Clinical Response to Olaparib in a Patient With Leptomeningeal Carcinomatosis in Newly Diagnosed Breast Cancer With Germline BRCA2 Mutation.

Case of LMC in a BRCA2-mutated breast cancer patient shows clinical improvement with Olaparib therapy.

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).

PURPOSE: Leptomeningeal metastases (LMs) exhibit a high incidence in patients with epidermal growth factor receptor (EGFR)-mutated non-small cell lung cancer (NSCLC) post-treatment with first- or second-generation EGFR tyrosine kinase inhibitors (TKIs). This investigation evaluates the efficacy, safety, and pharmacokinetics of 80 mg once daily osimertinib in patients with LMs resistant to prior first- or second-generation EGFR TKIs. MATERIALS AND METHODS: In this phase II multicenter, open-label, single-arm study, 80 mg osimertinib was administered to patients with EGFR-mutated NSCLC who had developed LMs subsequent to treatment with prior EGFR TKIs. The primary end point was overall survival (OS), assessed alongside objective response rate by the blinded independent central review (BICR) and a pharmacokinetic analysis of plasma and cerebrospinal fluid (CSF) on the first day of cycles 3 and 6. RESULTS: A total of 73 patients diagnosed with LM were treated with osimertinib, including 64 patients evaluable for the LM efficacy set-T790M negative (n = 62) and T790M positive (n = 2). The median OS in the full-analysis set was 15.6 months (95% CI, 11.5 to 20.2). The objective response rate for LM was 51.6%, including a 15.6% complete response, and the disease control rate was 81.3% by BICR in the LM efficacy evaluable set. The median LM progression-free survival by BICR was 11.2 months (95% CI, 7.7 to 15.3), the duration of response was 12.6 months (95% CI, 7.6 to 17.7), and OS was 15.0 months (95% CI, 11.3 to 18.7). Pharmacokinetic analysis showed that the CSF to free plasma osimertinib ratio was 22%. Most safety profiles were grade 1 and 2. CONCLUSION: The study demonstrates significant intracranial efficacy and survival benefits of 80 mg once daily osimertinib in NSCLC patients with LMs. The data support considering daily 80 mg of osimertinib as a treatment option for EGFR-mutated NSCLC patients with LMs, irrespective of T790M mutation status.

High-dose furmonertinib combined with intraventricular chemotherapy as salvage therapy for leptomeningeal metastasis from EGFR exon 20 insertion-mutated lung cancer.

PURPOSE: The treatment of leptomeningeal metastasis (LM), a serious complication of advanced non-small cell lung cancer (NSCLC), presents challenges, particularly in patients with EGFR exon 20 insertion (ex20ins) mutations. METHODS: This study retrospectively analyzed data from 10 EGFR ex20ins-mutated NSCLC patients with LM admitted at our institution from May 2011 to June 2023. Circulating tumor DNA (ctDNA) from cerebrospinal fluid (CSF) and matched plasma samples was analyzed using next-generation sequencing. All patients received high-dose furmonertinib combined with intraventricular chemotherapy (IVC) as salvage therapy. Data on patient demographics, treatment efficacy, and safety outcomes were collected. RESULTS: The most common insertion mutation identified in this study was p.A767_V769dup (n = 4, 40%), followed by D770-N771insY (n = 2, 20%). Nine patients had EGFR ex20ins occurring in the EGFR loop region following the C-helix, whereas only one patient had an EGFR ex20ins (A763_Y764insFQEA) occurring in the C-helix of the tyrosine kinase domain. LM response assessment using the RANO-LM criteria revealed that 6 patients (60%, 95% CI 26.2-87.8%) achieved a response, 3 had stable disease, and 1 had progressive disease. The median progression-free survival and overall survival were estimated to be 6.5 months and 8.8 months, respectively. The most commonly reported treatment-related adverse events were rash (n = 7) and diarrhea (n = 7), with no treatment-related deaths occurring. CONCLUSIONS: The current study demonstrated that high-dose furmonertinib plus IVC as salvage treatment for patients with LM harboring EGFR ex20ins mutations had promising clinical benefits and a manageable safety profile.

[Intrathecal chemotherapy for leptomeningeal metastases in patients with breast cancer]. / Intratekal'naya khimioterapiya pri leptomeningeal'nom metastazirovanii u bol'nykh rakom molochnoi zhelezy.

Leptomeningeal metastases are lesions of brain and/or spinal cord sheaths by tumor cells. They occur in 5% of patients with solid tumors, although autopsies reveal these lesions much more often (10-20% of cases). Leptomengeal metastases are an unfavorable prognostic factor. Despite the modern NCCN treatment standards, including intrathecal therapy (ITT), such patients receive only irradiation of the entire brain and/or spinal cord in most cases. OBJECTIVE: To evaluate the effectiveness of ITT in patients with leptomeningeal metastases in breast cancer. MATERIAL AND METHODS: Twenty-five patients with breast cancer and leptomeningeal metastases underwent intrathecal administration of methotrexate between 2016 and 2022. Intrathecal chemotherapy was administered through lumbar puncture. We performed an intensive course (intrathecal methotrexate 15 mg 2 times a week for 1 month (8 injections), then intrathecal methotrexate 15 mg 1 time a week (4 injections), and then 15 mg 1 time a month until progression or unacceptable toxicity). RESULTS: The median duration of ITT was 2.5 months. Complete neurological responses were observed in 3 out of 25 (12%) patients, partial neurological response - in 15 out of 25 (60%) patients, progression of neurological symptoms - in 7 (28%) patients. The number of complete cytological responses was observed in 6 out of 25 (24%) patients. The median overall survival after ITT was 6.7 months. CONCLUSION: Effectiveness of ITT is confirmed by higher quality of life (72% of patients), complete cytological responses (24%) and improvement in neuroimaging data. This is an important criterion for severe patients with limited treatment options. First-stage ITT before whole-brain irradiation is preferable, as this approach increases overall survival by 3 months. Undoubtedly, ITT is a treatment option that can be used in routine clinical practice for lesions of brain and spinal cord sheaths.

Nasopharyngeal carcinoma with leptomeningeal metastases has been treated with comprehensive treatment for long-term survival: A case report and literature review.

RATIONALE: Nasopharyngeal carcinoma has a high incidence in East and Southeast Asia, often with distant metastasis. However, leptomeningeal metastasis (LM) is extremely rare and usually has a poor prognosis. This paper reports the clinical treatment of a patient with meningeal metastasis of nasopharyngeal carcinoma (NPC) in order to improve the clinician's understanding of the disease. Early diagnosis of the disease can alleviate the pain of patients and prolong their survival time. PATIENT CONCERNS: We report the case of a 55-year-old female with a history of NPC with LM. Brain magnetic resonance imaging showed temporal lobe enhancement, peripheral edema, and enhancement of the adjacent meninges. Cerebrospinal fluid cytology suggests the presence of malignant tumor cells. DIAGNOSES: The patient was diagnosed with LM from NPC. INTERVENTIONS: The patients were regularly given targeted therapy with nimotuzumab, immunotherapy with karyolizumab, and lumbar intrathecal methotrexate chemotherapy and supportive treatment. OUTCOMES: The patient had survived for 3 years since the diagnosis of LM and was in good condition and still under active antitumor treatment. LESSONS: Leptomeningeal metastasis of NPC is a rare disease. Although there is currently no unified treatment plan, the neurological symptoms can still be controlled and the quality of life can be improved through active treatment.

Demographic and clinical characteristics of patients with metastatic breast cancer and leptomeningeal disease: a single center retrospective cohort study.

PURPOSE: Leptomeningeal disease (LMD) is a devastating complication of metastatic breast cancer (MBC). It is critical to better understand the risk factors, natural history, and treatment outcomes, including patients in a modern cohort. METHODS: In this single center retrospective cohort study, we identified patients with MBC and LMD who received care from 2000 to 2024 and abstracted key clinical, treatment, and survival data. RESULTS: We identified 111 patients with MBC and LMD, including patients with the following subtypes: HR+/HER2- (n = 53, 47.7%), HER2+ (n = 30, 27.0%), and triple negative breast cancer (TNBC; n = 28, 25.2%). Median time from the diagnosis of MBC to LMD was 16.4 months (range 0-101.3 months). After the diagnosis of LMD, most patients received systemic therapy (n = 66, 59.5%) and/or central nervous system (CNS)-directed therapy (n = 94, 84.7%) including intrathecal therapy (n = 42, 37.8%) and/or CNS-directed radiation therapy (n = 70, 63.1%). In all patients, median overall survival (OS) from the diagnosis of LMD to death was 4.1 months (range 0.1-78.1 months) and varied by subtype, with HR+/HER2- or HER2+ MBC patients living longer than those with TNBC (4.2 and 6.8 months respectively vs. 2.0 months, p < 0.01, HR 2.15, 95% CI 1.36-3.39). Patients who received CNS-directed therapy lived longer than those who did not (4.2 vs. 1.3, p = 0.02 HR 0.54, 0.32-0.91). Patients diagnosed with LMD from 2015 to 2024 lived longer than those diagnosed from 2000 to 2014 (6.4 vs. 2.9 months, p = 0.04, HR 0.67, 95% CI 0.46-0.99). On multivariable analysis, having TNBC was associated with shorter OS from time of LMD to death (p = 0.004, HR 2.03, 95% CI 1.25-3.30). CONCLUSION: This is one of the largest case series of patients with MBC and LMD. Patients diagnosed with LMD from 2015 to 2024 lived longer than those diagnosed from 2000 to 2014, although median OS was short overall. Patients with TNBC and LMD had particularly short OS. Novel therapeutic strategies for LMD remain an area of unmet clinical need.

Clinical Outcomes of Patients with Non-Small Cell Lung Cancer Leptomeningeal Disease Following Receipt of EGFR-Targeted Therapy, Immune-Checkpoint Blockade, Intrathecal Chemotherapy, or Radiation Therapy Alone.

BACKGROUND: EGFR-targeted therapy (ETT) and immune-checkpoint blockade (ICB) have shown promising results in treating NSCLC brain metastases (BM). However, little is known of their effect in treating leptomeningeal disease (LMD). PATIENTS AND METHODS: This is a retrospective review of 80 patients diagnosed with NSCLC LMD from January 2014 to March 2021. Patients were grouped based on initial LMD treatment: radiotherapy (RT) alone, ETT, ICB, and intrathecal chemotherapy (ITC). RESULTS: EGFR mutation was present in 22 patients (28%). Twenty patients had positive cytology in cerebrospinal fluid, while 60 patients were diagnosed based on MRI with clinical correlation. The RT alone group consisted primarily of whole brain radiation (n = 20; 77%), stereotactic radiation (n = 3; 12%), and palliative spine radiation (n = 2; 7%). There were no significant differences amongst the treatment groups in age, performance status, or neurologic symptoms. Overall, the 6-month overall survival (OS) and craniospinal progression free survival (CS-PFS) were 35% and 24%, respectively. The 6-month OS for the ETT, ICB, ITC, and RT alone groups was 64%, 33%, 57%, and 29% respectively (log-rank P = .026). The 6-month CS-PFS for the ETT, ICB, ITC, and RT alone groups was 43%, 33%, 29%, and 19% respectively (log-rank P = .049). Upon univariate analysis, receipt of ETT compared to RT alone reached significance for OS (HR 0.35, P = .006) and CS-PFS (HR 0.39, P = .013). CONCLUSIONS: The prognosis for patients with NSCLC LMD remains poor overall. However, the receipt of ETT for patients with EGFR-positive disease was associated with improved outcomes.

Outcomes, responses, and prognostic analyses of intrathecal combined treatment for leptomeningeal metastasis from lung adenocarcinoma.

BACKGROUND: Leptomeningeal metastasis (LM) is a severe lung cancer complication, with potentially fatal consequences. The use of intrathecal therapy (IT) combined with systemic therapy has shown promise as a treatment approach for LM. Thus, this study aimed to evaluate the features and responses to IT combined therapy and identify determinants affecting patients with leptomeningeal metastasis resulting from lung adenocarcinoma (LM-LA). METHODS: A retrospective analysis of medical records from our hospital database was performed, covering from April 2018 to August 2022, for 37 patients diagnosed with LM-LA and treated with IT combined therapy. Patients who received IT combined therapy for LM-LA were evaluated for demographic characteristics, treatment efficacy, survival, and variables that impacted them. RESULTS: The median overall survival (mOS) of 37 patients was 16.0 months, and the survival rates at 6 and 12 months were 75.7% and 35.1%, respectively. Among the 21 patients with LM-LA who received IT combined with tyrosine kinase inhibitors (TKIs), the mOS was 17.0 months, which was significantly longer than that of patients treated with IT combined with chemotherapy (7.0 months, P = 0.010) and the best supportive care (6.0 months, P = 0.001). However, no significant survival benefit was observed in patients treated with IT combined with TKIs when compared with those treated with IT combined with PD-1 (5.0 months, P = 0.249). Multivariate analysis indicated that the combination of TKIs was an independent favorable prognostic factor for patients with LM-LA. CONCLUSION: Combination treatment is regarded as an additional option for patients with LM-LA. Compared with other combination therapies in our study, IT combined with TKI therapy provided a better survival outcome for patients with LM-LA.

PROTAC EZH2 degrader-1 overcomes the resistance of podophyllotoxin derivatives in refractory small cell lung cancer with leptomeningeal metastasis.

BACKGROUND: Leptomeningeal metastasis (LM) of small cell lung cancer (SCLC) is a highly detrimental occurrence associated with severe neurological disorders, lacking effective treatment currently. Proteolysis-targeting chimeric molecules (PROTACs) may provide new therapeutic avenues for treatment of podophyllotoxin derivatives-resistant SCLC with LM, warranting further exploration. METHODS: The SCLC cell line H128 expressing luciferase were mutated by MNNG to generate H128-Mut cell line. After subcutaneous inoculation of H128-Mut into nude mice, H128-LM and H128-BPM (brain parenchymal metastasis) cell lines were primarily cultured from LM and BPM tissues individually, and employed to in vitro drug testing. The SCLC-LM mouse model was established by inoculating H128-LM into nude mice via carotid artery and subjected to in vivo drug testing. RNA-seq and immunoblotting were conducted to uncover the molecular targets for LM. RESULTS: The SCLC-LM mouse model was successfully established, confirmed by in vivo live imaging and histological examination. The upregulated genes included EZH2, SLC44A4, VEGFA, etc. in both BPM and LM cells, while SLC44A4 was particularly upregulated in LM cells. When combined with PROTAC EZH2 degrader-1, the drug sensitivity of cisplatin, etoposide (VP16), and teniposide (VM26) for H128-LM was significantly increased in vitro. The in vivo drug trials with SCLC-LM mouse model demonstrated that PROTAC EZH2 degrader-1 plus VM26 or cisplatin/ VP16 inhibited H128-LM tumour significantly compared to VM26 or cisplatin/ VP16 alone (P < 0.01). CONCLUSION: The SCLC-LM model effectively simulates the pathophysiological process of SCLC metastasis to the leptomeninges. PROTAC EZH2 degrader-1 overcomes chemoresistance in SCLC, suggesting its potential therapeutic value for SCLC LM.

Malignant transformation and subsequent leptomeningeal carcinomatosis of a gastric polyp in a dog.

Progressive carcinogenesis of a gastric polyp with transformation to gastric adenocarcinoma and subsequent development of leptomeningeal carcinomatosis is described in an adult male Scottish terrier. Presenting clinical signs consisted of vomiting with intermittent hematemesis. Surgical biopsies over the course of 14 months documented the progression from gastric polyp to minimally invasive gastric carcinoma to invasive gastric adenocarcinoma, a pathogenesis not previously documented in veterinary oncology. The patient ultimately developed neurologic pathology and was euthanized, and necropsy evaluation identified widespread carcinomatosis with accompanying leptomeningeal metastasis. As in humans, gastric polyps in dogs rarely have malignant potential.

Furmonertinib and intrathecal pemetrexed chemotherapy rechallenges osimertinib-refractory leptomeningeal metastasis in a non-small cell lung cancer patient harboring EGFR20 R776S, C797S, and EGFR21 L858R compound EGFR mutations: a case report.

Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) are considered the first-line treatment for advanced or metastatic non-small cell lung cancer (NSCLC) patients harboring EGFR mutations. However, due to the rarity of cases, the response of EGFR-TKIs in patients harboring uncommon compound EGFR mutations still needs to be determined. Here, we demonstrated the case of a 47-year-old smoker diagnosed with leptomeningeal metastasis from NSCLC and had EGFR20 R776S, C797S, and EGFR21 L858R compound mutations. He was treated with furmonertinib combined with intrathecal pemetrexed chemotherapy following progression on osimertinib, which led to clinical improvement and successfully prolonged his survival by 3 months. Regrettably, the patient eventually died from heart disease. This report provides the first reported evidence for the use of furmonertinib and intrathecal pemetrexed chemotherapy in NSCLC patients harboring EGFR R776S/C797S/L858R mutations who progressed on previous EGFR-TKIs.

Prognostic impact of clinical and radiological factors on leptomeningeal metastasis from solid cancers.

PURPOSE: The number of leptomeningeal metastasis (LM) patients has increased in recent years, as the cancer survival rates increased. An optimal prediction of prognosis is essential for selecting an appropriate treatment. The European Association of Neuro-Oncology-European Society for Medical Oncology (EANO-ESMO) guidelines for LM proposed a classification based on the cerebrospinal fluid cytological findings and contrast-enhanced magnetic resonance imaging (MRI) pattern. However, few studies have validated the utility of this classification. This study aimed to investigate the prognostic factors of LM, including the radiological and cytological types. METHODS: We retrospectively analyzed the data of 240 adult patients with suspected LM who had undergone lumbar puncture between April 2014 and September 2021. RESULTS: The most common primary cancer types were non-small-cell lung cancer (NSCLC) (143 (60%)) and breast cancer (27 (11%)). Positive cytology results and the presence of leptomeningeal lesions on contrast-enhanced MRI correlated with decreased survival in all patients. Nodular lesions detected on contrast-enhanced magnetic resonance were a poor prognostic factor in cytology-negative patients, while contrast-enhanced patterns had no prognostic significance in cytology-positive patients. Systemic therapy using cytotoxic agents and molecular-targeted therapy after LM diagnosis correlated with prolonged survival, regardless of the cytology results. Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor treatment and systemic chemotherapy after LM improved the survival of EGFR-mutated and wild-type NSCLC patients with positive cytology results. CONCLUSIONS: This study validated the efficacy of prognostication according to the EANO-ESMO guidelines for LM. Systemic therapy after LM diagnosis improves the survival of NSCLC patients.

Prognostic Role of Ventricular Size and Its Dynamics in Patients With Leptomeningeal Metastasis From Solid Tumors.

BACKGROUND AND OBJECTIVES: Hydrocephalus is a common radiologic sign in patients with leptomeningeal metastasis (LM) from solid tumors which can be assessed using the Evans index (EI). Here, we explored the prognostic value of ventricular size in LM. METHODS: We identified patients with LM from solid tumors by chart review at 3 academic hospitals to explore the prognostic associations of the EI at diagnosis, first follow-up, and progression. RESULTS: We included 113 patients. The median age was 58.3 years (interquartile range [IQR] 46.1-65.8), 41 patients (36%) were male, and 72 patients (64%) were female. The most frequent cancers were lung cancer (n = 39), breast cancer (n = 36), and melanoma (n = 23). The median EI at baseline was 0.28 (IQR 0.26-0.31); the EI value was 0.27 or more in 67 patients (59%) and 0.30 or more in 37 patients (33%). Among patients with MRI follow-up, the EI increased by 0.01 or more in 16 of 31 patients (52%), including 8 of 30 patients (30%) without and 10 of 17 patients (59%) with LM progression at first follow-up. At LM progression, an increase of EI of 0.01 or more was noted in 18 of 34 patients (53%). The median survival was 2.9 months (IQR 1-7.2). Patients with a baseline EI below 0.27 had a longer survival than those with an EI of 0.27 or more (5.3 months, IQR 2.4-10.8, vs 1.3 months, IQR 0.6-4.1) (HR 1.70, 95% CI 1.135-2.534, p = 0.0099). The median survival was 3.7 months (IQR 1.4-8.3) with an EI below 0.30 vs 1.8 months (IQR 0.8-4.1) with an EI of 0.30 or more (HR 1.40, 95% CI 0.935-1.243, p = 0.1113). Among patients with follow-up scans available, the overall survival was 9.4 months (IQR 5.6-21.0) for patients with stable or decreased EI at first follow-up as opposed to 5.6 months (IQR 2.5-10.5) for those with an increase in the EI (HR 1.08, 95% CI 0.937-1.243; p = 0.300). DISCUSSION: The EI at baseline is prognostic in LM. An increase of EI during follow-up may be associated with inferior LM progression-free survival. Independent validation cohorts with larger sample size and evaluation of confounding factors will help to better define the clinical utility of EI assessments in LM.

The efficacy of slow-rate ventriculolumbar perfusion chemotherapy for leptomeningeal carcinomatosis: a phase II study.

PURPOSE: This study aimed to evaluate the symptomatic response and side effects of ventriculolumbar perfusion (VLP) methotrexate chemotherapy with a low perfusion rate in patients with leptomeningeal metastasis. METHODS: Patients in a single-arm, two-stage phase II trial based on Simon's minimax design received VLP with a reduced (15 cc/h) perfusion rate with the purpose of decreasing constitutional side effects such as nausea/vomiting, insomnia, and confusion. The primary outcome was control of increased intracranial pressure (ICP). The secondary outcome was an occurrence of side effects. The results were compared with those of a previous trial of VLP with a 20-cc/h perfusion rate. RESULTS: Total 90 patients were enrolled. Out of 65 patients with increased ICP, 32 achieved normalized ICP after VLP chemotherapy (bias-adjusted response rate = 51%). The incidence of moderate-to-severe nausea/vomiting was reduced to 46% from 64% in the previous study, and that of sleep disturbance was increased to 13% from 9%, but both failed to reach statistical significance. The incidence of moderate-to-severe confusion was significantly reduced to 12% from 23% in the previous study (p = 0.04). Median overall survival was better among patients with controlled ICP than among those who remained with increased ICP (193 days vs. 94 days, p = 0.013). CONCLUSION: Compared with a higher perfusion rate, the low perfusion rate failed to provide non-inferior ICP control or improved side effects, except for confusion. The relationship between VLP perfusion rate and ICP control needs to be evaluated in future trials adjusting for bias from uncompleted protocol due to poor general condition.

A Retrospective Real-World Study of Prognostic Factors Associated With EGFR Mutated Lung Cancer With Leptomeningeal Metastasis.

OBJECTIVE: To analyze the factors associated with EGFR-mutated lung cancer with leptomeningeal metastasis (LM) in the real world that affects the prognosis of patients. MATERIALS AND METHODS: The clinical data of 123 patients with advanced EGFR mutated lung cancer combined with LM treated at Henan Cancer Hospital and confirmed by histology between January 2016 and December 2020 were retrospectively collected, and all patients were followed up until September 2021. Analyze the median overall survival (mOS) time of patients with clinical characteristics and treatment factors to explore the factors influencing the prognosis of lung cancer patients with LM. RESULTS: A total of 123 patients with EGFR-mutated lung cancer and LM were included in this study. Overall, patients with exon 19 deletion (19del) in the classical mutation of the EGFR gene had a prolonged mOS compared to patients with exon 21 L858R mutation (21L858R) (30.1 months vs. 26.0 months); patients with primary LM (mOS 21.2 months) had a significantly shorter mOS than those with secondary LM (mOS 28.3 months); mOS was also significantly shorter in patients with combined brain metastases (mOS of 25.4 months) than in patients without combined brain metastases (mOS of 33.4 months); Patients treated with tyrosine kinase inhibitors (TKI) combined with antiangiogenic therapy (bevacizumab) experienced delayed onset of LM (mOS1: 19.4 months vs. 13.9 months), and prolonged survival after LM compared with those treated with EGFR-TKI alone (mOS2: 14.5 months vs. 10.0 months); There is no survival benefit to the patients treated with EGFR-TKI combined with chemotherapy compared to the patients treated with EGFR-TKI alone. CONCLUSION: Among NSCLC-LM patients with EGFR mutation, receiving EGFR-TKI combined with antiangiogenic therapy may result in a better survival benefit. The factors of primary LM, combined brain metastasis may be prognostic factors for poor OS.

Efficacy and safety of intrathecal pemetrexed for TKI-failed leptomeningeal metastases from EGFR+ NSCLC: an expanded, single-arm, phase II clinical trial.

BACKGROUND: This study aimed to evaluate the efficacy and safety of intrathecal pemetrexed (IP) for treating patients with leptomeningeal metastases (LM) from non-small-cell lung cancer (NSCLC) who progressed from epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor (TKI) treatment in an expanded, prospective, single-arm, phase II clinical study (ChiCTR1800016615). PATIENTS AND METHODS: Patients with confirmed NSCLC-LM who progressed from TKI received IP (50 mg, day 1/day 5 for 1 week, then every 3 weeks for four cycles, and then once monthly) until disease progression or intolerance. Objectives were to assess overall survival (OS), response rate, and safety. Measurable lesions were assessed by investigator according to RECIST version 1.1. LM were assessed according to the Response Assessment in Neuro-Oncology (RANO) criteria. RESULTS: The study included 132 patients; 68% were female and median age was 52 years (31-74 years). The median OS was 12 months (95% confidence interval 10.4-13.6 months), RANO-assessed response rate was 80.3% (106/132), and the most common adverse event was myelosuppression (n = 42; 31.8%), which reversed after symptomatic treatment. The results of subgroup analysis showed that absence of brain parenchymal metastasis, good Eastern Cooperative Oncology Group score, good response to IP treatment, negative cytology after treatment, and patients without neck/back pain/difficult defecation had longer survival. Gender, age, previous intrathecal methotrexate/cytarabine, and whole-brain radiotherapy had no significant influence on OS. CONCLUSIONS: This study further showed that IP is an effective and safe treatment method for the EGFR-TKI-failed NSCLC-LM, and should be recommended for these patients in clinical practice and guidelines.

Effectiveness of high-dose third-generation EGFR-tyrosine kinase inhibitors in treating EGFR-mutated non-small cell lung cancer patients with leptomeningeal metastasis.

BACKGROUND: Leptomeningeal metastasis (LM) is associated with an extremely poor prognosis in patients with epidermal growth factor receptor (EGFR)-mutated non-small cell lung cancer (NSCLC). The third-generation EGFR-tyrosine kinase inhibitors (TKIs), currently the preferred drug of choice, have significantly improved treatment outcomes in these patients. However, the optimal dose of third-generation EGFR-TKIs for clinical use remains undetermined in NSCLC patients with LM. METHODS: We retrospectively analyzed the clinical characteristics and treatment outcomes of 105 patients with EGFR-mutated NSCLC and cytologically confirmed LM who had received third-generation EGFR-TKI treatment after LM diagnosis. Patients were stratified into high- and standard-dose groups based on the treatment dose of third-generation EGFR-TKI. Subsequent treatments for LM were collected, particularly the efficacy of different doses of third-generation EGFR-targeted drugs. RESULTS: The median follow-up period was 28.7 months (range 0.6-40.2) at the cut-off date of August 27, 2023. The 105 included patients who received third-generation EGFR-TKI treatment had a clinical response rate (CRR) of 54.3 % (57/105), and the median overall survival (OS) from LM diagnosis was 12.3 months (95 % confidence interval [CI] = 10.0-15.0). Among them, 46 (43.8 %) patients received a high-dose regimen, and the remaining 59 (56.2 %) patients were treated with standard-dose drugs. Patients treated with high-dose third-generation EGFR-TKIs showed a higher CRR and longer OS than those treated with standard-dose therapy (65.2 % vs. 45.8 %, p = 0.047; 15.0 vs. 10.2 months, p = 0.014). Importantly, high-dose third-generation EGFR-TKI showed superior OS than standard-dose treatment in all subgroups (prior first-/second-generation EGFR-TKI resistance group, 19.5 vs. 9.8 months, p = 0.047; third-generation EGFR-TKI resistance group, 10.0 vs. 4.3 months, p = 0.045; EGFR-TKI naive group, not reach vs. 15.6 months, p = 0.031). Multivariate analysis revealed that high-dose third-generation EGFR-TKIs, intrathecal chemotherapy, previous TKI treatment history, and Karnofsky Performance Status score were independent predictors of OS (all p < 0.05). CONCLUSIONS: High-dose third-generation EGFR-TKIs are effective treatments for NSCLC patients with EGFR mutations and LM, regardless of previous EGFR-TKI exposure.