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Abstract Background Leptomeningeal metastasis (LM) is an advanced complication of lung cancer with a poor prognosis. It remains unknown whether intrathecal pemetrexed (IP) can improve the outcomes of patients with LM from lung adenocarcinoma (LUAD). This study explored the efficacy of intrathecal pemetrexed (IP) and proteomic biomarkers in LM from LUAD. Patients and Methods We conducted a retrospective survival analysis of 157 confirmed LM patients (54 IP vs 103 non-IP). To balance the baseline, propensity score matching (PSM) was implemented. We investigated clinical baseline characteristics and treatment factors to identify those influencing the outcomes of LM patients. Plasma and cerebrospinal fluid (CSF) samples underwent proteomic profiling using Olink Immuno-Oncology panels to identify IP response biomarkers and build a prediction model. Results After PSM, 82 patients were included in two matched cohort (41 IP vs 41 non-IP). IP treatment (HR = 0.427, P = .022) and ECOG performance status (HR = 2.737, P = .005) were independent predictors of overall survival (OS). Stratified analysis showed IP significantly improved OS in patients with poor performance status (ECOG 3-4: IP vs non-IP, 11.2 vs 2.5 months, P = .0029). Proteomics revealed low plasma MCP-2 (AUC = 0.873) and high CSF ARG1 (AUC = 0.875) levels distinguished IP responders from nonresponders. Conclusions IP therapy improves OS in LUAD patients with LM, particularly offering significant benefit as salvage treatment for those with ECOG 3-4. Proteomic analysis suggests plasma MCP-2 and CSF ARG1 are promising predictive biomarkers for IP response. The small sample size in biomarker analysis may limit these findings, necessitating validation through multicenter studies.

Background The treatments for refractory leptomeningeal metastasis (RLM) of non-small cell lung cancer (NSCLC) are limited, and response assessment is complex and challenging. This clinical trial aimed to evaluate the efficacy of intrathecal pemetrexed (IP) and response assessment using cerebrospinal fluid (CSF) tumor marker in RLM. Methods This was a single-center, single-arm, phase II adaptive clinical trial. Patients with RLM of NSCLC were eligible for inclusion. Patients were assigned to receive 30 mg of IP every 3 weeks for a total of 6 cycles. The primary endpoint was overall survival (OS). The secondary endpoints included progression-free survival (PFS) evaluated according to EANO-ESMO response assessment, disease control rate, the concordance of CSF tumor marker response with EANO-ESMO response assessment, and safety. Results A total of 29 patients were enrolled in the trial. The median PFS was 10.03 months (95% CI, 6.42–13.64), and the median OS was 20.37 months (95% CI, 14.86–25.88), respectively. A ± 35% threshold for CSF tumor marker level change (TML) yielded the optimal predictive performance, with AUCs of 0.890 (95% CI, 0.833–0.947), 0.911 (95% CI, 0.870–0.951), and 0.784 (95% CI, 0.717–0.850) for EANO-ESMO response, progression, and stable, respectively. Most patients (93.1%) experienced grade 1–2 treatment-related adverse events. Conclusions Our therapeutic regimen of IP provided a practical, survival-extending, and tolerant option for RLM patients. CSF tumor marker response was correlated with EANO-ESMO response assessment, offering an effective tool for response monitoring of RLM. Trial registration Chinese Clinical Trial Register (ChiCTR) ChiCTR2200057235. Registered on March 1, 2022. Date of the first patient enrollment: April 29, 2022.

Objective This retrospective study aimed to investigate the clinical features of lung cancer patients with leptomeningeal metastasis (LM) and explore the clinical efficacy and tolerance of intrathecal pemetrexed (IP) combined with systemic antitumor therapy. Methods Thirty-four lung cancer patients (11 men, 23 women) with LM receiving IP at our hospital were retrospectively reviewed between August 2018 and December 2019. Identified cases showed either positive cerebrospinal fluid cytology or typical findings (leptomeningeal enhancement or ventricle broadening) upon imaging examination. Results Before the diagnosis of LM, 24 (70.6%) patients received EGFR-TKI therapy with or without other agents (antivascular therapy, or chemotherapy), 5 (14.7%) patients received chemotherapy, 1 (2.9%) patient received antivascular therapy, and 3 (8.8%) patients received ALK inhibitors. Fourteen (41.2%) patients did not change the systematic regimen at the beginning of IP, while 20 (58.8%) patients changed to antitumor agents. IP was administered for a median of 3 times (range, 1-12 times). The IP dose was 15, 20, 25, 30, and 40 mg in 8 (23.5%), 21 (58.8%), 2 (5.9%), 2 (5.9%), and 1 (5.9%) patient, respectively. In all IP dose levels, the major adverse events were myelosuppression and elevation of hepatic aminotransferases (EHA). Grade 1/2 myelosuppression occurred in 4 (11.8%) patients. Grade 1/2 EHA also occurred in 4 (11.8%) patients. Grades 3/4 adverse events were not observed. After IP and systematic therapy, the clinical manifestations related to LM in 26 (76.5%) patients improved. In the whole cohort, the median overall survival was 20 months. The median time from the initial IP administration until death or the last follow-up was 3.5 months. Conclusions IP showed controllable toxicity and good efficacy, prolonged the survival time, and improved the quality of life when combined with tailored systemic antitumor therapy in lung cancer patients.

Leptomeningeal metastasis (LM) is a devastating complication of epidermal growth factor receptor (EGFR)-mutated non-small cell lung cancer (NSCLC), with a poor prognosis. While high-dose third-generation EGFR-tyrosine kinase inhibitors (EGFR-TKIs) can enhance drug concentrations in the central nervous system, their efficacy as monotherapy remains limited. Intrathecal Pemetrexed (IP) offers a promising local treatment approach by bypassing the blood-brain barrier and acting directly within the cerebrospinal fluid. However, clinical data on the efficacy and safety of combining high-dose third-generation EGFR-TKIs Furmonertinib (160 mg/d) with IP in EGFR-mutant NSCLC-LM patients are still scarce. Therefore, this study aims to evaluate the efficacy and safety of this combination regimen in this population to provide real-world data support for clinical practice. In this retrospective study, 40 patients with EGFR-mutant NSCLC-LM were enrolled at Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, N

Background Leptomeningeal metastasis (LM) is an almost universally fatal complication of solid tumors. Intrathecal pemetrexed (IP) has preliminary activity; however, robust efficacy and safety data are lacking. Methods Data of 112 patients with newly diagnosed, cytologically and/or radiologically confirmed LM from solid tumors between May 2021 and June 2024 were retrospectively analyzed. All patients received IP as first-line intrathecal therapy. The efficacy and safety of IP were evaluated, and prognostic factors associated with overall survival in the entire cohort and a non-small-cell lung cancer (NSCLC) subgroup were identified. Results The primary tumor types were NSCLC (63.4%), small-cell lung cancer (14.3%), breast cancer (9.8%), and colorectal cancer (5.4%). The median overall survival (mOS) for the entire cohort was 8.0 months (95% confidence interval [CI], 6.5–9.5), with an overall clinical response rate of 75% (84/112). In the NSCLC subgroup, the mOS was 6.0 months (95% CI, 3.6–8.4). Multivariable analysis identified three independent predictors of improved survival: >6 IP administrations (hazard ratio [HR], 0.38; 95% CI, 0.23–0.62; P  < 0.001), achievement of a clinical response (HR, 0.53; 95% CI, 0.32–0.88), and negative cerebrospinal fluid cytology after treatment (HR, 0.44; 95% CI, 0.28–0.70; P  < 0.001). Importantly, among patients with NSCLC who received > 6 IP cycles, the mOS was 16 months. Treatment-related adverse events were predominantly grades 1–2. The most common symptoms were myelosuppression (41.1%) and elevated hepatic transaminase levels (36.6%). Conclusions Intrathecal pemetrexed could confer clinically meaningful survival benefits with acceptable toxicity in patients with solid tumor LM.

Background Leptomeningeal metastasis in EGFR -mutant ( EGFR m) non-small-cell lung cancer (NSCLC) is a severe complication particularly prevalent in patients who have previously been treated with EGFR-tyrosine kinase inhibitors (EGFR-TKIs). However, an optimal treatment strategy for dealing with leptomeningeal metastases in patients with NSCLC has yet to be developed. High-dose EGFR-TKIs in combination with intrathecal chemotherapy may offer a promising treatment strategy for this patient population. Methods We retrospectively identified patients with EGFR m NSCLC who were diagnosed at the First Affiliated Hospital of Gannan Medical University between January 1, 2018, and December 31, 2023. All patients developed leptomeningeal metastases after EGFR-TKI treatment and then received intrathecal pemetrexed chemotherapy in combination with high-dose third-generation EGFR-TKIs (osimertinib 160 mg/day, furmonertinib 160 mg/day, or aumolertinib 165 mg/day), with or without other therapies. Intracranial response, intracranial progression-free survival, overall survival, and safety were evaluated. Results Twenty-three patients were enrolled. The median follow-up was 20 months (range, 2–35). The median number of intrathecal pemetrexed injections was 4 (range, 2–26). The intracranial symptom relief rate was 91.3% (21/23), intracranial disease control rate was 86.96% (20/23), median intracranial progression-free survival was 10 months (95% CI, 1.52–18.48), and median overall survival was 12 months (95% CI, 5.43–18.57). The most frequent adverse event was myelosuppression ( n  = 10, 43.48%), which was limited to grade 1 or 2. Two grade 3 adverse events were observed, including one case of interstitial pneumonia and one case of diarrhea. Univariate and multivariate analyses demonstrated that the combination of bevacizumab and an Eastern Cooperative Oncology Group performance status of ≤ 1 were favorable prognostic factors for survival. Conclusions High-dose third-generation EGFR-TKIs combined with pemetrexed intrathecal chemotherapy demonstrated a high rate of intracranial symptom relief and manageable safety in patients with EGFR m NSCLC who developed leptomeningeal metastases after previous EGFR-TKI therapy.

Leptomeningeal metastasis (LM) is a fatal complication of malignant tumors with limited treatment options. Finding more effective therapeutic strategies is of significant importance. This case reports an LM patient from breast cancer treated with intrathecal pemetrexed (15 mg) combined with PD-1 inhibitors (40 mg). The pemetrexed dosing regimen included an induction phase (twice weekly for 2 weeks), a consolidation phase (once weekly for 4 weeks), and a maintenance phase (once monthly). The PD-1 inhibitor dosing regimen included an induction phase (once every 2 weeks for 6 weeks) and a maintenance phase (once monthly). The patient showed good tolerance, with no severe adverse events observed, and achieved favorable therapeutic outcomes, including complete resolution of neurological symptoms, negative conversion of cerebrospinal fluid cytology, and significant reduction of imaging-detected lesions. This case provides a new approach to the treatment of LM, suggesting that intrathecal immunotherapy combined with intrathecal chemotherapy may be a safe and effective treatment option, offering valuable insights for future clinical applications.

Purpose To explore the impact of intrathecal pemetrexed (IP) on the survival of lung adenocarcinoma (LUAC) patients with leptomeningeal metastasis (LM). Methods We analyzed patients with LUAC and LM who received systemic therapy after LM diagnosis at the Fujian Cancer Hospital between July 2018 and March 2022. Patients who underwent IP were assigned to the IP group; those without IP treatment were designated as the non-IP group. Propensity score matching (PSM) was performed between the two groups. Results 165 patients were enrolled: 83 and 82 in the IP and non-IP groups, respectively. After 1:1 PSM, we included 114 patients in the matched cohort. Median overall survival (OS) was 13.2 months (95% CI 10.8–15.6 months) in the IP group versus 10.1 months (95% CI 5.3–14.9 months) in the non-IP group (P = 0.488). Only Eastern Cooperative Oncology Group Performance Status (ECOG PS) was confirmed as an independent predictor for OS in the matched cohort (hazard ratio (HR) 2.03; P = 0.023). Multivariate competing-risks analysis showed that IP significantly correlated with central nervous system-related death (HR 0.31; P = 0.046). When stratified by ECOG PS, IP improved survival in patients with poor ECOG PS (PS = 2) (14.3 months vs. 1.6 months; P = 0.003). Conclusions Intrathecal pemetrexed did not enhance OS for the entire LUAC patient with LM compared to non-intrathecal chemotherapy. However, it exhibited the potential to reduce the risk of central nervous system-related mortality and improve survival in patients with poor ECOG PS.

Background Leptomeningeal metastasis (LM) is the most devastating complication of non-small cell lung cancer (NSCLC), and its incidence is increasing. There is currently no standard treatment for LM, and the efficacy of traditional intravenous drug treatment is low, making refractory LM a difficult problem. In this study, we evaluated the efficacy and safety of intrathecal chemotherapy (IC)-based regimens in patients with refractory LM. Methods We retrospectively enrolled NSCLC patients with confirmed LM who received IC and systemic therapy at the Second Affiliated Hospital of Nanchang University from December 2017 to July 2022. We analysed overall survival (OS), intracranial progression-free survival (iPFS), clinical response, and safety in these patients. Results A total of 41 patients were enrolled. The median number of IC treatments was seven (range: 2–22). Seven patients received intrathecal methotrexate, and 34 patients received intrathecal pemetrexed. Clinical manifestations related to LM improved after IC and systemic therapy in 28 (68.3%) patients. The median iPFS in the whole cohort was 8 months (95% confidence interval [CI]: 6.4–9.7 months), and the median OS was 10.1 months (95% CI: 6.8–13.4 months). Multivariate analysis of the 41 patients with LM using a Cox proportional risk model showed that bevacizumab was an independent prognostic factor in patients treated with combination therapy (p = 0.002; hazard ratio [HR] 0.240; 95% CI: 0.097–0.595). Poor ECOG performance status remained a significant predictor of poor prognosis for survival (p = 0.048; HR 2.560; 95% CI: 1.010–6.484). Myelosuppression was the major adverse event over all IC dose levels. There were 18 cases of myelosuppression, 15 cases of leukopenia, and nine cases of thrombocytopenia. Eleven patients had myelosuppression above grade 3, including four with thrombocytopenia and seven with leukopenia. Conclusions Combination therapy based on IC had good curative effects, was safe to use, and was associated with prolonged survival in NSCLC patients with LM. The use of bevacizumab is a good prognostic factor for NSCLC LM patients with combination therapy.

Purpose: A phase I/II study of intrathecal pemetrexed (IP) combined with involved-field radiotherapy (IFRT) was performed to determine feasibility, safety, and antitumor activity for leptomeningeal metastases (LM) from solid tumors. Methods: Participants first received induction IP administration, followed by concomitant radiotherapy within 3 days. The concomitant regimen consisted of IP (pemetrexed 10 mg, dexamethasone 5 mg, once per week, 4 times in 4 weeks) and IFRT (40 Gy in 20 fractions). Six participants were recruited to assess feasibility in phase I, and then 28 patients were recruited further. All patients were assessed to investigate safety, efficacy, and outcomes. Results: Between April 2018 and December 2018, 34 patients (male: 15; female: 19; median age: 56 years) were enrolled, including non-small-cell lung cancer (21), small-cell lung cancer (5), breast cancer (4), and others (4). Thirty-two patients received concurrent therapy and 25 (74%) patients completed the treatment. Major adverse events (AEs) consisted of myelosuppression, the elevation of hepatic aminotransferases, and radiculitis. Total AEs rate was 53% (18/34), including 6 (18%) patients with grade 3 and 1 (3%) with grade 4 AEs. The response rate was 68% (23/34). The median overall survival was 5.5 (0.3–16.6) months. Median neurological progression-free survival (NPFS) was 3.5 (0.3–15.2) months. Six-month NPFS rate was 47%. One-year survival rate was 21.6%. Conclusion: IP at a 10 mg dose on a schedule of 1–2 times per week presented good efficacy and safety in CSF. The concomitant regimen is an efficacious therapeutic option for LM patients with solid tumors. Trial Registration: This study (IPLM) was registered at https://register.clinicaltrials.gov [ClinicalTrials.gov identifier: NCT03507244].