Exelixis Completes Rolling Submission for Cabozantinib in RCC

Michael M.

Morrissey, PhD

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

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

Data for the application were submitted on a rolling basis as part of a breakthrough therapy designation received by the multikinase inhibitor for RCC in August 2015. Under the Prescription Drug User Fee Act, the FDA is scheduled to review the application within 60 days, at which point the agency will assign a review deadline. Exelixis has requested a priority review, which would provide a decision within 6 months compared with 10 months under a standard review.

“Completing the submission of our rolling New Drug Application brings us closer to our goal of improving the treatment options for patients with advanced kidney cancer,” Michael M. Morrissey, PhD, president and chief executive officer of Exelixis, said in a statement. “Following the release of positive top-line results from our phase III pivotal trial in July, the Exelixis team worked expeditiously to complete the US regulatory filing by year end. We look forward to continuing to work with the FDA team during the review process.”

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.

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).

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.

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.

“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. "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."

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).

In Europe, Exelixis aims to complete a Marketing Authorization Application in early 2016. The Committee for Medicinal Products for Human Use has already granted an accelerated assessment to cabozantinib for RCC, which makes the application eligible for a 150-day review instead of the standard 210-day review period.

References:

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.