|
By Charles Bankhead, Staff Writer, MedPage Today
Published: June 06, 2012
Reviewed by Zalman S. Agus, MD; Emeritus Professor, Perelman School of Medicine at the University of Pennsylvania.
Action Points
CHICAGO -- Patients with heavily pretreated metastatic renal cell carcinoma (RCC) lived more than a year without progression when treated with the multitargeted agent cabozantinib, results of a small clinical trial showed.
Median overall survival has yet to be reached after a median follow-up of 14.7 months, but the 25 patients in the study had a week-16 disease control rate of 72% (18 of 25), including seven partial responses (28%).
The safety profile of cabozantinib was similar to that of other tyrosine kinase inhibitors, Toni Choueiri, MD, reported here at the American Society of Clinical Oncology meeting.
"Cabozantinib demonstrates encouraging activity in this heavily pretreated renal cell carcinoma population," said Choueiri, of Dana-Farber Cancer Institute in Boston. "We have observed examples of bone lesion resolution in some patients. An evaluation of cabozantinib in first-line renal cell carcinoma is planned."
Cabozantinib inhibits the MET and VEGFR2 pathways, which addresses the issue of acquired resistance to VEGF inhibitors. The resistance can be overcome by inhibition of MET, said Choueiri.
Clear-cell RCC often arises from loss of functionality in the VHL tumor suppressor gene. The loss of functionality leads to upregulation of hypoxia-inducible factor, which is associated with increased expression of VEGF and MET.
As demonstrated in preclinical models, MET knockdown preferentially reduced the viability of VHL-negative RCC cells, said Choueiri. Moreover, clinical studies have shown that cabozantinib can induce resolution of metastatic bone lesions in multiple tumor types.
The brief history of cabozantinib suggested the agent might have activity in RCC, so to examine the issue, the investigators enrolled 25 patients who had relapsed or refractory RCC. The patients were a subset of a group who participated in a previous drug-drug interaction study.
The patients received cabozantinib 140 mg a day until progression or intolerable toxicity. The primary endpoints were safety, tolerability, and anti-tumor activity of cabozantinib.
All but three of the patients had a history of anti-VEGF therapy. A majority had received anti-mTOR therapy, and about half had received both anti-VEGF and anti-mTOR therapy. All patients had received at least one prior therapy for metastatic RCC, and eight patients had a treatment history that included four or more systemic therapies.
The cohort had a median progression-free survival of 14.7 months, but the upper limit of 95% confidence intervals had yet to be met, said Choueiri. Median overall survival had not been met.
In addition to the seven partial responses, 13 patients had stable disease. One patient had confirmed progression, and tumor assessments were unavailable for four patients.
Objective responses and stable disease were observed in patients who ranged the gamut of prior therapies, both in number and type.
Bone scans at baseline and during follow-up showed resolution of bone lesions in some patients. Additionally, some of the patients had substantial improvement in bone-related pain and need for narcotic analgesics.
The most common adverse events were fatigue (20, 80%), diarrhea (16, 64%), and hypophosphatemia (14, 56%). Other adverse events included hypothyroidism, nausea, hypomagnesemia, proteinuria, decreased appetite, vomiting, hyponatremia, hand-foot syndrome, and dyspnea, occurring in eight to 11 patients each.
Hypertension, an adverse event of particular interest, occurred in four patients and was grade 3+ in two, said Choueiri.
The most common grade 3+ adverse events were hypophosphatemia (9, 36%) and hyponatremia (5, 20%).
In her discussion of the study, Lauren C. Harshman, MD, of Stanford University in Palo Alto, Calif., said treatment with cabozantinib achieved "intriguing efficacy" as reflected in the median PFS and objective response rate.
However, she noted that a quarter of the patients discontinued treatment because of adverse events, and she questioned whether cabozantinib would maintain its efficacy if the dose were reduced to minimize toxicity.
The study was supported by Exelixis.
Choueiri disclosed a relationship with Exelixis. Co-investigators disclosed relationships with Exelixis, and Exelixis employees participated in the study.
Harshman had no relevant disclosures.
Primary source:American Society of Clinical Oncology
Source reference:
Choueiri TI, et al "Efficacy of cabozantinib (XL184) in patients with metastatic, refractory renal cell carcinoma" ASCO2012; Abstract 4504.
 Add Your Knowledge ™
Take Posttest
Charles Bankhead
Staff Writer
Working from Houston, home to one of the world’s largest medical complexes, Charles Bankhead has more than 20 years of experience as a medical writer and editor. His career began as a science and medical writer at an academic medical center. He later spent almost a decade as a writer and editor for Medical World News, one of the leading medical trade magazines of its era. His byline has appeared in medical publications that have included Cardio, Cosmetic Surgery Times, Dermatology Times, Diagnostic Imaging, Family Practice, Journal of the National Cancer Institute, Medscape, Oncology News International, Oncology Times, Ophthalmology Times, Patient Care, Renal and Urology News, The Medical Post, Urology Times, and the International Medical News Group newspapers. He has a BA in journalism and MA in mass communications, both from Texas Tech University.
|
Log in to explore the world's most comprehensive database of dialysis centres for free! 
Professional dialysis recruitment
