Novartis has announced results from a phase II study showing a durable survival benefit for some patients with BRAF V600 mutation-positive metastatic melanoma (MM) when treated with the combination of Tafinlar (dabrafenib) + Mekinist (trametinib). The findings from the landmark five-year analysis of the trial, BRF113220, represent the longest follow-up to date of a BRAF and MEK inhibitor combination therapy in this patient population, and were presented at the 53rd Annual Meeting of the American Society of Clinical Oncology (ASCO) in Chicago.

A total of 162 patients received either Tafinlar monotherapy (150 mg BID) (n = 54) or the Tafinlar + Mekinist combination (150 mg BID/2 mg QD) (n = 54). After five years, 20 patients (37%) remain in the study, including seven (13%) in the Tafinlar monotherapy arm and 13 (24%) in the combination therapy arm, demonstrating that overall survival (OS) with combination therapy is superior to monotherapy.

The four-and five-year OS rates with monotherapy were 23% and 21%, respectively. The four- and five-year OS rates with combination therapy were 30% and 28%, respectively, reflecting a stabilization of OS in patients enrolled in the study. Progression-free survival (PFS) in the monotherapy arm was consistently 3% whereas PFS at both four and five years was 13%, also demonstrating stabilization. Forty-five of 54 patients (83%) in the Tafinlar monotherapy arm included in this updated analysis had crossed over to Tafinlar + Mekinist combination (150 mg BID/2 mg QD) the survival outcomes in these crossover patients continued to be followed under the Tafinlar arm.

"These recent results from the longest follow-up of a BRAF and MEK inhibitor targeted study show that a significant cohort of patients with metastatic melanoma positive for the BRAF V600 mutation can achieve long-term survival with Tafinlar + Mekinist combination therapy," said lead investigator Jeff Weber, MD, PhD, deputy director, Laura and Isaac Perlmutter Cancer Center, Co-Director, Melanoma Program & Head of Experimental Therapeutics NYU Langone Medical Center. "This combination of targeted therapy should be considered by physicians when making treatment decisions."

Adverse events were consistent with other Tafinlar + Mekinist studies, and additional follow-up revealed no new safety signals.

"These data demonstrate the long-term benefit of Tafinlar in combination with Mekinist for certain patients living with metastatic melanoma," said Vas Narasimhan, global head drug development and chief medical officer, Novartis. "We are gratified to see these data showing that patients can benefit long-term from Tafinlar + Mekinist, and we look forward to evaluating additional Phase III long-term survival data."

Additionally, Novartis presented results from a Phase II study showing a positive, statistically significant intracranial response for patients with BRAF V600 mutation-positive metastatic melanoma (MM) when treated with the combination of Tafinlar + Mekinist. The findings from the 30-month trial, COMBI-MB, represent the first report of a Phase II trial evaluating a BRAF and MEK inhibitor combination therapy in patients with BRAF V600-mutant melanoma brain metastases (MBM).

The COMBI-MB study evaluated Tafinlar + Mekinist in 125 patients enrolled in four cohorts. In Cohort A (patients who were BRAF V600E mutation-positive, had asymptomatic MBM and no local prior treatment), investigator-assessed intracranial response rate (IRR) was 58% (95% CI: 46, 69). Extracranial response rate (ERR) was 55% (95% CI: 43, 67) and overall response rate (ORR) was 58% (95% CI: 46, 69). Median PFS was 5.6 months (95% CI: 5.3, 7.4). Six-month OS was 79%; with 31 patients (41%) still in follow-up. Preliminary median OS was 10.8 months (95% CI: 8.7, 19.6).

Adverse events across cohorts (any, 98%; grade 3/4, 48%) were consistent with prior Tafinlar + Mekinist studies; 10% of patients (8% in cohort A) discontinued due to adverse events.

Additional poster and oral presentations related to the investigational use of Tafinlar and Mekinist were also presented at the meeting, including an updated five year landmark analysis of phase II (BREAK-2) and phase III (BREAK-3) studies evaluating Tafinlar monotherapy in patients with BRAF V600-mutant melanoma, and studies in BRAF V600E-mutated advanced thyroid cancer (ATC) and non-small cell lung cancer (NSCLC).