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

High-dose furmonertinib combined with intraventricular chemotherapy as salvage therapy for leptomeningeal metastasis from EGFR exon 20 insertion-mutated lung cancer | 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 High-dose furmonertinib combined with intraventricular chemotherapy as salvage therapy for leptomeningeal metastasis from EGFR exon 20 insertion-mutated lung cancer Chuanyong Yu, Ting Xu, Hehui Fang, Xiaoyue Wang, Na Liu, Liangfeng Yang, and 1 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-4301016/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 25 Jun, 2024 Read the published version in Journal of Neuro-Oncology → Version 1 posted 10 You are reading this latest preprint version Abstract 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. Furmonertinib Leptomeningeal metastasis EGFR ex20ins NSCLC Intraventricular chemotherapy Figures Figure 3 Background Leptomeningeal metastasis (LM), a severe complication of advanced non-small cell lung cancer (NSCLC), is characterized by cancer cell infiltration into the cerebrospinal fluid and leptomeninges. Unfortunately, no standard treatment strategies are currently available for LM due to the paucity of clinical studies. LM has been increasing in prevalence, occurring in up to 10% of patients with advanced NSCLC carrying epidermal growth factor receptor (EGFR) mutations [1]. Yang et al. also found that LMs occurred more frequently in tumors with EGFR mutations (9.4%) than in those with wild-type EGFR (1.7%) [2]. Although the mechanisms underlying the increased frequency of LM in patients with EGFR mutations are multifaceted, increased survival and inadequate blood brain barrier (BBB) penetration might be the primary reasons. EGFR exon 20 insertion (EGFR ex20ins) is the third most common EGFR mutation, accounting for approximately 4%–10% of EGFR mutations, and is generally resistant to EGFR tyrosine kinase inhibitors (TKIs) approved for their treatment [3]. Although various novel targeted therapies for EGFR ex20ins mutations are currently under clinical investigation, no approved targeted therapies have yet been developed. Platinum-based doublet chemotherapy remains the standard first-line treatment for patients with EGFR ex20ins, followed by amivantamab as second-line treatment [4]. However, given the lack of detailed reports on LM with EGFR ex20ins mutations, its incidence, optimal therapy, and prognosis in these patients remain unclear. Hence, a tolerable regimen with satisfactory clinical activity is urgently needed for patients with LM, especially those harboring EGFR ex20ins, which has been associated with a dismal prognosis. The current study evaluated the efficacy and safety of high-dose furmonertinib plus intraventricular chemotherapy (IVC) with pemetrexed as later-line treatment for patients with LM harboring EGFR ex20ins. Patients and Methods Patients We retrospectively reviewed patients who were treated at the Nanjing Chest Hospital from May 2011 to June 2023. Advanced NSCLC with LM was diagnosed based on the EANO-ESMO criteria [5]. The inclusion criteria were advanced NSCLC with LM harboring EGFR ex20ins. The following general information of the enrolled patients was extracted: sex, age, smoking history, histological subtype, Eastern Cooperative Oncology Group (ECOG) performance status (PS) score, gene features, and history of treatments. Genomic profiling Approximately 15 mL of cerebrospinal fluid (CSF) was obtained from each patient through Ommaya reservoir upon establishing a diagnosis of LM. Next-generation sequencing of CSF and matched plasma circulating tumor DNA (ctDNA) was performed using 1100-gene targeted panel. DNA extraction, sequencing library preparation, and Illumina sequencing were performed as previously described [6]. We assessed all classes of genomic alterations, including single base substitution (SNV), insertions/deletions, copy number variants, and gene rearrangement and fusions. For all patients diagnosed with LM, genetic status was also determined through next-generation sequencing prior to IVC. Treatment strategy Combination therapy comprising furmonertinib (160 mg daily) and IVC was administrated to the patients. All patients underwent stereotactic installation of an Ommaya reservoir (Medtronic Inc). IVC via the Ommaya reservoir was started the day after surgery. Treatment regimens were as follows: (1) the consolidation phase wherein the patients received intraventricular injection chemotherapy of 30 mg pemetrexed (Lilly Pharmaceuticals) and 5 mg dexamethasone twice weekly for 2 weeks; (2) the maintenance phase wherein treatment was repeated every 3 to 4 weeks until disease progression or unacceptable toxicity, or patient refusal occurred. During the treatment period, all patients receive folic acid (1,000 μg, qd, po) and vitamin B12 (1,000 μg, intramuscular injection prior to the pemetrexed and repeated every 9 weeks) to avoid adverse reactions to pemetrexed. Response evaluation and follow-ups The LM response assessment was documented according to the modified Response Assessment in Neurooncology (RANO)-LM radiological criteria, which are based on three basic elements: standardized neurological examination, CSF cytology, and imaging evaluation [7]. Responses of extracranial and brain parenchymal lesions were evaluated according to Response Evaluation Criteria in Solid Tumors (RECIST). Toxicities were assessed using the Common Toxicity Criteria for Adverse Events. Statistical analysis Intracranial progression-free survival (iPFS) was defined as period from the start of treatment until LM disease progression or death. Overall survival (OS) was defined as the period from the start of treatment for LM to death for any reason. The last follow-up was December 2023. All statistical analyses were performed using SPSS 21 software. Survival analyses were performed using Kaplan–Meier estimates with 95% CIs. Objective response rate (ORR) and disease control rate (DCR) were calculated at a 95% confidence level. A P value <.05 indicated was considered statistical significance. Results Patient characteristics Among the 176 patients with LM reviewed, 10 with NSCLC harboring EGFR ex20ins mutations were eventually enrolled (Figure 1). The patients’ baseline characteristics are summarized in Table 1. Notably, the 10 patients, 6 of whom were males, were never smokers and were 39 to 66 years of age at the time of LM diagnosis. All patients were diagnosed with adenocarcinoma and had poor ECOG PS score (3 to 4). All patients had LM while showing bone metastasis, with 6 patients being accompanied by brain parenchymal metastasis. Headache, nausea, and vomiting due to intracranial hypertension were the most common symptoms. The median number of systemic anticancer therapy lines was 5 (range, 3–10). All patients had undergone previous systemic chemotherapy and antiangiogenic treatment, with 7 receiving TKI treatment, 6 receiving immunotherapy, and 4 receiving whole-brain radiotherapy (WBRT) (Table 2). Genomic profile analysis The most prevalent insertion mutation was p.A767_V769dup (n = 4, 40%), followed by D770-N771insY (n = 2, 20%). Moreover, 9 patients developed EGFR ex20ins in the EGFR loop region following the C-helix, whereas only 1 patient (NO.3) developed EGFR ex20ins (A763_Y764insFQEA) in the C-helix of the tyrosine kinase domain (Figure 2A). Comutation analysis showed that TP53 was the most common mutant gene in NSCLC patients with EGFR ex20ins (n = 6, 60%) (Figure 2B). Clinical outcomes Clinical responses are detailed in Table 3. A total of 90% (9/10) of the patients experienced a decrease in PS and RANO scores after treatments compared to baseline. Symptom assessment and neurological examination showed that 9 (90%) patients achieved improvement, whereas 1 (10%) experienced deterioration. CSF cytology showed negative results after treatment in 6 (60%) patients. Cranial magnetic resonance imaging (MRI) in all patients revealed that 2 (20%) experienced improvement, 7 (70%) remained stable, and only 1 (10%) experienced worsening. Figure 3 presents the significant changes in the cranial MRI of two patients before and after treatment. At the cutoff for data analysis (December 2023), the median follow-up duration was 9.3 months. LM response assessment based on the RANO-LM criteria revealed that 6 patients (60%, 95% CI, 26.2–87.8%) achieved a response, whereas 3 and 1 demonstrated stable disease (SD) and progressive disease (PD), respectively. Assessment of tumor response to systemic therapy according to the RECIST criteria revealed a ORR of 40.0% with 4 patients achieving partial response (PR) (n = 4, 95% CI, 12.2%–73.8%), and a DCR of 100% (n = 10, 95% CI, 69.2%–100%). The median iPFS was estimated to be 6.5 (95% CI, 2.2–10.8) months. At the cutoff for data analysis, 5 patients (50%) succumb to their disease, with a median OS of 8.8 (95% CI, 3.4–14.2) months (Figure 4). Toxicity The most frequent treatment-related adverse events (TRAEs) were rash and diarrhea (both 70%), followed by oral ulcer (20%), anorexia (10%), nausea (10%), and elevated transaminase (10%). Only 2 patients had grade 3 or over TRAEs, namely nausea and rash. None of our patients experienced grade 5 TRAEs. Discussion Evidence has shown that NSCLC patients with EGFR mutations are predisposed to developing LM, a devastating complication associated with high incidence rates and symptoms of cerebral nerve compression. However, only a limited number of clinical trials have been available on LM patients with EGFR mutations who have failed multiline therapy, particularly those with EGFR ex20ins mutations. The present study evaluated the effects of a new treatment regimen that combines high-dose furmonertinib with IVC as salvage treatment for 10 LM patients with EGFR ex20ins after multiline treatment failures. Our results have been extremely encouraging as evidence by a median iPFS and OS of 6.5 and 8.8 months, respectively, 2 patients surviving for 10.5 and 10.3+ months, and manageable toxic side effects. Patients with NSCLC with EGFR ex20ins are usually resistant to EGFR-TKIs due to steric hindrance affecting TKI binding. As such, platinum-based chemotherapy had been the standard first-line treatment until recently. Studies have shown that EGFR ex20ins NSCLC patients undergoing first-line chemotherapy had an ORR of 30.95%–41.56% and median PFS of 5.5–6.4 months [8]. Nevertheless, individuals with central nervous system (CNS) metastases experience lesser benefits from first-line chemotherapy than do individuals without brain involvement. Immune checkpoint inhibitors (ICIs) have also been found to be ineffective in this population. In fact, one study showed that immunotherapy as first-line treatment produced an ORR of only 9.1% and a PFS of 3.1 months, whereas immunotherapy combined with chemotherapy produced an ORR of 18.8% and a PFS of 4.5 months [9]. Similarly, the latest observational study based on real-world data revealed that this subset of patients might not benefit from chemotherapy combined with ICIs [10]. Considerable obstacles have hindered the treatment of EGFR ex20ins-positive NSCLC patients who experience limited benefits from chemotherapy, EGFR-TKIs, and immunotherapy. The approval of novel EGFR ex20ins-targeting drugs, such as amivantamab and mobocertinib, for the treatment of NSCLC patient who have failed platinum chemotherapy offers renewed optimism for patients with EGFR ex20ins mutations. Amivantamab, a larger monoclonal antibody, often has difficulty crossing the BBB and is therefore typically expected to have low CNS activity [11]. Furthermore, given that patients with active brain metastases were excluded from the CHRYSALIS study, assessing the CNS activity of amivantamab was not possible [12]. Unfortunately, mobocertinib, which underwent global delisting due to unsatisfactory first-line treatment results, may have limited intracranial activity. To evaluate the intracranial activity of mobocertinib, a phase 1/2 open-label clinical trial used rates of first-site disease progression in the brain [13]. Their results demonstrated that the brain was primary site of disease progression in 38% (22/58) of all PD patients and 68% (17/25) of PD patients with brain metastases at baseline. Moreover, real-world studies have shown that mobocertinib possessed limited intracranial activity, with a median treatment duration of 5.4 and 14.8 months for patients with and without baseline brain metastases, respectively [14]. Furmonertinib is a novel third-generation, highly brain-penetrant, pan-EGFR mutation inhibitor targeting both EGFR-sensitizing mutations and T790M mutation. In fact, one retrospective study showed that high-dose furmonertinib as salvage therapy exhibited remarkable efficacy and safety for EGFR-positive advanced NSCLC patients who developed LM progression from prior EGFR-TKI treatment [15]. In addition, preclinical and clinical data have shown that high-dose furmonertinib had an encouraging antitumor activity in NSCLC with EGFR ex20ins mutations [16]. Another real-world study found that furmonertinib treatment in 53 patients with advanced NSCLC harboring EGFR ex20ins mutations produced an overall ORR of 37.7% and DCR of 92.5%. Furthermore, patients with brain metastases at baseline responded similarly to those without brain metastases (33.3% vs. 40.6%; P = 0.773) [17]. Our results presented in the current study echo those reported in the aforementioned reports. Accordingly, our results showed that patients with LM receiving 160 mg/day of furmonertinib had an ORR and DCR of 40% and 100%, respectively. However, the LM-ORR reached as high as 60% when furmonertinib was combined with IVC as a local treatment. Evading the BBB through subarachnoid administration is essential in the management of LM. Chemotherapeutic agents can be delivered into the subarachnoid space using two methods, one by a subgaleal reservoir system and the other by lumbar puncture (LP). Compared to LP, IVC via the reservoir system is more comfortable for patients, promotes more uniform drug distribution throughout the intrathecal space, and ensures more consistent drug levels in the CSF [18, 19]. Moreover, studies have shown that disorders in CSF flow promoted increased intracranial pressure and obstructed drug distribution, resulting in ineffective intrathecal chemotherapy via LP. IVC via the Ommaya reservoir, which is less affected by impaired CSF circulation, promoted a decrease in intracranial pressure and improvement in altered mental status [20, 21]. In terms of survival, considerable evidence suggests that intraventricular administration via the Ommaya reservoir was superior to LP. For example, one previous study demonstrated that IVC promoted significantly better OS than did LP chemotherapy administration (9.2 vs. 4 months; P = 0.0006) [22]. Another retrospective study involving 108 NSCLC patients with LM showed that IVC can prolong survival time. Moreover, the group that received systemic chemotherapy and EGFR-TKI treatment in addition to IVC achieved the longest survival benefit, with a survival of 15.8 months [23], which could explain the superior survival benefits observed in the current study. Conclusion Overall, the present study showed that the combination of high-dose furmonertinib and IVC could be a promising treatment option for EGFR ex20ins NSCLC after multiline treatment failure, highlighting the need for further large-scale prospective trials. Abbreviations Leptomeningeal metastasis LM Non-small cell lung cancer NSCLC Epidermal growth factor receptor EGFR EGFR exon 20 insertion EGFR ex20ins Circulating tumor DNA ctDNA Cerebrospinal fluid CSF Intraventricular chemotherapy IVC tyrosine kinase inhibitors TKIs Eastern Cooperative Oncology Group ECOG Performance status PS Intracranial progression-free survival iPFS Overall survival OS Objective response rate ORR Disease control rate DCR Whole-brain radiotherapy WBRT Magnetic resonance imaging MRI Central nervous system CNS Blood brain barrier BBB Declarations Author Contributions All authors contributed to the study conception and design. Data acquiring and analyzing were performed by YCY, XT and FSC; YCY, WXY, LN and YLF contributed to writing—original draft preparation; YZ, YLZ, YYL, LLY and JL contributed to Investigation; FSC contributed to project administration and acquired funding. All authors have read and approved the final manuscript. Funding This work was supported by Norman Bethune Specialized Research Fund(HSKY-021) Data availability The data (deidentified patients data, informed consent forms, clinical study report) that support the findings of this study are available on request from the corresponding author after publication,after providing a methodologically sound proposal. Declarations Conflict of interest All authors declare no conflict of interest in respect of this manuscript. Ethics approval This study was performed in line with the principles of the Declaration of Helsinki. Approval was granted by the Ethics Committee of the Nanjing Chest Hospital (2023-KL023-02). Consent to participate Written informed consent was obtained from all participants before enrolment. References Li YS, Jiang BY, Yang JJ, Tu HY, Zhou Q, Guo WB, Yan HH, Wu YL (2016) Leptomeningeal Metastases in Patients with NSCLC with EGFR Mutations. 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Patient characteristics No. Age (years) Sex Tumor history (months) Accompanying BM Extracranial lesions Neurological symptoms 1 54 Male 12 yes Bone Dizziness, headache, nausea, and vomiting 2 42 Female 10 no Bone and lung Dizziness, headache, gait disorder, and vomiting 3 65 Male 50 no Bone Dizziness, headache 4 49 Male 37 yes Bone and peritoneum Dizziness, headache, and mental retardation 5 53 Male 7 yes Bone Dizziness and headache 6 57 Female 42 no Bone Headache and nausea 7 51 Male 30 yes Bone Dizziness, headache, nausea, and vomiting 8 66 Female 70 yes Bone Headache 9 66 Female 16 yes Bone Headache, nausea, and vomiting 10 39 Male 20 yes Bone Headache BM Brain metastasis Table 2. Summary of the treatment history in all 10 patients No. Treatment line WBRT Chemotherapy Antiangiogenic therapy EGFR-TKI treatment Immunotherapy 1 4 No Yes Yes Osimertinib No 2 4 No Yes Yes No Yes 3 5 No Yes Yes Afatinib No 4 6 No Yes Yes Afatinib Yes 5 3 yes Yes Yes No No 6 4 No Yes Yes Osimertinib Yes 7 7 yes Yes Yes No Yes 8 10 yes Yes Yes Mobocertinib and furmonertinib Yes 9 5 No Yes Yes Mobocertinib Yes 10 5 yes Yes Yes Osimertinib No WBRT Whole-brain radiotherapy; EGFR-TKI Epidermal growth factor receptor tyrosine kinase inhibitors Table 3. Summary of the treatments and clinical responses No. PS score RANO score Neurological exam Symptom assessment CSF cytology CNS imaging LM response assessment Systemic response assessment Pretreatments Posttreatments Pretreatments Posttreatments 1 4 2 16 8 Improved Improved Negative Stable Response SD 2 3 2 6 2 Improved Improved Negative stable Response SD 3 3 2 10 5 Improved Improved Negative Improved Response PR 4 4 3 12 8 Improved Improved Positive Improved SD SD 5 3 2 9 6 Stable Improved Positive Stable SD SD 6 4 1 6 1 Improved Improved Negative Stable Response PR 7 4 1 12 2 Improved Improved Negative Stable Response PR 8 4 3 17 12 Improved Improved Positive Stable SD SD 9 4 4 18 18 Stable Stable Positive Worse PD SD 10 3 1 6 1 Improved Improved Negative Stable Response SD PS Performance status; RANO Response Assessment in Neurooncology; CSF Cerebrospinal fluid; CNS Central nervous system; LM Leptomeningeal metastasis; SD stable disease; PR Partial response; PD Progressive disease Table 4. Toxicities and adverse events. No. Grade 1 Grade 2 Grade 3 Grade 4 1 Rash Diarrhea 2 Rash Diarrhea 3 Rash and Oral ulcer 4 Diarrhea Anorexia Nausea Rash 5 Rash Oral ulcer 6 Diarrhea 7 Oral ulcer 8 Rash Diarrhea 9 Elevated transaminase Diarrhea 10 Diarrhea Rash Additional Declarations No competing interests reported. Cite Share Download PDF Status: Published Journal Publication published 25 Jun, 2024 Read the published version in Journal of Neuro-Oncology → Version 1 posted Editorial decision: Revision requested 11 May, 2024 Reviews received at journal 09 May, 2024 Reviews received at journal 04 May, 2024 Reviewers agreed at journal 29 Apr, 2024 Reviewers agreed at journal 29 Apr, 2024 Reviewers agreed at journal 24 Apr, 2024 Reviewers invited by journal 22 Apr, 2024 Editor assigned by journal 22 Apr, 2024 Submission checks completed at journal 22 Apr, 2024 First submitted to journal 21 Apr, 2024 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. 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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-4301016","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Case Report","associatedPublications":[],"authors":[{"id":295175172,"identity":"12343430-00f3-4bb6-b167-d1810d802215","order_by":0,"name":"Chuanyong Yu","email":"","orcid":"","institution":"The Affiliated Brain Hospital of Nanjing Medical University","correspondingAuthor":false,"prefix":"","firstName":"Chuanyong","middleName":"","lastName":"Yu","suffix":""},{"id":295175174,"identity":"feed9aec-15e7-418f-b0e2-132fb71a621b","order_by":1,"name":"Ting Xu","email":"","orcid":"","institution":"Nanjing Chest hospital, The Affiliated Brain Hospital of Nanjing Medical University","correspondingAuthor":false,"prefix":"","firstName":"Ting","middleName":"","lastName":"Xu","suffix":""},{"id":295175176,"identity":"89c2f629-1181-4966-bf81-e3e72b988453","order_by":2,"name":"Hehui Fang","email":"","orcid":"","institution":"Nanjing Chest hospital, The Affiliated Brain Hospital of Nanjing Medical University","correspondingAuthor":false,"prefix":"","firstName":"Hehui","middleName":"","lastName":"Fang","suffix":""},{"id":295175178,"identity":"251c6bd3-eccb-4899-abb2-3bed4219f2a0","order_by":3,"name":"Xiaoyue Wang","email":"","orcid":"","institution":"Nanjing Chest hospital, The Affiliated Brain Hospital of Nanjing Medical University","correspondingAuthor":false,"prefix":"","firstName":"Xiaoyue","middleName":"","lastName":"Wang","suffix":""},{"id":295175180,"identity":"a597a5fa-8320-46b4-86ca-0f7d77849f70","order_by":4,"name":"Na Liu","email":"","orcid":"","institution":"Nanjing Chest hospital, The Affiliated Brain Hospital of Nanjing Medical University","correspondingAuthor":false,"prefix":"","firstName":"Na","middleName":"","lastName":"Liu","suffix":""},{"id":295175182,"identity":"354a5976-bd85-4192-ba36-f5a846820103","order_by":5,"name":"Liangfeng Yang","email":"","orcid":"","institution":"Nanjing Gaochun People's Hospital","correspondingAuthor":false,"prefix":"","firstName":"Liangfeng","middleName":"","lastName":"Yang","suffix":""},{"id":295175183,"identity":"af2e27a5-a719-463a-8dcf-9857ff37d8eb","order_by":6,"name":"Shencun Fang","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA30lEQVRIiWNgGAWjYBAC9gYgkVBhw8zPwNxwgCgtPCBlD86ksUs2MJKghfFh22F+gwOMDcQ5jIf97OEXiW1p0sbHDzYe5m27w8Df3p2AXwtPXppFwjkbY7MziQ1ALc8YJM6c3YBXiz1DjplBQllastkBsJbDDAYSufi18PC/AWphO1y/uf8hsVokcowfJLQdZjaQINoWiTdmDAln0pglbjxsODjn3GEegn7h4c8x/vgDFJX9yYc/vCk7LMff3otfCxCwScBYTDxAMwgpBwHmDzAW4w9i1I+CUTAKRsGIAwDvmU9K4vgF+wAAAABJRU5ErkJggg==","orcid":"","institution":"Nanjing Chest hospital, The Affiliated Brain Hospital of Nanjing Medical University","correspondingAuthor":true,"prefix":"","firstName":"Shencun","middleName":"","lastName":"Fang","suffix":""}],"badges":[],"createdAt":"2024-04-21 13:56:47","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-4301016/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-4301016/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1007/s11060-024-04716-0","type":"published","date":"2024-06-25T10:18:14+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":55530592,"identity":"df9c93f8-e065-4bc8-80a9-79eed353e060","added_by":"auto","created_at":"2024-04-29 15:38:01","extension":"jpg","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":143066,"visible":true,"origin":"","legend":"\u003cp\u003eComparison of contrast-enhanced cranial magnetic resonance imaging (MRI) scans before and after treatment in two patients. (A) Cranial MRI of case 3 showing extensive linear enhancement on the leptomeninges of the brain and cerebellum before treatment. (B) The linear enhancement lesions in case 3 completely disappeared after 2 months of treatment. (C) Cranial MRI of case 6 showing extensive linear and patchy enhancement on the leptomeninges before treatment. (D) Most of the linear and patchy enhancement lesions in case 6 disappeared after 2 months of treatment.\u003c/p\u003e","description":"","filename":"Fig3.jpg","url":"https://assets-eu.researchsquare.com/files/rs-4301016/v1/940fbb5dc79050246781f66b.jpg"},{"id":60987007,"identity":"966aa009-e785-423d-9d10-38f21bccd0d1","added_by":"auto","created_at":"2024-07-24 10:18:18","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":764329,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-4301016/v1/fbaa8451-dde5-470b-b917-27d7c8d4c2af.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"High-dose furmonertinib combined with intraventricular chemotherapy as salvage therapy for leptomeningeal metastasis from EGFR exon 20 insertion-mutated lung cancer","fulltext":[{"header":"Background","content":"\u003cp\u003eLeptomeningeal metastasis (LM), a severe complication of advanced non-small cell lung cancer (NSCLC), is characterized by cancer cell infiltration into the cerebrospinal fluid and leptomeninges. Unfortunately, no standard treatment strategies are currently available for LM due to the paucity of clinical studies. LM has been increasing in prevalence, occurring in up to 10% of patients with advanced NSCLC carrying epidermal growth factor receptor (EGFR) mutations [1].\u0026nbsp;Yang et al. also found that LMs occurred more frequently in tumors with \u003cem\u003eEGFR\u003c/em\u003e mutations (9.4%) than in those with wild-type \u003cem\u003eEGFR\u003c/em\u003e (1.7%) [2]. Although the mechanisms underlying the increased frequency of LM in patients with EGFR mutations are multifaceted, increased survival and inadequate blood brain barrier (BBB) penetration might be the primary reasons. EGFR exon 20 insertion (EGFR ex20ins) is the third most common EGFR mutation, accounting for approximately 4%\u0026ndash;10% of EGFR mutations, and is generally resistant to EGFR tyrosine kinase inhibitors (TKIs) approved for their treatment [3]. Although various novel targeted therapies for EGFR ex20ins mutations are currently under clinical investigation, no approved targeted therapies have yet been developed. Platinum-based doublet chemotherapy remains the standard first-line treatment for patients with EGFR ex20ins, followed by amivantamab as second-line treatment [4]. However, given the lack of detailed reports on LM with EGFR ex20ins mutations, its incidence, optimal therapy, and prognosis in these patients remain unclear. Hence, a tolerable regimen with satisfactory clinical activity is urgently needed for patients with LM, especially those harboring EGFR ex20ins, which has been associated with a dismal prognosis. The current study evaluated the efficacy and safety of high-dose furmonertinib plus intraventricular chemotherapy (IVC) with pemetrexed as later-line treatment for patients with LM harboring EGFR ex20ins.\u003c/p\u003e"},{"header":"Patients and Methods","content":"\u003cp\u003ePatients\u003c/p\u003e\n\u003cp\u003eWe retrospectively reviewed patients who were treated at the Nanjing Chest Hospital from May 2011 to June 2023. Advanced NSCLC with LM was diagnosed based on the EANO-ESMO criteria [5]. The inclusion criteria were advanced NSCLC with LM harboring EGFR ex20ins. The following general information of the enrolled patients was extracted: sex, age, smoking history, histological subtype, Eastern Cooperative Oncology Group (ECOG) performance status (PS) score, gene features, and history of treatments.\u003c/p\u003e\n\u003cp\u003eGenomic profiling\u003c/p\u003e\n\u003cp\u003eApproximately 15 mL of cerebrospinal fluid (CSF) was obtained from each patient through Ommaya reservoir upon establishing a diagnosis of LM. Next-generation sequencing of CSF and matched plasma circulating tumor DNA (ctDNA) was performed using\u0026nbsp;1100-gene targeted panel. DNA extraction, sequencing library preparation, and Illumina sequencing were performed as previously described [6]. We assessed all classes of genomic alterations, including single base substitution (SNV), insertions/deletions, copy number variants, and gene rearrangement and fusions. For all patients diagnosed with LM, genetic status was also determined through next-generation sequencing prior to IVC.\u003c/p\u003e\n\u003cp\u003eTreatment strategy\u003c/p\u003e\n\u003cp\u003eCombination therapy comprising \u003ca href=\"http://www.baidu.com/link?url=7U6GpglScQBjTNMlTqB816qxoLFAK_EALuk_hD1_keS6KDMMXiRmpkBoB_zSMXFy70-SjeIb4-5nmRUyCAjtWa\" target=\"https://www.baidu.com/_blank\"\u003efurmonertinib\u003c/a\u003e (160 mg daily) and IVC was administrated to the patients. All patients underwent stereotactic installation of an Ommaya reservoir (Medtronic Inc). IVC via the Ommaya reservoir was started the day after surgery. Treatment regimens were as follows: (1) the consolidation phase wherein the patients received intraventricular injection chemotherapy of 30 mg pemetrexed (Lilly Pharmaceuticals) and 5 mg dexamethasone twice weekly for 2 weeks; (2) the maintenance phase wherein treatment was repeated every 3 to 4 weeks until disease progression or unacceptable toxicity, or patient refusal occurred. During the treatment period, all patients receive folic acid (1,000 \u0026mu;g, qd, po) and vitamin B12 (1,000 \u0026mu;g, intramuscular injection prior to the pemetrexed and repeated every 9 weeks) to avoid adverse reactions to pemetrexed.\u003c/p\u003e\n\u003cp\u003eResponse evaluation and follow-ups\u003c/p\u003e\n\u003cp\u003eThe LM response assessment was documented according to the modified Response Assessment in Neurooncology (RANO)-LM radiological criteria, which are based on three basic elements: standardized neurological examination, CSF cytology, and imaging evaluation [7]. Responses of extracranial and brain parenchymal lesions were evaluated according to Response Evaluation Criteria in Solid Tumors (RECIST). Toxicities were assessed using the Common Toxicity Criteria for Adverse Events.\u003c/p\u003e\n\u003cp\u003eStatistical analysis\u003c/p\u003e\n\u003cp\u003eIntracranial progression-free survival (iPFS) was defined as period from the start of treatment until LM disease progression or death. Overall survival (OS) was defined as the period from the start of treatment for LM to death for any reason. The last follow-up was December 2023. All statistical analyses were performed using SPSS 21 software. Survival analyses were performed using Kaplan\u0026ndash;Meier estimates with 95% CIs. Objective response rate (ORR) and disease control rate (DCR) were calculated at a 95% confidence level. A \u003cem\u003eP\u003c/em\u003e value \u0026lt;.05 indicated was considered statistical significance.\u003c/p\u003e"},{"header":"Results","content":"\u003cp\u003ePatient characteristics\u003c/p\u003e\n\u003cp\u003eAmong the 176 patients with LM reviewed, 10 with NSCLC harboring EGFR ex20ins mutations were eventually enrolled (Figure 1). The patients\u0026rsquo; baseline characteristics are summarized in Table 1. Notably, the 10 patients, 6 of whom were males, were never smokers and were 39 to 66 years of age at the time of LM diagnosis. All patients were diagnosed with adenocarcinoma and had poor ECOG PS score (3 to 4). All patients had LM while showing bone metastasis, with 6 patients being accompanied by brain parenchymal metastasis. Headache, nausea, and vomiting due to intracranial hypertension were the most common symptoms. The median number of systemic anticancer therapy lines was 5 (range, 3\u0026ndash;10). All patients had undergone previous systemic chemotherapy and antiangiogenic treatment, with 7 receiving TKI treatment, 6 receiving immunotherapy, and 4 receiving whole-brain radiotherapy (WBRT) (Table 2).\u003c/p\u003e\n\u003cp\u003eGenomic profile analysis\u003c/p\u003e\n\u003cp\u003eThe most prevalent insertion mutation was p.A767_V769dup (n = 4, 40%), followed by D770-N771insY (n = 2, 20%). Moreover, 9 patients developed EGFR ex20ins in the EGFR loop region following the C-helix, whereas only 1 patient (NO.3) developed EGFR ex20ins (A763_Y764insFQEA) in the C-helix of the tyrosine kinase domain (Figure 2A). Comutation analysis showed that TP53 was the most common mutant gene in NSCLC patients with EGFR ex20ins (n = 6, 60%) (Figure 2B).\u003c/p\u003e\n\u003cp\u003eClinical outcomes\u003c/p\u003e\n\u003cp\u003eClinical responses are detailed in Table 3. A total of 90% (9/10) of the patients experienced a decrease in PS and RANO scores after treatments compared to baseline. Symptom assessment and neurological examination showed that 9 (90%) patients achieved improvement, whereas 1 (10%) experienced deterioration. CSF cytology showed negative results after treatment in 6 (60%) patients. Cranial magnetic resonance imaging (MRI) in all patients revealed that 2 (20%) experienced improvement, 7 (70%) remained stable, and only 1 (10%) experienced worsening. Figure 3\u0026nbsp;presents the significant changes in the cranial MRI of two patients before and after treatment. At the cutoff for data analysis (December 2023), the median follow-up duration was 9.3 months. LM response assessment based on the RANO-LM criteria revealed that 6 patients (60%, 95% CI, 26.2\u0026ndash;87.8%) achieved a response, whereas 3 and 1 demonstrated stable disease (SD) and progressive disease (PD), respectively. Assessment of tumor response to systemic therapy according to the RECIST criteria revealed a ORR of 40.0% with 4 patients achieving partial response (PR) (n = 4, 95% CI, 12.2%\u0026ndash;73.8%), and a DCR of 100% (n = 10, 95% CI, 69.2%\u0026ndash;100%). The median iPFS was estimated to be 6.5 (95% CI, 2.2\u0026ndash;10.8) months. At the cutoff for data analysis, 5 patients (50%) succumb to their disease, with a median OS of 8.8 (95% CI, 3.4\u0026ndash;14.2) months (Figure 4).\u003c/p\u003e\n\u003cp\u003eToxicity\u003c/p\u003e\n\u003cp\u003eThe most frequent treatment-related adverse events (TRAEs) were rash and diarrhea (both 70%), followed by oral ulcer (20%), anorexia (10%), nausea (10%), and elevated transaminase (10%). Only 2 patients had grade 3 or over TRAEs, namely nausea and rash. None of our patients experienced grade 5 TRAEs.\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eEvidence has shown that NSCLC patients with EGFR mutations are predisposed to developing LM, a devastating complication associated with high incidence rates and symptoms of cerebral nerve compression. However, only a limited number of clinical trials have been available on LM patients with EGFR mutations who have failed multiline therapy, particularly those with EGFR ex20ins mutations. The present study evaluated the effects of a new treatment regimen that combines high-dose furmonertinib with IVC as salvage treatment for 10 LM patients with EGFR ex20ins after multiline treatment failures. Our results have been extremely encouraging as evidence by a median iPFS and OS of 6.5 and 8.8 months, respectively, 2 patients surviving for 10.5 and 10.3+ months, and manageable toxic side effects.\u003c/p\u003e\n\u003cp\u003ePatients with NSCLC with EGFR ex20ins are usually resistant to EGFR-TKIs due to steric hindrance affecting TKI binding. As such, platinum-based chemotherapy had been the standard first-line treatment until recently. Studies have shown that EGFR ex20ins NSCLC patients undergoing first-line chemotherapy had an ORR of 30.95%\u0026ndash;41.56% and median PFS of 5.5\u0026ndash;6.4 months [8]. Nevertheless, individuals with central nervous system (CNS) metastases experience lesser benefits from first-line chemotherapy than do individuals without brain involvement. Immune checkpoint inhibitors (ICIs) have also been found to be ineffective in this population. In fact, one study showed that immunotherapy as first-line treatment produced an ORR of only 9.1% and a PFS of 3.1 months, whereas immunotherapy combined with chemotherapy produced an ORR of 18.8% and a PFS of 4.5 months [9]. Similarly, the latest observational study based on real-world data revealed that this subset of patients might not benefit from chemotherapy combined with ICIs [10]. Considerable obstacles have hindered the treatment of EGFR ex20ins-positive NSCLC patients who experience limited benefits from chemotherapy, EGFR-TKIs, and immunotherapy.\u003c/p\u003e\n\u003cp\u003eThe approval of novel EGFR ex20ins-targeting drugs, such as amivantamab and mobocertinib, for the treatment of NSCLC patient who have failed platinum chemotherapy offers renewed optimism for patients with EGFR ex20ins mutations. Amivantamab, a larger monoclonal antibody, often has difficulty crossing the BBB and is therefore typically expected to have low CNS activity [11]. Furthermore, given that patients with active brain metastases were excluded from the CHRYSALIS study, assessing the CNS activity of amivantamab was not possible [12]. Unfortunately, mobocertinib, which underwent global delisting due to unsatisfactory first-line treatment results, may have limited intracranial activity. To evaluate the intracranial activity of mobocertinib, a phase 1/2 open-label clinical trial used rates of first-site disease progression in the brain [13]. Their results demonstrated that the brain was primary site of disease progression in 38% (22/58) of all PD patients and 68% (17/25) of PD patients with brain metastases at baseline. Moreover, real-world studies have shown that mobocertinib possessed limited intracranial activity, with a median treatment duration of 5.4 and 14.8 months for patients with and without baseline brain metastases, respectively [14].\u003c/p\u003e\n\u003cp\u003eFurmonertinib is a novel third-generation, highly brain-penetrant, pan-EGFR mutation inhibitor targeting both EGFR-sensitizing mutations and T790M mutation. In fact, one retrospective study showed that high-dose furmonertinib as salvage therapy exhibited remarkable efficacy and safety for EGFR-positive advanced NSCLC patients who developed LM progression from prior EGFR-TKI treatment\u0026nbsp;[15]. In addition, preclinical and clinical data have shown that high-dose furmonertinib had an encouraging antitumor activity in NSCLC with EGFR ex20ins mutations\u0026nbsp;[16]. Another real-world study found that furmonertinib treatment in 53 patients with advanced NSCLC harboring EGFR ex20ins mutations produced an overall ORR of 37.7% and DCR of 92.5%. Furthermore, patients with brain metastases at baseline responded similarly to those without brain metastases (33.3% vs. 40.6%; \u003cem\u003eP\u0026nbsp;\u003c/em\u003e= 0.773)\u0026nbsp;[17]. Our results presented in the current study echo those reported in the aforementioned reports. Accordingly, our results showed that patients with LM receiving 160 mg/day of furmonertinib had an ORR and DCR of 40% and 100%, respectively. However, the LM-ORR reached as high as 60% when furmonertinib was combined with IVC as a local treatment.\u003c/p\u003e\n\u003cp\u003eEvading the BBB through subarachnoid administration is essential in the management of LM. Chemotherapeutic agents can be delivered into the subarachnoid space using two methods, one by a subgaleal reservoir system and the other by lumbar puncture (LP). Compared to LP, IVC via the reservoir system is more comfortable for patients, promotes more uniform drug distribution throughout the intrathecal space, and ensures more consistent drug levels in the CSF [18, 19]. Moreover, studies have shown that disorders in CSF flow promoted increased intracranial pressure and obstructed drug distribution, resulting in ineffective intrathecal chemotherapy via LP. IVC via the Ommaya reservoir, which is less affected by impaired CSF circulation, promoted a decrease in intracranial pressure and improvement in altered mental status [20, 21]. In terms of survival, considerable evidence suggests that intraventricular administration via the Ommaya reservoir was superior to LP. For example, one previous study demonstrated that IVC promoted significantly better OS than did LP chemotherapy administration\u0026nbsp;(9.2 vs. 4 months; \u003cem\u003eP\u003c/em\u003e = 0.0006) [22]. Another retrospective study involving 108 NSCLC patients with LM showed that IVC can prolong survival time. Moreover, the group that received systemic chemotherapy and EGFR-TKI treatment in addition to IVC achieved the longest survival benefit, with a survival of 15.8 months [23], which could explain the superior survival benefits observed in the current study.\u003c/p\u003e"},{"header":"Conclusion","content":"\u003cp\u003eOverall, the present study showed that the combination of high-dose furmonertinib and IVC could be a promising treatment option for EGFR ex20ins NSCLC after multiline treatment failure, highlighting the need for further large-scale prospective trials.\u003c/p\u003e\n\u003cp\u003e\u003cbr\u003e\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003ctable border=\"0\" cellspacing=\"0\" cellpadding=\"0\" width=\"355\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd width=\"67.13483146067416%\"\u003e\n \u003cp\u003eLeptomeningeal metastasis\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"32.86516853932584%\"\u003e\n \u003cp\u003eLM\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"67.13483146067416%\"\u003e\n \u003cp\u003eNon-small cell lung cancer\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"32.86516853932584%\"\u003e\n \u003cp\u003eNSCLC\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"67.13483146067416%\"\u003e\n \u003cp\u003eEpidermal growth factor receptor\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"32.86516853932584%\"\u003e\n \u003cp\u003eEGFR\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"67.13483146067416%\"\u003e\n \u003cp\u003eEGFR exon 20 insertion\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"32.86516853932584%\"\u003e\n \u003cp\u003eEGFR ex20ins\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"67.13483146067416%\"\u003e\n \u003cp\u003eCirculating tumor DNA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"32.86516853932584%\"\u003e\n \u003cp\u003ectDNA\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"67.13483146067416%\"\u003e\n \u003cp\u003eCerebrospinal fluid\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"32.86516853932584%\"\u003e\n \u003cp\u003eCSF\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"67.13483146067416%\"\u003e\n \u003cp\u003eIntraventricular chemotherapy\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"32.86516853932584%\"\u003e\n \u003cp\u003eIVC\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"67.13483146067416%\"\u003e\n \u003cp\u003etyrosine kinase inhibitors\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"32.86516853932584%\"\u003e\n \u003cp\u003eTKIs\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"67.13483146067416%\"\u003e\n \u003cp\u003eEastern Cooperative Oncology Group\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"32.86516853932584%\"\u003e\n \u003cp\u003eECOG\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"67.13483146067416%\"\u003e\n \u003cp\u003ePerformance status\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"32.86516853932584%\"\u003e\n \u003cp\u003ePS\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"67.13483146067416%\"\u003e\n \u003cp\u003eIntracranial progression-free survival\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"32.86516853932584%\"\u003e\n \u003cp\u003eiPFS\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"67.13483146067416%\"\u003e\n \u003cp\u003eOverall survival\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"32.86516853932584%\"\u003e\n \u003cp\u003eOS\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"67.13483146067416%\"\u003e\n \u003cp\u003eObjective response rate\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"32.86516853932584%\"\u003e\n \u003cp\u003eORR\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"67.13483146067416%\"\u003e\n \u003cp\u003eDisease control rate\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"32.86516853932584%\"\u003e\n \u003cp\u003eDCR\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"67.13483146067416%\"\u003e\n \u003cp\u003eWhole-brain radiotherapy\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"32.86516853932584%\"\u003e\n \u003cp\u003eWBRT\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"67.13483146067416%\"\u003e\n \u003cp\u003eMagnetic resonance imaging\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"32.86516853932584%\"\u003e\n \u003cp\u003eMRI\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"67.13483146067416%\"\u003e\n \u003cp\u003eCentral nervous system\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"32.86516853932584%\"\u003e\n \u003cp\u003eCNS\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"67.13483146067416%\"\u003e\n \u003cp\u003eBlood brain barrier\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"32.86516853932584%\"\u003e\n \u003cp\u003eBBB\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eAuthor Contributions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAll authors contributed to the study conception and design. Data acquiring and analyzing were performed by YCY, XT and FSC; YCY, WXY, LN and YLF contributed to writing\u0026mdash;original draft preparation; YZ, YLZ, YYL, LLY and JL contributed to Investigation; FSC contributed to project administration and acquired funding. All authors have read and approved the final manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis work was supported by Norman Bethune Specialized Research Fund(HSKY-021)\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eData availability\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe data (deidentified patients data, informed consent forms, clinical study report) that support the findings of this study are available on request from the corresponding author after publication,after providing a methodologically sound proposal.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eDeclarations\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConflict of interest\u0026nbsp;\u003c/strong\u003eAll authors declare no conflict of interest in respect of this manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEthics approval\u003c/strong\u003e This study was performed in line with the principles of the Declaration of Helsinki. Approval was granted by the Ethics Committee of the Nanjing Chest Hospital (2023-KL023-02).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent to participate\u003c/strong\u003e Written informed consent was obtained from all participants before enrolment.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eLi YS, Jiang BY, Yang JJ, Tu HY, Zhou Q, Guo WB, Yan HH, Wu YL (2016) Leptomeningeal Metastases in Patients with NSCLC with EGFR Mutations. J Thorac Oncol 11: 1962-1969 doi:10.1016/j.jtho.2016.06.029\u003c/li\u003e\n\u003cli\u003eLiao BC, Lee JH, Lin CC, Chen YF, Chang CH, Ho CC, Shih JY, Yu CJ, Yang JC (2015) Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitors for Non-Small-Cell Lung Cancer Patients with Leptomeningeal Carcinomatosis. J Thorac Oncol 10: 1754-1761 doi:10.1097/JTO.0000000000000669\u003c/li\u003e\n\u003cli\u003eHou J, Li H, Ma S, He Z, Yang S, Hao L, Zhou H, Zhang Z, Han J, Wang L, Wang Q (2022) EGFR exon 20 insertion mutations in advanced non-small-cell lung cancer: current status and perspectives. Biomark Res 10: 21 doi:10.1186/s40364-022-00372-6\u003c/li\u003e\n\u003cli\u003eLow JL, Lim SM, Lee JB, Cho BC, Soo RA (2023) Advances in the management of non-small-cell lung cancer harbouring EGFR exon 20 insertion mutations. Ther Adv Med Oncol 15: 17588359221146131 doi:10.1177/17588359221146131\u003c/li\u003e\n\u003cli\u003eLe Rhun E, Weller M, Brandsma D, Van den Bent M, de Azambuja E, Henriksson R, Boulanger T, Peters S, Watts C, Wick W, Wesseling P, Ruda R, Preusser M, Board EE, Committee EG (2017) EANO-ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up of patients with leptomeningeal metastasis from solid tumours. Ann Oncol 28: iv84-iv99 doi:10.1093/annonc/mdx221\u003c/li\u003e\n\u003cli\u003eZhang C, Zhang J, Xu FP, Wang YG, Xie Z, Su J, Dong S, Nie Q, Shao Y, Zhou Q, Yang JJ, Yang XN, Zhang XC, Li Z, Wu YL, Zhong WZ (2019) Genomic Landscape and Immune Microenvironment Features of Preinvasive and Early Invasive Lung Adenocarcinoma. J Thorac Oncol 14: 1912-1923 doi:10.1016/j.jtho.2019.07.031\u003c/li\u003e\n\u003cli\u003eChamberlain M, Junck L, Brandsma D, Soffietti R, Ruda R, Raizer J, Boogerd W, Taillibert S, Groves MD, Le Rhun E, Walker J, van den Bent M, Wen PY, Jaeckle KA (2017) Leptomeningeal metastases: a RANO proposal for response criteria. Neuro Oncol 19: 484-492 doi:10.1093/neuonc/now183\u003c/li\u003e\n\u003cli\u003eXu CW, Wang WX, Wang D, Wang QM, Pu XX, Zhu YC, Huang JH, Yu ZY, Cui ZL, Chen XH, Li JL, Fang Y, Wang H, Zhuang W, Lan SJ, Cai X, Zhang YB, Gao WB, Wang LP, She KL, Rao CZ, Zhou YF, Fang MY, Miao LY, Lei L, Lv TF, Song Y (2020) Pemetrexed-based chemotherapy for non-small-cell lung cancer patients with EGFR exon 20 insertion mutation: a multicenter study. Transl Lung Cancer Res 9: 1853-1861 doi:10.21037/tlcr-20-382\u003c/li\u003e\n\u003cli\u003eKian W, Christopoulos P, Remilah AA, Levison E, Dudnik E, Shalata W, Krayim B, Marei R, Yakobson A, Faehling M, Kahala D, Sara Granot I, Levitas D, Peled N, Roisman LC (2022) Real-world efficacy and safety of mobocertinib in EGFR exon 20 insertion-mutated lung cancer. Front Oncol 12: 1010311 doi:10.3389/fonc.2022.1010311\u003c/li\u003e\n\u003cli\u003eYang G, Yang Y, Liu R, Li W, Xu H, Hao X, Li J, Zhang S, Xu F, Lei S, Wang Y (2023) First-line immunotherapy or angiogenesis inhibitor combined with chemotherapy for advanced non-small cell lung cancer with EGFR exon 20 insertions: Real-world evidence from China. Cancer Med 12: 335-344 doi:10.1002/cam4.4852\u003c/li\u003e\n\u003cli\u003eCavaco M, Gaspar D, Arb Castanho M, Neves V (2020) Antibodies for the Treatment of Brain Metastases, a Dream or a Reality? Pharmaceutics 12 doi:10.3390/pharmaceutics12010062\u003c/li\u003e\n\u003cli\u003ePark K, Haura EB, Leighl NB, Mitchell P, Shu CA, Girard N, Viteri S, Han JY, Kim SW, Lee CK, Sabari JK, Spira AI, Yang TY, Kim DW, Lee KH, Sanborn RE, Trigo J, Goto K, Lee JS, Yang JC, Govindan R, Bauml JM, Garrido P, Krebs MG, Reckamp KL, Xie J, Curtin JC, Haddish-Berhane N, Roshak A, Millington D, Lorenzini P, Thayu M, Knoblauch RE, Cho BC (2021) Amivantamab in EGFR Exon 20 Insertion-Mutated Non-Small-Cell Lung Cancer Progressing on Platinum Chemotherapy: Initial Results From the CHRYSALIS Phase I Study. J Clin Oncol 39: 3391-3402 doi:10.1200/JCO.21.00662\u003c/li\u003e\n\u003cli\u003eZhou C, Ramalingam SS, Kim TM, Kim SW, Yang JC, Riely GJ, Mekhail T, Nguyen D, Garcia Campelo MR, Felip E, Vincent S, Jin S, Griffin C, Bunn V, Lin J, Lin HM, Mehta M, Janne PA (2021) Treatment Outcomes and Safety of Mobocertinib in Platinum-Pretreated Patients With EGFR Exon 20 Insertion-Positive Metastatic Non-Small Cell Lung Cancer: A Phase 1/2 Open-label Nonrandomized Clinical Trial. JAMA Oncol 7: e214761 doi:10.1001/jamaoncol.2021.4761\u003c/li\u003e\n\u003cli\u003eOu SI, Lin HM, Hong JL, Yin Y, Jin S, Lin J, Mehta M, Nguyen D, Neal JW (2023) Real-World Response and Outcomes in Patients With NSCLC With EGFR Exon 20 Insertion Mutations. JTO Clin Res Rep 4: 100558 doi:10.1016/j.jtocrr.2023.100558\u003c/li\u003e\n\u003cli\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: 206 doi:10.1186/s12885-023-10676-x\u003c/li\u003e\n\u003cli\u003eB. Han CZ, L. Wu, X. Yu, Q. Li, F. Liu, C. Shen (2021) Preclinical and preliminary clinical investigations of furmonertinib in NSCLC with EGFR exon 20 insertions (20ins). Annals of Oncology. p S964\u003c/li\u003e\n\u003cli\u003eSa H, Shi Y, Ding C, Ma K (2023) A real-world study of the efficacy and safety of furmonertinib for patients with non-small cell lung cancer with EGFR exon 20 insertion mutations. J Cancer Res Clin Oncol 149: 7729-7742 doi:10.1007/s00432-023-04726-x\u003c/li\u003e\n\u003cli\u003eShapiro WR, Young DF, Mehta BM (1975) Methotrexate: distribution in cerebrospinal fluid after intravenous, ventricular and lumbar injections. N Engl J Med 293: 161-166 doi:10.1056/NEJM197507242930402\u003c/li\u003e\n\u003cli\u003eJang SM, Gwak HS, Kwon JW, Shin SH, Yoo H (2023) Clinical Safety and Efficiency of the H-Port for Treatment of Leptomeningeal Metastasis. J Korean Neurosurg Soc doi:10.3340/jkns.2023.0178\u003c/li\u003e\n\u003cli\u003eGwak HS, Joo J, Shin SH, Yoo H, Han JY, Kim HT, Yun T, Ro J, Lee JS, Lee SH (2014) Ventriculolumbar perfusion chemotherapy with methotrexate for treating leptomeningeal carcinomatosis: a Phase II Study. Oncologist 19: 1044-1045 doi:10.1634/theoncologist.2014-0199\u003c/li\u003e\n\u003cli\u003eGaietto A, Panetta JC, Pauley JL, Relling MV, Ribeiro R, Ehrhardt MJ, Pui CH, Inaba H, Swanson HD (2024) Ommaya reservoir use in pediatric ALL and NHL: a review at St. Jude Children's Research Hospital. Cancer Chemother Pharmacol doi:10.1007/s00280-024-04653-9\u003c/li\u003e\n\u003cli\u003eMontes de Oca Delgado M, Cacho Diaz B, Santos Zambrano J, Guerrero Juarez V, Lopez Martinez MS, Castro Martinez E, Avendano Mendez-Padilla J, Mejia Perez S, Reyes Moreno I, Gutierrez Aceves A, Gonzalez Aguilar A (2018) The Comparative Treatment of Intraventricular Chemotherapy by Ommaya Reservoir vs. Lumbar Puncture in Patients With Leptomeningeal Carcinomatosis. Front Oncol 8: 509 doi:10.3389/fonc.2018.00509\u003c/li\u003e\n\u003cli\u003eGwak HS, Joo J, Kim S, Yoo H, Shin SH, Han JY, Kim HT, Lee JS, Lee SH (2013) Analysis of treatment outcomes of intraventricular chemotherapy in 105 patients for leptomeningeal carcinomatosis from non-small-cell lung cancer. J Thorac Oncol 8: 599-605 doi:10.1097/JTO.0b013e318287c943\u003c/li\u003e\n\u003c/ol\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e"},{"header":"Tables","content":"\u003cp\u003e\u003cstrong\u003eTable 1.\u003c/strong\u003e Patient characteristics\u003c/p\u003e\n\u003ctable border=\"0\" cellspacing=\"0\" cellpadding=\"0\" width=\"701\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd width=\"8.41654778887304%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eNo.\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.273894436519258%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eAge\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e(years)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.7018544935806%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eSex\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.978601997146933%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eTumor history (months)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.407988587731811%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eAccompanying BM\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.546362339514978%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eExtracranial lesions\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"27.674750356633382%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eNeurological symptoms\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"8.41654778887304%\" valign=\"top\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.273894436519258%\" valign=\"top\"\u003e\n \u003cp\u003e54\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.7018544935806%\" valign=\"top\"\u003e\n \u003cp\u003eMale\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.978601997146933%\" valign=\"top\"\u003e\n \u003cp\u003e12\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.407988587731811%\" valign=\"top\"\u003e\n \u003cp\u003eyes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.546362339514978%\" valign=\"top\"\u003e\n \u003cp\u003eBone\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"27.674750356633382%\" valign=\"top\"\u003e\n \u003cp\u003eDizziness, headache, nausea, and vomiting\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"8.41654778887304%\" valign=\"top\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.273894436519258%\" valign=\"top\"\u003e\n \u003cp\u003e42\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.7018544935806%\" valign=\"top\"\u003e\n \u003cp\u003eFemale\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.978601997146933%\" valign=\"top\"\u003e\n \u003cp\u003e10\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.407988587731811%\" valign=\"top\"\u003e\n \u003cp\u003eno\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.546362339514978%\" valign=\"top\"\u003e\n \u003cp\u003eBone and lung\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"27.674750356633382%\" valign=\"top\"\u003e\n \u003cp\u003eDizziness, headache, gait disorder, and vomiting\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"8.41654778887304%\" valign=\"top\"\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.273894436519258%\" valign=\"top\"\u003e\n \u003cp\u003e65\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.7018544935806%\" valign=\"top\"\u003e\n \u003cp\u003eMale\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.978601997146933%\" valign=\"top\"\u003e\n \u003cp\u003e50\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.407988587731811%\" valign=\"top\"\u003e\n \u003cp\u003eno\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.546362339514978%\" valign=\"top\"\u003e\n \u003cp\u003eBone\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"27.674750356633382%\" valign=\"top\"\u003e\n \u003cp\u003eDizziness, headache\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"8.41654778887304%\" valign=\"top\"\u003e\n \u003cp\u003e4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.273894436519258%\" valign=\"top\"\u003e\n \u003cp\u003e49\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.7018544935806%\" valign=\"top\"\u003e\n \u003cp\u003eMale\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.978601997146933%\" valign=\"top\"\u003e\n \u003cp\u003e37\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.407988587731811%\" valign=\"top\"\u003e\n \u003cp\u003eyes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.546362339514978%\" valign=\"top\"\u003e\n \u003cp\u003eBone and peritoneum\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"27.674750356633382%\" valign=\"top\"\u003e\n \u003cp\u003eDizziness, headache, and mental retardation\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"8.41654778887304%\" valign=\"top\"\u003e\n \u003cp\u003e5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.273894436519258%\" valign=\"top\"\u003e\n \u003cp\u003e53\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.7018544935806%\" valign=\"top\"\u003e\n \u003cp\u003eMale\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.978601997146933%\" valign=\"top\"\u003e\n \u003cp\u003e7\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.407988587731811%\" valign=\"top\"\u003e\n \u003cp\u003eyes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.546362339514978%\" valign=\"top\"\u003e\n \u003cp\u003eBone\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"27.674750356633382%\" valign=\"top\"\u003e\n \u003cp\u003eDizziness and headache\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"8.41654778887304%\" valign=\"top\"\u003e\n \u003cp\u003e6\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.273894436519258%\" valign=\"top\"\u003e\n \u003cp\u003e57\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.7018544935806%\" valign=\"top\"\u003e\n \u003cp\u003eFemale\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.978601997146933%\" valign=\"top\"\u003e\n \u003cp\u003e42\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.407988587731811%\" valign=\"top\"\u003e\n \u003cp\u003eno\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.546362339514978%\" valign=\"top\"\u003e\n \u003cp\u003eBone\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"27.674750356633382%\" valign=\"top\"\u003e\n \u003cp\u003eHeadache and nausea\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"8.41654778887304%\" valign=\"top\"\u003e\n \u003cp\u003e7\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.273894436519258%\" valign=\"top\"\u003e\n \u003cp\u003e51\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.7018544935806%\" valign=\"top\"\u003e\n \u003cp\u003eMale\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.978601997146933%\" valign=\"top\"\u003e\n \u003cp\u003e30\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.407988587731811%\" valign=\"top\"\u003e\n \u003cp\u003eyes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.546362339514978%\" valign=\"top\"\u003e\n \u003cp\u003eBone\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"27.674750356633382%\" valign=\"top\"\u003e\n \u003cp\u003eDizziness, headache, nausea, and vomiting\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"8.41654778887304%\" valign=\"top\"\u003e\n \u003cp\u003e8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.273894436519258%\" valign=\"top\"\u003e\n \u003cp\u003e66\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.7018544935806%\" valign=\"top\"\u003e\n \u003cp\u003eFemale\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.978601997146933%\" valign=\"top\"\u003e\n \u003cp\u003e70\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.407988587731811%\" valign=\"top\"\u003e\n \u003cp\u003eyes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.546362339514978%\" valign=\"top\"\u003e\n \u003cp\u003eBone\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"27.674750356633382%\" valign=\"top\"\u003e\n \u003cp\u003eHeadache\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"8.41654778887304%\" valign=\"top\"\u003e\n \u003cp\u003e9\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.273894436519258%\" valign=\"top\"\u003e\n \u003cp\u003e66\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.7018544935806%\" valign=\"top\"\u003e\n \u003cp\u003eFemale\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.978601997146933%\" valign=\"top\"\u003e\n \u003cp\u003e16\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.407988587731811%\" valign=\"top\"\u003e\n \u003cp\u003eyes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.546362339514978%\" valign=\"top\"\u003e\n \u003cp\u003eBone\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"27.674750356633382%\" valign=\"top\"\u003e\n \u003cp\u003eHeadache, nausea, and vomiting\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"8.41654778887304%\" valign=\"top\"\u003e\n \u003cp\u003e10\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.273894436519258%\" valign=\"top\"\u003e\n \u003cp\u003e39\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.7018544935806%\" valign=\"top\"\u003e\n \u003cp\u003eMale\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.978601997146933%\" valign=\"top\"\u003e\n \u003cp\u003e20\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.407988587731811%\" valign=\"top\"\u003e\n \u003cp\u003eyes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.546362339514978%\" valign=\"top\"\u003e\n \u003cp\u003eBone\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"27.674750356633382%\" valign=\"top\"\u003e\n \u003cp\u003eHeadache\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003e\u003cem\u003eBM\u003c/em\u003e Brain metastasis\u003c/p\u003e\n\u003cp\u003e\u003cbr\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTable 2.\u003c/strong\u003e Summary of the treatment history in all 10 patients\u003c/p\u003e\n\u003ctable border=\"0\" cellspacing=\"0\" cellpadding=\"0\" width=\"591\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd width=\"6.081081081081081%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eNo.\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.66891891891892%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eTreatment line\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.628378378378379%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eWBRT\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.22972972972973%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eChemotherapy\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.905405405405407%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eAntiangiogenic therapy\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"21.62162162162162%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eEGFR-TKI\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003etreatment\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.864864864864865%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eImmunotherapy\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"6.081081081081081%\" valign=\"top\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.66891891891892%\" valign=\"top\"\u003e\n \u003cp\u003e4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.628378378378379%\" valign=\"top\"\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.22972972972973%\" valign=\"top\"\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.905405405405407%\" valign=\"top\"\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"21.62162162162162%\" valign=\"top\"\u003e\n \u003cp\u003eOsimertinib\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.864864864864865%\" valign=\"top\"\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"6.081081081081081%\" valign=\"top\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.66891891891892%\" valign=\"top\"\u003e\n \u003cp\u003e4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.628378378378379%\" valign=\"top\"\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.22972972972973%\" valign=\"top\"\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.905405405405407%\" valign=\"top\"\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"21.62162162162162%\" valign=\"top\"\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.864864864864865%\" valign=\"top\"\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"6.081081081081081%\" valign=\"top\"\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.66891891891892%\" valign=\"top\"\u003e\n \u003cp\u003e5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.628378378378379%\" valign=\"top\"\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.22972972972973%\" valign=\"top\"\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.905405405405407%\" valign=\"top\"\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"21.62162162162162%\" valign=\"top\"\u003e\n \u003cp\u003eAfatinib\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.864864864864865%\" valign=\"top\"\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"6.081081081081081%\" valign=\"top\"\u003e\n \u003cp\u003e4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.66891891891892%\" valign=\"top\"\u003e\n \u003cp\u003e6\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.628378378378379%\" valign=\"top\"\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.22972972972973%\" valign=\"top\"\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.905405405405407%\" valign=\"top\"\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"21.62162162162162%\" valign=\"top\"\u003e\n \u003cp\u003eAfatinib\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.864864864864865%\" valign=\"top\"\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"6.081081081081081%\" valign=\"top\"\u003e\n \u003cp\u003e5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.66891891891892%\" valign=\"top\"\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.628378378378379%\" valign=\"top\"\u003e\n \u003cp\u003eyes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.22972972972973%\" valign=\"top\"\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.905405405405407%\" valign=\"top\"\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"21.62162162162162%\" valign=\"top\"\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.864864864864865%\" valign=\"top\"\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"6.081081081081081%\" valign=\"top\"\u003e\n \u003cp\u003e6\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.66891891891892%\" valign=\"top\"\u003e\n \u003cp\u003e4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.628378378378379%\" valign=\"top\"\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.22972972972973%\" valign=\"top\"\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.905405405405407%\" valign=\"top\"\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"21.62162162162162%\" valign=\"top\"\u003e\n \u003cp\u003eOsimertinib\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.864864864864865%\" valign=\"top\"\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"6.081081081081081%\" valign=\"top\"\u003e\n \u003cp\u003e7\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.66891891891892%\" valign=\"top\"\u003e\n \u003cp\u003e7\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.628378378378379%\" valign=\"top\"\u003e\n \u003cp\u003eyes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.22972972972973%\" valign=\"top\"\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.905405405405407%\" valign=\"top\"\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"21.62162162162162%\" valign=\"top\"\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.864864864864865%\" valign=\"top\"\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"6.081081081081081%\" valign=\"top\"\u003e\n \u003cp\u003e8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.66891891891892%\" valign=\"top\"\u003e\n \u003cp\u003e10\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.628378378378379%\" valign=\"top\"\u003e\n \u003cp\u003eyes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.22972972972973%\" valign=\"top\"\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.905405405405407%\" valign=\"top\"\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"21.62162162162162%\" valign=\"top\"\u003e\n \u003cp\u003eMobocertinib and furmonertinib\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.864864864864865%\" valign=\"top\"\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"6.081081081081081%\" valign=\"top\"\u003e\n \u003cp\u003e9\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.66891891891892%\" valign=\"top\"\u003e\n \u003cp\u003e5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.628378378378379%\" valign=\"top\"\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.22972972972973%\" valign=\"top\"\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.905405405405407%\" valign=\"top\"\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"21.62162162162162%\" valign=\"top\"\u003e\n \u003cp\u003eMobocertinib\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.864864864864865%\" valign=\"top\"\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"6.081081081081081%\" valign=\"top\"\u003e\n \u003cp\u003e10\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.66891891891892%\" valign=\"top\"\u003e\n \u003cp\u003e5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.628378378378379%\" valign=\"top\"\u003e\n \u003cp\u003eyes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.22972972972973%\" valign=\"top\"\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.905405405405407%\" valign=\"top\"\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"21.62162162162162%\" valign=\"top\"\u003e\n \u003cp\u003eOsimertinib\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.864864864864865%\" valign=\"top\"\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003e\u003cem\u003eWBRT\u003c/em\u003e Whole-brain radiotherapy; \u003cem\u003eEGFR-TKI\u0026nbsp;\u003c/em\u003eEpidermal growth factor receptor tyrosine kinase inhibitors\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTable 3.\u003c/strong\u003e Summary of the treatments and clinical responses\u003c/p\u003e\n\u003ctable border=\"0\" cellspacing=\"0\" cellpadding=\"0\" width=\"738\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd width=\"5.555555555555555%\" rowspan=\"2\" valign=\"bottom\"\u003e\n \u003cp\u003e\u003cstrong\u003eNo.\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20.73170731707317%\" colspan=\"2\" valign=\"bottom\"\u003e\n \u003cp\u003e\u003cstrong\u003ePS\u0026nbsp;score\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20.18970189701897%\" colspan=\"2\"\u003e\n \u003cp\u003e\u003cstrong\u003eRANO score\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.672086720867208%\" rowspan=\"2\"\u003e\n \u003cp\u003e\u003cstrong\u003eNeurological exam\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.775067750677507%\" rowspan=\"2\"\u003e\n \u003cp\u003e\u003cstrong\u003eSymptom assessment\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.672086720867208%\" rowspan=\"2\"\u003e\n \u003cp\u003e\u003cstrong\u003eCSF cytology\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.07859078590786%\" rowspan=\"2\"\u003e\n \u003cp\u003e\u003cstrong\u003eCNS imaging\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.401084010840108%\" rowspan=\"2\"\u003e\n \u003cp\u003e\u003cstrong\u003eLM response assessment\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.924119241192411%\" rowspan=\"2\"\u003e\n \u003cp\u003e\u003cstrong\u003eSystemic response assessment\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"24.503311258278146%\"\u003e\n \u003cp\u003e\u003cstrong\u003ePretreatments\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"26.158940397350992%\"\u003e\n \u003cp\u003e\u003cstrong\u003ePosttreatments\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"23.178807947019866%\"\u003e\n \u003cp\u003e\u003cstrong\u003ePretreatments\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"26.158940397350992%\"\u003e\n \u003cp\u003e\u003cstrong\u003ePosttreatments\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"5.555555555555555%\" valign=\"bottom\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.02710027100271%\" valign=\"bottom\"\u003e\n \u003cp\u003e4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.70460704607046%\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.48509485094851%\"\u003e\n \u003cp\u003e16\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.70460704607046%\"\u003e\n \u003cp\u003e8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.672086720867208%\"\u003e\n \u003cp\u003eImproved\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.775067750677507%\"\u003e\n \u003cp\u003eImproved\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.672086720867208%\"\u003e\n \u003cp\u003eNegative\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.07859078590786%\"\u003e\n \u003cp\u003eStable\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.401084010840108%\"\u003e\n \u003cp\u003eResponse\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.924119241192411%\"\u003e\n \u003cp\u003eSD\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"5.555555555555555%\" valign=\"bottom\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.02710027100271%\" valign=\"bottom\"\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.70460704607046%\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.48509485094851%\"\u003e\n \u003cp\u003e6\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.70460704607046%\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.672086720867208%\"\u003e\n \u003cp\u003eImproved\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.775067750677507%\"\u003e\n \u003cp\u003eImproved\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.672086720867208%\"\u003e\n \u003cp\u003eNegative\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.07859078590786%\"\u003e\n \u003cp\u003estable\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.401084010840108%\"\u003e\n \u003cp\u003eResponse\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.924119241192411%\"\u003e\n \u003cp\u003eSD\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"5.555555555555555%\" valign=\"bottom\"\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.02710027100271%\" valign=\"bottom\"\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.70460704607046%\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.48509485094851%\"\u003e\n \u003cp\u003e10\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.70460704607046%\"\u003e\n \u003cp\u003e5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.672086720867208%\"\u003e\n \u003cp\u003eImproved\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.775067750677507%\"\u003e\n \u003cp\u003eImproved\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.672086720867208%\"\u003e\n \u003cp\u003eNegative\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.07859078590786%\"\u003e\n \u003cp\u003eImproved\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.401084010840108%\"\u003e\n \u003cp\u003eResponse\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.924119241192411%\"\u003e\n \u003cp\u003ePR\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"5.555555555555555%\" valign=\"bottom\"\u003e\n \u003cp\u003e4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.02710027100271%\" valign=\"bottom\"\u003e\n \u003cp\u003e4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.70460704607046%\"\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.48509485094851%\"\u003e\n \u003cp\u003e12\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.70460704607046%\"\u003e\n \u003cp\u003e8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.672086720867208%\"\u003e\n \u003cp\u003eImproved\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.775067750677507%\"\u003e\n \u003cp\u003eImproved\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.672086720867208%\"\u003e\n \u003cp\u003ePositive\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.07859078590786%\"\u003e\n \u003cp\u003eImproved\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.401084010840108%\"\u003e\n \u003cp\u003eSD\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.924119241192411%\"\u003e\n \u003cp\u003eSD\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"5.555555555555555%\" valign=\"bottom\"\u003e\n \u003cp\u003e5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.02710027100271%\" valign=\"bottom\"\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.70460704607046%\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.48509485094851%\"\u003e\n \u003cp\u003e9\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.70460704607046%\"\u003e\n \u003cp\u003e6\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.672086720867208%\"\u003e\n \u003cp\u003eStable\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.775067750677507%\"\u003e\n \u003cp\u003eImproved\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.672086720867208%\"\u003e\n \u003cp\u003ePositive\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.07859078590786%\"\u003e\n \u003cp\u003eStable\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.401084010840108%\"\u003e\n \u003cp\u003eSD\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.924119241192411%\"\u003e\n \u003cp\u003eSD\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"5.555555555555555%\" valign=\"bottom\"\u003e\n \u003cp\u003e6\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.02710027100271%\" valign=\"bottom\"\u003e\n \u003cp\u003e4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.70460704607046%\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.48509485094851%\"\u003e\n \u003cp\u003e6\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.70460704607046%\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.672086720867208%\"\u003e\n \u003cp\u003eImproved\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.775067750677507%\"\u003e\n \u003cp\u003eImproved\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.672086720867208%\"\u003e\n \u003cp\u003eNegative\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.07859078590786%\"\u003e\n \u003cp\u003eStable\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.401084010840108%\"\u003e\n \u003cp\u003eResponse\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.924119241192411%\"\u003e\n \u003cp\u003ePR\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"5.555555555555555%\" valign=\"bottom\"\u003e\n \u003cp\u003e7\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.02710027100271%\" valign=\"bottom\"\u003e\n \u003cp\u003e4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.70460704607046%\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.48509485094851%\"\u003e\n \u003cp\u003e12\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.70460704607046%\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.672086720867208%\"\u003e\n \u003cp\u003eImproved\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.775067750677507%\"\u003e\n \u003cp\u003eImproved\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.672086720867208%\"\u003e\n \u003cp\u003eNegative\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.07859078590786%\"\u003e\n \u003cp\u003eStable\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.401084010840108%\"\u003e\n \u003cp\u003eResponse\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.924119241192411%\"\u003e\n \u003cp\u003ePR\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"5.555555555555555%\" valign=\"bottom\"\u003e\n \u003cp\u003e8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.02710027100271%\" valign=\"bottom\"\u003e\n \u003cp\u003e4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.70460704607046%\"\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.48509485094851%\"\u003e\n \u003cp\u003e17\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.70460704607046%\"\u003e\n \u003cp\u003e12\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.672086720867208%\"\u003e\n \u003cp\u003eImproved\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.775067750677507%\"\u003e\n \u003cp\u003eImproved\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.672086720867208%\"\u003e\n \u003cp\u003ePositive\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.07859078590786%\"\u003e\n \u003cp\u003eStable\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.401084010840108%\"\u003e\n \u003cp\u003eSD\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.924119241192411%\"\u003e\n \u003cp\u003eSD\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"5.555555555555555%\" valign=\"bottom\"\u003e\n \u003cp\u003e9\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.02710027100271%\" valign=\"bottom\"\u003e\n \u003cp\u003e4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.70460704607046%\"\u003e\n \u003cp\u003e4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.48509485094851%\"\u003e\n \u003cp\u003e18\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.70460704607046%\"\u003e\n \u003cp\u003e18\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.672086720867208%\"\u003e\n \u003cp\u003eStable\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.775067750677507%\"\u003e\n \u003cp\u003eStable\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.672086720867208%\"\u003e\n \u003cp\u003ePositive\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.07859078590786%\"\u003e\n \u003cp\u003eWorse\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.401084010840108%\"\u003e\n \u003cp\u003ePD\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.924119241192411%\"\u003e\n \u003cp\u003eSD\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"5.555555555555555%\" valign=\"bottom\"\u003e\n \u003cp\u003e10\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.02710027100271%\"\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.70460704607046%\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.48509485094851%\"\u003e\n \u003cp\u003e6\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.70460704607046%\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.672086720867208%\"\u003e\n \u003cp\u003eImproved\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.775067750677507%\"\u003e\n \u003cp\u003eImproved\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.672086720867208%\"\u003e\n \u003cp\u003eNegative\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.07859078590786%\"\u003e\n \u003cp\u003eStable\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.401084010840108%\"\u003e\n \u003cp\u003eResponse\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.924119241192411%\"\u003e\n \u003cp\u003eSD\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003e\u0026nbsp;\u003cem\u003ePS\u003c/em\u003e Performance status; \u003cem\u003eRANO\u0026nbsp;\u003c/em\u003eResponse Assessment in Neurooncology;\u003cem\u003e\u0026nbsp;CSF\u003c/em\u003e Cerebrospinal fluid; \u003cem\u003eCNS\u003c/em\u003e Central nervous system;\u003cem\u003e\u0026nbsp;LM\u003c/em\u003e Leptomeningeal metastasis; \u003cem\u003eSD\u003c/em\u003e stable disease; \u003cem\u003ePR\u003c/em\u003e Partial response; \u003cem\u003ePD\u003c/em\u003e Progressive disease\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTable 4.\u003c/strong\u003e Toxicities and adverse events.\u003c/p\u003e\n\u003ctable border=\"0\" cellspacing=\"0\" cellpadding=\"0\" width=\"429\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd width=\"21.261682242990656%\" valign=\"bottom\"\u003e\n \u003cp\u003e\u003cstrong\u003eNo.\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"21.261682242990656%\"\u003e\n \u003cp\u003e\u003cstrong\u003eGrade 1\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"27.570093457943926%\"\u003e\n \u003cp\u003e\u003cstrong\u003eGrade 2\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.953271028037383%\"\u003e\n \u003cp\u003e\u003cstrong\u003eGrade 3\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.953271028037383%\"\u003e\n \u003cp\u003e\u003cstrong\u003eGrade 4\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"bottom\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003eRash\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003eDiarrhea\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"bottom\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003eRash\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003eDiarrhea\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"bottom\"\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003eRash and Oral ulcer\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"bottom\"\u003e\n \u003cp\u003e4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003eDiarrhea\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003eAnorexia\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003eNausea\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003eRash\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"bottom\"\u003e\n \u003cp\u003e5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003eRash\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003eOral ulcer\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"bottom\"\u003e\n \u003cp\u003e6\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003eDiarrhea\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"bottom\"\u003e\n \u003cp\u003e7\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003eOral ulcer\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"bottom\"\u003e\n \u003cp\u003e8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003eRash\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003eDiarrhea\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"bottom\"\u003e\n \u003cp\u003e9\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003eElevated transaminase\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003eDiarrhea\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"bottom\"\u003e\n \u003cp\u003e10\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003eDiarrhea\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003eRash\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\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":"Furmonertinib, Leptomeningeal metastasis, EGFR ex20ins, NSCLC, Intraventricular chemotherapy","lastPublishedDoi":"10.21203/rs.3.rs-4301016/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-4301016/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003ePurpose: \u003c/strong\u003eThe\u003cstrong\u003e \u003c/strong\u003etreatment 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.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMethods:\u003c/strong\u003e 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.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eResults: \u003c/strong\u003eThe 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.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConclusions: \u003c/strong\u003eThe 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.\u003c/p\u003e","manuscriptTitle":"High-dose furmonertinib combined with intraventricular chemotherapy as salvage therapy for leptomeningeal metastasis from EGFR exon 20 insertion-mutated lung cancer","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-04-29 15:29:56","doi":"10.21203/rs.3.rs-4301016/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2024-05-11T10:57:26+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2024-05-10T01:59:28+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2024-05-04T23:28:09+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"3b0d20af-851a-40f8-a473-0f4f5bbb4089","date":"2024-04-29T15:58:19+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"152475371309192640459097078052485832426","date":"2024-04-29T14:39:42+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"fce42029-0e54-425b-a3c8-98c6aba9282f","date":"2024-04-24T12:17:39+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2024-04-22T12:21:26+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2024-04-22T11:21:46+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2024-04-22T11:21:45+00:00","index":"","fulltext":""},{"type":"submitted","content":"Journal of Neuro-Oncology","date":"2024-04-21T13:47:32+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":"36fe1364-bdc5-458f-9ea5-879aa26bd3ed","owner":[],"postedDate":"April 29th, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[],"tags":[],"updatedAt":"2024-07-24T10:18:14+00:00","versionOfRecord":{"articleIdentity":"rs-4301016","link":"https://doi.org/10.1007/s11060-024-04716-0","journal":{"identity":"journal-of-neuro-oncology","isVorOnly":false,"title":"Journal of Neuro-Oncology"},"publishedOn":"2024-06-25 10:18:14","publishedOnDateReadable":"June 25th, 2024"},"versionCreatedAt":"2024-04-29 15:29:56","video":"","vorDoi":"10.1007/s11060-024-04716-0","vorDoiUrl":"https://doi.org/10.1007/s11060-024-04716-0","workflowStages":[]},"version":"v1","identity":"rs-4301016","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-4301016","identity":"rs-4301016","version":["v1"]},"buildId":"qtupq5eGEP_6zYnWcrvyt","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}