Exelixis, Inc and Ipsen announced overall survival (OS) results from the phase 3 METEOR trial of Cabometyx (cabozantinib) tablets in patients with advanced renal cell carcinoma (RCC) who have received prior anti-angiogenic therapy. The findings will be presented during an oral abstract session today at the 2016 American Society of Clinical Oncology (ASCO) Annual Meeting in Chicago, and were published in The Lancet Oncology. The OS results demonstrate that Cabometyx reduces the risk of death by one third versus everolimus.

Exelixis previously announced that METEOR met its primary endpoint, progression-free survival (PFS), and secondary endpoints, OS and objective response rate.

“The overall survival benefit conferred by treatment with Cabometyx — which was consistently favorable across a variety of prespecified and post-hoc patient subgroups — is a strong complement to the progression-free survival and objective response rate findings previously reported,” said Toni Choueiri, M.D., Clinical Director, Lank Center for Genitourinary Oncology, Dana-Farber Cancer Institute. “With the recent FDA approval of Cabometyx, patients in need of additional options now have access to a differentiated treatment demonstrated to help them live longer while also delaying the progression of their cancer.”

In METEOR, at a median follow-up of nearly 19 months, Cabometyx demonstrated an increase in median OS of nearly 5 months versus everolimus: 21.4 months versus 16.5 months for everolimus (HR 0.66, 95% CI [0.53-0.83], P=0.0003), corresponding to a 34 percent reduction in the risk of death.

Cabometyx treatment resulted in consistent benefits in OS and PFS across various pre-specified and post-hoc analysis subgroups. Benefits were independent of Memorial Sloan Kettering Cancer Center risk group (favorable, intermediate, or poor), number and type of prior vascular endothelial growth factor receptor (VEGFR) tyrosine kinase inhibitor (TKI) therapies (one, or more than one), duration of first VEGFR TKI treatment (6 months or less, or more than 6 months), presence of bone and/or visceral metastases, and levels of the MET biomarker in tumors (high, low, or unknown).

“We are excited to share the detailed overall survival results from the METEOR trial with the oncology community at this year’s ASCO Annual Meeting,” said Michael M. Morrissey, Ph.D., president and chief executive officer of Exelixis. “The five-year survival rate for patients diagnosed with advanced kidney cancer is only 12 percent, underscoring the need for new treatment options that help patients live longer while delaying the progression of their disease. Critically, Cabometyx — the first FDA-approved therapy to demonstrate a benefit in all three key efficacy parameters — now shows consistent survival benefit across all subgroups of patients evaluated in METEOR.”

“Recent data from the METEOR trial confirms the benefit in median overall survival of almost 5 months that Cabometyx can provide to patients with advanced renal cell carcinoma,” said Marc de Garidel, chairman and CEO, Ipsen. “We are dedicated to diligently working with Exelixis and regulatory authorities to bring cabozantinib to patients who seek new therapeutic options with established survival benefits.”

At the time of the analysis, the median duration of treatment in the trial was 8.3 months with Cabometyx versus 4.4 months with everolimus. Dose reductions occurred for 62 per cent and 25 per cent of patients, respectively. Discontinuation rate due to an adverse event not related to disease progression was 12 per cent with Cabometyx and 11 per cent with everolimus.

The most common grade 3 or 4 adverse events were hypertension (15 per cent), diarrhea (13 per cent) and fatigue (11 percent) in the CABOMETYX arm and anemia (17 per cent), fatigue (7 per cent) and hyperglycemia (5 percent) in the everolimus arm. Serious adverse events = grade 3 occurred in 130 (39 per cent) of cabozantinib-treated patients and in 129 (40 per cent) of everolimus-treated patients.

On April 25, 2016 Cabometyx was approved by the US Food and Drug Administration (FDA) for the treatment of patients with advanced RCC who have received prior anti-angiogenic therapy.

METEOR was an open-label, event-driven trial of 658 patients with advanced renal cell carcinoma who had failed at least one prior VEGFR TKI therapy. The primary endpoint was PFS in the first 375 patients treated. Secondary endpoints included OS and objective response rate in all enrolled subjects. 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 VEGFR TKI therapies received and on MSKCC risk criteria. No cross-over was allowed between the study arms.

METEOR met its primary endpoint of significantly improving PFS. Compared with everolimus, Cabometyx was associated with a 42 percent reduction in the rate of disease progression or death. Median PFS for Cabometyx 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 (P<0.0001). These data were presented at the European Cancer Congress in September 2015 and published in The New England Journal of Medicine.

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 RCC is high; for patients with advanced or late-stage metastatic RCC, however, the five-year survival rate is only 12 percent, 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 of a protein called von Hippel-Lindau, which leads to higher levels of MET, AXL and VEGF. These proteins promote tumor angiogenesis (blood vessel growth), growth, invasiveness and metastasis. MET and AXL may provide escape pathways that drive resistance to VEGFR 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 tumor angiogenesis, invasiveness, metastasis and drug resistance.

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

On April 25, 2016, the FDA approved Cabometyx tablets for the treatment of patients with advanced renal cell carcinoma who have received prior anti-angiogenic therapy.

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.