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Cabozantinib in RCC
How Cabozantinib Is Transforming RCC Clinical Practice

Released: December 19, 2016

Expiration: December 18, 2017

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Recently, the FDA has approved 3 new agents for the treatment of advanced renal cell carcinoma (RCC) that is refractory to first-line tyrosine kinase inhibitor (TKI) therapy: nivolumab (in November 2015), cabozantinib (in April 2016), and lenvatinib in combination with everolimus (in May 2016). The NCCN guidelines now list these 3 options, along with axitinib as Category 1 recommendations for subsequent therapy following first-line treatment of patients with advanced RCC (predominantly for patients with clear-cell histology). Moreover, cabozantinib and nivolumab now carry a “preferred” designation due to demonstrated OS benefit in phase III clinical trials. Here, I discuss the data for cabozantinib and share my thoughts on its current and future role in advanced RCC.

METEOR: Cabozantinib vs Everolimus in Advanced RCC
The phase III METEOR trial compared cabozantinib with everolimus in patients with advanced RCC (with any clear-cell component) and radiographic disease progression on at least 1 previous VEGFR-targeted TKI (with no limit on number and type of previous therapies). The primary endpoint was PFS, with OS and ORR as secondary endpoints. However, the study was powered to achieve appropriate statistical power for the analysis of the OS endpoint.

In total, 658 patients were randomized 1:1 to cabozantinib or everolimus. Results published in the New England Journal of Medicine showed that median PFS was 7.4 months with cabozantinib vs 3.9 months with everolimus (HR: 0.51; P < .0001). The ORR was also significantly improved in the cabozantinib-treated patients (RECIST PR rates: 17% vs 3%; P < .001). Final results presented at the 2016 ASCO annual meeting showed significantly improved OS in patients who received cabozantinib: median of 21.4 months vs 16.5 months with everolimus (HR 0.66; P = .0003). This strongly positive study led to the approval of cabozantinib in RCC and its designation as a Category 1 recommendation in the NCCN guideline.

CABOSUN: Cabozantinib vs Sunitinib in First-line Treatment of Advanced RCC
The phase II CABOSUN trial compared cabozantinib with sunitinib in the first-line setting for International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) intermediate-risk and poor-risk patients with advanced RCC (with clear-cell component). The primary endpoint was duration of PFS, and secondary endpoints included OS, ORR, and safety.

In total, 157 patients were randomized 1:1 to cabozantinib or sunitinib. Most (81%) of the patients were IMDC intermediate risk (19% were IMDC poor risk). Recent results reported by Choueiri and colleagues demonstrated superior clinical efficacy in cabozantinib-treated patients. Median PFS was 8.2 months with cabozantinib vs 5.6 months with sunitinib (HR: 0.66; P = .012). PFS favored cabozantinib in both IMDC risk groups. In addition, confirmed ORR (either CR or PR) of 46% was reported for patients treated with cabozantinib compared with 18% in the sunitinib group. There was no statistically significant difference in OS at the time of data analysis (median: 30.3 months with cabozantinib vs 21.8 months with sunitinib). However, further follow-up is planned to assess mature OS data, even though the study was not designed for this endpoint. Safety profiles were comparable, with similar rates of all-grade AEs, grade ≥ 3 AEs, and treatment discontinuation. Thus, cabozantinib may also be a potential first-line treatment option for patients with intermediate-risk and high-risk advanced RCC.

What Does This All Mean for the Future of Cabozantinib?
The results of the METEOR and CABOSUN studies clearly demonstrate the strong clinical efficacy of cabozantinib in patients with RCC. Cabozantinib is now one of 2 agents that have demonstrated OS benefit in advanced RCC (nivolumab is the other) and is the first to show superior clinical efficacy compared with sunitinib, the standard-of-care first-line option for advanced RCC for the past decade.

This leads to the question, “why is cabozantinib so effective?” In addition to inhibiting VEGFR as a target, cabozantinib also inhibits MET, AXL, RET and c-KIT, among other tyrosine kinases. It is unclear what role these tyrosine kinases play in the tumorigenesis as well as disease progression in RCC, but these additional targets may explain the superior clinical efficacy of cabozantinib. For example, intratumoral MET expression did not predict for the clinical activity of cabozantinib over everolimus in the METEOR trial. However, further preclinical and clinical research regarding the role of these additional targets, as well as their potential to act as biomarkers, is necessary.

A second issue for clinicians is how to choose which agent to use for individual patients with advanced RCC. Whereas the CABOSUN data suggest that cabozantinib should at least be an option for patients with intermediate-risk and poor-risk disease, it is not yet approved in the first-line setting. Regardless, with results pending from multiple phase III studies of immunotherapy-based combination regimens, decision making regarding first-line therapy is sure to become more complicated. In the second-line setting, whereas cabozantinib and nivolumab have demonstrated OS benefit, there are no definitive data that either or both of these agents, along with the novel lenvatinib/everolimus combination, are clearly superior to the standard-of-care axitinib. Currently, no biomarkers or other objective measures exist to help clinicians and their patients make decisions on the optimal treatment in the second-line setting.

Finally, despite the profound clinical impact demonstrated by cabozantinib in these studies, patients with advanced RCC inevitably progress and die from their disease. In addition to knowing when to use cabozantinib as a single agent, we also need to investigate its role in combination approaches. Particularly given its immunomodulatory potential, as well as the clear efficacy of immunotherapy in RCC, the use of cabozantinib in combination with checkpoint inhibition or other immunotherapy approaches is promising.

A New Tool to Help Guide RCC Treatment Decisions
To help you address the challenges associated with treatment decisions for your patients with RCC, my colleagues (Thomas E. Hutson, DO, PharmD, FACP; Robert Motzer, MD; Elizabeth R. Plimack, MD, MS; and Brian Rini, MD, FACP) and I are updating an Interactive Treatment Decision Tool along with several more commentaries on managing patients with RCC, so check back in on the CCO Web site for more information soon. An older version of this Interactive Treatment Decision Tool is available here, and an updated version will be published on the CCO Web site in early 2017. This tool is designed to help you rapidly select individualized treatment options based on your patient’s specific characteristics by offering recommendations from each of the experienced faculty listed above specifically for the case you enter into the tool.

Please share your questions or thoughts on your current management approaches for patients with RCC in the comment box below.