The US Food and Drug Administration (FDA) has approved Exelixis' Cabometyx (cabozantinib) tablets 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. 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 RCC, robust and clinically meaningful improvements in all three key efficacy parameters — overall survival, progression-free survival and objective response rate.

“With today’s announcement, patients with previously treated advanced kidney cancer now have a new option, the first and only approved product demonstrated to help patients live longer while also delaying the progression of their cancer,” said Michael M. Morrissey, Ph.D., president and chief executive officer of Exelixis. “We are proud to bring new hope to this community, who are looking for more therapies that can help extend lives. Exelixis is committed to making Cabometyx available to patients in need within the next couple weeks.”

“The efficacy profile demonstrated by Cabometyx in the METEOR trial, now complemented by the overall survival benefit, is highly compelling,” said Toni Choueiri, MD, Clinical Director, Lank Center for Genitourinary Oncology, Dana-Farber Cancer Institute. “Cabometyx is distinct from other approved treatment options, as it targets multiple tyrosine kinases involved in the development of RCC, including MET, AXL and three VEGF receptors. At the same time, physicians are very familiar with this class of drug and how to use dose adjustments to balance safety and efficacy. The approval of Cabometyx is wonderful news for physicians who are looking for a new option for their previously treated patients with advanced kidney cancer.”

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, Cabometyx was associated with a 42 per cent 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 (HR=0.58, 95% CI 0.45-0.74, P<0.0001). Cabometyx also significantly improved the objective response rate compared with everolimus. These data were presented at the European Cancer Congress in September 2015 and published in The New England Journal of Medicine.

As announced in February 2016, Cabometyx also demonstrated a statistically significant and clinically meaningful increase in overall survival in the METEOR trial. Compared with everolimus, Cabometyx was associated with a 34 percent reduction in the rate of death. Median overall survival was 21.4 months for patients receiving Cabometyx versus 16.5 months for those receiving everolimus (HR=0.66, 95% CI 0.53-0.83, P=0.0003).

The most common (frequency =25 per cent) adverse reactions in Cabometyx-treated patients include diarrhoea, fatigue, nausea, decreased appetite, hand-foot syndrome, high blood pressure, vomiting, weight loss, and constipation. Dose reduction rates were 60 percent for Cabometyx and 24 percent for everolimus. The rate of treatment discontinuation due to adverse reactions was low (10 percent 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 Cabometyx 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 US. 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 RCC is high; for patients with advanced or late-stage metastatic RCC, however, the five-year survival rate is only 12 per cent, with no identified cure for the disease. Approximately 17,000 patients in the US 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 tumour angiogenesis (blood vessel growth), growth, invasiveness and metastasis. MET and AXL may also provide escape pathways that drive resistance to VEGF receptor inhibitors.

Cabometyx 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 tumour angiogenesis, invasiveness, metastasis and drug resistance.

Cabometyx, the tablet formulation of cabozantinib, will be available in 20 mg, 40 mg or 60 mg doses. The recommended dose is 60 mg orally, once daily.

On January 28, 2016, the European Medicines Agency (EMA) validated Exelixis’ Marketing Authorization Application (MAA) for cabozantinib as a treatment for patients with advanced renal cell carcinoma who have received one prior therapy. The MAA has been granted accelerated assessment, making it eligible for a 150-day review, versus the standard 210 days. On February 29, 2016, Exelixis and Ipsen jointly announced an exclusive licensing agreement for the commercialization and further development of cabozantinib indications outside of the United States, Canada and Japan.

Exelixis, Inc. is a biopharmaceutical company committed to the discovery, development and commercialization of new medicines with the potential to improve care and outcomes for people with cancer.