The US Food & Drug Administration (FDA) has granted Breakthrough Therapy designation to biopharmaceutical company Exelixis Inc's lead compound, cabozantinib as a potential treatment for patients with advanced renal cell carcinoma (RCC) who have received one prior therapy.

Created in 2012, FDA’s Breakthrough Therapy designation expedites the development and review of drugs that are intended to treat serious or life-threatening diseases, and for which preliminary clinical evidence indicates the drug may demonstrate substantial improvement over existing therapies on one or more clinically significant endpoints. Drugs that receive Breakthrough Therapy designation may benefit from involvement of FDA senior managers in the review process, potential rolling submission and/or Priority Review of a sponsor’s New Drug Application (NDA), and other benefits.

“Receiving Breakthrough Therapy designation is an important regulatory achievement for cabozantinib in renal cell carcinoma,” said Michael M. Morrissey, Ph.D., president and chief executive officer of Exelixis.

“Following the positive top-line results announced in July and a productive dialogue with the FDA, Exelixis believes we can expedite our regulatory timelines and complete the cabozantinib NDA submission in advanced RCC prior to the end of 2015. We look forward to working closely with the FDA during the submission and review process, keeping in mind our ultimate goal of bringing a new therapeutic option to the renal cell carcinoma community as soon as possible.”

Cabozantinib received Breakthrough Therapy designation based on the results of METEOR, the phase 3 pivotal trial comparing cabozantinib to everolimus in patients with RCC who experienced disease progression following treatment with a VEGF receptor tyrosine kinase inhibitor (TKI). In top-line results announced in July 2015, METEOR met its primary endpoint, demonstrating a statistically significant increase in progression-free survival (PFS) for cabozantinib as compared to everolimus in the first 375 patients randomized as determined by an independent radiology review committee. Cabozantinib reduced the rate of disease progression or death by 42 per cent compared to everolimus (hazard ratio [HR]=0.58, 95 per cent confidence interval [CI] 0.45-0.75, p<0.0001).

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. A distinct tablet formulation of cabozantinib is under investigation for advanced renal cell carcinoma and other types of cancer. Cometriq is not indicated for patients with advanced RCC or any other form of the disease.

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 United States. Clear cell renal cell carcinoma 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 per cent, with no identified cure for the disease.

Treatments for advanced RCC had historically been limited to cytokine therapy (e.g., interleukin-2 and interferon) until the introduction of targeted therapies into the RCC setting a decade ago. In the second and later-line setting, which encompasses approximately 17,000 drug-eligible patients in the US and 37,000 globally, two therapies have been approved for the treatment of patients who have received prior VEGF receptor TKIs. However, despite the availability of several therapeutic options, currently approved agents have shown little differentiation in terms of efficacy and have demonstrated only modest PFS benefit in patients refractory to sunitinib, a commonly-used first-line therapy.

The majority of clear cell RCC tumours exhibit down-regulation of von Hippel-Lindau (VHL) protein function, resulting in a stabilization of the hypoxia-inducible transcription factors (HIFs) 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 tumour phenotype, and reduced overall survival. Up-regulation of MET 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 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, tumour angiogenesis, and maintenance of the tumor microenvironment.

The most commonly reported adverse drug reactions (=25 per cent) with cabozantinib are diarrhea, 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.