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.).

Figure 1. Progression-free Survival and Subgroup Analyses

Panel A shows Kaplan–Meier curves for progression-free survival, with progression assessed by the site investigators, in an analysis comparing two doses of combination therapy — 150 mg of dabrafenib twice daily plus once-daily trametinib at a dose of either 1 mg (combination 150/1) or 2 mg (combination 150/2) — with dabrafenib monotherapy (mono). Panel B shows subgroup analyses for patients receiving either combination 150/2 or monotherapy. Both these analyses were performed in part C of the study. The melanoma staging criteria of the American Joint Committee on Cancer are defined as follows: stage IIIc, metastases to 4 or more nodes (or in-transit metastasis); and stage IV, metastases beyond nodes. The criteria for distant metastasis are defined as follows: M0, no detectable evidence of distant metastases; M1a, metastases to skin, subcutaneous tissue, or distant lymph nodes; M1b, metastases to lung; and M1c, metastases to all other visceral sites or distant metastases to any site combined with an elevated serum lactate dehydrogenase (LDH) level. ULN denotes upper limit of the normal range.