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Table 5. Studies on ALK inhibitors in patients with LM from non-small-cell lung cancer
Study No. of patients Treatment Outcomes
Costa et al. [28] , 2011 1 WBRT plus crizotinib 250 mg twice daily PFS:9 months
Ahn et al. [114] , 2012 2 Intrathecal MTX plus crizotinib 250 mg twice PFS 5 and 10 months, respectively
daily
Arrondeau et al. [117] , 2014 1 Ceritinib 750 mg daily PFS: 5.5 months
Dudnik et al. [118] , 2015 3 WBRT plus ceritinib 500 mg/daily PFS - Patients 1: 18 months
Patient 2 and 3: 7 months
Gainor et al. [122] , 2015 4 Alectinib 600 mg twice daily Radiological and neurological improvement
in 4/4 patients (75%)
Ou et al. [123] , 2015 1 Alectinib 600-750 mg twice daily Long-lasting complete response (15 months)
Gainor et al. [124] 2016 2 Alectinib 900 mg twice daily Radiological and neurological improvement
for 3.5 and 6 months, respectively
Gaye et al. [126] , 2019 1 Brigatinib 180 mg once daily with a 7-day PFS 14 months
lead-in period at 90 mg
Pellerino et al. [128] , 2019 1 Lorlatinib 100 mg once daily PFS 12 months
Complete radiological response
ALK: anaplastic lymphoma kinase; LM: leptomeningeal metastases; CR: complete response; PR: partial response; SD: stable disease; PFS:
progression-free survival; OS: overall survival; MTX: methotrexate; WBRT: whole-brain radiotherapy

reduction of EGFR expression on the cell surface, and one patient had a CSF conversion in two consecutive
[110]
[109]
samples . Cho et al. have investigated the efficacy of AZD3759 at two different doses (200 mg or 300 mg)
reporting in 5/18 patients (27.8%) a radiological response, and in 9/18 patients (50%) a stable disease.
A new anti-EGFR monoclonal antibody, nimotuzumab, has demonstrated some activity in BM from
NSCLC . Xu et al. have used nimotuzumab in association with erlotinib in 3 patients with advanced
[112]
[111]
LM reporting clinical improvement within 6-8 months from the start of treatment and a radiological
response in 2/3 patients.

Role of ALK inhibitors in LM from NSCLC
LM in ALK rearranged NSCLC tends to occur in approximately 5% of patients as a late complication after
a median time of 9 months from the diagnosis of the systemic tumor . Although the benefit from ALK
[6]
inhibitors has been established in BM, data regarding the activity in LM are limited to case-reports. The
first-generation ALK, ROS1, and MET inhibitor crizotinib has demonstrated remarkable CNS disease
control rate (55% and 65% at 12 and 24 weeks, respectively) in patients with BM [23,113] . Three case reports
described the activity from the association of crizotinib and WBRT or intrathecal methotrexate in LM,
reporting a PFS of 6-10 months [Table 5] [19,114] . The second-generation ALK/ROS1 inhibitor ceritinib
displayed significant systemic and intracranial activity in patients with ALK rearrangement who were
pretreated with crizotinib [115,116] . Ceritinib has been also reported to be active in LM in association with
either traditional chemotherapy or WBRT in patients who progressed after failure of crizotinib, with a
median PFS of 5-18 months [117,118] . The phase II ASCEND 7 trial has investigated ceritinib in BM and
LM from ALK rearranged NSCLC. Forty-two patients previously treated with radiotherapy and an ALK
inhibitor were assigned to arm 1; 40 patients with prior ALK inhibitor alone were assigned to arm 2; 12
patients with prior radiotherapy alone were assigned to arm 3; and 44 patients not previously treated with
radiotherapy or an ALK inhibitor were assigned to arm 4. Evaluation of the intracranial response was
done in 28, 29, 7, and 33 patients in the respective arms having measurable BM at baseline, and showed
an intracranial objective response rate (ORR) of 39.3%, 27.6%, 28.6%, and 51.5% in arms 1, 2, 3, and
4, respectively. Unfortunately, the trial reported the intracranial ORR for BM only, without any details
[119]
regarding LM response . Alectinib, which is a second-generation ALK/RET inhibitor, has been approved
either after crizotinib and as a first-line treatment for ALK rearranged NSCLC [120,121] . Different case series
on LM have reported significant and durable radiological responses with both standard (600 mg twice
daily) and increased dose (900 mg twice daily) [122-124] . Moreover, the J-ALEX trial has compared the efficacy
of alectinib or crizotinib as first line-treatment in BM and asymptomatic LM; however, results for the last