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Pellerino et al. J Cancer Metastasis Treat 2020;6:41 I http://dx.doi.org/10.20517/2394-4722.2020.80 Page 13 of 20

subgroup have not been reported [120] . Brigatinib, a potent ALK/ROS/EGFR inhibitor, had an impressive
[125]
[126]
intracranial ORR of 53%-67% with a median PFS > 12 months when used in BM . Gaye et al. reported
a case of LM pretreated with first- and second-generation ALK inhibitors, and achieved a median PFS of
14 months following brigatinib. Overall, the efficacy of brigatinib in LM needs to be further investigated,
and the phase 3 ALTA-1L trial includes patients with any CNS recurrence. Preliminarly, the intracranial
ORR was 67% with a median PFS of 11 months, but response of LM was not analyzed separately from
that of BM [127] . Lorlatinib, which is an ALK/ROS1 inhibitor with an excellent BBB penetration, led to an
intracranial ORR of 44% in ALK rearranged NSCLC patients heavily pretreated with ALK inhibitors .
[23]
Moreover, a recent case report described a significant and long-lasting response of a spinal LM, achieving a
[128]
PFS of 12 months from the start of treatment .
Immunotherapy for LM from NSCLC
Inhibitors of the programmed death-1 (PD-1)/PD-ligand 1 pathways, such nivolumab and pembrolizumab,
have shown some efficacy in patients with advanced NSCLC patients with pretreated BM [129-132] . The PD-L1
expression and tumor-infiltrating lymphocytes have been suggested to be predictive factors for response
to immune checkpoint inhibitors (ICIs) [133] , but their expression in LM remain unknown. Gion et al. [134]
described neurological improvement lasting 7 months in patients with LM treated with nivolumab, and
Dudnik et al. [135] reported 1 partial response and 1 stable disease lasting > 21 and 10 weeks, respectively,
in 2 patients with LM after a treatment with nivolumab. A prospective evaluation of 19 patients with LM
from NSCLC, who were treated with ICIs (13 with nivolumab and 6 with pembrolizumab), showed a
[137]
[136]
median PFS of 3.7 months, and a 6- and 12-months OS of 36.8 and 21.1%, respectively . Brastianos et al.
have investigated the efficacy of pembrolizumab in a phase 2 trial of 20 patients with LM (2 from NSCLC).
The study met the primary endpoint, as 12/20 (60%, 90%CI: 0.39-0.78) patients were alive at 3 months after
enrollment. The activity of pembrolizumab is now being investigated in a phase 2 study focused on LM
from NSCLC (NCT03091478). The Table 6 summarizes the ongoing clinical trials on LM from NSCLC.

Steroids in the management of LM
Steroids are frequently used in daily clinical practice for the treatment of neurological symptoms from
LM. Considering the long half-life that allows the administration in a single daily dose, dexamethasone
is the most used steroid. The main advantage is represented by the significant glucocorticoid potency,
associated with the virtual absence of mineralocorticoid effects, resulting in a decreased risk of electrolyte
imbalances compared with other steroids. The main effects are to decrease the permeability of the BBB and
limit the extravasation of fluid [138,139] , and antiemetic properties by reducing the cellular 5-HT3 receptor
expression on the medulla oblongata [140,141] . In general, steroids are employed to reduce meningeal irritation
[57]
and radicular pain from LM or chemical meningitis following intrathecal chemotherapy . Studies on
dosing and tapering of dexamethasone in LM have not been performed thus far, therefore the dose should
be tailored to each patient’s individual needs. In general, the lowest dose of steroids should be used for
the shortest time possible to limit adverse events, such as arterial hypertension, increased risk of fungal
infections, osteoporosis, diabetes, myopathy, and psychiatric effects (e.g., insomnia, emotional lability,
hypomanic and manic episodes) .
[142]

Prognostic factors
In general, there are two models used for predicting outcomes in patients with LM. The first is based on
the general condition of patients detected by Karnofsky performance score (KPS), neurologic symptoms,
and presence of extracranial metastases. In this regard, the US National Comprehensive Cancer Network
(NCCN) guidelines (version 2, 2020) for patients with LM stratifies patients as “good risk” or “poor risk” .
[85]
Good risk patients have KPS ≥ 60, mild neurologic deficits, no bulky disease, stable systemic disease,
and available therapeutic options for systemic disease, resulting in a prolonged survival compared with
“poor risk patients. The MRI presentation of LM has been suggested to impact the survival: in particular,