Abstract
BRAF plus MEK-targeted drugs have out-performed BRAF inhibitor monotherapy in three randomized phase 3 studies, and such combinations have become a new standard of treatment for BRAF-mutant advanced melanoma. With an overall response rate of about 70%, no other therapy in melanoma has shown a better response rate in late-phase clinical trials than combined BRAF and MEK inhibitors; the rapid kinetics of response make them the ideal front-line treatment for symptomatic, BRAF-mutant advanced melanoma patients. Nevertheless, the development of mechanisms of resistance limits the duration of response to such treatment in the majority of cases, with only about 20% of patients treated with the combination being progression-free at 3 years. The aim of this review is to report the efficacy and safety outcomes of the combination of BRAF plus MEK inhibitors compared with BRAF inhibitor monotherapy and immunotherapy, as well as to discuss future perspectives to improve outcomes based on current clinical and translational research studies.
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Korn, E. L., Liu, P.-Y., Lee, S. J., Chapman, J.-A. W., Niedzwiecki, D., Suman, V. J., et al. (2008). Meta-analysis of phase II cooperative group trials in metastatic stage IV melanoma to determine progression-free and overall survival benchmarks for future phase II trials. Journal of Clinical Oncology, 26(4), 527–534.
Davies, H., Bignell, G. R., Cox, C., Stephens, P., Edkins, S., Clegg, S., et al. (2002). Mutations of the BRAF gene in human cancer. Nature, 417(6892), 949–954.
McArthur, G. A., Chapman, P. B., Robert, C., Larkin, J., Haanen, J. B., Dummer, R., et al. (2014). Safety and efficacy of vemurafenib in BRAFV600E and BRAFV600 K mutation-positive melanoma (BRIM-3): extended follow-up of a phase 3, randomised, open-label study. The Lancet Oncology, 15(3), 323–332.
Hauschild, A., Grob, J.-J., Demidov, L. V., Jouary, T., Gutzmer, R., Millward, M., et al. (2012). Dabrafenib in BRAF-mutated metastatic melanoma: a multicentre, open-label, phase 3 randomised controlled trial. The Lancet, 380(9839), 358–365.
Paraiso, K. H. T., Fedorenko, I. V., Cantini, L. P., Munko, A. C., Hall, M., Sondak, V. K., et al. (2010). Recovery of phospho-ERK activity allows melanoma cells to escape from BRAF inhibitor therapy. British Journal of Cancer, 102(12), 1724–1730.
Ascierto, P. A., McArthur, G. A., Dréno, B., Atkinson, V., Liszkay, G., Di Giacomo, A. M., et al. (2016). Cobimetinib combined with vemurafenib in advanced BRAFV600-mutant melanoma (coBRIM): updated efficacy results from a randomised, double-blind, phase 3 trial. The Lancet Oncology, 17(9), 1248–1260.
Long, G. V., Stroyakovskiy, D., Gogas, H., Levchenko, E., de Braud, F., Larkin, J., et al. (2015). Dabrafenib and trametinib versus dabrafenib and placebo for Val600 BRAF-mutant melanoma: a multicentre, double-blind, phase 3 randomised controlled trial. The Lancet, 386(9992), 444–451.
Robert, C., Karaszewska, B., Schachter, J., Rutkowski, P., Mackiewicz, A., Stroiakovski, D., et al. (2014). Improved overall survival in melanoma with combined dabrafenib and trametinib. The New England Journal of Medicine, 372(1), 30–39.
Johnson, D. B., Flaherty, K. T., Weber, J. S., Infante, J. R., Kim, K. B., Kefford, R. F., et al. (2014). Combined BRAF (dabrafenib) and MEK inhibition (trametinib) in patients with BRAF(V600)-mutant melanoma experiencing progression with single-agent BRAF inhibitor. Journal of Clinical Oncology, 32(33), 3697–3704.
Schadendorf, D., Hodi, F. S., Robert, C., Weber, J. S., Margolin, K., Hamid, O., et al. (2015). Pooled analysis of long-term survival data from phase II and phase III trials of ipilimumab in unresectable or metastatic melanoma. Journal of Clinical Oncology, 33(17), 1889–1894.
Robert, C., Long, G. V., Brady, B., Dutriaux, C., Maio, M., Mortier, L., et al. (2015). Nivolumab in previously untreated melanoma without BRAF mutation. The New England Journal of Medicine, 372(4), 320–330.
Weber, J. S., D’Angelo, S. P., Minor, D., Hodi, F. S., Gutzmer, R., Neyns, B., et al. (2015). Nivolumab versus chemotherapy in patients with advanced melanoma who progressed after anti-CTLA-4 treatment (CheckMate 037): a randomised, controlled, open-label, phase 3 trial. The Lancet Oncology, 16(4), 375–384.
Robert, C., Ribas, A., Wolchok, J. D., Hodi, F. S., Hamid, O., Kefford, R., et al. (2014). Anti-programmed-death-receptor-1 treatment with pembrolizumab in ipilimumab-refractory advanced melanoma: a randomised dose-comparison cohort of a phase 1 trial. The Lancet, 384(9948), 1109–1117.
Robert, C., Schachter, J., Long, G. V., Arance, A., Grob, J. J., Mortier, L., et al. (2015). Pembrolizumab versus Ipilimumab in advanced melanoma. The New England Journal of Medicine. doi:10.1056/NEJMoa1503093.
Larkin, J., Chiarion-Sileni, V., Gonzalez, R., Grob, J. J., Cowey, C. L., Lao, C. D., et al. (2015). Combined nivolumab and Ipilimumab or monotherapy in untreated melanoma. The New England Journal of Medicine, 373(1), 23–34.
McArthur GA, Dréno B, Atkinson V, Larkin J, Ascierto PA, Daud A et al. (2016). Efficacy of long-term cobimetinib + vemurafenib in advanced brafv600-mutated melanoma: 3-year follow-uP of coBRIM (Phase 3) and 4-year follow-up of BRIM7 (Phase 1b). Society for Melanoma Research 2016 Congress.
Flaherty K, Davies MA, Grob JJ, Long GV, Nathan PD, Ribas A, et al. (2016). Genomic analysis and 3-y efficacy and safety update of COMBI-d: a phase 3 study of dabrafenib (D) + trametinib (T) vs D monotherapy in patients (pts) with unresectable or metastatic BRAF V600E/K-mutant cutaneous melanoma. J Clin Oncol 34 (suppl; abstr 9502).
Robert, C., Karaszewska, B., Schachter, J., Rutkowski, P., Mackiewicz, A., Stroyakovskiy, D., et al. (2016). Three-year estimate of overall survival in COMBI-v, a randomized phase 3 study evaluating first-line dabrafenib + trametinib in patients with unresectable or metastatic BRAF V600E/K–mutant cutaneous melanoma. Annals of Oncology, 27(Supplement 6), 552–587.
Long, G. V., Stroyakovskiy, D., Gogas, H., Levchenko, E., de Braud, F., Larkin, J., et al. (2014). Combined BRAF and MEK inhibition versus BRAF inhibition alone in melanoma. The New England Journal of Medicine, 371(20), 1877–1888.
Larkin, J., Lao, C. D., Urba, W. J., McDermott, D. F., Horak, C., Jiang, J., et al. (2015). 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 Oncology, 1(4), 433–440.
Devji, T., Levine, O., Neupane, B., Beyene, J., & Xie, F. (2016). Systemic therapy for previously untreated advanced braf-mutated melanoma: a systematic review and network meta-analysis of randomized clinical trials. JAMA Oncology. doi:10.1001/jamaoncol.2016.4877.
Gibney, G. T., Weiner, L. M., & Atkins, M. B. (2016). Predictive biomarkers for checkpoint inhibitor-based immunotherapy. The Lancet Oncology, 17(12), 542–e551.
Tumeh, P. C., Harview, C. L., Yearley, J. H., Shintaku, I. P., Taylor, E. J., Robert, L., et al. (2014). PD-1 blockade induces responses by inhibiting adaptive immune resistance. Nature, 515(7528), 568–571.
Chen, P. L., Roh, W., Reuben, A., Cooper, Z. A., Spencer, C. N., Prieto, P. A., et al. (2016). Analysis of immune signatures in longitudinal tumor samples yields insight into biomarkers of response and mechanisms of resistance to immune checkpoint blockade. Cancer Discovery, 6(8), 827–837.
Snyder, A., Makarov, V., Merghoub, T., Yuan, J., Zaretsky, J. M., Desrichard, A., et al. (2014). Genetic basis for clinical response to CTLA-4 blockade in melanoma. The New England Journal of Medicine, 371(23), 2189–2199.
McGranahan, N., Furness, A. J., Rosenthal, R., Ramskov, S., Lyngaa, R., Saini, S. K., et al. (2016). Clonal neoantigens elicit T cell immunoreactivity and sensitivity to immune checkpoint blockade. Science, 351(6280), 1463–1469.
Ferrucci, P. F., Ascierto, P. A., Pigozzo, J., Del Vecchio, M., Maio, M., Antonini Cappellini, G. C., et al. (2016). Baseline neutrophils and derived neutrophil-to-lymphocyte ratio: prognostic relevance in metastatic melanoma patients receiving ipilimumab. Annals of Oncology, 27(4), 732–738.
Wolchok, J. D., Kluger, H., Callahan, M. K., Postow, M. A., Rizvi, N. A., Lesokhin, A. M., et al. (2013). Nivolumab plus ipilimumab in advanced melanoma. The New England Journal of Medicine, 369(2), 122–133.
Postow, M. A., Chesney, J., Pavlick, A. C., Robert, C., Grossmann, K., McDermott, D., et al. (2015). Nivolumab and ipilimumab versus ipilimumab in untreated melanoma. The New England Journal of Medicine, 372(21), 2006–2017.
Spagnolo, F., Picasso, V., Lambertini, M., Ottaviano, V., Dozin, B., & Queirolo, P. (2016). Survival of patients with metastatic melanoma and brain metastases in the era of MAP-kinase inhibitors and immunologic checkpoint blockade antibodies: a systematic review. Cancer Treatment Reviews, 45, 38–45.
Long, G. V., Trefzer, U., Davies, M. A., Kefford, R. F., Ascierto, P. A., Chapman, P. B., et al. (2012). Dabrafenib in patients with Val600Glu or Val600Lys BRAF-mutant melanoma metastatic to the brain (BREAK-MB): a multicentre, open-label, phase 2 trial. The Lancet Oncology, 13(11), 1087–1095.
Flaherty, K. T., Robert, C., Hersey, P., Nathan, P., Garbe, C., Milhem, M., et al. (2012). Improved survival with MEK inhibition in BRAF-mutated melanoma. The New England Journal of Medicine, 367(2), 107–114.
Dummer R, Schadendorf D, Ascierto PA, Arance Fernández AM, Dutriaux C, Maio M et al. (2016) Results of NEMO: a phase III trial of binimetinib (BINI) vs dacarbazine (DTIC) in NRAS-mutant cutaneous melanoma. J Clin Oncol 34, (suppl; abstr 9500).
Hodi, F. S., O’Day, S. J., McDermott, D. F., Weber, R. W., Sosman, J. A., Haanen, J. B., et al. (2010). Improved survival with ipilimumab in patients with metastatic melanoma. The New England Journal of Medicine, 363(8), 711–723.
Spagnolo, F., Ghiorzo, P., & Queirolo, P. (2014). Overcoming resistance to BRAF inhibition in BRAF-mutated metastatic melanoma. Oncotarget, 5(21), 10206–10221.
Spagnolo, F., Ghiorzo, P., Orgiano, L., Pastorino, L., Picasso, V., Tornari, E., et al. (2015). BRAF-mutant melanoma: treatment approaches, resistance mechanisms, and diagnostic strategies. OncoTargets Ther., 8, 157–168.
Queirolo, P., Picasso, V., & Spagnolo, F. (2015). Combined BRAF and MEK inhibition for the treatment of BRAF-mutated metastatic melanoma. Cancer Treatment Reviews, 41(6), 519–526.
Larkin, J., Ascierto, P. A., Dréno, B., Atkinson, V., Liszkay, G., Maio, M., et al. (2014). Combined vemurafenib and cobimetinib in BRAF-mutated melanoma. The New England Journal of Medicine, 371(20), 1867–1876.
Hu-Lieskovan, S., Robert, L., Homet Moreno, B., & Ribas, A. (2014). Combining targeted therapy with immunotherapy in BRAF-mutant melanoma: promise and challenges. Journal of Clinical Oncology, 32(21), 2248–2254.
Homet Moreno, B., Mok, S., Comin-Anduix, B., Hu-Lieskovan, S., & Ribas, A. (2016). Combined treatment with dabrafenib and trametinib with immune-stimulating antibodies for BRAF mutant melanoma. Oncoimmunology, 5(7), e1052212.
Hu-Lieskovan, S., Mok, S., Moreno, B. H., Tsoi, J., Faja, L. R., Goedert, L., et al. (2015). Improved antitumor activity of immunotherapy with BRAF and MEK inhibitors in BRAF(V600E) melanoma. Sci. Transl. Med. doi. doi:10.1126/scitranslmed.aaa4691.
Manzini C, Venè R, Cossu I, Gualco M, Zupo S, Dono M, et al. (2016). Cytokines can counteract the inhibitory effect of MEK-i on NK-cell function. Oncotarget. doi: 10.18632/oncotarget.11504.
Cooper, Z. A., Reuben, A., Austin-Breneman, J., & Wargo, J. A. (2015). Does it MEK a difference? Understanding immune effects of targeted therapy. Clinical Cancer Research, 21(14), 3102–3104.
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Queirolo, P., Spagnolo, F. BRAF plus MEK-targeted drugs: a new standard of treatment for BRAF-mutant advanced melanoma. Cancer Metastasis Rev 36, 35–42 (2017). https://doi.org/10.1007/s10555-017-9660-6
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DOI: https://doi.org/10.1007/s10555-017-9660-6