Advances in the research of leptomeningeal metastases in non-small cell lung cancer: a narrative review

Introduction

About 3–5% of individuals with non-small cell lung cancer (NSCLC) have developed leptomeningeal metastases (LMs), also referred to as leptomeningeal cancer (LC) (1), which severely impacts the prognosis and survival of patients with advanced-stage NSCLC (2). With advancements in diagnostic methods, targeted therapies, and the widespread use of magnetic resonance imaging (MRI), the overall survival (OS) of NSCLC patients has improved, and the prevalence of LM has been increasing (3,4). Tyrosine kinase inhibitors (TKIs), particularly for patients with actionable mutations such as epidermal growth factor receptor (EGFR), anaplastic lymphoma kinase (ALK), and c-ros oncogene 1 (ROS1), have been shown to prolong OS, leading to a higher incidence of LM (5). For example, NSCLC patients with EGFR mutations have a 9.4% risk of developing LM, while those with ALK gene fusions have a 10.3% risk (3).

Patients with NSCLC-related LM often experience significant neurological deterioration, with untreated individuals having a median survival of just 4–6 weeks (6,7). Even with conventional treatments like EGFR-TKIs, systemic chemotherapy, and whole brain radiotherapy (WBRT), the median OS (mOS) for these patients is only 3–11 months, underscoring the poor prognosis (8). The primary therapeutic objectives for this patient group are to stabilize neurological function, improve quality of life, and extend survival while minimizing drug toxicity (9). This article summarizes the latest developments and challenges in the diagnosis and treatment of NSCLC-related LM, with a particular focus on genetic mutations. We present this article in accordance with the Narrative Review reporting checklist (available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-2025-163/rc).

Methods

Information used to write this paper was collected from the sources listed in Table 1 and Table S1.

Mechanisms of leptomeningeal metastases

LM occurs when tumor cells invade the leptomeninges (the pia and arachnoid membranes), subarachnoid space, or cerebrospinal fluid (CSF) (10). Tumor cells outside the central nervous system (CNS) can enter the leptomeningeal cavity through various routes, including direct infiltration of peripheral nerves, hematogenous dissemination, and indirect secondary metastasis (11). For metastasis to occur, cancer cells must bypass the blood-brain barrier (BBB), which typically protects the brain and spinal cord from harmful agents. However, when the BBB is disrupted, its permeability increases, allowing tumor cells to infiltrate the leptomeninges and subarachnoid space. The exact mechanisms behind barrier disruption and subsequent cancer progression remain unclear and require further investigation. Below, we outline the key brain barriers involved in the metastatic process (Figure 1).

Figure 1 Mechanism and treatment of meningeal metastasis. (A) The blood-brain barrier, (B) the blood-CSF barrier, (C) the CSF-brain barrier, (D) intrathecal chemotherapy by direct injection into the ventricles via the Ommaya capsule, (E) intrathecal chemotherapy via LP into the lumbar dural sac the blood-brain barrier, the blood-CSF barrier, and the CSF-brain barrier together form the brain barrier. (A-C) The process of metastasis of cancer cells to the soft meninges. (D,E) The main routes of administration of intrathecal chemotherapy. CSF, cerebrospinal fluid; LP, lumbar puncture.

The BBB

The BBB is the primary defense protecting the CNS. It prevents many macromolecules from entering the brain and selectively pumps out harmful substances (12). It is located between the microvascular endothelial cells and the nerve cells of the brain and spinal cord (13). The BBB consists of tightly connected capillary endothelial cells surrounded by pericytes and astrocyte end feet (14). As the central vascular system of the CNS crosses the chondrocephalic cavity into the brain parenchyma, the vessels are surrounded by perivascular fibroblasts and perivascular interstitial spaces (15). When compromised, cancer cells can invade the brain parenchyma and break through the glial cells to enter the CSF-filled perivascular spaces, known as Virchow-Robin spaces.

The blood-CSF barrier

The blood-CSF barrier lies between blood and CSF in the ventricular choroid plexus (CP) (16). In patients with advanced NSCLC, cancer cells can enter the bloodstream through tumor vasculature and then cross the endothelial gaps of the CP. The epithelial cells of the CP form tight junctions that usually prevent the entry of cells and macromolecules into the CSF (16). However, systemic inflammation can disrupt these tight junctions, enabling cancer cells to penetrate the barrier and enter the CSF (11). Recent studies have also shown that complement component 3, produced by cancer cells, can contribute to this disruption, promoting cancer cell growth within the CSF (17).

The CSF-brain barrier

The CSF-brain barrier lies between the CSF in the cerebral ventricles and the nerve cells of the brain and spinal cord. It is composed of the ventricular epithelium, limbic meninges, and sublaminar glial membranes. Unlike the BBB, this barrier is less effective at preventing the passage of macromolecules due to gaps between the epithelial cells of the ventricular epithelium. When compromised, cancer cells in the venous sinuses can destroy the arachnoid membrane, facilitating LM. Cancer cells in the low-pressure spinal cord or Batson’s venous plexus may also damage the spinal arachnoid membrane and enter the CSF (11).

Other

Besides the aforementioned routes, cancer cells can also exploit existing tissue planes to travel along cranial nerves and enter the CSF via the perineural space. Cancer cells from bone marrow can also use bridging veins to access the leptomeningeal space (11).

Diagnosis

Clinical diagnosis

LM is diagnosed through a combination of imaging, CSF biopsy, and clinical presentation. However, only about 50% of patients with LM have a positive CSF cytology result after the first examination. Sensitivity increases to 75–85% with a second examination, but CSF cytology remains negative in about 10% of cases, even after multiple tests (18).

Approximately 98% of patients with molluscum contagiosum metastases clinically exhibit neurologic signs and symptoms, which vary depending on the area of the CNS involved (cranial nerves, spine, and brain). Statistically, the most common brain symptom reported by 88% of patients was headache (82%); 56% of patients reported cranial neuropathy primarily in the form of tinnitus and hearing loss (40%) and diplopia (37%); 15% of patients reported spinal symptoms primarily in the form of motor and sensory deficits (13%) and nerve root pain (8%) (19). NSCLC patients presenting with relevant symptoms should be carefully and thoroughly evaluated, and early intervention may result in prolonged OS for the patient (20).

Imaging for leptomeningeal metastases typically involves gadolinium-enhanced MRI of the brain and spine, which is currently the most effective diagnostic imaging tool. In patients with NSCLC showing typical clinical manifestations of LM, characteristic abnormal enhancement on MRI can be diagnostic. Typical MRI features of LM include small, geometrically complex lesions with nodular, linear, or curvilinear enhancement patterns that can be focal or diffuse. Common locations of enhancement include cranial nerves, spinal nerve roots, the brain’s surface, the cerebellar lobules, and the cerebral sulcus (21). Gadolinium-enhanced MRI has a sensitivity of 66–98% and a specificity of 77–97% (22). However, approximately 20–30% of patients with LM have normal or false-negative MRI results. While typical clinical presentation and MRI findings can complement a CSF-negative diagnosis, they cannot be the primary diagnostic tool. False-positive MRI results can also occur following neurological interventions. Notably, about 20% of NSCLC patients with negative CSF cytology exhibit definitive clinical or imaging signs of LM (3). Therefore, probable LM can be diagnosed when typical clinical symptoms and characteristic MRI enhancement are present. This group generally has a more prolonged OS than patients with CSF cytology-positive LM (22).

Potential diagnostic methods

The clinical diagnosis of LM in NSCLC remains limited by low sensitivity and specificity. Recent studies have explored novel molecular markers with higher sensitivity and specificity through liquid biopsy, including circulating tumor DNA (ctDNA), circulating tumor cells (CTCs), and extracellular vesicles (EVs). However, these methods are not widely adopted due to small sample sizes, high diagnostic costs, and time constraints. Further research with larger sample sizes is needed to determine whether these markers could replace CSF cytology for diagnostic or prognostic purposes (Table 2).

ctDNA

Due to the protective brain barrier, molecular markers from CSF are more sensitive for detection than those obtained from plasma and serum. Among these, CSF ctDNA is the most widely studied, and its efficacy in guiding treatment for intracranial lesions has been well established (28). In a prospective study, CSF ctDNA detected using next-generation sequencing (NGS) demonstrated 100% sensitivity (11/11) for NSCLC-related LM (24). This high sensitivity was confirmed in a subsequent study, where a ctDNA analysis of 27 LM patients also achieved 100% sensitivity (22).

CTCs

A prospective study demonstrated that CTCs in CSF were more sensitive than conventional cytology and MRI for diagnosing LM. The optimal threshold for diagnosing LM by CSF-CTC was found to be ≥1 CTC/mL, with this threshold achieving a sensitivity of 93% [95% confidence interval (CI): 84–100%], specificity of 95% (95% CI: 90–100%), positive predictive value (PPV) of 90% (95% CI: 79–100%), and negative predictive value (NPV) of 97% (95% CI: 93–100%) (23). Further follow-up studies showed that CSF-CTC could be a decisive prognostic factor for LM, with each increase in CSF-CTC counts correlating with a 1% increase in the risk of patient death. In a study by Diaz et al., newly diagnosed LM patients with CSF-CTC levels ≥61 CTC/3 mL had more than twice the risk of death compared to those with lower levels [hazard ratio (HR) =2.84] (29).

EVs

This study analyzed exosomal microRNA concentrations in CSF samples from patients with LM and found three microRNAs (miR-183-5p, miR-96-5p, and miR-182-5p) highly expressed in CSF EVs. These microRNAs may serve as biomarkers for diagnosing or monitoring the progression of NSCLC-related LM (25). The study highlights the potential of exosomal microRNAs in LM diagnosis and monitoring.

In addition to gene-level biomarkers, in recent years, fibronectin 1 (FN1) has been identified as a potential indicator of the occurrence of leptomeningeal metastases in patients with NSCLC in the proteomic analysis of CSF exosomes. FN1 levels were significantly higher in NSCLC with LM than in NSCLC without LM (P=0.029). FN1 may disrupt intercellular tight junctions, promoting tumor migration, invasion, angiogenesis, and endocytosis. Therefore, FN1 could serve as a diagnostic biomarker and a new therapeutic target for LM (26).

Serum marker

While lumbar puncture (LP) is a relatively low-risk diagnostic method, patients with LM are often in poor physical condition, and complications such as infection, CSF leakage, and spinal injury can occur with repeated procedures. In addition to CSF molecular markers, researchers have explored noninvasive diagnostic biomarkers. Increasing evidence suggests that exosomal miRNAs from plasma are crucial in lung cancer diagnosis. This study found that the levels of EV-miR-374a-5p in serum and CSF were consistent in the same patient, likely due to the ability of EVs to travel between the CNS and peripheral circulation, bypassing the brain barrier. Their study found that serum EV-miR-374a-5p levels were significantly higher in patients with LM than those without, showing the potential for serum markers to replace CSF biomarkers (27) eventually.

Therapy

Chemotherapy

The physicochemical properties of chemotherapeutic agents and their ability to penetrate the CSF are key determinants of their therapeutic efficacy in LM (Table 3).

The delivery of drugs to the CNS and the leptomeningeal space is hindered by the BBB, making it challenging for systemic plasma drugs to reach therapeutic concentrations in the CSF. One of the main obstacles to efficient drug transport into the brain and leptomeningeal space is P-glycoprotein, an export protein located in the luminal membranes of the endothelial cells of cerebral capillaries (43). In 2019, a study demonstrated that systemic therapy with pemetrexed significantly improved survival in patients with EGFR-mutant NSCLC-LM, with an mOS of 13.7 months compared to just 4.0 months for patients not receiving pemetrexed. It suggested that pemetrexed has potential antitumor activity in EGFR-mutant NSCLC-LM patients (31). The concentration of drugs in the CSF depends on the concentration of free drugs in the plasma and the CSF permeability of the drug, with the ratio of bound CSF concentration to unbound plasma or blood concentration serving as a key measure of drug effectiveness (14). However, pemetrexed has poor CSF permeability due to its large molecular size, high hydrophilicity, low lipophilicity, and protein binding in blood (9). Current strategies for increasing drug concentrations in the CSF primarily involve adjusting the therapeutic dose and improving the drug’s ability to cross the BBB. The most important research direction is how to get the drug concentration in the CSF up to the therapeutic dose using a drug concentration that does not produce strong toxic side effects in a systemic mode of administration.

Researchers have turned to intrathecal chemotherapy (IC) to address the challenge of drug concentration in the CSF. This method allows for the direct delivery of antitumor drugs into the subarachnoid space, enabling more effective treatment of tumor foci in the leptomeninges and tumor cells floating in the CSF. Compared with systemic administration, local therapy allows for more targeted treatment at the lesion site, reducing the risk of toxic effects on other tissues (44). The most effective localized chemotherapy methods for LM are intracerebroventricular (ICV) chemotherapy via the Ommaya reservoir and LP chemotherapy. Both methods have shown clinical benefits in LM patients (1). ICV chemotherapy via the Ommaya reservoir is a safer and more convenient alternative to LP, bypassing the BBB (35,45). Unlike multiple LPs, the Ommaya reservoir ensures that CSF can be drained anytime, relieving intracranial hypertension symptoms, monitoring drug concentrations, and assessing treatment efficacy (25). While ICV drug delivery via the Ommaya reservoir is one of the best options for IC (46), the lack of prospective randomized trials makes it difficult to determine the most optimal method definitively. Intrathecal pemetrexed (IP) has demonstrated good therapeutic effects in phase I and II clinical trials. Based on phase I studies identified an optimal dose of 50 mg for IP. The phase I trial showed an objective response rate (ORR) of 84.6% (22/26) (47), and subsequent phase II studies reported an ORR of 80.3% (106/132) and an mOS of 12 months in 132 EGFR-mutant NSCLC-LM patients who had failed TKI treatment. Grade III and above adverse events (AEs) occurred in 12.9% (17/132) of cases (36). This study also found no significant difference in OS between the Ommaya reservoir and LP delivery modalities, contradicting previous studies. This discrepancy may be due to the small sample size of patients treated via the Ommaya reservoir (only nine patients). Clinical cases in recent years suggest that adding IP to other drug therapies can result in significant symptomatic relief in patients with EGFR mutations and ALK mutations (30,32,37).

A retrospective controlled study comparing methotrexate and pemetrexed in IC showed that both treatments were effective. However, no significant difference in median progression-free survival (mPFS) and mOS was observed between the two groups (34). Pharmacokinetic analysis indicated higher concentrations of pemetrexed achieve longer half-lives in the CSF with the Ommaya reservoir compared to LP. A study demonstrated that intrathecal injection of pemetrexed via the Ommaya reservoir at 30 mg was safe and effective. This study reported an ORR of 43.5% (10/23), a disease control rate (DCR) of 82.6% (19/23), and mPFS and mOS of 6.3 and 9.5 months, respectively, with only 8.7% (2/23) of patients experiencing dose-limiting toxicity (35). Although the study suggested that IP may not significantly improve OS compared to non-IC, it showed potential in prolonging survival in the CNS and improving outcomes in patients with poor Eastern Cooperative Oncology Group performance status (33).

Recent studies indicate that IP has a high safety and responsiveness profile, with milder toxicities compared to older chemotherapeutic agents. The most common adverse effect is myelosuppression, which can be managed with vitamin supplementation (48). In conclusion, IP offers good tolerability, high safety, and high responsiveness, making it a promising therapeutic option for LM patients.

Molecularly targeted therapy

EGFR mutations

TKIs are the first-line treatment for patients with EGFR-mutant NSCLC (49) (Tables 4,5).

Mills et al. compared EGFR-targeted therapy (ETT), immune checkpoint inhibitors (ICIs), IC, and radiotherapy (RT) alone, finding that ETT provided superior survival outcomes for patients with EGFR-mutated LM (4). Compared to cytotoxic chemotherapy or best supportive care, EGFR-TKIs were associated with better survival outcomes (HR =2.222) (69). This study analyzed 44 patients with EGFR-mutant NSCLC-LM and found that treatment with EGFR-TKIs resulted in a DCR of 75.0% and an mOS of 16 months (54). Clinical cases show that second-generation TKIs dacomitinib is a novel treatment option for NSCLC-LM patients with EGFR mutations. Nine weeks of treatment with dacomitinib resulted in the disappearance of symptoms, regression of leptomeningeal seeding and brain metastases on MRI imaging, and sustained shrinkage of lung lesions (63).

The first- and second-generation EGFR-TKIs have limited CNS penetration, leading to CNS metastases in many patients. However, third-generation EGFR-TKIs, such as osimertinib, overcome this limitation with significantly better brain penetration (70). The ratio of osimertinib in CSF to free plasma is 22% (55), which has been shown to improve prognosis in EGFR-mutant NSCLC-LM patients. Studies have demonstrated that 80 mg of osimertinib yields favorable clinical benefits in patients with LM (71). A retrospective study conducted similarly supported the use of osimertinib at 80 mg every day as an effective and well-tolerated therapeutic option for patients with EGFR-mutated LM (52). Clinical case reports over the past 6 years show that osimertinib at 80 mg has provided varying degrees of symptomatic relief in patients with EGFR-mutant LM, with some achieving OS beyond 12 months (59,60).

A study explored the effects of doubling the osimertinib dose to 160 mg in 41 patients with EGFR-mutant NSCLC-LM. The higher dose showed controlled safety and positive outcomes regarding imaging response, neurological improvement, and CSF clearance. However, the incidence and severity of AEs were higher than those reported for the 80 mg dose (50). The study found that high-dose third-generation EGFR-TKIs resulted in higher complete remission rates (CRRs) and longer OS compared to standard doses, suggesting that increasing the dose may provide better clinical benefits for LM patients (65.2% vs. 45.8%, P=0.047; 15.0 vs. 10.2 months, P=0.01). Patients on the high-dose therapy also had a longer duration of response (DOR) than patients on the standard-dose regimens (8.2 vs. 6.1 months, P=0.02) (56).

We found that some patients with LM had previously been treated with EGFR-TKIs but still developed LM as the outcome. The study re-administered EGFR-TKIs to patients with LM who had previously used EGFR-KTI drugs and still obtained 28% clinical response and 60% clinical benefit. Among TKI-failed patients, LM patients treated with TKIs demonstrated prolonged OS compared to those who did not receive TKIs again (7.6 vs. 4.2 months) (51). A study performed a survival analysis of patients with prior TKIs using osimertinib or erlotinib and found no significant difference in OS between the Switch-TKI and Rechallenge-TKI groups, regardless of the EGFR-TKI used (P=0.86) (53). This study highlights that various EGFR-TKI treatment strategies can provide benefits in terms of OS for LM patients. For the patients with EGFR-mutated NSCLC, after the failure of EGFR-TKI therapy, re-initiation of previously administered drugs or switching to previously unadministered EGFR-TKIs are viable therapeutic options for LM patients.

However, with the widespread use of EGFR-TKIs, a new problem has also arisen. As more drug-resistant mutation genes, such as EGFR L858R, T790 M, L718Q, etc., are discovered, the number of TKI-resistant patients is on the rise year by year (72). Overcoming this resistance barrier has become a critical challenge in improving OS for LM patients.

Several studies have confirmed the efficacy of osimertinib in treating refractory LM after failure of first- and second-generation EGFR-TKIs. A study successfully treated first- and second-generation TKI-resistant patients with the third-generation TKI osimertinib, achieving an mOS of 15.6 months and an overall response rate (ORR) of 51.6% in LM patients. This study supports using 80 mg of osimertinib as a therapeutic option for EGFR-mutated NSCLC-LM patients, regardless of T790M mutation status (55). In cases of osimertinib resistance, afatinib may be a promising alternative. Afatinib was used to treat osimertinib-resistant LM patients, stabilizing the disease for 11 months (68). Additionally, the study found that increasing the dose of the third-generation EGFR-TKI could improve OS in resistant patients. For the first- and second-generation EGFR-TKI-resistant patients, high-dose third-generation EGFR-TKI therapy resulted in significantly better OS than standard-dose treatment (19.5 vs. 9.8 months, P=0.047). Similarly, in third-generation EGFR-TKI-resistant patients, high-dose therapy showed superior OS to standard-dose treatment (10.0 vs. 4.3 months, P=0.045) (56). Clinical cases collected over the past 6 years suggest that varying TKI strategies can still offer hope in improving OS for TKI-resistant patients. A vitro study showed that the model harboring EGFR L858R/T790 M/L718Q was resistant to all EGFR TKIs, but the L858R/L718Q mutant remained sensitive to gefitinib and afatinib. This case provides clinical evidence of the second-generation EGFR TKIs’ effectiveness in treating L858R and L718Q variants with CNS metastases. Afatinib successfully treated a patient with LM harboring the L858R/L718Q variant and osimertinib resistance (57). Moreover, a later case of postoperative clinical improvement in NSCLC-LM patients with EGFR complex mutations (exon 19 deletion + K754E) treated with afatinib further supports this approach (62); these findings suggest that afatinib therapy may be an effective option not only for patients with EGFR compound mutations resistant to icotinib and osimertinib but also for overcoming resistance to both first- and third-generation TKIs (68).

Effective treatments for LM patients harboring some uncommon EGFR mutations have been continuously explored through clinical cases. These cases reveal that certain TKIs are effective against these uncommon mutations. For example, a combination of crizotinib and gefitinib resulted in 6-month progression-free survival (PFS) in patients with advanced NSCLC-LM harboring MET amplification after resistance to gefitinib (58). In the first report of poziotinib for LM patients harboring the HER2 exon 20 insertion mutation, the patient’s symptoms significantly improved within 3 days of treatment, and the 2-month PFS was achieved (65). In addition, osimertinib may be a promising option for the first treatment of patients with leptomeningeal metastases carrying an uncommon EGFR mutation; this LM patient carrying the uncommon EGFR S768I mutation produced a durable response to treatment with osimertinib, and by the end of the study, the patient had been on continuous effective therapy for 10 months (61). Further evidence suggests that 160 mg of osimertinib may offer durable clinical responses in NSCLC-LM patients harboring the rare EGFR mutations such as G719s and L861Q, with patients maintaining stable disease (SD) for up to 1 year (64). In another case, 160 mg of osimertinib significantly improved clinical symptoms of LM patients carrying the EGFR 21 exon L858R mutation combined with the EGFR 20 exon T790M mutation, with neurological symptoms disappearing after treatment. The patient’s PFS was prolonged by 7 months, and by the end of the study, the OS had been sustained for 5 years without intolerable toxicity or side effects (67). The preclinical study has shown that the combination treatment with osimertinib and trametinib can overcome drug resistance in the mouse model of LC (73).

Additionally, combining pralsetinib with osimertinib may provide clinical benefits for LM patients harboring acquired coexisting RET fusions (66). However, due to the limited number of cases, systematic studies are not yet possible, and specific clinical protocols for resistance mutations are challenging to determine. As a result, clinicians must rely on their judgment to determine appropriate treatment strategies. Despite this, these findings lay the groundwork for clinical trials to study the effects of novel therapies targeting specific EGFR mutations and accompanying drug-resistant mutations in LM patients. Regardless of the treatment approach, the overall prognosis for NSCLC-LM patients remains poor, and improving both the quality and duration of survival for these patients remains a significant challenge that calls for continued breakthroughs.

ALK rearrangements and other mutation types

ALK inhibitors are now widely recognized as the standard treatment for ALK-positive NSCLC patients (Table S2). However, for NSCLC patients with LM, the first- and second-generation ALK inhibitors have shown poorer CSF drug concentrations than plasma. In contrast, the third-generation ALK and ROS1 TKI, lorlatinib, has determined excellent meningeal penetration, with a CSF to plasma ratio 0.77 (74). Over the last 6 years, clinical case reports have shown that lorlatinib exhibits strong intracranial efficacy in both ALK-positive and ROS1-positive patients (74-77). The favorable clinical benefit extends to LM patients who have failed treatment with the first- and second-generation ALK inhibitors (78,79). In a phase II study, investigators found that lorlatinib had potent intracranial activity in patients with isolated CNS progression after second-generation ALK TKI treatment, achieving a 95% intracranial DCR (80).

In response to the growing issue of drug resistance, similar to EGFR TKIs, dose escalation of ALK inhibitors may be an effective strategy to overcome resistance. A case report demonstrated that escalating the dose of alectinib and lorlatinib can overcome resistance to ALK inhibitors in a non-EML4-ALK-positive LM patient (81). Additionally, dual-targeting of ALK and EGFR has proven beneficial in ALK-rearranged NSCLC LM patients resistant to alectinib (82). Sequential treatment with different ALK inhibitors could benefit ALK-positive LM patients. This approach has been shown to significantly extend OS in several clinical cases, with some patients experiencing more than 36 months of OS after sequential treatment with three different ALK inhibitors (76) and others achieving long-term survival benefits by sequential administration of five ALK inhibitors (83).

Beyond lorlatinib, the novel ROS1-TKI repotrectinib has also shown promise for high concentrations in the CSF, with a CSF-to-plasma ratio of approximately 1%. Our case provides the first evidence suggesting that repotrectinib could be effective in ROS 1-positive NSCLC patients with meningeal carcinomatosis (84).

Immunotherapy

The efficacy of ICI in NSCLC patients with oncogenic mutations is suboptimal, as EGFR mutations are associated with reduced PD-L1 expression, lack of T-cell infiltration, and reduced TMB (85). Immunotherapy alone is generally not a treatment option for patients with driver gene-positive NSCLC. However, immunotherapy combined with chemotherapy may be a viable option for NSCLC-LM patients who are driver gene negative or carry uncommon mutant genes (86,87). A study found that pembrolizumab induced a CNS response in patients with PD-L1-positive NSCLC (88). In the use of immunotherapy in patients with LM study, a patient with NSCLC LM remained in complete remission for 4 years after treatment with nivolumab (38) (Table 3). A later study on the efficacy of pembrolizumab similarly demonstrated that immunotherapy is a viable treatment for patients with NSCLC-LM, which showed a 100% (3/3) CNS response rate to pembrolizumab in patients with soft meningeal metastases from NSCLC and demonstrated a complete CNS remission of 33.3% (1/3) in clinical and imaging (39). Despite promising initial findings, research on immunotherapy in recent years has been limited. While it is known that ICIs can cross the BBB, their intracranial activity remains uncertain. Recent evidence suggests that ICIs may maintain anticancer activity against active and treated CNS metastases, even in challenging environments (89). There is an unresolved dilemma in the use of ICI for the treatment of NSCLC-LM patients; LM patients often require high-dose steroids to alleviate the symptoms associated with cancer, but data have shown that high-dose steroids can reduce the effectiveness of immunotherapy (90). Breaking through the current dilemma of steroid requirements in LM patients is one of the difficulties in treating LM patients with immunological agents. Although surgery has been suggested to rapidly relieve brain oedema and thus reduce the need for steroids, the feasibility of the treatment has yet to be proven (91).

Other treatments

RT

RT plays a primary role in the treatment of LM by reducing the burden of nodal disease, correcting CSF flow to alleviate intracranial pressure, and providing symptomatic relief (9) (Table 3). It is a well-tolerated and effective approach for delaying neurological deterioration in patients with LM, ultimately improving their quality of life (92). However, due to the lack of survival benefit, RT should not be considered as a standard treatment but as a palliative intervention. The European Society for Medical Oncology (ESMO) guidelines recommend focal RT for limited, symptomatic lesions and WBRT for extensive nodal or linear lesions (93). Standard methods for focal RT include involved field radiation therapy (IFRT) and craniospinal irradiation (CSI).

The therapeutic role of WBRT for LM remains controversial due to concerns about neurotoxicity. There is still no consensus on whether WBRT improves the survival of NSCLC-LM patients. The early study showed no significant difference in survival between WBRT-treated and non-WBRT-treated LM patients, although a survival benefit was observed in patients with EGFR mutations (8). Analysis of 51 patients with EGFR-mutated NSCLC LM suggested that WBRT might positively impact progression-free survival (iPFS; 3.9 vs. 2.8 months) in patients with EGFR mutations. However, statistical significance was not reached (40). A retrospective study conducted by Oyoshi et al. demonstrated that WBRT significantly prolonged OS in EGFR- and ALK-mutated NSCLC-LM patients, compared to the wild-type group (mOS 10.4 vs. 3.8 months; HR =0.49) (94). However, a study by Zhen et al. found that WBRT significantly improved in LM patients (mOS, 11.4 months) but that EGFR-mutant LM patients may not derive the same clinical benefit from WBRT as wild-type EGFR patients (42). Thus, the role of WBRT in LM remains unclear, though it may offer survival benefits for specific LM subtypes. Further prospective randomized controlled trials in EGFR-mutant patients must confirm whether WBRT is effective for this group.

Conventional focal RT such as conventional photon CSI (xCSI), has limited clinical benefit for LM patients due to high toxicity and poor intolerance. In contrast, a novel approach, proton craniospinal irradiation (pCSI), has shown efficacy in LM with lower toxicity in phase II trials, marking a breakthrough in its broader applicability (41). A phase II trial demonstrated that pCSI improved PFS and OS without increasing severe AEs compared to photon IFRT, with mPFS of 7.5 months and mOS of 9.9 months. Myelosuppression was the most common AE (6).

The current clinical use of RT is ineffective in clearing LM lesions, with little survival benefit, but there is a benefit in the quality of survival of patients with LM (8). Although focal RT, like CSI, has shown clinical benefits for LM, further studies are needed to explore ways to minimize toxic effects, and large-scale prospective trials are required to determine whether these effects can be adequately controlled.

Surgical treatment

Due to the location of the lesions, many patients are not candidates for surgical resection. However, some minimally invasive procedures can improve these patients’ quality of life and survival. Surgical interventions, such as ventriculoperitoneal (VP) shunting, extraventricular drainage (EVD), or lumbar continued drainage (LCD), can be offered to patients with significant meningeal irritation or elevated intracranial pressure, especially before RT. Choroidal sinus stenting may relieve patients with severe headaches and visual symptoms (95). These palliative interventions can offer survival benefits for advanced patients with soft meningeal metastases.

Outlook

The diagnosis of LM remains challenging, characterized by low sensitivity and poor specificity. The current treatment options offer limited survival benefits, and the prognosis for patients with advanced NSCLC with meningeal metastasis is generally poor. In recent years, efforts to improve LM patients’ diagnosis and treatment strategies have become key research goals.

Recent studies have identified meaningful diagnostic markers in CSF and serum, such as ctDNA and EVmiR-374a-5p, to enhance diagnostic sensitivity and specificity. These markers have shown high sensitivity and could facilitate early identification and intervention for LM progression. However, further studies with larger sample sizes are needed to determine whether these markers could replace CSF cytology as the standard diagnostic method.

Regarding treatment, current options provide limited survival benefits for LM patients. Third-generation TKIs, which demonstrate stronger meningeal permeability and improved drug concentration in the CSF, are a promising choice. These TKIs have improved intracranial response rates and OS in LM patients. Moreover, patients with driver gene-positive NSCLC are more likely to develop LM than those with driver gene-negative NSCLC (96). For LM patients with driver gene-positive, targeted therapy is the mainstay, supplemented by local therapy or anti-angiogenic agents. If drug resistance occurs, dose optimization of the targeted agent or drug sequencing may be considered. For LM patients with driver gene-negative, chemotherapy combined with immunotherapy is the mainstay, and if treatment is not adequate, anti-angiogenic drugs can be combined.

Emerging therapeutic modalities, such as IC and pCSI, have shown the potential to prolong survival and improve the quality of life for LM patients. Moreover, recent research suggests that adjusting drug dosages, sequential therapies, and multi-regimen combinations could significantly enhance OS. While these approaches offer clinical benefits, developing new drugs remains a top priority to improve the OS of LM patients significantly.

Conclusions

In conclusion, a multidisciplinary approach with individualized treatment plans is essential for LM patients. By integrating current therapies and exploring new treatment options, we can improve the quality of life and survival rates for patients with this challenging condition.

Acknowledgments

We thank Quazi Shubhra for his professional English editing of this thesis to ensure clarity, grammatical accuracy, and adherence to academic writing conventions.

Footnote

Reporting Checklist: The authors have completed the Narrative Review reporting checklist. Available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-2025-163/rc

Peer Review File: Available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-2025-163/prf

Funding: This study was supported by the National Natural Science Foundation of China (No. 81873277), Key Project of Jiangsu Administration of Traditional Chinese Medicine (No. ZD202207), Suqian Sci & Tech Program (No. K202222), Key Project of Jiangsu Administration of Traditional Chinese Medicine (No. YJZ202455), and The Construction Project of the Fourth Batch of Inheritance Workshops of Famous Veteran Traditional Chinese Medicine Experts in Jiangsu Province [2021].

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-2025-163/coif). The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

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