Pembrolizumab With or Without Axitinib for Clear Cell Kidney Cancer in Patients Undergoing Surgery

PRIMARY OBJECTIVE: I. To determine the impact of pembrolizumab-based therapy on the composition, phenotype, and function of tumor-infiltrating immune cells (TIICs) in subjects with advanced renal cell carcinoma (RCC) undergoing cytoreductive nephrectomy (CN)/metastasectomy (MET). SECONDARY OBJECTIVES: I. To determine the clinical efficacy of preoperative pembrolizumab-based therapy in subjects with advanced RCC undergoing CN/MET. II. To explore the clinical efficacy of continued pembrolizumab-based therapy following CN/MET in subjects with advanced RCC. III. To determine the safety and tolerability of pembrolizumab-based therapy in subjects with advanced RCC undergoing CN/MET. EXPLORATORY OBJECTIVES: I. To explore the clinical efficacy of preoperative pembrolizumab-based therapy in subjects with advanced RCC, by pathologic response. (Clinical). II. To explore the relationship between changes in TIICs and clinical efficacy in subjects with advanced RCC treated with pembrolizumab-based therapy. (Scientific). III. To characterize changes in the frequency and number of circulating T cells induced by pembrolizumab-based therapy in subjects with advanced RCC. (Scientific). IV. To determine the impact of pembrolizumab-based therapy on the composition and phenotype of the tumor microenvironment (including tumor and stromal cells) in subjects with advanced RCC. (Scientific). V. To determine whether locally advanced versus metastatic RCC exhibit differences in immune composition or phenotype at baseline and in response to pembrolizumab-based therapy. (Scientific). VI. To determine the change in T cell repertoire within the tumor and blood induced by pembrolizumab-based therapy in subjects with advanced RCC. (Scientific). VII. To explore molecular profiles to identify potentially predictive biomarkers for subjects with advanced RCC treated with immunotherapy (Scientific). OUTLINE: Patients are assigned to 1 of 2 cohorts. COHORT A: Patients receive pembrolizumab intravenously (IV) over 30 minutes on day 1. Treatment repeats every 21 days for 3 cycles in the absence of disease progression or unacceptable toxicity. Within 14-21 days following the end of treatment, patients will undergo standard of care CN or MET. Patients with progressive disease (PD) may undergo CN or MET per physician discretion. Within 21-42 days after surgery, patients with no disease (R0 resection) or microscopic disease (R1 resection) receive pembrolizumab IV every 42 days for up to 9 cycles (1 year) and patients with macroscopic disease (R2 resection) receive pembrolizumab IV every 42 days for up to 18 cycles (2 years) in the absence of disease progression or unacceptable toxicity COHORT B: Patients receive pembrolizumab IV over 30 minutes on day 1 and standard of care axitinib orally (PO) twice daily (BID) on days 1-42. Treatment repeats every 21 days for 3 cycles in the absence of disease progression or unacceptable toxicity. Within 14-21 days following the end of treatment, patients undergo standard of care CN or MET. Patients with PD may undergo CN or MET per physician discretion. Within 21-42 days after surgery, patients with an R0 or R1 resection receive pembrolizumab IV over 30 minutes on day 1 and axitinib PO BID on days 1-42. Treatments repeat every 42 days for up to 9 cycles (1 year) in the absence of disease progression or unacceptable toxicity. Patients with an R2 resection receive pembrolizumab IV over 30 minutes on day 1 and axitinib PO BID on days 1-42. Treatment repeats every 42 days for up to 18 cycles (2 years) in the absence of disease progression or unacceptable toxicity. Follow-up will occur at treatment discontinuation, 30 days post-discontinuation, and then every 12 weeks for up to 1 year post-discontinuation. Subjects who discontinue study participation due to progressive disease will return for a mandatory safety follow-up visit within 30 days of(+7 days) after the final dose of study treatment.