FDA Approves Combination Therapy for Unresectable or Metastatic Melanoma With BRAF V600E/K Mutations


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The U.S. Food and Drug Administration (FDA) has approved trametinib (Mekinist) for use in combination with dabrafenib (Tafinlar) for the treatment of patients with unresectable melanoma or metastatic melanoma with BRAF V600E or V600K mutations. These mutations must be detected by an FDA-approved test.

The approval of the combination is based on the demonstration of response rate and median duration of response in a phase I/II study. Improvement in disease-related symptoms or overall survival has not been demonstrated. The accelerated approval is contingent on the results of an ongoing phase III trial.

Phase II Results

Results from the randomized phase II part of a phase I/II open-label study evaluating the combination of trametinib and dabrafenib vs single-agent dabrafenib, demonstrated an investigator-assessed overall response rate of 76% (95% confidence interval [CI] = 62–87) for patients treated with the combination vs 54% (95% CI = 40–67) for those treated with single-agent dabrafenib. The median duration of response was 10.5 months (95% CI = 7–15) for patients treated with the combination, and 5.6 months (95% CI = 5–7) for patients treated with single-agent dabrafenib.

Data analyses of the blinded independent radiologic review committee supported the investigator results, with an overall response rate of 57% (95% CI = 43–71) for patients treated with the combination, and 46% (95% CI = 33–60) for patients receiving single-agent dabrafenib. The median duration of response as assessed by the independent radiologic review committee was 7.6 months (95% CI = 7 to not reached) for patients treated with the combination, and 7.6 months (95% CI = 6 to not reached) for patients treated with single-agent dabrafenib.

Adverse Events

Trametinib in combination with dabrafenib can cause serious side effects, some of which can be life-threatening, including new primary cutaneous malignancies, tumor promotion in wild-type BRAF melanoma, hemorrhagic events, venous thromboembolic events, cardiomyopathy, ocular toxicities, interstitial lung disease, serious febrile drug reactions, serious skin toxicity, hyperglycemia, hemolytic anemia in patients with glucose-6-phosphate dehydrogenase deficiency, and embryofetal toxicity.

The most frequently occurring adverse reactions included pyrexia  (71%), chills (58%), fatigue (53%), rash (45%), nausea (44%), vomiting (40%), diarrhea (36%), abdominal pain (33%), peripheral edema (31%), cough (29%), headache (29%), arthralgia (27%), night sweats (24%), decreased appetite (22%), constipation (22%), and myalgia (22%).

The most common grade 3 or 4 adverse events observed in the combination group in this study were renal failure (7%), pyrexia (5%), back pain (5%), hemorrhage (5%), fatigue (4%), chills (2%), nausea (2%), vomiting (2%), diarrhea (2%), abdominal pain (2%), myalgia (2%), and urinary tract infection (2%). ■



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