Mark Middleton, MD
Combination treatment with selumetinib and dacarbazine significantly improved progression-free survival (PFS) in patients with BRAF-positive melanoma, according to phase II data presented at the 2013 ASCO Annual Meeting. However, the regimen failed to significantly improve overall survival (OS), the study’s primary endpoint.
Selumetinib is a selective inhibitor of the MEK1 and MEK2 kinases, found as part of the MAPK pathway, which includes BRAF. Preclinical models with cell lines with BRAF
mutations have shown sensitivity toward selumetinib, and other models showed that selumetinib was able to slow tumor growth, with this effect greatly enhanced with the addition of chemotherapy.
“We set out on the basis of this evidence to explore the potential for improving the efficacy of dacarbazine chemotherapy with the addition of selumetinib,” said Mark Middleton, MD, professor of Experimental Cancer Medicine at the University of Oxford and a consultant medical oncologist at the Oxford Cancer and Haematology Centre in Oxford, England.
In this study, a total of 91 patients were randomized to either 75 mg of selumetinib twice a day plus 1000 mg/m2 of dacarbazine once every 21 days (n = 45) or a placebo twice a day plus the same dose of dacarbazine (n = 46).
In patients receiving the selumetinib combination, the median OS was 13.9 months versus 10.5 months in the placebo arm; however, the improvement was not statistically significant (hazard ratio [HR] = 0.93; 80% CI, 0.67-1.28; P
A significant improvement in PFS was observed in the treatment versus the control arm at 5.6 months versus 3.0 months, respectively (HR = 0.63; 80% CI, 0.47-0.84; P
The ORR was 40% in the selumetinib combination arm compared with 26.1% in the placebo arm, although this improvement was not statistically significant (odds ratio = 1.95; 80% CI, 1.06-3.66; P
The researchers concluded that the safety and tolerability of the combination of selumetinib and dacarbazine was generally consistent with the monotherapy safety profiles of those agents. The most frequently reported adverse events of any grade in the selumetinib arm were acneiform dermatitis, diarrhea, vomiting, and peripheral edema. Dermatologic disorders were observed in 88.6% of patients receiving the combination. Adverse events of grade 3 or higher occurred more frequently in patients in the experimental arm (68.2%) versus the placebo arm (42.2%).
Since three studies have investigated the use of selumetinib with chemotherapeutic agents and have shown an improvement in PFS, the researchers concluded that further investigation is warranted.
“It suggests that there’s some merit in pursuing combinations of selumetinib with chemotherapeutics, and that the therapeutic index for this combination might be at its best when used in a situation where there’s genetic dependency on the MAPK pathway,” Middleton said.
Middleton MR, Dummer R, Gutzmer R, et al. Phase II double-blind, randomized study of selumetinib (SEL) plus dacarbazine (DTIC) versus placebo (PBO) plus DTIC as first-line treatment for advanced BRAF-mutant cutaneous or unknown primary melanoma. J Clin Oncol. 2013;31 (suppl; abstr 9004).