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Journal of Neuro-Oncology

, Volume 123, Issue 1, pp 75–84 | Cite as

Survival patterns following brain metastases for patients with melanoma in the MAP-kinase inhibitor era

  • Daniel A. Wattson
  • Ryan J. Sullivan
  • Andrzej Niemierko
  • Ryan M. Merritt
  • Donald P. Lawrence
  • Kevin S. Oh
  • Keith T. Flaherty
  • Helen A. Shih
Clinical Study

Abstract

Survival with BRAF-mutant metastatic melanoma is prolonged with MAP-kinase pathway inhibitors (MAPKi). Among patients with brain metastases (BM), however, the clinical course of MAPKi-treated patients is not well described. We therefore explored these patients’ survival patterns compared to contemporary patients not treated with MAPKi. We analyzed 106 patients who developed melanoma BM between 2007 and 2013. Of these, 37 (35 %) received de novo MAPKi for BRAF-mutant disease, which preceded BM in 49 %. Immunotherapy was given to 54 % of MAPKi-treated patients and 94 % of those who did not receive MAPKi. We evaluated the potential influence of patient characteristics, systemic therapies, and BM-directed treatments on time to appearance of new BM and overall survival. With a median follow-up of 8.0 months after initial BM, MAPKi use was an independent predictor of prolonged survival after BM diagnosis (median 14.1 vs 7.0 months, P = 0.03, adjusted hazard ratio 0.39). This survival advantage was driven by the 16.6-month median survival of patients who initiated MAPKi after BM were diagnosed, versus 5.6 months if initiated prior to BM development (P = 0.03). Median survival from the onset of any systemic metastases was 22 months regardless of the timing of MAPKi relative to BM appearance. Time to in-brain progression was longer among patients whose MAPKi course was started after BM diagnosis, but MAPKi initiation prior to BM diagnosis was associated with longer time to intracranial involvement. These findings are consistent with potential MAPKi activity in intracranial melanoma.

Keywords

Melanoma Brain metastases MAP-kinase inhibitors Immunotherapy Radiotherapy 

Notes

Acknowledgments

The authors would like to thank all study participants for their time and generosity. This work was not funded by any external Grants.

Conflict of interest

Keith T. Flaherty is a paid consultant to Roche/Genentech and GlaxoSmithKline.

Supplementary material

11060_2015_1761_MOESM1_ESM.tif (11.4 mb)
Supplementary material 1 (TIFF 11657 kb)

References

  1. 1.
    Korn EL, Liu PY, Lee SJ, Chapman JA, Niedzwiecki D, Suman VJ, Moon J, Sondak VK, Atkins MB, Eisenhauer EA, Parulekar W, Markovic SN, Saxman S, Kirkwood JM (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. J Clin Oncol 26(4):527–534. doi: 10.1200/JCO.2007.12.7837 CrossRefPubMedGoogle Scholar
  2. 2.
    Davies MA, Liu P, McIntyre S, Kim KB, Papadopoulos N, Hwu WJ, Hwu P, Bedikian A (2011) Prognostic factors for survival in melanoma patients with brain metastases. Cancer 117(8):1687–1696. doi: 10.1002/cncr.25634 CrossRefPubMedGoogle Scholar
  3. 3.
    Sperduto PW, Kased N, Roberge D, Xu Z, Shanley R, Luo X, Sneed PK, Chao ST, Weil RJ, Suh J, Bhatt A, Jensen AW, Brown PD, Shih HA, Kirkpatrick J, Gaspar LE, Fiveash JB, Chiang V, Knisely JP, Sperduto CM, Lin N, Mehta M (2011) Summary report on the graded prognostic assessment: an accurate and facile diagnosis-specific tool to estimate survival for patients with brain metastases. J Clin Oncol 30(4):419–425. doi: 10.1200/JCO.2011.38.0527 CrossRefPubMedCentralPubMedGoogle Scholar
  4. 4.
    Eigentler TK, Figl A, Krex D, Mohr P, Mauch C, Rass K, Bostroem A, Heese O, Koelbl O, Garbe C, Schadendorf D (2011) Number of metastases, serum lactate dehydrogenase level, and type of treatment are prognostic factors in patients with brain metastases of malignant melanoma. Cancer 117(8):1697–1703. doi: 10.1002/cncr.25631 CrossRefPubMedGoogle Scholar
  5. 5.
    Sampson JH, Carter JH Jr, Friedman AH, Seigler HF (1998) Demographics, prognosis, and therapy in 702 patients with brain metastases from malignant melanoma. J Neurosurg 88(1):11–20. doi: 10.3171/jns.1998.88.1.0011 CrossRefPubMedGoogle Scholar
  6. 6.
    Staudt M, Lasithiotakis K, Leiter U, Meier F, Eigentler T, Bamberg M, Tatagiba M, Brossart P, Garbe C (2010) Determinants of survival in patients with brain metastases from cutaneous melanoma. Br J Cancer 102(8):1213–1218. doi: 10.1038/sj.bjc.6605622 CrossRefPubMedCentralPubMedGoogle Scholar
  7. 7.
    Fertil B, Malaise EP (1985) Intrinsic radiosensitivity of human cell lines is correlated with radioresponsiveness of human tumors: analysis of 101 published survival curves. Int J Radiat Oncol Biol Phys 11(9):1699–1707.CrossRefPubMedGoogle Scholar
  8. 8.
    Sambade MJ, Peters EC, Thomas NE, Kaufmann WK, Kimple RJ, Shields JM (2011) Melanoma cells show a heterogeneous range of sensitivity to ionizing radiation and are radiosensitized by inhibition of B-RAF with PLX-4032. Radiother Oncol 98(3):394–399. doi: 10.1016/j.radonc.2010.12.017 CrossRefPubMedCentralPubMedGoogle Scholar
  9. 9.
    Agarwala SS, Kirkwood JM, Gore M, Dreno B, Thatcher N, Czarnetski B, Atkins M, Buzaid A, Skarlos D, Rankin EM (2004) Temozolomide for the treatment of brain metastases associated with metastatic melanoma: a phase II study. J Clin Oncol 22(11):2101–2107. doi: 10.1200/JCO.2004.11.044 CrossRefPubMedGoogle Scholar
  10. 10.
    Avril MF, Aamdal S, Grob JJ, Hauschild A, Mohr P, Bonerandi JJ, Weichenthal M, Neuber K, Bieber T, Gilde K, Guillem Porta V, Fra J, Bonneterre J, Saiag P, Kamanabrou D, Pehamberger H, Sufliarsky J, Gonzalez Larriba JL, Scherrer A, Menu Y (2004) Fotemustine compared with dacarbazine in patients with disseminated malignant melanoma: a phase III study. J Clin Oncol 22(6):1118–1125. doi: 10.1200/JCO.2004.04.165 CrossRefPubMedGoogle Scholar
  11. 11.
    Hodi FS, O'Day SJ, McDermott DF, Weber RW, Sosman JA, Haanen JB, Gonzalez R, Robert C, Schadendorf D, Hassel JC, Akerley W, van den Eertwegh AJ, Lutzky J, Lorigan P, Vaubel JM, Linette GP, Hogg D, Ottensmeier CH, Lebbe C, Peschel C, Quirt I, Clark JI, Wolchok JD, Weber JS, Tian J, Yellin MJ, Nichol GM, Hoos A, Urba WJ (2010) Improved survival with ipilimumab in patients with metastatic melanoma. N Engl J Med 363(8):711–723. doi: 10.1056/NEJMoa1003466 CrossRefPubMedCentralPubMedGoogle Scholar
  12. 12.
    Robert C, Thomas L, Bondarenko I, O'Day S, Weber J, Garbe C, Lebbe C, Baurain JF, Testori A, Grob JJ, Davidson N, Richards J, Maio M, Hauschild A, Miller WH Jr, Gascon P, Lotem M, Harmankaya K, Ibrahim R, Francis S, Chen TT, Humphrey R, Hoos A, Wolchok JD (2011) Ipilimumab plus dacarbazine for previously untreated metastatic melanoma. N Engl J Med 364(26):2517–2526. doi: 10.1056/NEJMoa1104621 CrossRefPubMedGoogle Scholar
  13. 13.
    Brahmer JR, Tykodi SS, Chow LQ, Hwu WJ, Topalian SL, Hwu P, Drake CG, Camacho LH, Kauh J, Odunsi K, Pitot HC, Hamid O, Bhatia S, Martins R, Eaton K, Chen S, Salay TM, Alaparthy S, Grosso JF, Korman AJ, Parker SM, Agrawal S, Goldberg SM, Pardoll DM, Gupta A, Wigginton JM (2012) Safety and activity of anti-PD-L1 antibody in patients with advanced cancer. N Engl J Med 366(26):2455–2465. doi: 10.1056/NEJMoa1200694 CrossRefPubMedCentralPubMedGoogle Scholar
  14. 14.
    Hamid O, Robert C, Daud A, Hodi FS, Hwu WJ, Kefford R, Wolchok JD, Hersey P, Joseph RW, Weber JS, Dronca R, Gangadhar TC, Patnaik A, Zarour H, Joshua AM, Gergich K, Elassaiss-Schaap J, Algazi A, Mateus C, Boasberg P, Tumeh PC, Chmielowski B, Ebbinghaus SW, Li XN, Kang SP, Ribas A (2013) Safety and tumor responses with lambrolizumab (anti-PD-1) in melanoma. N Engl J Med 369(2):134–144. doi: 10.1056/NEJMoa1305133 CrossRefPubMedCentralPubMedGoogle Scholar
  15. 15.
    Hamid O, Sosman J, Lawrence D, Sullivan RJ, Ibrahim N, Kluger H, Boasberg PD, Flaherty K, Hwu P, Ballinger M, Mokatrin A, Kowanetz M, Chen D, Hodi FS (2013) Clinical activity, safety, and biomarkers of MPDL3280A, an engineered PD-L1 antibody in patients with locally advanced or metastatic melanoma. In: ASCO annual meeting proceedings, Chicago. J Clin Oncol, p Abstr 9010Google Scholar
  16. 16.
    Topalian SL, Hodi FS, Brahmer JR, Gettinger SN, Smith DC, McDermott DF, Powderly JD, Carvajal RD, Sosman JA, Atkins MB, Leming PD, Spigel DR, Antonia SJ, Horn L, Drake CG, Pardoll DM, Chen L, Sharfman WH, Anders RA, Taube JM, McMiller TL, Xu H, Korman AJ, Jure-Kunkel M, Agrawal S, McDonald D, Kollia GD, Gupta A, Wigginton JM, Sznol M (2012) Safety, Activity, and Immune Correlates of Anti-PD-1 Antibody in Cancer. N Engl J Med. doi: 10.1056/NEJMoa1200690 Google Scholar
  17. 17.
    Margolin K, Ernstoff MS, Hamid O, Lawrence D, McDermott D, Puzanov I, Wolchok JD, Clark JI, Sznol M, Logan TF, Richards J, Michener T, Balogh A, Heller KN, Hodi FS (2012) Ipilimumab in patients with melanoma and brain metastases: an open-label, phase 2 trial. Lancet Oncol 13(5):459–465. doi: 10.1016/S1470-2045(12)70090-6 CrossRefPubMedGoogle Scholar
  18. 18.
    Long GV, Menzies AM, Nagrial AM, Haydu LE, Hamilton AL, Mann GJ, Hughes TM, Thompson JF, Scolyer RA, Kefford RF (2011) Prognostic and clinicopathologic associations of oncogenic BRAF in metastatic melanoma. J Clin Oncol 29(10):1239–1246. doi: 10.1200/JCO.2010.32.4327 CrossRefPubMedGoogle Scholar
  19. 19.
    Menzies AM, Haydu LE, Visintin L, Carlino MS, Howle JR, Thompson JF, Kefford RF, Scolyer RA, Long GV (2012) Distinguishing clinicopathologic features of patients with V600E and V600K BRAF-mutant metastatic melanoma. Clin Cancer Res 18(12):3242–3249. doi: 10.1158/1078-0432.CCR-12-0052 CrossRefPubMedGoogle Scholar
  20. 20.
    Chapman PB, Hauschild A, Robert C, Haanen JB, Ascierto P, Larkin J, Dummer R, Garbe C, Testori A, Maio M, Hogg D, Lorigan P, Lebbe C, Jouary T, Schadendorf D, Ribas A, O'Day SJ, Sosman JA, Kirkwood JM, Eggermont AM, Dreno B, Nolop K, Li J, Nelson B, Hou J, Lee RJ, Flaherty KT, McArthur GA (2011) Improved survival with vemurafenib in melanoma with BRAF V600E mutation. N Engl J Med 364(26):2507–2516. doi: 10.1056/NEJMoa1103782 CrossRefPubMedCentralPubMedGoogle Scholar
  21. 21.
    Hauschild A, Grob JJ, Demidov LV, Jouary T, Gutzmer R, Millward M, Rutkowski P, Blank CU, Miller WH Jr, Kaempgen E, Martin-Algarra S, Karaszewska B, Mauch C, Chiarion-Sileni V, Martin AM, Swann S, Haney P, Mirakhur B, Guckert ME, Goodman V, Chapman PB (2012) Dabrafenib in BRAF-mutated metastatic melanoma: a multicentre, open-label, phase 3 randomised controlled trial. Lancet 380(9839):358–365. doi: 10.1016/S0140-6736(12)60868-X CrossRefPubMedGoogle Scholar
  22. 22.
    Flaherty KT, Robert C, Hersey P, Nathan P, Garbe C, Milhem M, Demidov LV, Hassel JC, Rutkowski P, Mohr P, Dummer R, Trefzer U, Larkin JM, Utikal J, Dreno B, Nyakas M, Middleton MR, Becker JC, Casey M, Sherman LJ, Wu FS, Ouellet D, Martin AM, Patel K, Schadendorf D (2012) Improved survival with MEK inhibition in BRAF-mutated melanoma. N Engl J Med 367(2):107–114. doi: 10.1056/NEJMoa1203421 CrossRefPubMedGoogle Scholar
  23. 23.
    Long GV, Stroyakovskiy D, Gogas H, Levchenko E, de Braud F, Larkin J, Garbe C, Jouary T, Hauschild A, Grob JJ, Chiarion Sileni V, Lebbe C, Mandala M, Millward M, Arance A, Bondarenko I, Haanen JB, Hansson J, Utikal J, Ferraresi V, Kovalenko N, Mohr P, Probachai V, Schadendorf D, Nathan P, Robert C, Ribas A, DeMarini DJ, Irani JG, Casey M, Ouellet D, Martin AM, Le N, Patel K, Flaherty K (2014) Combined BRAF and MEK inhibition versus BRAF inhibition alone in melanoma. N Engl J Med 371(20):1877–1888. doi: 10.1056/NEJMoa1406037 CrossRefPubMedGoogle Scholar
  24. 24.
    Robert C, Karaszewska B, Schachter J, Rutkowski P, Mackiewicz A, Stroiakovski D, Lichinitser M, Dummer R, Grange F, Mortier L, Chiarion-Sileni V, Drucis K, Krajsova I, Hauschild A, Lorigan P, Wolter P, Long GV, Flaherty K, Nathan P, Ribas A, Martin AM, Sun P, Crist W, Legos J, Rubin SD, Little SM, Schadendorf D (2015) Improved overall survival in melanoma with combined dabrafenib and trametinib. N Engl J Med 372(1):30–39. doi: 10.1056/NEJMoa1412690 CrossRefPubMedGoogle Scholar
  25. 25.
    Long GV, Trefzer U, Davies MA, Kefford RF, Ascierto PA, Chapman PB, Puzanov I, Hauschild A, Robert C, Algazi A, Mortier L, Tawbi H, Wilhelm T, Zimmer L, Switzky J, Swann S, Martin AM, Guckert M, Goodman V, Streit M, Kirkwood JM, Schadendorf D (2012) Dabrafenib in patients with Val600Glu or Val600Lys BRAF-mutant melanoma metastatic to the brain (BREAK-MB): a multicentre, open-label, phase 2 trial. Lancet Oncol 13(11):1087–1095. doi: 10.1016/S1470-2045(12)70431-X CrossRefPubMedGoogle Scholar
  26. 26.
    Azer MW, Menzies AM, Haydu LE, Kefford RF, Long GV (2014) Patterns of response and progression in patients with BRAF-mutant melanoma metastatic to the brain who were treated with dabrafenib. Cancer 120(4):530–536. doi: 10.1002/cncr.28445 CrossRefPubMedGoogle Scholar
  27. 27.
    Dummer R, Goldinger SM, Turtschi CP, Eggmann NB, Michielin O, Mitchell L, Veronese L, Hilfiker PR, Felderer L, Rinderknecht JD (2013) Vemurafenib in patients with BRAF mutation-positive melanoma with symptomatic brain metastases: final results of an open-label pilot study. Eur J Cancer. doi: 10.1016/j.ejca.2013.11.002 Google Scholar
  28. 28.
    Narayana A, Mathew M, Tam M, Kannan R, Madden KM, Golfinos JG, Parker EC, Ott PA, Pavlick AC (2013) Vemurafenib and radiation therapy in melanoma brain metastases. J Neurooncol. doi: 10.1007/s11060-013-1127-1 PubMedGoogle Scholar
  29. 29.
    Arozarena I, Sanchez-Laorden B, Packer L, Hidalgo-Carcedo C, Hayward R, Viros A, Sahai E, Marais R (2011) Oncogenic BRAF induces melanoma cell invasion by downregulating the cGMP-specific phosphodiesterase PDE5A. Cancer Cell 19(1):45–57. doi: 10.1016/j.ccr.2010.10.029 CrossRefPubMedGoogle Scholar
  30. 30.
    Jakob JA, Bassett RL Jr, Ng CS, Curry JL, Joseph RW, Alvarado GC, Rohlfs ML, Richard J, Gershenwald JE, Kim KB, Lazar AJ, Hwu P, Davies MA (2012) NRAS mutation status is an independent prognostic factor in metastatic melanoma. Cancer 118(16):4014–4023. doi: 10.1002/cncr.26724 CrossRefPubMedCentralPubMedGoogle Scholar
  31. 31.
    Mittapalli RK, Vaidhyanathan S, Sane R, Elmquist WF (2012) Impact of P-glycoprotein (ABCB1) and breast cancer resistance protein (ABCG2) on the brain distribution of a novel BRAF inhibitor: vemurafenib (PLX4032). J Pharmacol Exp Ther 342(1):33–40. doi: 10.1124/jpet.112.192195 CrossRefPubMedCentralPubMedGoogle Scholar
  32. 32.
    Mittapalli RK, Vaidhyanathan S, Dudek AZ, Elmquist WF (2013) Mechanisms limiting distribution of the threonine-protein kinase B-RaF(V600E) inhibitor dabrafenib to the brain: implications for the treatment of melanoma brain metastases. J Pharmacol Exp Ther 344(3):655–664. doi: 10.1124/jpet.112.201475 CrossRefPubMedCentralPubMedGoogle Scholar
  33. 33.
    Gerstner ER, Fine RL (2007) Increased permeability of the blood-brain barrier to chemotherapy in metastatic brain tumors: establishing a treatment paradigm. J Clin Oncol 25(16):2306–2312. doi: 10.1200/JCO.2006.10.0677 CrossRefPubMedGoogle Scholar
  34. 34.
    Colombino M, Capone M, Lissia A, Cossu A, Rubino C, De Giorgi V, Massi D, Fonsatti E, Staibano S, Nappi O, Pagani E, Casula M, Manca A, Sini M, Franco R, Botti G, Caraco C, Mozzillo N, Ascierto PA, Palmieri G (2012) BRAF/NRAS mutation frequencies among primary tumors and metastases in patients with melanoma. J Clin Oncol 30(20):2522–2529. doi: 10.1200/JCO.2011.41.2452 CrossRefPubMedGoogle Scholar
  35. 35.
    Hamilton R, Krauze M, Romkes M, Omolo B, Konstantinopoulos P, Reinhart T, Harasymczuk M, Wang Y, Lin Y, Ferrone S, Whiteside T, Bortoluzzi S, Werley J, Nukui T, Fallert-Junecko B, Kondziolka D, Ibrahim J, Becker D, Kirkwood J, Moschos S (2013) Pathologic and gene expression features of metastatic melanomas to the brain. Cancer 119(15):2737–2746. doi: 10.1002/cncr.28029 CrossRefPubMedCentralPubMedGoogle Scholar
  36. 36.
    Chan M, Haydu LE, Menzies AM, Azer MW, Klein O, Guminski A, Kefford R, Long GV (2013) Clinical characteristics and survival of BRAF-mutant (BRAF+) metastatic melanoma patients (pts) treated with BRAF inhibitor (BRAFi) dabrafenib or vemurafenib beyond disease progression (PD). J Clin Oncol 31(15_suppl):abstr 9062Google Scholar
  37. 37.
    Davies MA, Stemke-Hale K, Lin E, Tellez C, Deng W, Gopal YN, Woodman SE, Calderone TC, Ju Z, Lazar AJ, Prieto VG, Aldape K, Mills GB, Gershenwald JE (2009) Integrated molecular and clinical analysis of AKT activation in metastatic melanoma. Clin Cancer Res 15(24):7538–7546. doi: 10.1158/1078-0432.CCR-09-1985 CrossRefPubMedCentralPubMedGoogle Scholar
  38. 38.
    Niessner H, Forschner A, Klumpp B, Honegger JB, Witte M, Bornemann A, Dummer R, Adam A, Bauer J, Tabatabai G, Flaherty K, Sinnberg T, Beck D, Leiter U, Mauch C, Roesch A, Weide B, Eigentler T, Schadendorf D, Garbe C, Kulms D, Quintanilla-Martinez L, Meier F (2013) Targeting hyperactivation of the AKT survival pathway to overcome therapy resistance of melanoma brain metastases. Cancer Med 2(1):76–85. doi: 10.1002/cam4.50 CrossRefPubMedCentralPubMedGoogle Scholar
  39. 39.
    Knisely JP, Yu JB, Flanigan J, Sznol M, Kluger HM, Chiang VL (2012) Radiosurgery for melanoma brain metastases in the ipilimumab era and the possibility of longer survival. J Neurosurg 117(2):227–233. doi: 10.3171/2012.5.JNS111929 CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2015

Authors and Affiliations

  • Daniel A. Wattson
    • 1
  • Ryan J. Sullivan
    • 2
  • Andrzej Niemierko
    • 3
  • Ryan M. Merritt
    • 2
  • Donald P. Lawrence
    • 2
  • Kevin S. Oh
    • 3
  • Keith T. Flaherty
    • 2
  • Helen A. Shih
    • 3
  1. 1.Harvard Radiation Oncology ProgramBostonUSA
  2. 2.Massachusetts General Hospital Cancer CenterBostonUSA
  3. 3.Department of Radiation OncologyMassachusetts General HospitalBostonUSA

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