Experimental Treatments for Leptomeningeal Metastases From Solid Malignancies

Solmaz Sahebjam, MD; Peter A. Forsyth, MD; Keiran S. Smalley, PhD; Nam D. Tran, MD, PhD

Disclosures

Cancer Control. 2017;24(1):42-46. 

In This Article

Targeted Therapies

Melanoma

BRAF Inhibitors. Several case series and retrospective reviews have shown an intracranial benefit for patients with active brain metastases harboring BRAF V600 mutations treated with vemurafenib.[4,5,19] An intracranial response rate of 48.1% was reported by Gibney et al.[19] However, the activity of vemurafenib in patients with leptomeningeal metastasis is less clear. In 2 patients with tumors harboring BRAF V600 mutations, treatment with either vemurafenib alone or in sequence with whole-brain radiotherapy resulted in marked responses and the long-term stabilization of leptomeningeal disease.[4,5] Schäfer et al[4] studied the drug in a person with leptomeningeal metastasis whose disease was unresponsive to whole-brain radiotherapy. Dosing of vemurafenib was given at 960 mg twice per day. Twelve weeks after the initiation of vemurafenib, the patient had a complete resolution of clinical symptoms, achieved a cytological response in CSF, and had marked radiographic regression of the meningeal lesions on magnetic resonance imaging.[4] However, analyses of the CSF concentration of vemurafenib in patients with brain metastases have revealed very low ratios of CSF:plasma concentration (0.98% ± 0.84%) and large rates of interindividual variability.[20]

Dabrafenib has demonstrated intracranial antitumor activity in patients with BRAF V600E or V600K–mutant melanoma brain metastases.[21] In a phase 2 trial evaluating dabrafenib in patients with active brain metastases from BRAF V600E or V600K–mutant melanoma, the overall intracranial response rates (complete response + partial response) of 39.2% and 6.7% were observed in those with no previous local treatment and BRAF V600E or V600K–mutant tumors, respectively.[21] These results suggest that dabrafenib can functionally penetrate the disrupted blood–brain barrier within melanoma brain metastases.

Wilgenhof and Neyns[3] reported a patient with leptomeningeal metastasis from BRAF V600E–mutant melanoma treated with dabrafenib 150 mg twice a day. Complete imaging and cytological response were observed after 4 weeks of dabrafenib and continued at the time of report (15 weeks after the initiation of dabrafenib), suggesting that dabrafenib may have potential benefit in patients with leptomeningeal metastasis from BRAF V600E or V600K–mutant melanoma.[3]

Non–Small-Cell Lung Cancer

Epidermal Growth Factor Receptor–Tyrosine Kinase Inhibitors.High-dose epidermal growth factor receptor–tyrosine kinase inhibitors: High-dose tyrosine kinase inhibitors (TKIs) have been used to treat leptomeningeal metastasis from EGFR-mutant non–small-cell lung cancer (NSCLC) based on the hypothesis that higher concentrations in the CSF can be reached by using higher, systemic concentrations of TKI.[6,22] Using standard doses of epidermal growth factor receptor (EGFR)–TKIs, CSF concentrations of the drug can be as low as 1% plasma levels below half maximal inhibitory concentration.[6,22] Therefore, the CSF concentration of EGFR-TKIs achieved by standard daily dosing may be insufficient for a therapeutic effect.

By contrast, the intermittent "pulsatile" administration of high-dose erlotinib (1500 mg once weekly) has been shown to be well tolerated and does achieve therapeutic drug levels in the CSF.[22] With this regimen, concentrations of the drug in the CSF exceeded the half maximal inhibitory concentration for EGFR-mutant lung cancer cells in a patient with leptomeningeal metastasis.[22]

Grommes et al[11] reported on a series of 9 patients with EGFR-mutant NSCLC who had developed CNS metastases despite conventional daily erlotinib therapy or other EGFR-TKIs. Eight patients had leptomeninge-al metastasis. Pulsatile erlotinib was administered as monotherapy to all patients at a median weekly dose of 1500 mg (range, 900–1500 mg).[11] Median time to CNS progression was 2.7 months (range, 0.8–14.5 months), and the median overall survival rate was 12 months.[11]

Several reports of patients with leptomeningeal metastasis from EGFR-mutant NSCLC have described similar responses with pulsatile high-dose erlotinib or daily high-dose gefitinib.[6,12–14] These data suggest that high-dose EGFR-TKI therapy can be effective in achieving higher CSF concentrations of the drug and, therefore, may control leptomeningeal metastasis in a subset of patients with EGFR-mutant NSCLC.

Dual-targeting of epidermal growth factor: receptor. Dual targeting of EGFR has been reported as a potential therapy for patients with leptomeningeal metastasis from EGFR-mutant NSCLC.[23] A phase 1b trial combining afatinib, a second-generation EGFR-TKI, and cetuximab observed an objective response rate of 29% in individuals with advanced EGFR-mutant NSCLC with systemic disease progression after receiving gefitinib or erlotinib.[23] This result has raised the question as to whether this strategy might be effective in controlling leptomeningeal metastasis in patients with EGFR-positive NSCLC.

Lin et al[7] reported on 1 patient with exon 19 deleted NSCLC who developed leptomeningeal metastasis after 4 years of multiple treatments, including gefitinib and erlotinib. Treatment with 1 month of pulsatile erlotinib, at a dose of 1050 mg weekly, did not control leptomeningeal metastasis, but subsequent treatment with afatinib 40 mg daily and cetuximab 250 mg/m2 biweekly resulted in clinical improvement as well as improvement seen on imaging.[7] The improvement in leptomeningeal metastasis remained stable until the patient died from systemic disease progression 4 months later.[7] The authors suggest that dual-targeted therapy may still benefit patients with leptomeningeal metastasis from EGFR-positive NSCLC whose disease has progressed on a high-dose TKI.[7]

Tyrosine Kinase Inhibitors of Anaplastic Lymphoma Kinase in Lung Cancer. The CNS is a frequent site of relapse among patients with ALK-rearranged NSCLC who have been treated with crizotinib.[24] The poor penetration of crizotinib to the brain ("pharmacokinetic relapse"), rather than cellular resistance, has been suspected as the mechanism of treatment failure.[24,25]

Ceritinib is a potent inhibitor of anaplastic lymphoma kinase (ALK) that has shown significant benefit in ALK-rearranged NSCLC refractory to crizotinib therapy.[26] It also has activity in the CNS: Partial responses have been seen in brain metastases among crizotinibnaive and crizotinib-refractory tumors, suggesting possible activity in patients with leptomeningeal metastasis.[26] Arrondeau et al[8] reported on 1 patient with crizotinib-refractory leptomeningeal metastasis who was treated with daily ceritinib (initially 750 mg and then 600 mg). The patient achieved stable disease seen on imaging and durable clinical improvements that lasted for more than 6 months.[8] However, ceritinib has been shown to cross the blood–brain barrier in rat models at a brain-to-blood exposure ratio (AUCinf) of 15%.[27] Although its penetration into the CSF in patients with leptomeningeal metastasis is unknown, CSF concentration is likely higher due to a disrupted blood–CSF barrier in the setting of leptomeningeal metastasis.

Alectinib is a second-generation TKI of ALK that has shown promising CNS activity in study patients with ALK-rearranged NSCLC. It is approximately 5 times more potent than crizotinib against ALK, and it inhibits RET with similar potency to ALK.[28] Preclinical studies have suggested that alectinib is not a substrate of P-glycoprotein, a key factor in the blood–brain barrier, and that it achieves high brain-to-plasma ratios (range, 0.63–0.94) in intracranial tumor implantation murine models of EML4-ALK–positive NSCLC.[28]

In a phase 2 study of alectinib in crizotinib-refractory ALK-rearranged NSCLC, a complete CNS response rate of 27% was observed.[29] Alectinib also resulted in an overall CNS response rate of 57% in study patients with measurable CNS metastases.[29] Alectinib has shown efficacy in symptomatic individuals who have crizotinib- or ceritinib-refractory leptomeningeal metastasis.[9] In a case series by Gainor et al,[9] alectinib 600 mg twice daily resulted in significant clinical and radiographic improvements in 3 out of 4 of patients with crizotinib- or ceritinib-refractory leptomeningeal metastasis from ALK-rearranged NSCLCs. The fourth patient achieved stable disease for approximately 4 months.[9]

PF-06463922 is an investigational agent with superior potency against all known clinically acquired ALK mutations, including the highly resistant G1202R mutant, and is designed to minimize P-glycoprotein– mediated drug efflux and optimize penetration of the CNS.[30] It has shown significant regression of EML4-ALK–driven brain metastases in murine models, which led to prolonged rates of survival.[30] This drug is being investigated in a phase 1/2 trial.

Breast Cancer

Intrathecal Trastuzumab ERBB2 (formerly known as HER2/neu)-positive breast cancers have a high affinity for CNS involvement.[31] Better control of systemic ERBB2-positive breast cancer with agents such as trastuzumab has led to a higher prevalence of CNS and leptomeningeal metastases. Trastuzumab can be intrathecally administered, either alone or in combination with different chemotherapy agents (eg, methotrexate) and has shown promising results in participants with leptomeningeal metastasis from ERBB2-positive breast cancer.[10,15–18] Although this treatment regimen has not yet been reported in a clinical trial setting, numerous case reports have demonstrated its safety and efficacy in patients with ERBB2-positive breast cancer–associated leptomeningeal metastasis.[18] Systemic review and pooled analyses of 17 patients treated with intrathecal trastuzumab alone or in combination with chemotherapy reported a median overall survival rate of 13.5 months (compared with 5.9 months in historical cohorts) and a median CNS progression-free survival rate of 7.5 months.[18] The continued administration of intrathecal trastuzumab beyond disease progression and switching intrathecal chemotherapy agents appeared to be safe and resulted in significant clinical benefit (median CNS progression-free survival of 9.4 months beyond progression).[18] The recommended dosing schedule of intrathecal trastuzumab administration is unknown, and different dosing ranges (eg, 20–100 mg weekly, 100–150 mg biweekly) have been used with no safety issues.[18] In our experience, intrathecal trastuzumab is a safe and effective therapy for patients with ERBB2-positive breast cancer leptomeningeal metastasis, which can delay the need for whole-brain radiotherapy and provide clinical and cytological improvements as well as improvements seen on imaging.

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