Cabozantinib (Cabometyx) Wins FDA Nod for Patients With Advanced Renal Cell Carcinoma

Therapy improves overall survival, progression-free survival, and objective response rate in phase 3 trial

The FDA has approved cabozantinib tablets (Cabometyx, Exelixis, Inc.) for the treatment of patients with advanced renal cell carcinoma (RCC) who have received prior anti-angiogenic therapy. RCC is the most common form of kidney cancer in adults. Cabozantinib, which was granted fast track and breakthrough therapy designations, is the first therapy to demonstrate clinically meaningful improvements in all three key efficacy parameters—progression-free survival (PFS), overall survival (OS), and the objective response rate (ORR)––in a phase 3 study of patients with advanced RCC.

Cabozantinib’s targets include MET, AXL, and vascular endothelial growth factor receptor (VEGFR)-1, -2 and -3. In preclinical models, the drug inhibited the activity of these receptors, which are involved in both normal cellular function and pathologic processes, such as tumor angiogenesis, invasiveness, metastasis, and drug resistance.

The FDA’s approval of cabozantinib tablets was based on results from the phase 3 METEOR trial, which met its primary endpoint of improving PFS. METEOR was an open-label study of 658 patients with advanced RCC who had failed at least one VEGFR tyrosine kinase inhibitor (TKI) therapy. The study’s primary endpoint was PFS. Secondary endpoints included OS and the ORR. The patients were randomly assigned to receive cabozantinib (60 mg per day) or everolimus (10 mg per day), the standard of care for second-line RCC. No crossover was allowed between the study arms. The trial was conducted at approximately 200 sites in 26 countries.

Compared with everolimus, cabozantinib was associated with a 42% reduction in the rate of disease progression or death. Median PFS for cabozantinib was 7.4 months compared with 3.8 months for everolimus (hazard ratio [HR], 0.58; P < 0.0001). Cabozantinib also significantly improved the ORR compared with everolimus. These data were published in the New England Journal of Medicine.

As announced in February 2016, cabozantinib also demonstrated a statistically significant and clinically meaningful increase in OS in the METEOR trial. Compared with everolimus, cabozantinib was associated with a 34% reduction in the rate of death. Median OS was 21.4 months for patients receiving cabozantinib compared with 16.5 months for those receiving everolimus (HR, 0.66; P = 0.0003).

The most common adverse events associated with cabozantinib included diarrhea, fatigue, nausea, decreased appetite, hand–foot syndrome, hypertension, vomiting, weight loss, and constipation. The dose-reduction rates were 60% for cabozantinib and 24% for everolimus. The rates of treatment discontinuation due to adverse events were low (10% in each arm).

Source: Exelixis, Inc.; April 25, 2016.