Combination Treatment of Patients with BRAF-Mutant Melanoma: A New Standard of Care

Abstract

Raf-mitogen-activated protein kinase (Raf-MAPK) pathway inhibition with the BRAF inhibitors vemurafenib and dabrafenib, alone or in combination with a MEK inhibitor, has become a standard therapeutic approach in patients with BRAF-mutated metastatic melanoma. Both vemurafenib and dabrafenib have shown good safety and efficacy as monotherapy compared with chemotherapy. However, the duration of response is limited in the majority of patients treated with BRAF inhibitor monotherapy because of the development of acquired resistance. The addition of a MEK inhibitor can improve blockade of the MAPK pathway and may help to overcome resistance and thereby prolong efficacy, as well as reduce cutaneous toxicity. Combinations of BRAF inhibitors and MEK inhibitors (dabrafenib plus trametinib and vemurafenib plus cobimetinib) have been approved for the treatment of BRAF-mutant metastatic melanoma and may become a new standard of care. However, acquired resistance is still a significant concern with BRAF and MEK inhibitor combination therapy, and other strategies are being investigated, including the use of sequential and intermittent schedules. The combination of BRAF or MEK inhibitors with immunotherapy has been shown to hold considerable promise, with several combinations being evaluated in clinical trials. Preliminary results from clinical trials involving triple combination therapy with BRAF-MEK inhibitors and anti-PD-L1 antibodies appear promising and may indicate a new strategy to treat patients with BRAF-mutated metastatic melanoma. Biomarkers are needed to help identify patients with BRAFV600 mutations most likely to benefit from first-line BRAF/MEK inhibitor therapy rather than immunotherapy and vice versa.

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Acknowledgements

The authors extend special thanks to Alessandra Trocino for providing excellent bibliography service and assistance.

Author contributions

ES and PAA prepared the manuscript collaboratively with input from and the approval of all co-authors. All authors read and approved the final manuscript.

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Correspondence to Paolo A. Ascierto.

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No funding was received for the preparation of this review.

Conflict of interest

ES has participated on an advisory board for Bristol Myers Squibb (BMS) and received honoraria from BMS and Novartis. AMG has participated on an advisory board for Novartis and received honoraria from BMS and Novartis. PAA has had consultant and advisory roles for BMS, Merck Sharp & Dohme, Roche-Genentech, Novartis, Amgen, Array, and Merck-Serono. He has received research funds from BMS, Roche-Genentech, and Array. LF, VV, and MP have no conflicts of interest.

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Simeone, E., Grimaldi, A.M., Festino, L. et al. Combination Treatment of Patients with BRAF-Mutant Melanoma: A New Standard of Care. BioDrugs 31, 51–61 (2017). https://doi.org/10.1007/s40259-016-0208-z

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Keywords

  • Overall Survival
  • Brain Metastasis
  • Median Overall Survival
  • Ipilimumab
  • Vemurafenib