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Network indirect comparison of 3 BRAF + MEK inhibitors for the treatment of advanced BRAF mutated melanoma

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Abstract

Backgroud

Synergistic combinations between BRAF and MEK inhibitors, such as dabrafenib plus trametinib, vemurafenib plus cobimetinib or encorafenib plus binimetinib, represent the current standard of care in metastatic or locally advanced BRAF V600 mutated malignant melanomas (MM). However, no studies explored the direct head-to-head comparison between the three different combinations. In this paper, we performed a network meta-analysis to evaluate their efficacy in terms of overall survival (OS), progression-free survival (PFS), overall response rate (ORR) and safety profile.

Method

We performed a systematic review of the literature about published first line trials of BRAF and MEK inhibitors doublets in advanced mutated malignant melanoma. We compared then the results with an adjusted indirect analysis of randomized-controlled trials. Our primary survival outcome was OS. Secondary endpoints were PFS, ORR, G3-4 toxicities described in at least 5% of patients in experimental arms.

Results

We identified three phase-3 trials: coBRIM (vemurafenib and cobimetinib), COMBI-v (dabrafenib and trametinib) and Columbus study (encorafenib and binimetinib) for a total of 1230 included patients. The control arm was vemurafenib in all studies. The indirect comparison revealed no statistically differences for OS, PFS and ORR across trials, while safety profile differed between the three couples of agents.

Conclusion

This indirect adjusted meta-analysis suggests a similar efficacy and a slightly different safety profile, related to specific molecular properties of the three different BRAF and MEK inhibitors currently approved in the management of advanced MM.

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References

  1. Ugurel S, Rohmel J, Ascierto PA, Flaherty KT, Grob JJ, Hauschild A, et al. Survival of research involving human participants and/or animals with advanced metastatic melanoma: the impact of the novel therapies: update 2017. Eur J Cancer. 2017;83:247–57. https://doi.org/10.1016/j.ejca.2017.06.028.

    Article  PubMed  Google Scholar 

  2. Dankner M, Rose AAN, Rajkumar S, Siegel PM, Watson IR. Classifying braf alterations in cancer: new rational therapeutic strategies for actionable mutations. Oncogene. 2018;37(24):3183–99. https://doi.org/10.1038/s41388-018-0171-x.

    Article  CAS  PubMed  Google Scholar 

  3. Cheng L, Lopez-Beltran A, Massari F, MacLennan GT, Montironi R. Molecular testing for BRAF mutations to inform melanoma treatment decisions: a move toward precision medicine. Mod Pathol. 2018;31(1):24–38. https://doi.org/10.1038/modpathol.2017.104.

    Article  CAS  PubMed  Google Scholar 

  4. Eggermont AM, Robert C. New drugs in melanoma: it's a whole new world. Eur J Cancer. 2011;47(14):2150–7. https://doi.org/10.1016/j.ejca.2011.06.052.

    Article  PubMed  Google Scholar 

  5. Chapman PB, Hauschild A, Robert C, et al. Improved survival with vemurafenib in melanoma with BRAF V600E mutation. N Engl J Med. 2011;364(26):2507–16. https://doi.org/10.1056/NEJMoa1103782.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Hauschild A, Grob JJ, Demidov LV, Jouary T, Gutzmer R, Millward M, et al. Dabrafenib in BRAF-mutated metastatic melanoma: a multicentre, open–label, phase 3 randomized controlled trial. Lancet. 2012;380(9839):358–65. https://doi.org/10.1016/S0140-6736(12)60868-X.

    Article  CAS  PubMed  Google Scholar 

  7. Larkin J, Del Vecchio M, Ascierto PA, Krajsova I, Schachter J, Neyns B, et al. Vemurafenib in patients with BRAF (V600) mutated metastatic melanoma: an open-label, multicentre, safety study. Lancet Oncol. 2014;15(4):436–44. https://doi.org/10.1016/S1470-2045(14)70051-8.

    Article  CAS  PubMed  Google Scholar 

  8. 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. https://doi.org/10.1016/S1470-2045(14)70012-9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. 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. https://doi.org/10.1056/NEJMoa1406037.

    Article  CAS  PubMed  Google Scholar 

  10. Su F, Viros A, Milagre C, Trunzer K, Bollag G, Spleiss O, et al. Ras mutations in cutaneous squamous-cell carcinoma in patients treated with BRAF inhibitors. N Engl J Med. 2012;366(3):207–15. https://doi.org/10.1056/NEJMoa1105358.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Robert C, Karaszewska B, Schachter J, et al. Improved Overall survival in melanoma with combined dabrafenib and trametinib. N Engl J Med. 2015;372(1):30–9. https://doi.org/10.1056/NEJMoa1412690.

    Article  CAS  PubMed  Google Scholar 

  12. Ascierto PA, McArthur GA, Dréno B, et al. Cobimetinib combined with vemurafenib in advanced BRAFV600-mutant melanoma (coBRIM): updated efficacy results from a randomised, double-blind, phase 3 trial. Lancet Oncol. 2016;17(9):1248–60. https://doi.org/10.1016/S1470-2045(16)30122-X.

    Article  CAS  PubMed  Google Scholar 

  13. Dummer R, Ascierto PA, Gogas HJ, Arance A, Mandala M, Liszkay G, et al. Overall survival in patients with BRAF-mutant melanoma receiving encorafenib plus binimetinib versus vemurafenib or encorafenib (COLUMBUS): a multicentre, open-label, randomised, phase 3 trial. Lancet Oncol. 2018;19(10):1315–27. https://doi.org/10.1016/S1470-2045(18)30497-2.

    Article  CAS  PubMed  Google Scholar 

  14. Dummer R, Ascierto PA, Gogas HJ, Arance A, Mandala M, Liszkay G, et al. Encorafenib plus binimetinib versus vemurafenib or encorafenib in patients with BRAF-mutant melanoma (COLUMBUS): a multicentre, open-label, randomised phase 3 trial. Lancet Oncol. 2018;19(5):603–15. https://doi.org/10.1016/S1470-2045(18)30142-6.

    Article  CAS  PubMed  Google Scholar 

  15. Schadendorf D, Long GV, Stroiakovski D, Karaszewska B, Hauschild A, Levchenko E, et al. Three-year pooled analysis of factors associated with clinical outcome across dabrafenib and trametinib combination therapy phase 3 randomized trials. Eur J Cancer. 2017;82:45–55. https://doi.org/10.1016/j.ejca.2017.05.033.

    Article  CAS  PubMed  Google Scholar 

  16. Bucher HC, Guyatt GH, Griffith LE, Walter SD. The results of direct and indirect treatment comparisons in meta-analysis of randomized controlled trials. J Clin Epidemiol. 1997;50(6):683–91. https://doi.org/10.1016/S0895-4356(97)00049-8.

    Article  CAS  PubMed  Google Scholar 

  17. Schadendorf D, van Akkooi ACJ, Berking C, Griewank KG, Gutzmer R, Hauschild A, et al. Melanoma. Lancet. 2018;392(10151):971–84. https://doi.org/10.1016/S0140-6736(18)31559-9.

    Article  PubMed  Google Scholar 

  18. Karoulia Z, Gavathiotis E, Poulikakos PI. New perspectives for targeting RAF kinase in human cancer. Nat Rev Cancer. 2017;17(11):676–91. https://doi.org/10.1038/nrc.2017.79.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Hatzivassiliou G, Song K, Yen I, Brandhuber BJ, Anderson DJ, Alvarado R, Ludlam MJ, et al. RAF inhibitors prime wild-type RAF to activate the MAPK pathway and enhance growth. Nature. 2010;464(7287):431–5. https://doi.org/10.1038/nature08833.

    Article  CAS  PubMed  Google Scholar 

  20. Daud A, Gill J, Kamra S, Chen L, Ahuja A. Indirect treatment comparison of dabrafenib plus trametinib versus vemurafenib plus cobimetinib in previously untreated metastatic melanoma patients. J Hematol Oncol. 2017;10(1):3. https://doi.org/10.1186/s13045-016-0369-8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Sun J, Zager JS, Eroglu Z. Encorafenib/binimetinib for the treatment of BRAF mutant advanced, unresectable, or metastatic melanoma: design, development, and potential place in therapy. Onco Target Ther. 2018;2018(11):9081–9. https://doi.org/10.2147/OTT.S171693.eCollection.

    Article  Google Scholar 

  22. Koelblinger P, Thuerigen O, Dummer R. Development of encorafenib for BRAF-mutated advanced melanoma. Curre Opin Oncol. 2018;30(2):125–33. https://doi.org/10.1097/CCO.0000000000000426.

    Article  CAS  Google Scholar 

  23. Delord JP, Robert C, Nyakas M, McArthur GA, Kudchakar R, Mahipal A, et al. Phase I dose-escalation and -expansion study of the BRAF inhibitor encorafenib (LGX818) in metastatic BRAF-mutant melanoma. Clin Cancer Res. 2017;23(18):5339–488. https://doi.org/10.1158/1078-0432.CCR-16-2923.

    Article  CAS  PubMed  Google Scholar 

  24. Poulikakos PI, Zhang C, Bollag G, Shokat KM, Rosen N, et al. RAF inhibitors transactivate RAF dimers and ERK signalling in cells with wild-type BRAF. Nature. 2010;464(7287):427–30. https://doi.org/10.1038/nature08902.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. King AJ, Arnone MR, Bleam MR, Moss KG, Yang J, Fedorowicz KE, et al. Dabrafenib; preclinical characterization, increased efficacy when combined with trametinib, while BRAF/MEK tool combination reduced skin lesions. PLoS ONE. 2013;8(7):e67583. https://doi.org/10.1371/journal.pone.0067583.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Adelmann CH, Ching G, Du L, Saporito RC, Bansal V, Pence LJ, et al. Comparative profiles of BRAF inhibitors: the paradox index as a predictor of clinical toxicity. Oncotarget. 2016;7(21):30453–60. https://doi.org/10.18632/oncotarget.8351.

    Article  PubMed  PubMed Central  Google Scholar 

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Authors and Affiliations

  1. Department of Medical and Surgical Specialties, Radiological Sciences, and Public Health, Medical Oncology, University of Brescia at ASST-Spedali Civili, Brescia, Italy

    F. Consoli, S. Grisanti & A. Berruti

  2. Oncology Unit, University Hospital of Parma, Parma, Italy

    M. Bersanelli

  3. Università Degli Studi Di Milano, Facoltà Di Farmacia, Pharmacy Unit, ASST Bergamo Ovest, Treviglio, BG, Italy

    G. Perego

  4. Oncology Unit, ASST Papa Giovanni XXIII, Bergamo, Italy

    B. Merelli

  5. Oncology Unit, ASST Bergamo Ovest, Piazzale Ospedale 1, 24047, Treviglio, BG, Italy

    F. Petrelli

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  1. F. Consoli
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Correspondence to F. Petrelli.

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Consoli, F., Bersanelli, M., Perego, G. et al. Network indirect comparison of 3 BRAF + MEK inhibitors for the treatment of advanced BRAF mutated melanoma. Clin Transl Oncol 22, 900–907 (2020). https://doi.org/10.1007/s12094-019-02207-7

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  • DOI: https://doi.org/10.1007/s12094-019-02207-7

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