The Committee for Medicinal Products for Human Use ( CHMP ), the scientific committee of the European Medicines Agency ( EMA ) has provided a positive opinion for Cabometyx ( Cabozantinib ) 20, 40, 60 mg for the treatment of advanced renal cell carcinoma ( RCC ) in adults following prior vascular endothelial growth factor (VEGF)-targeted therapy.
The positive CHMP opinion was adopted following an accelerated review procedure reserved for medicinal products expected to be of major public health interest, based on METEOR phase 3 pivotal trial.
METEOR was an open-label, event-driven trial of 658 patients with advanced renal cell carcinoma who had failed at least one prior VEGFR TKI therapy. The primary endpoint was progression-free survival ( PFS ) in the first 375 patients treated. Secondary endpoints included overall survival ( OS ) and objective response rate in all enrolled patients. Patients were randomized 1:1 to receive 60 mg of Cabozantinib daily or 10 mg of Everolimus ( Afinitor ) daily and were stratified based on the number of prior VEGFR TKI therapies received and on MSKCC risk criteria.
No cross-over was allowed between the study arms.
METEOR met its primary endpoint of significantly improving progression-free survival. Compared with Everolimus, Cabozantinib was associated with a 42% reduction in the rate of disease progression or death. Median progression-free survival for Cabozantinib was 7.4 months versus 3.8 months for Everolimus ( HR=0.58, 95% CI 0.45-0.74, P less than 0.0001 ).
Cabozantinib has also significantly improved the objective response rate compared with Everolimus ( p less than 0.0001 ).
Cabozantinib has also demonstrated a statistically significant and clinically meaningful increase in overall survival in the METEOR trial. Compared with Everolimus, Cabozantinib was associated with a 34% reduction in the rate of death. Median overall survival was 21.4 months for patients receiving Cabozantinib versus 16.5 months for those receiving Everolimus ( HR=0.66, 95% CI 0.53-0.83, P=0.0003 ).
Cabozantinib benefit in overall survival was robust and consistent across all pre-specified subgroups. In particular, benefit was observed regardless of risk category, location and extent of tumor metastases, and tumor MET expression level.
The most frequent adverse events regardless of causality were diarrhea, fatigue, decreased appetite and hypertension for Cabozantinib and fatigue, anemia, decreased appetite and cough for Everolimus.
Dose reductions occurred for 62% and 25% of patients, respectively.
Discontinuation rate due to an adverse event not related to disease progression was 12% with Cabozantinib and 11% with Everolimus.
Cabozantinib targets include MET, AXL and VEGFR-1, -2 and -3. In preclinical models, Cabozantinib has been shown to inhibit the activity of these receptors, which are involved in normal cellular function and pathologic processes such as tumor angiogenesis, invasiveness, metastasis and drug resistance. ( Xagena )
Source: Ipsen, 2016