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

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

Durable responses to trastuzumab deruxtecan in patients with leptomeningeal metastases from breast cancer with variable HER2 expression.

PURPOSE: Emerging data suggest that trastuzumab deruxtecan (T-DXd) is an active treatment for brain metastases from HER2 + breast cancer. We aimed to characterize the activity of T-DXd in the treatment of leptomeningeal metastases (LM) from a range of HER2-altered cancers. METHODS: We reviewed neuro-oncology clinic records between July 2020 and December 2023 to identify patients who received T-DXd to treat LM. RESULTS: Of 18 patients identified, 6 had HER2 + breast cancer, 8 had HER2-low/negative breast cancer, 2 had HER2 + gastroesophageal cancer, and 2 had HER2-mutant non-small cell lung cancer (NSCLC). 10/18 (56%) patients had cytologically confirmed LM by CSF cytology or circulating tumor cell (CTC) capture. A partial response (PR) on MRI using the EORTC/RANO-LM Revised-Scorecard occurred in 4/6 (67%) patients with HER2 + breast LM, 2/8 (25%) patients with HER2-low/negative breast cancer, and 0/4 (0%) patients with HER2 + gastroesophageal cancer or HER2-mutant NSCLC. Median overall survival after initiating T-DXd was 5.8 months. Survival after initiating T-DXd was numerically longer for HER2 + breast cancer patients compared with HER2-low/negative breast and HER2-altered non-breast cancer patients (13.9 months vs. 5.2 months and 4.6 months, respectively). Landmark analysis showed that patients with radiologic LM response to T-DXd by 2.5 months had longer survival than non-responders (14.2 months vs. 2.6 months, HR 0.18, 95% CI 0.05-0.63, p < 0.05), and landmark analyses at 3.5 and 4.5 months after starting T-DXd showed a similar but nonsignificant trend. CONCLUSION: T-DXd induces LM responses in a subset of patients, and such responses may be associated with prolongation of survival. Prospective trials are needed to clarify the role of T-DXd in treating LM and which patients are most likely to benefit.

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

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

Cerebrospinal fluid circulating tumor DNA contributes to the detection and characterization of leptomeningeal metastasis in non-small cell lung cancer.

PURPOSE: Cerebrospinal fluid (CSF) has revealed the unique genetic characteristics of leptomeningeal metastasis (LM) from non-small cell lung cancer (NSCLC). However, the research in this area is still very limited. METHODS: Patients with LM from NSCLC (n = 80) were retrospectively analyzed. Circulating tumor DNA (ctDNA) in CSF was tested by next-generation sequencing (NGS), with paired extracranial tissue or plasma samples included for comparison. An independent non-LM cohort (n = 100) was also analyzed for comparative purposes. Clinical outcomes were compared with Kaplan-Meier log-rank test and Cox proportional hazards methodologies. RESULTS: An overwhelming 93.8% of patients carried druggable mutations in NSCLC LM, with EGFR (78.8%) being the most prevalent. Notably, 4 patients who tested negative for driver genes in extracranial samples surprisingly showed EGFR mutations in their CSF and subsequently benefited from targeted therapy. There was a clear difference in genetic profiles between CSF and extracranial samples, with CSF showing more driver gene detections, increased Copy Number Variations (CNVs), and varied resistance mechanisms among individuals. Abnormalities in cell-cycle regulatory molecules were highly enriched in LM (50.9% vs 31.0%, p = 0.017), and CDKN2A/2B deletions were identified as an independent poor prognostic factor for LM patients, with a significant reduction in median OS (p = 0.013), supported by multivariate analysis (HR 2.63, 95% CI 1.32-5.26, p = 0.006). CONCLUSIONS: CSF-based ctDNA analysis is crucial for detecting and characterizing genetic alterations in NSCLC LM. The distinct genetic profiles in CSF and extracranial tissues emphasize the need for personalized treatment approaches.

Cerebrospinal fluid circulating tumour DNA genotyping and survival analysis in lung adenocarcinoma with leptomeningeal metastases.

PURPOSE: The prognosis of patients with leptomeningeal metastasis (LM) remains poor. Circulating tumour DNA (ctDNA) has been proven to be abundantly present in cerebrospinal fluid (CSF); hence, its clinical implication as a biomarker needs to be further verified. METHODS: We conducted a retrospective study of 35 lung adenocarcinoma (LUAD) patients with LM, and matched CSF and plasma samples were collected from all patients. All paired samples underwent next-generation sequencing (NGS) of 139 lung cancer-associated genes. The clinical characteristics and genetic profiling of LM were analysed in association with survival prognosis. RESULTS: LM showed genetic heterogeneity, in which CSF had a higher detection rate of ctDNA (P = 0.003), a higher median mutation count (P < 0.0001), a higher frequency of driver mutations (P < 0.01), and more copy number variation (CNV) alterations (P < 0.001) than plasma. The mutation frequencies of the EGFR, TP53, CDKN2A, MYC and CDKN2B genes were easier to detect in CSF than in LUAD tissue (P < 0.05), possibly reflecting the underlying mechanism of LM metastasis. CSF ctDNA is helpful for analysing the mechanism of EGFR-TKI resistance. In cohort 1, which comprised patients who received 1/2 EGFR-TKIs before the diagnosis of LM, TP53 and CDKN2A were the most common EGFR-independent resistant mutations. In cohort 2, comprising those who progressed after osimertinib and developed LM, 7 patients (43.75%) had EGFR CNV detected in CSF but not plasma. Furthermore, patient characteristics and various genes were included for interactive survival analysis. Patients with EGFR-mutated LUAD (P = 0.042) had a higher median OS, and CSF ctDNA mutation with TERT (P = 0.013) indicated a lower median OS. Last, we reported an LM case in which CSF ctDNA dynamic changes were well correlated with clinical treatment. CONCLUSIONS: CSF ctDNA could provide a more comprehensive genetic landscape of LM, indicating the potential metastasis-related and EGFR-TKI resistance mechanisms of LM patients. In addition, genotyping of CSF combined with clinical outcomes can predict the prognosis of LUAD patients with LM.

Trametinib overcomes KRAS-G12V-induced osimertinib resistance in a leptomeningeal carcinomatosis model of EGFR-mutant lung cancer.

Leptomeningeal carcinomatosis (LMC) occurs frequently in non-small cell lung cancer (NSCLC) harboring epidermal growth factor receptor (EGFR) mutations and is associated with acquired resistance to EGFR tyrosine kinase inhibitors (EGFR-TKIs). However, the mechanism by which LMC acquires resistance to osimertinib, a third-generation EGFR-TKI, is unclear. In this study, we elucidated the resistance mechanism and searched for a novel therapeutic strategy. We induced osimertinib resistance in a mouse model of LMC using an EGFR-mutant NSCLC cell line (PC9) via continuous oral osimertinib treatment and administration of established resistant cells and examined the resistance mechanism using next-generation sequencing. We detected the Kirsten rat sarcoma (KRAS)-G12V mutation in resistant cells, which retained the EGFR exon 19 deletion. Experiments involving KRAS knockdown in resistant cells and KRAS-G12V overexpression in parental cells revealed the involvement of KRAS-G12V in osimertinib resistance. Cotreatment with trametinib (a MEK inhibitor) and osimertinib resensitized the cells to osimertinib. Furthermore, in the mouse model of LMC with resistant cells, combined osimertinib and trametinib treatment successfully controlled LMC progression. These findings suggest a potential novel therapy against KRAS-G12V-harboring osimertinib-resistant LMC in EGFR-mutant NSCLC.

Leptomeningeal recurrence after long-term alectinib therapy for non-small cell lung cancer harboring an EML4-ALK fusion protein.

The recent approval of anaplastic lymphoma kinase (ALK) inhibitors for the treatment of ALK-rearranged non-small cell lung cancer (NSCLC) has dramatically transformed cancer therapy. However, leptomeningeal metastases (LM) are frequent and often devastating complications of ALK-rearranged NSCLC, and treatment against LM remains challenging. Herein we report a case of a 19-year-old male diagnosed with ALK-rearranged NSCLC with LM. He experienced heavy treatment before introduction of alectinib therapy, which continued for approximately 5.5 years with marked efficacy. However, he experienced recurrence of a bulbar metastasis after discontinuation of alectinib. Reintroduction of standard-dose alectinib therapy resolved the lesion again. Our findings suggest that ALK-tyrosine kinase inhibitor therapy should be continued in patients showing a long-term complete response, unless intolerable toxicities are present, and that rechallenge treatment with alectinib may represent a therapeutic option for central nervous system metastases.

Afatinib helped overcome subsequent resistance to osimertinib in a patient with NSCLC having leptomeningeal metastasis baring acquired EGFR L718Q mutation: a case report.

BACKGROUND: The epidermal growth factor receptor (EGFR)-mutated advanced non-small-cell lung cancer has been successfully treated with tyrosine kinase inhibitors (TKIs). Acquired resistance becomes a tough issue when patients fail to respond to the third-generation TKI osimertinib. This study aimed to report a case baring acquired EGFR L858R/L718Q mutation in the central nervous system induced by osimertinib, which was successfully overcome using afatinib. CASE PRESENTATION: A 65-year-old female patient was diagnosed with stage IV non-small-cell lung adenocarcinoma with synchronic brain metastasis in February 2015. Before and during treatment, 416 tumor-related genes were monitored dynamically by liquid biopsies using next-generation sequencing, and the treatment strategy was decided according to the gene status. At baseline, an EGFR L858R mutation in exon 21 was detected, so treatment with icotinib was started. After 8 months, she experienced disease progression with leptomeningeal metastasis and switched to osimertinib based on an acquired EGFR T790 M mutation. After 9 months, her disease progressed and an EGFR L718Q mutation was found in the cerebrospinal fluid. The patient was then challenged with afatinib, and her disease was under control for 4 months. In January 2017, the patient passed away, with an overall survival time of 23 months, 15 months after leptomeningeal metastasis. CONCLUSION: The acquired EGFR L718Q mutation in the cerebrospinal fluid resulted in subsequent resistance to osimertinib and could be partly overcome using afatinib, indicating a promising treatment option in the clinic.

The therapeutic value of cerebrospinal fluid ctDNA detection by next-generation sequencing for meningeal carcinomatosis: a case report.

BACKGROUND: It is usually very complicated to treat meningeal carcinomatosis, and it is important to treat it as soon as possible. CASE PRESENTATION: The 19-Del mutation was found in the exon for the epidermal growth factor receptor gene in the pleural effusion of a patient on March 11th, 2015. He took 250 mg of oral gefitinib once a day for 11 months beginning in December of 2015. On the 3rd of November 2016, he arrived at the hospital and presented with dizziness, headache and transient blurred vision. At this time, he began to take 4 mg of oral zoledronic acid once a month to prevent bone metastases. The result of a cytology exam of the cerebrospinal fluid showed that the man had meningeal carcinomatosis. The 19-Del mutation and the 20-T790 M mutation in the exon of the epidermal growth factor receptor gene was found by the next generation sequencing of the CSF. Then, he discontinued taking gefitinib and began to take 90-100 mg of oral AZD9291 once a day in November 2016. After adjusting the medication dose based on the NGS, his headache was noticeably reduced, and his condition gradually stabilized. CONCLUSIONS: Cerebrospinal fluid ctDNA detection by next generation sequencing may become a suitable biomarker to monitor clinical treatment response in meningeal carcinomatosis.

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

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

Phase II Efficacy and Safety of 80 mg Osimertinib in Patients With Leptomeningeal Metastases Associated With Epidermal Growth Factor Receptor Mutation-Positive Non-Small Cell Lung Cancer (BLOSSOM).

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

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

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

Intrathecal administration of trastuzumab for the treatment of meningeal carcinomatosis in HER2-positive metastatic breast cancer: a systematic review and pooled analysis.

Leptomeningeal carcinomatosis (MC) represents an uncommon, but devasting manifestation of metastatic breast cancer. This is the first systematic review/pooled analysis to synthesize all available data evaluating the efficacy and safety of intrathecal (IT) administration of trastuzumab for the treatment of MC in HER2-positive breast cancer patients. This study was performed in accordance with the PRISMA guidelines. A total of 13 articles (17 patients) were eligible. The mean age of patients at IT trastuzumab administration was 48.2 years (SD 8.4, range 38-66). The mean total dose was 399.8 mg (SD 325.4, range 35-1,110 mg). IT trastuzumab alone or as part of combination therapies seemed to be safe; no serious adverse events were reported in 88.2 % of cases. In 68.8 % of cases, a significant clinical improvement was observed, while stabilization or progression of the disease was noticed in 31.2 % of cases. Cerebrospinal fluid (CSF) response was noted in 66.7 % of cases. The median overall survival was 13.5 months, whereas the median central nervous system progression-free survival (CNS-PFS) was 7.5 months. In 23.5 % of cases, IT trastuzumab was administered beyond CNS progression with a response noticed in 75 % of cases and a CNS-PFS of 9.4 months. The cumulative dose of IT trastuzumab given was 1,040 mg (SD 697.9, median 1,215, range 55-1,675). The protective effect of prior radio- or neurosurgery upon CNS-PFS was sizeable but did not reach formal statistical significance (HR 0.28, 95 % CI 0.06-1.37). Clinical improvement (HR 0.14, 95 % CI 0.02-0.91) and CSF response (HR 0.09, 95 % CI 0.01-0.89) were associated with longer CNS-PFS. IT trastuzumab administration seems to represent a safe and in some cases effective option for the treatment of HER2-positive breast cancer patients with leptomeningeal involvement. However, clinical trials are urgently needed to establish the definite role of IT trastuzumab in HER2-positive metastatic breast cancer patients with MC.

[A case of lung adenocarcinoma with coexisting G719X and T790M EGFR mutations in which erlotinib was effective for the treatment of leptomeningeal carcinomatosis].

A 68-year-old man was referred to our hospital because of an abnormal chest shadow. Adenocarcinoma was detected using percutaneous needle aspiration cytology from the left supraclavicular lymph node. The patient was diagnosed as having primary adenocarcinoma of the lung(cT1bN3M1b: BRA OSS). Exon 18G 719X and exon 20 T790M mutations of the EGFR gene were detected in the same specimen. For first-line chemotherapy, four courses of cisplatin plus docetaxel were used. The primary lesion and a brain metastasis were reduced after the first-line chemotherapy. About four months later, he developed a recurrent brain metastasis and leptomeningeal carcinomatosis. He was treated with erlotinib(150mg/day)after wholebrain irradiation. The leptomeningeal carcinomatosis findings on a head CT image and the patient's consciousness disorder improved after treatment. EGFR-TKI therapy was effective in a case with leptomeningeal carcinomatosis, and coexisting EGFRsensitive and EGFR-resistant mutations.

Osimertinib Combined with Systemic Chemotherapy for EGFR Mutant, T790M-Negative, Non-Small Cell Lung Cancer Patients Who Develop Leptomeningeal Metastases with Extracranial Progression to Prior EGFR TKI.

Leptomeningeal metastasis (LM) is a rare but fatal clinical condition with a short survival time. The incidence of LM from epidermal growth factor receptor mutant (EGFRm) non-small cell lung cancer (NSCLC) has increased due to the limited efficacy of first- or second-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) in the central nervous system (CNS). Osimertinib is a third-generation, irreversible, CNS penetrant, oral EGFR TKI that demonstrates promising efficacy in CNS metastases regardless of T790M. Herein, we report four cases of T790M-negative EGFRm NSCLC patients treated with osimertinib combined with systemic chemotherapy, who progressed on prior EGFR TKI and developed LM with extracranial lesions. The combination treatment was well tolerated, and the mean overall survival from LM diagnosis was 14.7 months (95% confidence interval, 10.4 to 19.0). These results suggest that osimertinib combined with systemic chemotherapy would be a reasonable treatment option for T790M-negative EGFRm NSCLC patients who develop LM with extracranial progression to prior EGFR TKI. A further prospective study is warranted.

Clinical Outcomes of Patients with Epidermal Growth Factor Receptor-Mutated Non-Small-Cell Lung Cancer with Leptomeningeal Metastasis in the Modern Target Therapy Era.

BACKGROUND: Leptomeningeal metastasis (LM) is a severe complication in patients with non-small-cell lung cancer (NSCLC) and the optimal treatment strategy remains a challenge. This study aimed to investigate the treatment strategies and clinical outcomes in these patients. METHODS: We retrospectively reviewed the data of 44 patients with epidermal growth factor receptor (EGFR)-mutated NSCLC with LM between 2014 and 2020 at our institute. The patient characteristics, treatment approaches, LM progression-free survival (LMPFS) and overall survival (OS) after the diagnosis of LM (OSLM) were analyzed. RESULTS: The median OSLM was 16.0 months and the 3-year OS rate was 22.5%. The PFSLM in EGFR T790M-positive NSCLC patients with leptomeingeal disease was significantly improved by initiation of third-generation tyrosine kinase inhibitors (TKIs) compared with that of patients who were T790M negative (14.0 vs. 7.0 months; P = 0.030). A significantly higher LM disease control rate was shown in patients who received third-generation TKIs compared with previous generations of TKIs (90.1% vs. 60.0%; P = 0.024). Better Eastern Cooperative Oncology Group performance status, EGFR exon 19del, and clinical improvement of LM after therapy were independently associated with better OS. CONCLUSIONS: The survival of patients with NSCLC with LM has improved in the target therapy era. Our study provided real-world clinical evidence that patients with EGFR-mutated NSCLC who developed LM from previous TKIs can be benefit from third-generation EGFR-TKIs, especially for patients with EGFR T790M-positive.

Molecular characteristics and prognostic factors of leptomeningeal metastasis in non-small cell lung cancer.

BACKGROUND: Non-small cell lung cancer with leptomeningeal metastasis (NSCLC-LM) is emerging as a new management challenge for oncologists and is associated with poor prognosis. This study aimed to investigate the molecular characteristics and prognostic factors of NSCLC-LM. METHODS: This retrospective study included 97 patients with NSCLC-LM between January 2015 and October 2021. Progression-free survival (PFS) and overall survival (OS) were evaluated. Gene mutations were detected by next-generation sequencing (NGS). RESULTS: The median PFS and OS were 8.4 (95 % confidence interval [CI]: 4.839-11.901) and 14.0 (95 % CI: 9.254-18.746) months, respectively. Sixty-seven patients harboured epidermal growth factor receptor-mutated (EGFRm): L858R (34), 19del (29), T790M (13), and G719C with L861Q (1). Other mutations included ALK (5), ROS1 (3), KRAS (1), TP53 (14), MET amplification (6). The detection rate and types of circulating tumour DNA (ctDNA) in the cerebrospinal fluid (CSF) samples were higher than the paired plasma samples. Patients with EGFR mutations had a longer median OS than those without mutations (19.0 vs. 13.0 months, P = 0.015). Patients with gene mutations had shorter median OS than those without mutations, such as ALK (11.8 vs. 19.9 months, P = 0.014), ROS1 (12.7 vs. 19.8 months, P = 0.014), KRAS (4.0 vs. 19.0 months, P = 0.005), TP53 (15.0 vs. 19.0 months, P = 0.014), and MET amplification (6.0 vs. 19.0 months, P = 0.003). Multivariate analysis indicated that MET amplification was an independent predictor of poor survival. Along with Eastern Cooperative Oncology Group Performance Status (ECOG PS) ≥ 3, LM accompanied with brain parenchymal metastasis (BPM), extracranial disease, and seizures were independent predictors of poor survival, whereas intrathecal chemotherapy, and third-generation EGFR-TKIs were independent predictors of favorable survival. CONCLUSIONS: CSF ctDNA detected using NGS had a high sensitivity for NSCLC-LM, showing high potential in detecting driver and drug-resistant gene mutations. Genomic profiles, combined with clinically relevant prognostic factors, will guide individualised treatments and improve the outcomes of NSCLC-LM patients.

Efficacy of different platforms in detecting EGFR mutations using cerebrospinal fluid cell-free DNA from non-small-cell lung cancer patients with leptomeningeal metastases.

BACKGROUND: Cell-free tumor DNA (ctDNA) obtained through liquid biopsy is useful for the molecular analysis of advanced non-small-cell lung cancer (NSCLC). Few studies have directly compared analysis platforms in terms of their diagnostic performance in analyzing ctDNA obtained from the cerebrospinal fluid (CSF) of patients with leptomeningeal metastasis (LM). METHODS: We prospectively analyzed patients with epidermal growth factor receptor (EGFR)-mutant NSCLC who were subjected to CSF analysis for suspected LM. To detect EGFR mutations, CSF ctDNA was analyzed using the cobas EGFR Mutation Test and droplet digital polymerase chain reaction (ddPCR). CSF samples from osimertinib-refractory patients with LM were also subjected to next-generation sequencing (NGS). RESULTS: Significantly higher rates of valid results (95.1% vs. 78%, respectively, p = 0.04) and EGFR common mutation detection (94.3% vs. 77.1%, respectively, p = 0.047) were obtained through ddPCR than through the cobas EGFR Mutation Test. The sensitivities of ddPCR and cobas were 94.3% and 75.6%, respectively. The concordance rate for EGFR mutation detection through ddPCR and the cobas EGFR Mutation Test was 75.6% and that for EGFR mutation detection in CSF and plasma ctDNA was 28.1%. In osimertinib-resistant CSF samples, all original EGFR mutations were detected through NGS. MET amplification and CCDC6-RET fusion were demonstrated in one patient each (9.1%). CONCLUSIONS: The cobas EGFR Mutation Test, ddPCR, and NGS appear to be feasible methods for analyzing CSF ctDNA in patients with NSCLC and LM. In addition, NGS may provide comprehensive information regarding the mechanisms underlying osimertinib resistance.

Prognostic impact of EGFR/ALK alterations in leptomeningeal metastasis from lung adenocarcinoma treated with whole-brain radiotherapy.

The prognosis and prognostic factors of patients receiving whole-brain radiotherapy (WBRT) for leptomeningeal metastasis (LM) from lung adenocarcinoma have not been established. Particularly, the impact of EGFR mutations and ALK rearrangements on survival remains unclear. This retrospective study evaluated the prognosis and prognostic factors of patients receiving WBRT for LM. We evaluated overall survival (OS) from WBRT initiation and clinical variables in 80 consecutive patients receiving WBRT for LM from lung adenocarcinoma at our institution between June 2013 and June 2021. After a median follow-up of 5.2 (range 0.5-56.5) months, the median OS was 6.2 months (95% CI 4.4-12.4). Of the 80 patients, 51 were classified as EGFR/ALK mutant (EGFR: 44; ALK: 6; both: 1) and 29 as wild-type. The median OS was 10.4 (95% CI 5.9-20.9) versus 3.8 (95% CI 2.5-7.7) months in the EGFR/ALK-mutant versus wild-type patients (HR = 0.49, P = 0.0063). Multivariate analysis indicated that EGFR/ALK alterations (HR = 0.54, P = 0.021) and Eastern Cooperative Oncology Group performance status (ECOG PS) of 0-1 (HR = 0.25, P < 0.001) were independent factors associated with favorable OS. Among the patients who underwent brain MRI before and after WBRT, intracranial progression-free survival was longer in the 26 EGFR/ALK-mutant than 13 wild-type patients (HR = 0.31, P = 0.0039). Although the prognosis of patients receiving WBRT for LM remains poor, EGFR/ALK alterations and good ECOG PS may positively impact OS in those eligible for WBRT.

Prognosticators of osimertinib treatment outcomes in patients with EGFR-mutant non-small cell lung cancer and leptomeningeal metastasis.

PURPOSE: Leptomeningeal metastasis (LM) is a serious complication of non-small cell lung cancer (NSCLC), particularly in patients with EGFR mutations. In this study, we investigated the survival outcomes of patients with EGFR-mutant NSCLC who have developed LM and explored the factors associated with their survival. METHODS: From April 2018 to November 2021, patients with EGFR-mutant NSCLC who underwent cerebrospinal fluid (CSF) sampling under the clinical suspicion of LM were enrolled. The patients' clinicodemographic characteristics, treatment history including whole-brain radiation therapy (WBRT), overall survival (OS), and intracranial progression-free survival (icPFS) were measured. EGFR mutations in cell-free tumor DNA (ctDNA) of CSF, including T790M mutation, were analyzed. RESULTS: We enrolled 62 patients with NSCLC. The median time form diagnosis to LM was 23.1 months and 16 (25.8%) patients had history of prior third-generation EGFR-TKI use. EGFR mutation in CSF ctDNA was detected in 53 patients (85.5%); of them, 10 (16.1%) had T790M mutation. The patients' icPFS and OS after osimertinib were 6.43 and 9.37 months, respectively, and were comparable among patients with different sensitive EGFR mutations, indicating that EGFR mutation status did not affect osimertinib efficacy. Patients who received WBRT after LM had numerically higher icPFS and OS compared to those without. Multivariate analysis revealed that lack of prior exposure to third-generation EGFR-TKI was associated with better OS. CONCLUSIONS: Osimertinib is effective in patients with EGFR-mutant NSCLC who developed LM and prior third-generation EGFR-TKI use was associated with poor survival in these patients. The role of WBRT warrants further investigation.