Cabozantinib (Cometriq) nearly doubled progression-free survival compared with standard everolimus (Afinitor) therapy in patients with advanced renal cell carcinoma, according to the phase III METEOR trial.1 Additionally, a preplanned interim analysis found an encouraging trend toward overall survival in patients treated with cabozantinib.
“I am very excited by this outcome. This study can change the standard of care for patients with advanced kidney cancer who have received prior standard therapy targeting the VEGF [vascular endothelial growth factor] receptor,” said Toni Choueiri, MD, Associate Professor of Medicine at Harvard Medical School and Kidney Cancer Center Director at The Lank Center for Genitourinary Oncology, Dana-Farber Cancer Institute, Boston. “Cabozantinib is an option for second-line therapy of renal cell carcinoma.”
Dr. Choueiri presented these results of the METEOR trial at the 2015 European Cancer Congress, and they were published online in The New England Journal of Medicine to coincide with his presentation.2 See "Nivolumab and Cabozantinib Improve Outcomes vs Everolimus in Previously Treated Advanced Renal Cell Carcinoma" for more details on the METEOR trial as reported in the published paper.
Although drugs that target the VEGF receptor (VEGFR) are now standard treatment for advanced renal cell carcinoma, resistance to these drugs is a major challenge, Dr. Choueiri explained.
Cabozantinib, approved for the treatment of advanced thyroid cancer, is an oral small-molecule multitargeted inhibitor of tyrosine kinases, including MET, VEGFRs, and AXL. Increased expression of both MET and AXL is associated with the development of resistance and poor prognosis in renal cell carcinoma, suggesting that cabozantinib is worthy of study in renal cell carcinoma, Dr. Choueiri told listeners.
METEOR Trial Details
The METEOR trial enrolled 658 patients diagnosed with advanced renal cell carcinoma and clear cell histology from 173 centers in 26 countries; all patients had received at least one prior VEGFR-targeted tyrosine kinase inhibitor and had radiographic progression within 6 months after the most recent dose.
No crossover was allowed in the trial, which met its primary endpoint of progression-free survival. Patients were randomly assigned 1:1 to oral cabozantinib at 60 mg/d or oral everolimus at 10 mg/d and treated as long as benefit was observed or until the development of unacceptable toxicity. No crossover was allowed.
The study met its primary endpoint of progression-free survival. Median progression-free survival—as assessed by an independent radiology review committee—was 7.4 months for cabozantinib vs 3.8 months for everolimus, representing a 42% reduction in risk of progression or death (P < .001). Objective tumor responses were observed in 21% of the cabozantinib group vs 5% of patients treated with everolimus.
At a prespecified interim analysis of overall survival, a trend toward longer survival was seen with cabozantinib vs everolimus (a 37% reduction in risk of death favoring cabozantinib, P = .005). The survival trend favored cabozantinib despite more frequent use of subsequent anticancer therapies in the everolimus group (47% of patients) compared with cabozantinib (38% of patients), he noted.
“We think this interim overall survival, although immature, is very encouraging,” Dr. Choueiri said. “Putting this in context, in patients with renal cell carcinoma treated with other drugs, cabozantinib compares favorably with everolimus, axitinib [Inlyta], and sorafenib [Nexavar] in patients previously treated with only sunitinib [Sutent].”
Median duration of treatment was 7.6 months for cabozantinib and 4.4 months for everolimus.
Adverse Events
“Dose reductions were more frequent with cabozantinib to manage adverse events [60% vs 25% of patients who received everolimus], underlining the need for careful adverse-event monitoring, as is the case with other VEGFR inhibitors. But the rate of discontinuation due to treatment-related adverse events was similar in both arms, around 10%,” Dr. Choueiri said.
The most common adverse events with cabozantinib were diarrhea, fatigue, nausea, decreased appetite, palmar-plantar syndrome, and hypertension. Higher rates of pneumonitis, peripheral edema, anemia, and hypoglycemia were observed with cabozantinib than with everolimus. ■
Disclosure: The study was supported by Exelixis. Dr. Choueiri has served as a consult/advisor for AVEO, GlaxoSmithKline, Novartis, Pfizer, and Exelixis and has received research funding from Pfizer.
References
1. Choueiri T, Escudier B, Powles T, et al: Cabozantinib versus everolimus in patients with advanced renal cell carcinoma. 2015 European Cancer Congress. Abstract 4LBA. Presented September 26, 2015.
2. Choueiri TK, Escudier B, Powles T, et al: Cabozantinib versus everolimus in advanced renal-cell carcinoma. N Engl J Med. September 25, 2015 (early release online).
