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Trametinib–dabrafenib combination extended PFS in BRAF-mutated melanoma
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The addition of trametinib to dabrafenib significantly prolonged PFS in patients with metastatic melanoma who harbored BRAF V600E or V600K mutations, according to phase 3 study results presented at the European Society for Medical Oncology Annual Congress in Madrid.
Georgina V. Long, MD, PhD, of Melanoma Institute Australia, and colleagues sought to evaluate the safety and efficacy of BRAF inhibition with dabrafenib (Tafinlar, GlaxoSmithKline) plus MEK inhibition with trametinib (Mekinist, GlaxoSmithKline) in patients with BRAF V600E- or V600K-mutated melanoma.
The analysis included 423 previously untreated patients with unresectable stage IIIC or IV melanoma. The median age of the population was 56 years (range, 22-89) and 53% were male.
Researchers randomly assigned 211 patients to receive 150 mg dabrafenib twice daily plus 2 mg trametinib once daily. The other 212 patients received dabrafenib plus placebo.
Median follow-up was 9 months (range, 0-16).
Patients assigned to the combination regimen demonstrated significantly longer median PFS than patients in the control arm (9.3 months vs. 8.8 months; HR=0.75; 95% CI, 0.57-0.99). The improvement in PFS observed with the combination persisted among patients with an elevated lactate dehydrogenase level (7.1 months vs. 3.8 months; HR=0.64; 95% CI, 0.42-0.95).
A significantly higher percentage of patients in the combination arm demonstrated a response to treatment (67% vs. 51%; P=.002).
Long and colleagues conducted an interim OS analysis at 6 months. At that time, OS rates were 93% in the combination arm and 85% in the control arm (HR=0.63; 95% CI, 0.42-0.94). However, this difference did not reach the pre-specified stopping boundary (P=.00028).
Adverse events were comparable between the arms, although more patients assigned the combination required a dose reduction (25% vs. 13%) and treatment interruption (49% vs. 33%) due to an adverse event.
More patients in the control arm experienced incident cutaneous squamous-cell carcinoma (9% vs. 2%); however, more patients in the combination arm experienced any-grade (51% vs. 28%) or severe (6% vs. 2%) pyrexia. Researchers reported no treatment-related deaths in either study arm.
“In our study involving previously untreated patients who had metastatic melanoma with BRAF V600E or V600K mutations, the combination of dabrafenib and trametinib, as compared with dabrafenib alone, reduced the risk for progression by 25% and improved response rate,” Long and colleagues concluded. “At the time of the interim analysis, OS was longer in the combination group, but the pre-specified stopping boundary was not crossed.”
Disclosure: The study was funded by GlaxoSmithKline. See the study for a full list of the researchers’ relevant financial disclosures.
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