Regulatory Decision Summary for MEKINIST

The Phase III randomized controlled trial (MEK115306) supporting this submission compared the safety and efficacy of the combination of Mekinist and dabrafenib to dabrafenib monotherapy in patients with BRAF V600 mutation-positive metastatic melanoma. The study met its primary endpoint of progression-free survival (PFS) assessed by the investigator, demonstrating a statistically significant benefit for the combination therapy (hazard ratio [HR] 0.75, 95% CI: 0.57 - 0.99, p = 0.04). The magnitude of PFS benefit (difference in median survival <1 month; 9.3 versus. 8.8 months), however, was small. In support of this result, investigator and independent assessments for objective response rate both reported an improvement of 15% for combination therapy over dabrafenib monotherapy. There were also more deaths in the dabrafenib monotherapy arm (55) compared to the combination arm (40) at the time of the final PFS analysis; the overall survival (OS) benefit (HR = 0.63) observed at this interim analysis, while promising, was not conclusive.

In terms of safety, there were additional concerns for the combination therapy that included major hemorrhagic events, and deep vein thrombosis and pulmonary embolism. Fever, which is associated with dabrafenib monotherapy, was increased in incidence and severity with the combination therapy. However, importantly, there were fewer reports of cutaneous squamous cell carcinoma and hyperkeratosis for the combination therapy compared to dabrafenib monotherapy. The additional risks associated with the combination therapy were considered manageable in the treatment of BRAF V600 mutation-positive advanced melanoma patients. The labelling updates in the Mekinist Product Monograph will help prescribers manage and mitigate the risks of the combination therapy appropriately.

The Therapeutic Products Directorate considered that the small magnitude in PFS benefit reported for the combination therapy versus an active standard of care (dabrafenib monotherapy) in the ongoing Phase III study did not provide substantial evidence of clinical effectiveness. However, the small PFS benefit reported in this study over an already active monotherapy agent with improvement in response rate and a trend for an OS benefit was considered promising nonetheless, and based on the benefit risk assessment; the safety profile was considered acceptable. As such, this submission was considered acceptable for market authorization under the Notice of Compliance with Conditions (NOC/c) Guidance. The sponsor has committed to carry out additional clinical trials to verify the anticipated benefit.