Drug Granted Breakthrough Therapy Designation for Refractory Renal Cell Carcinoma


Patients with renal cell carcinoma (RCC) who have not responded to prior therapy may soon have a new treatment option.

Patients with renal cell carcinoma (RCC) who have not responded to prior therapy may soon have a new treatment option. It is a drug already approved for progressive, metastatic medullary thyroid cancer (MTC). On August 24, 2015, The US Food and Drug Administration (FDA) granted Breakthrough Therapy Designation for cabozantinib as a potential treatment for patients with advanced RCC who have received one prior therapy.1

Cabozantinib inhibits the activity of tyrosine kinases including MET, VEGF receptors, AXL, and RET and may help improve overall survival in patients who have experienced disease progression following treatment with a VEGF receptor tyrosine kinase inhibitor (TKI). 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, PhD, who is the president and chief executive officer of Exelixis, Inc., San Francisco, Calif. “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.”

The Breakthrough Therapy Designation was based on the results of METEOR, a pivotal phase III trial comparing cabozantinib to everolimus (Afinitor) in patients with RCC who experienced disease progression following treatment with a TKI. METEOR met its primary endpoint and demonstrated a statistically significant increase in progression-free survival (PFS) for cabozantinib as compared to everolimus in the first 375 patients randomized. The study demonstrated that cabozantinib reduced the rate of disease progression or death by 42% compared to everolimus.

This agent currently is marketed in capsule form under the brand name COMETRIQ® in the US for the treatment of progressive MTC, and in the European Union for the treatment of adult patients with progressive, unresectable locally advanced, or metastatic MTC.

The majority of clear cell RCC tumors exhibit down-regulation of von Hippel-Lindau (VHL) protein function. This results 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. It is believed that the expression of MET or AXL may be associated with tumor cell viability, a more invasive tumor phenotype, and reduced overall survival.

If detected in its early stages, the 5-year survival rate for RCC is high. However, the 5-year survival rate for patients with advanced or late-stage metastatic RCC is under 10%, according to the American Cancer Society (ACS).2 Clinicians have been disappointed in recent years because the 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 most commonly reported adverse drug reactions (≥25%) reported with this agent 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%) are increased AST, increased ALT, lymphopenia, increased alkaline phosphatase, hypocalcemia, neutropenia, thrombocytopenia, hypophosphatemia, and hyperbilirubinemia.





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