Abstract
Back ground
We executed a comparative systematic review and meta-analysis of the efficacy and toxicity of doublet BRAF/MEK inhibition versus single-agent BRAF inhibitor in the management of BRAF-mutant advanced melanoma.
Methods
Eligible studies included prospective studies evaluating doublet regimens versus BRAF-inhibitor monotherapy for the management of BRAF-mutant advanced melanoma.
Results
Our search strategy yielded 200 potentially relevant citations from searched databases. After preclusion of ineligible studies, four studies were included in the final analysis. Efficacy analyses demonstrate that BRAF/MEK inhibition strategy is associated with a significant improvement in ORR [OR 1.35; 95 % CI (1.16, 1.58); P = 0.0002], PFS [HR 0.56; 95 % CI (0.49, 0.64); P < 0.00001] and OS [HR 0.70; 95 % CI (0.58, 0.84); P = 0.0001]. Moreover, this combination is associated with a higher RR for diarrhea [1.30; 95 % CI (1.30, 1.49); P = 0.0002], decreased ejection fraction [4.63; 95 % CI (2.56, 8.37); P = <0.00001], acneiform dermatitis [1.61; 95 % CI (1.03, 2.53); P = 0.04] and pyrexia [1.98; 95 % CI (1.72, 2.27); P < 0.00001].
Conclusions
Our meta-analysis has demonstrated that combination of MEK/BRAF inhibitors is associated with higher ORR, PFS and OS. However, this comes at the expense of a higher risk of selected toxicities.
Similar content being viewed by others
References
Song X, Zhao Z, Barber B, Farr AM, Ivanov B, Novich M. Overall survival in patients with metastatic melanoma. Curr Med Res Opin. 2015;31(5):987–91.
Bishop KD, Olszewski AJ. Epidemiology and survival outcomes of ocular and mucosal melanomas: a population-based analysis. Int J Cancer. 2014;134(12):2961–71.
Michielin O, Höller C. Gaining momentum: new options and opportunities for the treatment of advanced melanoma. Cancer Treat Rev. 2015.
Weise AM, Flaherty LE. New options for the adjuvant treatment of cutaneous melanoma? Curr Oncol Rep. 2014;16(11):1–6.
Chapman PB, Hauschild A, Robert C, Haanen JB, Ascierto P, Larkin J, et al. Improved survival with vemurafenib in melanoma with BRAF V600E mutation. N Engl J Med. 2011;364(26):2507–16.
Robert C, Karaszewska B, Schachter J, Rutkowski P, Mackiewicz A, Stroiakovski D, et al. Improved overall survival in melanoma with combined dabrafenib and trametinib. N Engl J Med. 2015;372(1):30–9.
Hodi FS, O’Day SJ, McDermott DF, Weber RW, Sosman JA, Haanen JB, et al. Improved survival with ipilimumab in patients with metastatic melanoma. N Engl J Med. 2010;363(8):711–23.
Chang L, Karin M. Mammalian MAP kinase signalling cascades. Nature. 2001;410(6824):37–40.
Thompson N, Lyons J. Recent progress in targeting the Raf/MEK/ERK pathway with inhibitors in cancer drug discovery. Curr Opin Pharmacol. 2005;5(4):350–6.
Roskoski R. RAF protein-serine/threonine kinases: structure and regulation. Biochem Biophys Res Commun. 2010;399(3):313–7.
Cantwell-Dorris ER, O’Leary JJ, Sheils OM. BRAFV600E: implications for carcinogenesis and molecular therapy. Mol Cancer Ther. 2011;10(3):385–94.
Wan PT, Garnett MJ, Roe SM, Lee S, Niculescu-Duvaz D, Good VM, et al. Mechanism of activation of the RAF–ERK signaling pathway by oncogenic mutations of B-RAF. Cell. 2004;116(6):855–67.
Boussemart L, Malka-Mahieu H, Girault I, Allard D, Hemmingsson O, Tomasic G, et al. eIF4F is a nexus of resistance to anti-BRAF and anti-MEK cancer therapies. Nature. 2014.
Moher D, Liberati A, Tetzlaff J, Altman DG. Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. Ann Intern Med. 2009;151(4):264–9.
Jadad AR, Moore RA, Carroll D, Jenkinson C, Reynolds DJM, Gavaghan DJ, et al. Assessing the quality of reports of randomized clinical trials: is blinding necessary? Control Clin Trials. 1996;17(1):1–12.
Long GV, Stroyakovskiy D, Gogas H, Levchenko E, de Braud F, Larkin J, et al. Combined BRAF and MEK inhibition versus BRAF inhibition alone in melanoma. N Engl J Med. 2014;371(20):1877–88.
Flaherty KT, Infante JR, Daud A, Gonzalez R, Kefford RF, Sosman J, et al. Combined BRAF and MEK inhibition in melanoma with BRAF V600 mutations. N Engl J Med. 2012;367(18):1694–703.
Larkin J, Ascierto PA, Dréno B, Atkinson V, Liszkay G, Maio M, et al. Combined vemurafenib and cobimetinib in BRAF-mutated melanoma. N Engl J Med. 2014;371(20):1867–76.
Sosman JA, Kim KB, Schuchter L, Gonzalez R, Pavlick AC, Weber JS, et al. Survival in BRAF V600-mutant advanced melanoma treated with vemurafenib. N Engl J Med. 2012;366(8):707–14.
McArthur GA, Chapman PB, Robert C, Larkin J, Haanen JB, Dummer R, et al. Safety and efficacy of vemurafenib in BRAF V600E and BRAF V600K mutation-positive melanoma (BRIM-3): extended follow-up of a phase 3, randomised, open-label study. Lancet Oncol. 2014;15(3):323–32.
Hauschild A, Grob J-J, Demidov LV, Jouary T, Gutzmer R, Millward M, et al. Dabrafenib in BRAF-mutated metastatic melanoma: a multicentre, open-label, phase 3 randomised controlled trial. Lancet. 2012;380(9839):358–65.
Abdel-Rahman O, ElHalawani H, Ahmed H, Ellithy M. Risk of selected gastrointestinal toxicities in cancer patients treated with MEK inhibitors: a comparative systematic review and meta-analysis. Expert Rev Gastroenterol Hepatol. 2015 (ahead-of-print):1–13.
Abdel-Rahman O, ElHalawani H, Ahmed H. Risk of selected cardiovascular toxicities in cancer patients treated with MEK inhibitors: a comparative systematic review and meta-analysis. J Glob Oncol. 2015 (ahead-of-print):1–13.
Abdel-Rahman O, ElHalawani H, Ahmed H. Risk of selected dermatological toxicities in cancer patients treated with MEK inhibitors: a comparative systematic review and meta-analysis. Future Oncol. 2015 (ahead-of-print):1–13.
Gutzmer R, Hassel J, Kähler K, Loquai C, Mössner R, Ugurel S, et al. Cutaneous side effects of anti-tumor therapy with BRAF and MEK inhibitors. Der Hautarzt Z Dermatol Venerol Verwandte Geb. 2014;65(7):582–9.
Carlos G, Anforth R, Clements A, Menzies AM, Carlino MS, Chou S, et al. Cutaneous toxic effects of BRAF inhibitors alone and in combination with MEK inhibitors for metastatic melanoma. JAMA Dermatol. 2015.
Yaeger R, Cercek A, O’Reilly E, Reidy E, editors. Pilot study ofvemurafenib and panitumumab combination therapy in patients with BRAF V600E mutated metastatic colorectal cancer. American Society of Clinical Oncology, 50th annual meeting, Chicago.
Planchard D, Groen H., Kim T, Rigas J, Souquet P, Baik C et al. Interim results of a phase II study of the BRAF inhibitor (BRAFi) dabrafenib (D) in combination with the MEK inhibitor trametinib (T) in patients (pts) with BRAF V600E mutated (mut) metastatic non-small cell lung cancer (NSCLC). J Clin Oncol. [2015 ASCO annual meeting (29 May–2 June 2015)]. 2015;33(15_suppl, May 20 supplement):8006.
Ribas A, Puzanov I, Dummer R, Schadendorf D, Hamid O, Robert C, et al. Pembrolizumab versus investigator-choice chemotherapy for ipilimumab-refractory melanoma (KEYNOTE-002): a randomised, controlled, phase 2 trial. Lancet Oncol. 2015.
Larkin J, Lao CD, Urba WJ, McDermott DF, Horak C, Jiang J, et al. Efficacy and safety of Nivolumab in patients with BRAF V600 mutant and BRAF wild-type advanced melanoma a pooled analysis of 4 clinical trials. JAMA Oncol. 2015.
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
This study has not funded by any organizational body.
Conflict of interest
All authors declare that they have no conflict of interest.
Ethical approval
This article does not contain any studies with human participants performed by any of the authors.
Rights and permissions
About this article
Cite this article
Abdel-Rahman, O., ElHalawani, H. & Ahmed, H. Doublet BRAF/MEK inhibition versus single-agent BRAF inhibition in the management of BRAF-mutant advanced melanoma, biological rationale and meta-analysis of published data. Clin Transl Oncol 18, 848–858 (2016). https://doi.org/10.1007/s12094-015-1438-0
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s12094-015-1438-0