Combined BRAF and MEK Inhibition in Melanoma with BRAF V600 Mutations

Abstract

BACKGROUND Resistance to therapy with BRAF kinase inhibitors is associated with reactivation of the mitogen-activated protein kinase (MAPK) pathway. To address this problem, we conducted a phase 1 and 2 trial of combined treatment with dabrafenib, a selective BRAF inhibitor, and trametinib, a selective MAPK kinase (MEK) inhibitor. METHODS In this open-label study involving 247 patients with metastatic melanoma and BRAF V600 mutations, we evaluated the pharmacokinetic activity and safety of oral dabrafenib (75 or 150 mg twice daily) and trametinib (1, 1.5, or 2 mg daily) in 85 patients and then randomly assigned 162 patients to receive combination therapy with dabrafenib (150 mg) plus trametinib (1 or 2 mg) or dabrafenib monotherapy. The primary end points were the incidence of cutaneous squamous-cell carcinoma, survival free of melanoma progression, and response. Secondary end points were overall survival and pharmacokinetic activity. RESULTS Dose-limiting toxic effects were infrequently observed in patients receiving combination therapy with 150 mg of dabrafenib and 2 mg of trametinib (combination 150/2). Cutaneous squamous-cell carcinoma was seen in 7% of patients receiving combination 150/2 and in 19% receiving monotherapy (P = 0.09), whereas pyrexia was more common in the combination 150/2 group than in the monotherapy group (71% vs. 26%). Median progression-free survival in the combination 150/2 group was 9.4 months, as compared with 5.8 months in the monotherapy group (hazard ratio for progression or death, 0.39; 95% confidence interval, 0.25 to 0.62; P<0.001). The rate of complete or partial response with combination 150/2 therapy was 76%, as compared with 54% with monotherapy (P = 0.03). CONCLUSIONS Dabrafenib and trametinib were safely combined at full monotherapy doses. The rate of pyrexia was increased with combination therapy, whereas the rate of proliferative skin lesions was nonsignificantly reduced. Progression-free survival was significantly improved. (Funded by GlaxoSmithKline; ClinicalTrials.gov number, NCT01072175.)

Emerging findings into molecular mechanism of brain metastasis

“…BRAF inhibitors dabrafenib combined with mitogen‐activated extracellular signal‐regulated kinase (MEK) inhibitors like trametinib could increase anti‐tumor activity and reduce side‐effect 105, 106. In conclusion, targeted therapy such as small molecule kinase inhibitors have achieved outstanding development, but still needs to pay more attention and take more effort on investigation and preferable application in clinic.…”

Oncogenic BRAF induces chronic ER stress condition resulting in increased basal autophagy and apoptotic resistance of cutaneous melanoma

“…[11][12][13] Oncogenic mutations, however, in the Ras/Raf pathway are the most well-described genetic mutations associated with melanoma development and progression. 14 Indeed, up to 90% of all melanomas harbour activating NRAS or BRAF mutations, with BRAF V600E representing more than 90% of BRAF mutations, 15,16 the consequence of which is the constitutive activation of RAF-extracellular signal-regulated kinase/ERK signalling promoting melanoma proliferation and resistance to apoptosis. 17 Nevertheless, mutation of NRAS/ BRAF alone is not sufficient to initiate melanomagenesis, because these common mutations are also present in benign nevi, thereby highlighting the requirement of other factors to drive melanocyte transformation and melanoma development.…”

NCCN Working Group Report: Designing Clinical Trials in the Era of Multiple Biomarkers and Targeted Therapies

“…When a patient harbors an activating mutation in BRAF, the downstream kinase MEK is also activated. This recognition led to the development of trametinib, a MEK inhibitor 45,47,48 . Trametinib is indicated as a single agent and in combination with dabrafenib in patients with unresectable or metastatic melanoma that harbor a BRAF V600E or V600K mutation.…”

“…However, the combination of BRAF and MEK inhibition in the appropriate patient population does improve response rate and PFS, although somewhat more modestly than one would hope. 45,49 Collectively, these targeted therapies represent a substantial step forward in the treatment of patients with BRAF-mutated melanoma.…”