Leptomeningeal metastasis (LM) is the diffuse metastasis of malignant tumor cells in the subarachnoid space of the brain and spinal cord and is one of the serious complications of advanced non-small cell lung cancer (NSCLC). Currently, the literature reports that approximately 3%-5% of patients with advanced NSCLC develop meningeal metastases. Among NSCLC patients diagnosed with LM, lung adenocarcinoma is the most common pathological type, accounting for approximately 84% to 97%, while lung squamous carcinoma accounts for only 1% to 6%.
The blood-brain barrier is the main reason for the poor treatment outcome of LM
The main reason for the unsatisfactory treatment of LM is the presence of the “blood-brain barrier. The blood-brain barrier is a dynamic interface between blood and brain tissue that selectively blocks the passage of substances, and is the invisible gate that separates the brain from the outside world, through which external substances must first pass to enter the brain.
The presence of the blood-brain barrier makes it difficult for drugs to cross and even more difficult for them to reach effective therapeutic concentrations in the brain. Therefore, LM has become a difficult area of treatment for NSCLC, and the development of drugs that increase cerebrospinal fluid concentrations is the key to current research.
Currently, we can improve the ability of drugs to penetrate the blood-brain barrier by means of chemical modifications (e.g., lowering molecular weight, lowering efflux levels, increasing lipid solubility). One of the most typical representative drugs is AZD3759, a novel targeted drug (EGFR-TKI class) that can be chemically modified to avoid binding to efflux transporter proteins, which is equivalent to taking the VIP pathway during security screening, with a penetration rate close to 100%.
What are the principles of treatment for NSCLC-LM?
For advanced NSCLC meningeal metastases, the main treatment approach is currently palliative, with the goal of improving symptoms, quality of life, and prolonging survival.
While there is no accepted standard of care, retrospective studies have shown a decreased risk of death in patients who received systemic therapy, including EGFR-TKI, AP regimen chemotherapy, etc., compared with those who did not.
The 2017 edition of the US NCCN guidelines classify LM patients into high-risk and low-risk categories. For low-risk patients (good physical status score, no major neurological deficits, few systemic diseases, and reasonable systemic therapy options if necessary), systemic therapy is recommended. For high-risk patients, best supportive care is recommended.
New molecular therapies are now also showing high blood-brain barrier permeability and antitumor activity, promising to rewrite the guidelines for the management of LM.
How is NSCLC-LM treated?
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1. Systemic chemotherapy
Systemic chemotherapy is the treatment of choice for patients without mutations in NSCLC-LM. A retrospective analysis showed that systemic chemotherapy with cytotoxic agents significantly prolonged the median overall survival of patients with NSCLC-LM (13.3 months versus 4.1 months). Current options for systemic chemotherapy for NSCLC-LM include pemetrexed, vincristine, gemcitabine, docetaxel, and cisplatin, but no standard treatment regimen has been established clinically .
2. Intrathecal chemotherapy
Intrathecal chemotherapy refers to the injection of drugs into the subarachnoid space to achieve a certain concentration in the cerebrospinal fluid and act directly on the tumor site. Intrathecal chemotherapy is a fairly effective treatment, but specific treatment protocols have not been unified. Currently, the most commonly used intrathecal chemotherapeutic agents are methotrexate, cytarabine, and thiotepa, with the best efficacy being methotrexate . A retrospective analysis study found that of 149 patients with NSCLC-LM, 109 patients who received intrathecal chemotherapy had significantly longer survival (17 weeks versus 8 weeks).
3. Molecularly targeted therapy
Molecularly targeted therapy is one of the biggest new advances in the treatment of NSCLC-LM. So, what are the characteristics of each of the different mutational targets for NSCLC with meningeal metastases? And what new options do we have?
(1) EFGR mutations
A retrospective study found that EGFR-TKI treatment prolonged OS compared with patients who did not receive TKI treatment (10 months vs 3.3 months; p less than 0.001).
Like other drugs, the efficiency of EGFR-TKI therapy was associated with blood-brain barrier permeability. Researchers measured cerebrospinal fluid concentrations of multiple EGFR-TKI drugs, and they found that erlotinib had higher cerebrospinal fluid concentrations and better blood-brain barrier penetration than gefitinib.
But overall, the blood-brain barrier penetration of most EGFR-TKIs is suboptimal. Researchers are now working to increase the dose of the drug, develop next-generation TKI with greater ability to penetrate the blood-brain barrier, and combine therapy. Here is a look at each of these.
① Increasing the dose: A retrospective study showed that treatment of NSCLC-LM with high-dose erlotinib resulted in better treatment response and symptom improvement compared with standard dose, but median survival time was not prolonged .
② Combination therapy: One study found that EGFR-TKI combined with the antiangiogenic agent bevacizumab was effective in preventing soft meningeal metastases in patients with EGFR-mutant NSCLC.
③ New drug development: AZD3759 is the most representative next-generation EGFR-TKI that has shown good blood-brain barrier penetration and has been shown to result in significant intracranial tumor volume reduction in animal studies. In phase I clinical trials, investigators found that AZD3759 performed similarly to other EGFR-targeted drugs for the control of extracranial lesions, but showed greater activity for the control of intracranial lesions.
(2) ALK rearrangement
The incidence of ALK rearrangement in NSCLC patients with CNS metastases is approximately 30%-50%, and meningeal metastases occur in approximately 5% of ALK-positive patients. As with EGFR-TKI, blood-brain barrier permeability is the most important factor determining the efficacy of ALK inhibitors.
Crizotinib (crizotinib) was the first targeted agent approved by the FDA for the treatment of ALK-positive NSCLC, and although crizotinib has a low penetration rate in the CNS (only 0.26%), studies have shown that it still provides better disease control than standard chemotherapy.
Ceritinib (ceritinib) is a more potent second-generation ALK/ROS1 inhibitor than crizotinib, and it has higher CNS penetration (15%) compared with crizotinib. It has excellent systemic and intracranial therapeutic efficacy in patients who develop ALK rearrangement after crizotinib treatment. One study of patients who developed brain and meningeal metastases and were treated with chemotherapy sequential crizotinib-targeted therapy followed by cretinib after progression found that patients achieved more than 5 months of disease control.
Alectinib (erlotinib) is another second-generation ALK/RET inhibitor with higher CNS penetration (63% to 94%) and significant efficacy for crizotinib as a systemic and CNS treatment for patients with ALK rearranged NSCLC after first-line therapy. A patient with a confirmed diagnosis of NSCLC-LM was reported to be in complete remission for more than 15 months after treatment with erlotinib. The FDA has now approved meningeal metastases as one of the indications for erlotinib.
Brigatinib (brugitinib) is a potent ALK/ROS/EGFR inhibitor with intracranial response rates of 53% to 67% and median intracranial progression-free survival of more than a year in patients with ALK-positive NSCLC. However, its treatment for LM is still under investigation (study number NCT02737501).
In addition, the anti-meningeal metastatic activity of Lorlatinib (lorlatinib) and other novel ALK inhibitors, such as entrectinib and ensartinib, are being investigated.
(3) Other genes
Other genetic mutations in NSCLC include ROS1 fusions, BRAF V600 mutations, and others. However, ROS1 fusions occur in only 0.6% of patients with brain metastases, and the incidence of ROS1 fusions and BRAF V600 mutations in LM remains unclear. Therefore, the effectiveness of the corresponding targeted inhibitors in NSCLC-LM needs to be further investigated.
The options for targeted therapy are sorted out in a flowchart below.
4. Immunotherapy
Newly used PD-1/PD-L1 inhibitors in the clinic have improved the treatment of NSCLC. However, the large molecular weight of the PD-1/PD-L1 antibody (>140,000 Da) makes it difficult to penetrate the blood-brain barrier, and in addition, it works primarily by activating systemic immune cells, so its therapeutic value in NSCLC-LM is greatly diminished.
There is now literature that nivolumab improves neurological function in patients with NSCLC brain and meningeal metastases, and there are studies reporting the effectiveness of pembrolizumab in treating NSCLC brain metastases, but its efficacy in meningeal metastases is unknown in a phase 2 study (NCT03091478).
Summary
NSCLC-LM is one of the serious complications of NSCLC, and the efficacy of combination therapy remains unsatisfactory, but some progress has been made. Molecular targeted therapy, an emerging treatment modality, has significantly prolonged the survival of patients with genetic mutations, and immunotherapy may also have some efficacy. However, more information is yet to be revealed by in-depth studies.