Exelixis, Inc. announced the European Medicines Agency (EMA) has accepted for review the Marketing Authorization Application (MAA) for cabozantinib as a treatment for patients with advanced renal cell carcinoma (RCC) who have received one prior therapy. The completion of the MAA validation process confirms that the submission is sufficient to permit a substantive review for marketing authorization in the European Union.

The EMA’s Committee for Medicinal Products for Human Use (CHMP) previously granted accelerated assessment to cabozantinib for advanced RCC. As a result, the MAA will be eligible for a 150-day review, versus the standard 210 days (excluding clock stops when information is requested by CHMP).

The MAA is based on the results of METEOR, a phase 3 pivotal trial comparing cabozantinib to everolimus in patients with advanced RCC who experienced disease progression following treatment with a VEGF receptor tyrosine kinase inhibitor. In July 2015, Exelixis announced top-line results from METEOR demonstrating that the trial had met its primary endpoint of improving progression-free survival; compared with everolimus, a standard of care for second line RCC therapy, cabozantinib was associated with a 42 per cent reduction in the rate of disease progression or death. These data were later presented at the European Cancer Congress in September 2015 and concurrently published in The New England Journal of Medicine.

In the United States, in late December 2015, Exelixis announced that it completed the submission of its rolling New Drug Application (NDA) for cabozantinib as a treatment for patients with advanced RCC who have received one prior therapy. The U.S. Food and Drug Administration (FDA) subsequently determined the NDA to be sufficiently complete to permit a substantive review, granted Priority Review, and assigned a Prescription Drug User Fee Act action date of June 22, 2016. The NDA will be considered officially filed 60 days from the date of the completion of the submission, or February 20, 2016. The FDA previously granted Breakthrough Therapy and Fast Track designations to cabozantinib for its potential advanced RCC indication.

Cabozantinib is currently marketed in capsule form under the brand name Cometriq in the United States for the treatment of progressive, metastatic medullary thyroid cancer (MTC), and in the European Union for the treatment of adult patients with progressive, unresectable locally advanced or metastatic MTC. Cometriq is not indicated for patients with RCC. In the METEOR trial, and all other cancer trials currently underway, Exelixis is investigating a tablet formulation of cabozantinib distinct from the Cometriq capsule form. The tablet formulation of cabozantinib is the subject of the MAA for advanced RCC.

The American Cancer Society’s 2015 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; however, the five-year survival rate for patients with advanced or late-stage metastatic RCC is under 10 percent, with no identified cure for the disease.

Until the introduction of targeted therapies into the RCC setting a decade ago, treatments for metastatic RCC had historically been limited to cytokine therapy (e.g., interleukin-2 and interferon). In the second and later-line settings, which encompass approximately 17,000 drug-eligible patients in the US and 37,000 globally, two small-molecule therapies and an immune checkpoint inhibitor have been approved for the treatment of patients with advanced RCC who have received prior systemic therapy. The currently approved small-molecule agents have shown little differentiation in terms of efficacy and have demonstrated only modest progression-free survival benefit in patients refractory to sunitinib, a commonly-used first-line therapy.

The majority of clear cell RCC tumors exhibit down-regulation of von Hippel-Lindau protein function, either due to gene inactivation or epigenetic silencing, resulting in a stabilization of the hypoxia-inducible transcription factors and consequent up-regulation of VEGF, MET and AXL. The up-regulation of VEGF may contribute to the angiogenic nature of clear cell RCC, and expression of MET or AXL may be associated with tumor cell viability, a more invasive tumor phenotype and reduced overall survival. Up-regulation of MET and AXL in clear cell RCC has also been shown to occur in response to treatment with VEGF receptor TKIs in preclinical models, indicating a potential role for MET and AXL in the development of resistance to these therapies.

Cabozantinib inhibits the activity of tyrosine kinases including MET, VEGF receptors, AXL 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.

Cabozantinib, marketed under the brand name Cometriq, 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.