Johnson, Douglas B

Flaherty, Keith T

Weber, Jeffrey S

Infante, Jeffrey R

Kim, Kevin B

Kefford, Richard F

Hamid, Omid

Schuchter, Lynn

Cebon, Jonathan S

Sharfman, William H

McWilliams, Robert R

Sznol, Mario

Lawrence, Donald P

Gibney, Geoffrey T

Burris, Howard A

Falchook, Gerald S

Algazi, Alain

Lewis, Karl

Long, Georgina V

Patel, Kiran

Ibrahim, Nageatte

Sun, Peng

Little, Shonda

Cunningham, Elizabeth

Sosman, Jeffrey A

Daud, Adil

Gonzalez, Rene

2014-10-06

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.

Journal of Clinical Oncology 2014; 32(33): 3697-704

Journal of Clinical Oncology

https://ahro.austin.org.au/austinjspui/handle/1/12419

Combined BRAF (Dabrafenib) and MEK inhibition (Trametinib) in patients with BRAFV600-mutant melanoma experiencing progression with single-agent BRAF inhibitor.

Journal Article