Cabozantinib for Renal Cell Carcinoma: Current and Future Paradigms

Opinion statement

Cabozantinib was approved by the FDA in April 2016 for the treatment of advanced renal cancer, pretreated with at least one prior antiangiogenic therapy. This is the first agent in the therapy of kidney cancer to show a statistically significant improvement in all three endpoints of clinical efficacy, response rate, progression free survival, and overall survival (OS), in a phase III randomized trial. The reporting of METEOR coincided with that of the Checkmate 025 study which randomized similarly eligible patients to receive nivolumab or everolimus 10 mg daily. As the drug development has occurred in parallel for cabozantinib and nivolumab, no evidence exists for decision making regarding optimal sequencing of these agents. A third option of lenvatinib and everolimus was also rapidly approved based on a phase II randomized trial demonstrating promising magnitude of improvement in response, progression-free survival (PFS), and OS. The differences in toxicity profiles, duration and toxicities of prior therapy, presence of brain metastases, concomitant immunosuppressive therapies, or autoimmune conditions are the factors that are taken into account when choosing therapy. The patients who have demonstrated response, prolonged clinical benefit and tolerability, and with anti-VEGF therapy are likely to benefit from continued antiangiogenic activity combined with MET and HGF inhibition with cabozantinib at progression. The patients who have intolerance or poor response to anti-VEGF TKI should be switched to nivolumab as the preferential therapy of choice. Clearly, better predictors are required to aid in guiding therapeutic decisions. The CABOSUN trial will likely shift the entire paradigm. The CABOSUN trial demonstrated superior PFS and response rates favoring cabozantinib as compared to sunitinib in untreated, intermediate, or poor-risk RCC and can be predicted to become the front-line therapy of choice. Immune-based regimens such as the combinations of nivolumab + ipilimumab and bevacizumab + atezolizumab have completed phase III trials, comparing to sunitinib, and results are awaited. In the future, a similar clinical dilemma will be shifted to the front-line therapy and the nuances of trial eligibility, and patient comorbidities will remain important factors. Optimal sequencing and predictive biomarkers are the questions that need to be incorporated in future clinical trials within RCC.