The European Commission has approved Tafinlar ( Dabrafenib ) in combination with Mekinist ( Trametinib ) for the adjuvant treatment of stage III patients with BRAF V600 mutation-positive melanoma after complete surgical resection.
This approval is the third for Tafinlar in combination with Mekinist in European Union across a variety of tumor types identified with a high level of BRAF mutation.
The approval is based on results from the phase III COMBI-AD global study, which enrolled more than 870 patients with stage III, BRAF V600E/K-mutant melanoma without prior anticancer therapy, and who were randomized within 12 weeks of complete surgical resection.
Patients received Tafinlar ( 150 mg BID ) and Mekinist ( 2 mg QD ) combination (n = 438) or matching placebos ( n = 432 ).
In the primary analysis, and after a median follow-up of 2.8 years, the primary endpoint was met, with the combination therapy significantly reducing the risk of disease recurrence or death by 53% versus placebo.
Based on updated data, with an additional 10 months of follow-up compared to the primary analysis ( minimum follow-up of 40 months ), treatment with the combination therapy reduced the risk of recurrence or death by 51% versus placebo.
Additionally, the relapse free survival ( RFS ) benefit among the combination arm was observed across all patient subgroups, including stage III A, B and C.
The combination treatment group also saw an improvement in a key secondary endpoint of overall survival.
The BRAF gene belongs to a class of genes known as oncogenes and provides instructions for making a protein that helps transmit chemical signals from outside the cell to the cell's nucleus. This protein is part of a signaling pathway known as the RAS/MAPK pathway, which controls several important cell functions. Specifically, the RAS/MAPK pathway regulates the growth and division ( proliferation ) of cells, the process by which cells mature to carry out specific functions ( differentiation ), cell movement ( migration ) and the self-destruction of cells ( apoptosis ).
Chemical signaling through this pathway is essential for normal development before birth.
When mutated, oncogenes have the potential to cause normal cells to become cancerous.
During cancer treatment, targeted therapies may inhibit the mutation from occurring, thus slowing the growth of the cancer tumor.
Adverse events were consistent with other Tafinlar and Mekinist studies and no new safety signals were reported.
Of patients treated with the combination, 97% experienced an adverse events, with 41% having grade 3/4 adverse effects and 26% having adverse effects leading to treatment discontinuation ( versus 88%, 14%, and 3%, respectively, with placebo ).
The COMBI-AD study evaluated Tafinlar plus Mekinist among patients with stage III, BRAF V600E/K-mutant melanoma without prior anticancer therapy, randomized within 12 weeks of complete surgical resection.
In the initial primary analysis, and after a median follow-up of 2.8 years, the primary endpoint was met in that the combination therapy significantly reduced the risk of disease recurrence or death by 53% versus placebo ( hazard ratio, HR=0.47 [ 95% CI: 0.39-0.58 ]; median not yet reached vs. 16.6 months, respectively; p less than 0.001 ).
Based on updated data with minimum follow-up of 10 months ( a minimum follow up of 40 months ), the relapse free survival benefit was maintained with an estimated reduction in the risk of disease recurrence or death by 51% vs placebo ( HR: 0.49 [ 95% CI: ( 0.40-0.59 )] .
The relapse-free survival benefit among the combination arm was observed across all patient subgroups, including stage III A, B and C.
The estimated one-year, two-year, and three-year relapse free survival were consistently higher than placebo ( one year: 88% vs. 56%; two year: 67% vs. 44%; three year: 59% vs. 40% ).
The combination treatment group also saw an improvement in a key secondary endpoint of overall survival ( OS ) ( HR: 0.57 [ 95% CI: 0.42-0.79 ] p=0.0006, which did not cross the predefined interim analysis boundary of p=0.000019 to claim statistical significance ).
Other secondary endpoints where the combination demonstrated a clinically meaningful benefit have included distant metastasis-free survival ( DMFS ) ( HR: 0.51 [ 95% CI: 0.40-0.65 ] ), and freedom from relapse ( FFR ) ( HR: 0.47 [ 95% CI: 0.39-0.57 ] ).
There are about 200,000 new diagnoses of melanoma ( stages 0-IV ) worldwide each year, approximately half of which have BRAF mutations.
Melanoma is staged by how far it has metastasized. In stage III melanoma, tumors have spread to the regional lymph nodes, presenting a higher risk of recurrence or metastases.
Patients who receive surgical treatment for stage III melanoma may have a high risk of recurrence because melanoma cells can remain in the body after surgery; almost half ( 44% ) of patients receiving placebo per the COMBI-AD study had a recurrence of disease within the first year.
Adjuvant therapy is additional treatment given after surgical resection, and may be recommended for patients with high-risk melanoma to help reduce the risk of melanoma returning. ( Xagena )
Source: Novartis, 2018