Dabrafenib Plus Trametinib in Metastatic Melanoma
Dabrafenib Plus Trametinib in Metastatic Melanoma
TAKE-HOME MESSAGE
- The authors of this analysis pooled extended survival data from two trials involving previously untreated patients who had received BRAF inhibitor dabrafenib plus MEK inhibitor trametinib in the COMBI-d (n = 211) and COMBI-v (n = 352) trials. Progression-free survival was 21% at 4 years and 19% at 5 years. The overall survival rates were 37% at 4 years and 34% at 5 years. In multivariate analysis, several baseline factors (performance status, age, gender, number of organ sites with metastasis, and lactate dehydrogenase level) were significantly associated with both progression-free survival and overall survival. A complete response occurred in 109 patients (19%) and was associated with an improved long-term outcome, with an overall survival rate of 71% at 5 years.
- First-line treatment with dabrafenib plus trametinib offered long-term benefit in as many as one-third of patients with unresectable or metastatic melanoma with the BRAF V600E or V600K mutation.
– Jeffrey Wiisanen, MD
- Written by
This is a 5-year follow-up for the COMBI trials, which treated patients with unresectable or metastatic melanoma with dabrafenib (a BRAF inhibitor) and trametinib (a MEK inhibitor). Interim analyses have been published and all have shown significant overall and progression-free survivals. There are several key points. About one-third (34%) of the patients are alive at 5 years with the combination dabrafenib + trametinib (D+T). There is also the hint that the rate of death is decelerating, if not arrested completely, by year 5. Those patients with a lower burden of disease (normal LDH and fewer than three disease sites) have about a 50% 5-year survival. About 80% of the patients have progressed by year 5. It is important to note that patients who did progress were often given immunotherapy as rescue. This study provides a critical follow-up point for combination BRAF + MEK inhibition, although the main message has been reported over the course of several years.
BACKGROUND
Patients who have unresectable or metastatic melanoma with a BRAF V600E or V600K mutation have prolonged progression-free survival and overall survival when receiving treatment with BRAF inhibitors plus MEK inhibitors. However, long-term clinical outcomes in these patients remain undefined. To determine 5-year survival rates and clinical characteristics of the patients with durable benefit, we sought to review long-term data from randomized trials of combination therapy with BRAF and MEK inhibitors.
METHODS
We analyzed pooled extended-survival data from two trials involving previously untreated patients who had received BRAF inhibitor dabrafenib (at a dose of 150 mg twice daily) plus MEK inhibitor trametinib (2 mg once daily) in the COMBI-d and COMBI-v trials. The median duration of follow-up was 22 months (range, 0 to 76). The primary end points in the COMBI-d and COMBI-v trials were progression-free survival and overall survival, respectively.
RESULTS
A total of 563 patients were randomly assigned to receive dabrafenib plus trametinib (211 in the COMBI-d trial and 352 in the COMBI-v trial). The progression-free survival rates were 21% (95% confidence interval [CI], 17 to 24) at 4 years and 19% (95% CI, 15 to 22) at 5 years. The overall survival rates were 37% (95% CI, 33 to 42) at 4 years and 34% (95% CI, 30 to 38) at 5 years. In multivariate analysis, several baseline factors (e.g., performance status, age, sex, number of organ sites with metastasis, and lactate dehydrogenase level) were significantly associated with both progression-free survival and overall survival. A complete response occurred in 109 patients (19%) and was associated with an improved long-term outcome, with an overall survival rate of 71% (95% CI, 62 to 79) at 5 years.
CONCLUSIONS
First-line treatment with dabrafenib plus trametinib led to long-term benefit in approximately one third of the patients who had unresectable or metastatic melanoma with a BRAF V600E or V600K mutation.
Five-Year Outcomes With Dabrafenib Plus Trametinib in Metastatic Melanoma
N. Engl. J. Med 2019 Jun 04;[EPub Ahead of Print], C Robert, JJ Grob, D Stroyakovskiy, B Karaszewska, A Hauschild, E Levchenko, V Chiarion Sileni, J Schachter, C Garbe, I Bondarenko, H Gogas, M Mandalá, JBAG Haanen, C Lebbé, A Mackiewicz, P Rutkowski, PD Nathan, A Ribas, MA Davies, KT Flaherty, P Burgess, M Tan, E Gasal, M Voi, D Schadendorf, GV LongSkin Care Physicians of Costa Rica
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posted by dermatica at
September 27, 2019
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