Exelixis, announced that the enrollment target of 650 patients has been reached for METEOR, the company’s phase 3 pivotal trial of cabozantinib in patients with metastatic renal cell carcinoma (RCC) who have experienced disease progression following treatment with at least one VEGFR tyrosine kinase inhibitor (TKI). Top-line efficacy and safety data from METEOR are now expected in the second quarter of 2015.
“METEOR was designed to evaluate cabozantinib’s potential as a treatment for metastatic renal cell carcinoma, an aggressive form of the disease that is usually incurable,” said Toni Choueiri, MD, clinical director of the Lank Center for Genitourinary Oncology and director of the kidney cancer center, Dana-Farber Cancer Institute. “Recent drug development efforts in RCC have focused on single targets, but there is a compelling body of evidence suggesting a potential advantage in targeting the VEGFR and MET signaling pathways simultaneously. Since cabozantinib inhibits both of these pathways, this trial provides an exciting test of this hypothesis.”
Michael M. Morrissey, president and chief executive officer, of Exelixis, commented: “With enrollment in METEOR completed, Exelixis has achieved one of its major objectives for the second half of the year. We are grateful for the oncology community’s interest and support, as reflected in the trial’s rapid enrollment, and we look forward to delivering top-line results from METEOR in the second quarter of 2015.”
METEOR is an open-label, event-driven trial with the primary endpoint of progression-free survival (PFS). The trial is being conducted at up to 200 sites in up to 26 countries, and enrollment has been weighted toward Western Europe, North America, and Australia. Patients are randomized 1:1 to receive 60 mg of cabozantinib daily or 10 mg of everolimus daily and have been stratified based on the number of prior VEGFR TKI therapies received, and on commonly applied RCC risk criteria developed by Motzer et al. No cross-over is allowed between the study arms.
Based on available clinical trial data, the primary endpoint of METEOR assumes a median PFS of 5 months for the everolimus arm and 7.5 months for the cabozantinib arm. The trial protocol specifies that the primary analysis will be conducted on the first 375 patients enrolled, and will be triggered after at least 259 events occur, providing 90 per cent power to detect a hazard ratio (HR) of 0.67. Enrollment of the first 375 patients was completed in June 2014.
Secondary endpoints for METEOR include overall survival and objective response rate. The secondary endpoint assumes a median OS of 15 months for the everolimus arm and 20 months for the cabozantinib arm. The study was designed to observe 408 deaths in the entire intention-to-treat population, providing 80 per cent power to detect a HR of 0.75.
Cabozantinib inhibits the activity of tyrosine kinases including MET, VEGFRs and RET. These receptor tyrosine kinases are involved in both normal cellular function and in pathologic processes such as oncogenesis, metastasis, tumor angiogenesis, and maintenance of the tumor microenvironment.
Cometriq (cabozantinib) is currently approved by the US Food and Drug Administration for the treatment of progressive, metastatic medullary thyroid cancer (MTC).
The European Commission granted Cometriq conditional approval for the treatment of adult patients with progressive, unresectable locally advanced or metastatic MTC. Similar to another drug approved in this setting, the approved indication states that for patients in whom Rearranged during Transfection (RET) mutation status is not known or is negative, a possible lower benefit should be taken into account before individual treatment decisions.
Serious and sometimes fatal gastrointestinal perforations and fistulas occur in Cometriq-treated patients.Severe and sometimes fatal hemorrhage occurs in Cometriq-treated patients.
Cometriq treatment results in an increase in thrombotic events, such as heart attacks.Wound complications have been reported with Cometriq.
Cometriq treatment results in an increase in hypertension. Osteonecrosis of the jaw has been observed in Cometriq-treated patients. Palmar-Plantar Erythrodysesthesia Syndrome (PPES) occurs in patients treated with Cometriq.
The kidneys can be adversely affected by Cometriq. Proteinuria and nephrotic syndrome have been reported in patients receiving Cometriq.
Reversible Posterior Leukoencephalopathy Syndrome has been observed with Cometriq. Avoid administration of Cometriq with agents that are strong CYP3A4 inducers or inhibitors.Cometriq is not recommended for use in patients with moderate or severe hepatic impairment.Cometriq can cause fetal harm when administered to a pregnant woman.
Adverse Reactions The most commonly reported adverse drug reactions (=25 per cent) are diarrhoea, stomatitis, palmar-plantar erythrodysesthesia syndrome (PPES), decreased weight, decreased appetite, nausea, fatigue, oral pain, hair color changes, dysgeusia, hypertension, abdominal pain, and constipation. The most common laboratory abnormalities (=25 per cent) are increased AST, increased ALT, lymphopenia, increased alkaline phosphatase, hypocalcemia, neutropenia, thrombocytopenia, hypophosphatemia, and hyperbilirubinemia.