Cabozantinib (Cabometyx) has received a positive recommendation from the EMA's Committee for Medicinal Products for Human Use (CHMP) for use as treatment for patients with advanced renal cell carcinoma (RCC) after the failure of VEGF-targeted therapy, according to Exelixis and Ipsen, the manufacturers of the multikinase inhibitor.
The recommendation was based on data from the phase III METEOR trial, in which the most recent data
showed that cabozantinib produced a 4.9-month median overall survival (OS) benefit versus everolimus. The risk of disease progression was reduced by 49% with cabozantinib over everolimus.
The CHMP opinion suggests cabozantinib is likely to be approved for this indication when the European Commission (EC) issues its final decision, which is expected within 2 months. An EC approval would authorize cabozantinib for use in the 28 countries of the European Union, Norway, and Iceland.
“The positive CHMP opinion for Cabometyx is a significant milestone for both Exelixis and Ipsen as we work together to bring this important treatment option to patients with advanced renal cell carcinoma,” Michael M. Morrissey, PhD, president and CEO of Exelixis, said in a statement. “With our shared mission of delivering innovative therapies to improve the treatment of cancer, we have the opportunity to change the way this patient population is treated. If approved by the European Commission, Cabometyx will provide a new treatment option with proven clinically significant benefit across all 3 efficacy endpoints addressing a serious unmet medical need.”
In the METEOR study, 658 patients with clear cell RCC were randomized in a 1:1 ratio to receive daily cabozantinib at 60 mg (n = 330) or everolimus at 10 mg (n = 328). The median age of patients was approximately 62 years (range, 31-86). By MSK criteria, approximately 46% of patients in each arm were in the favorable prognostic risk category, 41% were intermediate, and 13% were poor.
A majority of patients in each arm had received 1 prior VEGFR TKI (71%), with approximately 30% of patients having received ≥2 prior VEGFR TKIs. Use of prior VEGFR TKIs included sunitinib (64% in the cabozantinib arm vs 62% in the everolimus arm), pazopanib (44% vs 41%), axitinib (16% vs 17%), and sorafenib (6% vs 9%). The rates of prior cytokines, PD-1/PD-L1 agents, and bevacizumab between the cabozantinib and everolimus arms were similar as well, at 12% versus 16%, 5% versus 4%, and 2% versus 3%, respectively. Across the study, approximately 33% of patients had received radiotherapy and 86% of patients had undergone nephrectomy.
Median OS was 21.4 months (95% CI, 18.7 to not estimable) for patients receiving cabozantinib versus 16.5 months (95% CI, 14.7-18.8) for those receiving everolimus (HR, 0.66; 95% CI 0.53-0.83; P
= .0003). The OS benefit with cabozantinib was sustained across all prespecified patient subgroups, including MSKCC risk groups, prior VEGFR TKIs, bone metastases, visceral bone metastases, and tumor MET status.
Median progression-free survival (PFS) by independent review was 7.4 months with cabozantinib compared with 3.9 months with everolimus (HR, 0.51; 95% CI, 0.41-0.62; P
<.0001). Cabozantinib was superior to everolimus for PFS across all subgroups.
The median duration of treatment with cabozantinib was 8.3 versus 4.4 months with everolimus. The objective response rate (ORR) per independent review was 17% (95% CI, 13-22) in the cabozantinib arm versus 3% (95% CI, 2-6) in the everolimus arm. The stable disease rates were 65% versus 62% and the progressive rates were 12% versus 27%, respectively. The investigator-assessed ORR was 24% (95% CI, 19-29) with cabozantinib compared with 4% (95% CI, 2-7) with everolimus. Stables disease rates per investigator assessment were 63% in both arms and the progressive disease rates were 9% and 27%, respectively.
The most common all-grade adverse events (AEs) with cabozantinib were diarrhea (75%), fatigue (59%), nausea (52%), decreased appetite (47%), PPES (43%), hypertension (37%), weight decrease (34%), and vomiting (34%). With everolimus, the most common all-grade AEs were fatigue (48%), anemia (39%), decreased appetite (35%), cough (34%), and dyspnea (30%).
The most common grade 3/4 AEs with cabozantinib were hypertension (15%), diarrhea (13%), and fatigue (11%), compared to anemia (17%), fatigue (7%), and hyperglycemia (5%) with everolimus.
Serious AEs occurred in 39% of the cabozantinib group and 40% of the everolimus arm. Dose reductions were required for 62% and 25% of patients in the cabozantinib and everolimus arms, respectively. Adverse events led to treatment discontinuation in 12% of the cabozantinib arm and 11% of the everolimus arm. There was 1 treatment-related death in the cabozantinib cohort and 2 among patients who received everolimus.
Following treatment discontinuation, some of the subsequent anticancer therapies received included VEGFR TKIs (24% in the cabozantinib arm vs 47% in the everolimus arm), everolimus (29% vs 5%), and PD-1/PD-L1 agents (5% vs 6%).
Commenting on the CHMP action, David Meek, CEO of Ipsen, said, “We are pleased that European patients with renal cell cancer may soon have access to Cabometyx. Ipsen is very proud to receive this positive CHMP opinion for Cabometyx, a new drug with unprecedented clinical results in the treatment of advanced renal cell carcinoma. Cabometyx has demonstrated robust and consistent benefits regardless of prior treatment, location and extent of tumor metastases in previously treated patients suffering from advanced renal cell carcinoma.”
In the United States, the FDA approved cabozantinib in April 2016 as a treatment for patients with advanced RCC who have received prior antiangiogenic therapy.
- Choueiri TK, Powles T, Escudier BJ, et al. Overall survival (OS) in METEOR, a randomized phase 3 trial of cabozantinib (Cabo) versus everolimus (Eve) in patients (pts) with advanced renal cell carcinoma (RCC). J Clin Oncol 34, 2016 (suppl; abstr 4506).
- Choueiri TK, Escudier BJ, Powles T, et al. Cabozantinib versus everolimus in advanced renal cell carcinoma (METEOR): final results from a randomised, open-label, phase 3 trial [published online June 5, 2016]. Lancet Oncol. doi: http://dx.doi.org/10.1016/S1470-2045(16)30107-3.