The U.S. Food and Drug Administration ( FDA ) has approved Cabometyx ( Cabozantinib ) tablets for the treatment of patients with advanced renal cell carcinoma ( RCC ) who have received prior anti-angiogenic therapy.

Cabozantinib targets include MET, AXL and VEGFR-1, -2 and -3. In preclinical models, Cabozantinib has been shown to inhibit the activity of these receptors, which are involved in normal cellular function and pathologic processes such as tumor angiogenesis, invasiveness, metastasis and drug resistance.

Cabometyx, which was granted Fast Track and Breakthrough Therapy designations by the FDA, is the first therapy to demonstrate in a phase 3 trial for patients with advanced renal cell carcinoma, robust and clinically meaningful improvements in all three key efficacy parameters ( overall survival, progression-free survival and objective response rate ).

The approval of Cabometyx is based on results of the phase 3 METEOR trial, which met its primary endpoint of improving progression-free survival. Compared with Everolimus, a standard of care therapy for second-line RCC, Cabozantinib was associated with a 42% reduction in the rate of disease progression or death.
Median progression-free survival for Cabozantinib was 7.4 months versus 3.8 months for Everolimus ( hazard ratio, HR=0.58, 95% CI 0.45-0.74, P less than 0.0001 ).
Cabozantinib also significantly improved the objective response rate compared with Everolimus.

Cabozantinib has also demonstrated a statistically significant and clinically meaningful increase in overall survival in the METEOR trial. Compared with Everolimus, Cabozantinib was associated with a 34% reduction in the rate of death. Median overall survival was 21.4 months for patients receiving Cabozantinib versus 16.5 months for those receiving Everolimus ( HR=0.66, 95% CI 0.53-0.83, P=0.0003 ).

The most common ( frequency greater than or equal to 25% ) adverse reactions in Cabozantinib-treated patients include diarrhea, fatigue, nausea, decreased appetite, hand-foot syndrome, high blood pressure, vomiting, weight loss, and constipation. Dose reduction rates were 60% for Cabozantinib and 24% for Everolimus.
The rate of treatment discontinuation due to adverse reactions was low ( 10% in each arm ) and consistent with that previously reported for Everolimus.

METEOR was an open-label, event-driven trial of 658 patients with advanced renal cell carcinoma who had failed at least one prior vascular endothelial growth factor ( VEGF ) receptor tyrosine kinase inhibitor ( TKI ) therapy.
The primary endpoint was progression-free survival. Secondary endpoints included overall survival and objective response rate. The trial was conducted at approximately 200 sites in 26 countries, and enrollment was weighted toward Western Europe, North America, and Australia.
Patients were randomized 1:1 to receive 60 mg of Cabozantinib daily or 10 mg of Everolimus daily and were stratified based on the number of prior VEGF receptor TKI therapies received and on MSKCC risk criteria.
No cross-over was allowed between the study arms.

The American Cancer Society’s 2016 statistics cite kidney cancer as among the top ten most commonly diagnosed forms of cancer among both men and women in the U.S.
Clear cell RCC is the most common type of kidney cancer in adults. If detected in its early stages, the five-year survival rate for renal cell carcinoma is high; for patients with advanced or late-stage metastatic renal cell carcinoma, however, the five-year survival rate is only 12%, with no identified cure for the disease.
Approximately 17,000 patients in the U.S. and 37,000 globally require second-line or later treatment.

The majority of clear cell RCC tumors have lower than normal levels or function of the von Hippel-Lindau protein, which leads to higher levels of MET, AXL and VEGF. Higher than normal levels of these proteins can promote tumor angiogenesis ( blood vessel growth ), growth, invasiveness and metastasis. MET and AXL may also provide escape pathways that drive resistance to VEGF receptor inhibitors. ( Xagena )

Source: Exelixis, 2016