Regulatory Decision Summary for Tafinlar

Clinical efficacy and safety of dabrafenib plus trametinib for the adjuvant treatment of patients with high-risk (Stage III) melanoma with BRAF V600E or V600K mutations following surgical resection is supported by the pivotal trial, BRF115532. The study was a randomized, double-blind Phase III trial of melanoma patients treated with dabrafenib plus trametinib or two matching placebos for 12 months. Treatment decreased the risk of disease recurrence or death from any cause by 53% compared to placebo. This result is robust based on statistical significance and sensitivity analyses, and the fact that it exceeded the pre-specified threshold of success of 30%. Efficacy was consistent across subgroups, regardless of mutation status, gender, age, and disease characteristics. The probability of being alive and relapse-free at 3 years was 58% in the dabrafenib and trametinib arm and 39% in the placebo arm. The improvement in relapse-free survival was supported by the following secondary endpoints: distant metastasis-free survival and freedom from relapse. Overall survival data were immature and not statistically significant at the time of primary analysis, but encouraging compared to placebo.

The pattern of toxicity in the adjuvant melanoma setting was consistent with the established risks for unresectable or metastatic melanoma and no new safety signals were detected. Higher incidences of severe and serious adverse events leading to treatment discontinuations were observed with combination therapy compared to placebo. The most common adverse events in ≥20% of patients were pyrexia, fatigue, chills, nausea, headache, diarrhea, vomiting, arthralgia, myalgia, and rash. Toxicity was manageable with dose adjustment, treatment interruption, or therapeutic intervention and most patients were able to complete all 12 months of dabrafenib (63%) and trametinib (64%) treatment. Female patients experienced higher rates of treatment-related adverse events, serious adverse events, and treatment-related serious adverse events, with correspondingly higher dose reductions, interruptions, and discontinuations compared to male patients. Elderly patients (≥65 years) were also more likely to discontinue treatment than younger patients. No treatment-related deaths occurred.

Health Canada concluded that adjuvant treatment with dabrafenib plus trametinib combination therapy demonstrates a statistically significant and clinically meaningful benefit in delaying melanoma recurrence or death. Combination therapy was associated with serious and severe toxicities; however, given the seriousness of the condition and current unmet medical need for adjuvant therapy options in Canada, the safety profile of dabrafenib plus trametinib is considered manageable.

The submission was filed under Health Canadas NOC/c regulatory pathway; however, following review of the clinical data the department granted regular approval for the indications based on the totality of the evidence and the benefit-harm-uncertainty profiles of Mekinist and Tafinlar. As part of granting the Notice of Compliance, the sponsor committed to provide Health Canada with new clinical and post-market information pertaining to adjuvant use as it becomes available and to update the product information accordingly.