Treatment patterns and outcomes in BRAF V600E-mutant melanoma patients with brain metastases receiving vemurafenib in the real-world setting

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Abstract:
Brain metastases are a common and serious complication among patients with metastatic melanoma. The selective BRAF inhibitor vemurafenib has demonstrated clinical efficacy in patients with BRAF V600E-mutant melanoma brain metastases (MBM). We examined the real-world application and clinical outcomes of vemurafenib in this patient population. Demographic, treatment patterns, response, and survival data were collected from medical charts. Clinical data on 283 patients with active BRAF V600E-mutant MBM treated with vemurafenib were provided by 70 US oncologists. Mean age was 57.2 years, 60.8% were male, 67.5% had ECOG performance status of 0–1, and 43.1% used corticosteroids at vemurafenib initiation. Median follow-up was 5.7 months. Following vemurafenib initiation, 48.1% of patients experienced intracranial response and 45.6% experienced extracranial response. The Kaplan–Meier estimate for overall survival was 59% at 12 months. Multivariate analyses showed associations between intracranial response and both corticosteroid use and vemurafenib as initial therapy after MBM diagnosis. Larger size (5–10 mm vs. <5 mm) and number of brain metastases (≥5 vs. <2) and progressive extracranial disease at treatment initiation were associated with decreased intracranial response and increased risk of disease progression. Multiple extracranial sites (2 vs. <2) and the absence of local treatments were also associated with increased risk of progression. Increased risk of death was associated with ≥2 extracranial disease sites, progressive extracranial disease, and ≥5 brain metastases. Subgroups of MBM patients may derive more benefit with vemurafenib, warranting prospective investigation.

Keywords:
BRAF mutation; brain metastases; melanoma brain metastases; metastatic melanoma; vemurafenib

Autoři: Geoffrey T. Gibney ¹; Geneviève Gauthier ²; Charles Ayas ²; Philip Galebach ²; Eric Q. Wu ²; Sarang Abhyankar ³; Carolina Reyes ³; Annie Guérin ²; Yeun Mi Yim ^3,*
Působiště autorů: Moffitt Cancer Center, Tampa, Florida ¹; Analysis Group Inc., Boston, Massachusetts ²; Genentech Inc., South San Francisco, California ³
Vyšlo v časopise: Cancer Medicine 2015; 4(8)
Kategorie: Original Research
prolekare.web.journal.doi_sk: https://doi.org/10.1002/cam4.475

© 2015 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.
This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited. © 2015 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.

Souhrn

Keywords:
BRAF mutation; brain metastases; melanoma brain metastases; metastatic melanoma; vemurafenib

Zdroje

1.Chamberlain, M. C. 2010. Brain metastases: a medical neuro-oncology perspective. Expert Rev. Neurother.10:563–573.

2.Carlino, M., M. Atkins, and C. Warneke. 2010. Differences between Australia (OZ) and the United States (US) in the patterns, prognosis, and treatment of melanoma CNS metastases: analysis from the PHAMOUS (prognostic heterogeneity in patients with advanced melanoma between OZ & the US) study. Pigment Cell Melanoma Res 23: 874–1004.

3.Lotze, M., R. Dallal, J. M. Kirkwood, and J. Flickinger. 2001. Pp. 2012–2069 in Cancer: principles & practice of oncology, 6th ed. Lippincott Williams and Wilkins, Philadelphia.

4.Lagerwaard, F. J., P. C. Levendag, P. J. Nowak, W. M. Eijkenboom, P. E. Hanssens, and P. I. Schmitz. 1999.Identification of prognostic factors in patients with brain metastases: a review of 1292 patients. Int. J. Radiat. Oncol. Biol. Phys. 43:795–803.

5.Fife, K. M., M. H. Colman, G. N. Stevens, I. C. Firth, D. Moon, K. F. Shannon, et al. 2004. Determinants of outcome in melanoma patients with cerebral metastases. J. Clin. Oncol. 22: 1293–1300.

6.Staudt, M., K. Lasithiotakis, U. Leiter, F. Meier, T. Eigentler, M. Bamberg, et al. 2010. Determinants of survival in patients with brain metastases from cutaneous melanoma. Br. J. Cancer 102:1213–1218.

7.Gibney, G. T., P. A. Forsyth, and V. K. Sondak. 2012. Melanoma in the brain: biology and therapeutic options.Melanoma Res. 22: 177–183.

8.Ewend, M. G., D. E. Morris, L. A. Carey, A. M. Ladha, and S. Brem. 2008. Guidelines for the initial management of metastatic brain tumors: role of surgery, radiosurgery, and radiation therapy. J. Natl. Compr. Canc. Netw. 6: 505–513; quiz 514.

9.Mornex, F., L. Thomas, P. Mohr, A. Hauschild, M. M. Delaunay, T. Lesimple, et al. 2003. A prospective randomized multicentre phase III trial of fotemustine plus whole brain irradiation versus fotemustine alone in cerebral metastases of malignant melanoma. Melanoma Res. 13:97–103.

10.Margolin, K., B. Atkins, A. Thompson, S. Ernstoff, J. Weber, L. Flaherty, et al. 2002. Temozolomide and whole brain irradiation in melanoma metastatic to the brain: a phase II trial of the cytokine working group. J. Cancer Res. Clin. Oncol. 128:214–218.

11.Hwu, W.-11.J., E. Lis, J. H. Menell, K. S. Panageas, L. A. Lamb, J. Merrell, et al. 2005. Temozolomide plus thalidomide in patients with brain metastases from melanoma: a phase II study. Cancer 103:2590–2597.

12.Atkins, M. B., J. A. Sosman, S. Agarwala, T. Logan, J. I. Clark, M. S. Ernstoff, et al. 2008. Temozolomide, thalidomide, and whole brain radiation therapy for patients with brain metastasis from metastatic melanoma: a phase II Cytokine Working Group study. Cancer 113:2139–2145.

13.Agarwala, S. S., J. M. Kirkwood, M. Gore, B. Dreno, N. Thatcher, B. Czarnetski, et al. 2004. Temozolomide for the treatment of brain metastases associated with metastatic melanoma: a phase II study. J. Clin. Oncol.22:2101–2107.

14.Guirguis, L. M., J. C. Yang, D. E. White, S. M. Steinberg, D. J. Liewehr, S. A. Rosenberg, et al. 2002. Safety and efficacy of high-dose interleukin-2 therapy in patients with brain metastases. J. Immunother. 25:82–87.

15.Margolin, K., M. S. Ernstoff, O. Hamid, D. Lawrence, D. McDermott, I. Puzanov, et al. 2012. Ipilimumab in patients with melanoma and brain metastases: an open-label, phase 2 trial. Lancet Oncol. 13:459–465.

16.Hong, J. J., S. A. Rosenberg, M. E. Dudley, J. C. Yang, D. E. White, J. A. Butman, et al. 2010. Successful treatment of melanoma brain metastases with adoptive cell therapy. Clin. Cancer Res. 16:4892–4898.

17.Long, G. V., U. Trefzer, M. A. Davies, R. F. Kefford, P. A. Ascierto, P. B. Chapman, 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. Lancet Oncol. 13:1087–1095.

18.Long, G. V., A. M. Menzies, A. M. Nagrial, L. E. Haydu, A. L. Hamilton, G. J. Mann, et al. 2011. Prognostic and clinicopathologic associations of oncogenic BRAF in metastatic melanoma. J. Clin. Oncol. 29:1239–1246.

19.Rizos, H., A. M. Menzies, G. M. Pupo, M. S. Carlino, C. Fung, J. Hyman, et al. 2014. BRAF inhibitor resistance mechanisms in metastatic melanoma: spectrum and clinical impact. Clin. Cancer Res. 20:1965–1977.

20.Bollag, G., P. Hirth, J. Tsai, J. Zhang, P. N. Ibrahim, H. Cho, et al. 2010. Clinical efficacy of a RAF inhibitor needs broad target blockade in BRAF-mutant melanoma. Nature 467:596–599.

21.Salama, A. K. S., and K. T. Flaherty. 2013. BRAF in melanoma: current strategies and future directions. Clin. Cancer Res. 19:4326–4334.

22.Dummer, R., S. M. Goldinger, C. P. Turtschi, N. B. Eggmann, O. Michielin, L. Mitchell, et al. 2014. Vemurafenib in patients with BRAF(V600) mutation-positive melanoma with symptomatic brain metastases: final results of an open-label pilot study. Eur. J. Cancer 50:611–621.

23.Kefford, G. M. R., Mi. Maio, A. Arance, P. Nathan, C. Blank, M. F. Avril, et al. 2013. Vemurafenib in metastatic melanoma patients with brain metastases: an open-label, single-arm, phase 2, multicenter study. Presented at the 10th International Meeting Society Melanoma Research, Philadelphia, Pennsylvania, USA.

24.Genentech, Inc. 2014. Vemurafenib [package insert]. Genentech, Inc, South San Francisco, CA.

25.Larkin, J., M. Del Vecchio, P. A. Ascierto, I. Krajsova, J. Schachter, B. Neyns, et al. 2014. Vemurafenib in patients with BRAF(V600) mutated metastatic melanoma: an open-label, multicentre, safety study. Lancet Oncol. 15:436–444.

26.Davies, M. A., P. Liu, S. McIntyre, K. B. Kim, N. Papadopoulos, W.-J. Hwu, et al. 2011. Prognostic factors for survival in melanoma patients with brain metastases. Cancer 117:1687–1696.

27.Eigentler, T. K., A. Figl, D. Krex, P. Mohr, C. Mauch, K. Rass, et al. 2011. Number of metastases, serum lactate dehydrogenase level, and type of treatment are prognostic factors in patients with brain metastases of malignant melanoma. Cancer 117:1697–1703.

28.Larkin, J., P. A. Ascierto, B. Dréno, V. Atkinson, G. Liszkay, M. Maio, et al. 2014. Combined Vemurafenib and Cobimetinib in BRAF-Mutated Melanoma,” N. Engl. J. Med. 371:1867–1876.

29.Long, G. V., D. Stroyakovskiy, H. Gogas, E. Levchenko, de Braud F., J. Larkin, et al. 2014. Combined BRAF and MEK Inhibition versus BRAF Inhibition Alone in Melanoma. N. Engl. J. Med. 371:1877–1888.

30.Robert, C., B. Karaszewska, J. Schachter, P. Rutkowski, A. Mackiewicz, D. Stroiakovski, et al. 2014. Improved overall survival in melanoma with combined Dabrafenib and Trametinib. N. Engl. J. Med. 372:30–39.

31.Flaherty, K. T., C. Robert, P. Hersey, P. Nathan, C. Garbe, M. Milhem, et al. 2012. Improved survival with MEK inhibition in BRAF-mutated melanoma. N. Engl. J. Med. 367:107–114.

32.Ribas, A., P. Hersey, M. R. Middleton, H. Gogas, K. T. Flaherty, V. K. Sondak, et al. 2012. New challenges in endpoints for drug development in advanced melanoma. Clin. Cancer Res. 18:336–341.

33.Kefford, R., R. J. Sullivan, W. H. Miller, E. M. Elez, D. Tan, K. B. Kim, et al. 2014. Phase Ib/II, open-label, dose-escalation study of LGX818, an oral selective BRAF inhibitor, in combination with MEK162, an oral MEK1/2 inhibitor, in patients with BRAF V600-dependent advanced solid tumors: preliminary results. J. Transl. Med.12(Suppl. 1):P5.