We searched PubMed for all publications published in English with the terms “intracranial” or “CNS” or “brain” or “leptomeningeal” and “metastases” and “ALK” or “crizotinib” or “alectinib” or “ceritinib” or “brigatinib” for the patients included in our review. Articles meeting these criteria that were available on PubMed before May 1, 2015, were included. Because of the novelty of the ALK inhibitors, there are several trials in progress that are of relevance. We searched the ClincalTrials.gov
ReviewTargeting brain metastases in ALK-rearranged non-small-cell lung cancer
Introduction
The presence of brain metastases in non-small-cell lung cancer (NSCLC) traditionally has a poor prognosis with a median survival of 7 months (95% CI 2·63–18·8).1 However, tumour-specific mutations are emerging targets for these metastatic brain tumours, and could improve overall survival. Rearrangement of ALK is seen in about 2–7% of NSCLC, and is a therapeutic target in advanced NSCLC. Crizotinib was the first approved anti-ALK tyrosine kinase inhibitor, after showing excellent systemic efficacy; however, this efficacy has not translated to intracranial control of disease. The CNS is frequently a site of disease progression, where up to 60% of patients develop metastases during treatment with crizotinib. The high rate of CNS disease is attributable to both poor intracranial penetration of drugs and the emergence of intrinsic tumour resistance mechanisms. Second-generation ALK inhibitors have shown better, but variable, intracranial control, necessitating the exploration of other treatment options. This Review discusses the role of ALK in CNS metastases, ALK-targeted therapy in relation to intracranial disease, and mechanisms to combat resistance to existing therapies. The importance of ALK inhibitors in brain metastases cannot be understated—patients with ALK-rearranged tumours have a good outlook in the presence of targeted therapies, and intracranial resistance to therapy is arguably the greatest limitation to long-lasting disease control.
Section snippets
The role of the blood–brain barrier
The blood–brain barrier protects the brain from toxic insults; however, it also prevents systemic drugs reaching the brain parenchyma. Several characteristics of the blood–brain barrier form this obstacle, for example, continuous tight junctions between endothelial cells with a complex structural support system that includes pericytes and astrocytic end-feet that modulate the permeability of the blood–brain barrier via paracrines.2 High electrical resistance, about 100 times that recorded in
ALK rearrangements
Translocations associated with the ALK gene are identified in about 2–7% of NSCLC, the most common of which is the EML4-ALK translocation.9 Rearrangements cause autophosphorylation and constitutive activity of ALK, activating the RAS and P13K signalling cascades (figure).9 RAS activation acts as an oncogenic driver through unregulated cell cycle progression, growth, and metastases.10 The effects of RAS activation might lead to more aggressive tumour characteristics and possibly worse clinical
Activity of crizotinib in brain metastases
Crizotinib (Pfizer) is a US Food and Drug Administration (FDA)-approved small molecule inhibitor of ALK, MET, and ROS1 tyrosine kinases for use in advanced NSCLC with the ALK rearrangement.23, 24, 25, 26 By inhibiting the ALK and MET tyrosine kinases, crizotinib inhibits tyrosine phosphorylation of activated ALK.27, 28 Many studies, including a phase 3 trial of crizotinib versus standard chemotherapy in previously-treated advanced ALK-rearranged NSCLC,23 have shown greater progression-free
Ceritinib
Ceritinib (Novartis), the second ALK-specific tyrosine kinase inhibitor approved by the FDA, also targets IGF-1R, insulin receptor, and ROS1. Among other pathways, ceritinib inhibits ALK autophosphorylation and the downstream STAT3 pathway. In a phase 1 study,51 ASCEND-1, 62% of crizotinib-naive patients responded, providing the background for two in-progress phase 2 trials of ceritinib.50 In the ASCEND-1 trial,51 14 of 124 patients with brain metastases had measurable intracranial lesions at
Activity of ALK inhibitors in leptomeningeal metastases
Leptomeningeal metastases in the setting of ALK-rearranged disease have been little studied because of their overall poor prognosis and the difficulty in quantifying response to treatment. Morris and colleagues67 reviewed 125 patients with leptomeningeal metastases from NSCLC showing no improvement in overall survival with whole brain radiation therapy (WBRT), but longer survival with the use of intrathecal chemotherapy. Another retrospective study68 of 149 patients with leptomeningeal
Combating tyrosine kinase inhibitor resistance
Most patients given crizotinib develop acquired resistance, many within the CNS. One technique that attempts to increase the effectiveness of crizotinib intracranially is dose escalation: in one case report, dose escalation to 1000 mg from the standard 250 mg given twice daily led to control of progressive brain metastases for 2 weeks before rapid progression within 1 month.40 Another patient was given a combination of dose escalation of crizotinib to 600 mg with high-dose pemetrexed after the
Modification of ALK inhibitors to improve CNS penetration or activity
Second-generation ALK inhibitors with unique characteristics offer an alternative solution to dose escalation for penetrating the blood–brain barrier. X-396 has shown similar brain penetration as crizotinib in mouse models; however, unlike crizotinib, whose CSF concentration falls under the half IC50, X-396 reaches a theoretical concentration of 65 nmol/L, which far surpasses its IC50 of 15 nmol/L.66 The increased potency of X-396 is thought to be from the additional hydrogen bond formations by
Modification of the blood–brain barrier to increase permeability
Another possibility of increasing the CSF concentration of the drugs is increasing the permeability of the blood–brain barrier. As previously mentioned, the blood–brain barrier has both a passive and active role, with P-glycoprotein as a major contributor to active removal of substrates that cross the barrier. One avenue of research is the concurrent inhibition of P-glycoprotein with crizotinib to increase the accumulation of the drug intracranially.48 In mouse models, the concurrent
Modification on the tumour microenvironment
There is substantial evidence that the microenvironment that metastatic tumour cells preferentially invade, including blood vessels, lymphatics, and extracellular matrix, is abnormal.85 This abnormal microenvironment increases tumour progression, metastasis, and treatment resistance, which is especially important in mutations causing more metastases. One hypothesis is that normalisation of healthy tissue physiology can improve patient outcomes.86, 87, 88, 89 A major target of normalisation is
The role of brain radiation in ALK-rearranged NSCLC
The relatively low age of patients with ALK-rearranged tumours is an important consideration when considering treatment for intracranial disease, because many of these patients are still working, have young children, and might be providers for their families; this makes the preservation of cognitive function particularly important. With the discovery of ALK inhibitors, the expected survival of these patients is in the range of years, and long-term control with minimum long-term toxic effect is
Guidelines and future directions
In the case of presentation with, or development of, brain metastases, a multidisciplinary approach composed of medical oncology, radiation oncology, and neurosurgery should be considered for these patients, because there are a range of symptoms that might arise from metastases or treatment. The US National Comprehensive Cancer Network recommends that patients who present with asymptomatic brain metastases be given crizotinib alone. With progression of intracranial disease, symptomatic patients
Conclusion
The prevalence of brain metastases from all cancers is increasing. One promising avenue for increasing the effectiveness of therapy is focusing on the genetic makeup of individual cancers, such as focusing on ALK rearrangments. Crizotinib has already shown better effectiveness compared with standard chemotherapy in ALK-rearranged lung cancers; however, its control of intracranial disease might be restricted. This restriction, and the emergence of mutations that hamper the effectiveness of
Search strategy and selection criteria
References (97)
- et al.
Diagnosis-specific prognostic factors, indexes, and treatment outcomes for patients with newly diagnosed brain metastases: a multi-institutional analysis of 4,259 patients
Int J Radiat Oncol Biol Phys
(2010) - et al.
Tight junctions of the blood-brain barrier: development, composition and regulation
Vascul Pharmacol
(2002) - et al.
Structure and function of the blood-brain barrier
Neurobiol Dis
(2010) - et al.
The blood-brain barrier and oncology: new insights into function and modulation
Cancer Treat Rev
(2000) - et al.
Worse disease-free survival in never-smokers with ALK+ lung adenocarcinoma
J Thorac Oncol
(2012) - et al.
Clinical characteristics associated with ALK rearrangements in never-smokers with pulmonary adenocarcinoma
Lung Cancer
(2014) - et al.
ALK gene translocations and amplifications in brain metastases of non-small cell lung cancer
Lung Cancer
(2013) - et al.
Activity of crizotinib (PF02341066), a dual mesenchymal-epithelial transition (MET) and anaplastic lymphoma kinase (ALK) inhibitor, in a non-small cell lung cancer patient with de novo MET amplification
J Thorac Oncol
(2011) - et al.
Ineffectiveness of crizotinib on brain metastases in two cases of lung adenocarcinoma with EML4-ALK rearrangement
J Thorac Oncol
(2013) - et al.
ALK inhibitor crizotinib combined with intrathecal methotrexate treatment for non-small cell lung cancer with leptomeningeal carcinomatosis
Lung Cancer
(2012)
Adenocarcinoma of the lung with miliary brain and pulmonary metastases with echinoderm microtubule-associated protein like 4-anaplastic lymphoma kinase translocation treated with crizotinib: a case report
Lung Cancer
Clinical impact of continued crizotinib administration after isolated central nervous system progression in patients with lung cancer positive for ALK rearrangement
J Thorac Oncol
Disease flare after treatment discontinuation in a patient with EML4-ALK lung cancer and acquired resistance to crizotinib
J Thorac Oncol
Rapid response of brain metastasis to crizotinib in a patient with ALK rearrangement-positive non-small-cell lung cancer
J Thorac Oncol
High-dose crizotinib for brain metastases refractory to standard-dose crizotinib
J Thorac Oncol
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
Alectinib salvages CNS relapses in ALK-positive lung cancer patients previously treated with crizotinib and ceritinib
J Thorac Oncol
Local ablative therapy of oligoprogressive disease prolongs disease control by tyrosine kinase inhibitors in oncogene-addicted non-small-cell lung cancer
J Thorac Oncol
CH5424802 (RO5424802) for patients with ALK-rearranged advanced non-small-cell lung cancer (AF-001JP study): a single-arm, open-label, phase 1-2 study
Lancet Oncol
Safety and activity of alectinib against systemic disease and brain metastases in patients with crizotinib-resistant ALK-rearranged non-small-cell lung cancer (AF-002JG): results from the dose-finding portion of a phase 1/2 study
Lancet Oncol
CH5424802, a selective ALK inhibitor capable of blocking the resistant gatekeeper mutant
Cancer Cell
Leptomeningeal metastasis from non-small cell lung cancer: survival and the impact of whole brain radiotherapy
J Thorac Oncol
Leptomeningeal carcinomatosis in non-small-cell lung cancer patients: impact on survival and correlated prognostic factors
J Thorac Oncol
Activity of pemetrexed on brain metastases from non-small cell lung cancer
Lung Cancer
Drug metabolism and pharmacokinetics, the blood-brain barrier, and central nervous system drug discovery
NeuroRx
Disruption of the blood-brain barrier as the primary effect of CNS irradiation
Radiother Oncol
Clinical benefit of continuing ALK inhibition with crizotinib beyond initial disease progression in patients with advanced ALK-positive NSCLC
Ann Oncol
Electrical resistance across the blood-brain barrier in anaesthetized rats: a developmental study
J Physiol
Astrocyte-endothelial interactions at the blood-brain barrier
Nat Rev Neurosci
Claudin-1 and claudin-5 expression and tight junction morphology are altered in blood vessels of human glioblastoma multiforme
Acta Neuropathol
The blood-brain barrier and cancer: transporters, treatment, and Trojan horses
Clin Cancer Res
Identification of the transforming EML4-ALK fusion gene in non-small-cell lung cancer
Nature
Inhibition of ALK signaling for cancer therapy
Clin Cancer Res
Targeting anaplastic lymphoma kinase in lung cancer
Clin Cancer Res
EML4-ALK fusion gene in lung cancer and its biological function
Zhongguo Fei Ai Za Zhi
Oncogene status predicts patterns of metastatic spread in treatment-naive nonsmall cell lung cancer
Cancer
Clinical features and outcome of patients with non-small-cell lung cancer who harbor EML4-ALK
J Clin Oncol
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
Predictive and prognostic value of ALK gene rearrangement in non-small cell lung cancer
Epidemiology
Prevalence and clinical outcomes for patients with ALK-positive resected stage I to III adenocarcinoma: results from the European Thoracic Oncology Platform Lungscape Project
J Clin Oncol
Prophylactic cranial irradiation in extensive small-cell lung cancer
N Engl J Med
Prophylactic cranial irradiation for patients with small-cell lung cancer in complete remission
N Engl J Med
Crizotinib versus chemotherapy in advanced ALK-positive lung cancer
N Engl J Med
Anaplastic lymphoma kinase inhibition in non-small-cell lung cancer
N Engl J Med
ROS1 rearrangements define a unique molecular class of lung cancers
J Clin Oncol
Genomic alterations of anaplastic lymphoma kinase may sensitize tumors to anaplastic lymphoma kinase inhibitors
Cancer Res
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
Clinical experience with crizotinib in patients with advanced ALK-rearranged non-small-cell lung cancer and brain metastases
J Clin Oncol
Cited by (167)
Machine-Learning-Aided Prediction of Brain Metastases Development in Non–Small-Cell Lung Cancers
2023, Clinical Lung CancerBrigatinib Versus Alectinib in ALK-Positive NSCLC After Disease Progression on Crizotinib: Results of Phase 3 ALTA-3 Trial
2023, Journal of Thoracic OncologyQuantitation of osimertinib, alectinib and lorlatinib in human cerebrospinal fluid by UPLC-MS/MS
2023, Journal of Pharmaceutical and Biomedical AnalysisLong-Term Efficacy and Safety of Brigatinib in Crizotinib-Refractory ALK+ NSCLC: Final Results of the Phase 1/2 and Randomized Phase 2 (ALTA) Trials
2022, JTO Clinical and Research ReportsCitation Excerpt :Although crizotinib provides improved efficacy and tolerability compared with chemotherapy, most patients experience disease progression on crizotinib within a year.5,6 The central nervous system (CNS) is often the first site of disease progression on crizotinib, reflecting inadequate drug penetration into the brain.7–9 Other mechanisms of resistance to crizotinib include the acquisition of secondary mutations in ALK that interfere with crizotinib binding, amplification of the ALK fusion gene, and up-regulation of bypass signaling pathways.10