In addition to cabozantinib, nivolumab is an anti-PD-1 antibody newly approved as a second-line option for metastatic RCC. Currently, there are no trials comparing cabozantinib with nivolumab, but an ongoing combination trial could prove to be beneficial.72 Nivolumab is an anti-PD-1 antibody that was initially developed for patients with advanced melanoma and non-small-cell lung cancer and has shown activity in advanced RCC. In a large Phase III trial, Checkmate-025, nivolumab prolonged overall survival when compared with everolimus as a second-line therapy in patients progressing after initial treatment with a VEGF TKI. The toxicity profile was notably low with grade 3 or 4 treatment-related adverse events occurring in only 19% of patients receiving nivolumab.73 Nivolumab competes with cabozantinib after progression on first-line agents or for patients unable to tolerate cabozantinib. While these drugs have distinct mechanisms of action, the combination of cabozantinib and nivolumab may also lead to a potential benefit of immune modulation in genitourinary tumors. In a study of metastatic urothelial cancer, regulatory T cell levels prior to cabozantinib treatment have been shown predictive of therapeutic responsiveness and overall survival. When assessing myeloid-derived suppressor cells and regulatory T cells in patients undergoing treatment with cabozantinib after 2 cycles, patients with low regulatory T cells measured in peripheral blood samples at baseline had an improved response rate, PFS, and OS. Regulatory T cells decreased and PD-1 expression in regulatory T cells increased after cabozantinib treatment (P=0.015 and P=0.011, respectively). Patients with less change in PD-1 levels showed a trend to an improved PFS, and a decrease in myeloid-derived suppressor cells’ expression on treatment was associated with an improved PFS. These results suggest that changes in regulatory T cell checkpoint molecule expression and myeloid-derived suppressor cells expression may be prognostic and/or predictive markers in patients with metastatic urothelial carcinoma treated with cabozantinib.74 Such results have led to investigation of a Phase I trial of cabozantinib and nivolumab with or without ipilimumab in treating patients with genitourinary tumors (NCT02496208). Currently, there are no other cabozantinib-based combination therapies under trial but this remains a tantalizing area of investigation.

Cabozantinib should also be compared with other second-line agents approved for RCC. Cabozantinib has yet to be compared with axitinib in clinical trials, and given that both agents are now approved in the second-line setting, this would have merit. Cabozanitinib should also be compared with the combination of levatinib + everolimus, which recently was shown to be superior to everolimus alone.75 An ongoing randomized Phase II trial comparing PFS with cabozantinib, crizotinib, volitinib, or sunitinib in metastatic papillary RCC will provide efficacy and toxicity data.76

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There may also be a role of cabozantinib in the adjuvant setting. The ASSURE trial looked at 1,943 patients with resected, intermediate- or high-risk kidney cancer (both clear cell and nonclear cell) and randomly assigned them to 1 year of adjuvant sorafenib, sunitinib, or placebo. There were no significant differences in disease-free survival or overall survival between the drug and placebo arm. The median disease-free survival was 5.8 years in both the sorafenib and sunitinib arms and 6 years in the placebo arm.77 Though these results suggest a lack of benefit of TKIs in the adjuvant setting, the ongoing SORCE, S-TRAC, and ATLAS trials investigate the use of adjuvant sorafenib and axitinib for 3 years, respectively.78–80 If these studies prove positive, it raises the possibility that cabozantinb could also be beneficial in the adjuvant setting after surgery, radiofrequency ablation, or cryoablation.

Currently, there are no biomarkers related to cabozantinib in RCC, but such a discovery might improve the utility of cabozantinib. In prostate cancer, cabozantinib had some activity in reducing circulating tumor cells and bone biomarkers on treatment, but the drug did not impact PSA in the Phase III COMET 1 study. In an analysis of a Phase II trial, plasma concentrations of VEGFR2, Trap5b, Angiopoietin-2, TIMP-2, and TIE-2 significantly decreased during treatment with cabozantinib; there was no significant associations between any biomarker and type of response.62 Carbozantinib also inhibits RET, ROS1, NTRK, MET, and AXL, and there may be utility in investigating its role in specific cancer genotypes. A Phase II study in patients with advanced non-small cell lung cancer is currently investigating cabozantinib in patients whose tumors express changes in RET, ROS1, or NTRK fusion or increased MET or AXL activity. In lung cancer, RET, ROS1, or NTRK fusion or increased MET or AXL activity gene leads to increased cell growth.81 If effective in non-small-cell lung cancer, similar studies with specific genotypes may be warranted in RCC. The MET pathway has been studied in papillary RCC with patients harboring a germline MET mutation showing high response rate in a Phase II study.82 Some patients with chromosome 7 and/or c-MET local alterations have also been shown to respond very well to pathway blockade, offering a potential area of investigation.83 In addition, cabozantinib has effects on immune markers and may counteract tumor-induced immunosuppression, providing a rationale for combining cabozantinib with immunotherapeutic strategies. In a study characterizing the pharmacodynamic effect of cabozantinib, cabozantinib had an effect on PDL-1 and CTLA-4 expression on regulatory T cells, and T regulatory cell levels may be future prognostic markers.84 If such biomarkers could be validated in RCC and followed throughout treatment, it may facilitate dynamic targeted intervention in advanced RCC.