Regulatory Decision Summary for Cabometyx

Review decision

The Regulatory Decision Summary explains Health Canada’s decision for the product seeking market authorization. The Regulatory Decision Summary includes the purpose of the submission and the reason for the decision.

Product type:


Medicinal ingredient(s):


Therapeutic area:

Antineoplastic Agents

Type of submission:

Priority New Drug Submission (New Active Substance)

Control number:

What was the purpose of this submission?


This New Drug Submission (NDS) was filed to gain market authorisation for the use of Cabometyx (20 mg, 40 mg and 60 mg cabozantinib) tablets for the treatment of patients with advanced renal cell carcinoma (RCC) who have received prior therapy.


Why was the decision issued?


Cabometyx (cabozantinib) is recommended as monotherapy for the second-line treatment of adult patients with advanced RCC who have received prior vascular endothelial growth factor (VEGF)-targeted therapy based on the safety and efficacy results of Study 308. Study 308 was an open-label, randomized, multicenter, Phase 3 trial that compared cabozantinib 60 mg (n = 330) taken orally once daily to everolimus 10 mg (n = 328) taken orally once daily.

Study 308 met its primary objective and demonstrated a 3.6 month improvement in progression-free survival (PFS) assessed by blinded independent review. The median PFS for cabozantinib-treated subjects was 7.4 months (95% CI: 5.6-9.1) compared to 3.8 months (95%CI: 3.7-5.4) for everolimus-treated subjects. The observed reduction in risk of disease progression or death was 41% (hazard ratio [HR]: 0.59; 95% CI: 0.46-0.76).

The main secondary endpoints were investigator-assessed Objective Response Rate (ORR) and Overall Survival (OS). The ORRs were 24% (95% CI: 19, 29) and 4% (95% CI: 2, 7) for subjects in the cabozantinib and everolimus arms, respectively. The OS was 17% (95% CI: 13, 22) and 3% (95% CI: 2, 6), for subjects in the cabozantinib and everolimus arms, respectively. A follow-up final analysis with a cut-off date of October 2, 2016 showed that the OS benefit was maintained with a median OS of 21.4 months (95% CI: 18.6-23.5) for cabozantinib vs. 17.1 months (95% CI: 14.9-18.9) for everolimus. The reduction in the risk of death was 30% (HR: 0.70; 95% CI: 0.58-0.85).

The Adverse Events (AEs) that led to dose reductions in the cabozantinib arm include diarrhea, palmar-plantar erythrodysesthesia syndrome (PPES), fatigue and hypertension. The AEs that needed dose interruptions in more than 10% of subjects in the cabozantinib arm were diarrhea, PPES and fatigue. The AEs that led to treatment discontinuation in more than 1% of subjects were decreased appetite and fatigue. There was no difference in the rates of AEs that led to treatment discontinuation (cabozantinib: 9.7% vs everolimus: 9.6%).

Safety findings in Study 308 indicate that all subjects in both study arms experienced AEs. No significant difference in the overall incidence of serious AEs was noted between cabozantinib-treated subjects (40%) and everolimus-treated patients (43%). Serious AEs reported in more than 1.5% of subjects in the cabozantinib arm included abdominal pain, pleural effusion, diarrhea, nausea, anemia, back pain, dyspnea, fatigue, pneumonia, pulmonary embolism, vomiting and pain. The AEs that were grade 3 or 4 in severity in the cabozantinib arm reported in more than 1.5% of subjects were hypertension, diarrhea, fatigue, PPES, anemia, hypomagnesemia, hypokalemia, asthenia, hyponatremia, nausea, abdominal pain, hypophosphatemia, dyspnea, decreased appetite, increased lipase, pleural effusion, increased alanine transaminase , proteinuria, pulmonary embolism, stomatitis, back pain, increased aspartate transaminase , hypocalcaemia, decreased weight and increased bilirubin.

Cabozantinib provided clinically significant gains in PFS and OS over everolimus, a standard of care in the second line setting for RCC patients. The risks associated with the use of cabozantinib are not unexpected for a tyrosine kinase inhibitor (TKI) targeting vascular endothelial growth factor receptor (VEGFR) and are adequately managed with dose reductions. The overall benefit-harm-uncertainty profile for cabozantinib is considered favourable for the second line treatment of adult patients with advanced RCC who have received prior VEGFR-targeted therapy.


Decision issued

Approved; issued a Notice of Compliance in accordance with the Food and Drug Regulations.