Abstract
Brain metastases are a major cause of morbidity and mortality in cancer patients. While the mainstay treatment comprises surgery and radiation therapy, the role of systemic agents remains controversial. In general, it has been presumed that poor blood–brain barrier (BBB) penetration and inherently more resistant metastatic brain disease preclude a favorable systemic treatment approach. However, a better understanding of tumor biology and the subsequent development of targeted drugs have reawakened interest in systemic therapy. Despite still limited brain distribution, a variety of targeted drugs have demonstrated activity in brain metastases in early clinical trials. Nevertheless, disease progression commonly occurs, and it remains to be elucidated whether limited CNS drug distribution or the acquisition of resistant metastatic clones must be held responsible for this prognosis. Moreover, micrometastatic brain disease beyond an intact BBB—and ultimately prevention of brain metastasis formation—may generally remain inaccessible for first-generation targeted agents with poor CNS penetration. To overcome limited brain distribution and possibly emerging acquired resistance, highly potent next-generation targeted drugs with enhanced CNS distribution have been developed. In view of this emerging but yet undefined role of targeted therapies in the treatment of brain metastases from solid tumors, this review aims to summarize the current knowledge from clinical trials and discusses clinically relevant obstacles to overcome.
Similar content being viewed by others
References
Barnholtz-Sloan JS, Sloan AE, Davis FG, et al. Incidence proportions of brain metastases in patients diagnosed (1973 to 2001) in the Metropolitan Detroit Cancer Surveillance System. J Clin Oncol. 2004;22:2865–72.
Nussbaum ES, Djalilian HR, Cho KH, et al. Brain metastases. Histology, multiplicity, surgery, and survival. Cancer. 1996;78:1781–8.
Owonikoko TK, Arbiser J, Zelnak A, et al. Current approaches to the treatment of metastatic brain tumours. Nat Rev Clin Oncol. 2014;11:203–22.
Langley RE, Stephens RJ, Nankivell M, et al. Interim data from the Medical Research Council QUARTZ Trial: does whole brain radiotherapy affect the survival and quality of life of patients with brain metastases from non-small cell lung cancer? Clin Oncol (R Coll Radiol). 2013;25:e23–30.
Tsao MN, Rades D, Wirth A, et al. Radiotherapeutic and surgical management for newly diagnosed brain metastasis(es): an American Society for Radiation Oncology evidence-based guideline. Pract Radiat Oncol. 2012;2:210–25.
Tsao MN, Lloyd N, Wong RK, et al. Whole brain radiotherapy for the treatment of newly diagnosed multiple brain metastases. Cochrane Database Syst Rev. 2012;4:CD003869.
Lin NU. Targeted therapies in brain metastases. Curr Treat Options Neurol. 2014;16:276.
Mehta MP, Paleologos NA, Mikkelsen T, et al. The role of chemotherapy in the management of newly diagnosed brain metastases: a systematic review and evidence-based clinical practice guideline. J Neurooncol. 2010;96:71–83.
Buckner JC. The role of chemotherapy in the treatment of patients with brain metastases from solid tumors. Cancer Metastasis Rev. 1991;10:335–41.
Abbott NJ, Ronnback L, Hansson E. Astrocyte-endothelial interactions at the blood–brain barrier. Nat Rev Neurosci. 2006;7:41–53.
Neuwelt EA. Mechanisms of disease: the blood–brain barrier. Neurosurgery. 2004;54:131–40.
Jain RK, di Tomaso TE, Duda DG, et al. Angiogenesis in brain tumours. Nat Rev Neurosci. 2007;8:610–22.
Bullitt E, Zeng D, Gerig G, et al. Vessel tortuosity and brain tumor malignancy: a blinded study. Acad Radiol. 2005;12:1232–40.
Fukumura D, Xu L, Chen Y, et al. Hypoxia and acidosis independently up-regulate vascular endothelial growth factor transcription in brain tumors in vivo. Cancer Res. 2001;61:6020–4.
Monsky WL, Fukumura D, Gohongi T, et al. Augmentation of transvascular transport of macromolecules and nanoparticles in tumors using vascular endothelial growth factor. Cancer Res. 1999;59:4129–35.
Zhang RD, Price JE, Fujimaki T, et al. Differential permeability of the blood–brain barrier in experimental brain metastases produced by human neoplasms implanted into nude mice. Am J Pathol. 1992;141:1115–24.
Deeken JF, Loscher W. The blood–brain barrier and cancer: transporters, treatment, and Trojan horses. Clin Cancer Res. 2007;13:1663–74.
Gerstner ER, Fine RL. Increased permeability of the blood–brain barrier to chemotherapy in metastatic brain tumors: establishing a treatment paradigm. J Clin Oncol. 2007;25:2306–12.
Rampling R, Cruickshank G, Lewis AD, et al. Direct measurement of pO2 distribution and bioreductive enzymes in human malignant brain tumors. Int J Radiat Oncol Biol Phys. 1994;29:427–31.
Stohrer M, Boucher Y, Stangassinger M, et al. Oncotic pressure in solid tumors is elevated. Cancer Res. 2000;60:4251–5.
Fidler IJ. The role of the organ microenvironment in brain metastasis. Semin Cancer Biol. 2011;21:107–12.
Kim SJ, Kim JS, Park ES, et al. Astrocytes upregulate survival genes in tumor cells and induce protection from chemotherapy. Neoplasia. 2011;13:286–98.
Valiente M, Obenauf AC, ** X, et al. Serpins promote cancer cell survival and vascular co-option in brain metastasis. Cell. 2014;156:1002–16.
Brastianos PK, Carter SL, Santagata S, et al. Genomic characterization of brain metastases reveals branched evolution and potential therapeutic targets. Cancer Discov. 2015;5:1164–77.
Hanahan D, Weinberg RA. Hallmarks of cancer: the next generation. Cell. 2011;144:646–74.
Jain RK. Normalization of tumor vasculature: an emerging concept in antiangiogenic therapy. Science. 2005;307:58–62.
Trevisan E, Bertero L, Bosa C, et al. Antiangiogenic therapy of brain tumors: the role of bevacizumab. Neurol Sci. 2014;35:507–14.
Besse B, Lasserre SF, Compton P, et al. Bevacizumab safety in patients with central nervous system metastases. Clin Cancer Res. 2010;16:269–78.
Socinski MA, Langer CJ, Huang JE, et al. Safety of bevacizumab in patients with non-small-cell lung cancer and brain metastases. J Clin Oncol. 2009;27:5255–61.
Besse B, Le MS, Mazieres J et al. Bevacizumab in Patients with Non-Squamous Non-Small-Cell Lung Cancer and Asymptomatic, Untreated Brain Metastases (BRAIN): a Non-Randomised, Phase II Study. Clin Cancer Res 2015;1896–903.
Lu YS, Chen BB, Lin CH et al. Normalization of tumor vasculature by anti-angiogenesis therapy in metastatic tumor: a clinical study to determine the timing and effect [abstract no. 2984]. Cancer Res 2014;74:2984. doi:10.1158/1538-7445.AM2014-2984.
Lu YS, Chen TW, Lin CH et al. Bevacizumab Preconditioning Followed by Etoposide and Cisplatin Is Highly Effective in Treating Brain Metastases of Breast Cancer Progressing from Whole-Brain Radiotherapy. Clin Cancer Res 2015;21:1851–8.
Cocconi G, Lottici R, Bisagni G, et al. Combination therapy with platinum and etoposide of brain metastases from breast carcinoma. Cancer Invest. 1990;8:327–34.
Franciosi V, Cocconi G, Michiara M, et al. Front-line chemotherapy with cisplatin and etoposide for patients with brain metastases from breast carcinoma, nonsmall cell lung carcinoma, or malignant melanoma: a prospective study. Cancer. 1999;85:1599–605.
Carlomagno F, Anaganti S, Guida T, et al. BAY 43–9006 inhibition of oncogenic RET mutants. J Natl Cancer Inst. 2006;98:326–34.
Rini BI, Small EJ. Biology and clinical development of vascular endothelial growth factor-targeted therapy in renal cell carcinoma. J Clin Oncol. 2005;23:1028–43.
Wilhelm SM, Carter C, Tang L, et al. BAY 43–9006 exhibits broad spectrum oral antitumor activity and targets the RAF/MEK/ERK pathway and receptor tyrosine kinases involved in tumor progression and angiogenesis. Cancer Res. 2004;64:7099–109.
Stadler WM, Figlin RA, McDermott DF, et al. Safety and efficacy results of the advanced renal cell carcinoma sorafenib expanded access program in North America. Cancer. 2010;116:1272–80.
Massard C, Zonierek J, Gross-Goupil M, et al. Incidence of brain metastases in renal cell carcinoma treated with sorafenib. Ann Oncol. 2010;21:1027–31.
Agarwal S, Sane R, Ohlfest JR, et al. The role of the breast cancer resistance protein (ABCG2) in the distribution of sorafenib to the brain. J Pharmacol Exp Ther. 2011;336:223–33.
Tang SC, de Vries N, Sparidans RW, et al. Impact of P-glycoprotein (ABCB1) and breast cancer resistance protein (ABCG2) gene dosage on plasma pharmacokinetics and brain accumulation of dasatinib, sorafenib, and sunitinib. J Pharmacol Exp Ther. 2013;346:486–94.
Gore ME, Hariharan S, Porta C, et al. Sunitinib in metastatic renal cell carcinoma patients with brain metastases. Cancer. 2011;117:501–9.
Motzer RJ, Hutson TE, Cella D, et al. Pazopanib versus sunitinib in metastatic renal-cell carcinoma. N Engl J Med. 2013;369:722–31.
Laskin JJ, Sandler AB. Epidermal growth factor receptor: a promising target in solid tumours. Cancer Treat Rev. 2004;30:1–17.
Slamon DJ, Clark GM, Wong SG, et al. Human breast cancer: correlation of relapse and survival with amplification of the HER-2/neu oncogene. Science. 1987;235:177–82.
Kennecke H, Yerushalmi R, Woods R, et al. Metastatic behavior of breast cancer subtypes. J Clin Oncol. 2010;28:3271–7.
Graus-Porta D, Beerli RR, Daly JM, et al. ErbB-2, the preferred heterodimerization partner of all ErbB receptors, is a mediator of lateral signaling. EMBO J. 1997;16:1647–55.
Worthylake R, Opresko LK, Wiley HS. ErbB-2 amplification inhibits down-regulation and induces constitutive activation of both ErbB-2 and epidermal growth factor receptors. J Biol Chem. 1999;274:8865–74.
Wada T, Qian XL, Greene MI. Intermolecular association of the p185neu protein and EGF receptor modulates EGF receptor function. Cell. 1990;61:1339–47.
Rusnak DW, Affleck K, Cockerill SG, et al. The characterization of novel, dual ErbB-2/EGFR, tyrosine kinase inhibitors: potential therapy for cancer. Cancer Res. 2001;61:7196–203.
Polli JW, Olson KL, Chism JP, et al. An unexpected synergist role of P-glycoprotein and breast cancer resistance protein on the central nervous system penetration of the tyrosine kinase inhibitor lapatinib (N-{3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}-6-[5-({[2-(methylsulfonyl)ethyl]amino }methyl)-2-furyl]-4-quinazolinamine; GW572016). Drug Metab Dispos. 2009;37:439–42.
Taskar KS, Rudraraju V, Mittapalli RK, et al. Lapatinib distribution in HER2 overexpressing experimental brain metastases of breast cancer. Pharm Res. 2012;29:770–81.
Gori S, Lunardi G, Inno A, et al. Lapatinib concentration in cerebrospinal fluid in two patients with HER2-positive metastatic breast cancer and brain metastases. Ann Oncol. 2014;25:912–3.
Saleem A, Searle GE, Kenny LM, et al. Lapatinib access into normal brain and brain metastases in patients with Her-2 overexpressing breast cancer. EJNMMI Res. 2015;5:30.
Bachelot T, Romieu G, Campone M, et al. Lapatinib plus capecitabine in patients with previously untreated brain metastases from HER2-positive metastatic breast cancer (LANDSCAPE): a single-group phase 2 study. Lancet Oncol. 2013;14:64–71.
Lin NU, Carey LA, Liu MC, et al. Phase II trial of lapatinib for brain metastases in patients with human epidermal growth factor receptor 2-positive breast cancer. J Clin Oncol. 2008;26:1993–9.
Lin NU, Dieras V, Paul D, et al. Multicenter phase II study of lapatinib in patients with brain metastases from HER2-positive breast cancer. Clin Cancer Res. 2009;15:1452–9.
Lin NU, Eierman W, Greil R, et al. Randomized phase II study of lapatinib plus capecitabine or lapatinib plus topotecan for patients with HER2-positive breast cancer brain metastases. J Neurooncol. 2011;105:613–20.
Pao W, Chmielecki J. Rational, biologically based treatment of EGFR-mutant non-small-cell lung cancer. Nat Rev Cancer. 2010;10:760–74.
Weber B, Winterdahl M, Memon A, et al. Erlotinib accumulation in brain metastases from non-small cell lung cancer: visualization by positron emission tomography in a patient harboring a mutation in the epidermal growth factor receptor. J Thorac Oncol. 2011;6:1287–9.
Togashi Y, Masago K, Fukudo M, et al. Cerebrospinal fluid concentration of erlotinib and its active metabolite OSI-420 in patients with central nervous system metastases of non-small cell lung cancer. J Thorac Oncol. 2010;5:950–5.
Park SJ, Kim HT, Lee DH, et al. Efficacy of epidermal growth factor receptor tyrosine kinase inhibitors for brain metastasis in non-small cell lung cancer patients harboring either exon 19 or 21 mutation. Lung Cancer. 2012;77:556–60.
Heon S, Yeap BY, Lindeman NI, et al. The impact of initial gefitinib or erlotinib versus chemotherapy on central nervous system progression in advanced non-small cell lung cancer with EGFR mutations. Clin Cancer Res. 2012;18:4406–14.
Akimoto T, Hunter NR, Buchmiller L, et al. Inverse relationship between epidermal growth factor receptor expression and radiocurability of murine carcinomas. Clin Cancer Res. 1999;5:2884–90.
Chen DJ, Nirodi CS. The epidermal growth factor receptor: a role in repair of radiation-induced DNA damage. Clin Cancer Res. 2007;13:6555–60.
Chinnaiyan P, Huang S, Vallabhaneni G, et al. Mechanisms of enhanced radiation response following epidermal growth factor receptor signaling inhibition by erlotinib (Tarceva). Cancer Res. 2005;65:3328–35.
Welsh JW, Komaki R, Amini A, et al. Phase II trial of erlotinib plus concurrent whole-brain radiation therapy for patients with brain metastases from non-small-cell lung cancer. J Clin Oncol. 2013;31:895–902.
Lee SM, Lewanski CR, Counsell N et al. Randomized trial of erlotinib plus whole-brain radiotherapy for NSCLC patients with multiple brain metastases. J Natl Cancer Inst 2014; 106.
Pao W, Balak MN RG. Molecular analysis of NSCLC patients with acquired resistance to gefitinib or erlotinib [abstract no. 7078]. J Clin Oncol 2006; 24 (Supp1. 18): 7078.
Spicer JF, Rudman SM. EGFR inhibitors in non-small cell lung cancer (NSCLC): the emerging role of the dual irreversible EGFR/HER2 inhibitor BIBW 2992. Target Oncol. 2010;5:245–55.
Solca F, Dahl G, Zoephel A, et al. Target binding properties and cellular activity of afatinib (BIBW 2992), an irreversible ErbB family blocker. J Pharmacol Exp Ther. 2012;343:342–50.
Hoffknecht P, Tufman A, Wehler T, et al. Efficacy of the irreversible ErbB family blocker afatinib in epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI)-pretreated non-small-cell lung cancer patients with brain metastases or leptomeningeal disease. J Thorac Oncol. 2015;10:156–63.
Balak MN, Gong Y, Riely GJ, et al. Novel D761Y and common secondary T790M mutations in epidermal growth factor receptor-mutant lung adenocarcinomas with acquired resistance to kinase inhibitors. Clin Cancer Res. 2006;12:6494–501.
Clarke JL, Pao W, Wu N, et al. High dose weekly erlotinib achieves therapeutic concentrations in CSF and is effective in leptomeningeal metastases from epidermal growth factor receptor mutant lung cancer. J Neurooncol. 2010;99:283–6.
Grommes C, Oxnard GR, Kris MG, et al. “Pulsatile” high-dose weekly erlotinib for CNS metastases from EGFR mutant non-small cell lung cancer. Neuro Oncol. 2011;13:1364–9.
Jackman DM, Holmes AJ, Lindeman N, et al. Response and resistance in a non-small-cell lung cancer patient with an epidermal growth factor receptor mutation and leptomeningeal metastases treated with high-dose gefitinib. J Clin Oncol. 2006;24:4517–20.
Heon S, Yeap BY, Britt GJ, et al. Development of central nervous system metastases in patients with advanced non-small cell lung cancer and somatic EGFR mutations treated with gefitinib or erlotinib. Clin Cancer Res. 2010;16:5873–82.
Katakami N, Atagi S, Goto K, et al. LUX-Lung 4: a phase II trial of afatinib in patients with advanced non-small-cell lung cancer who progressed during prior treatment with erlotinib, gefitinib, or both. J Clin Oncol. 2013;31:3335–41.
Miller VA, Hirsh V, Cadranel J, et al. Afatinib versus placebo for patients with advanced, metastatic non-small-cell lung cancer after failure of erlotinib, gefitinib, or both, and one or two lines of chemotherapy (LUX-Lung 1): a phase 2b/3 randomised trial. Lancet Oncol. 2012;13:528–38.
Janne PA, Yang JC, Kim DW, et al. AZD9291 in EGFR inhibitor-resistant non-small-cell lung cancer. N Engl J Med. 2015;372:1689–99.
Sequist LV, Soria JC, Goldman JW, et al. Rociletinib in EGFR-mutated non-small-cell lung cancer. N Engl J Med. 2015;372:1700–9.
Cortes J, Dieras V, Ro J et al. Afatinib alone or afatinib plus vinorelbine versus investigator’s choice of treatment for HER2-positive breast cancer with progressive brain metastases after trastuzumab, lapatinib, or both (LUX-Breast 3): a randomised, open-label, multicentre, phase 2 trial. Lancet Oncol 2015;16(16):1700–10.
Hegedus C, Truta-Feles K, Antalffy G, et al. Interaction of the EGFR inhibitors gefitinib, vandetanib, pelitinib and neratinib with the ABCG2 multidrug transporter: implications for the emergence and reversal of cancer drug resistance. Biochem Pharmacol. 2012;84:260–7.
Zhao XQ, **e JD, Chen XG, et al. Neratinib reverses ATP-binding cassette B1-mediated chemotherapeutic drug resistance in vitro, in vivo, and ex vivo. Mol Pharmacol. 2012;82:47–58.
Freedman RA, Gelman RS, Wefel JS, et al. TBCRC 022: Phase II trial of neratinib for patients with human epidermal growth factor receptor 2 breast cancer and brain metastases. J Clin Oncol 2014; 32(Suppl. 5):528.
Kwak EL, Bang YJ, Camidge DR, et al. Anaplastic lymphoma kinase inhibition in non-small-cell lung cancer. N Engl J Med. 2010;363:1693–703.
Soda M, Choi YL, Enomoto M, et al. Identification of the transforming EML4-ALK fusion gene in non-small-cell lung cancer. Nature. 2007;448:561–6.
Solomon BJ, Mok T, Kim DW, et al. First-line crizotinib versus chemotherapy in ALK-positive lung cancer. N Engl J Med. 2014;371:2167–77.
Costa DB, Shaw AT, Ou SH et al. Clinical Experience With Crizotinib in Patients With Advanced ALK-Rearranged Non-Small-Cell Lung Cancer and Brain Metastases. J Clin Oncol 2015;33(17):1881–8.
Costa DB, Kobayashi S, Pandya SS, et al. CSF concentration of the anaplastic lymphoma kinase inhibitor crizotinib. J Clin Oncol. 2011;29:e443–5.
Shaw AT, Kim DW, Nakagawa K, et al. Crizotinib versus chemotherapy in advanced ALK-positive lung cancer. N Engl J Med. 2013;368:2385–94.
Shaw AT, Kim DW, Mehra R, et al. Ceritinib in ALK-rearranged non-small-cell lung cancer. N Engl J Med. 2014;370:1189–97.
Shaw AT, Mehra R, Tan DS. Evaluation of Ceritinib-treated patients with anaplastic lymphoma kinase (ALK+) non-small cell lung cancer (NSCLC) and brain metastases in the ASCEND-1 study [abstract no. 1293P]. Ann Oncol 2014; 25(Suppl. 4):iv426–iv470.
Gadgeel SM, Gandhi L, Riely GJ, et al. Safety and activity of alectinib against systemic disease and brain metastases in patients with crizotinib-resistant ALK-rearranged non-small-cell lung cancer (AF-002JG): results from the dose-finding portion of a phase 1/2 study. Lancet Oncol. 2014;15:1119–28.
Johnson TW, Bailey S, Burke BJ, et al. Is CNS availability for oncology a no-brainer? Discovery of PF-06463922, a novel small molecule inhibitor of ALK/ROS1 with preclinical brain availability and broad spectrum potency against ALK-resistant mutations [EORTC-NCI-AACR abstract PR10]. Mol Cancer Ther 2013; 12:PR10; doi:10.1158/1535-7163.TARG-13-PR10.
Zou HY, Engstrom LR, Li Q, et al. PF-06463922, a novel ROS1/ALK inhibitor, demonstrates subnanomolar potency against oncogenic ROS1 fusions and capable of blocking the resistant ROS1G2032R mutant in preclinical tumor models [EORTC-NCI-AACR abstract A277]. Mol Cancer Ther 2013; 12:A277; doi:10.1158/1535-7163.TARG-13-A277.
Zou HY, Engstrom LR, Li Q, et al. PF-06463922, a novel brain-penetrating small molecule inhibitor of ALK/ROS1 with potent activity against a broad spectrum of ALK resistant mutations in preclinical models in vitro and vivo [EORTC-NCI-AACR abstract C253]. Mol Cancer Ther 2013; 12:C253; doi:10.1158/1535-7163.TARG-13-C253.
Curtin JA, Fridlyand J, Kageshita T, et al. Distinct sets of genetic alterations in melanoma. N Engl J Med. 2005;353:2135–47.
Davies H, Bignell GR, Cox C, et al. Mutations of the BRAF gene in human cancer. Nature. 2002;417:949–54.
Jakob JA, Bassett Jr RL, Ng CS, et al. NRAS mutation status is an independent prognostic factor in metastatic melanoma. Cancer. 2012;118:4014–23.
Dummer R, Goldinger SM, Turtschi CP, et al. Vemurafenib in patients with BRAF(V600) mutation-positive melanoma with symptomatic brain metastases: final results of an open-label pilot study. Eur J Cancer. 2014;50:611–21.
Peuvrel L, Saint-Jean M, Quereux G, et al. Incidence and characteristics of melanoma brain metastases develo** during treatment with vemurafenib. J Neurooncol. 2014;120:147–54.
Durmus S, Sparidans RW, Wagenaar E, et al. Oral availability and brain penetration of the B-RAFV600E inhibitor vemurafenib can be enhanced by the P-GLYCOprotein (ABCB1) and breast cancer resistance protein (ABCG2) inhibitor elacridar. Mol Pharm. 2012;9:3236–45.
Mittapalli RK, Vaidhyanathan S, Sane R, et al. 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. 2012;342:33–40.
Narayana A, Mathew M, Tam M, et al. Vemurafenib and radiation therapy in melanoma brain metastases. J Neurooncol. 2013;113:411–6.
Long GV, Trefzer U, Davies MA, et al. 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. 2012;13:1087–95.
Mittapalli RK, Vaidhyanathan S, Dudek AZ, et al. 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. 2013;344:655–64.
Shi H, Hugo W, Kong X, et al. Acquired resistance and clonal evolution in melanoma during BRAF inhibitor therapy. Cancer Discov. 2014;4:80–93.
Solit DB, Rosen N. Resistance to BRAF inhibition in melanomas. N Engl J Med. 2011;364:772–4.
Van Allen EM, Wagle N, Sucker A, et al. The genetic landscape of clinical resistance to RAF inhibition in metastatic melanoma. Cancer Discov. 2014;4:94–109.
Cheng Y, Zhang G, Li G. Targeting MAPK pathway in melanoma therapy. Cancer Metastasis Rev. 2013;32:567–84.
Larkin J, Ascierto PA, Dreno B, et al. Combined vemurafenib and cobimetinib in BRAF-mutated melanoma. N Engl J Med. 2014;371:1867–76.
Robert C, Karaszewska B, Schachter J, et al. Improved overall survival in melanoma with combined dabrafenib and trametinib. N Engl J Med. 2015;372:30–9.
Choo EF, Ly J, Chan J, et al. Role of P-glycoprotein on the brain penetration and brain pharmacodynamic activity of the MEK inhibitor cobimetinib. Mol Pharm. 2014;11:4199–207.
Vaidhyanathan S, Mittapalli RK, Sarkaria JN, et al. Factors influencing the CNS distribution of a novel MEK-1/2 inhibitor: implications for combination therapy for melanoma brain metastases. Drug Metab Dispos. 2014;42:1292–300.
Jackman DM, Cioffredi LA, Jacobs L, et al. A phase I trial of high dose gefitinib for patients with leptomeningeal metastases from non-small cell lung cancer. Oncotarget. 2015;6:4527–36.
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Funding
Jan-Paul Bohn reports an unrestricted scientific grant from Mundipharma.
Conflicts of interest
Georg Pall reports personal fees from Roche, Boehringer Ingelheim, Novartis and Pfizer for advisory board participation and lectures. Jan-Paul Bohn, Guenther Stockhammer and Michael Steurer declare that they have no conflict of interest.
Rights and permissions
About this article
Cite this article
Bohn, JP., Pall, G., Stockhammer, G. et al. Targeted Therapies for the Treatment of Brain Metastases in Solid Tumors. Targ Oncol 11, 263–275 (2016). https://doi.org/10.1007/s11523-015-0414-5
Published:
Issue Date:
DOI: https://doi.org/10.1007/s11523-015-0414-5