FDA Approval Sought for Cabozantinib in Advanced RCC


Rolling submission of a new drug application for cabozantinib has been initiated for patients with advanced renal cell carcinoma who have received one prior therapy.

Michael M.

Morrissey, PhD

Rolling submission of a new drug application (NDA) for cabozantinib (Cometriq) has been initiated for patients with advanced renal cell carcinoma (RCC) who have received one prior therapy, according to a statement from the drug's developer, Exelixis.

Rolling submission of an NDA is allowed as part of a breakthrough therapy designation received by the multikinase inhibitor in August 2015. Once fully submitted, the FDA will review the application within 60 days, at which point the agency will assign a review deadline under the Prescription Drug User Fee Act. Exelixis anticipates that all data will be submitted by the end of the year.

“New treatment options are urgently needed for patients with advanced renal cell carcinoma,” Michael M. Morrissey, PhD, president and CEO of Exelixis, said in a statement. “The initiation of the NDA submission process for cabozantinib marks an important step forward in our efforts to make a meaningful difference in the lives of people with advanced kidney cancer, and we look forward to working closely with the FDA towards the goal of making cabozantinib available to these patients and their physicians as soon as possible.”

The application for cabozantinib was based on findings from the phase III METEOR trial, which demonstrated a 42% reduction in the risk of progression or death for cabozantinib versus everolimus in patients with advanced RCC. Results from the study were published in The New England Journal of Medicine and simultaneously presented at the 2015 European Cancer Congress.1,2

In the phase III 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.

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, the 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).

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).

The median duration of treatment with cabozantinib was 7.6 months versus 4.4 months with everolimus. The objective response rate was 21% in those treated with cabozantinib versus 5% with everolimus (P <.001).

“I am very excited about the outcome of the study, since the results may change the standard of care in patients with advanced kidney cancer who have received prior standard therapy that targets the vascular endothelial growth factor receptor," lead investigator Toni Choueiri, MD, director of the Kidney Cancer Center at the Dana-Farber Cancer Institute, said in a statement when the data were presented.

At the interim analysis of 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.

“An early evaluation of overall survival from the ongoing METEOR trial has shown a strong trend indicating that survival may be improved in patients receiving cabozantinib compared to standard therapy," said Choueiri.

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.

"Further studies include a randomized phase II study of cabozantinib versus standard of care with sunitinib as a first treatment for advanced renal cell cancer," Choueiri said. "Combinations with other emerging therapies, such as agents boosting the immune system, are of interest and an early stage clinical trial combining cabozantinib with immune checkpoint inhibitors has been initiated in urological cancers, including patients with kidney cancer.”

The FDA initially approved cabozantinib as a treatment for patients with metastatic medullary thyroid cancer in November 2012. The agent continues to be explored 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).


  1. Choueiri TK, Escudier B, Powles T, et al. Cabozantinib versus everolimus in patients with advanced renal cell carcinoma: Results of the randomized phase III METEOR trial. Presented at:2015 European Cancer Congress; September 25-29; Vienna, Austria. Abstract LBA4.
  2. 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.

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