Cometriq elicited a statistically significant improvement in survival compared with Afinitor as a treatment for patients with advanced renal cell carcinoma following progression on one prior therapy.
Cometriq (cabozantinib) elicited a statistically significant improvement in overall survival (OS) compared with Afinitor (everolimus) as a treatment for patients with advanced renal cell carcinoma (RCC) following progression on one prior therapy, according to the second interim analysis of the phase 3 METEOR trial. These data were announced by the drug's developer, Exelixis.
In the trial, a five-month benefit in OS was required in order to demonstrate statistical significance. The company did not release the exact benefit in OS. At the first interim analysis, the OS benefit 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 percent reduction in the risk of progression or death for Cometriq versus Afinitor. 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, [Cometriq] 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, 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 one-to-one ratio to receive daily Cometriq at 60 mg (330 patients) or Afinitor at 10 mg (328 patients). 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 Cometriq and 188 received Afinitor. OS was a secondary endpoint assessed on the entire population.
The median age of patients was approximately 62 years (ranging from 31 to 86) and a majority had received one prior VEGFR TKI (71 percent), with approximately 29 percent of patients having received at least two prior therapies. Previous systemic therapy primarily consisted of Sutent (sunitinib; 62 percent), Votrient (pazopanib; 43 percent) and Inlyta (axitinib; 16 percent). By MSK criteria, 46 percent of patients were in the favorable prognostic risk category, 41 percent were intermediate, and 13 percent were poor.
After a minimum of 11 months of follow-up, median PFS with Cometriq was 7.4 months compared with 3.8 months with Afinitor. By investigator assessment, the median PFS was 7.4 months with Cometriq and 5.3 months with Afinitor. The objective response rate was 21 percent in those treated with Cometriq versus 5 percent with Afinitor. The median duration of treatment with Cometriq was 7.6 versus 4.4 months with Afinitor. Cometriq was superior to Afinitor for PFS across all subgroups. For those treated with only one prior therapy, there was a 44 percent reduction in the risk of progression or death with Cometriq versus Afinitor.
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. The survival follow-up will continue until the data mature.
Grade 3/4 AEs occurred in 68 percent of patients treated with Cometriq versus 58 percent in those who received Afinitor. The most common grade 3/4 AEs with Cometriq were hypertension (15 percent), diarrhea (11 percent), and fatigue (9 percent) versus anemia (16 percent), fatigue (7 percent), and hyperglycemia (5 percent) with Afinitor. Grade 5 AEs occurred in 7 percent of patients treated with Cometriq and in 8 percent of those who received Afinitor.
The most common serious AEs in the Cometriq arm were abdominal pain (3 percent), pleural effusion (3 percent), and diarrhea (2 percent). In the Afinitor group, the most common serious AEs were anemia (4 percent), dyspnea (4 percent), and pneumonia (4 percent). Dose reductions were required for 60 percent and 25 percent of patients, in the cabozantinib and Afinitor arms, respectively. The discontinuation rate due to adverse events (AEs) was 9 percent in the Cometriq arm versus 10 percent with Afinitor.
In Europe, Exelixis completed a Marketing Authorization Application on January 11, 2016, for Cometriq in RCC. The Committee for Medicinal Products for Human Use has granted an accelerated assessment to Cometriq. Under this program, the agency will review the application in 150 days instead of the standard 210 days.
The FDA initially approved Cometriq 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 3 CELESTIAL trial, which is comparing Cometriq to placebo for patients with HCC following treatment with Nexavar (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.