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.
In this article, Dr. Abdelaziz does a nice job summarizing data to date of cabozantinib in RCC and identifying where this drug might be headed going forward.
It has been less than a year since the FDA approved cabozantinib for RCC treated with prior anti-angiogenesis agents. This followed on the heels of the publication of results of the METEOR study showing that cabozantinib has better OS, RR, and PFS than one of the prior standards—everolimus. This therapy coincided with an era when nivolumab and combination lenvatinib/everolimus also were found to be superior to everolimus.
This article summarized data on cabozantinib and puts it into context with other data in similar lines of therapy in attempt to delineate a place for each agent in second line, guiding toward therapy based on prior side effect profile, comorbidity, response to prior anti-angiogenesis agent, and site of metastasis. Moreover, it summarizes front-line data to date including the CABOSUN trial and looks toward the utility of cabozantinib in non–clear cell histology. The article is certainly worth reading to understand all the current data on cabozantinib and its emerging and evolving role in RCC.