Prognostic impact of complete metastasectomy in metastatic renal cell carcinoma in the era of immuno-oncology-based combination therapies

PURPOSE: Complete metastasectomy of renal cell carcinoma (RCC) is receding into the past due to the progress of immuno-oncology-based combinations (IO) in systemic therapy. The prognostic impact of curative intended complete metastasectomy vs. immediate IO-based therapy or tyrosine kinase inhibition (TKI) on progression-free survival (PFS) and cancer-specific survival (CSS) was investigated in the first-line setting. METHODS: 205 patients with synchronous or metachronous metastasis received complete metastasectomy (n = 80) or systemic therapy (n = 125, TKI: 87, TKI–IO: 13, IO–IO: 25) as first-line therapy. The prognostic impact of these therapies was assessed using Cox regression and Kaplan–Meier analyses. RESULTS: First-line complete metastasectomy significantly improved CSS compared to both TKI monotherapy (6.1 vs. 2.6 years, HR 0.45, p < 0.001) and IO-based combination therapy (IO–IO/TKI–IO, 6.1 vs. 3.5 years, HR 0.28, p = 0.007). Repetitive complete metastasectomy without ever receiving systemic therapy vs. systemic therapy in first-line significantly prolonged CSS (11.3 vs. 3.1 years, HR 0.34, p = 0.002). First-line complete metastasectomy and subsequent systemic therapy at tumor progression was associated with a significant CSS benefit vs. systemic therapy (5.8 vs. 3.1 years, HR 0.53, p = 0.003), also compared to IO-based combinations (5.8 vs. 3.5 years, HR 0.30, p = 0.017). Median PFS was improved by IO-based therapy compared to TKI monotherapy in the first-line setting (HR 0.61, p = 0.05), with maximal benefit of the TKI–IO combination vs. TKI monotherapy (HR 0.27, p = 0.01), as well as compared to PFS of complete metastasectomy (HR 0.34, p = 0.035). CONCLUSION: Despite the progress of IO-based combination therapies in first line, complete metastasectomy remains an integral part of the multimodality treatment of metastatic RCC.