Second-Line Cabozantinib Improves PFS in Advanced RCC

Toni Choueiri, MD

Second-line treatment with cabozantinib (Cometriq) reduced the risk of progression or death by 42% compared with everolimus in patients with advanced renal cell carcinoma (RCC), according to findings from the phase III METEOR study that were presented at the 2015 European Cancer Congress and simultaneously published in The New England Journal of Medicine.^1,2

After a minimum of 11 months of follow-up for the first 375 patients enrolled in the open-label trial, the median progression-free survival (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). In this same group, the objective response rate (ORR) was 21% in those treated with cabozantinib versus 5% with everolimus (P <.001).

At the interim analysis of the full study population (n = 658), a trend toward improvement in overall survival (OS) 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.

“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. “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."

In the full 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 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). A majority of patients 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.

According to 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 with a favorable risk, there was a 56% reduction in risk with cabozantinib (HR, 0.54; 95% CI, 0.37-0.79). In the poor risk group, the benefits of cabozantinib were less pronounced (HR, 0.84; 95% CI, 0.46-1.53).

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). In a post-hoc analysis of 153 patients who received only prior sunitinib, the median PFS with cabozantinib was 9.1 versus 3.7 months with everolimus (HR, 0.41). The ORR with cabozantinib in this group was 22% versus 3% with everolimus.

"The results of the METEOR trial indicate that cabozantinib is able to shrink tumors and slow down tumor growth much better than current standard treatment in patients who previously received VEGFR-targeted drugs," said Choueiri. "This has resulted in a significant reduction in the rate of disease progression or death in the cabozantinib arm as compared with the everolimus arm."

The median duration of treatment with cabozantinib was 7.6 months versus 4.4 months with everolimus. 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.

"Regaining tumor control after prior targeted therapy may reduce symptoms related to kidney cancer and eventually help patients live longer," Choueiri said. "Overall, these results should give new hope to patients diagnosed with advanced kidney cancer as cabozantinib may become a new treatment option.”

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%).

"Cabozantinib is a new drug that targets possible escape mechanisms of tumor cells, including the tyrosine kinases MET, VEGFR, and AXL," Choueiri explained. “The METEOR results are important from a clinical and scientific point of view. Overcoming mechanisms of tumor escape or resistance to standard therapies is critical for improving long-term outcome for our patients with advanced kidney cancer."

In late August 2015, cabozantinib received a breakthrough therapy designation from the FDA for patients with advanced RCC who had received one prior therapy. Under this program and a prior fast track designation, the company developing the drug, Exelixis, is able to interact with the FDA more frequently, and the company can complete a rolling submission of data for a supplemental new drug application (NDA).

“Exelixis is working quickly to share the data with regulators in the United States and European Union. We are on track to complete our US NDA filing by the end of this year, where cabozantinib has received breakthrough therapy designation, and expect a European filing to follow in early 2016," Michael M. Morrissey, PhD, president and chief executive officer at Exelixis, said in a statement. "We look forward to advancing these regulatory processes in hopes of bringing cabozantinib to the renal cell carcinoma community as soon as possible.”

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).

"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.”

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.

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