Regulatory Decision Summary for Mekinist

Two separate Supplements to New Drug Submissions (SNDS) for Mekinist (trametinib) and Tafinlar (dabrafenib mesylate) were filed with Health Canada in support of the use of Mekinist and Tafinlar in combination for two new drug indications: (1) treatment of pediatric patients 1 year of age and older with low-grade glioma (LGG) with a BRAF V600E mutation who require systemic therapy, and (2) the treatment of pediatric patients 1 year of age and older with high-grade glioma (HGG) with a BRAF V600E mutation who have received at least one prior radiation and/or chemotherapy treatment. Both indications are supported by a single pivotal Phase II clinical trial (CDRB436G2201; referred to as G2201).

These submissions were filed and accepted for review under the Priority Review Policy. The Sponsor consented to information sharing between Health Canada and Health Technology Assessment organizations as part of an aligned review pathway.

Clinical efficacy and safety for the proposed indications were supported primarily by a phase 2, open-label, 2-cohort, global study (G2201) that evaluated dabrafenib in combination with trametinib (D+T) in children and adolescents with BRAF V600-mutated LGG or HGG.

The LGG cohort was an open-label cohort of 110 patients aged 1 to 17 years with BRAF V600E-mutated LGG who required systemic therapy. Patients were randomized 2:1 to receive targeted D+T therapy (N = 73) or carboplatin plus vincristine (C+V) chemotherapy (N = 37). Upon disease progression (PD), patients randomized to C+V could cross-over to receive D+T therapy.

The HGG cohort was a single-arm, open-label cohort of 41 pediatric patients aged 2 to 17 years old with BRAF V600E-mutated HGG that relapsed, progressed, or failed to respond to frontline therapy.

In both cohorts, dosing of D+T was based on patient age and weight, with dabrafenib administered orally twice daily and trametinib administered orally once daily until PD, loss of clinical benefit, or unacceptable toxicity. Tumour responses were measured using the RANO criteria.

Efficacy in LGG was demonstrated by a statistically significant improvement in the primary and first secondary efficacy endpoints of objective response rate (ORR; the sum of complete [CR] and partial [PR] responses) and progression-free survival (PFS), respectively, in the D+T arm compared with the C+V arm. In the D+T arm, the ORR was 46.6% (95% confidence interval [CI]: 34.8, 58.6) compared with 10.8% in the C+V arm (95% CI: 3.0, 25.4) assessed by independent review committee (IRC), with an odds ratio of 7.19 (95% CI: 2.3, 22.4) and a 1-sided p-value <0.001. The PFS analysis by IRC resulted in an estimated 69% risk reduction in PD or death (hazard ratio [HR]: 0.31; 95% CI: 0.17, 0.55; p<0.001) in the D+T arm. The median PFS was 20.1 months and 7.4 months in the D+T and C+V arms, respectively. In the 9 patients who crossed over to D+T therapy, the ORR by IRC was 33.3% (95% CI: 7.5, 70.1).

Efficacy in HGG was demonstrated by an ORR of 56.1% (95% CI: 39.7, 71.5) assessed by IRC. The study achieved the predetermined threshold for a positive outcome, which required the lower bound of the 95% CI to exceed 20%. The detected responses appeared durable, with a median duration of response of 22.2 months (95% CI: 7.6, not estimable). The ORR was clinically meaningful, given that historically patients with HGG have a poor prognosis, with response rates of 5% to 12% in molecularly unselected relapsed or refractory HGG populations. Time-to-event endpoints (PFS and OS) could not be reliably assessed in a single-arm setting in this patient population.

The adverse event (AE) profile of D+T in pediatric patients with LGG and HGG was generally similar to the previously established profile of the combination therapy in adult patients with melanoma and non-small-cell lung cancer. The majority of all-grade AEs reported in at least 10% of patients in the pivotal G2201 trial were also commonly reported in other trials of D+T.

Significant safety risks in the pediatric population were similar to those previously identified in the adult population, including pyrexia and serious non-infectious febrile events, left ventricular dysfunction, venous thromboembolism, hypertension, hemorrhage, hepatotoxicity, ocular toxicities, and skin toxicities. A new safety signal of increased weight velocity was identified in pediatric patients, which had not been observed previously. Given the short duration of follow-up in the study, long-term impact on growth, as well as long-term risk of new primary malignancies, cardiomyopathy, and ocular toxicities is uncertain.

The dosing recommendations for Tafinlar and Mekinist in the pediatric population for both liquid and solid formulations were adequately supported.

Risk Management Plans (RMP) were submitted by the market authorization holder (MAH) for both Tafinlar and Mekinist. Upon review, both RMPs were acceptable with minor revisions. For Tafinlar, the MAH is asked to implement a specific AE follow-up checklist for the important potential risk of “Safety in patients <18 years of age (including potential adverse effects on skeletal maturation and sexual maturation)” to help further characterize and/or closely monitor potential effects of the drug on this vulnerable population to inform further risk mitigation strategies, if needed. For both Tafinlar and Mekinist, the MAH is asked to submit PBRERs/PSURs after 2 and 4 years of marketing in Canada as routine pharmacovigilance activity, to allow continuous monitoring of safety. Finally, interim/final safety results from ongoing, planned, and post-market studies should be submitted as soon as they are available. The primary tool for risk mitigation for both products is the Product Monograph.

The labelling material reviewed for this submission was considered to be acceptable.

Overall, the efficacy and safety results support the use of dabrafenib in combination with trametinib for the treatment of pediatric patients aged 1-17 years with LGG with a BRAF V600E mutation who require systemic therapy as well as HGG with a BRAF V600E mutation who have received at least one prior radiation and/or chemotherapy treatment. Therefore, Tafinlar in combination with Mekinist is considered to have a positive benefit-risk profile under the proposed conditions of use.