Clinical Use of Cabozantinib in the Treatment of Advanced Kidney Cancer: Efficacy, Safety, and Patient Selection
the ONA take:
Cabozantinib is an oral multikinase inhibitor that blocks the activity of MET; VEGFR-1, -2 and -3; AXL; RET; ROS1; TYRO3; MER; KIT; TRKB; FLT-3; and TIE-2. It is approved by the US Food and Drug Administration as Cometriq for the treatment of patients with progressive, metastatic medullary thyroid cancer and as Cabometyx for advanced renal cell carcinoma in patients who have received prior anti-angiogenic therapy.
Initial studies in renal cell carcinoma evaluated the activity and toxicity of cabozantinib at a dose of 140 mg once daily, which is the approved dose for medullary thyroid cancer, but considerable toxicity was observed. Phase 2 trials then assessed cabozantinib at lower doses in other tumor types, including metastatic prostate cancer, with 84% of patients receiving cabozantinib at a dose of 100 mg requiring at least 1 dose reduction. In addition, 25% discontinued treatment with the 100 mg dose due to an adverse event.
The phase 3 METEOR trial then examined the efficacy and safety of cabozantinib at a starting dose of 60 mg in patients with renal cell carcinoma. Notably, 60% of patients required dose reductions, but the rate of treatment discontinuation due to an adverse event was similar to that of the everolimus comparator arm.
Further studies are needed to determine the optimal dosing and schedule of cabozantinib to further improve the tolerability of cabozantinib while maintaining its efficacy.
OncoTargets and Therapy
Abstract: Clear cell (cc) renal cell carcinoma (RCC) is the most common type of cancer found in the kidney accounting for ~90% of all kidney cancers. In 2012, there were ~337,000 new cases of RCC diagnosed worldwide with an estimated 143,000 deaths, with the highest incidence and mortality in Western countries. Despite improvements in cancer control achieved with VEGF- and mTOR-targeted therapy for RCC, progression remains virtually universal and additional therapies are needed. The pivotal results of the METEOR trial led to cabozantinib's designation as a breakthrough drug by the US Food and Drug Administration and its approval for treatment of advanced RCC in 2016. Subsequent data from the CABOSUN trial, where caboxantinib is compared with sunitinib, will provide information on the relative activity of cabozantinib as first-line therapy for ccRCC. We review the development of cabozantinib in advanced RCC and its role in the treatment landscape for advanced RCC.
Keywords: cabozantinib, renal cell carcinoma, kidney cancer, clear cell carcinoma, tyrosine kinase inhibitor
Clear cell (cc) renal cell carcinoma (RCC) is the most common type of cancer found in the kidney accounting for ~90% of all kidney cancers. In 2012, there were ~337,000 new cases of RCC diagnosed worldwide with an estimated 143,000 deaths, with the highest incidence and mortality in North America and Europe. The USA is among the top four countries in incidence and mortality worldwide.1,2 The development of RCC is associated with smoking, obesity, male sex, and family history and genetic conditions such as von Hippel-Lindau disease as well as possibly type 2 diabetes mellitus and hepatitis C infection.3,4 In the USA, there were an estimated 62,000 new cases and ~14,000 deaths from RCC in 2015.5 Patients with localized disease have a nearly 92% 5-year survival with curative surgery, whereas patients with advanced RCC have 5-year survival rates of ~11%–12%.6 Despite improvements in cancer control achieved with VEGF- and mTOR-targeted therapy for RCC, progression remains virtually universal and additional therapies are needed. In this review, we delineate the differences between cabozantinib and preexisting VEGF-targeted therapy by reviewing the efficacy, safety, and patients who benefit from cabozantinib. We assess the quality of preclinical data and Phases I–III trials testing cabozantinib in various cancer types and identify gaps in knowledge where new trials are needed.