November 29, 2016
By Will Boggs MD
NEW YORK (Reuters Health) - Cabozantinib provides significantly better progression-free survival (PFS) and objective response rates (ORR) in patients with metastatic renal cell carcinoma (RCC) of poor or intermediate risk, according to results from the Alliance A031203 CABOSUN trial.
"Sunitinib has been a standard of care for first-line treatment of advanced clear cell renal cell carcinoma for over a decade, and no other agent has demonstrated superiority to sunitinib in this setting until now," said Dr. Toni K. Choueiri from Dana-Farber Cancer Institute in Boston.
"Cabozantinib has a similar but broader mechanism of action compared with sunitinib. Both drugs inhibit the tyrosine kinase VEGFR2, which blocks growth of blood vessels (antiangiogenesis) in the tumor," he told Reuters Health by email.
"Cabozantinib also inhibits two additional tyrosine kinases, MET and AXL, which are thought to play important roles in tumor progression," Dr. Choueiri explained. "The observed benefits suggest that targeting these additional pathways with cabozantinib improves the clinical outcome for patients with advanced renal cell cancer."
Metastatic clear cell RCC is largely incurable, but first-line therapy with VEGF-targeted agents like sunitinib has been associated with relapse-free survival of more than five months in patients with intermediate or poor risk.
Dr. Choueiri and colleagues compared cabozantinib with standard-of-care sunitinib in 157 intermediate and poor risk patients with advanced RCC as first-line treatment in a randomized, open-label phase 2 trial.
Median PFS, the primary endpoint, was 8.2 months with cabozantinib versus 5.6 months with sunitinib. Cabozantinib reduced the rate of disease progression or death by 34% compared with sunitinib (p=0.012), the researchers report in the Journal of Clinical Oncology, online November 14.
Cabozantinib significantly improved ORR: 46% of patients treated with cabozantinib had complete or partial responses, compared with only 18% of patients treated with sunitinib.
After a median follow-up of surviving patients of 21.4 months, median overall survival was 30.3 months with cabozantinib versus 21.8 months with sunitinib, a difference that fell short of statistical significance.
The incidence of adverse events was virtually identical for cabozantinib and sunitinib.
"Cabozantinib is already FDA-approved for use in patients with advanced renal cell carcinoma who have received prior antiangiogenic therapy, and the CABOSUN trial now demonstrates that cabozantinib is also active in patients who are untreated," Dr. Choueiri said.
"The subset of renal cell carcinoma patients with bone metastases is particularly difficult to treat," he explained. "Patients with bone metastases have reduced progression-free survival and overall survival compared to patients without bone metastases, and often have significant cancer-related symptoms."
"This subset of patients showed meaningful improvement with cabozantinib compared with sunitinib, demonstrating an almost doubling of median progression-free survival in the CABOSUN trial in the cabozantinib arm," Dr. Choueiri said. "Hence, treatment with cabozantinib would be an important option for renal cell cancer patients with bone metastases."
Dr. Eric Jonasch from MD Anderson Cancer Center in Houston, Texas, told Reuters Health by email, "We need to be careful in overgeneralizing these data. There were no good-risk patients on the trial. Whether this constitutes a new standard of care for patients with intermediate risk features is also questionable, as patients could receive sunitinib/pazopanib first, followed by nivolumab or cabozantinib in second-/third-line setting."
"Cabozantinib can be considered as front-line therapy for RCC patients with intermediate or poor risk features, but the overall treatment strategy for the patient needs to be considered," said Dr. Jonasch, who was not involved in the study.
Dr. Steven Yu from the University of Southern California's Norris Comprehensive Cancer Center in Los Angeles said, "I think you can make a strong argument that cabozantinib should now be first line. With a much larger ORR and almost double the PFS cabozantinib does seem to outperform sunitinib. We will have to see the final overall survival (OS) data to make a decision, but even if OS is the same, cancer drugs are often preferred based on PFS only. The FDA also often approves drugs based on improved PFS and I don't expect any different in this case."
"I think the consensus concern about cabozantinib is the toxicities at 60 mg," he told Reuters Health by email. "What we are finding is that patients really tolerate the drug much better at the 40-mg dose. The drug is so new that really as an oncology community we are still learning when to dose reduce and how to manage it. I think as we become more familiar with its use a lot of the toxicity concerns will be appeased and cabozantinib will become the new first-line treatment."
"There is also very exciting study being done with cabozantinib in liver cancer, which potentially gives treatment options to patients with hepatocellular carcinoma who right now have limited therapeutics," said Dr. Yu, who also was not involved in the CABOSUN trial.
Dr. Choueiri and two of his co-authors reported ties to Exelixis, which provided cabozantinib for the trial.
J Clin Oncol 2016.
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