Cyto-KIK: A phase II trial of cytoreductive surgery in kidney cancer plus immunotherapy (nivolumab) and targeted kinase inhibition (cabozantinib).

513 Background: Despite recent therapeutic advancements in metastatic clear cell renal cell carcinoma (mccRCC), only about 10% of patients will achieve a complete response (CR) to therapy. Cytoreductive nephrectomy (CN) removes a large portion of the tumor burden which may be a source of immunosuppression. Improved outcomes with neoadjuvant compared to adjuvant immune checkpoint inhibitors has been demonstrated in several tumor types including melanoma. In 2020, CheckMate9ER established cabozantinib (cabo) and nivolumab (nivo) as a first-line treatment regimen in mccRCC. We hypothesized that if tumor-specific immune responses to immunotherapy are greatest prior to nephrectomy, then treatment with cabo+nivo prior to CN will lead to maximal peripheral and intra-tumoral specific immune responses and higher rates of CR during treatment. Methods: This is an open label phase II, single arm, multicenter trial of combination cabo+nivo prior to and after CN in patients with mccRCC. 38 treatment-naïve subjects were enrolled with the primary endpoint of CR rate according to RECIST version 1.1. Subjects received cabo (40mg) daily and nivo (480mg) every 4 weeks for 12 weeks prior to nephrectomy and a 3+3 design was used to evaluate the safety of the interval (21 or 14 days) between the discontinuation of cabo and nephrectomy. Post-operatively, subjects resumed treatment with cabo+nivo until evidence of disease progression. Secondary endpoints include median size reduction of the primary tumor, response rate, surgical outcomes using the Clavien-Dindo classification system, PFS and OS. Results: Between June 2020 and April 2025, 38 patients were enrolled. 71% of subjects were male and 29% were female with median age 64 years at time of enrollment. 74% of patients had IMDC intermediate-risk disease and 26% of patients had IMDC poor- risk disease. The first 5 subjects were enrolled in cohort 1 and the subsequent 33 subjects enrolled in cohort 2 with a 14-day interval of discontinuation between cabo and CN. All subjects received at least one dose of the study drugs, however, 6 subjects did not complete CN. Out of 35 subjects, 22% experienced a partial response and 77% had stable disease prior to nephrectomy. The ORR was 50% (3CRs, 13 PRs) for 32 subjects post-CN. 6/13 PRs had RECIST responses ≥95%. Median size reduction of the primary tumor was 19%. There were no path CRs reported but 5 subjects experienced near path CRs, > 90% tumor necrosis. There was one Grade IIIa Clavien-Dindo surgical complication related to the study. All subjects experienced a grade 1-2 AE and 11% of subjects experienced a grade 3 or higher AE. There were no new safety signals. Conclusions: This novel phase II trial of cabo+nivo prior to cytoreductive nephrectomy demonstrates safety and feasibility of CN in the current IO+TKI era. The complete response rate was 9% in this high risk de-novo metastatic population. Clinical trial information: NCT04322955 .