Data from four published datasets were analyzed to determine whether preexisting MEK1P124 mutations affect radiologic response or progression-free survival (PFS) in patients with BRAFV600-mutant metastatic melanoma treated with vemurafenib or dabrafenib...In a pooled analysis of 123 patients, the presence of a pretreatment MEK1P124 mutation (N = 12, 10%) was associated with a poorer RECIST response (33% vs. 72% in MEK1P124Q/S vs. MEK1P124 wild-type, P = 0.018), and a shorter PFS (median 3.1 vs. 4.8 months, P = 0.004).

Five MAP2K1 gene mutations (encodes the MEK1 kinase) were detected in either drug-resistance specimens (3 mutations; MEK1V60E, MEK1G128V, and MEK1V154I in Patients 41, 32, and 28, respectively) or pre-treatment tumors that progressed rapidly in the face of clinical RAF inhibition (2 mutations; MEK1P124S and MEK1P124L in Patients 4 and 15, respectively) (Fig. 1B). Two additional MEK1 mutations (MEK1G276W and MEK1F53Y) occurred in pre-treatment tumor samples from patients (Patient 5 and 31) who experienced a clinical benefit from RAF inhibitors based on time on therapy (25–33 weeks; Fig. 1B).