Elsevier

Clinical Lung Cancer

Volume 18, Issue 4, July 2017, Pages 354-363
Clinical Lung Cancer

Review
Pulsatile Erlotinib in EGFR-Positive Non–Small-Cell Lung Cancer Patients With Leptomeningeal and Brain Metastases: Review of the Literature

https://doi.org/10.1016/j.cllc.2017.01.013Get rights and content

Abstract

Patients with epidermal growth factor receptor (EGFR)-positive (EGFR+) non–small-cell lung cancer (NSCLC) show improved response rates when treated with tyrosine kinase inhibitors (TKIs) such as erlotinib. However, standard daily dosing of erlotinib often does not reach therapeutic concentrations within the cerebrospinal fluid (CSF), resulting in progression of central nervous system (CNS) disease. Intermittent, high-dose administration of erlotinib reaches therapeutic concentrations within the CSF and is well tolerated in patients. Experience with “pulsatile” dosing, however, is limited. We review the literature on the pharmacology and clinical outcomes of pulsatile erlotinib in the treatment of EGFR+ NSCLC with brain and leptomeningeal metastases, and include available data on the use of next-generation TKIs in CNS progression. We also provide our institution's experience with patients treated with pulsatile erlotinib for CNS metastasis, and propose clinical criteria for its use. Pulsatile erlotinib is a reasonable alternative in EGFR+ patients with new or worsening CNS disease, without evidence of systemic progression, and without confirmed T790M resistance mutations within the CNS.

Introduction

Central nervous system (CNS) disease is a frequent and deadly complication of non–small-cell lung cancer (NSCLC), and includes brain as well as leptomeningeal metastases. Brain metastases develop in 10% to 40% of nonselected NSCLC patients, depending on stage, and is associated with a median overall survival (OS) of only 7 months.1, 2, 3 Leptomeningeal disease occurs less frequently, with an estimated incidence of 5% to 10%.4 However, survival for leptomeningeal disease is even poorer, with a median OS of only 2.5 months from diagnosis.4 Despite improvements in systemic treatment for advanced NSCLC, options for CNS disease remain fairly limited, and might include surgery, whole brain radiation therapy (WBRT), stereotactic radiosurgery (SRS), or systemic therapy.

In appropriately selected patients, there has been increased interest in the use of targeted therapy for the treatment of NSCLC with intracranial spread. Somatic epidermal growth factor receptor (EGFR) mutations occur in an estimated 15% of NSCLC patients, and are enriched in female, nonsmoking, and Asian populations.5 Ninety percent of these mutations are either exon 19 deletions or exon 21 L858R point mutations within the EGFR kinase domain.6 The discovery of EGFR mutations was an important turning point in the approach to NSCLC therapy, because EGFR-positive (EGFR+) patients show increased response rates and progression-free survival (PFS) when treated with tyrosine kinase inhibitors (TKIs).7, 8 Furthermore, there has been evidence to suggest that TKIs have CNS activity in EGFR+ patients, with up to an 88% response rate seen in one series.9

However, despite improvements in outcome, EGFR+ patients treated with a first-line TKI will still develop disease progression, with a median PFS of < 1 year.7, 10 In particular, CNS metastasis occurs in 30% of EGFR+ patients initially treated with a TKI.11, 12 Interestingly, the mechanisms of CNS progression might differ from the mechanisms of systemic progression. Most patients treated with TKIs experience worsening systemic disease because of the acquisition of TKI resistance mutations. However, genetic studies of brain metastasis in NSCLC patients show that intracranial lesions often do not harbor these resistance mutations.13, 14 It is thought that the mechanism of intracranial progression might instead have to do with the pharmacokinetics of TKI penetration into the CNS.

Previous studies have shown that standard daily dosing of erlotinib, a first-generation TKI, might not reach therapeutic concentrations within the CNS.14 However, pulsatile dosing can result in adequate CNS penetration14 and is well tolerated in patients.15 We review the literature on the use of pulsatile erlotinib in the treatment of EGFR+ NSCLC with brain and leptomeningeal metastases, including rationale, pharmacology, and clinical outcomes. We also include our institution's experience of patients treated with pulsatile erlotinib for CNS metastasis, and propose criteria in which pulsatile erlotinib can be initiated. Discussion of pulsatile erlotinib for non–CNS-related disease is beyond the scope of this review.

Section snippets

Efficacy of Standard-Dose TKIs in NSCLC With CNS Metastasis

Brain metastasis occurs at a higher rate in EGFR+ NSCLC patients, although this finding might be confounded by the longer survival seen in this subgroup of patients.16 Median OS from time of brain metastasis in NSCLC patients with EGFR mutations is 14.5 months, compared with 7.6 months for wild type patients in 1 retrospective analysis.17 Delivery of chemotherapy into the cerebrospinal fluid (CSF) is made difficult by the inability of most systemic chemotherapy to cross the blood-brain barrier

Standard-Dose TKI Failure in CNS Disease

As discussed previously, TKIs are promising in the treatment of CNS metastasis in EGFR+ patients, and are increasingly used for second- or even first-line treatment, in the case of leptomeningeal disease. However, CNS progression remains common during standard TKI treatment. In a series of 21 patients with nonselected NSCLC treated with gefitinib who initially attained partial response, 9 patients (43%) developed CNS recurrence after a median follow-up of 27 months.64 In larger studies of EGFR+

Pharmacology of TKI Penetration Into the CNS

The BBB excludes large hydrophilic molecules from crossing into the CSF, and transportation of drugs is mediated by active transport mechanisms, which are further counteracted by efflux pumps.67 However, brain metastasis disrupts the BBB and increases drug permeability across cell membranes, as evidenced by pharmacologic studies showing increased CSF concentrations in patients with brain tumors compared with normal primates.68 In a small case series of 4 patients, the mean steady-state CSF

Clinical Experience With Pulsatile Erlotinib in CNS Metastasis for EGFR+ NSCLC

Clinical experience with pulsatile erlotinib for the treatment of CNS metastasis in EGFR+ NSCLC has largely been restricted to case reports and case series in the literature. We performed a literature review on the use of pulsatile erlotinib in EGFR+ NSCLC patients with CNS metastasis, and also included our institution's experience with pulsatile erlotinib. For the literature review, studies were identified by searching PubMed with keywords including “pulsatile,” “erlotinib,” “tyrosine kinase

Clinical Experience With High-Dose TKI in CNS Metastasis for EGFR+ NSCLC

Alternative regimens besides pulsatile dosing have also been used to achieve adequate CSF levels (Table 1). Jackman et al reported successful control of leptomeningeal metastasis in a NSCLC patient treated with high-dose gefitinib.13 At a standard dose of 250 mg daily, CSF penetration was inadequate, and the dose was progressively increased from 500 mg/d to 1000 mg/d over a period of 10 weeks. CSF concentrations at this increased dose was 42 nmol/L, compared with 18 nmol/L at a dose of 500

Conclusions and Future Directions

The efficacy of pulsatile erlotinib is likely because of increased CNS penetration, and has been shown to result in remarkable disease control in patients with leptomeningeal or brain metastasis. Because clear evidence exists for TKI activity in the CNS at standard doses, there are likely individual differences in TKI penetration resulting in variable response to pulsatile scheduling.28, 61 In some patients with refractory CNS disease, the benefits can be impressive. Thus, pulsatile erlotinib

Disclosure

The authors have stated that they have no conflicts of interest.

References (85)

  • Y.L. Wu 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)
  • G.L. Ceresoli et al.

    Gefitinib in patients with brain metastases from non–small-cell lung cancer: a prospective trial

    Ann Oncol

    (2004)
  • K. Hotta et al.

    Effect of gefitinib (‘Iressa,’ ZD1839) on brain metastases in patients with advanced non–small-cell lung cancer

    Lung Cancer

    (2004)
  • Y. Namba et al.

    Gefitinib in patients with brain metastases from non–small-cell lung cancer: review of 15 clinical cases

    Clin Lung Cancer

    (2004)
  • C.H. Chiu et al.

    Gefitinib is active in patients with brain metastases from non–small-cell lung cancer and response is related to skin toxicity

    Lung Cancer

    (2005)
  • C. Wu et al.

    Gefitinib as palliative therapy for lung adenocarcinoma metastatic to the brain

    Lung Cancer

    (2007)
  • Z. Song et al.

    Gefitinib and erlotinib for non–small-cell lung cancer patients who fail to respond to radiotherapy for brain metastases

    J Clin Neurosci

    (2014)
  • P. Hoffknecht et al.

    Efficacy of the irreversible ErbB family blocker afatinib in epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI)-pretreated non–small-cell lung cancer patients with brain metastases or leptomeningeal disease

    J Thorac Oncol

    (2015)
  • M. Schuler et al.

    First-line afatinib versus chemotherapy in patients with non–small-cell lung cancer and common epidermal growth factor receptor gene mutations and brain metastases

    J Thorac Oncol

    (2016)
  • L. Gong et al.

    Icotinib might be effective for the treatment of leptomeningeal carcinomatosis in non–small-cell lung cancer with sensitive EGFR mutations

    Lung Cancer

    (2015)
  • T. Katayama 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)
  • H.G. Yi et al.

    Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) are effective for leptomeningeal metastasis from non–small-cell lung cancer patients with sensitive EGFR mutation or other predictive factors of good response for EGFR TKI

    Lung Cancer

    (2009)
  • R. Kanemaru et al.

    Successful treatment with weekly high-dose erlotinib against meningeal metastases from epidermal growth factor receptor (EGFR)-mutated lung adenocarcinoma

    Respir Investig

    (2016)
  • N.K. Gerber et al.

    Erlotinib versus radiation therapy for brain metastases in patients with EGFR-mutant lung adenocarcinoma

    Int J Radiat Oncol Biol Phys

    (2014)
  • P.W. Sperduto 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)
  • T. Jiang et al.

    EGFR TKIs plus WBRT demonstrated no survival benefit other than that of TKIs alone in patients with NSCLC and EGFR mutation and brain metastases

    J Thorac Oncol

    (2016)
  • Y.L. Wu et al.

    Afatinib versus cisplatin plus gemcitabine for first-line treatment of Asian patients with advanced non–small-cell lung cancer harbouring EGFR mutations (LUX-Lung 6): an open-label, randomised phase 3 trial

    Lancet Oncol

    (2014)
  • C.S. Tan et al.

    Next-generation epidermal growth factor receptor tyrosine kinase inhibitors in epidermal growth factor receptor -mutant non–small-cell lung cancer

    Lung Cancer

    (2016)
  • S. Umemura et al.

    Clinical outcome in patients with leptomeningeal metastasis from non–small-cell lung cancer: Okayama Lung Cancer Study Group

    Lung Cancer

    (2012)
  • P.G. Morris et al.

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

    J Thorac Oncol

    (2012)
  • J.H. Park et al.

    Clinical outcomes of leptomeningeal metastasis in patients with non–small-cell lung cancer in the modern chemotherapy era

    Lung Cancer

    (2012)
  • Y.S. Li et al.

    Leptomeningeal metastases in patients with NSCLC with EGFR mutations

    J Thorac Oncol

    (2016)
  • E. Lee et al.

    Erlotinib versus gefitinib for control of leptomeningeal carcinomatosis in non–small-cell lung cancer

    J Thorac Oncol

    (2013)
  • P.E. Postmus et al.

    Chemotherapy for brain metastases of lung cancer: a review

    Ann Oncol

    (1999)
  • Y. Togashi 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)
  • M. Hidalgo et al.

    Pharmacokinetics and pharmacodynamics: maximizing the clinical potential of erlotinib (Tarceva)

    Semin Oncol

    (2003)
  • J.L. Kuiper et al.

    High-dose, pulsatile erlotinib in two NSCLC patients with leptomeningeal metastases–one with a remarkable thoracic response as well

    Lung Cancer

    (2013)
  • A. Hata et al.

    High-dose erlotinib for refractory brain metastases in a patient with relapsed non–small-cell lung cancer

    J Thorac Oncol

    (2011)
  • R. Kanemaru et al.

    Successful treatment with weekly high-dose erlotinib against meningeal metastases from epidermal growth factor receptor (EGFR)-mutated lung adenocarcinoma

    Respir Investig

    (2016)
  • S.B. Goldberg et al.

    Pembrolizumab for patients with melanoma or non–small-cell lung cancer and untreated brain metastases: early analysis of a non-randomised, open-label, phase 2 trial

    Lancet Oncol

    (2016)
  • P.W. Sperduto et al.

    Summary report on the graded prognostic assessment: an accurate and facile diagnosis-specific tool to estimate survival for patients with brain metastases

    J Clin Oncol

    (2012)
  • P.H. Goncalves et al.

    Risk of brain metastases in patients with nonmetastatic lung cancer: analysis of the Metropolitan Detroit Surveillance, Epidemiology, and End Results (SEER) data

    Cancer

    (2016)
  • Cited by (42)

    • High-Dose Osimertinib for CNS Progression in EGFR+ NSCLC: A Multi-Institutional Experience

      2022, JTO Clinical and Research Reports
      Citation Excerpt :

      Side effects of first- and second-generation EGFR TKIs, primarily mediated by EGFR wild-type inhibition, prohibited the possibility of simply raising the daily dose to achieve this effect. Pulsatile dosing was initially attempted with gefitinib19 and erlotinib,20–22 but suggested only transient clinical benefit. For example, the largest series reporting efficacy for pulse-dose erlotinib (1500 mg once weekly) was a retrospective study that included nine patients with either new CNS disease (three patients) or CNS progression on standard-dose EGFR TKI (six patients).20

    • Brain metastases: An update on the multi-disciplinary approach of clinical management

      2022, Neurochirurgie
      Citation Excerpt :

      One such study evaluating intracranial tumor burden and outcomes in patients with EGFR-mutant or ALK-rearranged lung cancer with cerebral metastasis found that most patients who were treated with tyrosine kinase inhibitors achieved an early and sustained volumetric intracranial response regardless of presenting intracranial tumor burden or presence of neurological symptoms [214]. In patients with EGFR-mutant BM, the use of first generation EGFR inhibitors, such as gefitinib and erlotinib, has been shown to be associated with improved response rates, progression free survival (PFS) and overall survival (OS) [215,216], but studies evaluating the combined use of these agents plus radiotherapy have failed to produce consistent results [217–219]. The development of second- and third-generation inhibitors, afatinib and osimertinib, which target the EGFRT790M mutation, has led to even more promising results.

    • Leptomeningeal Carcinomatosis: Molecular Landscape, Current Management, and Emerging Therapies

      2020, Neurosurgery Clinics of North America
      Citation Excerpt :

      Similarly, Capecitabine has been reported to offer clinical benefit to patients with breast cancer LMC.79–82 To treat EGFR-mutated NSCLC LMC, the TKI Erlotinib is “pulsed” intermittently at high doses to deliver therapeutic concentrations to the CSF.83 For LMC arising from nonsolid tumors, high-dose Cytarabine has been effective against CNS leukemias.84,85

    • Phase I dose-escalation trial of tucatinib in combination with trastuzumab in patients with HER2-positive breast cancer brain metastases

      2020, Annals of Oncology
      Citation Excerpt :

      Thus we believed a phase Ib study to determine the MTD of tucatinib with trastuzumab was warranted. In addition, we were interested in exploring a q.d. schedule of tucatinib, given observations that pulse doses of erlotinib or lapatinib provided additional CNS efficacy in patients with EGFR-mutant non-small-cell lung cancer and HER2-positive breast cancer, respectively, by driving higher drug levels into the brain.7–9 We thus launched a prospective phase Ib study to determine the MTD of tucatinib tablet formulation, given on either a b.i.d. or a q.d. schedule, in combination with trastuzumab.

    • Neurological Death is Common in Patients With EGFR Mutant Non-Small Cell Lung Cancer Diagnosed With Brain Metastases

      2020, Advances in Radiation Oncology
      Citation Excerpt :

      The strongest predictor of that outcome was LMD, which likely occurs more frequently in patients with EGFRm NSCLC compared with non-EGFRm NSCLC.22 Although LMD in EGFRm NSCLC sometimes responds to pulsed dosed erlotinib,23 third-generation EGFR TKIs such as osimertinib,24 or WBRT,25 LMD ultimately results in ND in most if not all patients with EGFRm NSCLC and represents a critical endpoint in this disease. A previous report from our institution describing a cohort of ALK+ and EGFRm patients reported similar rates of OS regardless of first-line BrM treatment.13

    View all citing articles on Scopus
    View full text