(EAY 131-H MATCH): Phase II Study of Dabrafenib and Trametinib in Patients with Tumors with BRAF V600E or V600K Mutations (Excluding Melanoma and Thyroid Cancer)
Given the efficacy of dabrafenib and trametinib monotherapy, preclinical work began to explore the anti-tumor activity of the combination. Experimental data generated with a BRAF- and MEK-inhibitor administered in combination in BRAF-mutant melanoma cell lines in vitro and xenografts in vivo demonstrated the efficacy combination therapy in models of acquired dabrafenib resistance. More importantly, superior anti-tumor activity of the BRAF- and MEK-inhibitor combination as compared to each agent as monotherapy was also observed in BRAF-sensitive models [GSK1120212 and GSK2118496 Investigator¿s Brochure version 03 23-JUN-2014]. This finding was confirmed in a randomized, phase 2 study of a combination of dabrafenib and trametinib, as compared with dabrafenib alone in patients with metastatic BRAF V600E and V600K mutated melanoma. In this trial, the investigators demonstrated a longer progression free survival with the combination (9.4 vs 5.8 months), as well as less squamous skin carcinoma (7% vs 19%).17 Based on this study, the combination is now FDA approved for the treatment of V600E or V600K BRAF mutant melanoma. Recently, a double-blind, randomized, phase 3 study without crossover was published comparing the combination of dabrafenib and trametinib to dabrafenib plus placebo as first-line therapy in patients who had metastatic melanoma with BRAF V600E or V600K mutations.13 The median progression-free survival was 9.3 months in the dabrafenib¿trametinib group and 8.8 months in the dabrafenib-only group (P=0.03). The overall response rate was 67% in the dabrafenib¿trametinib group and 51% in the dabrafenib-only group (P=0.002). At 6 months, the interim overall survival rate was 93% with dabrafenib¿trametinib and 85% with dabrafenib alone (P=0.02). Available efficacy data of dabrafenib and trametinib in patients with solid tumors are listed in Table 1.
NCG 275215 H