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Clinical Trial
. 2014 Nov 20;32(33):3697-704.
doi: 10.1200/JCO.2014.57.3535. Epub 2014 Oct 6.

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

Douglas B Johnson  1 , Keith T Flaherty  2 , Jeffrey S Weber  2 , Jeffrey R Infante  2 , Kevin B Kim  2 , Richard F Kefford  2 , Omid Hamid  2 , Lynn Schuchter  2 , Jonathan Cebon  2 , William H Sharfman  2 , Robert R McWilliams  2 , Mario Sznol  2 , Donald P Lawrence  2 , Geoffrey T Gibney  2 , Howard A Burris 3rd  2 , Gerald S Falchook  2 , Alain Algazi  2 , Karl Lewis  2 , Georgina V Long  2 , Kiran Patel  2 , Nageatte Ibrahim  2 , Peng Sun  2 , Shonda Little  2 , Elizabeth Cunningham  2 , Jeffrey A Sosman  2 , Adil Daud  2 , Rene Gonzalez  2
Affiliations
Clinical Trial

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

Douglas B Johnson et al. J Clin Oncol. .

Abstract

Purpose: 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.

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.

Trial registration: ClinicalTrials.gov NCT01072175.

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Conflict of interest statement

Authors' disclosures of potential conflicts of interest are found in the article online at www.jco.org. Author contributions are found at the end of this article.

Figures

Fig 1.
Fig 1.
Study design. Gold areas show the study population reported in this article. BRAFi, BRAF inhibitor; HPMC, hydroxypropyl methylcellulose.
Fig 2.
Fig 2.
Maximum tumor reduction in BRAF inhibitor (BRAFi) –resistant patients in (A) parts B and (B) C. CR, complete response; PD, progressive disease; PR, partial response; SD, stable disease.
Fig 3.
Fig 3.
(A) Progression-free survival (PFS) for patients with BRAF inhibitor (BRAFi) –resistant melanoma (Part B 150/2 BRAFi failure: patients failed to respond to BRAFi off study, then received 150 mg dabrafenib twice per day and 2 mg of trametinib once per day); (B) overall survival (OS) from combination therapy for BRAFi-resistant patients (parts B and C); (C) duration of treatment with dabrafenib monotherapy followed by duration of treatment with combination therapy (part C); and (D) PFS with dabrafenib and trametinib for patients with rapid progression with BRAFi monotherapy versus patients with delayed resistance.
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