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Page 10 of 20 Pellerino et al. J Cancer Metastasis Treat 2020;6:41 I http://dx.doi.org/10.20517/2394-4722.2020.80

Thirty-seven patients were treated with intrathecal chemotherapy alone, and 552 patients received multiple
interventions (intrathecal chemotherapy, WBRT, EGFR TKIs, traditional chemotherapy, and supportive
care). The clinical response of the patients receiving intrathecal chemotherapy alone ranged between 71%
to 79% with a median OS longer (7.5 months) than that of patients who received combined treatments (3.0-
5.0 months). Overall, the efficacy of intrathecal therapy is modest, and careful evaluation of clinical factors
helps clinicians to identify the subgroups of patients who may benefit.

Systemic chemotherapy for LM from NSCLC
A standard treatment is not validated thus far, but platinum based-chemotherapy with or without RT is
recommended in patients with LM from NSCLC, who have no druggable mutations or programmed death-
[3]
ligand 1 (PD-L1) tumor proportion score < 50 . The median OS in patients with good prognostic factors
[94]
is approximately 11.5 months following traditional chemotherapy . Bevacizumab has been investigated
in LM after failure of first-generation EGFR TKIs with clinical and radiological response in 2 patients with
[95]
LM from EGFR mutated NSCLC, who progressed after first-line treatment with erlotinib .

Targeted agents
Approximately 20%-25% of patients with NSCLC have oncogene driver mutations: the most frequent is
the EGFR (10%-15%) followed by the ALK rearrangement (3%-5%), while PD-L1 expression ranges from
21.9% to 32.9%. Less frequent mutations are KRAS, MET, ROS1, BRAF, and HER2. Targeting some of these
mutations has shown a significant advantage in BM from NSCLC. Now, the activity of targeted therapy in
LM is under investigation in clinical trials.

Role of EGFR tyrosine kinase inhibitors in LM from NSCLC
Two retrospective studies have shown that LM is more common in patients with EGFR mutations (9.4%)
than in EGFR wild-type (1.7%) [96,97] . Different studies have investigated the efficacy of first- and second-
generation EGFR TKIs in LM [Table 4]. A low CSF level (1%-3%) of the first-generation EGFR TKIs
has been found, suggesting an inability to adequately penetrate the BBB. Therefore, higher or “pulsatile”
doses of either gefitinib or erlotinib have been administered in order to achieve adequate therapeutic
concentrations, reporting a median OS ranging from 3 to 12 months [31,98-101] . The second-generation EGFR
TKI, afatinib, has shown some activity in 11 LM patients with uncommon EGFR mutation (Gly719X)
that were pre-treated with erlotinib or gefitinib. Twenty-seven percent of patients achieved significant
radiological response, with a median PFS and OS of 2 months and 3.8 months, respectively . The third-
[15]
generation EGFR TKI osimertinib has demonstrated remarkable activity to control systemic and CNS
disease . In light of that, osimertinib represents the first-line treatment, regardless of T790M mutation,
[102]
and it is considered the preferred initial therapy when feasible [103] . The increased ability to cross the BBB
makes osimertinib an attractive compound to be investigated in LM. Nanjo et al. have investigated the
[17]
standard dose of osimertinib (80 mg) in LM after failure of first- and second-generation TKIs. The Authors
reported a CSF clearance in 2 patients out of 5 with a definitive diagnosis of LM, and a median PFS of
7.2 months. Notably, osimertinib was active on CSF malignant cells either with T790M or Leu858Arg
mutations . The phase I BLOOM study demonstrated good activity of high-dose osimertinib (160 mg/day)
[17]
in 41 patients with LM who were heavily pretreated with TKIs. The intracranial objective response rate
(ORR) was 62% (95%CI: 45-78), the median OS was 11.0 months (95%CI: 8.0-18.0 months), and a CSF
tumor cell clearance was confirmed in 11 patients (28%) [104] . Saboundji et al. [105] retrospectively analyzed
a cohort of 20 patients treated with osimertinib: all patients (100%) displayed neurological improvement,
and 5 patients (20%) showed prompt radiological response within 15 days from the start of treatment. For
this cohort, median PFS and OS were of 17.2 and 18 months, respectively. Similar results were reported by
[106]
Ahn et al. , retrospectively analyzing 22 patients with LM from EGFR T790M mutated NSCLC treated
with osimertinib 80 mg/day: ORR was 55% (95%CI: 32-76), and median OS was 18.8 months (95%CI: 6.3-
[107]
NC). Park et al. also reported an intracranial ORR of 55.0%, median PFS of 7.6 months (95%CI: 5.0-16.6),