Regulatory Decision Summary for Cabometyx

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.