Intrathecal pemetrexed in patients with epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI) resistant refractory leptomeningeal metastasis lung adenocarcinoma: a retrospective study

Introduction

Recent advancements in the treatment of brain metastases in advanced tumors have shown promise, yet leptomeningeal metastases remain a significant challenge, severely impacting patients’ quality of life (QoL) and often leading to fatal outcomes. The incidence of leptomeningeal metastasis in advanced tumors is 5–15% (1), primarily involving breast cancer, lung cancer, malignant melanoma, and hematological tumors (2-4). In advanced non-small cell lung cancer, the incidence is approximately 3–5%, with a higher rate in epidermal growth factor receptor (EGFR)-mutated lung adenocarcinoma, accounting for about 9.4% (5,6). With the improvement of the 5-year survival rate of advanced lung cancer, the incidence of leptomeningeal metastasis has gradually increased.

Diagnosis of meningeal metastasis relies on imaging evidence and clinical manifestations, with positive cerebrospinal fluid (CSF) cytology remaining the gold standard. Meningeal metastasis can cause damage to the brain hemispheres, cranial nerves, spinal cord, and nerve roots, leading to diverse clinical manifestations (7). The treatment goal, based on a multidisciplinary comprehensive diagnosis and treatment model, is to improve or stabilize the patient’s neurological status, maintain or restore their QoL, and prolong survival (8). Targeted therapy is the preferred treatment for leptomeningeal metastasis in EGFR-mutated lung adenocarcinoma. However, most patients develop primary or acquired resistance to targeted drugs. Subsequent systemic treatments include anti-angiogenic therapy, palliative chemotherapy, immunotherapy, and radiation therapy (9). Due to the blood-brain barrier, there is a significant difference in drug concentration between the CSF and peripheral blood, leading to poor prognosis with a median survival time of only about 3 months (6). The severe clinical manifestations and poor prognosis of leptomeningeal metastasis in lung adenocarcinoma highlight the urgent need for more effective treatments to address clinical symptoms and improve patients’ QoL.

Intrathecal chemotherapy involves intrathecal injection of chemotherapy drugs to achieve therapeutic drug concentrations in the CSF. Previous intrathecal injection drugs include methotrexate, cytarabine, and thiotepa. A meta-analysis showed that in the combined treatment mode of intrathecal chemotherapy, the cytological, clinical, and radiological response rates of meningeal metastasis were 55%, 64%, and 53%, respectively, with a median survival time of 6.0 months [95% confidence interval (CI): 5.2–6.8] (10). Recent studies have shown that pemetrexed can also be used in intrathecal chemotherapy. A prospective open-label single-arm phase 1/2 clinical study demonstrated that the clinical response rate of intrathecal pemetrexed in EGFR-mutated non-small cell lung cancer was 84.6% (22/26), with a median overall survival (OS) of 9.0 months (11). Another retrospective cohort study showed that in the mode of intrathecal chemotherapy (pemetrexed or methotrexate) combined with systemic therapy, the median intracranial progression-free survival (iPFS) of non-small cell lung cancer with leptomeningeal metastasis was 8 months (95% CI: 6.4–9.7), and the median OS was 10.1 months (95% CI: 6.8–13.4) (12). However, current literature reports and clinical studies on intrathecal pemetrexed are still limited. This study retrospectively collected data from 10 cases of intrathecal pemetrexed injection for the treatment of EGFR-tyrosine kinase inhibitor (TKI)-resistant refractory lung adenocarcinoma with leptomeningeal metastasis to evaluate its efficacy and safety. We present this article in accordance with the STROBE reporting checklist (available at https://jtd.amegroups.com/article/view/10.21037/jtd-2025-1303/rc).

Methods

Research design

Patients diagnosed with EGFR-TKI-resistant refractory lung adenocarcinoma with leptomeningeal metastasis who received pemetrexed intrathecal chemotherapy were retrospectively collected from November 1, 2020 to November 1, 2022, at Huashan Hospital, Fudan University. The follow-up time was until July 1, 2023. The inclusion criteria were as follows: (I) lung adenocarcinoma confirmed by pathology, and blood or tissue genetic testing suggested the presence of an EGFR mutation; (II) meningeal metastases of lung adenocarcinoma accompanied by obvious neurological symptoms were diagnosed by cerebrospinal fluid cytology, regardless of whether there were brain parenchymal metastases and imaging findings; (III) patients with refractory meningeal metastases: patients who failed to receive standard treatment before intrathecal injection (TKI drugs, chemotherapy, anti-angiogenic therapy, etc.); (IV) received at least greater than or equal to intrathecal chemotherapy with pemetrexed; (V) at least one cerebrospinal fluid next-generation sequencing (NGS) test should be performed. The exclusion criteria were as follows: (I) presence of central nervous system infectious diseases; (II) fatal or accompanied by uncontrollable systemic diseases; (III) combined with organ failure; (IV) severe encephalopathy, grade III–IV white matter lesion confirmed by imaging examination; (V) inability to cooperate with the lumbar puncture position; (VI) infection at the lumbar puncture site. Patients received pemetrexed intrathecal chemotherapy, and a comprehensive treatment plan for leptomeningeal metastasis was selected based on previous treatments, including systemic chemotherapy, TKI drug re-challenge and dose increase, radiotherapy, or ventriculoperitoneal shunt.

Clinical data collection

Clinical data were obtained from the electronic medical record database, including gender, age, general health status score [performance status (PS)] during intrathecal treatment, tumor-related characteristics, gene status, diagnosis time of leptomeningeal metastasis, and evidence of diagnosis. All treatment options, including various TKI drugs, chemotherapy, anti-angiogenesis inhibitors, surgery, and radiotherapy, were recorded. Detailed records of the intrathecal injection scheme, CSF pressure before and after injection, cytology and tumor marker (CEA), imaging changes, clinical symptoms, tumor patient QoL score, and combined medications during intrathecal injection were maintained. The QoL score used in this study is the Quality of Life Score for Cancer Patients established in China in 1990. Treatment-related adverse events were recorded according to the Common Terminology Criteria for Adverse Events (CTCAE) 5.0 standard. The study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. The study was approved by the Ethics Committee of Huashan Hospital, Fudan University (KY2017-089). Written informed consent was obtained from all participants.

Intrathecal treatment

All 10 patients exhibited symptoms of intracranial hypertension. Before intrathecal treatment, mannitol (250 mL q12h–q8h) was administered to lower intracranial pressure. Detailed injection plan: CSF pressure was measured before injection, and tumor markers and cytology were performed on approximately 10 mL of CSF. Dexamethasone (5 mg) dissolved in 2 mL of normal saline was injected intrathecally, followed by pemetrexed (10, 20, or 40 mg) dissolved in 10 mL of normal saline. The injection method involved massage, slow injection, and continuous dilution with CSF, taking approximately 15–20 minutes. During intrathecal injection therapy, folic acid (400 mg, once daily) and vitamin B12 (1 g, once every 9 weeks) were supplemented.

Evaluation

The clinical efficacy evaluation in neuro-oncology was primarily based on the Response Assessment in Neuro-Oncology (RANO) criteria, considering clinical symptoms, neuroimaging [head-enhanced magnetic resonance imaging (MRI) and/or spine-enhanced MRI], and CSF cytology (7,12). However, given the limitations of the RANO criteria for leptomeningeal metastasis, this study combined revised recommendations with relevant clinical studies, including clinical symptoms and CSF cytology as evaluation criteria (13-15). Changes in CSF tumor marker CEA were also recorded. Negative CSF cytology indicated complete remission. Compared to baseline, improvements, significant improvements, stable disease (SD), and progression were defined based on tumor cell counts in CSF cytology reports. Clinical status was assessed weekly, with improvement in clinical symptoms defined as an increase in QoL score greater than or equal to 10. Among the 10 patients, 6 patients could not be evaluated due to follow-up times less than 4 weeks.

Statistical analysis

The follow-up deadline was July 1, 2023. Intrathecal progression-free survival (PFS_IT) was defined as the time from the start of intrathecal injection therapy to disease progression. Intrathecal injection survival (OS_IT) was defined as the time from the start of intrathecal injection therapy to death or last follow-up. Leptomeningeal metastasis survival (OS_LM) was defined as the time from the diagnosis of leptomeningeal metastasis to death or last follow-up. OS was defined as the time from the diagnosis of lung adenocarcinoma to death or last follow-up. Patient characteristics and treatment plans were analyzed using descriptive statistics. The Kaplan-Meier method was used to calculate survival curves and periods, and Prism 8 software was used for statistical analysis.

Results

Patients characteristics

From November 1, 2020 to November 1, 2022, a total of 10 patients were included in the study, with a median age of 50 years (range, 35–71 years), including 5 males (50%) and 5 females (50%). All patients were initially diagnosed with EGFR-mutated lung adenocarcinoma, including one case of 20ins and one case of 19Del + L858R + T790M. The L858R mutation accounted for 50% (5/10), and 19Del accounted for 30% (3/10). Imaging evidence of leptomeningeal metastasis was present in 60% (6/10) of the patients, with a median time from lung adenocarcinoma to leptomeningeal metastasis of 19.95 months (range, 1.2–44.4 months). NGS of CSF revealed HER2 amplification (HER2amp) in 50% (5/10) of patients, MET amplification (METamp) in 20% (2/10), and one case with a 19Del + L858R mutation. Notably, one patient had L858R + T790M + HER2amp + METamp in CSF. Among the patients, 10% (1/10) had single meningeal metastasis, 70% (7/10) had brain parenchymal metastasis, 40% (4/10) had bone metastasis, and the rest had intrapulmonary, pleural, and lymph node metastases.

Ninety percent of patients had developed TKI resistance by the time they were diagnosed with meningeal metastasis. All patients were resistant to TKI and pemetrexed (primary or secondary) before intrathecal injection therapy and had received multiple treatments (median 6; range, 4–8), including chemotherapy drugs, anti-angiogenic drugs, and immunotherapy. Two patients had undergone ventricular-peritoneal (VP) shunt, two had received radiotherapy, and one had received immunotherapy. The time from the diagnosis of leptomeningeal metastasis to intrathecal injection treatment was 5.15 months (range, 0.1–34.1 months). Before intrathecal injection treatment, all patients had symptoms of intracranial hypertension, PS score greater than or equal to 2, and 20% (2/10) had a PS score of 3; they could not tolerate other anti-tumor therapies (see Table 1).

Intrathecal treatment

Among the 10 enrolled cases, the maximum dose of intrathecal pemetrexed was 40 mg (5/10), and the minimum dose was 10 mg (1/10), with 60% (6/10) receiving 20 mg. One patient had previously received three intrathecal bevacizumab injections (100 mg each). One patient received three intrathecal methotrexate injections (12.5 mg each) after pemetrexed intrathecal injection treatment progressed. Four patients simultaneously combined intrathecal bevacizumab (20 mg) with pemetrexed. The median number of intrathecal injections was 3.5 (range, 1–11). Some patients showed improved symptoms and PS scores after intrathecal injection treatment and subsequently underwent VP shunt surgery and whole-brain radiotherapy (see Table 2). Nine of ten patients received systemic treatment during IT treatment. Eight patients were treated with TKI plus anti-angiogenic drugs (bevacizumab/anlotinib), and one patient was treated with DS8201 and pembrolizumab sequentially. Six patients had concurrent extracranial progression at the time of LM diagnosis. All patients had adopted resistance strategies before intrathecal injection treatment, such as METamp patients using osimertinib + savolitinib before intrathecal injection, HER2amp patients using DS8201, and other patients adjusting chemotherapy drugs or doubling the dose of TKI drugs.

Intracranial response evaluation

All patients were followed up until July 1, 2023. Among the nine evaluable patients, seven showed improved clinical symptoms, and six had a QoL score improvement greater than or equal to 10. Combined with the tumor patient QoL rating scale, the main improved symptoms included consciousness, cognitive function, appetite, fatigue, dizziness and headache, nausea and vomiting, neck stiffness, and lower limb numbness. After intrathecal injection, one patient had negative CSF cytology, and two patients showed a decrease in tumor cells in CSF. Neuroimaging improved in one patient. According to the RANO standard, the disease control rate [partial response (PR) + SD] after intrathecal injection was 88.8% (8/9). After intrathecal injection, the QoL score improved significantly, and the CSF CEA index decreased significantly (see Table 3).

During the follow-up period, nine patients died. Eight patients reached PFS_IT, with the longest PFS_IT exceeding 10.8 months and a median of 5 months (range, 1.4–10.8 months). Additionally, all 10 patients had intrathecal treatment OS (OS_IT), with the longest OS_IT being 18 months and a median of 8.15 months (range, 0.7–18 months). Regarding leptomeningeal metastasis OS (OS_LM), the longest OS_LM reached 43.6 months, with a median of 8.55 months (range, 5.6–43.6 months). As for OS, the longest recorded was 67 months, with a median of 39.35 months (range, 13–67 months) (see Figure 1).

Figure 1 Kaplan-Meier curve for intracranial response evaluation. (A) Total OS for leptomeningeal metastasis patients. (B) OS_LM. (C) OS_IT. (D) PFS_IT. OS, overall survival; OS_IT, overall survival from intrathecal treatment; OS_LM, OS from leptomeningeal metastasis; PFS_IT, progression-free survival of intrathecal treatment.

Safety

A total of nine cases (90%) of the enrolled patients experienced related adverse events, including nausea, vomiting, dizziness, back pain, alanine transaminase (ALT)/aspartate aminotransferase (AST) elevation, electrolyte disturbance, myelosuppression, and leukoencephalopathy. The most common adverse events were myelosuppression (40%, 4/10) and gastrointestinal symptoms (40%, 4/10), with grade three and above adverse events being myelosuppression (two cases of thrombocytopenia, three cases of white blood cell reduction). All grade three-four adverse events improved with symptomatic treatment.

There was a certain correlation between the dose of pemetrexed used in this study and adverse reactions. Patient ID10 received 10 mg of intrathecal pemetrexed quaque week (qw) without any drug-related adverse reactions. A total of 5 patients received 40 mg of intrathecal pemetrexed qw, with 2 cases of grade IV myelosuppression, 3 cases of gastrointestinal reactions, and 1 case of oral sensory abnormalities. A total of 4 patients received 20 mg of intrathecal pemetrexed qw, with 2 cases of grade III myelosuppression, 1 case of gastrointestinal reaction, and 1 case of oral sensory abnormality. During the treatment period, no intracranial infection, intrathecal injection area infection, local adhesion, nerve root injury, treatment-related headache, limb pain, paralysis, acute meningitis, or other adverse events were observed; no patient died from treatment-related side effects (Table 4).

Discussion

This retrospective study demonstrates that intrathecal injection of pemetrexed in EGFR-TKI-resistant lung adenocarcinoma patients with refractory leptomeningeal metastasis is well-tolerated and can improve patients’ QoL and survival benefits. The high disease control rate (88.8%) and PFS_IT of 5.0 months suggest that intrathecal pemetrexed has potential clinical application prospects. Regarding drug dosage, patient ID10 used 10 mg of pemetrexed. This patient did not experience any adverse reactions, and the therapeutic effect was evaluated as SD. The survival data in this study are better than those reported in previous studies on re-challenge of targeted therapy for EGFR-mutated patients with meningeal metastasis (median survival time 6.1 months) (16).

Leptomeningeal metastasis remains the most fatal complication in advanced lung adenocarcinoma with EGFR mutations, severely affecting patients’ QoL. For patients with resistance to EGFR-TKI, alternative options include targeted drugs for resistance genes (such as savolitinib, osimertinib 160 mg, amivantamab), chemotherapy, immunotherapy [programmed cell death protein 1 (PD-1)/programmed death ligand 1 (PD-L1) inhibitors, ivonescimab, lparomlimab], and combination therapies (such as amivantamab + lazertinib). The patients in this study all received salvage treatment after resistance to conventional therapies, having used the systemic treatments available at the time. Intrathecal injection therapy delivers drugs directly to the subarachnoid space via lumbar puncture, allowing even distribution along the subarachnoid space and increasing drug concentration at the site of action. Recent studies have shown that intrathecal injection is effective against tumor leptomeningeal metastasis in solid tumors such as breast cancer and lung cancer (11,15,17-19). All patients in this study had severe neurological symptoms that significantly impacted their QoL. After intrathecal injection, 60% of patients had improved QoL scores, lower than the 68.3% reported in previous studies (20). Possible reasons include the refractory nature of the meningeal metastasis, intrathecal injection as a late-line salvage therapy, PS scores greater than or equal to 2, and a low ratio of sensitizing mutations (T790M).

Commonly used intrathecal injection drugs include methotrexate, cytarabine, and thiotepa (21). Recent explorations have included intrathecal bevacizumab for solid tumor leptomeningeal metastasis and intrathecal trastuzumab for HER2-positive breast cancer leptomeningeal metastasis (4,17,18). Intrathecal injection of rituximab in central nervous system lymphoma has been proven to be safe and effective (22). Pemetrexed, similar to methotrexate, is a multi-target folic acid antagonist and an antimetabolite drug. Intravenous administration can reduce the risk of brain metastasis and leptomeningeal metastasis in lung adenocarcinoma. In the study, all patients had previously been resistant to intravenous pemetrexed, yet intrathecal injection still showed some efficacy, independent of prior intravenous pemetrexed benefits (23,24). A pilot phase 1 study (NCT03101579) of intrathecal pemetrexed in non-small cell lung cancer meningeal metastasis showed that a 10 mg dose of pemetrexed intrathecal injection 1–2 times a week had moderate toxicity and good efficacy (25). A phase 1/2 clinical trial study on pemetrexed intrathecal dose (ChiCTR1800016615) recommended a dose of 50 mg, twice a week in the induction phase, once a week in the consolidation phase for 3 weeks, and once a week in the maintenance phase, showing good efficacy and safety (11). The doses used in this study (10, 20, and 40 mg) all demonstrated certain efficacy and safety. Although intrathecal pemetrexed is effective against refractory leptomeningeal metastasis in lung adenocarcinoma, there is no consensus on the optimal drug dose, frequency, timing of intrathecal injection, and duration of treatment. Future large-sample prospective studies are needed.

The median OS_LM in this study was 8.55 months, with the highest OS_LM reaching 43.6 months. Relevant clinical research on intrathecal injection in advanced non-small cell lung cancer meninges revealed that the survival period of meningeal metastasis was irrespective of gender, age, brain metastasis, EGFR-TKI treatment during intrathecal injection, and CSF protein, glucose, and chloride levels before and after. The main relevant factors reported were Karnofsky Performance Status (KPS) score (median OS 12 vs. 6 months) and high Eastern Cooperative Oncology Group (ECOG) score as an important predictor of poor prognosis. Univariate analysis suggested that a history of whole-brain radiotherapy was associated with better prognosis, and multivariate analysis suggested that the combination of bevacizumab was an independent prognostic factor for intrathecal injection therapy (11,15,20,26). The OS_LM of one patient who combined whole-brain radiotherapy was significantly better than the median OS_LM, suggesting that whole-brain radiotherapy may be a prognostic factor affecting lung cancer leptomeningeal metastasis. Additionally, bevacizumab has good efficacy in the central nervous system (penetrating the blood-brain barrier and reaching high concentrations in CSF), and the combination of bevacizumab with pemetrexed intrathecal injection in the treatment of EGFR-mutated non-small cell lung cancer deserves further study.

Our study confirmed the efficacy and safety of intrathecal pemetrexed in the treatment of refractory leptomeningeal metastasis in EGFR-TKI-resistant lung adenocarcinoma. However, there are limitations. First, this is a small-sample retrospective case study, and all patients had EGFR mutations. More research is needed in EGFR wild-type lung adenocarcinoma. Second, the small sample size may affect statistical analysis results, and subgroup analysis and related factor analysis cannot be performed. A larger sample size is needed to confirm the current results. Finally, there are differences in the regimen, dose, and frequency of intrathecal pemetrexed injection in this study, and the timing and regimen of intrathecal injection therapy need further discussion to reach a consensus. Despite these limitations, this study provides an important basis for intrathecal injection therapy in refractory leptomeningeal metastasis in EGFR-TKI-resistant lung adenocarcinoma.

Conclusions

This study retrospectively analyzed the efficacy of intrathecal pemetrexed in the treatment of refractory meningeal metastasis after EGFR-TKI resistance. The results showed that intrathecal injection of 20 or 40 mg of pemetrexed once a week is highly safe, can improve the QoL of patients with meningeal metastasis, and can be used as a salvage treatment for refractory meningeal metastasis after EGFR-TKI resistance.

Acknowledgments

None.

Footnote

Reporting Checklist: The authors have completed the STROBE reporting checklist. Available at https://jtd.amegroups.com/article/view/10.21037/jtd-2025-1303/rc

Data Sharing Statement: Available at https://jtd.amegroups.com/article/view/10.21037/jtd-2025-1303/dss

Peer Review File: Available at https://jtd.amegroups.com/article/view/10.21037/jtd-2025-1303/prf

Funding: This study was supported by the Scientific Research Foundation of Huashan Hospital, Fudan University (No. 2020QD010).

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://jtd.amegroups.com/article/view/10.21037/jtd-2025-1303/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. The study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. The study was approved by the Ethics Committee of Huashan Hospital, Fudan University (KY2017-089). Written informed consent was obtained from all participants.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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