Regulatory Decision Summary for Mekinist

The safety and efficacy of dabrafenib plus trametinib combination therapy for treatment-naïve metastatic NSCLC patients with a BRAFV 600 mutation was evaluated in a single pivotal study (BRF113928). This study was a phase II open label non-comparative trial consisting of metastatic NSCLC patients who were sequentially enrolled in three cohorts. Supportive efficacy data is derived from patients enrolled in Cohort C (n = 36), who had not been previously treated with anti-cancer therapy and were treated with the combination of dabrafenib (150 mg twice daily) and trametinib (2 mg once daily). The primary efficacy endpoint was Overall Response Rate (ORR).

Benefits
The ORR primary endpoint according to the investigator was 61.1% (95% CI: 43.5, 76.9), which is considered clinically meaningful. These results are robust given the high concordance (88%) with the endpoint as evaluated by an Independent Review Committee (IRC). The median Duration of Response in months was not yet reached at time of primary analysis, with the lower and upper 95% CI boundaries of 6.9, and not estimable, respectively. Responses were rapid, with a median time to ORR of 1.4 months.

Harms
Overall, the safety profile of the combination therapy in treatment naïve patients was generally consistent with what has been observed from early data from pivotal studies and other indications, with no new safety signals identified. The most common adverse events observed were pyrexia, nausea, diarrhea, edema peripheral, dry skin, fatigue, and vomiting. The most common grade 3/4 adverse events were pyrexia, vomiting, dyspnea, hypotension, ALT increased, ejection fraction decreased, and hypertension. Adverse events were generally manageable through dose adjustment, treatment interruption, or drug/non-drug intervention, with few discontinuations.

Uncertainties
The small sample size in Cohort C in Study BRF113928 along with the lack of a comparator arm were limitations of the data related to the efficacy of the dabrafenib and Tafinlar combination in the BRAF V600 mutation positive NSCLC population. In addition, only 1 response (3%) was evaluated by the IRC as a Complete Response. There is currently limited information available on the natural history of BRAF V600 mutation positive NSCLC treated with standard chemotherapy, and Progression-Free Survival and Overall Survival benefit could not be demonstrated without an appropriate comparator arm.

In conclusion, the combination of dabrafenib plus trametinib demonstrated clinically meaningful and durable anti-tumor activity in previously untreated metastatic NSCLC patients harbouring the BRAF V600 mutation. In the context of this rare, life-threatening, incurable disease not adequately managed by available therapies in Canada, the evidence of efficacy is considered substantial, with clinical benefit that outweighs the associated risks.