgroups separately, using a stratified log-rank test assuming exponential failure, at 0.05 two-sided alpha level. HRs will be reported using a univariable cox proportional hazards model.	Up to 10 years
DFS by KIM-1 in pembrolizumab arm	Will assess whether a decrease in KIM-1 after one cycle of adjuvant therapy identifies patients who derive benefit from treatment. Among patients that consent to biomarker study and get randomized to pembrolizumab arm (n=180), DFS will be compared between pembrolizumab arm patients with a clinically meaningful drop in KIM-1 level after cycle 1 vs. no clinically meaningful drop in KIM-1 level using log-rank test at 0.05 two-sided alpha level. HRs will be reported using a univariable cox proportional hazards model.	Post-cycle 1 (cycle length = 6 weeks)
DFS in patients with any KIM-1 increase and not	Will evaluate whether an increase in KIM-1 at any timepoint is associated with better DFS. Among patients that consent to biomarker study (n=360), DFS will be compared between patients with a clinically meaningful increase in KIM-1 level at any timepoint vs. no clinically meaningful increase in KIM-1 level using log-rank test at 0.05 two-sided alpha level. Hazard ratios will be reported using a univariable cox proportional hazards model.	Up to 10 years
Recurrence rate in C-reactive protein (CRP) groups	Will evaluate whether persistently elevated CRP is associated with recurrence. Among the patients that consent to biomarker study (n=360), comparison between those with persistently elevated CRP vs. don't will be compared in recurrence rate, using Fisher's exact test at 0.05 two-sided alpha level. Odds ratio will be reported to summarize the strength of association between elevation of CRP (yes vs. no) and development of recurrence disease (yes vs. no).	Up to 10 years

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
DFS by sex	Estimates of the primary outcome treatment effect and the corresponding 95% confidence interval will be provided by sex.	Up to 10 years
DFS by race	Estimates of the primary outcome treatment effect and the corresponding 95% confidence interval will be provided by race.	Up to 10 years
DFS by ethnicity	Estimates of the primary outcome treatment effect and the corresponding 95% confidence interval will be provided by ethnicity.	Up to 10 years

Collaborators and Investigators

• Sponsor: National Cancer Institute (NCI)
• Investigators: Principal Investigator: Mehmet A Bilen, ECOG-ACRIN Cancer Research Group

Study record dates

Study Major Dates

• Study Start (Estimated): February 10, 2027
• Primary Completion (Estimated): January 1, 2032
• Study Completion (Estimated): January 1, 2032

Study Registration Dates

• First Submitted: July 7, 2026
• First Submitted That Met QC Criteria: July 7, 2026
• First Posted (Actual): July 8, 2026

Study Record Updates

• Last Update Posted (Actual): July 8, 2026
• Last Update Submitted That Met QC Criteria: July 7, 2026
• Last Verified: July 1, 2026

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Urogenital Diseases; Urogenital Neoplasms; Neoplasms by Site; Neoplasms; Male Urogenital Diseases; Kidney Diseases; Urologic Diseases; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Neoplasms by Histologic Type; Neoplasms, Glandular and Epithelial; Adenocarcinoma; Urologic Neoplasms; Carcinoma; Kidney Neoplasms; Carcinoma, Renal Cell; Health Services Administration; Investigative Techniques; Methods; Clinical Laboratory Techniques; Diagnostic Techniques and Procedures; Diagnosis; Quality of Health Care; Chemistry Techniques, Analytical; Spectrum Analysis; Outcome Assessment, Health Care; Outcome and Process Assessment, Health Care; Observation; Specimen Handling; pembrolizumab; Magnetic Resonance Spectroscopy; Watchful Waiting
• Other Study ID Numbers: NCI-2026-04730 (Registry Identifier: CTRP (Clinical Trial Reporting Program)); U10CA180820 (U.S. NIH Grant/Contract); EA8252 (Other Identifier: CTEP)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: NCI is committed to sharing data in accordance with NIH policy. For more details on how clinical trial data is shared, access the link to the NIH data sharing policy page.

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No