Intrathecal pemetrexed for newly diagnosed leptomeningeal metastases: A multicenter, open-label, phase I/II study

Intrathecal pemetrexed for newly diagnosed leptomeningeal metastases: A multicenter, open-label, phase I/II study | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Case Report Intrathecal pemetrexed for newly diagnosed leptomeningeal metastases: A multicenter, open-label, phase I/II study Zhenyu Pan, Xiaojun Ye, Yushan Huang, Panpan Tai, Miaomiao Liu, and 8 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-6572942/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 23 Jul, 2025 Read the published version in Journal of Neuro-Oncology → Version 1 posted 13 You are reading this latest preprint version Abstract Background This phase I/II study evaluated the maximum-tolerated dose (MTD) of intrathecal pemetrexed (IP) with vitamin supplementation, and its safety, feasibility and therapeutic activity for newly diagnosed leptomeningeal metastasis (LM) from solid tumors. Methods The phase I study followed the classic 3 + 3 design, with IP dose escalating from 15 mg. The recommended dose was applied in the phase II study. The MTD, adverse events (AEs), overall survival (OS), clinical response rate (CRR) and disease control rate (DCR) were evaluated. Results A total of 34 patients were enrolled. In the phase I study, 2 patients in the 20 mg group experienced dose-limiting toxicity. The MTD was established as 15 mg. Among 28 patients in the MTD group, 24 completed induction therapy, 19 completed consolidation therapy and 11 proceeded to maintenance therapy. The overall AEs rate was 74% (25/34), and severe AEs rate (> grade 3) was 15% (5/34). In the MTD group, the CRR, DCR and median OS were 46% (13/28), 75% (21/28) and 8.1 months. Conclusion IP at 15 mg with prior folic acid and vitamin B12 supplementation demonstrated safety and feasibility, offering a new treatment option with therapeutic activity for newly diagnosed LM patients with solid tumors. Trial registration: ClinicalTrials.gov Identifier: NCT05289908 Leptomeningeal metastasis Intrathecal chemotherapy Pemetrexed Figures Figure 1 Figure 2 Introduction Leptomeningeal metastasis (LM) is a devastating complication of multiple malignancies, characterized by cancer cell involvement in the cerebrospinal fluid (CSF) and leptomeninges, with the typical median overall survival (OS) of only 3–4 months [ 1 ]. Approximately 10% of patients with solid tumors develop LM during their disease course, with lung cancer, breast cancer, and melanoma representing the three most common primary malignancies [ 2 ]. Intrathecal chemotherapy remains a primary treatment for LM, offering the advantage of direct CSF drug delivery to maximize therapeutic exposure to tumor cells [ 3 ]. Compared with systemic administration, low-dose intra-CSF administration can achieve higher CSF drug concentration with a better cytotoxic effect [ 4 ]. However, chemotherapeutic agents that can be safely administered intrathecally for the treatment of LM are extremely limited [ 5 ]. It is crucial to identify novel agents with both favorable safety profiles and potential activity. In 2017, we conducted the first study of intrathecal pemetrexed (IP) in the world, which established the feasibility of administering IP in patients with recurrent and refractory LM from lung adenocarcinoma [ 6 ]. The recommended dose of IP for LM was 10 mg on a schedule of 1–2 times per week based on pharmacokinetic studies. In that study, prophylactic folic acid and vitamin B12 supplementation was not used, as the intrathecal dose was less than 3% of the systemic dose, potentially impacting treatment efficacy [ 6 ]. However, our subsequent research revealed that vitamin supplementation significantly reduced the incidence of hematological toxicity, a primary adverse effect and dose-limiting toxicity (DLT) of pemetrexed administered intrathecally [ 7 ]. Consequently, our previous study was limited by an inadequate investigation of patients with recurrent or refractory disease [ 6 ]. Also, the maximum tolerated dose (MTD) and safety profile of IP with prior folic acid and vitamin B12 supplementation remain undefined, particularly in newly diagnosed LM patients who have not previously undergone intrathecal chemotherapy [ 6 ]. Subsequent to our earlier research, several other studies on IP have been conducted, typically employing dosing intervals of once every 1–3 weeks [ 8 , 9 ]. However, the MTD reported in these studies (30–50 mg) was significantly higher than in our previous work, while the incidence of adverse events (AEs) was notably lower [ 6 – 10 ]. The significant variability between studies, along with some unreliable findings, has caused confusion regarding the treatment regimen and dosage of IP in clinical practice. Therefore, further studies are urgently needed to evaluate its true tolerability, optimal dosage, safety profile, side-effect management, and potential activity of IP using a scientific regimen based on the previous study on animal models [ 11 ]. Based on our previous findings [ 7 ], this prospective phase I/II study was designed to determine the MTD, safety, feasibility and clinical activity of IP with prior folic acid and vitamin B12 supplementation in patients with newly diagnosed LM from various solid tumors. Patients and Methods Study Design and Participants This was a multicenter, open-label, single-arm phase I/II clinical study (ClinincalTrials.gov identifier: NCT05289908). Eligible patients were aged 18–75 years, had pathologically confirmed malignant solid tumors with normal organ and marrow function, life expectancy of greater than 2 months, and had a newly diagnosed LM confirmed by positive CSF cytology or LM-related specific imaging findings and neurological signs if CSF cytology was negative. The diagnosis of LM was ascertained according to the guidelines by the European Association of Neuro-Oncology–European Society for Medical Oncology (EANO-ESMO) co-published [ 2 ]. Hematologic malignancy or primary central nervous system (CNS) malignancy, or other reasons that made them unsuitable for this study, including serious central nervous system disorders, hydrocephalus or other factors suggestive of CSF obstruction, lethal or extensive systemic diseases with few treatment options, psychiatric illness, or poor compliance, were excluded. Procedures and Treatment Regimen Phase I of the study was a 3 + 3 dose escalation trial (Fig. 1 ). Based on the data of our previous study [ 6 ], we chose to treat patients starting at a dose of 15 mg IP with prior folic acid and vitamin B12 supplementation and escalating each dose group by 5 mg (20 mg, …). DLT was assessed during the first 6 weeks of treatment. If 2 or more of the 6 patients experienced a DLT, dosing escalation would cease and MTD would be reached. The MTD, also the recommended dose for phase II, was the next lower dose at which < 2/6 subjects experienced a DLT. The DLT was defined as ≥ grade 3 neurological toxicities (e.g., chemical meningitis) or other ≥ grade 4 toxicity. Pemetrexed (Alimta, Eli Lilly and Company) was administrated by intrathecal injection, with 5 mg dexamethasone, first as induction therapy, twice per week for 2 weeks, followed by consolidation therapy, once per week for 4 weeks. If LM progresses or DLT occurs during therapy, the treatment will be discontinued. For patients who were evaluated to be effective or stable, maintenance therapy was initiated and administered once per month until the patient’s death, LM progresses, or intolerable severe AEs occurred. The treatment regimen is provided in Supplementary Fig. 1. In addition, folic acid 400 µg was administered orally once daily, prior to the first IP, until 21 days after the last IP. A single dose of vitamin B12 1000 µg was administered by intramuscular injection before the first IP, once every 2 months. Involved-field radiotherapy (IFRT) encompassing whole-brain irradiation, focal intracranial lesions, and/or segmental spinal irradiation was used in selected patients [ 3 ]. Patients who had received systemic treatment prior to enrollment were allowed to continue their original regimens, including tyrosine kinase inhibitors (TKIs) or chemotherapy. However, since these patients developed LM progression while receiving the same therapies, this suggests a failure of the systemic treatments against LM. The observed CNS progression thus reflects the inherent limitations of these systemic regimens in controlling LM. In addition, symptomatic and supportive treatment was permitted for patients with severe conditions. Endpoints and Assessments As a phase I/II study, it focused on evaluating the feasibility and safety of the treatment protocol. The primary objectives were to determine the MTD of IP with prior folic acid and vitamin B12 supplementation and safety based on the incidence of treatment-related AEs. The secondary objective was OS. In addition, the clinical response rate (CRR) and disease control rate (DCR) were also evaluated. The clinical response was evaluated by RANO-LM working group proposal criteria [ 12 ], which were based on three levels of assessment, CSF cytology, neurological status and neuroimaging findings. CRR was defined as the incidence of at least one of the evaluations of CSF cytology, neurological status and neuroimaging findings rated as improved, and there was no disease worsening at the same time. The DCR was defined as the incidence of patients who did not experience disease progression during the initial treatment period (induction and consolidation therapy). Disease progression was defined as the worsening of neuroimaging or neurological dysfunction. CSF cytology examination was performed at baseline and each time of IP using Thinprep plus Papanicolaou staining during induction and consolidation therapy, and then every month during maintenance therapy. Patients with positive baseline CSF cytology were evaluated as having a cytological response when CSF cytology turned negative for 4 weeks or more after IP. Neurological function examination was performed at baseline, weekly thereafter during induction and consolidation therapies, and then monthly during maintenance therapy to record changes in neurological symptoms and signs. The improvement of neurological function for 2 consecutive weeks was evaluated as effective. Neuroimaging evaluation was performed at baseline, at the end of consolidation therapy, 4 weeks after that, and then every 2–3 months during maintenance therapy. Neuroimaging assessment was performed according to the proposal for a revised Leptomeningeal Metastasis Working Group grid by 3 neuro-radiologists and 2 neuro-oncologists [ 13 ]. All patients were followed up until death or for at least 12 months after treatment. AEs were graded according to the Common Terminology Criteria for Adverse Events (CTCAE, version 5.0). A Grade 4–5 was defined as serious AEs. Survival time was defined from the enrollment until death or the last follow-up. Statistical Analysis Since the CRR varies greatly in the clinical study of LM due to the subjective evaluation of researchers [ 14 ], we opted for OS to estimate the sample size for this study. The PASS 15.0 software was used to calculate the sample size and the target number was estimated by the median OS. Based on the previous study [ 6 ], we hypothesized H0 as an OS of 3.8 months and H1 as 6.8 months, 28 patients were needed in the Phase II study to achieve 80% power with a predefined one-sided alpha of 5%. The R tools 4.0 software was used for data analyses. Fisher’s exact tests were used to evaluate the difference in CRR between patients with various pathological types. Survival analyses were performed using the Kaplan–Meier method. P < 0.05 demonstrated a significant difference. Results Characteristics Between February 2022 and January 2023, 34 patients (16 males and 18 females) were enrolled sequentially (Fig. 1 ). Patients’ basic clinical characteristics and disease-related variables were displayed in Table 1 and Supplementary Table 1. LM diagnosis was confirmed in 97% of patients (N = 33) by positive CSF cytology and probable in 3% (N = 1) by neuroimaging findings and typically LM-related neurological system symptoms and signs according to the EANO-ESMO guidelines [ 2 ]. Of all participants, 21% (N = 7) of cases had progressive systemic disease and 76% (N = 26) had stable systemic disease outside the CNS. 76% (N = 26) had received systemic chemotherapy and 15% (N = 5) of patients had received immunotherapy before enrollment. 59% of the participants were NSCLC (N = 20) and 47% (N = 16) received TKIs treatment prior to the diagnosis of LM. Table 1 Baseline characteristics of the patients All Eligible Patients (n = 34) Patients in the MTD group (n = 28) Gender Male 16 (47%) 12 (43%) Female 18 (53%) 16 (57%) Median age (years) 56 (45–68) 56 (45–67) GCS < 15 7 (21%) 7 (25%) KPS < 60 16 (47%) 12 (43%) ≥ 60 18 (53%) 16 (57%) CSF cytology Positive 33 (97%) 27(96%) Negative 1 (3%) 1 (4%) Neuroimaging features Positive 31 (91%) 26 (93%) Negative 3 (9%) 2 (7%) Onset as LM a 3 (9%) 3 (11%) Pathological types of primary disease NSCLC b 20 (59%) 16 (57%) SCLC 3 (9%) 3 (11%) Breast cancer 8 (24%) 7 (25%) Gastric adenocarcinoma 1 (3%) 1 (4%) Esophagus carcinoma 1(3%) 0 Nasopharyngeal carcinoma 1(3%) 1 (4%) Elevated intracranial pressure Yes 16 (47%) 14 (50%) No 18 (53%) 14 (50%) Systemic disease progressive 7 (21%) 5 (18%) Stable 26 (76%) 22 (79%) Not observed 1 (3%) 1 (4%) Breast cancer 8 (24%) 7 (25%) Triple-negative 2 (6%) 2 (7%) Her-2 + 4 (12%) 3 (11%) Luminal A 1 (3%) 1 (4%) Luminal B 1 (3%) 1 (4%) NSCLC 20 (59%) 17 (61%) EGFR mutation 14 (41%) 11 (39%) ALK mutation 1 (3%) 1 (4%) ALK&MET mutation 1 (3%) 1 (4%) Not detected 4 (12%) 4 (14%) Continued Table 1 . Baseline characteristics of the patients All Eligible Patients (n=34) Patients in the MTD group (n=28) TKI treatment prior to enrollment 16 (47%) 13 (46%) First-generation EGFR-TKIs 10 (29%) 10 (36%) Second-generation EGFR-TKIs 3 (9%) 1 (4%) Third-generation EGFR-TKIs 9 (26%) 8 (29%) AKL-TKIs 2 (6%) 2 (7%) MET-TKIs 1 (3%) 1 (4%) Systemic chemotherapy prior to enrollment 26 (76%) 23 (82%) Pemetrexed-based chemotherapy 12 (35%) 11 (39%) Non pemetrexed-based chemotherapy 14 (41%) 12 (43%) Immunotherapy prior to enrollment 5 (15%) 4 (14%) MTD, maximum-tolerated dose; GCS, glasgow coma scale; KPS, karnofskyperformance status; CSF, cerebrospinal fluid; LM, Leptomeningeal metastasis; NSCLC, non-small cell lung cancer; SCLC, small cell lung cancer; Her-2, human epidermal growth factor receptor 2; EGFR, epidermal growth factor receptor; ALK, anaplastic lymphoma kinase; MET, mesenchymal-epithelial transformation factor; TKI, tyrosine kinase inhibitor. a LM was the initial manifestation of malignancy. b Includes lung adenocarcinoma (n = 18), lung squamous cell carcinoma (n = 1) and unable to specify the type of NSCLC (n=1). DLT and MTD In the phase I study, a total of 4 patients were enrolled at the first IP dose level of 15 mg because 1 patient withdrew from the study after the first IP for personal reasons. No DLT occurred. The IP dose was subsequently escalated to the second dose level of 20 mg, and an additional 6 patients were enrolled, 2 of whom experienced DLT. One case occurred grade 4 leukopenia after the fourth IP (accompanied by grade 2 thrombocytopenia), which was relieved after stopping IP, administering recombinant human granulocyte colony-stimulating factor (rhG-CSF), recombinant human interleukin 11 (rhIL-11), recombinant human thrombopoietin (rhTPO) and increasing the dose of folic acid to 800 µg orally once daily. The other case experienced grade 5 chemical arachnoiditis after the first IP and died 3 days later. Therefore, the MTD of IP with prior folic acid and vitamin B12 supplementation for LM patients was defined as 15 mg, which was also the recommended dose for phase II. Subsequently, an additional 24 patients were enrolled in phase II and received 15 mg of IP. The 4 patients treated at the MTD during phase I were included in the phase II analysis to achieve the pre-specified sample size requirement of a total of 28 cases. Treatment and feasibility Of the 34 participants, 28 patients completed induction IP (Table 2 ). Among the remaining 6 patients who did not complete induction therapy, 2 died 3–5 days following their third IP attributed to LM progression; 1 terminated treatment after developing chemical arachnoiditis after the first IP and 3 withdrew consent for personal reasons. A total of 21 patients completed the consolidation IP, and 12 patients received maintenance IP subsequently. Among 28 patients in the MTD group, 24 completed induction therapy, 19 completed consolidation therapy, and 11 proceeded to maintenance therapy (Table 2 ). Table 2 The treatment of the patients Treatment All Eligible Patients (n = 34) Patients in the MTD group (n = 28) Induction IP Completion of induction IP 28 (82%) 24 (86%) Incompletion of induction IP 6 (18%) 4 (14%) Consolidation IP Completion of consolidation IP 21 (62%) 19 (68%) Incompletion of consolidation IP 13 (9%) 9 (32%) Maintenance IP 12 (35%) 11 (39%) Other treatments during trial participation CNS radiation therapy 8 (24%) 6 (21%) Systemic chemotherapy 3 (9%) 3 (11%) Targeted therapy 11 (32%) 8 (29%) MTD, maximum-tolerated dose; IP, intrathecal pemetrexed; CNS, central nervous system. Eight patients received concurrent IFRT, including 5 with whole brain radiotherapy and 3 with segmental spinal canal radiotherapy. Thirteen patients maintained their prior systemic therapy during the study, including prior TKIs treatment in 11 cases and prior systemic chemotherapy regimens in 3 cases. The remaining 7 patients with progressive systemic diseases did not receive systemic treatment during IP therapy owing to low score (less than 50), severe neurological status or personal factors. Safety All participants were assessed for safety. The overall AEs rate was 74% (25/34) (Supplementary Table 2), and the severe AEs rate (> grade 3) was 15% (5/34, 95% exact CI, 4.95–31.05%). Twenty-one of 28 patients in the MTD group experienced one or more AEs (Table 3 ). In all participants, the most frequent AEs were hematologic toxicity (53%, 18/34) and elevated hepatic aminotransferases (EHA, 38%, 13/34). Hematologic toxicity occurred mainly after 4–6 times of IP, which was manifested as thrombocytopenia (N = 11) and leukopenia (N = 12). Severe hematologic toxicity occurred in 4 cases including 1 grade 4 leukopenia with 20 mg of IP and 3 grade 4 leukopenia and thrombocytopenia with 15 mg of IP. EHA mainly occurred after 2–5 times of IP. 26% of patients required aminotransferase-lowing drugs for management of EHA. In addition, 3 patients (9%) experienced arachnoiditis, including 1 patient of grade 5 at 20 mg dose level (died within 1 week after abandoning treatment) and 2 patients of grade 2 at 15 mg dose level (completely relieved following glucocorticoid therapy). Radiculitis was noted in 9% (3/34) of patients, and mainly in grade 1 and grade 3. No symptomatic treatment was required and no patient discontinued treatment due to radiculitis. Grade 3 hepatocellular jaundice in 1 patient (3%), grade 1–2 transient cognitive disturbance in 2 patients (6%), grade 3 fatigue in 1 patient (3%), and grade 2 nausea in 1 patient (3%) were also observed in this study. Table 3 Adverse events in the MTD group (n = 28) Adverse events Grade N (%) 1 2 3 4 5 Hematologic toxicity 5 (18%) 2 (7%) 6 (21%) 3 (11%) 0 Elevation of hepatic aminotransferases 2 (7%) 3 (11%) 6 (21%) 0 0 Elevation of blood bilirubin 0 0 1 (4%) 0 0 Arachnoiditis 0 2 (7%) 0 0 0 Radiculitis 2 (7%) 0 0 0 0 Transient cognitive disturbance 1 (4%) 1 (4%) 0 0 0 Fatigue 0 0 1 (4%) 0 0 Nausea 0 1 (4%) 0 0 0 MTD, maximum-tolerated dose. Clinical Outcomes According to the response assessment criteria of Response Assessment in Neuro-Oncology (RANO)-LM [ 12 ], 15 patients were assessed as a response (11 with improvement of neurological function, 8 with improvement of neuroimaging, and 11 with negative conversion of CSF cytology); 10 patients were assessed as stable; and 4 patients were assessed as LM progressive based on worse neurological function and neuroimaging assessment (Table 4 ). The remaining 5 patients were unevaluable without neuroimaging or CSF cytology re-examination. Table 4 Clinical response evaluation of the patients Characteristics All Eligible Patients (n = 34) Patients in the MTD group (n = 28) Clinical response evaluation a Response b 15 (44%) 13 (46%) Stable disease 10 (29%) 8 (29%) Progressive disease c 4 (12%) 4 (14%) Non-evaluable 5 (15%) 3 (11%) Neurological function assessment Improved 11 (32%) 10 (36%) Stable 14 (41%) 11 (39%) Worse 4 (12%) 4 (14%) Non-evaluable 5 (15%) 3 (11%) CSF cytological assessment Response 11 (32%) 10 (36%) Stable 16 (47%) 13 (46%) Non-evaluable 7 (21%) 5 (18%) Neuroimaging assessment Improved 8 (24%) 7 (25%) Stable/equivocal 17 (50%) 15 (54%) Worse 1 (3%) 1 (4%) Non-evaluable 8 (24%) 5 (18%) Neurological symptoms assessment Improved 23 (68%) 19 (68%) Stable 4 (12%) 4 (14%) Worse 4 (12%) 3 (11%) Non-evaluable 3 (9%) 2 (7%) Median OS, months (95% CI) 8.1 (6.5–11.3) 8.1(6.5–11.9) MTD, maximum-tolerated dose; CSF, cerebrospinal fluid; OS, overall survival. a The clinical response was evaluated by Response Assessment in Neuro-Oncology (RANO)-LM working group proposal criteria, which was based on three levels of assessment, CSF cytology, neurological status and neuroimaging findings. b Response was defined as the incidence of at least one of the evaluations of CSF cytology, neurological status and neuroimaging findings rated as improved, and there was no disease worsening at the same time. c Progressive disease was defined as worsening of neuroimaging or neurological dysfunction. Of a total of 29 patients who were available for neurological function assessment, 11 were evaluated as improved, 14 were stable and 4 were worse. Of 27 patients with available CSF cytology data, 11 patients were assessed as having CSF cytological response, and 16 patients were stable. For neuroimaging assessment, 26 patients were available for assessment, including 8 improved, 17 stable/equivocal, and 1 progressive. In addition, 68% (23/34) of patients had improvement of LM-related symptoms. The overall CRR for all patients was 44% (15/34) and the overall DCR was 74% (25/34) with intention-to-treat (ITT) analysis (Table 4 ). The CRR and DCR for patients in the MTD group were 46% (13/28) and 75% (21/28) respectively. The CRR based on pathological types were 40% (8/20) of NSCLC, 50% (4/8) of breast cancer, and 50% (3/6) of other tumors (including small-cell lung cancer, esophageal cancer, nasopharyngeal cancer, and gastric cancer, Supplementary Table 3). No statistical difference was observed in CRR with various primary tumors ( P = 0.899). Notably, the CRR of EGFR-mutated NSCLC patients who developed LM during the course of TKIs treatment was 50% (7/14). Follow-Up and Survival All participants were followed up for at least 12 months until death or March 1, 2024. The median follow-up time was 8.1 months. The median OS for all patients was 8.1 months (95% confidence interval [CI], 6.5–11.3, Fig. 2 A), and the 12-month survival rate was 35.3% (12/34). The median OS for patients in the MTD group was 8.1 months (95% CI, 6.5–11.9), and the 12-month survival rate was 35.7% (10/28). The median OS for 15 patients with clinical response was 14.9 months (95% CI, 10.7–17.3), and 3.1 months (95% CI, 2.6–7.1) for 19 patients without clinical response (Fig. 2 B, P < 0.001). The median OS of the 12 patients who continued maintenance therapy was 16.9 months (95% CI, 11.6–18.9), and 3.9 months (95% CI, 3.3–7.6) for 22 patients who did not enter the maintenance stage (Fig. 2 C, P < 0.001). Median survival for patients with NSCLC, breast cancer, and other tumors was 8.2, 6.3, and 4.8 months respectively, with no statistical difference between the 3 groups (Fig. 2 D, P = 0.7). Besides, 14 patients who developed LM during the course of TKIs treatment had a median OS of 11.8 months (95% CI, 7.1–15.7). By the end of follow-up, 85% (29/34) of patients died. Among them, death was attributed to extra-CNS disease progression in 7 patients, to LM progression in 17 patients, to a combination of LM and extra-CNS disease in 2 patients, and not directly related to disease progression in 3 patients (1 treatment-related toxicity and 2 severe intrapulmonary infections). Discussion This study indicated that the MTD for IP administration with vitamin supplementation was 15 mg per single dose. A dosing regimen consisting of twice-weekly administration for 2 weeks as induction therapy, followed by once-weekly administration for 4 weeks as consolidation therapy, and subsequently monthly administration as maintenance therapy, was demonstrated to be safe and feasible. Furthermore, this treatment protocol exhibited clinical activity. This study established a feasible and safe IP regimen for newly diagnosed LM from solid tumors. Pemetrexed, a multitargeted antifolate, has demonstrated broad antitumor activity across diverse solid tumors, including CNS malignancies [ 15 – 20 ]. The anti-tumor efficacy of chemotherapeutic drugs, including pemetrexed, is related to drug concentration, duration of exposure, and rational drug administration regimens, which are mainly influenced by the half-lives of the drugs [ 21 ]. A rat model study for IP in 2011 demonstrated sustained high pemetrexed concentrations in CSF following a 1 mg/kg dose, with CSF levels at 24 hours post-injection at 0.143 µM, close to the half maximal inhibitory concentration (IC50) observed in human solid tumor cell lines [ 11 ]. Based on CSF volume and drug concentration, and considering safety, this study suggests an optimal starting dose of 5–10 mg pemetrexed for human studies. More importantly, half-lives of pemetrexed for the initial distribution/elimination and terminal elimination phases were 0.43 and 1.43 h in rat CSF [ 11 ], respectively, which were similar to those of classical intrathecal chemotherapeutic drugs (methotrexate, cytarabine and thiotepa) in the CSF [ 22 ]. Thus, the administration regimen of IP was developed following that of classic intrathecal chemotherapeutic drugs: induction therapy twice a week, followed by consolidation therapy weekly, and then maintenance therapy monthly until the disease progresses or severe AEs cannot be tolerated. Several other studies have been conducted, typically employing a regimen of IP once every 1–3 weeks [ 8 , 9 ]. These regimens lack scientificity and rationality, casting doubt on the credibility of their findings [ 4 ]. This is mainly due to the fact that the half-life of pemetrexed only exists for very few hours, a regimen of IP once every 1–3 weeks is unable to maintain an effective drug concentration in CSF, deviating from fundamental pharmacological principles [ 4 , 6 , 11 ]. This study revealed that a single 20 mg dose of intrathecal pemetrexed could induce grade 4–5 severe adverse events, which is inconsistent with previous research findings and warrants clinical attention. Building upon our previous researches [ 6 , 7 ], this study further clinically validated a scientifically rational treatment protocol for IP, providing a novel therapeutic option for LM patients with solid tumors. The incidence of treatment-related toxicity constitutes a primary determinant of drug dosing regimens. Previous studies have found that hematological toxicity and EHA are the main treatment-related AEs of IP [ 6 , 23 ]. Building upon previous clinical trials [ 6 , 7 ], this study continued dose escalation of IP with prior folic acid and vitamin B12 supplementation. The results showed that the prior supplementation of folic acid and vitamin B12 elevated the MTD of IP from 10 mg to 15 mg. However, hematological toxicity is still one of the main factors interfering with the completion of treatment. In this study, the incidence of grade 3 or higher hematological toxicity was 32% in the 15 mg dose group. Furthermore, grade 3 EHA was observed in 21% of participants in the 15 mg dose group, which was higher than the previous incidence of 9% at the 10 mg dose level [ 7 ], and most of them occurred during the induction IP period (IP, twice a week). Thus, higher dose and frequency of induced IP may increase the incidence of high-grade hematological toxicity and EHA. Compared with conventional systemic administration of pemetrexed, the markedly shortened dosing interval of induction IP may lead to hematopoietic cell depletion and hepatic metabolic impairment. Therefore, in order to avoid the occurrence of severe AEs, the regimen of induction IP is recommended to be twice-weekly administration (maximum 4 doses over 2 weeks). In addition, moderate IP-related chemical arachnoiditis was observed in this study, which has never been reported for systematic chemotherapy with pemetrexed. Obviously, combined with our previous clinical studies [ 6 , 7 ], this study further confirmed that there was a dose gradient effect in the toxicities for IP, indicating an increase in the incidence of AEs with increasing dosage, particularly the occurrence of severe treatment-related AEs such as neurological toxicity. In this study, the 15 mg dose regimen yielded a 46% CRR, 75% DCR, and median OS of 8.1 months, which were obviously better than those in our previous study on 10 mg of IP (CRR 31%, DCR 54%, and OS 3.8 months) [ 6 ]. These results suggest that with prior folic acid and vitamin B12 supplementation, the 15 mg IP might have better activity with controllable AEs. Moreover, this study once again confirmed that IP was effective for LM from various primary solid tumors, similar to previous studies on 10 mg IP combined with IFRT [ 7 ], and CRR was not affected by the pathological type of the primary tumor. Moreover, these results surpassed the historical median survival time previously reported for this disease [ 1 ]. In recent years, third-generation EGFR TKIs have been approved as the standard first-line therapy for patients with advanced EGFR-mutant NSCLC. Moreover, some studies have demonstrated the efficacy of third-generation EGFR TKIs therapy in LM patients with EGFR-mutant NSCLC [ 14 , 24 – 28 ]. However, acquired resistance involving EGFR-dependent or non-EGFR-dependent mechanisms inevitably occurs and hampers their clinical benefits [ 29 – 31 ]. LM exhibits a high incidence in patients with EGFR–mutant NSCLC during the course of third-generation EGFR TKIs treatment. Among 20 LM patients with NSCLC in this study, 14 developed LM during the course of EGFR TKIs treatment, including 9 patients who had received the third-generation TKIs therapy. For those patients, the CRR and median OS were 50% and 11.8 months respectively. These results suggested that IP was effective for LM patients of NSCLC who have previously received TKIs therapy, and we will further validate the activity of IP in NSCLC patients with LM progression after third-generation TKIs treatment (NCT06296745). In addition to studies on NSCLC-related targeted agents for the treatment of LM, some evidence supports the activity of trastuzumab emtansine (T-DM1), trastuzumab deruxtecan (T-DXd), pyrotinib and tucatinib in LM patients with human epidermal growth factor receptor 2 (Her-2) positive breast cancer [ 32 – 35 ]. Whether the combination of targeted agents and intrathecal chemotherapy can further improve the survival of patients deserves exploration in the future. There were several limitations in this study. First, radiotherapy serves as one of the therapeutic modalities for LM. It is particularly recommended for patients with: imaging-confirmed intracranial parenchymal brain metastases, intraspinal metastatic nodules with significant cauda equina involvement, or impaired cerebrospinal fluid circulation. Radiotherapy may potentially impact AEs and efficacy outcomes. In this study, 8 patients received radiotherapy. Radiotherapy did not increase the incidence of AEs, with no more than grade 3 toxicities observed. It suggested that combining 15 mg IP with radiotherapy maintains a comparable safety profile to the previous study [ 7 ]. However, although the survival benefit of radiotherapy for LM remains controversial [ 36 , 37 ], its impact on treatment efficacy (notably CRR) cannot be disregarded. Further large-scale studies should be required to validate the therapeutic efficacy of IP. Second, since LM lesions are non-measurable by neuroimaging criteria, traditional response evaluation criteria in solid tumors (RECIST) are inappropriate for assessment [ 38 ]. This limitation precludes the use of objective response rate as a primary endpoint and complicates accurate determination of progression-free survival. Although the RANO criteria have been widely adopted, significant variability in CRR reporting persists across LM studies [ 14 ]. Consequently, we selected OS as a secondary endpoint with a more objective efficacy measure, while designating CRR as other pre-specified outcome. However, it should be noted that OS interpretation may be confounded by systemic tumor burden and subsequent treatment interventions. Therapeutic evaluation in LM remains particularly challenging due to the disease's complex nature and multiple confounding factors. Conclusion This phase I/II study demonstrated that intrathecal injection of 15 mg pemetrexed with vitamin supplementation was feasible and safe with therapeutic activity, which provides a potential new treatment option for newly diagnosed LM patients with solid tumors. Moreover, it provides a validated pemetrexed dose and schedule of IP in subsequent trials. Abbreviations AEs: Adverse events; CNS: Central nervous system; CRR: Clinical response rate; CSF: Cerebrospinal fluid; DCR: Disease control rate; DLT: Dose-limiting toxicity; IP: Intrathecal pemetrexed; LM: Leptomeningeal metastasis; MTD: Maximum-tolerated dose; OS: Overall survival. Declarations Ethics Statement This phase I/II study was conducted according to the guidelines of the Declaration of Helsinki and was approved by the Institutional Review Board of the First Hospital of Jilin University, Changchun, China (Approval number: 2017-246). Informed consent was obtained from all subjects. (ClinicalTrials.gov Identifier: NCT05289908) Data Availability Statement The data used and/or analyzed will be made available upon reasonable request. Conflict of interest statement The authors have no conflict of interest to declare. Funding: This study was supported by grants from Guangdong Basic and Applied Basic Research Foundation (2023A1515140145), Guangzhou Medical University Research Ability Enhancement Project (2024SRP215), and Huizhou Science and Technology Innovation Team Project (2023EQ050012). Authors’ contributions Conceptualization: Z. Pan; Project Administration: Z. Pan, G. Yang; Writing-Reviewing and Editing: Z. Pan, G. Yang; Writing-Original Draft Preparation: X. Ye, Y. Huang, P. Tai; Formal Analysis: X. Ye, Y. Huang; Data Curation: Z. Wang; Assisting in Data Curation: M. Liu, L. Shen; Interpretation of Data: X. Pang, T. Yuan; Assisting in interpretation of clinical data: X. Sun, R. Tang, A. Gu. All authors have read and approved the final version of the manuscript. Acknowledgments: We gratefully acknowledge our colleague Yu Wu for her assistance with manuscript editing. References Beauchesne P (2010) Intrathecal chemotherapy for treatment of leptomeningeal dissemination of metastatic tumours. Lancet Oncol 11(9):871–879 Le Rhun E, Weller M, Brandsma D, Van den Bent M, de Azambuja E, Henriksson R, Boulanger T, Peters S, Watts C, Wick W et al (2017) EANO-ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up of patients with leptomeningeal metastasis from solid tumours. Ann Oncol 28(suppl4):iv84–iv99 Wilcox JA, Chukwueke UN, Ahn MJ, Aizer AA, Bale TA, Brandsma D, Brastianos PK, Chang S, Daras M, Forsyth P et al (2024) Leptomeningeal metastases from solid tumors: A Society for Neuro-Oncology and American Society of Clinical Oncology consensus review on clinical management and future directions. Neuro Oncol 26(10):1781–1804 Fleischhack G, Jaehde U, Bode U (2005) Pharmacokinetics following intraventricular administration of chemotherapy in patients with neoplastic meningitis. Clin Pharmacokinet 44(1):1–31 Le Rhun E, Preusser M, van den Bent M, Andratschke N, Weller M (2019) How we treat patients with leptomeningeal metastases. ESMO Open 4(Suppl 2):e000507 Pan Z, Yang G, Cui J, Li W, Li Y, Gao P, Jiang T, Sun Y, Dong L, Song Y et al (2019) A Pilot Phase 1 Study of Intrathecal Pemetrexed for Refractory Leptomeningeal Metastases From Non-small-cell Lung Cancer. Front Oncol 9:838 Pan Z, Yang G, He H, Cui J, Li W, Yuan T, Chen K, Jiang T, Gao P, Sun Y et al (2020) Intrathecal pemetrexed combined with involved-field radiotherapy as a first-line intra-CSF therapy for leptomeningeal metastases from solid tumors: a phase I/II study. Ther Adv Med Oncol 12:1758835920937953 Fan C, Zhao Q, Li L, Shen W, Du Y, Teng C, Gao F, Song X, Jiang Q, Huang D et al (2021) Efficacy and Safety of Intrathecal Pemetrexed Combined With Dexamethasone for Treating Tyrosine Kinase Inhibitor-Failed Leptomeningeal Metastases From EGFR-Mutant NSCLC-a Prospective, Open-Label, Single-Arm Phase 1/2 Clinical Trial (Unique Identifier: ChiCTR1800016615). J Thorac Oncol 16(8):1359–1368 Li H, Zheng S, Lin Y, Yu T, Xie Y, Jiang C, Liu X, Qian X, Yin Z (2023) Safety, Pharmacokinetic and Clinical Activity of Intrathecal Chemotherapy With Pemetrexed via the Ommaya Reservoir for Leptomeningeal Metastases From Lung Adenocarcinoma: A Prospective Phase I Study. Clin Lung Cancer 24(2):e94–e104 Pan Z (2022) Focusing on Intrathecal Pemetrexed for Treating Leptomeningeal Metastases From NSCLC. J Thorac Oncol 17(3):e31–e32 Sun JM, Nam MH, Chung JY, Im B, Lee SY, Suh YL, Ahn JS, Park K, Ahn MJ (2011) Safety and pharmacokinetics of intrathecal administration of pemetrexed in rats. Cancer Chemother Pharmacol 68(2):531–538 Chamberlain M, Junck L, Brandsma D, Soffietti R, Rudà R, Raizer J, Boogerd W, Taillibert S, Groves MD, Rhun EL et al (2016) Leptomeningeal metastases: a RANO proposal for response criteria. Neurooncology 19(4):484–492 Le Rhun E, Devos P, Boulanger T, Smits M, Brandsma D, Rudà R, Furtner J, Hempel JM, Postma TJ, Roth P et al (2019) The RANO Leptomeningeal Metastasis Group proposal to assess response to treatment: lack of feasibility and clinical utility and a revised proposal. Neuro Oncol 21(5):648–658 Yang JCH, Kim SW, Kim DW, Lee JS, Cho BC, Ahn JS, Lee DH, Kim TM, Goldman JW, Natale RB et al (2020) Osimertinib in Patients With Epidermal Growth Factor Receptor Mutation-Positive Non-Small-Cell Lung Cancer and Leptomeningeal Metastases: The BLOOM Study. J Clin Oncol 38(6):538–547 Raizer JJ, Rademaker A, Evens AM, Rice L, Schwartz M, Chandler JP, Getch CC, Tellez C, Grimm SA (2012) Pemetrexed in the treatment of relapsed/refractory primary central nervous system lymphoma. Cancer 118(15):3743–3748 Lee DW, Jung KH, Lee KH, Park YH, Lee KS, Sohn J, Ahn HK, Jeong JH, Koh SJ, Kim JH et al (2024) Pemetrexed plus vinorelbine versus vinorelbine monotherapy in patients with metastatic breast cancer (KCSG-BR15-17): A randomized, open-label, multicenter, phase II trial. Eur J Cancer 197:113456 Celio L, Sternberg CN, Labianca R, La Torre I, Amoroso V, Barone C, Pinotti G, Cascinu S, Di Costanzo F, Cetto GL et al (2009) Pemetrexed in combination with oxaliplatin as a first-line therapy for advanced gastric cancer: a multi-institutional phase II study. Ann Oncol 20(6):1062–1067 Jatoi A, Soori G, Foster NR, Hiatt BK, Knost JA, Fitch TR, Callister MD, Nichols FC 3rd, Husted TM, Alberts SR (2010) Phase II study of preoperative pemetrexed, carboplatin, and radiation followed by surgery for locally advanced esophageal cancer and gastroesophageal junction tumors. J Thorac Oncol 5(12):1994–1998 Zhang Y, Zhao L, Huang P, Wu J, Wang F, Huang Y, Zhang L (2012) Open-label, single-arm phase II study of pemetrexed in the treatment of patients with recurrent or metastatic nasopharyngeal carcinoma who have had prior platinum-based chemotherapy. Cancer Chemother Pharmacol 70(4):611–615 Socinski MA (2005) Pemetrexed (Alimta) in small cell lung cancer. Semin Oncol 32(2 Suppl 2):S1–4 Giovannetti E, Mey V, Nannizzi S, Pasqualetti G, Marini L, Del Tacca M, Danesi R (2005) Cellular and pharmacogenetics foundation of synergistic interaction of pemetrexed and gemcitabine in human non-small-cell lung cancer cells. Mol Pharmacol 68(1):110–118 Le Rhun E, Weller M, van den Bent M, Brandsma D, Furtner J, Rudà R, Schadendorf D, Seoane J, Tonn JC, Wesseling P et al (2023) Leptomeningeal metastasis from solid tumours: EANO-ESMO Clinical Practice Guideline for diagnosis, treatment and follow-up. ESMO Open 8(5):101624 Pan ZY, Song YY, Jiang TC, Yang X, Yang GZ (2022) [Clinical trials on intrathecal pemetrexed treated leptomeningeal metastases from solid tumors]. Zhonghua Zhong Liu Za Zhi 44(1):112–119 Xu Z, Hao X, Wang Q, Yang K, Li J, Xing P (2023) Intracranial efficacy and safety of furmonertinib 160 mg with or without anti-angiogenic agent in advanced NSCLC patients with BM/LM as salvage therapy. BMC Cancer 23(1):206 Park S, Lee MH, Seong M, Kim ST, Kang JH, Cho BC, Lee KH, Cho EK, Sun JM, Lee SH et al (2020) A phase II, multicenter, two cohort study of 160 mg osimertinib in EGFR T790M-positive non-small-cell lung cancer patients with brain metastases or leptomeningeal disease who progressed on prior EGFR TKI therapy. Ann Oncol 31(10):1397–1404 Chen T, Chen J, Liu DS, Shu YL, Fu MY, Gou HJ, Lei KJ, Jia YM (2023) Successful therapy using high-dose furmonertinib for non-small cell lung cancer with leptomeningeal metastasis: a case report and literature review. Front Oncol 13:1233198 Ahn MJ, Chiu CH, Cheng Y, Han JY, Goldberg SB, Greystoke A, Crawford J, Zhao Y, Huang X, Johnson M et al (2020) Osimertinib for Patients With Leptomeningeal Metastases Associated With EGFR T790M-Positive Advanced NSCLC: The AURA Leptomeningeal Metastases Analysis. J Thorac Oncol 15(4):637–648 Park S, Baldry R, Jung HA, Sun JM, Lee SH, Ahn JS, Kim YJ, Lee Y, Kim DW, Kim SW et al (2024) Phase II Efficacy and Safety of 80 mg Osimertinib in Patients With Leptomeningeal Metastases Associated With Epidermal Growth Factor Receptor Mutation-Positive Non-Small Cell Lung Cancer (BLOSSOM). J Clin Oncol 42(23):2747–2756 Zhang H, Wang Y, Wu H, Zhou S, Li S, Meng X, Tao R, Yu J (2022) Olaparib Combined With Dacomitinib in Osimertinib-Resistant Brain and Leptomeningeal Metastases From Non-Small Cell Lung Cancer: A Case Report and Systematic Review. Front Oncol 12:877279 Zheng MM, Li YS, Tu HY, Sun H, Yin K, Jiang BY, Yang JJ, Zhang XC, Zhou Q, Xu CR et al (2022) Subsequent treatments beyond progression on osimertinib in EGFR-mutated NSCLC and leptomeningeal metastases. BMC Med 20(1):197 Leonetti A, Sharma S, Minari R, Perego P, Giovannetti E, Tiseo M (2019) Resistance mechanisms to osimertinib in EGFR-mutated non-small cell lung cancer. Br J Cancer 121(9):725–737 Yan F, Rinn KJ, Kullnat JA, Wu AY, Ennett MD, Scott EL, Kaplan HG (2022) Response of Leptomeningeal Metastasis of Breast Cancer With a HER2/neu Activating Variant to Tucatinib: A Case Report. J Natl Compr Canc Netw 20(7):745–752 Chi Y, Shang M, Xu L, Gong H, Tao R, Song L, Zhang B, Yin S, Cong B, Li H (2022) Durable Effect of Pyrotinib and Metronomic Vinorelbine in HER2-Positive Breast Cancer With Leptomeningeal Disease: A Case Report and Literature Review. Front Oncol 12:811919 Alder L, Trapani D, Bradbury C, Van Swearingen AED, Tolaney SM, Khasraw M, Anders CK, Lascola CD, Hsu L, Lin NU et al (2023) Durable responses in patients with HER2 + breast cancer and leptomeningeal metastases treated with trastuzumab deruxtecan. NPJ Breast Cancer 9(1):19 Ricciardi GRR, Russo A, Franchina T, Schifano S, Mastroeni G, Santacaterina A, Adamo V (2018) Efficacy of T-DM1 for leptomeningeal and brain metastases in a HER2 positive metastatic breast cancer patient: new directions for systemic therapy - a case report and literature review. BMC Cancer 18(1):97 Hitchins RN, Bell DR, Woods RL, Levi JA (1987) A prospective randomized trial of single-agent versus combination chemotherapy in meningeal carcinomatosis. J Clin Oncol 5(10):1655–1662 Morris PG, Reiner AS, Szenberg OR, Clarke JL, Panageas KS, Perez HR, Kris MG, Chan TA, DeAngelis LM, Omuro AM (2012) Leptomeningeal metastasis from non-small cell lung cancer: survival and the impact of whole brain radiotherapy. J Thorac Oncol 7(2):382–385 Le Rhun E, Taillibert S, Chamberlain MC (2013) Carcinomatous meningitis: Leptomeningeal metastases in solid tumors. Surg Neurol Int 4(Suppl 4):S265–288 Additional Declarations No competing interests reported. Supplementary Files SupplementalFiguresandTables20250430.doc StudyProtocol20250430.doc Cite Share Download PDF Status: Published Journal Publication published 23 Jul, 2025 Read the published version in Journal of Neuro-Oncology → Version 1 posted Editorial decision: Revision requested 29 May, 2025 Reviewers agreed at journal 18 May, 2025 Reviewers agreed at journal 16 May, 2025 Reviews received at journal 16 May, 2025 Reviews received at journal 15 May, 2025 Reviews received at journal 13 May, 2025 Reviewers agreed at journal 05 May, 2025 Reviewers agreed at journal 05 May, 2025 Reviewers agreed at journal 03 May, 2025 Reviewers invited by journal 02 May, 2025 Editor assigned by journal 02 May, 2025 Submission checks completed at journal 02 May, 2025 First submitted to journal 01 May, 2025 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-6572942","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Case Report","associatedPublications":[],"authors":[{"id":452222683,"identity":"1e450922-9302-4b30-9519-e28f2fe28c8a","order_by":0,"name":"Zhenyu Pan","email":"","orcid":"","institution":"The Affiliated Huizhou Hospital, Guangzhou Medical University","correspondingAuthor":false,"prefix":"","firstName":"Zhenyu","middleName":"","lastName":"Pan","suffix":""},{"id":452222687,"identity":"33dd2193-6c68-4009-8053-230e169419d4","order_by":1,"name":"Xiaojun Ye","email":"","orcid":"","institution":"The Affiliated Huizhou Hospital, Guangzhou Medical University","correspondingAuthor":false,"prefix":"","firstName":"Xiaojun","middleName":"","lastName":"Ye","suffix":""},{"id":452222689,"identity":"19581aef-9315-420f-a801-70eaa17b71e8","order_by":2,"name":"Yushan Huang","email":"","orcid":"","institution":"The Affiliated Huizhou Hospital, Guangzhou Medical University","correspondingAuthor":false,"prefix":"","firstName":"Yushan","middleName":"","lastName":"Huang","suffix":""},{"id":452222690,"identity":"62a72f34-1391-42c8-9e81-3fcc5a58b197","order_by":3,"name":"Panpan Tai","email":"","orcid":"","institution":"The Affiliated Huizhou Hospital, Guangzhou Medical University","correspondingAuthor":false,"prefix":"","firstName":"Panpan","middleName":"","lastName":"Tai","suffix":""},{"id":452222691,"identity":"31c8d1cf-b2b3-4069-a4e4-b22af00c780a","order_by":4,"name":"Miaomiao Liu","email":"","orcid":"","institution":"The Affiliated Huizhou Hospital, Guangzhou Medical University","correspondingAuthor":false,"prefix":"","firstName":"Miaomiao","middleName":"","lastName":"Liu","suffix":""},{"id":452222692,"identity":"2891a868-c165-4cde-b727-fbc1232a17cc","order_by":5,"name":"Xingru Sun","email":"","orcid":"","institution":"The Affiliated Huizhou Hospital, Guangzhou Medical University","correspondingAuthor":false,"prefix":"","firstName":"Xingru","middleName":"","lastName":"Sun","suffix":""},{"id":452222693,"identity":"a15dbf87-556f-4a3c-b2f0-4a714e781c6a","order_by":6,"name":"Ran Tang","email":"","orcid":"","institution":"The Affiliated Huizhou Hospital, Guangzhou Medical University","correspondingAuthor":false,"prefix":"","firstName":"Ran","middleName":"","lastName":"Tang","suffix":""},{"id":452222694,"identity":"79cba1c0-228b-43ae-9553-d92e4025e9ea","order_by":7,"name":"Anyan Gu","email":"","orcid":"","institution":"The Affiliated Huizhou Hospital, Guangzhou Medical University","correspondingAuthor":false,"prefix":"","firstName":"Anyan","middleName":"","lastName":"Gu","suffix":""},{"id":452222695,"identity":"b0883960-a060-457d-91ea-1520d5504189","order_by":8,"name":"Zhuo Wang","email":"","orcid":"","institution":"The First Hospital of Jilin University","correspondingAuthor":false,"prefix":"","firstName":"Zhuo","middleName":"","lastName":"Wang","suffix":""},{"id":452222696,"identity":"0f2fac5f-d132-4404-a0ee-ab01760aa328","order_by":9,"name":"Longhai Shen","email":"","orcid":"","institution":"Panjin Liaoyou Gem Flower Hospital","correspondingAuthor":false,"prefix":"","firstName":"Longhai","middleName":"","lastName":"Shen","suffix":""},{"id":452222697,"identity":"0e9fdac4-7af2-4cef-8bf2-12b2c29f8de4","order_by":10,"name":"Xiaochuan Pang","email":"","orcid":"","institution":"The First Hospital of Jilin University","correspondingAuthor":false,"prefix":"","firstName":"Xiaochuan","middleName":"","lastName":"Pang","suffix":""},{"id":452222699,"identity":"c0b3cc1b-1437-4161-aa35-e78c100b9445","order_by":11,"name":"Tingting Yuan","email":"","orcid":"","institution":"The First Hospital of Jilin University","correspondingAuthor":false,"prefix":"","firstName":"Tingting","middleName":"","lastName":"Yuan","suffix":""},{"id":452222700,"identity":"490a039f-76a5-4a04-9540-ae43ceab8b7f","order_by":12,"name":"Guozi Yang","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAABD0lEQVRIie3Qv0rEMBzA8ZRCi/CTrr9SPF8hpXB0u1dJlk43CILccEgOIU7i2s1ncKm6VQKd8gAHdSgUDgSHHjfdIva6OaR0FMx3+A0hH/KHEJvtDxa4rmq6FcLiqS2JI4ZFOkrCe5nFuU5nlGRsGqFa0+hMrhJKlnQaIVtGE+IhfyH68Hl8Lbjw7wok6w+jcHLG2itA/rZ5KNJQ11xAdYOk2hmJi6xMckQu1HlBY9kTXM7REcpI+iuJCGg/K9hRfiKXX+MEQJEIGCZUg9u8D6fAOEFfenFe4izMvbmzkXUiIbtOWWUmCxUcmv33LQTotvujrC8effW87dZm8vtdwzwNNgn0v9dN3Giz2Wz/rB9/81vUs+2EMQAAAABJRU5ErkJggg==","orcid":"","institution":"The Affiliated Huizhou Hospital, Guangzhou Medical University","correspondingAuthor":true,"prefix":"","firstName":"Guozi","middleName":"","lastName":"Yang","suffix":""}],"badges":[],"createdAt":"2025-05-01 15:38:09","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-6572942/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-6572942/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1007/s11060-025-05160-4","type":"published","date":"2025-07-23T15:57:54+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":82309794,"identity":"70e4822b-7ca2-4e31-ade5-cec453e80513","added_by":"auto","created_at":"2025-05-09 01:49:10","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":32764,"visible":true,"origin":"","legend":"\u003cp\u003eThe flow chart for the trial. LM, Leptomeningeal metastasis; IP, intrathecal pemetrexed; CNS, central nervous system; MTD, maximum-tolerated dose; AEs, adverse events.\u003c/p\u003e","description":"","filename":"Figure1.png","url":"https://assets-eu.researchsquare.com/files/rs-6572942/v1/761ab4fb38d16d81ad5f5e7d.png"},{"id":82311903,"identity":"7073f1c8-254a-465d-84f2-effb48f11109","added_by":"auto","created_at":"2025-05-09 02:05:10","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":711303,"visible":true,"origin":"","legend":"\u003cp\u003eKaplan-Meier survival curves showing the survival. (A) Survival for total population; (B) Survival for patients with clinical response and without clinical response; (C) Survival for patients receiving and not receiving maintenance therapy; (D) Survival of patients with different primary tumor types.\u003c/p\u003e","description":"","filename":"Figure2.png","url":"https://assets-eu.researchsquare.com/files/rs-6572942/v1/056e107a4e03723962f74d7e.png"},{"id":87756745,"identity":"e65ce6a3-0ef0-4edd-985b-7cb5f8ba88b6","added_by":"auto","created_at":"2025-07-28 16:08:38","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1695292,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-6572942/v1/bfcc39d9-77d9-4c92-9ad8-fe50e8dafa79.pdf"},{"id":82309803,"identity":"8a54b485-2d73-4cb1-ab69-d6c186119008","added_by":"auto","created_at":"2025-05-09 01:49:11","extension":"doc","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":178688,"visible":true,"origin":"","legend":"","description":"","filename":"SupplementalFiguresandTables20250430.doc","url":"https://assets-eu.researchsquare.com/files/rs-6572942/v1/389946fc858f0571f51593a5.doc"},{"id":82309800,"identity":"2416e6ff-1f91-4a88-946d-1cb3b2372f77","added_by":"auto","created_at":"2025-05-09 01:49:10","extension":"doc","order_by":2,"title":"","display":"","copyAsset":false,"role":"supplement","size":1444352,"visible":true,"origin":"","legend":"","description":"","filename":"StudyProtocol20250430.doc","url":"https://assets-eu.researchsquare.com/files/rs-6572942/v1/db238a0f2dddc4e8c15b4c87.doc"}],"financialInterests":"No competing interests reported.","formattedTitle":"Intrathecal pemetrexed for newly diagnosed leptomeningeal metastases: A multicenter, open-label, phase I/II study","fulltext":[{"header":"Introduction","content":"\u003cp\u003eLeptomeningeal metastasis (LM) is a devastating complication of multiple malignancies, characterized by cancer cell involvement in the cerebrospinal fluid (CSF) and leptomeninges, with the typical median overall survival (OS) of only 3\u0026ndash;4 months [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]. Approximately 10% of patients with solid tumors develop LM during their disease course, with lung cancer, breast cancer, and melanoma representing the three most common primary malignancies [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]. Intrathecal chemotherapy remains a primary treatment for LM, offering the advantage of direct CSF drug delivery to maximize therapeutic exposure to tumor cells [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]. Compared with systemic administration, low-dose intra-CSF administration can achieve higher CSF drug concentration with a better cytotoxic effect [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e]. However, chemotherapeutic agents that can be safely administered intrathecally for the treatment of LM are extremely limited [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e]. It is crucial to identify novel agents with both favorable safety profiles and potential activity.\u003c/p\u003e \u003cp\u003eIn 2017, we conducted the first study of intrathecal pemetrexed (IP) in the world, which established the feasibility of administering IP in patients with recurrent and refractory LM from lung adenocarcinoma [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e]. The recommended dose of IP for LM was 10 mg on a schedule of 1\u0026ndash;2 times per week based on pharmacokinetic studies. In that study, prophylactic folic acid and vitamin B12 supplementation was not used, as the intrathecal dose was less than 3% of the systemic dose, potentially impacting treatment efficacy [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e]. However, our subsequent research revealed that vitamin supplementation significantly reduced the incidence of hematological toxicity, a primary adverse effect and dose-limiting toxicity (DLT) of pemetrexed administered intrathecally [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e]. Consequently, our previous study was limited by an inadequate investigation of patients with recurrent or refractory disease [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e]. Also, the maximum tolerated dose (MTD) and safety profile of IP with prior folic acid and vitamin B12 supplementation remain undefined, particularly in newly diagnosed LM patients who have not previously undergone intrathecal chemotherapy [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eSubsequent to our earlier research, several other studies on IP have been conducted, typically employing dosing intervals of once every 1\u0026ndash;3 weeks [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e, \u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e]. However, the MTD reported in these studies (30\u0026ndash;50 mg) was significantly higher than in our previous work, while the incidence of adverse events (AEs) was notably lower [\u003cspan additionalcitationids=\"CR7 CR8 CR9\" citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e]. The significant variability between studies, along with some unreliable findings, has caused confusion regarding the treatment regimen and dosage of IP in clinical practice. Therefore, further studies are urgently needed to evaluate its true tolerability, optimal dosage, safety profile, side-effect management, and potential activity of IP using a scientific regimen based on the previous study on animal models [\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eBased on our previous findings [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e], this prospective phase I/II study was designed to determine the MTD, safety, feasibility and clinical activity of IP with prior folic acid and vitamin B12 supplementation in patients with newly diagnosed LM from various solid tumors.\u003c/p\u003e"},{"header":"Patients and Methods","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003eStudy Design and Participants\u003c/h2\u003e \u003cp\u003eThis was a multicenter, open-label, single-arm phase I/II clinical study (ClinincalTrials.gov identifier: NCT05289908). Eligible patients were aged 18\u0026ndash;75 years, had pathologically confirmed malignant solid tumors with normal organ and marrow function, life expectancy of greater than 2 months, and had a newly diagnosed LM confirmed by positive CSF cytology or LM-related specific imaging findings and neurological signs if CSF cytology was negative. The diagnosis of LM was ascertained according to the guidelines by the European Association of Neuro-Oncology\u0026ndash;European Society for Medical Oncology (EANO-ESMO) co-published [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]. Hematologic malignancy or primary central nervous system (CNS) malignancy, or other reasons that made them unsuitable for this study, including serious central nervous system disorders, hydrocephalus or other factors suggestive of CSF obstruction, lethal or extensive systemic diseases with few treatment options, psychiatric illness, or poor compliance, were excluded.\u003c/p\u003e \u003c/div\u003e\n\u003ch3\u003eProcedures and Treatment Regimen\u003c/h3\u003e\n\u003cp\u003ePhase I of the study was a 3\u0026thinsp;+\u0026thinsp;3 dose escalation trial (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e). Based on the data of our previous study [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e], we chose to treat patients starting at a dose of 15 mg IP with prior folic acid and vitamin B12 supplementation and escalating each dose group by 5 mg (20 mg, \u0026hellip;). DLT was assessed during the first 6 weeks of treatment. If 2 or more of the 6 patients experienced a DLT, dosing escalation would cease and MTD would be reached. The MTD, also the recommended dose for phase II, was the next lower dose at which\u0026thinsp;\u0026lt;\u0026thinsp;2/6 subjects experienced a DLT. The DLT was defined as \u0026ge;\u0026thinsp;grade 3 neurological toxicities (e.g., chemical meningitis) or other\u0026thinsp;\u0026ge;\u0026thinsp;grade 4 toxicity.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003ePemetrexed (Alimta, Eli Lilly and Company) was administrated by intrathecal injection, with 5 mg dexamethasone, first as induction therapy, twice per week for 2 weeks, followed by consolidation therapy, once per week for 4 weeks. If LM progresses or DLT occurs during therapy, the treatment will be discontinued. For patients who were evaluated to be effective or stable, maintenance therapy was initiated and administered once per month until the patient\u0026rsquo;s death, LM progresses, or intolerable severe AEs occurred. The treatment regimen is provided in Supplementary Fig.\u0026nbsp;1. In addition, folic acid 400 \u0026micro;g was administered orally once daily, prior to the first IP, until 21 days after the last IP. A single dose of vitamin B12 1000 \u0026micro;g was administered by intramuscular injection before the first IP, once every 2 months. Involved-field radiotherapy (IFRT) encompassing whole-brain irradiation, focal intracranial lesions, and/or segmental spinal irradiation was used in selected patients [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]. Patients who had received systemic treatment prior to enrollment were allowed to continue their original regimens, including tyrosine kinase inhibitors (TKIs) or chemotherapy. However, since these patients developed LM progression while receiving the same therapies, this suggests a failure of the systemic treatments against LM. The observed CNS progression thus reflects the inherent limitations of these systemic regimens in controlling LM. In addition, symptomatic and supportive treatment was permitted for patients with severe conditions.\u003c/p\u003e\n\u003ch3\u003eEndpoints and Assessments\u003c/h3\u003e\n\u003cp\u003eAs a phase I/II study, it focused on evaluating the feasibility and safety of the treatment protocol. The primary objectives were to determine the MTD of IP with prior folic acid and vitamin B12 supplementation and safety based on the incidence of treatment-related AEs. The secondary objective was OS. In addition, the clinical response rate (CRR) and disease control rate (DCR) were also evaluated. The clinical response was evaluated by RANO-LM working group proposal criteria [\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e], which were based on three levels of assessment, CSF cytology, neurological status and neuroimaging findings. CRR was defined as the incidence of at least one of the evaluations of CSF cytology, neurological status and neuroimaging findings rated as improved, and there was no disease worsening at the same time. The DCR was defined as the incidence of patients who did not experience disease progression during the initial treatment period (induction and consolidation therapy). Disease progression was defined as the worsening of neuroimaging or neurological dysfunction.\u003c/p\u003e \u003cp\u003eCSF cytology examination was performed at baseline and each time of IP using Thinprep plus Papanicolaou staining during induction and consolidation therapy, and then every month during maintenance therapy. Patients with positive baseline CSF cytology were evaluated as having a cytological response when CSF cytology turned negative for 4 weeks or more after IP. Neurological function examination was performed at baseline, weekly thereafter during induction and consolidation therapies, and then monthly during maintenance therapy to record changes in neurological symptoms and signs. The improvement of neurological function for 2 consecutive weeks was evaluated as effective. Neuroimaging evaluation was performed at baseline, at the end of consolidation therapy, 4 weeks after that, and then every 2\u0026ndash;3 months during maintenance therapy. Neuroimaging assessment was performed according to the proposal for a revised Leptomeningeal Metastasis Working Group grid by 3 neuro-radiologists and 2 neuro-oncologists [\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eAll patients were followed up until death or for at least 12 months after treatment. AEs were graded according to the Common Terminology Criteria for Adverse Events (CTCAE, version 5.0). A Grade 4\u0026ndash;5 was defined as serious AEs. Survival time was defined from the enrollment until death or the last follow-up.\u003c/p\u003e \u003cdiv id=\"Sec6\" class=\"Section2\"\u003e \u003ch2\u003eStatistical Analysis\u003c/h2\u003e \u003cp\u003eSince the CRR varies greatly in the clinical study of LM due to the subjective evaluation of researchers [\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e], we opted for OS to estimate the sample size for this study. The PASS 15.0 software was used to calculate the sample size and the target number was estimated by the median OS. Based on the previous study [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e], we hypothesized H0 as an OS of 3.8 months and H1 as 6.8 months, 28 patients were needed in the Phase II study to achieve 80% power with a predefined one-sided alpha of 5%. The R tools 4.0 software was used for data analyses. Fisher\u0026rsquo;s exact tests were used to evaluate the difference in CRR between patients with various pathological types. Survival analyses were performed using the Kaplan\u0026ndash;Meier method. \u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.05 demonstrated a significant difference.\u003c/p\u003e \u003c/div\u003e"},{"header":"Results","content":"\u003cdiv id=\"Sec8\" class=\"Section2\"\u003e \u003ch2\u003eCharacteristics\u003c/h2\u003e \u003cp\u003eBetween February 2022 and January 2023, 34 patients (16 males and 18 females) were enrolled sequentially (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e). Patients\u0026rsquo; basic clinical characteristics and disease-related variables were displayed in Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e and Supplementary Table\u0026nbsp;1. LM diagnosis was confirmed in 97% of patients (N\u0026thinsp;=\u0026thinsp;33) by positive CSF cytology and probable in 3% (N\u0026thinsp;=\u0026thinsp;1) by neuroimaging findings and typically LM-related neurological system symptoms and signs according to the EANO-ESMO guidelines [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]. Of all participants, 21% (N\u0026thinsp;=\u0026thinsp;7) of cases had progressive systemic disease and 76% (N\u0026thinsp;=\u0026thinsp;26) had stable systemic disease outside the CNS. 76% (N\u0026thinsp;=\u0026thinsp;26) had received systemic chemotherapy and 15% (N\u0026thinsp;=\u0026thinsp;5) of patients had received immunotherapy before enrollment. 59% of the participants were NSCLC (N\u0026thinsp;=\u0026thinsp;20) and 47% (N\u0026thinsp;=\u0026thinsp;16) received TKIs treatment prior to the diagnosis of LM.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eBaseline characteristics of the patients\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"3\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eAll Eligible Patients\u003c/p\u003e \u003cp\u003e(n\u0026thinsp;=\u0026thinsp;34)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003ePatients in the MTD group\u003c/p\u003e \u003cp\u003e(n\u0026thinsp;=\u0026thinsp;28)\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eGender\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMale\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e16 (47%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e12 (43%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eFemale\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e18 (53%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e16 (57%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMedian age (years)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e56 (45\u0026ndash;68)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e56 (45\u0026ndash;67)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eGCS\u0026thinsp;\u0026lt;\u0026thinsp;15\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e7 (21%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e7 (25%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eKPS\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;60\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e16 (47%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e12 (43%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u0026ge;\u0026thinsp;60\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e18 (53%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e16 (57%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCSF cytology\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePositive\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e33 (97%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e27(96%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNegative\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1 (3%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1 (4%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNeuroimaging features\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePositive\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e31 (91%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e26 (93%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNegative\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e3 (9%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e2 (7%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eOnset as LM\u003csup\u003e\u003cem\u003ea\u003c/em\u003e\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e3 (9%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e3 (11%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePathological types of primary disease\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNSCLC\u003csup\u003e\u003cem\u003eb\u003c/em\u003e\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e20 (59%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e16 (57%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSCLC\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e3 (9%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e3 (11%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBreast cancer\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e8 (24%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e7 (25%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eGastric adenocarcinoma\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1 (3%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1 (4%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eEsophagus carcinoma\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1(3%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNasopharyngeal carcinoma\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1(3%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1 (4%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eElevated intracranial pressure\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eYes\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e16 (47%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e14 (50%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e18 (53%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e14 (50%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSystemic disease\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eprogressive\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e7 (21%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e5 (18%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eStable\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e26 (76%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e22 (79%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNot observed\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1 (3%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1 (4%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBreast cancer\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e8 (24%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e7 (25%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTriple-negative\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e2 (6%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e2 (7%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHer-2 +\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e4 (12%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e3 (11%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eLuminal A\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1 (3%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1 (4%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eLuminal B\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1 (3%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1 (4%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNSCLC\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e20 (59%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e17 (61%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eEGFR mutation\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e14 (41%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e11 (39%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eALK mutation\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1 (3%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1 (4%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eALK\u0026amp;MET mutation\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1 (3%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1 (4%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNot detected\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e4 (12%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e4 (14%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"3\"\u003e\u003cb\u003eContinued\u003c/b\u003e Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e. \u003cb\u003eBaseline characteristics of the patients\u003c/b\u003e\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003c/div\u003e\u003cdiv\u003e\n \u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 272px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 170px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eAll Eligible Patients\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e(n=34)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 170px;\"\u003e\n \u003cp\u003e\u003cstrong\u003ePatients in the MTD group\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e(n=28)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 272px;\"\u003e\n \u003cp\u003eTKI treatment prior to enrollment\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 170px;\"\u003e\n \u003cp\u003e16 (47%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 170px;\"\u003e\n \u003cp\u003e13 (46%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 272px;\"\u003e\n \u003cp\u003eFirst-generation EGFR-TKIs\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 170px;\"\u003e\n \u003cp\u003e10 (29%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 170px;\"\u003e\n \u003cp\u003e10 (36%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 272px;\"\u003e\n \u003cp\u003eSecond-generation EGFR-TKIs\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 170px;\"\u003e\n \u003cp\u003e3 (9%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 170px;\"\u003e\n \u003cp\u003e1 (4%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 272px;\"\u003e\n \u003cp\u003eThird-generation EGFR-TKIs\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 170px;\"\u003e\n \u003cp\u003e9 (26%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 170px;\"\u003e\n \u003cp\u003e8 (29%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 272px;\"\u003e\n \u003cp\u003eAKL-TKIs\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 170px;\"\u003e\n \u003cp\u003e2 (6%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 170px;\"\u003e\n \u003cp\u003e2 (7%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 272px;\"\u003e\n \u003cp\u003eMET-TKIs\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 170px;\"\u003e\n \u003cp\u003e1 (3%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 170px;\"\u003e\n \u003cp\u003e1 (4%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 272px;\"\u003e\n \u003cp\u003eSystemic chemotherapy prior to enrollment\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 170px;\"\u003e\n \u003cp\u003e26 (76%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 170px;\"\u003e\n \u003cp\u003e23 (82%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 272px;\"\u003e\n \u003cp\u003ePemetrexed-based chemotherapy\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 170px;\"\u003e\n \u003cp\u003e12 (35%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 170px;\"\u003e\n \u003cp\u003e11 (39%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 272px;\"\u003e\n \u003cp\u003eNon pemetrexed-based chemotherapy\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 170px;\"\u003e\n \u003cp\u003e14 (41%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 170px;\"\u003e\n \u003cp\u003e12 (43%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 272px;\"\u003e\n \u003cp\u003eImmunotherapy prior to enrollment\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 170px;\"\u003e\n \u003cp\u003e5 (15%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 170px;\"\u003e\n \u003cp\u003e4 (14%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n \u003c/table\u003e\n\u003c/div\u003e\n\u003cp\u003eMTD,\u0026nbsp;maximum-tolerated dose; GCS, glasgow coma scale; KPS, karnofskyperformance status; CSF, cerebrospinal fluid; LM, Leptomeningeal metastasis; NSCLC, non-small cell lung cancer; SCLC, small cell lung cancer; Her-2, human epidermal growth factor receptor 2; EGFR, epidermal growth factor receptor; ALK, anaplastic lymphoma kinase; MET, mesenchymal-epithelial transformation factor; TKI, tyrosine kinase inhibitor.\u003c/p\u003e\n\u003cp\u003e\u003cem\u003e\u003csup\u003ea \u0026nbsp;\u003c/sup\u003e\u003c/em\u003eLM was the initial manifestation of malignancy.\u003c/p\u003e\n\u003cp\u003e\u003cem\u003e\u003csup\u003eb \u0026nbsp;\u003c/sup\u003e\u003c/em\u003eIncludes lung adenocarcinoma (n\u0026thinsp;=\u0026thinsp;18), lung squamous cell carcinoma (n\u0026thinsp;=\u0026thinsp;1) and unable to specify the type of NSCLC (n=1).\u003c/p\u003e\n\u003ch3\u003eDLT and MTD\u003c/h3\u003e\n\u003cp\u003eIn the phase I study, a total of 4 patients were enrolled at the first IP dose level of 15 mg because 1 patient withdrew from the study after the first IP for personal reasons. No DLT occurred. The IP dose was subsequently escalated to the second dose level of 20 mg, and an additional 6 patients were enrolled, 2 of whom experienced DLT. One case occurred grade 4 leukopenia after the fourth IP (accompanied by grade 2 thrombocytopenia), which was relieved after stopping IP, administering recombinant human granulocyte colony-stimulating factor (rhG-CSF), recombinant human interleukin 11 (rhIL-11), recombinant human thrombopoietin (rhTPO) and increasing the dose of folic acid to 800 \u0026micro;g orally once daily. The other case experienced grade 5 chemical arachnoiditis after the first IP and died 3 days later. Therefore, the MTD of IP with prior folic acid and vitamin B12 supplementation for LM patients was defined as 15 mg, which was also the recommended dose for phase II. Subsequently, an additional 24 patients were enrolled in phase II and received 15 mg of IP. The 4 patients treated at the MTD during phase I were included in the phase II analysis to achieve the pre-specified sample size requirement of a total of 28 cases.\u003c/p\u003e\n\u003ch3\u003eTreatment and feasibility\u003c/h3\u003e\n\u003cp\u003eOf the 34 participants, 28 patients completed induction IP (Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e). Among the remaining 6 patients who did not complete induction therapy, 2 died 3\u0026ndash;5 days following their third IP attributed to LM progression; 1 terminated treatment after developing chemical arachnoiditis after the first IP and 3 withdrew consent for personal reasons. A total of 21 patients completed the consolidation IP, and 12 patients received maintenance IP subsequently. Among 28 patients in the MTD group, 24 completed induction therapy, 19 completed consolidation therapy, and 11 proceeded to maintenance therapy (Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e).\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab2\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eThe treatment of the patients\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"3\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTreatment\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eAll Eligible Patients\u003c/p\u003e \u003cp\u003e(n\u0026thinsp;=\u0026thinsp;34)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003ePatients in the MTD group\u003c/p\u003e \u003cp\u003e(n\u0026thinsp;=\u0026thinsp;28)\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eInduction IP\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCompletion of induction IP\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e28 (82%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e24 (86%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eIncompletion of induction IP\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e6 (18%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e4 (14%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eConsolidation IP\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCompletion of consolidation IP\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e21 (62%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e19 (68%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eIncompletion of consolidation IP\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e13 (9%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e9 (32%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMaintenance IP\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e12 (35%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e11 (39%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eOther treatments during trial participation\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCNS radiation therapy\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e8 (24%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e6 (21%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSystemic chemotherapy\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e3 (9%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e3 (11%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTargeted therapy\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e11 (32%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e8 (29%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"3\"\u003eMTD, maximum-tolerated dose; IP, intrathecal pemetrexed; CNS, central nervous system.\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003eEight patients received concurrent IFRT, including 5 with whole brain radiotherapy and 3 with segmental spinal canal radiotherapy. Thirteen patients maintained their prior systemic therapy during the study, including prior TKIs treatment in 11 cases and prior systemic chemotherapy regimens in 3 cases. The remaining 7 patients with progressive systemic diseases did not receive systemic treatment during IP therapy owing to low score (less than 50), severe neurological status or personal factors.\u003c/p\u003e \u003cdiv id=\"Sec11\" class=\"Section2\"\u003e \u003ch2\u003eSafety\u003c/h2\u003e \u003cp\u003eAll participants were assessed for safety. The overall AEs rate was 74% (25/34) (Supplementary Table\u0026nbsp;2), and the severe AEs rate (\u0026gt;\u0026thinsp;grade 3) was 15% (5/34, 95% exact CI, 4.95\u0026ndash;31.05%). Twenty-one of 28 patients in the MTD group experienced one or more AEs (Table\u0026nbsp;\u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e3\u003c/span\u003e). In all participants, the most frequent AEs were hematologic toxicity (53%, 18/34) and elevated hepatic aminotransferases (EHA, 38%, 13/34). Hematologic toxicity occurred mainly after 4\u0026ndash;6 times of IP, which was manifested as thrombocytopenia (N\u0026thinsp;=\u0026thinsp;11) and leukopenia (N\u0026thinsp;=\u0026thinsp;12). Severe hematologic toxicity occurred in 4 cases including 1 grade 4 leukopenia with 20 mg of IP and 3 grade 4 leukopenia and thrombocytopenia with 15 mg of IP. EHA mainly occurred after 2\u0026ndash;5 times of IP. 26% of patients required aminotransferase-lowing drugs for management of EHA. In addition, 3 patients (9%) experienced arachnoiditis, including 1 patient of grade 5 at 20 mg dose level (died within 1 week after abandoning treatment) and 2 patients of grade 2 at 15 mg dose level (completely relieved following glucocorticoid therapy). Radiculitis was noted in 9% (3/34) of patients, and mainly in grade 1 and grade 3. No symptomatic treatment was required and no patient discontinued treatment due to radiculitis. Grade 3 hepatocellular jaundice in 1 patient (3%), grade 1\u0026ndash;2 transient cognitive disturbance in 2 patients (6%), grade 3 fatigue in 1 patient (3%), and grade 2 nausea in 1 patient (3%) were also observed in this study.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab3\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 3\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eAdverse events in the MTD group (n\u0026thinsp;=\u0026thinsp;28)\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"6\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eAdverse events\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colspan=\"5\" nameend=\"c6\" namest=\"c2\"\u003e \u003cp\u003eGrade N (%)\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003e3\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003e4\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c6\"\u003e \u003cp\u003e5\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHematologic toxicity\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e5 (18%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e2 (7%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e6 (21%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e3 (11%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eElevation of hepatic aminotransferases\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e2 (7%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e3 (11%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e6 (21%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eElevation of blood bilirubin\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1 (4%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eArachnoiditis\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e2 (7%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eRadiculitis\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e2 (7%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTransient cognitive disturbance\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1 (4%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1 (4%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eFatigue\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1 (4%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNausea\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1 (4%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"6\"\u003eMTD, maximum-tolerated dose.\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec12\" class=\"Section2\"\u003e \u003ch2\u003eClinical Outcomes\u003c/h2\u003e \u003cp\u003eAccording to the response assessment criteria of Response Assessment in Neuro-Oncology (RANO)-LM [\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e], 15 patients were assessed as a response (11 with improvement of neurological function, 8 with improvement of neuroimaging, and 11 with negative conversion of CSF cytology); 10 patients were assessed as stable; and 4 patients were assessed as LM progressive based on worse neurological function and neuroimaging assessment (Table\u0026nbsp;\u003cspan refid=\"Tab4\" class=\"InternalRef\"\u003e4\u003c/span\u003e). The remaining 5 patients were unevaluable without neuroimaging or CSF cytology re-examination.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab4\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 4\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eClinical response evaluation of the patients\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"3\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCharacteristics\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eAll Eligible Patients\u003c/p\u003e \u003cp\u003e(n\u0026thinsp;=\u0026thinsp;34)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003ePatients in the MTD group\u003c/p\u003e \u003cp\u003e(n\u0026thinsp;=\u0026thinsp;28)\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eClinical response evaluation \u003csup\u003e\u003cem\u003ea\u003c/em\u003e\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eResponse \u003csup\u003e\u003cem\u003eb\u003c/em\u003e\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e15 (44%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e13 (46%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eStable disease\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e10 (29%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e8 (29%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eProgressive disease \u003csup\u003e\u003cem\u003ec\u003c/em\u003e\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e4 (12%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e4 (14%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNon-evaluable\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e5 (15%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e3 (11%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNeurological function assessment\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eImproved\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e11 (32%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e10 (36%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eStable\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e14 (41%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e11 (39%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eWorse\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e4 (12%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e4 (14%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNon-evaluable\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e5 (15%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e3 (11%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCSF cytological assessment\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eResponse\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e11 (32%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e10 (36%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eStable\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e16 (47%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e13 (46%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNon-evaluable\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e7 (21%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e5 (18%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNeuroimaging assessment\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eImproved\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e8 (24%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e7 (25%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eStable/equivocal\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e17 (50%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e15 (54%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eWorse\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1 (3%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1 (4%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNon-evaluable\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e8 (24%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e5 (18%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNeurological symptoms assessment\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eImproved\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e23 (68%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e19 (68%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eStable\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e4 (12%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e4 (14%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eWorse\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e4 (12%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e3 (11%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNon-evaluable\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e3 (9%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e2 (7%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMedian OS, months (95% CI)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e8.1 (6.5\u0026ndash;11.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e8.1(6.5\u0026ndash;11.9)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"3\"\u003eMTD, maximum-tolerated dose; CSF, cerebrospinal fluid; OS, overall survival.\u003c/td\u003e\u003c/tr\u003e \u003ctr\u003e\u003ctd colspan=\"3\"\u003e\u003csup\u003e\u003cem\u003ea\u003c/em\u003e\u003c/sup\u003e The clinical response was evaluated by Response Assessment in Neuro-Oncology (RANO)-LM working group proposal criteria, which was based on three levels of assessment, CSF cytology, neurological status and neuroimaging findings.\u003c/td\u003e\u003c/tr\u003e \u003ctr\u003e\u003ctd colspan=\"3\"\u003e\u003csup\u003e\u003cem\u003eb\u003c/em\u003e\u003c/sup\u003e Response was defined as the incidence of at least one of the evaluations of CSF cytology, neurological status and neuroimaging findings rated as improved, and there was no disease worsening at the same time.\u003c/td\u003e\u003c/tr\u003e \u003ctr\u003e\u003ctd colspan=\"3\"\u003e\u003csup\u003e\u003cem\u003ec\u003c/em\u003e\u003c/sup\u003e Progressive disease was defined as worsening of neuroimaging or neurological dysfunction.\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003eOf a total of 29 patients who were available for neurological function assessment, 11 were evaluated as improved, 14 were stable and 4 were worse. Of 27 patients with available CSF cytology data, 11 patients were assessed as having CSF cytological response, and 16 patients were stable. For neuroimaging assessment, 26 patients were available for assessment, including 8 improved, 17 stable/equivocal, and 1 progressive. In addition, 68% (23/34) of patients had improvement of LM-related symptoms.\u003c/p\u003e \u003cp\u003eThe overall CRR for all patients was 44% (15/34) and the overall DCR was 74% (25/34) with intention-to-treat (ITT) analysis (Table\u0026nbsp;\u003cspan refid=\"Tab4\" class=\"InternalRef\"\u003e4\u003c/span\u003e). The CRR and DCR for patients in the MTD group were 46% (13/28) and 75% (21/28) respectively. The CRR based on pathological types were 40% (8/20) of NSCLC, 50% (4/8) of breast cancer, and 50% (3/6) of other tumors (including small-cell lung cancer, esophageal cancer, nasopharyngeal cancer, and gastric cancer, Supplementary Table\u0026nbsp;3). No statistical difference was observed in CRR with various primary tumors (\u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.899). Notably, the CRR of EGFR-mutated NSCLC patients who developed LM during the course of TKIs treatment was 50% (7/14).\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec13\" class=\"Section2\"\u003e \u003ch2\u003eFollow-Up and Survival\u003c/h2\u003e \u003cp\u003eAll participants were followed up for at least 12 months until death or March 1, 2024. The median follow-up time was 8.1 months. The median OS for all patients was 8.1 months (95% confidence interval [CI], 6.5\u0026ndash;11.3, Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003eA), and the 12-month survival rate was 35.3% (12/34). The median OS for patients in the MTD group was 8.1 months (95% CI, 6.5\u0026ndash;11.9), and the 12-month survival rate was 35.7% (10/28). The median OS for 15 patients with clinical response was 14.9 months (95% CI, 10.7\u0026ndash;17.3), and 3.1 months (95% CI, 2.6\u0026ndash;7.1) for 19 patients without clinical response (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003eB, P\u0026thinsp;\u0026lt;\u0026thinsp;0.001). The median OS of the 12 patients who continued maintenance therapy was 16.9 months (95% CI, 11.6\u0026ndash;18.9), and 3.9 months (95% CI, 3.3\u0026ndash;7.6) for 22 patients who did not enter the maintenance stage (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003eC, P\u0026thinsp;\u0026lt;\u0026thinsp;0.001). Median survival for patients with NSCLC, breast cancer, and other tumors was 8.2, 6.3, and 4.8 months respectively, with no statistical difference between the 3 groups (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003eD, P\u0026thinsp;=\u0026thinsp;0.7). Besides, 14 patients who developed LM during the course of TKIs treatment had a median OS of 11.8 months (95% CI, 7.1\u0026ndash;15.7).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eBy the end of follow-up, 85% (29/34) of patients died. Among them, death was attributed to extra-CNS disease progression in 7 patients, to LM progression in 17 patients, to a combination of LM and extra-CNS disease in 2 patients, and not directly related to disease progression in 3 patients (1 treatment-related toxicity and 2 severe intrapulmonary infections).\u003c/p\u003e \u003c/div\u003e"},{"header":"Discussion","content":"\u003cp\u003eThis study indicated that the MTD for IP administration with vitamin supplementation was 15 mg per single dose. A dosing regimen consisting of twice-weekly administration for 2 weeks as induction therapy, followed by once-weekly administration for 4 weeks as consolidation therapy, and subsequently monthly administration as maintenance therapy, was demonstrated to be safe and feasible. Furthermore, this treatment protocol exhibited clinical activity. This study established a feasible and safe IP regimen for newly diagnosed LM from solid tumors.\u003c/p\u003e \u003cp\u003ePemetrexed, a multitargeted antifolate, has demonstrated broad antitumor activity across diverse solid tumors, including CNS malignancies [\u003cspan additionalcitationids=\"CR16 CR17 CR18 CR19\" citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e]. The anti-tumor efficacy of chemotherapeutic drugs, including pemetrexed, is related to drug concentration, duration of exposure, and rational drug administration regimens, which are mainly influenced by the half-lives of the drugs [\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e]. A rat model study for IP in 2011 demonstrated sustained high pemetrexed concentrations in CSF following a 1 mg/kg dose, with CSF levels at 24 hours post-injection at 0.143 \u0026micro;M, close to the half maximal inhibitory concentration (IC50) observed in human solid tumor cell lines [\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e]. Based on CSF volume and drug concentration, and considering safety, this study suggests an optimal starting dose of 5\u0026ndash;10 mg pemetrexed for human studies. More importantly, half-lives of pemetrexed for the initial distribution/elimination and terminal elimination phases were 0.43 and 1.43 h in rat CSF [\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e], respectively, which were similar to those of classical intrathecal chemotherapeutic drugs (methotrexate, cytarabine and thiotepa) in the CSF [\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e]. Thus, the administration regimen of IP was developed following that of classic intrathecal chemotherapeutic drugs: induction therapy twice a week, followed by consolidation therapy weekly, and then maintenance therapy monthly until the disease progresses or severe AEs cannot be tolerated.\u003c/p\u003e \u003cp\u003eSeveral other studies have been conducted, typically employing a regimen of IP once every 1\u0026ndash;3 weeks [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e, \u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e]. These regimens lack scientificity and rationality, casting doubt on the credibility of their findings [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e]. This is mainly due to the fact that the half-life of pemetrexed only exists for very few hours, a regimen of IP once every 1\u0026ndash;3 weeks is unable to maintain an effective drug concentration in CSF, deviating from fundamental pharmacological principles [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e, \u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e, \u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e]. This study revealed that a single 20 mg dose of intrathecal pemetrexed could induce grade 4\u0026ndash;5 severe adverse events, which is inconsistent with previous research findings and warrants clinical attention. Building upon our previous researches [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e, \u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e], this study further clinically validated a scientifically rational treatment protocol for IP, providing a novel therapeutic option for LM patients with solid tumors.\u003c/p\u003e \u003cp\u003eThe incidence of treatment-related toxicity constitutes a primary determinant of drug dosing regimens. Previous studies have found that hematological toxicity and EHA are the main treatment-related AEs of IP [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e, \u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e]. Building upon previous clinical trials [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e, \u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e], this study continued dose escalation of IP with prior folic acid and vitamin B12 supplementation. The results showed that the prior supplementation of folic acid and vitamin B12 elevated the MTD of IP from 10 mg to 15 mg. However, hematological toxicity is still one of the main factors interfering with the completion of treatment. In this study, the incidence of grade 3 or higher hematological toxicity was 32% in the 15 mg dose group. Furthermore, grade 3 EHA was observed in 21% of participants in the 15 mg dose group, which was higher than the previous incidence of 9% at the 10 mg dose level [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e], and most of them occurred during the induction IP period (IP, twice a week). Thus, higher dose and frequency of induced IP may increase the incidence of high-grade hematological toxicity and EHA. Compared with conventional systemic administration of pemetrexed, the markedly shortened dosing interval of induction IP may lead to hematopoietic cell depletion and hepatic metabolic impairment. Therefore, in order to avoid the occurrence of severe AEs, the regimen of induction IP is recommended to be twice-weekly administration (maximum 4 doses over 2 weeks). In addition, moderate IP-related chemical arachnoiditis was observed in this study, which has never been reported for systematic chemotherapy with pemetrexed. Obviously, combined with our previous clinical studies [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e, \u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e], this study further confirmed that there was a dose gradient effect in the toxicities for IP, indicating an increase in the incidence of AEs with increasing dosage, particularly the occurrence of severe treatment-related AEs such as neurological toxicity.\u003c/p\u003e \u003cp\u003eIn this study, the 15 mg dose regimen yielded a 46% CRR, 75% DCR, and median OS of 8.1 months, which were obviously better than those in our previous study on 10 mg of IP (CRR 31%, DCR 54%, and OS 3.8 months) [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e]. These results suggest that with prior folic acid and vitamin B12 supplementation, the 15 mg IP might have better activity with controllable AEs. Moreover, this study once again confirmed that IP was effective for LM from various primary solid tumors, similar to previous studies on 10 mg IP combined with IFRT [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e], and CRR was not affected by the pathological type of the primary tumor. Moreover, these results surpassed the historical median survival time previously reported for this disease [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eIn recent years, third-generation EGFR TKIs have been approved as the standard first-line therapy for patients with advanced EGFR-mutant NSCLC. Moreover, some studies have demonstrated the efficacy of third-generation EGFR TKIs therapy in LM patients with EGFR-mutant NSCLC [\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e, \u003cspan additionalcitationids=\"CR25 CR26 CR27\" citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e]. However, acquired resistance involving EGFR-dependent or non-EGFR-dependent mechanisms inevitably occurs and hampers their clinical benefits [\u003cspan additionalcitationids=\"CR30\" citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e]. LM exhibits a high incidence in patients with EGFR\u0026ndash;mutant NSCLC during the course of third-generation EGFR TKIs treatment. Among 20 LM patients with NSCLC in this study, 14 developed LM during the course of EGFR TKIs treatment, including 9 patients who had received the third-generation TKIs therapy. For those patients, the CRR and median OS were 50% and 11.8 months respectively. These results suggested that IP was effective for LM patients of NSCLC who have previously received TKIs therapy, and we will further validate the activity of IP in NSCLC patients with LM progression after third-generation TKIs treatment (NCT06296745). In addition to studies on NSCLC-related targeted agents for the treatment of LM, some evidence supports the activity of trastuzumab emtansine (T-DM1), trastuzumab deruxtecan (T-DXd), pyrotinib and tucatinib in LM patients with human epidermal growth factor receptor 2 (Her-2) positive breast cancer [\u003cspan additionalcitationids=\"CR33 CR34\" citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR35\" class=\"CitationRef\"\u003e35\u003c/span\u003e]. Whether the combination of targeted agents and intrathecal chemotherapy can further improve the survival of patients deserves exploration in the future.\u003c/p\u003e \u003cp\u003eThere were several limitations in this study. First, radiotherapy serves as one of the therapeutic modalities for LM. It is particularly recommended for patients with: imaging-confirmed intracranial parenchymal brain metastases, intraspinal metastatic nodules with significant cauda equina involvement, or impaired cerebrospinal fluid circulation. Radiotherapy may potentially impact AEs and efficacy outcomes. In this study, 8 patients received radiotherapy. Radiotherapy did not increase the incidence of AEs, with no more than grade 3 toxicities observed. It suggested that combining 15 mg IP with radiotherapy maintains a comparable safety profile to the previous study [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e]. However, although the survival benefit of radiotherapy for LM remains controversial [\u003cspan citationid=\"CR36\" class=\"CitationRef\"\u003e36\u003c/span\u003e, \u003cspan citationid=\"CR37\" class=\"CitationRef\"\u003e37\u003c/span\u003e], its impact on treatment efficacy (notably CRR) cannot be disregarded. Further large-scale studies should be required to validate the therapeutic efficacy of IP.\u003c/p\u003e \u003cp\u003eSecond, since LM lesions are non-measurable by neuroimaging criteria, traditional response evaluation criteria in solid tumors (RECIST) are inappropriate for assessment [\u003cspan citationid=\"CR38\" class=\"CitationRef\"\u003e38\u003c/span\u003e]. This limitation precludes the use of objective response rate as a primary endpoint and complicates accurate determination of progression-free survival. Although the RANO criteria have been widely adopted, significant variability in CRR reporting persists across LM studies [\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e]. Consequently, we selected OS as a secondary endpoint with a more objective efficacy measure, while designating CRR as other pre-specified outcome. However, it should be noted that OS interpretation may be confounded by systemic tumor burden and subsequent treatment interventions. Therapeutic evaluation in LM remains particularly challenging due to the disease's complex nature and multiple confounding factors.\u003c/p\u003e"},{"header":"Conclusion","content":"\u003cp\u003eThis phase I/II study demonstrated that intrathecal injection of 15 mg pemetrexed with vitamin supplementation was feasible and safe with therapeutic activity, which provides a potential new treatment option for newly diagnosed LM patients with solid tumors. Moreover, it provides a validated pemetrexed dose and schedule of IP in subsequent trials.\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003cp\u003eAEs: Adverse events; CNS: Central nervous system; CRR: Clinical response rate; CSF: Cerebrospinal fluid; DCR: Disease control rate; DLT: Dose-limiting toxicity; IP: Intrathecal pemetrexed; LM: Leptomeningeal metastasis; MTD: Maximum-tolerated dose; OS: Overall survival.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eEthics Statement\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis phase I/II study was conducted according to the guidelines of the Declaration of Helsinki and was approved by the Institutional Review Board of the First Hospital of Jilin University, Changchun, China (Approval number: 2017-246). Informed consent was obtained from all subjects. (ClinicalTrials.gov\u0026nbsp;Identifier:\u0026nbsp;NCT05289908)\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eData Availability Statement\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe data used and/or analyzed will be made available upon reasonable request.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConflict of interest statement\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors have no conflict of interest to declare.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding:\u003c/strong\u003e This study was supported by grants from Guangdong Basic and Applied Basic Research Foundation (2023A1515140145), Guangzhou Medical University Research Ability Enhancement Project (2024SRP215), and Huizhou Science and Technology Innovation Team Project (2023EQ050012).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthors\u0026rsquo; contributions\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eConceptualization: Z. Pan; Project Administration: Z. Pan, G. Yang; Writing-Reviewing and Editing: Z. Pan, G. Yang; Writing-Original Draft Preparation: X. Ye, Y. Huang, P. Tai; Formal Analysis: X. Ye, Y. Huang; Data Curation: Z. Wang; Assisting in Data Curation: M. Liu, L. Shen; Interpretation of Data: X. Pang, T. Yuan; Assisting in interpretation of clinical data: X. Sun, R. Tang, A. Gu. All authors have read and approved the final version of the manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAcknowledgments:\u003c/strong\u003e We gratefully acknowledge our colleague Yu Wu for her assistance with manuscript editing.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eBeauchesne P (2010) Intrathecal chemotherapy for treatment of leptomeningeal dissemination of metastatic tumours. Lancet Oncol 11(9):871\u0026ndash;879\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eLe Rhun E, Weller M, Brandsma D, Van den Bent M, de Azambuja E, Henriksson R, Boulanger T, Peters S, Watts C, Wick W et al (2017) EANO-ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up of patients with leptomeningeal metastasis from solid tumours. Ann Oncol 28(suppl4):iv84\u0026ndash;iv99\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eWilcox JA, Chukwueke UN, Ahn MJ, Aizer AA, Bale TA, Brandsma D, Brastianos PK, Chang S, Daras M, Forsyth P et al (2024) Leptomeningeal metastases from solid tumors: A Society for Neuro-Oncology and American Society of Clinical Oncology consensus review on clinical management and future directions. Neuro Oncol 26(10):1781\u0026ndash;1804\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eFleischhack G, Jaehde U, Bode U (2005) Pharmacokinetics following intraventricular administration of chemotherapy in patients with neoplastic meningitis. Clin Pharmacokinet 44(1):1\u0026ndash;31\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eLe Rhun E, Preusser M, van den Bent M, Andratschke N, Weller M (2019) How we treat patients with leptomeningeal metastases. ESMO Open 4(Suppl 2):e000507\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003ePan Z, Yang G, Cui J, Li W, Li Y, Gao P, Jiang T, Sun Y, Dong L, Song Y et al (2019) A Pilot Phase 1 Study of Intrathecal Pemetrexed for Refractory Leptomeningeal Metastases From Non-small-cell Lung Cancer. Front Oncol 9:838\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003ePan Z, Yang G, He H, Cui J, Li W, Yuan T, Chen K, Jiang T, Gao P, Sun Y et al (2020) Intrathecal pemetrexed combined with involved-field radiotherapy as a first-line intra-CSF therapy for leptomeningeal metastases from solid tumors: a phase I/II study. Ther Adv Med Oncol 12:1758835920937953\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eFan C, Zhao Q, Li L, Shen W, Du Y, Teng C, Gao F, Song X, Jiang Q, Huang D et al (2021) Efficacy and Safety of Intrathecal Pemetrexed Combined With Dexamethasone for Treating Tyrosine Kinase Inhibitor-Failed Leptomeningeal Metastases From EGFR-Mutant NSCLC-a Prospective, Open-Label, Single-Arm Phase 1/2 Clinical Trial (Unique Identifier: ChiCTR1800016615). J Thorac Oncol 16(8):1359\u0026ndash;1368\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eLi H, Zheng S, Lin Y, Yu T, Xie Y, Jiang C, Liu X, Qian X, Yin Z (2023) Safety, Pharmacokinetic and Clinical Activity of Intrathecal Chemotherapy With Pemetrexed via the Ommaya Reservoir for Leptomeningeal Metastases From Lung Adenocarcinoma: A Prospective Phase I Study. Clin Lung Cancer 24(2):e94\u0026ndash;e104\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003ePan Z (2022) Focusing on Intrathecal Pemetrexed for Treating Leptomeningeal Metastases From NSCLC. J Thorac Oncol 17(3):e31\u0026ndash;e32\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSun JM, Nam MH, Chung JY, Im B, Lee SY, Suh YL, Ahn JS, Park K, Ahn MJ (2011) Safety and pharmacokinetics of intrathecal administration of pemetrexed in rats. Cancer Chemother Pharmacol 68(2):531\u0026ndash;538\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eChamberlain M, Junck L, Brandsma D, Soffietti R, Rud\u0026agrave; R, Raizer J, Boogerd W, Taillibert S, Groves MD, Rhun EL et al (2016) Leptomeningeal metastases: a RANO proposal for response criteria. Neurooncology 19(4):484\u0026ndash;492\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eLe Rhun E, Devos P, Boulanger T, Smits M, Brandsma D, Rud\u0026agrave; R, Furtner J, Hempel JM, Postma TJ, Roth P et al (2019) The RANO Leptomeningeal Metastasis Group proposal to assess response to treatment: lack of feasibility and clinical utility and a revised proposal. Neuro Oncol 21(5):648\u0026ndash;658\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eYang JCH, Kim SW, Kim DW, Lee JS, Cho BC, Ahn JS, Lee DH, Kim TM, Goldman JW, Natale RB et al (2020) Osimertinib in Patients With Epidermal Growth Factor Receptor Mutation-Positive Non-Small-Cell Lung Cancer and Leptomeningeal Metastases: The BLOOM Study. J Clin Oncol 38(6):538\u0026ndash;547\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eRaizer JJ, Rademaker A, Evens AM, Rice L, Schwartz M, Chandler JP, Getch CC, Tellez C, Grimm SA (2012) Pemetrexed in the treatment of relapsed/refractory primary central nervous system lymphoma. Cancer 118(15):3743\u0026ndash;3748\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eLee DW, Jung KH, Lee KH, Park YH, Lee KS, Sohn J, Ahn HK, Jeong JH, Koh SJ, Kim JH et al (2024) Pemetrexed plus vinorelbine versus vinorelbine monotherapy in patients with metastatic breast cancer (KCSG-BR15-17): A randomized, open-label, multicenter, phase II trial. Eur J Cancer 197:113456\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eCelio L, Sternberg CN, Labianca R, La Torre I, Amoroso V, Barone C, Pinotti G, Cascinu S, Di Costanzo F, Cetto GL et al (2009) Pemetrexed in combination with oxaliplatin as a first-line therapy for advanced gastric cancer: a multi-institutional phase II study. Ann Oncol 20(6):1062\u0026ndash;1067\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eJatoi A, Soori G, Foster NR, Hiatt BK, Knost JA, Fitch TR, Callister MD, Nichols FC 3rd, Husted TM, Alberts SR (2010) Phase II study of preoperative pemetrexed, carboplatin, and radiation followed by surgery for locally advanced esophageal cancer and gastroesophageal junction tumors. J Thorac Oncol 5(12):1994\u0026ndash;1998\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eZhang Y, Zhao L, Huang P, Wu J, Wang F, Huang Y, Zhang L (2012) Open-label, single-arm phase II study of pemetrexed in the treatment of patients with recurrent or metastatic nasopharyngeal carcinoma who have had prior platinum-based chemotherapy. Cancer Chemother Pharmacol 70(4):611\u0026ndash;615\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSocinski MA (2005) Pemetrexed (Alimta) in small cell lung cancer. Semin Oncol 32(2 Suppl 2):S1\u0026ndash;4\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eGiovannetti E, Mey V, Nannizzi S, Pasqualetti G, Marini L, Del Tacca M, Danesi R (2005) Cellular and pharmacogenetics foundation of synergistic interaction of pemetrexed and gemcitabine in human non-small-cell lung cancer cells. Mol Pharmacol 68(1):110\u0026ndash;118\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eLe Rhun E, Weller M, van den Bent M, Brandsma D, Furtner J, Rud\u0026agrave; R, Schadendorf D, Seoane J, Tonn JC, Wesseling P et al (2023) Leptomeningeal metastasis from solid tumours: EANO-ESMO Clinical Practice Guideline for diagnosis, treatment and follow-up. ESMO Open 8(5):101624\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003ePan ZY, Song YY, Jiang TC, Yang X, Yang GZ (2022) [Clinical trials on intrathecal pemetrexed treated leptomeningeal metastases from solid tumors]. Zhonghua Zhong Liu Za Zhi 44(1):112\u0026ndash;119\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eXu Z, Hao X, Wang Q, Yang K, Li J, Xing P (2023) Intracranial efficacy and safety of furmonertinib 160 mg with or without anti-angiogenic agent in advanced NSCLC patients with BM/LM as salvage therapy. BMC Cancer 23(1):206\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003ePark S, Lee MH, Seong M, Kim ST, Kang JH, Cho BC, Lee KH, Cho EK, Sun JM, Lee SH et al (2020) A phase II, multicenter, two cohort study of 160 mg osimertinib in EGFR T790M-positive non-small-cell lung cancer patients with brain metastases or leptomeningeal disease who progressed on prior EGFR TKI therapy. Ann Oncol 31(10):1397\u0026ndash;1404\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eChen T, Chen J, Liu DS, Shu YL, Fu MY, Gou HJ, Lei KJ, Jia YM (2023) Successful therapy using high-dose furmonertinib for non-small cell lung cancer with leptomeningeal metastasis: a case report and literature review. Front Oncol 13:1233198\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eAhn MJ, Chiu CH, Cheng Y, Han JY, Goldberg SB, Greystoke A, Crawford J, Zhao Y, Huang X, Johnson M et al (2020) Osimertinib for Patients With Leptomeningeal Metastases Associated With EGFR T790M-Positive Advanced NSCLC: The AURA Leptomeningeal Metastases Analysis. J Thorac Oncol 15(4):637\u0026ndash;648\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003ePark S, Baldry R, Jung HA, Sun JM, Lee SH, Ahn JS, Kim YJ, Lee Y, Kim DW, Kim SW et al (2024) Phase II Efficacy and Safety of 80 mg Osimertinib in Patients With Leptomeningeal Metastases Associated With Epidermal Growth Factor Receptor Mutation-Positive Non-Small Cell Lung Cancer (BLOSSOM). J Clin Oncol 42(23):2747\u0026ndash;2756\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eZhang H, Wang Y, Wu H, Zhou S, Li S, Meng X, Tao R, Yu J (2022) Olaparib Combined With Dacomitinib in Osimertinib-Resistant Brain and Leptomeningeal Metastases From Non-Small Cell Lung Cancer: A Case Report and Systematic Review. Front Oncol 12:877279\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eZheng MM, Li YS, Tu HY, Sun H, Yin K, Jiang BY, Yang JJ, Zhang XC, Zhou Q, Xu CR et al (2022) Subsequent treatments beyond progression on osimertinib in EGFR-mutated NSCLC and leptomeningeal metastases. BMC Med 20(1):197\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eLeonetti A, Sharma S, Minari R, Perego P, Giovannetti E, Tiseo M (2019) Resistance mechanisms to osimertinib in EGFR-mutated non-small cell lung cancer. Br J Cancer 121(9):725\u0026ndash;737\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eYan F, Rinn KJ, Kullnat JA, Wu AY, Ennett MD, Scott EL, Kaplan HG (2022) Response of Leptomeningeal Metastasis of Breast Cancer With a HER2/neu Activating Variant to Tucatinib: A Case Report. J Natl Compr Canc Netw 20(7):745\u0026ndash;752\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eChi Y, Shang M, Xu L, Gong H, Tao R, Song L, Zhang B, Yin S, Cong B, Li H (2022) Durable Effect of Pyrotinib and Metronomic Vinorelbine in HER2-Positive Breast Cancer With Leptomeningeal Disease: A Case Report and Literature Review. Front Oncol 12:811919\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eAlder L, Trapani D, Bradbury C, Van Swearingen AED, Tolaney SM, Khasraw M, Anders CK, Lascola CD, Hsu L, Lin NU et al (2023) Durable responses in patients with HER2\u0026thinsp;+\u0026thinsp;breast cancer and leptomeningeal metastases treated with trastuzumab deruxtecan. NPJ Breast Cancer 9(1):19\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eRicciardi GRR, Russo A, Franchina T, Schifano S, Mastroeni G, Santacaterina A, Adamo V (2018) Efficacy of T-DM1 for leptomeningeal and brain metastases in a HER2 positive metastatic breast cancer patient: new directions for systemic therapy - a case report and literature review. BMC Cancer 18(1):97\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eHitchins RN, Bell DR, Woods RL, Levi JA (1987) A prospective randomized trial of single-agent versus combination chemotherapy in meningeal carcinomatosis. J Clin Oncol 5(10):1655\u0026ndash;1662\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMorris PG, Reiner AS, Szenberg OR, Clarke JL, Panageas KS, Perez HR, Kris MG, Chan TA, DeAngelis LM, Omuro AM (2012) Leptomeningeal metastasis from non-small cell lung cancer: survival and the impact of whole brain radiotherapy. J Thorac Oncol 7(2):382\u0026ndash;385\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eLe Rhun E, Taillibert S, Chamberlain MC (2013) Carcinomatous meningitis: Leptomeningeal metastases in solid tumors. Surg Neurol Int 4(Suppl 4):S265\u0026ndash;288\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"journal-of-neuro-oncology","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"neon","sideBox":"Learn more about [Journal of Neuro-Oncology](https://www.springer.com/journal/11060)","snPcode":"11060","submissionUrl":"https://submission.nature.com/new-submission/11060/3","title":"Journal of Neuro-Oncology","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false},"keywords":"Leptomeningeal metastasis, Intrathecal chemotherapy, Pemetrexed","lastPublishedDoi":"10.21203/rs.3.rs-6572942/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-6572942/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eBackground\u003c/h2\u003e \u003cp\u003eThis phase I/II study evaluated the maximum-tolerated dose (MTD) of intrathecal pemetrexed (IP) with vitamin supplementation, and its safety, feasibility and therapeutic activity for newly diagnosed leptomeningeal metastasis (LM) from solid tumors.\u003c/p\u003e\u003ch2\u003eMethods\u003c/h2\u003e \u003cp\u003eThe phase I study followed the classic 3\u0026thinsp;+\u0026thinsp;3 design, with IP dose escalating from 15 mg. The recommended dose was applied in the phase II study. The MTD, adverse events (AEs), overall survival (OS), clinical response rate (CRR) and disease control rate (DCR) were evaluated.\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e \u003cp\u003eA total of 34 patients were enrolled. In the phase I study, 2 patients in the 20 mg group experienced dose-limiting toxicity. The MTD was established as 15 mg. Among 28 patients in the MTD group, 24 completed induction therapy, 19 completed consolidation therapy and 11 proceeded to maintenance therapy. The overall AEs rate was 74% (25/34), and severe AEs rate (\u0026gt;\u0026thinsp;grade 3) was 15% (5/34). In the MTD group, the CRR, DCR and median OS were 46% (13/28), 75% (21/28) and 8.1 months.\u003c/p\u003e\u003ch2\u003eConclusion\u003c/h2\u003e \u003cp\u003eIP at 15 mg with prior folic acid and vitamin B12 supplementation demonstrated safety and feasibility, offering a new treatment option with therapeutic activity for newly diagnosed LM patients with solid tumors.\u003c/p\u003e\u003ch2\u003eTrial registration:\u003c/h2\u003e \u003cp\u003eClinicalTrials.gov Identifier: NCT05289908\u003c/p\u003e","manuscriptTitle":"Intrathecal pemetrexed for newly diagnosed leptomeningeal metastases: A multicenter, open-label, phase I/II study","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-05-09 01:49:06","doi":"10.21203/rs.3.rs-6572942/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2025-05-30T02:47:56+00:00","index":"","fulltext":""},{"type":"reviewerAgreed","content":"115159286488110503333021917528874529541","date":"2025-05-18T20:18:03+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"187274948074608078456875652095649314085","date":"2025-05-16T21:58:18+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-05-16T12:47:07+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-05-15T19:21:12+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-05-13T12:35:01+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"58160073700391066177175512366495657057","date":"2025-05-05T17:06:38+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"172523864175870699964608851278552319001","date":"2025-05-05T15:09:04+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"262329673752029930087582385815650247906","date":"2025-05-03T13:26:14+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2025-05-02T13:48:27+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2025-05-02T11:51:22+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2025-05-02T11:50:23+00:00","index":"","fulltext":""},{"type":"submitted","content":"Journal of Neuro-Oncology","date":"2025-05-01T15:27:32+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"journal-of-neuro-oncology","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"neon","sideBox":"Learn more about [Journal of Neuro-Oncology](https://www.springer.com/journal/11060)","snPcode":"11060","submissionUrl":"https://submission.nature.com/new-submission/11060/3","title":"Journal of Neuro-Oncology","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false}}],"origin":"","ownerIdentity":"9e41434a-7776-470c-aa2d-9fef47e00d4e","owner":[],"postedDate":"May 9th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[],"tags":[],"updatedAt":"2025-07-28T16:02:40+00:00","versionOfRecord":{"articleIdentity":"rs-6572942","link":"https://doi.org/10.1007/s11060-025-05160-4","journal":{"identity":"journal-of-neuro-oncology","isVorOnly":false,"title":"Journal of Neuro-Oncology"},"publishedOn":"2025-07-23 15:57:54","publishedOnDateReadable":"July 23rd, 2025"},"versionCreatedAt":"2025-05-09 01:49:06","video":"","vorDoi":"10.1007/s11060-025-05160-4","vorDoiUrl":"https://doi.org/10.1007/s11060-025-05160-4","workflowStages":[]},"version":"v1","identity":"rs-6572942","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-6572942","identity":"rs-6572942","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}