Table 2.

Physicochemical and pharmacokinetic properties of new targeted therapies that may be useful for treatment of brain metastases in non–small cell lung cancer, breast cancer, and melanoma

Therapeutic Agent	MW, Daa	Log Pb	BCRP and P-gp		Median Inhibitory Concentration, ng/ml	CSF Concentration in Patients with BM, ng/ml	CSF Penetration Rate in Patients with BM, %c	Drug Efflux Transporters Restricted CNS Penetration, BCRP/P-gpd	Clinical Development Status
			Substrate	Inhibitor
Erlotinib	429.90	2.7	Yes183	Yes191	7.9 (EGFR-WT NSCLC)192	24−54 (N = 25)192–194	2.8−5.1192–194	Yes183 , 191	FDA approved for locally advanced or metastatic EGFR-mutant NSCLC and locally advanced, unresectable or metastatic pancreatic cancer, in combination with gemcitabine
Gefitinib	446.9	3.2	Yes195	Yes196	0.13 (EGFR-WT NSCLC)197	3.7−6.2 (N = 30)194 ,198	1.1−1.4194 ,198	Yes195	FDA approved for locally advanced or metastatic EGFR-mutant NSCLC
Afatinib	485.9	3.7	Yes199	Yes199	0.5200	0.5 (N = 1) 200	<1 200	Unknown	FDA approved for metastatic EGFR- mutant NSCLC
Crizotinib	450.3	1.8	Yes201	Yes198	108 (EML4-ALK E13;A20 translocation; NCI- H3122)202 ; 48 (H228)63	0.62 (N = 1) 202	0.26 202	Yes201	FDA approved for locally advanced or metastatic ALK-positive NSCLC
Ceritinib	558.1	5.0	Unknown	Unknown	11 (Ba/F3 NPM-ALK WT) 203 ; 2 (H228); 0.08 (ALK enzymatic assay)63	Unknown	Unknown	Yes204	FDA approved for patients with ALK- positive NSCLC who have progressed on or are intolerant to crizotinib
Alectinib	482.6	5.5	Noe,205	Unknown	0.92 (ALK cell-free assay)67	1.367	8667	No205	FDA breakthrough therapy designation for patients with ALK-positive NSCLC who have progressed on crizotinib
Nivolumab	146000	N/A	N/A	N/A		Not expected to cross intact BBB. Mechanism of action is in the periphery on T cells, which then cross the BBB			FDA approved for: (1) advanced squamous NSCLC after platinum- based chemotherapy; and (2) unresectable or metastatic melanoma and disease progression following ipilimumab and, if BRAF- V600-mutation positive, a BRAF inhibitor
Trastuzumab	145000	N/A	N/A	N/A	43.5 (p185HER2 extra-cellular domain)206	Not expected to cross intact BBB			FDA approved for HER2-overexpressing breast cancer, and HER2-overexpressing metastatic gastric or gastroesophageal junction adenocarcinoma
Lapatinib	580.5	5.1207	Yes207	Yes207	6 (EGFR and HER2)207	1.3−4.5 (N = 2)208	0.9−1.3208	Yes207	FDA approved as part of combination treatment for advanced or metastatic (with an anthracycline, a taxane, and trastuzumab) and postmenopausal (with letrozole) HER2- overexpressing breast cancer
Vemurafenib	489.9	5.1	Yes209 , 210	Yes210		470 (N = 6)211	0.98211	Yes209 , 212	FDA approved for unresectable or metastatic melanoma with BRAF- V600E mutation
Dabrafenib	615.7	5.4	Yes162 , 213	Unknown			Unknown	Yes162	FDA approved for unresectable or metastatic melanoma with BRAF- V600E mutation and in combination with trametinib for BRAF- V600E and BRAF-V600K mutations
Ipilimumab	148000	N/A	N/A	N/A	<148 (CTLA-4)214	Not expected to cross intact BBB. Mechanism of action is in the periphery on T cells, which then cross the BBB			FDA approved for unresectable or metastatic melanoma
Pembrolizumab	149000	N/A	N/A	N/A		Not expected to cross intact BBB. Mechanism of action is in the periphery on T cells, which then cross the BBB			FDA approved for unresectable or metastatic melanoma and disease progression following ipilimumab and, if BRAF-V600 mutation positive, a BRAF inhibitor

Abbreviations: ALK, anaplastic lymphoma kinase; BBB, blood-brain barrier; BCRP, breast cancer resistance protein; BM, brain metastases; BRAF, v-Raf murine sarcoma viral oncogene homolog B; CNS, central nervous system; CSF, cerebrospinal fluid; CTLA-4, cytotoxic T-lymphocyte antigen; EGFR, epidermal growth factor receptor; EML4, echinoderm microtubule associated protein like 4; FDA, U.S. Food and Drug Administration; HER2, human epidermal growth factor receptor 2; MW, molecular weight; N/A, not applicable; NCI, National Cancer Institute; NPM, nucleophosmin; NSCLC, non–small cell lung cancer; P-gp, P-glycoprotein; WT, wild type.

^aObtained from the PubChem Compound Database (http://www.ncbi.nlm.nih.gov/pccompound).

^bObtained from the Drugbank database (http://www.drugbank.ca/) and Chemspider database (http://www.chemspider.com).

^cAssessed using human blood and CSF samples.

^dBased on nonclinical studies using mouse models.

^eAlectinib was not transported by P-gp in cell transport assay, suggesting it is a poor or non-P-gp substrate.