Combined BRAF (dabrafenib) and MEK inhibition (trametinib) in patients with BRAFV600-mutant melanoma experiencing progression with single-agent BRAF inhibitor

Douglas B. Johnson*, Keith T. Flaherty, Jeffrey S. Weber, Jeffrey R. Infante, Kevin B. Kim, Richard F. Kefford, Omid Hamid, Lynn Schuchter, Jonathan Cebon, William H. Sharfman, Robert R. McWilliams, Mario Sznol, Donald P. Lawrence, Geoffrey T. Gibney, Howard A. Burris, Gerald S. Falchook, Alain Algazi, Karl Lewis, Georgina V. Long, Kiran PatelNageatte Ibrahim, Peng Sun, Shonda Little, Elizabeth Cunningham, Jeffrey A. Sosman, Adil Daud, Rene Gonzalez

*Corresponding author for this work

Research output: Contribution to journalArticle

133 Scopus citations

Abstract

Purpose: Preclinical and early clinical studies have demonstrated that initial therapy with combined BRAF and MEK inhibition is more effective in BRAFV600-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. Patients and Methods: 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). Results: 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%). Conclusion: 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.

Original languageEnglish (US)
Pages (from-to)3697-3704
Number of pages8
JournalJournal of Clinical Oncology
Volume32
Issue number33
DOIs
StatePublished - Nov 20 2014

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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    Johnson, D. B., Flaherty, K. T., Weber, J. S., Infante, J. R., Kim, K. B., Kefford, R. F., Hamid, O., Schuchter, L., Cebon, J., Sharfman, W. H., McWilliams, R. R., Sznol, M., Lawrence, D. P., Gibney, G. T., Burris, H. A., Falchook, G. S., Algazi, A., Lewis, K., Long, G. V., ... Gonzalez, R. (2014). Combined BRAF (dabrafenib) and MEK inhibition (trametinib) in patients with BRAFV600-mutant melanoma experiencing progression with single-agent BRAF inhibitor. Journal of Clinical Oncology, 32(33), 3697-3704. https://doi.org/10.1200/JCO.2014.57.3535