Cabozantinib in Patients with Advanced Renal Cell Carcinoma Primary Refractory to First-line Immunocombinations or Tyrosine Kinase Inhibitors

Background: A subset of patients with metastatic renal cell carcinoma (mRCC), deemed as primary refractory, shows progressive disease as the best response to first-line therapy even when treated with novel immune-based combos. Objective: We aimed to assess the outcome of patients treated with second-line cabozantinib for mRCC primary refractory to first-line therapy defined as Response Evaluation Criteria in Solid Tumors (RECIST) progression in the computed tomography scan as the best response to the upfront treatment. Design, setting, and participants: We retrospectively collected data from 11 worldwide centers. Outcome measurements and statistical analysis: Overall survival (OS) and progression-free survival (PFS) were analyzed using Kaplan-Meier curves. Cox proportional models were used at univariate and multivariate analyses. Results and limitations: We collected data from 108 patients with mRCC primary refractory to pembrolizumab plus axitinib (17%), nivolumab plus ipilimumab (36%), or tyrosine kinase inhibitors (TKIs; 31% sunitinib and 16% pazopanib). The median OS with cabozantinib was 9.11 mo, and it was 8.84 and 9.11 mo in patients primary refractory to immunocombinations and TKIs, respectively (p = 0.952). A significant difference was found between patients primary refractory to pembrolizumab plus axitinib (OS not reached) and those primary refractory to nivolumab plus ipilimumab (median OS 8.12 mo, p = 0.024). The median PFS with cabozantinib was 7.30 mo, without significant differences between patients primary refractory to immunocombinations and those primary refractory to TKIs (6.90 vs 7.59 mo, p = 0.435) or between patients primary refractory to pembrolizumab plus axitinib and those primary refractory to nivolumab plus ipilimumab (7.92 and 6.02, p = 0.509). Investigator-assessed overall response rates were 21% and 12% in patients primary refractory to first-line immunocombinations and TKIs, respectively, with a clinical benefit of 48% in the overall population. Conclusions: Our data show that cabozantinib is active in primary refractory mRCC patients regardless of which treatment is received as first-line therapy. Systemic options and prognosis of primary refractory patients with mRCC, particularly those treated with novel immune-based combos, are among the major challenges that we need to face in this field. Patient summary: Patients primary refractory to first-line therapy are characterized by a poor prognosis. Herein, we aimed to assess the outcome of patients treated with secondline cabozantinib for metastatic renal cell carcinoma (mRCC) primary refractory to firstline therapy. Our results suggest that cabozantinib is active in primary refractory mRCC patients. (C) 2022 European Association of Urology. Published by Elsevier B.V. All rights reserved.

Automated summary

Cabozantinib is an effective second-line treatment option for patients with primary refractory metastatic renal cell carcinoma (mRCC), regardless of whether first-line therapy is immune-based combination therapy or tyrosine kinase inhibitors.