This phase II trial tests the effect of botensilimab and balstilimab before surgery (neoadjuvant) in treating patients with high-risk clear cell renal cell cancer that has not spread from where it first started to other areas of the body (non-metastatic). The current standard treatment for patients with non-metastatic clear cell renal cell cancer may include surgery to completely remove the tumor. This typically involves removing the kidney or part of the kidney (nephrectomy). Immunotherapy with monoclonal antibodies, such as botensilimab and balstilimab, may help the body's immune system attack the tumor, and may interfere with the ability of tumor cells to grow and spread. Giving neoadjuvant botensilimab and balstilimab may be safe, tolerable, and/or effective in treating patients with high-risk non-metastatic clear cell renal cell cancer before undergoing a nephrectomy.
Patients must have biopsy-confirmed, non-metastatic, high-risk renal cell carcinoma (RCC) with a clear cell component, defined as clinical stage T2N0, T3N0, T4N0, or any T stage with N1 disease (i.e., T2a-T4NanyM0 or TanyN1M0), and no evidence of metastatic disease
Participants with resectable RCC are eligible, including those who have previously undergone surgical resection for RCC and subsequently developed resectable recurrent disease. Patients must be candidates for further curative-intent surgical resection. Prior systemic therapy for RCC (including VEGF-targeted therapy, immune checkpoint inhibitors, HIF-2α inhibitors, or other systemic anticancer therapies) is not allowed
Age ≥ 18 years. Because no dosing or adverse event data are currently available on the use of botensilimab in combination with balstilimab in patients < 18 years of age, children are excluded from this study
Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2 (or Karnofsky ≥ 60%)
Patients who have suspected or proven metastatic renal cell carcinoma
Patients who have not recovered from adverse events due to prior anti-cancer therapy (i.e., have residual toxicities > grade 1) with the exception of alopecia
Patients who are receiving any other investigational agents
History of allergic reactions attributed to compounds of similar chemical or biologic composition to botensilimab or balstilimab
Single group
Balstilimab
Biological/VaccineGiven IV
Biospecimen Collection
Procedure/SurgeryUndergo blood sample collection
Botensilimab
Biological/VaccineGiven IV
Computed Tomography
Procedure/SurgeryUndergo CT
Nephrectomy
Procedure/SurgeryUndergo nephrectomy
Questionnaire Administration
Other interventionAncillary studies
Proportion of patients successfully completing neoadjuvant treatment and undergoing planned definitive surgical resection of primary tumor (radical or partial nephrectomy) without significant treatment related delays
The intervention will be considered feasible if at least 80% of enrolled patients (13 out of 16) successfully undergo planned radical or partial nephrectomy following treatment.
Incidence and severity of treatment-related adverse events
Will be analyzed descriptively using frequencies and proportions, stratified by severity according to the National Cancer Institute Common Terminology Criteria for Adverse Events version 5.0.
Incidence and severity of surgical complications
Will be summarized using the Clavien-Dindo Classification.
Objective response rate (ORR)
Will be defined as the proportion of patients achieving a complete response or partial response of the primary tumor as defined by Response Evaluation Criteria for Solid Tumors 1.1 criteria. ORR will be summarized as a proportion with a 95% confidence interval (CI) using the Clopper-Pearson method (exact binomial CIs), and analyses conducted on both the intention-to-treat and per-protocol populations.
Major pathologic response (MPR) rate
Will be defined as the proportion of patients with \< 10% viable tumor cells. MPR rate will be determined through centralized pathology review of the surgical specimen, summarized as proportions with 95% CIs using Clopper-Pearson method, and a descriptive comparison between response categories will be presented.
Partial pathologic rate (PPR) rate
Will be defined as the proportion of patients with \< 50% viable tumor cells in the tumor bed of the resected specimen, will be assessed. PPR rate will be determined through centralized pathology review of the surgical specimen, summarized as proportions with 95% CIs using Clopper-Pearson method, and a descriptive comparison between response categories will be presented.
Rates of distant metastasis
Will be defined as proportion of patients experiencing distant metastatic disease. Will be summarized as proportions with 95% CIs.
Changes in immune biomarkers
Single-cell ribonucleic acid sequencing will be performed on tumor tissue to evaluate changes within the tumor microenvironment. Will be analyzed using paired t-tests or Wilcoxon signed-rank tests for non-normally distributed data, and multivariable models will be used to explore correlations between these changes and clinical endpoints (e.g., ORR, MPR).
Systemic immune activation markers
Peripheral blood mononuclear cell analysis will be conducted. Changes will be analyzed using paired t-tests or Wilcoxon signed-rank tests for non-normally distributed data, and multivariable models will be used to explore correlations between these changes and clinical endpoints (e.g., ORR, MPR).
T-cell clonality and diversity
T-cell receptor sequencing will be used to evaluate tumor and blood samples. Data will be summarized descriptively, with changes in clonality indices assessed using paired statistical tests, while associations between TCR clonality and clinical outcomes (e.g., ORR, DFS) will be explored using logistic or Cox regression models.
Immune cell subset analysis
Immunofluorescence immunohistochemistry will be employed to assess immune cell subsets, including CD8+, CD4+, and Treg populations, within the tumor microenvironment. Data will be summarized descriptively, with changes assessed using paired statistical tests, while associations between immune cell subsets and clinical outcomes (e.g., ORR, DFS) will be explored using logistic or Cox regression models.
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