The second interim analysis of the phase III METEOR trial has revealed a statistically significant improvement in overall survival (OS) with cabozantinib (Cometriq) versus everolimus (Afinitor) as a treatment for patients with advanced renal cell carcinoma (RCC) following progression on one prior therapy, according to a statement from the drug's developer, Exelixis.
In the trial, a 5-month benefit in OS was required in order to demonstrate statistical significance. This was equivalent to a hazard ratio of 0.75, with a P
value of .0019 representing significance. The company did not release the exact benefit in OS. At the first interim analysis, the hazard ratio for OS was 0.67 and the P value was .005, which barely missed the cutoff for significance. Findings from the follow-up analysis are being prepared for presentation at an upcoming medical meeting later this year.
The FDA is currently considering data from the first analysis of the METEOR trial, which showed 42% reduction in the risk of progression or death for cabozantinib versus everolimus. Under the Prescription Drug User Fee Act, the agency is scheduled to make a decision on the application by June 22, 2016.
“With these results, cabozantinib is now the first and only therapy evaluated in a large, pivotal study in previously treated patients with advanced renal cell carcinoma to demonstrate a benefit in all three key efficacy parameters–overall survival, progression-free survival, and objective response rate,” said Michael M. Morrissey, PhD, president and chief executive officer of Exelixis. “Exelixis will share these new results with regulators as part of ongoing review processes in the United States and European Union. Our highest priority is to bring this new option for advanced RCC to patients as quickly as possible.”
In the METEOR study, 658 patients were randomized in a 1:1 ratio to receive daily cabozantinib at 60 mg (n = 330) or everolimus at 10 mg (n = 328). The primary endpoint of progression-free survival (PFS) was assessed on the first 375 patients enrolled in the trial. In this portion of the study, 187 patients were randomized to cabozantinib and 188 received everolimus. OS was a secondary endpoint assessed on the entire population.
The median age of patients was approximately 62 years (range, 31-86) and a majority had received one prior VEGFR TKI (71%), with approximately 29% of patients having received ≥2 prior therapies. Previous systemic therapy primarily consisted of sunitinib (62%), pazopanib (43%), and axitinib (16%). By MSK criteria, 46% of patients were in the favorable prognostic risk category, 41% were intermediate, and 13% were poor.
After a minimum of 11 months of follow-up, median PFS with cabozantinib was 7.4 months compared with 3.8 months with everolimus (HR, 0.58; 95% CI, 0.45-0.75; P
<.001). By investigator assessment, the median PFS was 7.4 months with cabozantinib and 5.3 months with everolimus (HR, 0.60; 95% CI, 0.47-0.76; P
<.001). The objective response rate was 21% in those treated with cabozantinib versus 5% with everolimus (P
<.001). The median duration of treatment with cabozantinib was 7.6 versus 4.4 months with everolimus.
Cabozantinib was superior to everolimus for PFS across all subgroups. For those treated with only 1 prior therapy, there was a 44% reduction in the risk of progression or death with cabozantinib versus everolimus (HR, 0.56; 95% CI, 0.42-0.75).
At the interim analysis for the full study population, a trend toward improvement in overall survival was observed; however, this did not pass a high bar for statistical significance (HR, 0.67; 95% CI, 0.51-0.89; P
= .005). A P
value of ≤.0019 was required to achieve significance. The survival follow-up will continue until the data mature.
Grade 3/4 AEs occurred in 68% of patients treated with cabozantinib versus 58% in those who received everolimus. The most common grade 3/4 AEs with cabozantinib were hypertension (15%), diarrhea (11%), and fatigue (9%) versus anemia (16%), fatigue (7%), and hyperglycemia (5%) with everolimus. Grade 5 AEs occurred in 7% of patients treated with cabozantinib and in 8% of those who received everolimus.
The most common serious AEs in the cabozantinib arm were abdominal pain (3%), pleural effusion (3%), and diarrhea (2%). In the everolimus group, the most common serious AEs were anemia (4%), dyspnea (4%), and pneumonia (4%). Dose reductions were required for 60% and 25% of patients, in the cabozantinib and everolimus arms, respectively. The discontinuation rate due to adverse events (AEs) was 9% in the cabozantinib arm versus 10% with everolimus.
In Europe, Exelixis completed a Marketing Authorization Application on January 11, 2016, for cabozantinib in RCC. The Committee for Medicinal Products for Human Use has granted an accelerated assessment to cabozantinib. Under this program, the agency will review the application in 150 days instead of the standard 210-days.
The FDA initially approved cabozantinib in November 2012 as a treatment for patients with metastatic medullary thyroid cancer. Further trials continue to explore agent in a number of solid tumors, including the phase III CELESTIAL trial, which is comparing cabozantinib to placebo for patients with HCC following treatment with sorafenib (NCT01908426).
Choueiri TK, Escudier B, Powles T, et al. Cabozantinib versus everolimus in advanced renal-cell carcinoma [published online September 25, 2015]. N Engl J Med. doi:10.1056/NEJMoa1510016.