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Trametinib showed minimal clinical activity in BRAF-mutated melanoma
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The oral drug trametinib demonstrated only minimal clinical activity in patients with metastatic BRAF-mutated melanoma, according to results of a phase 2 trial.
BRAF mutations promote melanoma cell proliferation and survival through the activation of MEK proteins. The mutations occur in approximately 40% to 60% of cutaneous melanomas. Trametinib (GlaxoSmithKline) inhibits MEK1/MEK2 activation and kinase activity, resulting in decreased cell proliferation in cancers, according to background information in the study.
Kevin B. Kim, MD, associate professor in the department of melanoma medical oncology at The University of Texas MD Anderson Cancer Center, and colleagues examined the response rate associated with trametinib in patients with metastatic BRAF-mutant melanoma.
Kim and researchers enrolled 97 patients in the open-label, two-stage study. Researchers divided patients into two cohorts. Cohort A consisted of patients with metastatic BRAF-mutant melanoma previously treated with a BRAF inhibitor (n=40). Fifty percent of patients had received three or more prior treatments. Cohort B consisted of BRAF-naive patients who underwent prior chemotherapy and/or immunotherapy (n=57). Of them, 38% had undergone chemotherapy and 19% had undergone immunotherapy.
Patients in both cohorts received 2 mg trametinib orally once daily.
Median follow-up was 12 months for cohort A and 10 months for cohort B.
The results indicated no confirmed clinical responses for patients in cohort A. Eleven patients (28%) demonstrated stable disease and eight patients (20%) experienced tumor reduction.
In cohort B, researchers reported one (2%) complete response, 13 (23%) partial responses and 29 patients (51%) with stable disease. The confirmed response rate was 25%, and the median duration for response was 5.7 months (95% CI, 3.7-9.2).
Median PFS among patients in cohort A was 1.8 months (95% CI, 1.8-2) compared with 4 months (95% CI, 3.6-5.6) for patients in cohort B.
Eighty percent of patients across both cohorts discontinued treatment because of disease progression.
Trametinib was well tolerated among patients, according to the researchers. The most frequent treatment-related adverse events for all patients were skin-related toxicity, nausea, peripheral edema, diarrhea, pruritus and fatigue. Still, four patients (4%) discontinued study treatment because of adverse events — two due to ejection fraction decreases, one because of intestinal perforation and one because of pulmonary embolism.
Researchers did not observe any incidence of cutaneous squamous cell carcinoma.
Although trametinib as a single agent showed only minimal activity in patients with BRAF-mutant melanoma, researchers reported significant clinical activity in BRAF inhibitor-naive patients previously treated with chemotherapy or immunotherapy.
“These data suggest that BRAF-inhibitor resistance mechanisms likely confer resistance to MEK-inhibitor monotherapy,” Kim and colleagues wrote. “These data support further evaluation of trametinib in BRAF-inhibitor–naive BRAF-mutant melanoma, including rarer forms of BRAF-mutant melanoma.”
Disclosure: Kim reports no relevant financial disclosures. Other researchers involved in the study report funding/honoraria from, consulting/employment relationships with and stock ownership in AstraZeneca, Bristol-Myers Squibb, Genentech, GlaxoSmithKline, Millennium, Pfizer and Roche.
Perspective
Back to TopSanjiv S. Agarwala, MD
The objective of this trial was to determine the response rate for single agent MEK inhibitor therapy in patients with BRAF-mutated melanoma. The results were disappointing in that, in terms of BRAF-mutated melanoma, the response rates with a single agent MEK inhibitor are not as good as what we see with BRAF inhibitors. Even more disappointing was the fact that there was almost no activity for patients who had progressed after receiving previous therapy with a BRAF inhibitor.
Current research is evaluating combination therapy with BRAF and MEK inhibitors, which is the right way to go to try and improve efficacy, and potentially lower the toxicity of both agents. It would, however, be interesting to define the single agent activity of MEK inhibitors in other rare non-V600E BRAF mutations or in patients with NRAS positive melanoma. I do not see a major role for a single-agent MEK inhibitor as therapy in the front-line setting for patients who have metastatic BRAF-mutated melanoma based on these data.
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