Combined BRAF (dabrafenib) and MEK inhibition (trametinib) in patients with BRAF V600 -mutant melanoma experiencing progression with single-agent BRAF inhibitor Academic Article uri icon

abstract

  • Preclinical and early clinical studies have demonstrated that initial therapy with combined BRAF and MEK inhibition is more effective in BRAF(V600)-mutant melanoma than single-agent BRAF inhibitors. This study assessed the safety and efficacy of dabrafenib and trametinib in patients who had received prior BRAF inhibitor treatment.In this open-label phase I/II study, we evaluated the pharmacology, safety, and efficacy of dabrafenib and trametinib. Here, we report patients treated with combination therapy after disease progression with BRAF inhibitor treatment administered before study enrollment (part B; n = 26) or after cross-over at progression with dabrafenib monotherapy (part C; n = 45).In parts B and C, confirmed objective response rates (ORR) were 15% (95% CI, 4% to 35%) and 13% (95% CI, 5% to 27%), respectively; an additional 50% and 44% experienced stable disease ≥ 8 weeks, respectively. In part C, median progression-free survival (PFS) was 3.6 months (95% CI, 2 to 4), and median overall survival was 11.8 months (95% CI, 8 to 25) from cross-over. Patients who previously received dabrafenib ≥ 6 months had superior outcomes with the combination compared with those treated < 6 months; median PFS was 3.9 (95% CI, 3 to 7) versus 1.8 months (95% CI, 2 to 4; hazard ratio, 0.49; P = .02), and ORR was 26% (95% CI, 10% to 48%) versus 0% (95% CI, 0% to 15%).Dabrafenib plus trametinib has modest clinical efficacy in patients with BRAF inhibitor-resistant melanoma. This regimen may be a therapeutic strategy for patients who previously benefited from BRAF inhibitor monotherapy ≥ 6 months but demonstrates minimal efficacy after rapid progression with BRAF inhibitor therapy.

authors

  • Johnson, DB
  • Flaherty, KT
  • Weber, JS
  • Infante, JR
  • Kim, KB
  • Kefford, RF
  • Hamid, O
  • Schuchter, L
  • Cebon, J
  • Sharfman, WH
  • McWilliams, RR
  • Sznol, M
  • Lawrence, DP
  • Gibney, GT
  • Burris, HA
  • Falchook, GS
  • Algazi, A
  • Lewis, K
  • Long, GV
  • Patel, K
  • Ibrahim, N
  • Sun, P
  • Little, S
  • Cunningham, E
  • Sosman, JA
  • Daud, A
  • Gonzalez, R

publication date

  • 2014

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