Advertisement

Targeted Therapy for Brain Metastases in EGFR-Mutated and ALK-Rearranged Non-Small-Cell Lung Cancer

      Abstract

      Approximately half of all patients with non–small-cell lung cancer (NSCLC) develop brain metastases (BM) during the course of their disease, leading to significant challenges in treatment. Molecular targeted tyrosine kinase inhibitors have proven effective for patients with activating mutations in the epidermal growth factor receptor gene and chromosomal rearrangements involving the anaplastic lymphoma kinase gene. Despite their efficacy in systemic disease control, their effectiveness in patients with BM is not well established. In this article, we review recent data on the use of epidermal growth factor receptor and anaplastic lymphoma kinase tyrosine kinase inhibitors for treatment of patients with NSCLC and BM. These data highlight the potential for meaningful disease control within the central nervous system and the inherent challenges in treating patients with NSCLC and BM.

      Key Words

      Non–small-cell lung cancer (NSCLC) comprises 80% to 85% of lung cancers, and the majority of patients present with advanced disease.
      • Herbst RS
      • Heymach JV
      • Lippman SM
      Lung cancer.
      Surveillance, Epidemiology, and End Results (SEER) Program.
      Despite recent therapeutic advances, long-term prognosis remains poor, with an estimated overall 5-year survival rate less than 5% for patients with metastatic disease.
      Surveillance, Epidemiology, and End Results (SEER) Program.
      NSCLC is characterized by a high incidence of central nervous system (CNS) metastases, with 30% to 50% of patients with NSCLC developing brain metastases (BM).
      • Patchell RA
      The management of brain metastases.
      NCCN Clinical Practice Guidelines: Non–Small Cell Lung Cancer, Version 3.2014.
      Patients with BM experience significant morbidity and reduced quality of life, often with neurological dysfunction and cognitive impairment,
      • Patchell RA
      The management of brain metastases.
      NCCN Clinical Practice Guidelines: Non–Small Cell Lung Cancer, Version 3.2014.
      • Mehta M
      • Vogelbaum MA
      • Chang S
      • et al.
      Neoplasms of the central nervous system.
      • Cruz-Muñoz W
      • Kerbel RS
      Preclinical approaches to study the biology and treatment of brain metastases.
      and a poor prognosis, with a median survival of 3 to 6 months.
      • D’Antonio C
      • Passaro A
      • Gori B
      • et al.
      Bone and brain metastasis in lung cancer: recent advances in therapeutic strategies.
      • Patchell RA
      • Tibbs PA
      • Walsh JW
      • et al.
      A randomized trial of surgery in the treatment of single metastases to the brain.
      In the past decade, development of genotype-directed therapies for NSCLC has led to tumor response and progression-free survival (PFS) rates that are significantly higher than those associated with cytotoxic chemotherapy.
      • Mok TS
      • Wu YL
      • Thongprasert S
      • et al.
      Gefitinib or carboplatin-paclitaxel in pulmonary adenocarcinoma.
      • Shaw AT
      • Kim DW
      • Nakagawa K
      • et al.
      Crizotinib versus chemotherapy in advanced ALK-positive lung cancer.
      Several tyrosine kinase inhibitors (TKIs) are established as effective therapies for NSCLC, particularly in patients with activating mutations in the epidermal growth factor receptor (EGFR) gene and chromosomal rearrangements involving the anaplastic lymphoma kinase (ALK) gene.
      • Gori B
      • Ricciardi S
      • del Signore E
      • Fulvi A
      • de Marinis F
      Oral tyrosine kinase inhibitors in the first-line treatment of advanced non-small cell lung cancer.
      • Roengvoraphoj M
      • Tsongalis GJ
      • Dragnev KH
      • Rigas JR
      Epidermal growth factor receptor tyrosine kinase inhibitors as initial therapy for non-small cell lung cancer: focus on epidermal growth factor receptor mutation testing and mutation-positive patients.
      • Shaw AT
      • Engelman JA
      ALK in lung cancer: past, present, and future.
      • Iwama E
      • Okamoto I
      • Harada T
      • Takayama K
      • Nakanishi Y
      Development of anaplastic lymphoma kinase (ALK) inhibitors and molecular diagnosis in ALK rearrangement-positive lung cancer.
      Although the systemic efficacy of targeted agents is established, the intracranial efficacy of targeted therapies in patients with CNS disease is not as well characterized. This review summarizes data on the use of EGFR and ALK TKIs for the treatment of patients with NSCLC and BM and discusses novel strategies, including combination regimens with radiation therapy (RT) and other novel agents.

      STANDARD THERAPY FOR CNS METASTASIS IN NSCLC

      The CNS is considered a pharmacological sanctuary site for metastases, because the blood–brain barrier (BBB) restricts transit of chemotherapeutic agents into the brain parenchyma. Furthermore, many chemotherapeutic agents are substrates for drug efflux transporters, such as P-glycoprotein (P-gp), which is robustly expressed on the BBB, that further reduce intracellular drug levels and limit antitumor activity in the CNS.
      • Deeken JF
      • Löscher W
      The blood-brain barrier and cancer: transporters, treatment, and Trojan horses.
      Currently, surgical resection and radiotherapy (whole-brain radiotherapy [WBRT], stereotactic radiosurgery [SRS], and stereotactic radiotherapy) are the most common treatments used in the management of BM. Although intra-cerebrospinal fluid (CSF) therapy (i.e., intrathecal chemotherapy) can be used for patients with leptomeningeal disease, prognosis in this patient population is poor even with treatment, with a median survival of 2 to 3 months.
      • Chamberlain M
      • Soffietti R
      • Raizer J
      • et al.
      Leptomeningeal metastasis: a response assessment in neuro-oncology critical review of endpoints and response criteria of published randomized clinical trials.

      TARGETED THERAPIES FOR CNS METASTASES IN NSCLC

      Use of molecular targeted therapies, particularly oral TKIs, has significantly improved the outcomes of NSCLC with identified molecular drivers. An analysis of clinical outcomes in patients enrolled in the Lung Cancer Mutation Consortium demonstrated that patients in whom a driver mutation was identified and who received corresponding targeted therapy exhibited improved survival compared with those whose tumor did not harbor a driver mutation and those with a driver mutation who did not receive targeted therapy.
      • Kris MG
      • Johnson BE
      • Berry LD
      • et al.
      Using multiplexed assays of oncogenic drivers in lung cancers to select targeted drugs.
      However, favorable outcomes might have been limited by the development of CNS disease, likely due to poor CSF penetration of the systemic therapy.
      • Camidge DR
      • Bang YJ
      • Kwak EL
      • et al.
      Activity and safety of crizotinib in patients with ALK-positive non-small-cell lung cancer: updated results from a phase 1 study.
      • Costa DB
      • Kobayashi S
      • Pandya SS
      • et al.
      CSF concentration of the anaplastic lymphoma kinase inhibitor crizotinib.
      Given the limited efficacy of standard chemotherapy regimens in CNS disease, there is a need to develop more effective approaches, especially for those whose tumors harbor actionable mutations and in whom prolonged systemic disease control is possible. Efforts are now aimed toward developing such therapies, e.g., EGFR and ALK TKIs, for treatment of NSCLC-related CNS metastases in patients whose tumors express the corresponding molecular alterations.

      The BBB and Targeted Therapy for NSCLC and BM

      The structure of the BBB is characterized by both tight and adherens junctions between endothelial cells that regulate the transit of nutrients, ions, and cells into the brain (Fig. 1). Molecules cross the BBB either by passive diffusion (usually restricted to small [molecular weight <400 Da], nonpolar, and lipophilic compounds) or active transport (for polar compounds).
      • Pardridge WM
      The blood-brain barrier and neurotherapeutics.
      • Löscher W
      • Potschka H
      Drug resistance in brain diseases and the role of drug efflux transporters.
      • Löscher W
      • Potschka H
      Role of drug efflux transporters in the brain for drug disposition and treatment of brain diseases.
      The very low permeability of the brain microvascular endothelium restricts access of systemically administered agents into the CNS and brain lesions.
      Figure thumbnail gr1
      FIGURE 1Schematic of the blood-brain barrier. Reprinted with permission from Macmillan Publishers Ltd.
      • Abbott NJ
      • Rönnbäck L
      • Hansson E
      Astrocyte-endothelial interactions at the blood-brain barrier.
      Although tumor growth and metastases can disrupt the BBB, the molecular size restrictions limit large-molecule biologics, including monoclonal antibodies, from crossing the BBB.
      • Pardridge WM
      The blood-brain barrier and neurotherapeutics.
      Similarly, TKIs generally have poor BBB penetration; for instance, imatinib CSF level has been reported to be only 3% of plasma levels in patients with chronic myeloid leukemia.
      • Kast RE
      • Focosi D
      Three paths to better tyrosine kinase inhibition behind the blood-brain barrier in treating chronic myelogenous leukemia and glioblastoma with imatinib.
      Based on the pharmacokinetic (PK) data and the reduced efficacy of these agents in BM (discussed in the EGFR Inhibitors and ALK Inhibitors sections below), TKIs seem to have limited access to CNS metastases compared with extracranial metastases. A pharmacodynamic study using [
      • Gori B
      • Ricciardi S
      • del Signore E
      • Fulvi A
      • de Marinis F
      Oral tyrosine kinase inhibitors in the first-line treatment of advanced non-small cell lung cancer.
      C]-erlotinib positron emission tomography–computed tomography in a patient with NSCLC and multiple BM treated with erlotinib suggested that erlotinib may accumulate in some BM.
      • 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.
      However, there is evidence that drug efflux transporters, such as P-gp and breast cancer resistance protein, may limit BBB penetration of erlotinib and reduce its efficacy in the brain.
      • Elmeliegy MA
      • Carcaboso AM
      • Tagen M
      • Bai F
      • Stewart CF
      Role of ATP-binding cassette and solute carrier transporters in erlotinib CNS penetration and intracellular accumulation.
      • de Vries NA
      • Buckle T
      • Zhao J
      • Beijnen JH
      • Schellens JH
      • van Tellingen O
      Restricted brain penetration of the tyrosine kinase inhibitor erlotinib due to the drug transporters P-gp and BCRP.
      Consequently, modulating drug efflux is one potential theoretical approach to increase TKI levels in BM, and there is evidence from preclinical studies suggesting that this may be an effective approach.
      • Chuan Tang S
      • Nguyen LN
      • Sparidans RW
      • Wagenaar E
      • Beijnen JH
      • Schinkel AH
      Increased oral availability and brain accumulation of the ALK inhibitor crizotinib by coadministration of the P-glycoprotein (ABCB1) and breast cancer resistance protein (ABCG2) inhibitor elacridar.

      EGFR Inhibitors

      CNS metastasis in NSCLC with activating EGFR mutations.

      EGFR TKIs, such as erlotinib, gefitinib, and afatinib, have been established as effective first-line therapies in NSCLC harboring an activating EGFR mutation based on the several randomized trials.
      • Mok TS
      • Wu YL
      • Thongprasert S
      • et al.
      Gefitinib or carboplatin-paclitaxel in pulmonary adenocarcinoma.
      • Rosell R
      • Carcereny E
      • Gervais R
      • et al.
      Spanish Lung Cancer Group in collaboration with Groupe Français de Pneumo-Cancérologie and Associazione Italiana Oncologia Toracica
      Erlotinib versus standard chemotherapy as first-line treatment for European patients with advanced EGFR mutation-positive non-small-cell lung cancer (EURTAC): a multicentre, open-label, randomised phase 3 trial.
      • Sequist LV
      • Yang JC
      • Yamamoto N
      • et al.
      Phase III study of afatinib or cisplatin plus pemetrexed in patients with metastatic lung adenocarcinoma with EGFR mutations.
      Their efficacy in systemic disease is well recognized, with response rates ranging from 70% to 80% and a median PFS rate of approximately 12 months, as well as significant and clinically relevant improvements in PFS and quality of life compared with chemotherapy. However, efficacy in CNS metastatic disease is less well established. Although CNS is a common site of relapse in patients receiving EGFR TKIs,
      • Weickhardt AJ
      • Scheier B
      • Burke JM
      • et al.
      Local ablative therapy of oligoprogressive disease prolongs disease control by tyrosine kinase inhibitors in oncogene-addicted non-small-cell lung cancer.
      data from retrospective studies indicate lower rates of CNS progression in patients with EGFR NSCLC who receive first-line TKIs than in those who receive chemotherapy, with a 12-month risk of CNS progression of 6% in the TKI group compared with 19% in the chemotherapy group.
      • 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.
      Data from retrospective studies suggest that patients with mutated EGFR NSCLC and BM may have better outcomes than patients whose tumor is EGFR wild type. Longer survival has been reported for these patients, possibly due to higher intracranial response rates to radiation and intracranial activity of EGFR TKIs (Table 1). Studies show that treatment with EGFR TKIs, such as gefitinib and erlotinib, can result in intracranial response in patients with EGFR mutation–positive NSCLC. A retrospective analysis of patients who were previously treated with erlotinib (n = 69) reported a time to progression within the brain of 11.7 months in patients with EGFR mutations compared with 5.8 months in those whose tumors were either EGFR wild type or unassessed, despite the fact that only 16% of patients with EGFR mutations had received WBRT versus 85% of those in the control group.
      • Porta R
      • Sánchez-Torres JM
      • Paz-Ares L
      • et al.
      Brain metastases from lung cancer responding to erlotinib: the importance of EGFR mutation.
      This and other similar retrospective studies (Table 2) indicate that TKI therapy can result in clinically meaningful intracranial responses in some patients. Similarly, a prospective single-arm trial evaluated the role of second-line erlotinib in Asian patients (n = 48) with metastatic NSCLC and asymptomatic BM. In this patient population, 17% were known to be EGFR mutation positive, 31% EGFR wild type, and 52% of unknown status. Intracranial PFS was 10.1 months, and overall PFS was 9.7 months in the overall population. Among patients with EGFR mutations, overall PFS was 15.2 months, which was significantly longer than the 4.4 months in patients with EGFR wild-type tumors (p = 0.02).
      • Wu YL
      • Zhou C
      • Cheng Y
      • et al.
      Erlotinib as second-line treatment in patients with advanced non-small-cell lung cancer and asymptomatic brain metastases: a phase II study (CTONG-0803).
      TABLE 1Retrospective Studies Evaluating Outcomes by EGFR Mutation Status in Patients with NSCLC and Brain Metastases
      Efficacy Outcomes (EGFR Mutant vs. EGFR WT)
      StudyNo. of Patients (EGFR Mutant/WT)Prior CNS-Directed TherapyPatients Receiving EGFR TKI, EGFR Mutant/WTObjective Radiographic CNS ResponseMedian Time to CNS Progression (mo)Median Overall Survival (mo)Cause of Death
      Eichler et al.
      • Eichler AF
      • Kahle KT
      • Wang DL
      • et al.
      EGFR mutation status and survival after diagnosis of brain metastasis in non-small cell lung cancer.
      93 (41/52)83% WBRT
      Either alone (53%) or in combination with resection (22%) or SRS (8%).
      78%/19%
      Erlotinib or gefitinib received after diagnosis of brain metastases.
      Not evaluated by EGFR status12.4 vs. 8.4 (p = 0.39)14.5 vs. 7.6
      From time of diagnosis of brain metastases.
      (p = 0.09)
      62 deaths (7 CNS, 39 systemic,
      Includes 54% (22/41) of patients with EGFR mutations and 33% (17/52) of patients with WT EGFR.
      and 16 both CNS and systemic)
      Lee et al.
      • Lee HL
      • Chung TS
      • Ting LL
      • et al.
      EGFR mutations are associated with favorable intracranial response and progression-free survival following brain irradiation in non-small cell lung cancer patients with brain metastases.
      43 (30/13)100% WBRT50%/31%
      Erlotinib or gefitinib concurrent with WBRT
      80% vs. 46% (p = 0.037)21 vs. 12
      Intracranial radiographic progression-free survival.
      (p = 0.009)
      15 vs. 11 (p = 0.049)33 deaths (3 CNS, 22 systemic, and 8 other causes)
      CNS, central nervous system; EGFR, epidermal growth factor receptor; NSCLC, non-small-cell lung cancer; TKI, tyrosine kinase inhibitor; SRS, stereotactic radiosurgery; WBRT, whole-brain radiotherapy; WT, wild type.
      a Either alone (53%) or in combination with resection (22%) or SRS (8%).
      b Erlotinib or gefitinib received after diagnosis of brain metastases.
      c From time of diagnosis of brain metastases.
      d Includes 54% (22/41) of patients with EGFR mutations and 33% (17/52) of patients with WT EGFR.
      e Erlotinib or gefitinib concurrent with WBRT
      f Intracranial radiographic progression-free survival.
      TABLE 2Retrospective Studies of EGFR TKIs in NSCLC Patients with EGFR Mutations and Brain Metastases
      StudyNo. of Patients with EGFR MutationPrior CNS-Directed TherapyBest Overall ResponseProgression-Free SurvivalOverall Survival
      Heon et al.
      • 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.
      155 (101 EGFR TKI
      Eleven patients received gefitinib and 90 patients received erlotinib as a first-line EGFR TKI.
      and 54 Chemo)
      89% WBRT
      For patients with brain metastases at the time of diagnosis of advanced NSCLC (n = 24 in the EGFR TKI group and n = 12 in the chemo group). A small number of these patients received WBRT in combination with surgical resection.
      Not evaluated
      • Disease progression (EGFR TKI vs. chemo)
      • Rate of CNS progression: 33% vs. 48%
      • Time to CNS progression (mo): 56.0 vs. 31.6 (p = 0.010)
      • Cumulative risk of CNS progression at 1 and 2 yr:
      • 1 yr: 6% vs. 19%
      • 2 yr: 21% vs. 32% p = 0.026
      EGFR TKI 31.0 mo vs. chemo 29.8 mo (p = 0.131)
      Park et al.
      • 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.
      28
      Twenty-two patients received gefitinib and six patients received erlotinib as first-line EGFR TKI.
      NonePR: 83% SD: 11%6.6 mo15.9 mo
      CNS, central nervous system; chemo, chemotherapy; EGFR, epidermal growth factor receptor; NSCLC, non-small-cell lung cancer; PR, partial response; SD, stable disease; TKI, tyrosine kinase inhibitor; WBRT, whole-brain radiotherapy.
      a Eleven patients received gefitinib and 90 patients received erlotinib as a first-line EGFR TKI.
      b For patients with brain metastases at the time of diagnosis of advanced NSCLC (n = 24 in the EGFR TKI group and n = 12 in the chemo group). A small number of these patients received WBRT in combination with surgical resection.
      c Twenty-two patients received gefitinib and six patients received erlotinib as first-line EGFR TKI.
      Studies report that EGFR TKIs achieve therapeutic CSF concentrations, which accounts in part for intracranial responses (Table 3). Togashi et al.
      • 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.
      measured CSF concentrations of erlotinib and its active metabolite, OSI-420, in patients with NSCLC and BM. Mean CSF penetration rates of erlotinib and OSI-420 were 5.1% and 5.8% of total plasma concentration, respectively, which exceeds median half-maximal inhibitory concentration (IC50) values for EGFR inhibition. Additional studies have reported mean CSF penetration rates of 2.8% to 4.4% for erlotinib, with slightly lower rates for gefitinib (1.1%–1.3%). Preclinical studies have also shown that EGFR TKIs are both substrates and inhibitors of drug efflux transporters that limit CNS penetration (Table 3). These data and earlier PK studies
      • Broniscer A
      • Panetta JC
      • O’Shaughnessy M
      • et al.
      Plasma and cerebrospinal fluid pharmacokinetics of erlotinib and its active metabolite OSI-420.
      • Meany HJ
      • Fox E
      • McCully C
      • Tucker C
      • Balis FM
      The plasma and cerebrospinal fluid pharmacokinetics of erlotinib and its active metabolite (OSI-420) after intravenous administration of erlotinib in non-human primates.
      support the concept that erlotinib achieves clinically adequate concentrations in the CSF, although significantly lower compared with plasma concentration.
      TABLE 3CNS Penetration of Targeted Therapies for Patients with NSCLC and Brain Metastases
      Interactions with Efflux Transporters (BCRP and P-gp)CNS Penetration
      AgentMolecular Formula/Weight (Da)
      Obtained from the PubChem Compound Database (http://www.ncbi.nlm.nih.gov/pccompound).
      SubstrateInhibitorCSF Penetration Rate (%)
      Assessed using blood and CSF samples from patients with NSCLC ; mean ± standard deviation.
      Restricted Penetration Because of Drug Efflux Transporters (BCRP/P-gp)
      Based on the nonclinical studies using mouse models.
      ErlotinibC22H23N3O4/429.90Yes
      • Marchetti S
      • de Vries NA
      • Buckle T
      • et al.
      Effect of the ATP-binding cassette drug transporters ABCB1, ABCG2, and ABCC2 on erlotinib hydrochloride (Tarceva) disposition in in vitro and in vivo pharmacokinetic studies employing Bcrp1-/-/Mdr1a/1b-/- (triple-knockout) and wild-type mice.
      Yes
      • Shi Z
      • Peng XX
      • Kim IW
      • et al.
      Erlotinib (Tarceva, OSI-774) antagonizes ATP-binding cassette subfamily B member 1 and ATP-binding cassette subfamily G member 2-mediated drug resistance.
      Low/moderate 5.1 ± 1.9 (n = 4)
      • 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.
      2.8 ± 0.5 (n = 9)
      • Togashi Y
      • Masago K
      • Masuda S
      • et al.
      Cerebrospinal fluid concentration of gefitinib and erlotinib in patients with non-small cell lung cancer.
      4.4 ± 3.2 (n = 6)
      • Deng Y
      • Feng W
      • Wu J
      • et al.
      The concentration of erlotinib in the cerebrospinal fluid of patients with brain metastasis from non-small-cell lung cancer.
      Yes
      • Elmeliegy MA
      • Carcaboso AM
      • Tagen M
      • Bai F
      • Stewart CF
      Role of ATP-binding cassette and solute carrier transporters in erlotinib CNS penetration and intracellular accumulation.
      • de Vries NA
      • Buckle T
      • Zhao J
      • Beijnen JH
      • Schellens JH
      • van Tellingen O
      Restricted brain penetration of the tyrosine kinase inhibitor erlotinib due to the drug transporters P-gp and BCRP.
      GefitinibC22H24ClFN4O3/446.9Yes
      • Agarwal S
      • Sane R
      • Gallardo JL
      • Ohlfest JR
      • Elmquist WF
      Distribution of gefitinib to the brain is limited by P-glycoprotein (ABCB1) and breast cancer resistance protein (ABCG2)-mediated active efflux.
      Yes
      • Leggas M
      • Panetta JC
      • Zhuang Y
      • et al.
      Gefitinib modulates the function of multiple ATP-binding cassette transporters in vivo.
      Yes
      • Agarwal S
      • Sane R
      • Gallardo JL
      • Ohlfest JR
      • Elmquist WF
      Distribution of gefitinib to the brain is limited by P-glycoprotein (ABCB1) and breast cancer resistance protein (ABCG2)-mediated active efflux.
      AfatinibC24H25ClFN5O3/485.9Yes
      • Wind S
      • Giessmann T
      • Jungnik A
      • et al.
      Pharmacokinetic drug interactions of afatinib with rifampicin and ritonavir.
      Yes
      • Wind S
      • Giessmann T
      • Jungnik A
      • et al.
      Pharmacokinetic drug interactions of afatinib with rifampicin and ritonavir.
      UnknownUnknown
      CrizotinibC21H22Cl2FN5O/450.3Yes
      • Chuan Tang S
      • Nguyen LN
      • Sparidans RW
      • Wagenaar E
      • Beijnen JH
      • Schinkel AH
      Increased oral availability and brain accumulation of the ALK inhibitor crizotinib by coadministration of the P-glycoprotein (ABCB1) and breast cancer resistance protein (ABCG2) inhibitor elacridar.
      Yes
      • Zhou WJ
      • Zhang X
      • Cheng C
      • et al.
      Crizotinib (PF-02341066) reverses multidrug resistance in cancer cells by inhibiting the function of P-glycoprotein.
      Yes
      • Chuan Tang S
      • Nguyen LN
      • Sparidans RW
      • Wagenaar E
      • Beijnen JH
      • Schinkel AH
      Increased oral availability and brain accumulation of the ALK inhibitor crizotinib by coadministration of the P-glycoprotein (ABCB1) and breast cancer resistance protein (ABCG2) inhibitor elacridar.
      CeritinibC28H36ClN5O3S/558.1UnknownUnknown15
      ,
      Blood-to-brain exposure (AUCinf) ratio in rats.
      Unknown
      AlectinibC30H34N4O2/482.6No
      • Kodama T
      • Hasegawa M
      • Takanashi K
      • Sakurai Y
      • Kondoh O
      • Sakamoto H
      Antitumor activity of the selective ALK inhibitor alectinib in models of intracranial metastases.
      ,
      Alectinib was not transported by P-gp in cell transport assay, suggesting it as a poor or non-P-gp substrate.
      Unknown8752Unknown
      AUCinf, area under the plasma concentration-time curve from time 0 to infinity; BCRP, breast cancer resistance protein; CNS, central nervous system; CSF, cerebrospinal fluid; NSCLC, non-small-cell lung cancer; P-gp, P-glycoprotein.
      a Obtained from the PubChem Compound Database (http://www.ncbi.nlm.nih.gov/pccompound).
      b Assessed using blood and CSF samples from patients with NSCLC ; mean ± standard deviation.
      c Based on the nonclinical studies using mouse models.
      d Blood-to-brain exposure (AUCinf) ratio in rats.
      e Alectinib was not transported by P-gp in cell transport assay, suggesting it as a poor or non-P-gp substrate.
      Given the limited CNS penetration of TKIs, some reports suggest that increasing the dose of the EGFR inhibitor may be an effective strategy for the treatment of CNS disease.
      • 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.
      • Katayama T
      • Shimizu J
      • Suda K
      • et al.
      Efficacy of erlotinib for brain and leptomeningeal metastases in patients with lung adenocarcinoma who showed initial good response to gefitinib.
      Previous studies have shown a linear correlation between plasma and CSF concentration of EGFR TKIs such as erlotinib, suggesting that a higher dose may lead to higher CSF concentration and thereby improve CNS disease response.
      • Togashi Y
      • Masago K
      • Fukudo M
      • et al.
      Efficacy of increased-dose erlotinib for central nervous system metastases in non-small cell lung cancer patients with epidermal growth factor receptor mutation.
      A case report describes a patient with EGFR deletion 19 mutation who experienced CNS tumor response using high-dose gefitinib that achieved a therapeutic CSF concentration, suggesting that this may be a viable strategy in this patient population.
      • 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.
      However, a study of 10 patients who received pulsed-dose erlotinib 1000 to 1500 mg once weekly for CNS progression showed a modest response rate of 10%, with a median CNS PFS rate of 1.7 months.
      • Jackman DM
      • Mach SL
      • Heng JC
      Pulsed dosing of erlotinib for central nervous system progression in EGFR-mutant non-small cell lung cancer.
      The benefit and potential toxicity of this strategy have not yet been evaluated in a prospective clinical trial.
      There are other EGFR TKIs in development, and their efficacy in CNS disease is unknown at this time. Afatinib and dacomitinib are second-generation EGFR TKIs that cause irreversible inhibition of both EGFR and human EGFR 2 and 4 (HER2 and HER4, respectively). Afatinib is currently approved for first-line therapy in patients with EGFR mutation–positive NSCLC. Its efficacy in CNS metastasis is unclear, and although there is a report of CNS response in a patient receiving a high afatinib dose,
      • Yap TA
      • Vidal L
      • Adam J
      • et al.
      Phase I trial of the irreversible EGFR and HER2 kinase inhibitor BIBW 2992 in patients with advanced solid tumors.
      there is also a report of lack of CNS response.
      • Bordi P
      • Tiseo M
      • Bortesi B
      • Naldi N
      • Buti S
      • Ardizzoni A
      Overcoming T790M-driven acquired resistance to EGFR-TKIs in NSCLC with afatinib: a case report.
      A recent case report documented a partial response (PR) in the brain after dual treatment with afatinib and cetuximab in a patient with NSCLC who developed leptomeningeal carcinomatosis,
      • Lin CH
      • Lin MT
      • Kuo YW
      • Ho CC
      Afatinib combined with cetuximab for lung adenocarcinoma with leptomeningeal carcinomatosis.
      but this strategy should be evaluated in a prospective trial before routine clinical use as it is associated with significant cutaneous toxicity.
      • Janjigian YY
      • Smit EF
      • Groen HJ
      • et al.
      Dual inhibition of EGFR with afatinib and cetuximab in kinase inhibitor-resistant EGFR-mutant lung cancer with and without T790M mutations.
      Dacomitinib is not yet approved but has shown activity as a first-line treatment in EGFR mutation–positive patients with NSCLC, with an overall response rate (ORR) of 76% and median PFS of 18.2 months in a phase 2 study that enrolled 45 patients with activating EGFR mutations.
      • Jänne PA
      • Ou SH
      • Kim DW
      • et al.
      Dacomitinib as first-line treatment in patients with clinically or molecularly selected advanced non-small-cell lung cancer: a multicentre, open-label, phase 2 trial.
      An ongoing phase 3 trial is comparing dacomitinib with gefitinib as initial therapy in EGFR mutation–positive patients with NSCLC (NCT01774721); however, this study excludes patients with a history of brain or leptomeningeal metastases (LM). A phase 2 study is evaluating the efficacy and safety of dacomitinib in cancer patients with progressive BM, including patients with primary lung cancer (NCT02047747). Although this study is not specifically aimed toward EGFR mutation–positive NSCLC, it will allow further understanding of intracranial activity and CNS PK of this agent.
      There are emerging third-generation EGFR TKIs that show promising preliminary efficacy results in patients with acquired EGFR-resistance mutation such as T790M. Response rates of 58% and 64% have been reported with CO-1686 and AZD9291, respectively, in patients who harbor T790M mutation.
      • Jänne PA
      • Ramalingam SS
      • Chih-Hsin Yang J
      • et al.
      Clinical activity of the mutant-selective EGFR inhibitor AZD9291 in patients (pts) with EGFR inhibitor–resistant non-small cell lung cancer (NSCLC).
      • Sequist LV
      • Soria J-C
      • Gadgeel SM
      • et al.
      First-in-human evaluation of CO-1686, an irreversible, highly selective tyrosine kinase inhibitor of mutations of EGFR (activating and T790M).
      A case of CNS response with CO-1686 has been reported
      • Sequist LV
      • Soria J-C
      • Gadgeel SM
      • et al.
      First-in-human evaluation of CO-1686, an irreversible, highly selective tyrosine kinase inhibitor of mutations of EGFR (activating and T790M).
      ; however, currently, the overall CNS response rate with this agent is unknown. Preclinical data indicate that AZD-9291 achieves significant exposure in the brain and is active against BM.
      • Kim D
      • Yang J
      • Cross D
      • et al.
      Preclinical evidence and clinical cases of AZD9291 activity in EGFR-mutant non-small cell lung cancer (NSCLC) brain metastases (BM).
      In an ongoing phase 1 study, response in BM with AZD-9291 has been reported in some patients with EGFR mutation–positive NSCLC.
      • Kim D
      • Yang J
      • Cross D
      • et al.
      Preclinical evidence and clinical cases of AZD9291 activity in EGFR-mutant non-small cell lung cancer (NSCLC) brain metastases (BM).
      HM61713, another third-generation EGFR TKI, has shown activity in patients with EGFR mutation-positive NSCLC who had T790M mutation at baseline, although CNS activity with HM61713 has not yet been reported.
      • Kim D-W
      • Lee DH
      • Kang JH
      • et al.
      Clinical activity and safety of HM61713, an EGFR-mutant selective inhibitor, in advanced non-small cell lung cancer (NSCLC) patients (pts) with EGFR mutations who had received EGFR tyrosine kinase inhibitors (TKIs).

      EGFR inhibitors and RT

      One important question is whether EGFR inhibitors could be used concurrently with RT to improve intracranial efficacy. The role of EGFR inhibitors in CNS disease has been evaluated in combination with radiation because preclinical studies have shown that EGFR overexpression is associated with radioresistance in murine models,
      • Akimoto T
      • Hunter NR
      • Buchmiller L
      • Mason K
      • Ang KK
      • Milas L
      Inverse relationship between epidermal growth factor receptor expression and radiocurability of murine carcinomas.
      and EGFR blockade has shown to increase radiosensitivity in in vitro studies.
      • Chinnaiyan P
      • Huang S
      • Vallabhaneni G
      • et al.
      Mechanisms of enhanced radiation response following epidermal growth factor receptor signaling inhibition by erlotinib (Tarceva).
      A retrospective analysis of 63 patients with BM from lung adenocarcinoma (46 with EGFR mutations and 17 with wild-type EGFR) who were treated with WBRT (n = 45) or concurrently with an EGFR TKI (n = 18) found that EGFR TKIs and EGFR mutation were independently associated with response to WBRT at 1 month after radiation, suggesting that EGFR TKIs increased sensitivity to WBRT.
      • Gow CH
      • Chien CR
      • Chang YL
      • et al.
      Radiotherapy in lung adenocarcinoma with brain metastases: effects of activating epidermal growth factor receptor mutations on clinical response.
      In this study, patients who received WBRT with an EGFR TKI had a better response rate (67%) than those who received only WBRT (39%). This hypothesis was examined in a phase 2 single-arm trial (n = 40) that evaluated the combination of WBRT and erlotinib in NSCLC patients with BM regardless of EGFR mutation status. This study reported an ORR of 86% and an overall median survival of 11.8 months, which was significantly higher than survival reported in the literature.
      • 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.
      Among patients with known EGFR mutational status (n = 17), patients with an EGFR-activating mutation (n = 9) exhibited significantly higher ORR (89% versus 63%) and survival (19.1 versus 9.3 months) than patients with no EGFR mutations (n = 8). The combination therapy was well tolerated, and rash was the most common toxicity. There were no grade 4 or 5 toxicities, and there was no evidence of worse erlotinib-induced rash within the radiation port. In contrast to the earlier study, in a Radiation Therapy Oncology Group phase 3 trial of WBRT plus SRS with either temozolomide or erlotinib in unselected NSCLC patients with one to three BM, the addition of temozolomide or erlotinib seemed to have a deleterious effect on time to progression and survival, although this was not statistically significant.
      • Sperduto PW
      • Wang M
      • Robins HI
      • et al.
      A phase 3 trial of whole brain radiation therapy and stereotactic radiosurgery alone versus WBRT and SRS with temozolomide or erlotinib for non-small cell lung cancer and 1 to 3 brain metastases: Radiation Therapy Oncology Group 0320.
      Similarly, no significant benefit was observed with the addition of gefitinib to WBRT in a similar phase 2 randomized trial in unselected patients with BM by the Swiss Group for Clinical Cancer Research.
      • Pesce GA
      • Klingbiel D
      • Ribi K
      • et al.
      Outcome, quality of life and cognitive function of patients with brain metastases from non-small cell lung cancer treated with whole brain radiotherapy combined with gefitinib or temozolomide. A randomised phase II trial of the Swiss Group for Clinical Cancer Research (SAKK 70/03).
      The aforementioned studies indicate that the benefit and toxicity of EGFR TKIs in combination with WBRT are unclear at this time and need additional definitive studies, and until these studies are completed, it is not recommended that TKIs be combined with RT outside of clinical trials. Currently, there is an ongoing randomized phase 3 trial of WBRT with or without erlotinib (NCT01887795) that may clarify the role of erlotinib in combination with WBRT (Table 4).
      TABLE 4Ongoing Phase 2–3 Trials of Targeted Therapies for the Treatment of NSCLC Brain Metastases
      AgentNCT IdentifierPhaseDescriptionStatus
      Studies of EGFR TKIs in patients with NSCLC brain metastases
      ErlotinibNCT018877953WBRT vs. erlotinib with concurrent WBRT as first-line treatment in patients with multiple brain metastasesRecruiting
      NCT017633852Erlotinib with concurrent brain radiotherapy and secondary brain radiotherapy after recurrence with erlotinibRecruiting
      NCT008719232Erlotinib with concurrent WBRT in patients with brain metastasesOngoing, not recruiting
      GefitinibNCT019514692Gefitinib ± pemetrexed/cisplatin in patients with brain metastasesRecruiting
      Studies of ALK TKIs in ALK-positive NSCLC that include patients with asymptomatic/stable brain metastases
      CrizotinibNCT020758403Alectinib vs. crizotinib in treatment-naive patientsNot yet recruiting
      NCT016390013Crizotinib vs. chemo in previously untreated East Asian patientsRecruiting
      NCT021349122Pemetrexed ± crizotinib in patients who have progressed after crizotinibNot yet recruiting
      NCT009324512Crizotinib in ALK-positive NSCLCRecruiting
      CeritinibNCT018281123Ceritinib vs. chemo in patients previously treated with chemo and crizotinibRecruiting
      NCT018280993Ceritinib vs. chemo in previously untreated patientsRecruiting
      NCT016850602Ceritinib in patients previously treated with chemo and crizotinibOngoing, not recruiting
      NCT016851382Ceritinib in crizotinib-naive patientsOngoing, not recruiting
      NCT020408701/2Ceritinib in Chinese patients previously treated with crizotinibRecruiting
      AlectinibNCT018718051/2Alectinib in patients previously treated with chemo and crizotinibRecruiting
      NCT018011111/2Alectinib in patients who have failed crizotinibRecruiting
      AP26113NCT020945732AP26113 in patients previously treated with crizotinibRecruiting
      ALK, anaplastic lymphoma kinase; chemo, chemotherapy; EGFR, epidermal growth factor receptor; NCT, National Clinical Trial; NSCLC, non-small-cell lung cancer; TKI, tyrosine kinase inhibitor; WBRT, whole-brain radiotherapy.
      The studies described earlier suggest that EGFR TKI monotherapy may be a reasonable strategy for EGFR mutation–positive patients with asymptomatic CNS disease who are TKI naive. Some studies suggest that erlotinib may have better CSF penetration than gefitinib
      • Togashi Y
      • Masago K
      • Masuda S
      • et al.
      Cerebrospinal fluid concentration of gefitinib and erlotinib in patients with non-small cell lung cancer.
      ; thus, erlotinib may be preferred over gefitinib if TKI monotherapy is used upfront for asymptomatic patients with BM. The role of concurrent EGFR TKI and WBRT has not been established at this time, and more studies are needed to better delineate the benefit and safety of this strategy. As development of third-generation EGFR TKIs progresses, patients with EGFR mutation–positive NSCLC will have increasing treatment options that will result in prolonged systemic disease control. Studies
      evaluating the combination of second- and third-generation EGFR inhibitors with brain radiotherapy (SRS or WBRT) are needed to fully explore their potential in the treatment of patients with NSCLC and BM. Therefore, treatment strategies with effective CNS disease control will be crucial in improving the overall outcomes in this patient population.

      ALK Inhibitors

      CNS metastasis in ALK-positive NSCLC.

      The ALK gene encodes a receptor tyrosine kinase that is activated in a subset of patients with NSCLC and other tumors, and ALK inhibitors such as crizotinib have shown to be effective in tumor response and disease control.
      • Shaw AT
      • Kim DW
      • Nakagawa K
      • et al.
      Crizotinib versus chemotherapy in advanced ALK-positive lung cancer.
      • Shaw AT
      • Yeap BY
      • Mino-Kenudson M
      • et al.
      Clinical features and outcome of patients with non-small-cell lung cancer who harbor EML4-ALK.
      • Kim YH
      • Nagai H
      • Ozasa H
      • Sakamori Y
      • Mishima M
      Therapeutic strategy for non-small-cell lung cancer patients with brain metastases (Review).
      Despite an initial response, many patients with ALK-positive NSCLC will eventually progress, with the CNS being a common site of initial disease progression, including intramedullary spinal cord metastases and leptomeningeal carcinomatosis.
      • Gainor JF
      • Ou SH
      • Logan J
      • Borges LF
      • Shaw AT
      The central nervous system as a sanctuary site in ALK-positive non-small-cell lung cancer.
      In a retrospective analysis of patients with ALK-positive NSCLC receiving crizotinib treatment in phase 1 and 2 trials, 46% of patients progressed first in the CNS.
      • Weickhardt AJ
      • Scheier B
      • Burke JM
      • et al.
      Local ablative therapy of oligoprogressive disease prolongs disease control by tyrosine kinase inhibitors in oncogene-addicted non-small-cell lung cancer.
      Also, the overall incidence of BM in patients with ALK-positive NSCLC is high, evident in several recent trials in which 35% to 50% of enrolled patients had stable or asymptomatic BM.
      • Shaw AT
      • Kim DW
      • Nakagawa K
      • et al.
      Crizotinib versus chemotherapy in advanced ALK-positive lung cancer.
      • Shaw AT
      • Kim DW
      • Mehra R
      • et al.
      Ceritinib in ALK-rearranged non-small-cell lung cancer.
      This has created the need for a greater understanding of both the CNS activity of currently approved ALK inhibitors and the potential of those currently in development.

      Crizotinib

      Crizotinib is an adenosine triphosphate–competitive small-molecule inhibitor of ALK, MET, and ROS1 tyrosine kinases.
      • Ou SH
      • Bartlett CH
      • Mino-Kenudson M
      • Cui J
      • Iafrate AJ
      Crizotinib for the treatment of ALK-rearranged non-small cell lung cancer: a success story to usher in the second decade of molecular targeted therapy in oncology.
      In vitro, crizotinib exhibited dose-dependent inhibition of nucleophosmin–ALK xenograft models and reduced signaling of downstream effectors and therefore was further evaluated for clinical efficacy.
      • Christensen JG
      • Zou HY
      • Arango ME
      • et al.
      Cytoreductive antitumor activity of PF-2341066, a novel inhibitor of anaplastic lymphoma kinase and c-Met, in experimental models of anaplastic large-cell lymphoma.
      Crizotinib was the first ALK inhibitor approved for treatment of patients with metastatic NSCLC whose tumors harbor ALK rearrangement. Approval was based on the pivotal phase 1 trial of crizotinib in patients with ALK-positive NSCLC who received previous chemotherapy, in which ORR was 61% with a median duration of response of 49.1 weeks.
      • Camidge DR
      • Bang Y
      • Kwak EL
      • et al.
      Progression-free survival (PFS) from a phase I study of crizotinib (PF-02341066) in patients with ALK-positive non-small cell lung cancer (NSCLC).
      The efficacy of crizotinib was confirmed in subsequent randomized trials that compared it with chemotherapy in first- and second-line settings.
      • Shaw AT
      • Kim DW
      • Nakagawa K
      • et al.
      Crizotinib versus chemotherapy in advanced ALK-positive lung cancer.
      • Mok T
      • Kim D-W
      • Wu Y-L
      • et al.
      First-line crizotinib versus pemetrexed–cisplatin or pemetrexed–carboplatin in patients (patients) with advanced ALK-positive non-squamous non-small cell lung cancer (NSCLC): results of a phase III study (PROFILE 1014).
      However, it is important to note that patients develop resistance to crizotinib within 8 to 11 months.
      • Shaw AT
      • Kim DW
      • Nakagawa K
      • et al.
      Crizotinib versus chemotherapy in advanced ALK-positive lung cancer.
      • Camidge DR
      • Bang Y
      • Kwak EL
      • et al.
      Progression-free survival (PFS) from a phase I study of crizotinib (PF-02341066) in patients with ALK-positive non-small cell lung cancer (NSCLC).
      • Mok T
      • Kim D-W
      • Wu Y-L
      • et al.
      First-line crizotinib versus pemetrexed–cisplatin or pemetrexed–carboplatin in patients (patients) with advanced ALK-positive non-squamous non-small cell lung cancer (NSCLC): results of a phase III study (PROFILE 1014).
      The brain is the most common site for new lesion development in patients who develop crizotinib-resistant ALK-positive NSCLC. In the previously mentioned phase 1 study, 149 patients with ALK-positive NSCLC were treated with crizotinib. Of 39 patients who derived clinical benefit from and continued to receive crizotinib for more than 2 weeks after disease progression, the most common site of disease progression was the brain (n = 10), which was the only site of initial disease progression. The authors speculated that this may have been because of PK failure within the CNS as a sanctuary site.
      • Camidge DR
      • Bang YJ
      • Kwak EL
      • et al.
      Activity and safety of crizotinib in patients with ALK-positive non-small-cell lung cancer: updated results from a phase 1 study.
      Similarly, a retrospective study of 38 ALK-positive patients showed that among those progressing on crizotinib, 46% had first progressed in the CNS.
      • Weickhardt AJ
      • Scheier B
      • Burke JM
      • et al.
      Local ablative therapy of oligoprogressive disease prolongs disease control by tyrosine kinase inhibitors in oncogene-addicted non-small-cell lung cancer.
      In contrast, retrospective analyses of clinical trial data suggest that clinically meaningful disease control may be achieved with crizotinib in patients with CNS metastasis. In the second-line phase 3 randomized trial of crizotinib versus chemotherapy (PROFILE 1007), approximately one-third of patients had BM. Subgroup analysis showed that the hazard ratio for PFS was 0.67 in patients with BM versus 0.43 in those without BM, indicating a lower but still clinically meaningful benefit in patients with BM treated with crizotinib.
      • 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.
      In addition, a pooled analysis of a previous single-arm phase 2 trial (PROFILE 1005) and second-line randomized trial (PROFILE 1007) of crizotinib showed that the 12-week intracranial disease control rate was 56% among the 109 patients with untreated asymptomatic BM compared with 62% among the 166 patients with previously treated BM.
      • 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.
      In the small subset of patients with CNS target lesions at baseline, the confirmed intracranial response rate was 18% in patients who did not receive brain radiotherapy and 33% in patients with previously treated BM (Table 5). The above retrospective analyses suggest that CNS disease control may be achievable with crizotinib initially, but this likely is not durable as patients eventually demonstrate progression.
      TABLE 5Intracranial Response Rates with ALK Inhibitors
      StudyAgentNo. of Patients with NSCLC BM at BaselineIntracranial ORR
      Costa et al.
      • 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.
      Crizotinib22
      Patients with previously untreated BM and CNS target lesions at baseline.
      18%
      Based on confirmed CNS responses.
      18
      Patients with previously treated BM and CNS target lesions at baseline.
      33%
      Based on confirmed CNS responses.
      Shaw et al.

      Shaw AT, Mehra R, Tan DSW, et al. Evaluation of ceritinib-treated patients with anaplastic lymphoma kinase rearranged (ALK+) non-small cell lung cancer (NSCLC) and brain metastases in the ASCEND-1 study. Presented at the European Society for Medical Oncology Annual Meeting; September 26–30, 2014, Madrid, Spain, abstr 1293P.

      Ceritinib7434.5%
      Confirmed responses among the 29 patients with measurable BM at baseline by MRI.
      Gadgeel et al.
      • Gadgeel SM
      • Gandhi L
      • Riely GJ
      • et al.
      Safety and activity of alectinib against systemic disease and brain metastases in patients with crizo-tinib-resistant ALK-rearranged non-small-cell lung cancer (AF-002JG): results from the dose-finding portion of a phase ½ study.
      Alectinib2133%
      Based on confirmed CNS responses. An additional 19% of patients had unconfirmed responses in the CNS.
      Gettinger et al.
      • Gettinger SN
      • Bazhenova L
      • Salgia R
      • et al.
      Updated efficacy and safety of the ALK inhibitor AP26113 in patients (pts) with advanced malignancies, including ALK+ non-small cell lung cancer (NSCLC).
      AP261131060%
      Based on independent radiological review of patients with untreated or progressing BM.
      ALK, anaplastic lymphoma kinase; BM, brain metastases; CNS, central nervous system; MRI, magnetic resonance imaging; NSCLC, non–small-cell lung cancer; ORR, objective response rate.
      a Patients with previously untreated BM and CNS target lesions at baseline.
      b Patients with previously treated BM and CNS target lesions at baseline.
      c Based on confirmed CNS responses.
      d Confirmed responses among the 29 patients with measurable BM at baseline by MRI.
      e Based on confirmed CNS responses. An additional 19% of patients had unconfirmed responses in the CNS.
      f Based on independent radiological review of patients with untreated or progressing BM.
      Crizotinib has been considered to have lower efficacy in BM compared with other sites of metastasis because of poor penetration across the BBB.
      • Chun SG
      • Choe KS
      • Iyengar P
      • Yordy JS
      • Timmerman RD
      Isolated central nervous system progression on Crizotinib: an Achilles heel of non-small cell lung cancer with EML4-ALK translocation?.
      PK studies are limited, but a case report of a patient with ALK-positive NSCLC who was treated with crizotinib and subsequently developed BM reported drug levels in both plasma and CSF. Crizotinib level was 237 ng/ml in plasma versus 0.62 ng/ml in CSF, suggesting that the higher rate of CNS progression compared with systemic progression could result from a low plasma to CSF ratio.
      • Costa DB
      • Kobayashi S
      • Pandya SS
      • et al.
      CSF concentration of the anaplastic lymphoma kinase inhibitor crizotinib.
      Low CSF levels are seen with other TKIs, including gefitinib and erlotinib, although the penetration rate with EGFR TKIs seems to be higher compared with that of crizotinib (Table 3). This suggests that approaches to increase the concentration of crizotinib within the CNS or use of other ALK inhibitors with greater CSF penetration may have therapeutic potential.
      Potential future directions for crizotinib include chemical modification to improve bioavailability, development of an intra-CSF formulation, and combined modality approaches.
      • Chun SG
      • Choe KS
      • Iyengar P
      • Yordy JS
      • Timmerman RD
      Isolated central nervous system progression on Crizotinib: an Achilles heel of non-small cell lung cancer with EML4-ALK translocation?.
      Crizotinib is a P-gp substrate for efflux pumps, such as the ABCB1 transporter, which act to reduce its intracellular concentration.
      • Zhou WJ
      • Zhang X
      • Cheng C
      • et al.
      Crizotinib (PF-02341066) reverses multidrug resistance in cancer cells by inhibiting the function of P-glycoprotein.
      • Ou S-H
      • Gadgeel S
      • Chiappori AA
      • et al.
      Consistent therapeutic efficacy of CH5424802/RO5424802 in brain metastases among crizotinib-refractory ALK-positive non-small cell lung cancer (NSCLC) patients in an ongoing phase I/II study (AF-002JG/NP28761, NCT01588028).
      Combination of crizotinib and elacridar (inhibitor of ABCB1/ABCG2 efflux transporters) was shown to increase plasma and brain concentrations of crizotinib in mice,
      • Chuan Tang S
      • Nguyen LN
      • Sparidans RW
      • Wagenaar E
      • Beijnen JH
      • Schinkel AH
      Increased oral availability and brain accumulation of the ALK inhibitor crizotinib by coadministration of the P-glycoprotein (ABCB1) and breast cancer resistance protein (ABCG2) inhibitor elacridar.
      and this may be a promising approach in patients with ALK-positive NSCLC. Other approaches include use of high-dose crizotinib with WBRT
      • Peled N
      • Zach L
      • Liran O
      • Ilouze M
      • Bunn Jr, PA
      • Hirsch FR
      Effective crizotinib schedule for brain metastases in ALK rearrangement metastatic non-small-cell lung cancer.
      and use of high-dose crizotinib with chemotherapy,
      • Gandhi L
      • Drappatz J
      • Ramaiya NH
      • Otterson GA
      High-dose pemetrexed in combination with high-dose crizotinib for the treatment of refractory CNS metastases in ALK-rearranged non-small-cell lung cancer.
      but these approaches remain investigational and need further evaluation in clinical trial settings.

      Ceritinib

      Ceritinib (LDK378) was recently approved by the U.S. Food and Drug Administration for treatment of patients with ALK-positive metastatic NSCLC with disease progression on or who are intolerant to crizotinib. This agent is a next-generation ALK inhibitor that is selective for ALK at low concentrations (IC50, 0.15 nM) in vitro.
      • Friboulet L
      • Li N
      • Katayama R
      • et al.
      The ALK inhibitor ceritinib overcomes crizotinib resistance in non-small cell lung cancer.
      In ALK-positive NSCLC xenograft models, ceritinib exhibits antitumor activity, including in tumors resistant to crizotinib, and can overcome a variety of common crizotinib resistance mutations such as L1196M, G1269A, I1171T, and S1206Y.
      • Friboulet L
      • Li N
      • Katayama R
      • et al.
      The ALK inhibitor ceritinib overcomes crizotinib resistance in non-small cell lung cancer.
      A recent phase 1 trial (ASCEND-1) demonstrated clinical efficacy of single-agent ceritinib in patients with ALK-positive advanced solid tumors, approximately half of whom had BM at baseline.
      • Shaw AT
      • Kim DW
      • Mehra R
      • et al.
      Ceritinib in ALK-rearranged non-small-cell lung cancer.

      Felip E, Kim D-W, Mehra R, et al. Efficacy and safety of ceritinib in patients with advanced anaplastic lymphoma kinase (ALK)-rearranged (ALK+) non-small cell lung cancer (NSCLC): an update of ASCEND-1. Presented at the European Society for Medical Oncology Annual Meeting, September 26–30, 2014; Madrid, Spain, abstr 1295P.

      The ORR was 62% in patients with NSCLC treated with 750 mg ceritinib daily, with responses seen in both crizotinib-pretreated and crizotinib-naive patients. Median PFS was 18.4 months in ALK inhibitor–naïve patients and 6.9 months in crizotinib-pretreated patients. Responses were observed independent of type of ALK resistance mutation.
      Responses were also seen in untreated CNS lesions in patients previously treated with crizotinib, with some responses occurring after 6 weeks of therapy. In the aforementioned trial, 124 had BM at baseline, 74 had magnetic resonance imaging scans, and 29 of these were measurable lesions.

      Shaw AT, Mehra R, Tan DSW, et al. Evaluation of ceritinib-treated patients with anaplastic lymphoma kinase rearranged (ALK+) non-small cell lung cancer (NSCLC) and brain metastases in the ASCEND-1 study. Presented at the European Society for Medical Oncology Annual Meeting; September 26–30, 2014, Madrid, Spain, abstr 1293P.

      Ceritinib was associated with objective intracranial responses in 10 (34.5%) of these 29 patients (Table 5); another 5 of 45 patients with nonmeasurable brain lesions showed complete response after ceritinib treatment. The response was durable, with a median duration of response of 6.9 months in patients with previous ALK inhibitor therapy, and the median duration of response had not been reached in patients who were ALK inhibitor naive at the time data were reported. In addition, a recent case report documented prolonged stabilization of carcinomatous meningitis associated with BM after treatment with ceritinib in a patient with ALK-positive NSCLC who developed CNS progression after more than 2 years on crizotinib therapy.
      • Arrondeau J
      • Ammari S
      • Besse B
      • Soria JC
      LDK378 compassionate use for treating carcinomatous meningitis in an ALK translocated non-small-cell lung cancer.
      The efficacy and safety of ceritinib in patients with ALK-positive NSCLC and BM will be further evaluated in ongoing trials (Table 4). The ASCEND-2 phase 2 trial (NCT01685060) is evaluating ceritinib in patients with ALK-positive NSCLC previously treated with chemotherapy and crizotinib; a secondary end point in this trial will be overall intracranial response rate. The ASCEND-5 phase 3 trial (NCT01828112) will randomize patients who have received previous chemotherapy and crizotinib to either ceritinib or chemotherapy (docetaxel or pemetrexed). Both trials will enroll patients with BM who are asymptomatic and are neurologically stable. A prospective trial assessing intracranial responses and the efficacy of ceritinib in ALK-positive NSCLC patients with BM and leptomeningeal disease is planned to start patient accrual.

      Other ALK inhibitors in development

      Alectinib is another second-generation TKI with activity against ALK in vitro and in vivo (IC50, 1.9 nM).
      • Sakamoto H
      • Tsukaguchi T
      • Hiroshima S
      • et al.
      CH5424802, a selective ALK inhibitor capable of blocking the resistant gatekeeper mutant.
      Compared with crizotinib, alectinib is a less-effective substrate for drug efflux proteins such as P-gp,
      • Ou S-H
      • Gadgeel S
      • Chiappori AA
      • et al.
      Consistent therapeutic efficacy of CH5424802/RO5424802 in brain metastases among crizotinib-refractory ALK-positive non-small cell lung cancer (NSCLC) patients in an ongoing phase I/II study (AF-002JG/NP28761, NCT01588028).
      and, consequently, alectinib may be better able to achieve effective intra-CSF drug levels. A phase 1/2 trial of alectinib reported a PR of 54.5% among 44 evaluable patients with crizotinib-resistant advanced NSCLC, among whom 21 had BM at baseline.
      • Gadgeel SM
      • Gandhi L
      • Riely GJ
      • et al.
      Safety and activity of alectinib against systemic disease and brain metastases in patients with crizo-tinib-resistant ALK-rearranged non-small-cell lung cancer (AF-002JG): results from the dose-finding portion of a phase ½ study.
      • Ou S-H
      • Gadgeel S
      • Chiappori AA
      • et al.
      Consistent therapeutic efficacy of CH5424802/RO5424802 in brain metastases among crizotinib-refractory ALK-positive non-small cell lung cancer (NSCLC) patients in an ongoing phase I/II study (AF-002JG/NP28761, NCT01588028).
      Among the patients with CNS metastases, 11 (52%) had an objective response in the CNS (7 [33%] confirmed responses and 4 [19%] unconfirmed responses; Table 5), and among the 4 patients with no previous radiotherapy, 3 achieved response (2 had complete response, 1 PR, and 1 stable disease).
      • Ou S-H
      • Gadgeel S
      • Chiappori AA
      • et al.
      Consistent therapeutic efficacy of CH5424802/RO5424802 in brain metastases among crizotinib-refractory ALK-positive non-small cell lung cancer (NSCLC) patients in an ongoing phase I/II study (AF-002JG/NP28761, NCT01588028).
      Alectinib has also demonstrated activity against LM in ALK-positive NSCLC patients previously treated with crizotinib and ceritinib. One report documented a complete response with alectinib lasting for more than 15 months in patient with ALK-positive NSCLC who developed diffuse leptomeningeal carcinomatosis after a prolonged response to crizotinib,
      • Ou SH
      • Sommers KR
      • Azada MC
      • Garon EB
      Alectinib induces a durable (>15 months) complete response in an ALK-positive non-small cell lung cancer patient who progressed on crizotinib with diffuse leptomeningeal carcinomatosis.
      whereas another described clinical and radiographic improvements in three of four patients who developed LM after treatment with crizotinib and ceritinib.
      • Gainor JF
      • Sherman CA
      • Willoughby K
      • et al.
      Alectinib salvages CNS relapses in ALK-positive lung cancer patients previously treated with crizotinib and ceritinib.
      An ongoing phase 3 trial (NCT02075840) will compare crizotinib and alectinib in treatment-naive patients with advanced NSCLC and will evaluate time to CNS progression as a secondary end point. A second phase 3 trial is evaluating alectinib versus chemotherapy in chemotherapy-naive patients; intracranial and extracranial disease control rate will be assessed as secondary end points.
      AP26113 is a selective inhibitor of activated forms of ALK, EGFR, and ROS1, but not wild-type EGFR, which can overcome crizotinib resistance mutations.
      • Zhang S
      • Wang F
      • Keats J
      • et al.
      AP26113, a potent ALK inhibitor, overcomes mutations in EML4-ALK that confer resistance to PF-02341066 (PF1066).
      • Rivera VM
      • Wang F
      • Anjum R
      • et al.
      AP26113 is a dual ALK/EGFR inhibitor: characterization against EGFR T790M in cell and mouse models of NSCLC.
      • Katayama R
      • Khan TM
      • Benes C
      • et al.
      Therapeutic strategies to overcome crizotinib resistance in non-small cell lung cancers harboring the fusion oncogene EML4-ALK.
      A phase 1/2 trial assessed the safety and activity of AP26113 in patients with advanced malignancies that harbor ALK, EGFR, or ROS1 abnormalities. Among patients with ALK-positive NSCLC who received previous crizotinib, response rate was 63% (24/38). Response in BM was seen in 6 of 10 (60%) ALK–positive patients with untreated or progressing CNS lesions at baseline, including 4 with undetectable BM after AP26113.
      • Gettinger SN
      • Bazhenova L
      • Salgia R
      • et al.
      Updated efficacy and safety of the ALK inhibitor AP26113 in patients (pts) with advanced malignancies, including ALK+ non-small cell lung cancer (NSCLC).
      A number of other second-generation ALK inhibitors are in development, all with limited or in some cases no clinical data, including ASP3026,
      • Maitland ML
      • Ou S-H I
      • Tolcher AW
      • et al.
      Safety, activity, and pharmacokinetics of an oral anaplastic lymphoma kinase (ALK) inhibitor, ASP3026, observed in a “fast follower” phase 1 trial design.
      TSR-011,
      • Weiss GJ
      • Sachdev JC
      • Infante JR
      • et al.
      Phase (Ph) 1/2 study of TSR-011, a potent inhibitor of ALK and TRK, including crizotinib-resistant ALK mutations.
      X-396,
      • Horn L
      • Infante JR
      • Blumenschein GR
      • et al.
      A phase I trial of X-396, a novel ALK inhibitor, in patients with advanced solid tumors.
      RXDX101,
      • De Braud FG
      • Pilla L
      • Niger M
      • et al.
      Phase 1 open label, dose escalation study of RXDX101, an oral pan-trk, ROS1, and ALK inhibitor, in patients with advanced solid tumors with relevant molecular alterations.
      and CEP-28122
      • Cheng M
      • Quail MR
      • Gingrich DE
      • et al.
      CEP-28122, a highly potent and selective orally active inhibitor of anaplastic lymphoma kinase with antitumor activity in experimental models of human cancers.
      and CEP-37440.
      • Awad MM
      • Shaw AT
      ALK inhibitors in non-small cell lung cancer: crizotinib and beyond.
      Several of these agents have shown early clinical activity in ALK-positive NSCLC, with ORRs of 44% with ASP3026 (7 PRs in 15 patients), 60% with TSR-011 (3 PRs in 5 patients), and 83% with X-396 (5 PRs in 6 patients treated at doses ≥200 mg). CNS responses were observed in two patients treated with X-396 (one crizotinib naive and one crizotinib pretreated).
      Preclinical data with PF-06463922, a highly-potent third-generation ALK and ROS1 inhibitor, suggest that this agent may have substantial CNS activity. PF-06463922 has demonstrated significant brain exposure, supported by in vitro data indicating that this compound is not a substrate for the drug efflux transporters P-gp and breast cancer resistance protein.
      • Johnson TW
      • Richardson PF
      • Bailey S
      • et al.
      Discovery of (10R)-7-amino-12-fluoro-2,10,16-trimethyl-15-oxo-10,15,16,17-tetrahydro-2H-8,4-(metheno)pyrazolo[4,3-h][2,5,11]-benzoxadiazacy-clotetradecine-3-carbonitrile (PF-06463922), a macrocyclic inhibitor of anaplastic lymphoma kinase (ALK) and c-ros oncogene 1 (ROS1) with preclinical brain exposure and broad-spectrum potency against ALK-resistant mutations.
      A phase 1/2 trial in patients with ALK-positive and ROS1-positive NSCLC that includes intracranial ORR as a primary end point is ongoing (NCT01970865).
      The studies described earlier demonstrate that the CNS is a frequent site of disease progression in patients with ALK-positive NSCLC on crizotinib, likely due to inadequate CSF penetration. Next-generation ALK inhibitors, such as ceritinib, alectinib, and AP26113, have been shown to be effective in patients whose disease progressed on crizotinib, including those with active CNS disease. However, their clinical efficacy in the CNS has not yet been fully characterized. Future investigations will need to clarify optimal sequencing of the above TKIs in patients with CNS disease and whether these will be effective and safe in multimodality therapies, such as in combination with radiation.

      ALK inhibitors and RT

      Recent studies suggest that local ablative therapy (LAT) can be used to extend the clinical benefit of crizotinib in those who develop nonleptomeningeal CNS and limited (one to four sites) extra-CNS oligoprogressive disease.
      • Weickhardt AJ
      • Scheier B
      • Burke JM
      • et al.
      Local ablative therapy of oligoprogressive disease prolongs disease control by tyrosine kinase inhibitors in oncogene-addicted non-small-cell lung cancer.
      • Gan GN
      • Weickhardt AJ
      • Scheier B
      • et al.
      Stereotactic radiation therapy can safely and durably control sites of extra-central nervous system oligoprogressive disease in anaplastic lymphoma kinase-positive lung cancer patients receiving crizotinib.
      In the study by Weickhardt et al.,
      • Weickhardt AJ
      • Scheier B
      • Burke JM
      • et al.
      Local ablative therapy of oligoprogressive disease prolongs disease control by tyrosine kinase inhibitors in oncogene-addicted non-small-cell lung cancer.
      patients with nonleptomeningeal CNS and limited systemic progression who received LAT had a longer duration of TKI therapy compared with those who were not suitable for LAT with an additional 6-month disease control on TKI.
      An ongoing clinical trial is evaluating ALK inhibitors and other targeted therapies in combination with stereotactic brain treatment in patients with stage IV oncogene-driven (EGFR, ALK, or ROS1) NSCLC (NCT02314364). In this study, eligible patients include those with up to four BM who will receive stereotactic radiotherapy while continuing the appropriate TKI therapy.

      Emerging Targeted Therapies in NSCLC

      In addition to EGFR and ALK genetic aberrations, there are emerging molecular targets for which genotype-directed therapies are in development. Genetic abnormalities, such as ROS1 and RET rearrangements and mutations in the HER2 and BRAF genes, are emerging as clinically important molecular targets, and active research is ongoing to identify effective targeted therapies for these molecular subtypes.
      • Kris MG
      • Johnson BE
      • Berry LD
      • et al.
      Using multiplexed assays of oncogenic drivers in lung cancers to select targeted drugs.
      Currently, there are no data regarding the efficacy of these targeted therapies in patients with BM whose tumors harbor the aforementioned uncommon aberrations.

      CONCLUSION

      The advent of targeted therapies has improved disease control and survival of a subset of NSCLC patients with an identified driver mutation. These targeted therapies result in excellent systemic disease control, but their efficacy is often limited by CNS disease progression. The role of first-generation TKIs such as erlotinib and crizotinib in CNS metastasis is modest; however, limited CSF penetration has been observed, and corresponding low rates of intracranial responses also have been reported. Therefore, initial therapy with either erlotinib or crizotinib is a reasonable approach in patients with small, asymptomatic CNS metastases that harbor the appropriate targetable mutation. In patients with ALK-positive NSCLC, early data from clinical trials of second-generation ALK inhibitors have shown promising CNS responses, including in patients with leptomeningeal disease. There are ongoing prospective studies that will further elucidate whether these novel agents will be more active or effective in ALK-positive NSCLC patients with CNS disease. Surgical resection and RT remains the cornerstone of treatment for symptomatic CNS disease, and there are ongoing trials to determine the role of targeted therapies in combination with these modalities. Although systemic therapy in metastatic NSCLC has changed dramatically in the past decade with the development of effective targeted therapies, continued and further efforts are needed to develop effective therapies specifically for CNS disease to improve the outcome of advanced disease in patients with NSCLC.

      ACKNOWLEDGMENTS

      Writing assistance for this article was provided by QXV, a UDG Healthcare Company. This review was supported by Novartis.

      REFERENCES

        • Herbst RS
        • Heymach JV
        • Lippman SM
        Lung cancer.
        N Engl J Med. 2008; 359: 1367-1380
      1. Surveillance, Epidemiology, and End Results (SEER) Program.
        (Accessed September 24, 2014.)
        • Patchell RA
        The management of brain metastases.
        Cancer Treat Rev. 2003; 29: 533-540
      2. NCCN Clinical Practice Guidelines: Non–Small Cell Lung Cancer, Version 3.2014.
        (Accessed September 24, 2014.)
        • Mehta M
        • Vogelbaum MA
        • Chang S
        • et al.
        Neoplasms of the central nervous system.
        in: DeVita Jr, VT Lawrence TS Rosenberg SA Cancer: Principles and Practice of Oncology. 9th Ed. Lippincott Williams & Wilkins, Philadelphia2011: 1700-1749
        • Cruz-Muñoz W
        • Kerbel RS
        Preclinical approaches to study the biology and treatment of brain metastases.
        Semin Cancer Biol. 2011; 21: 123-130
        • D’Antonio C
        • Passaro A
        • Gori B
        • et al.
        Bone and brain metastasis in lung cancer: recent advances in therapeutic strategies.
        Ther Adv Med Oncol. 2014; 6: 101-114
        • Patchell RA
        • Tibbs PA
        • Walsh JW
        • et al.
        A randomized trial of surgery in the treatment of single metastases to the brain.
        N Engl J Med. 1990; 322: 494-500
        • Mok TS
        • Wu YL
        • Thongprasert S
        • et al.
        Gefitinib or carboplatin-paclitaxel in pulmonary adenocarcinoma.
        N Engl J Med. 2009; 361: 947-957
        • Shaw AT
        • Kim DW
        • Nakagawa K
        • et al.
        Crizotinib versus chemotherapy in advanced ALK-positive lung cancer.
        N Engl J Med. 2013; 368: 2385-2394
        • Gori B
        • Ricciardi S
        • del Signore E
        • Fulvi A
        • de Marinis F
        Oral tyrosine kinase inhibitors in the first-line treatment of advanced non-small cell lung cancer.
        Expert Opin Ther Targets. 2012; 16: S55-S60
        • Roengvoraphoj M
        • Tsongalis GJ
        • Dragnev KH
        • Rigas JR
        Epidermal growth factor receptor tyrosine kinase inhibitors as initial therapy for non-small cell lung cancer: focus on epidermal growth factor receptor mutation testing and mutation-positive patients.
        Cancer Treat Rev. 2013; 39: 839-850
        • Shaw AT
        • Engelman JA
        ALK in lung cancer: past, present, and future.
        J Clin Oncol. 2013; 31: 1105-1111
        • Iwama E
        • Okamoto I
        • Harada T
        • Takayama K
        • Nakanishi Y
        Development of anaplastic lymphoma kinase (ALK) inhibitors and molecular diagnosis in ALK rearrangement-positive lung cancer.
        Onco Targets Ther. 2014; 7: 375-385
        • Deeken JF
        • Löscher W
        The blood-brain barrier and cancer: transporters, treatment, and Trojan horses.
        Clin Cancer Res. 2007; 13: 1663-1674
        • Chamberlain M
        • Soffietti R
        • Raizer J
        • et al.
        Leptomeningeal metastasis: a response assessment in neuro-oncology critical review of endpoints and response criteria of published randomized clinical trials.
        Neuro Oncol. 2014; 16: 1176-1185
        • Kris MG
        • Johnson BE
        • Berry LD
        • et al.
        Using multiplexed assays of oncogenic drivers in lung cancers to select targeted drugs.
        JAMA. 2014; 311: 1998-2006
        • Camidge DR
        • Bang YJ
        • Kwak EL
        • et al.
        Activity and safety of crizotinib in patients with ALK-positive non-small-cell lung cancer: updated results from a phase 1 study.
        Lancet Oncol. 2012; 13: 1011-1019
        • Costa DB
        • Kobayashi S
        • Pandya SS
        • et al.
        CSF concentration of the anaplastic lymphoma kinase inhibitor crizotinib.
        J Clin Oncol. 2011; 29: e443-e445
        • Pardridge WM
        The blood-brain barrier and neurotherapeutics.
        NeuroRx. 2005; 2: 1-2
        • Löscher W
        • Potschka H
        Drug resistance in brain diseases and the role of drug efflux transporters.
        Nat Rev Neurosci. 2005; 6: 591-602
        • Löscher W
        • Potschka H
        Role of drug efflux transporters in the brain for drug disposition and treatment of brain diseases.
        Prog Neurobiol. 2005; 76: 22-76
        • Abbott NJ
        • Rönnbäck L
        • Hansson E
        Astrocyte-endothelial interactions at the blood-brain barrier.
        Nat Rev Neurosci. 2006; 7: 41-53
        • Kast RE
        • Focosi D
        Three paths to better tyrosine kinase inhibition behind the blood-brain barrier in treating chronic myelogenous leukemia and glioblastoma with imatinib.
        Transl Oncol. 2010; 3: 13-15
        • 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: 1287-1289
        • Elmeliegy MA
        • Carcaboso AM
        • Tagen M
        • Bai F
        • Stewart CF
        Role of ATP-binding cassette and solute carrier transporters in erlotinib CNS penetration and intracellular accumulation.
        Clin Cancer Res. 2011; 17: 89-99
        • de Vries NA
        • Buckle T
        • Zhao J
        • Beijnen JH
        • Schellens JH
        • van Tellingen O
        Restricted brain penetration of the tyrosine kinase inhibitor erlotinib due to the drug transporters P-gp and BCRP.
        Invest New Drugs. 2012; 30: 443-449
        • Chuan Tang S
        • Nguyen LN
        • Sparidans RW
        • Wagenaar E
        • Beijnen JH
        • Schinkel AH
        Increased oral availability and brain accumulation of the ALK inhibitor crizotinib by coadministration of the P-glycoprotein (ABCB1) and breast cancer resistance protein (ABCG2) inhibitor elacridar.
        Int J Cancer. 2014; 134: 1484-1494
        • Rosell R
        • Carcereny E
        • Gervais R
        • et al.
        • Spanish Lung Cancer Group in collaboration with Groupe Français de Pneumo-Cancérologie and Associazione Italiana Oncologia Toracica
        Erlotinib versus standard chemotherapy as first-line treatment for European patients with advanced EGFR mutation-positive non-small-cell lung cancer (EURTAC): a multicentre, open-label, randomised phase 3 trial.
        Lancet Oncol. 2012; 13: 239-246
        • Sequist LV
        • Yang JC
        • Yamamoto N
        • et al.
        Phase III study of afatinib or cisplatin plus pemetrexed in patients with metastatic lung adenocarcinoma with EGFR mutations.
        J Clin Oncol. 2013; 31: 3327-3334
        • Weickhardt AJ
        • Scheier B
        • Burke JM
        • et al.
        Local ablative therapy of oligoprogressive disease prolongs disease control by tyrosine kinase inhibitors in oncogene-addicted non-small-cell lung cancer.
        J Thorac Oncol. 2012; 7: 1807-1814
        • 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: 4406-4414
        • Porta R
        • Sánchez-Torres JM
        • Paz-Ares L
        • et al.
        Brain metastases from lung cancer responding to erlotinib: the importance of EGFR mutation.
        Eur Respir J. 2011; 37: 624-631
        • Wu YL
        • Zhou C
        • Cheng Y
        • et al.
        Erlotinib as second-line treatment in patients with advanced non-small-cell lung cancer and asymptomatic brain metastases: a phase II study (CTONG-0803).
        Ann Oncol. 2013; 24: 993-999
        • Eichler AF
        • Kahle KT
        • Wang DL
        • et al.
        EGFR mutation status and survival after diagnosis of brain metastasis in non-small cell lung cancer.
        Neuro Oncol. 2010; 12: 1193-1199
        • Lee HL
        • Chung TS
        • Ting LL
        • et al.
        EGFR mutations are associated with favorable intracranial response and progression-free survival following brain irradiation in non-small cell lung cancer patients with brain metastases.
        Radiat Oncol. 2012; 7: 181
        • 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: 556-560
        • 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: 950-955
        • Broniscer A
        • Panetta JC
        • O’Shaughnessy M
        • et al.
        Plasma and cerebrospinal fluid pharmacokinetics of erlotinib and its active metabolite OSI-420.
        Clin Cancer Res. 2007; 13: 1511-1515
        • Meany HJ
        • Fox E
        • McCully C
        • Tucker C
        • Balis FM
        The plasma and cerebrospinal fluid pharmacokinetics of erlotinib and its active metabolite (OSI-420) after intravenous administration of erlotinib in non-human primates.
        Cancer Chemother Pharmacol. 2008; 62: 387-392
        • Marchetti S
        • de Vries NA
        • Buckle T
        • et al.
        Effect of the ATP-binding cassette drug transporters ABCB1, ABCG2, and ABCC2 on erlotinib hydrochloride (Tarceva) disposition in in vitro and in vivo pharmacokinetic studies employing Bcrp1-/-/Mdr1a/1b-/- (triple-knockout) and wild-type mice.
        Mol Cancer Ther. 2008; 7: 2280-2287
        • Shi Z
        • Peng XX
        • Kim IW
        • et al.
        Erlotinib (Tarceva, OSI-774) antagonizes ATP-binding cassette subfamily B member 1 and ATP-binding cassette subfamily G member 2-mediated drug resistance.
        Cancer Res. 2007; 67: 11012-11020
        • Togashi Y
        • Masago K
        • Masuda S
        • et al.
        Cerebrospinal fluid concentration of gefitinib and erlotinib in patients with non-small cell lung cancer.
        Cancer Chemother Pharmacol. 2012; 70: 399-405
        • Deng Y
        • Feng W
        • Wu J
        • et al.
        The concentration of erlotinib in the cerebrospinal fluid of patients with brain metastasis from non-small-cell lung cancer.
        Mol Clin Oncol. 2014; 2: 116-120
        • Agarwal S
        • Sane R
        • Gallardo JL
        • Ohlfest JR
        • Elmquist WF
        Distribution of gefitinib to the brain is limited by P-glycoprotein (ABCB1) and breast cancer resistance protein (ABCG2)-mediated active efflux.
        J Pharmacol Exp Ther. 2010; 334: 147-155
        • Leggas M
        • Panetta JC
        • Zhuang Y
        • et al.
        Gefitinib modulates the function of multiple ATP-binding cassette transporters in vivo.
        Cancer Res. 2006; 66: 4802-4807
        • Zhao J
        • Chen M
        • Zhong W
        • et al.
        Cerebrospinal fluid concentrations of gefitinib in patients with lung adenocarcinoma.
        Clin Lung Cancer. 2013; 14: 188-193
        • Wind S
        • Giessmann T
        • Jungnik A
        • et al.
        Pharmacokinetic drug interactions of afatinib with rifampicin and ritonavir.
        Clin Drug Investig. 2014; 34: 173-182
        • Zhou WJ
        • Zhang X
        • Cheng C
        • et al.
        Crizotinib (PF-02341066) reverses multidrug resistance in cancer cells by inhibiting the function of P-glycoprotein.
        Br J Pharmacol. 2012; 166: 1669-1683
      3. Zykadia (Ceritinib) US Prescribing Information. Novartis Pharmaceuticals Corporation, East Hanover2014
        • Kodama T
        • Hasegawa M
        • Takanashi K
        • Sakurai Y
        • Kondoh O
        • Sakamoto H
        Antitumor activity of the selective ALK inhibitor alectinib in models of intracranial metastases.
        Cancer Chemother Pharmacol. 2014; 74: 1023-1028
        • Gadgeel SM
        • Gandhi L
        • Riely GJ
        • et al.
        Safety and activity of alectinib against systemic disease and brain metastases in patients with crizo-tinib-resistant ALK-rearranged non-small-cell lung cancer (AF-002JG): results from the dose-finding portion of a phase ½ study.
        Lancet Oncol. 2014; 15: 1119-1128
        • 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: 4517-4520
        • Katayama T
        • Shimizu J
        • Suda K
        • et al.
        Efficacy of erlotinib for brain and leptomeningeal metastases in patients with lung adenocarcinoma who showed initial good response to gefitinib.
        J Thorac Oncol. 2009; 4: 1415-1419
        • Togashi Y
        • Masago K
        • Fukudo M
        • et al.
        Efficacy of increased-dose erlotinib for central nervous system metastases in non-small cell lung cancer patients with epidermal growth factor receptor mutation.
        Cancer Chemother Pharmacol. 2011; 68: 1089-1092
        • Jackman DM
        • Mach SL
        • Heng JC
        Pulsed dosing of erlotinib for central nervous system progression in EGFR-mutant non-small cell lung cancer.
        J Clin Oncol. 2013; 31 (abstr 8116.)
        • Yap TA
        • Vidal L
        • Adam J
        • et al.
        Phase I trial of the irreversible EGFR and HER2 kinase inhibitor BIBW 2992 in patients with advanced solid tumors.
        J Clin Oncol. 2010; 28: 3965-3972
        • Bordi P
        • Tiseo M
        • Bortesi B
        • Naldi N
        • Buti S
        • Ardizzoni A
        Overcoming T790M-driven acquired resistance to EGFR-TKIs in NSCLC with afatinib: a case report.
        Tumori. 2014; 100: e20-e23
        • Lin CH
        • Lin MT
        • Kuo YW
        • Ho CC
        Afatinib combined with cetuximab for lung adenocarcinoma with leptomeningeal carcinomatosis.
        Lung Cancer. 2014; 85: 479-480
        • Janjigian YY
        • Smit EF
        • Groen HJ
        • et al.
        Dual inhibition of EGFR with afatinib and cetuximab in kinase inhibitor-resistant EGFR-mutant lung cancer with and without T790M mutations.
        Cancer Discov. 2014; 4: 1036-1045
        • Jänne PA
        • Ou SH
        • Kim DW
        • et al.
        Dacomitinib as first-line treatment in patients with clinically or molecularly selected advanced non-small-cell lung cancer: a multicentre, open-label, phase 2 trial.
        Lancet Oncol. 2014; 15: 1433-1441
        • Jänne PA
        • Ramalingam SS
        • Chih-Hsin Yang J
        • et al.
        Clinical activity of the mutant-selective EGFR inhibitor AZD9291 in patients (pts) with EGFR inhibitor–resistant non-small cell lung cancer (NSCLC).
        J Clin Oncol. 2014; 32 (abstr 8009.)
        • Sequist LV
        • Soria J-C
        • Gadgeel SM
        • et al.
        First-in-human evaluation of CO-1686, an irreversible, highly selective tyrosine kinase inhibitor of mutations of EGFR (activating and T790M).
        J Clin Oncol. 2014; 32 (abstr 8010.)
        • Kim D
        • Yang J
        • Cross D
        • et al.
        Preclinical evidence and clinical cases of AZD9291 activity in EGFR-mutant non-small cell lung cancer (NSCLC) brain metastases (BM).
        Ann Oncol. 2014; 25 (abstr 456P.)
        • Kim D-W
        • Lee DH
        • Kang JH
        • et al.
        Clinical activity and safety of HM61713, an EGFR-mutant selective inhibitor, in advanced non-small cell lung cancer (NSCLC) patients (pts) with EGFR mutations who had received EGFR tyrosine kinase inhibitors (TKIs).
        J Clin Oncol. 2014; 32 (abstr 8011.)
        • Akimoto T
        • Hunter NR
        • Buchmiller L
        • Mason K
        • Ang KK
        • Milas L
        Inverse relationship between epidermal growth factor receptor expression and radiocurability of murine carcinomas.
        Clin Cancer Res. 1999; 5: 2884-2890
        • 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: 3328-3335
        • Gow CH
        • Chien CR
        • Chang YL
        • et al.
        Radiotherapy in lung adenocarcinoma with brain metastases: effects of activating epidermal growth factor receptor mutations on clinical response.
        Clin Cancer Res. 2008; 14: 162-168
        • 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
        • Sperduto PW
        • Wang M
        • Robins HI
        • et al.
        A phase 3 trial of whole brain radiation therapy and stereotactic radiosurgery alone versus WBRT and SRS with temozolomide or erlotinib for non-small cell lung cancer and 1 to 3 brain metastases: Radiation Therapy Oncology Group 0320.
        Int J Radiat Oncol Biol Phys. 2013; 85: 1312-1318
        • Pesce GA
        • Klingbiel D
        • Ribi K
        • et al.
        Outcome, quality of life and cognitive function of patients with brain metastases from non-small cell lung cancer treated with whole brain radiotherapy combined with gefitinib or temozolomide. A randomised phase II trial of the Swiss Group for Clinical Cancer Research (SAKK 70/03).
        Eur J Cancer. 2012; 48: 377-384
        • Shaw AT
        • Yeap BY
        • Mino-Kenudson M
        • et al.
        Clinical features and outcome of patients with non-small-cell lung cancer who harbor EML4-ALK.
        J Clin Oncol. 2009; 27: 4247-4253
        • Kim YH
        • Nagai H
        • Ozasa H
        • Sakamori Y
        • Mishima M
        Therapeutic strategy for non-small-cell lung cancer patients with brain metastases (Review).
        Biomed Rep. 2013; 1: 691-696
        • Gainor JF
        • Ou SH
        • Logan J
        • Borges LF
        • Shaw AT
        The central nervous system as a sanctuary site in ALK-positive non-small-cell lung cancer.
        J Thorac Oncol. 2013; 8: 1570-1573
        • Shaw AT
        • Kim DW
        • Mehra R
        • et al.
        Ceritinib in ALK-rearranged non-small-cell lung cancer.
        N Engl J Med. 2014; 370: 1189-1197
        • Ou SH
        • Bartlett CH
        • Mino-Kenudson M
        • Cui J
        • Iafrate AJ
        Crizotinib for the treatment of ALK-rearranged non-small cell lung cancer: a success story to usher in the second decade of molecular targeted therapy in oncology.
        Oncologist. 2012; 17: 1351-1375
        • Christensen JG
        • Zou HY
        • Arango ME
        • et al.
        Cytoreductive antitumor activity of PF-2341066, a novel inhibitor of anaplastic lymphoma kinase and c-Met, in experimental models of anaplastic large-cell lymphoma.
        Mol Cancer Ther. 2007; 6: 3314-3322
        • Camidge DR
        • Bang Y
        • Kwak EL
        • et al.
        Progression-free survival (PFS) from a phase I study of crizotinib (PF-02341066) in patients with ALK-positive non-small cell lung cancer (NSCLC).
        J Clin Oncol. 2011; 29 (abstr 2501.)
        • Mok T
        • Kim D-W
        • Wu Y-L
        • et al.
        First-line crizotinib versus pemetrexed–cisplatin or pemetrexed–carboplatin in patients (patients) with advanced ALK-positive non-squamous non-small cell lung cancer (NSCLC): results of a phase III study (PROFILE 1014).
        J Clin Oncol. 2014; 32 (abstr 8002.)
        • 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: 1881-1888
      4. Shaw AT, Mehra R, Tan DSW, et al. Evaluation of ceritinib-treated patients with anaplastic lymphoma kinase rearranged (ALK+) non-small cell lung cancer (NSCLC) and brain metastases in the ASCEND-1 study. Presented at the European Society for Medical Oncology Annual Meeting; September 26–30, 2014, Madrid, Spain, abstr 1293P.

        • Gettinger SN
        • Bazhenova L
        • Salgia R
        • et al.
        Updated efficacy and safety of the ALK inhibitor AP26113 in patients (pts) with advanced malignancies, including ALK+ non-small cell lung cancer (NSCLC).
        J Clin Oncol. 2014; 32 (abstr 8047.)
        • Chun SG
        • Choe KS
        • Iyengar P
        • Yordy JS
        • Timmerman RD
        Isolated central nervous system progression on Crizotinib: an Achilles heel of non-small cell lung cancer with EML4-ALK translocation?.
        Cancer Biol Ther. 2012; 13: 1376-1383
        • Ou S-H
        • Gadgeel S
        • Chiappori AA
        • et al.
        Consistent therapeutic efficacy of CH5424802/RO5424802 in brain metastases among crizotinib-refractory ALK-positive non-small cell lung cancer (NSCLC) patients in an ongoing phase I/II study (AF-002JG/NP28761, NCT01588028).
        J Thorac Oncol. 2013; 8 (abstr O16.07.)
        • Peled N
        • Zach L
        • Liran O
        • Ilouze M
        • Bunn Jr, PA
        • Hirsch FR
        Effective crizotinib schedule for brain metastases in ALK rearrangement metastatic non-small-cell lung cancer.
        J Thorac Oncol. 2013; 8: e112-e113
        • Gandhi L
        • Drappatz J
        • Ramaiya NH
        • Otterson GA
        High-dose pemetrexed in combination with high-dose crizotinib for the treatment of refractory CNS metastases in ALK-rearranged non-small-cell lung cancer.
        J Thorac Oncol. 2013; 8: e3-e5
        • Friboulet L
        • Li N
        • Katayama R
        • et al.
        The ALK inhibitor ceritinib overcomes crizotinib resistance in non-small cell lung cancer.
        Cancer Discov. 2014; 4: 662-673
      5. Felip E, Kim D-W, Mehra R, et al. Efficacy and safety of ceritinib in patients with advanced anaplastic lymphoma kinase (ALK)-rearranged (ALK+) non-small cell lung cancer (NSCLC): an update of ASCEND-1. Presented at the European Society for Medical Oncology Annual Meeting, September 26–30, 2014; Madrid, Spain, abstr 1295P.

        • Arrondeau J
        • Ammari S
        • Besse B
        • Soria JC
        LDK378 compassionate use for treating carcinomatous meningitis in an ALK translocated non-small-cell lung cancer.
        J Thorac Oncol. 2014; 9: e62-e63
        • Sakamoto H
        • Tsukaguchi T
        • Hiroshima S
        • et al.
        CH5424802, a selective ALK inhibitor capable of blocking the resistant gatekeeper mutant.
        Cancer Cell. 2011; 19: 679-690
        • Ou SH
        • Sommers KR
        • Azada MC
        • Garon EB
        Alectinib induces a durable (>15 months) complete response in an ALK-positive non-small cell lung cancer patient who progressed on crizotinib with diffuse leptomeningeal carcinomatosis.
        Oncologist. 2015; 20: 224-226
        • Gainor JF
        • Sherman CA
        • Willoughby K
        • et al.
        Alectinib salvages CNS relapses in ALK-positive lung cancer patients previously treated with crizotinib and ceritinib.
        J Thorac Oncol. 2015; 10: 232-236
        • Zhang S
        • Wang F
        • Keats J
        • et al.
        AP26113, a potent ALK inhibitor, overcomes mutations in EML4-ALK that confer resistance to PF-02341066 (PF1066).
        Cancer Res. 2010; 70 (abstr LB-298.)
        • Rivera VM
        • Wang F
        • Anjum R
        • et al.
        AP26113 is a dual ALK/EGFR inhibitor: characterization against EGFR T790M in cell and mouse models of NSCLC.
        Cancer Res. 2012; 72 (abstr 1794.)
        • Katayama R
        • Khan TM
        • Benes C
        • et al.
        Therapeutic strategies to overcome crizotinib resistance in non-small cell lung cancers harboring the fusion oncogene EML4-ALK.
        Proc Natl Acad Sci USA. 2011; 108: 7535-7540
        • Maitland ML
        • Ou S-H I
        • Tolcher AW
        • et al.
        Safety, activity, and pharmacokinetics of an oral anaplastic lymphoma kinase (ALK) inhibitor, ASP3026, observed in a “fast follower” phase 1 trial design.
        J Clin Oncol. 2014; 32 (abstr 2624.)
        • Weiss GJ
        • Sachdev JC
        • Infante JR
        • et al.
        Phase (Ph) 1/2 study of TSR-011, a potent inhibitor of ALK and TRK, including crizotinib-resistant ALK mutations.
        J Clin Oncol. 2014; 32 (abstr e19005.)
        • Horn L
        • Infante JR
        • Blumenschein GR
        • et al.
        A phase I trial of X-396, a novel ALK inhibitor, in patients with advanced solid tumors.
        J Clin Oncol. 2014; 32 (abstr 8030.)
        • De Braud FG
        • Pilla L
        • Niger M
        • et al.
        Phase 1 open label, dose escalation study of RXDX101, an oral pan-trk, ROS1, and ALK inhibitor, in patients with advanced solid tumors with relevant molecular alterations.
        J Clin Oncol. 2014; 32 (abstr 2502.)
        • Cheng M
        • Quail MR
        • Gingrich DE
        • et al.
        CEP-28122, a highly potent and selective orally active inhibitor of anaplastic lymphoma kinase with antitumor activity in experimental models of human cancers.
        Mol Cancer Ther. 2012; 11: 670-679
        • Awad MM
        • Shaw AT
        ALK inhibitors in non-small cell lung cancer: crizotinib and beyond.
        Clin Adv Hematol Oncol. 2014; 12: 429-439
        • Johnson TW
        • Richardson PF
        • Bailey S
        • et al.
        Discovery of (10R)-7-amino-12-fluoro-2,10,16-trimethyl-15-oxo-10,15,16,17-tetrahydro-2H-8,4-(metheno)pyrazolo[4,3-h][2,5,11]-benzoxadiazacy-clotetradecine-3-carbonitrile (PF-06463922), a macrocyclic inhibitor of anaplastic lymphoma kinase (ALK) and c-ros oncogene 1 (ROS1) with preclinical brain exposure and broad-spectrum potency against ALK-resistant mutations.
        J Med Chem. 2014; 57: 4720-4744
        • Gan GN
        • Weickhardt AJ
        • Scheier B
        • et al.
        Stereotactic radiation therapy can safely and durably control sites of extra-central nervous system oligoprogressive disease in anaplastic lymphoma kinase-positive lung cancer patients receiving crizotinib.
        Int J Radiat Oncol Biol Phys. 2014; 88: 892-898