Adjuvant Dabrafenib plus Trametinib in Stage III BRAF-Mutated Melanoma
- PMID: 28891408
- DOI: 10.1056/NEJMoa1708539
Adjuvant Dabrafenib plus Trametinib in Stage III BRAF-Mutated Melanoma
Abstract
Background: Combination therapy with the BRAF inhibitor dabrafenib plus the MEK inhibitor trametinib improved survival in patients with advanced melanoma with BRAF V600 mutations. We sought to determine whether adjuvant dabrafenib plus trametinib would improve outcomes in patients with resected, stage III melanoma with BRAF V600 mutations.
Methods: In this double-blind, placebo-controlled, phase 3 trial, we randomly assigned 870 patients with completely resected, stage III melanoma with BRAF V600E or V600K mutations to receive oral dabrafenib at a dose of 150 mg twice daily plus trametinib at a dose of 2 mg once daily (combination therapy, 438 patients) or two matched placebo tablets (432 patients) for 12 months. The primary end point was relapse-free survival. Secondary end points included overall survival, distant metastasis-free survival, freedom from relapse, and safety.
Results: At a median follow-up of 2.8 years, the estimated 3-year rate of relapse-free survival was 58% in the combination-therapy group and 39% in the placebo group (hazard ratio for relapse or death, 0.47; 95% confidence interval [CI], 0.39 to 0.58; P<0.001). The 3-year overall survival rate was 86% in the combination-therapy group and 77% in the placebo group (hazard ratio for death, 0.57; 95% CI, 0.42 to 0.79; P=0.0006), but this level of improvement did not cross the prespecified interim analysis boundary of P=0.000019. Rates of distant metastasis-free survival and freedom from relapse were also higher in the combination-therapy group than in the placebo group. The safety profile of dabrafenib plus trametinib was consistent with that observed with the combination in patients with metastatic melanoma.
Conclusions: Adjuvant use of combination therapy with dabrafenib plus trametinib resulted in a significantly lower risk of recurrence in patients with stage III melanoma with BRAF V600E or V600K mutations than the adjuvant use of placebo and was not associated with new toxic effects. (Funded by GlaxoSmithKline and Novartis; COMBI-AD ClinicalTrials.gov, NCT01682083 ; EudraCT number, 2012-001266-15 .).
Comment in
-
Drug therapy: Moving on up - from stage IV into stage III.Nat Rev Clin Oncol. 2017 Nov;14(11):647. doi: 10.1038/nrclinonc.2017.159. Epub 2017 Sep 26. Nat Rev Clin Oncol. 2017. PMID: 28948976 No abstract available.
-
Adjuvant Melanoma Therapy - Head-Spinning Progress.N Engl J Med. 2017 Nov 9;377(19):1888-1890. doi: 10.1056/NEJMe1711199. N Engl J Med. 2017. PMID: 29117487 No abstract available.
-
Adjuvant Therapy in Resected Melanoma.N Engl J Med. 2018 Feb 15;378(7):678. doi: 10.1056/NEJMc1716071. N Engl J Med. 2018. PMID: 29446283 No abstract available.
-
A new era of proactive melanoma therapy: hit hard, hit early.Br J Dermatol. 2018 Apr;178(4):817-820. doi: 10.1111/bjd.16347. Br J Dermatol. 2018. PMID: 29668089 No abstract available.
-
Estimation of Distant Metastasis-free Survival in Trials of Adjuvant Therapy for Melanoma.N Engl J Med. 2019 Apr 4;380(14):1374-1376. doi: 10.1056/NEJMc1902228. N Engl J Med. 2019. PMID: 30943345 No abstract available.
Similar articles
-
Five-Year Analysis of Adjuvant Dabrafenib plus Trametinib in Stage III Melanoma.N Engl J Med. 2020 Sep 17;383(12):1139-1148. doi: 10.1056/NEJMoa2005493. Epub 2020 Sep 2. N Engl J Med. 2020. PMID: 32877599 Clinical Trial.
-
Patient-reported outcomes in patients with resected, high-risk melanoma with BRAFV600E or BRAFV600K mutations treated with adjuvant dabrafenib plus trametinib (COMBI-AD): a randomised, placebo-controlled, phase 3 trial.Lancet Oncol. 2019 May;20(5):701-710. doi: 10.1016/S1470-2045(18)30940-9. Epub 2019 Mar 27. Lancet Oncol. 2019. PMID: 30928620 Clinical Trial.
-
Adjuvant dabrafenib plus trametinib versus placebo in patients with resected, BRAFV600-mutant, stage III melanoma (COMBI-AD): exploratory biomarker analyses from a randomised, phase 3 trial.Lancet Oncol. 2020 Mar;21(3):358-372. doi: 10.1016/S1470-2045(20)30062-0. Epub 2020 Jan 30. Lancet Oncol. 2020. PMID: 32007138 Clinical Trial.
-
Dabrafenib plus Trametinib: a Review in Advanced Melanoma with a BRAF (V600) Mutation.Target Oncol. 2016 Jun;11(3):417-28. doi: 10.1007/s11523-016-0443-8. Target Oncol. 2016. PMID: 27246822 Review.
-
Trametinib (MEKINIST°) Metastatic or inoperable BRAF V600-positive melanoma: a few extra months of life.Prescrire Int. 2016 Dec;25(177):285-288. Prescrire Int. 2016. PMID: 30758923 Review.
Cited by
-
Management of Localized Melanoma in the Anti-PD-1 Era.Curr Oncol Rep. 2024 Jun 6. doi: 10.1007/s11912-024-01556-z. Online ahead of print. Curr Oncol Rep. 2024. PMID: 38842606 Review.
-
Immunomodulatory Precision: A Narrative Review Exploring the Critical Role of Immune Checkpoint Inhibitors in Cancer Treatment.Int J Mol Sci. 2024 May 17;25(10):5490. doi: 10.3390/ijms25105490. Int J Mol Sci. 2024. PMID: 38791528 Free PMC article. Review.
-
BRAF-Mutated Melanoma Journey in Latin America: Expert Recommendations From Diagnosis to Treatment.Cancer Control. 2024 Jan-Dec;31:10732748241251572. doi: 10.1177/10732748241251572. Cancer Control. 2024. PMID: 38751033 Free PMC article. Review.
-
Access to melanoma drugs in Spain: a cross-sectional survey.Clin Transl Oncol. 2024 May 16. doi: 10.1007/s12094-024-03501-9. Online ahead of print. Clin Transl Oncol. 2024. PMID: 38750345
-
SEOM-GEM clinical guidelines for cutaneous melanoma (2023).Clin Transl Oncol. 2024 May 15. doi: 10.1007/s12094-024-03497-2. Online ahead of print. Clin Transl Oncol. 2024. PMID: 38748192
Publication types
MeSH terms
Substances
Associated data
LinkOut - more resources
Full Text Sources
Other Literature Sources
Medical
Research Materials