Elsevier

The Lancet Oncology

Volume 16, Issue 13, October 2015, Pages e510-e521
The Lancet Oncology

Review
Targeting brain metastases in ALK-rearranged non-small-cell lung cancer

https://doi.org/10.1016/S1470-2045(15)00013-3Get rights and content

Summary

The incidence of brain metastases has increased as a result of improved systemic control and advances in imaging. However, development of novel therapeutics with CNS activity has not advanced at the same rate. Research on molecular markers has revealed many potential targets for antineoplastic agents, and a particularly important aberration is translocation in the ALK gene, identified in non-small-cell lung cancer (NSCLC). ALK inhibitors have shown systemic efficacy against ALK-rearranged NSCLC in many clinical trials, but the effectiveness of crizotinib in CNS disease is limited by poor blood–brain barrier penetration and acquired drug resistance. In this Review, we discuss potential pathways to target ALK-rearranged brain metastases, including next generation ALK inhibitors with greater CNS penetration and mechanisms to overcome resistance. Other important mechanisms to control CNS disease include targeting pathways downstream of ALK phosphorylation, increasing the permeability of the blood–brain barrier, modifying the tumour microenvironment, and adding concurrent radiotherapy.

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

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

References (97)

  • AT Falk et al.

    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

    (2012)
  • M Takeda et al.

    Clinical impact of continued crizotinib administration after isolated central nervous system progression in patients with lung cancer positive for ALK rearrangement

    J Thorac Oncol

    (2013)
  • O Pop et al.

    Disease flare after treatment discontinuation in a patient with EML4-ALK lung cancer and acquired resistance to crizotinib

    J Thorac Oncol

    (2012)
  • H Kaneda et al.

    Rapid response of brain metastasis to crizotinib in a patient with ALK rearrangement-positive non-small-cell lung cancer

    J Thorac Oncol

    (2013)
  • YH Kim et al.

    High-dose crizotinib for brain metastases refractory to standard-dose crizotinib

    J Thorac Oncol

    (2013)
  • L Gandhi et al.

    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)
  • JF Gainor et al.

    Alectinib salvages CNS relapses in ALK-positive lung cancer patients previously treated with crizotinib and ceritinib

    J Thorac Oncol

    (2015)
  • AJ Weickhardt 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)
  • T Seto et al.

    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

    (2013)
  • SM Gadgeel et al.

    Safety and activity of alectinib against systemic disease and brain metastases in patients with crizotinib-resistant ALK-rearranged non-small-cell lung cancer (AF-002JG): results from the dose-finding portion of a phase 1/2 study

    Lancet Oncol

    (2014)
  • H Sakamoto et al.

    CH5424802, a selective ALK inhibitor capable of blocking the resistant gatekeeper mutant

    Cancer Cell

    (2011)
  • PG Morris et al.

    Leptomeningeal metastasis from non-small cell lung cancer: survival and the impact of whole brain radiotherapy

    J Thorac Oncol

    (2012)
  • SJ Lee et al.

    Leptomeningeal carcinomatosis in non-small-cell lung cancer patients: impact on survival and correlated prognostic factors

    J Thorac Oncol

    (2013)
  • A Bearz et al.

    Activity of pemetrexed on brain metastases from non-small cell lung cancer

    Lung Cancer

    (2010)
  • MS Alavijeh et al.

    Drug metabolism and pharmacokinetics, the blood-brain barrier, and central nervous system drug discovery

    NeuroRx

    (2005)
  • P Rubin et al.

    Disruption of the blood-brain barrier as the primary effect of CNS irradiation

    Radiother Oncol

    (1994)
  • SH Ou et al.

    Clinical benefit of continuing ALK inhibition with crizotinib beyond initial disease progression in patients with advanced ALK-positive NSCLC

    Ann Oncol

    (2014)
  • AM Butt et al.

    Electrical resistance across the blood-brain barrier in anaesthetized rats: a developmental study

    J Physiol

    (1990)
  • NJ Abbott et al.

    Astrocyte-endothelial interactions at the blood-brain barrier

    Nat Rev Neurosci

    (2006)
  • S Liebner et al.

    Claudin-1 and claudin-5 expression and tight junction morphology are altered in blood vessels of human glioblastoma multiforme

    Acta Neuropathol

    (2000)
  • JF Deeken et al.

    The blood-brain barrier and cancer: transporters, treatment, and Trojan horses

    Clin Cancer Res

    (2007)
  • M Soda et al.

    Identification of the transforming EML4-ALK fusion gene in non-small-cell lung cancer

    Nature

    (2007)
  • YP Mossé et al.

    Inhibition of ALK signaling for cancer therapy

    Clin Cancer Res

    (2009)
  • AT Shaw et al.

    Targeting anaplastic lymphoma kinase in lung cancer

    Clin Cancer Res

    (2011)
  • T Yang et al.

    EML4-ALK fusion gene in lung cancer and its biological function

    Zhongguo Fei Ai Za Zhi

    (2012)
  • RC Doebele et al.

    Oncogene status predicts patterns of metastatic spread in treatment-naive nonsmall cell lung cancer

    Cancer

    (2012)
  • AT Shaw et al.

    Clinical features and outcome of patients with non-small-cell lung cancer who harbor EML4-ALK

    J Clin Oncol

    (2009)
  • SH Ou et al.

    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)
  • KWY Kulig et al.

    Predictive and prognostic value of ALK gene rearrangement in non-small cell lung cancer

    Epidemiology

    (2014)
  • FH Blackhall et al.

    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

    (2014)
  • B Slotman et al.

    Prophylactic cranial irradiation in extensive small-cell lung cancer

    N Engl J Med

    (2007)
  • A Aupérin et al.

    Prophylactic cranial irradiation for patients with small-cell lung cancer in complete remission

    N Engl J Med

    (1999)
  • AT Shaw et al.

    Crizotinib versus chemotherapy in advanced ALK-positive lung cancer

    N Engl J Med

    (2013)
  • EL Kwak et al.

    Anaplastic lymphoma kinase inhibition in non-small-cell lung cancer

    N Engl J Med

    (2010)
  • K Bergethon et al.

    ROS1 rearrangements define a unique molecular class of lung cancers

    J Clin Oncol

    (2012)
  • U McDermott et al.

    Genomic alterations of anaplastic lymphoma kinase may sensitize tumors to anaplastic lymphoma kinase inhibitors

    Cancer Res

    (2008)
  • JG Christensen 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)
  • DB Costa et al.

    Clinical experience with crizotinib in patients with advanced ALK-rearranged non-small-cell lung cancer and brain metastases

    J Clin Oncol

    (2015)
  • Cited by (167)

    • Long-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 Reports
      Citation 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

    View all citing articles on Scopus
    View full text