Regulatory Decision Summary for Cabometyx

This Supplement to a New Drug Submission (SNDS) was filed under the Priority Review Policy to obtain market authorization for Cabometyx (cabozantinib) for the treatment of adult and adolescent patients 12 years of age and older with differentiated thyroid carcinoma (DTC) that has progressed following prior therapy and who are radioactive iodine (RAI)-refractory or ineligible.

Upon review of the submitted data package, Health Canada authorized Cabometyx for the following indication:

Cabometyx is indicated for the treatment of adult patients with locally advanced or metastatic differentiated thyroid carcinoma (DTC) that has progressed following prior Vascular Endothelial Growth Factor Receptor (VEGFR)-targeted therapy and who are radioactive iodine-refractory or ineligible.

This submission was filed under the Priority Review Policy.

The efficacy of Cabometyx (cabozantinib) for the treatment of adult and adolescent patients 12 years of age and older with differentiated thyroid carcinoma (DTC) that has progressed following prior therapy and who are radioactive iodine-refractory (RAI) or ineligible was supported by the pivotal Study XL184-311 (COSMIC-311 trial). This was a randomized (2:1), double-blind, placebo-controlled, multicentre trial in patients with locally advanced or metastatic DTC (papillary or follicular thyroid carcinoma) that had progressed following prior VEGFR-targeted therapy and who were RAI-refractory or ineligible. The primary efficacy endpoints were progression-free survival (PFS) in the intent-to-treat (ITT) population and overall response rate (ORR) in the first 100 randomized patients, as assessed by blinded independent radiology committee (BIRC) per Response Evaluation Criteria in Solid Tumors (RECIST) 1.1.

The pivotal study met the primary endpoint of PFS. Based on the primary analysis of 187 patients in the ITT population, cabozantinib reduced the risk of disease progression or death by 78%, with a stratified hazard ratio (HR) of 0.22 (96% confidence interval [CI]: 0.13, 0.36; p < 0.0001). Median PFS was not reached in the cabozantinib arm and was 1.9 months in the placebo arm. Sensitivity and supplementary analyses of PFS were consistent with the primary analysis.

Following demonstration of significant improvement in PFS at the pre-specified interim analysis, the Independent Data Monitoring Committee (IDMC) recommended stopping enrollment and unblinding the study. Enrollment concluded with 258 subjects (170 in the cabozantinib arm and 88 in the placebo arm). A supportive analysis of all 258 patients in the full ITT population continued to show significant improvement in PFS in the cabozantinib arm compared to placebo (HR 0.22; 96% CI: 0.15, 0.32; p < 0.0001). Median PFS was 11.0 months in the cabozantinib arm versus 1.9 months in the placebo arm.

The study did not meet the multiple primary endpoint of ORR in the first 100 patients. The ORR was 15% (99% CI: 5.8, 29.3) in the cabozantinib arm and 0% (99% CI: 0.0, 14.8) in the placebo arm. The unstratified p-value of 0.0281 did not meet the pre-specified threshold of 0.01, although a numerical advantage was observed in favour of cabozantinib.

No adolescent patients were enrolled in the study. Adolescent exposures were extrapolated from a population pharmacokinetic (PK) model developed using adult data. However, due to limitations identified in the PK modelling and simulation data during the submission review, and previously reported preclinical safety signals in juvenile animals, the Pharmaceutical Drugs Directorate (PDD) rejected the proposed indication for use in adolescents aged 12 years and older.

The safety profile of cabozantinib in this study was consistent with its known safety profile. The median duration of exposure (including dose interruptions) was longer in the cabozantinib arm (4.4 months) compared to the placebo arm (2.3 months). The most frequently reported adverse events (≥ 20%) in the cabozantinib arm included diarrhea, palmar-plantar erythrodysesthesia (PPE), hypertension, fatigue, increased alanine aminotransferase (ALT), nausea, increased aspartate aminotransferase (AST), decreased appetite, and hypocalcemia. Grade 3/4 adverse events (≥ 5%) included PPE, hypertension, fatigue, diarrhea, and hypocalcemia.

Hypocalcemia was reported more frequently in Study XL184-311 than in previous pooled studies, consistent with the higher proportion of patients with prior thyroidectomy, a known risk factor for this complication.

The safety profile of cabozantinib administered at 60 mg once daily (tablets) in adult patients with RAI-refractory DTC was considered manageable with dose modifications. Appropriate dosing modification instructions are included in the Cabometyx Product Monograph. No new safety concerns were identified. A Risk Management Plan (RMP) was not reviewed for this submission.

The benefit-risk profile of Cabometyx for the treatment of adult patients with RAI-refractory DTC was considered favourable. The indication was revised to accurately reflect the study design, patient enrollment, and results of the pivotal trial as follows:

Cabometyx is indicated for the treatment of adult patients with locally advanced or metastatic differentiated thyroid carcinoma (DTC) that has progressed following prior VEGFR-targeted therapy and who are radioactive iodine-refractory or ineligible.

For further details about Cabometyx, please refer to the Product Monograph, approved by Health Canada and available through the Drug Product Database.