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Article

The Impact of Leptomeningeal Metastasis in Patients with Non-Small Cell Lung Cancer with EGFR Mutation: Survival Analysis of a Retrospective Cohort Study

by
Danilo Giffoni de Mello Morais Mata
1,2,*,
Tatianny P. Araujo Vargas
3,4,
Carlos Amir Carmona
3,4,
Abdullah Al-Humiqani
3,4,
Sara Gehlaut
2,
Alia Thawer
3,
Maria Romero
3,4,
Mark K. Doherty
3,4 and
Ines B. Menjak
3,4
1
Division of Medical Oncology, Verspeeten Family Cancer Centre, London Health Sciences Centre, London, ON N6A 5W9, Canada
2
Schulich School of Medicine and Dentistry, Western University, London, ON N6A 5C1, Canada
3
Division of Medical Oncology, Odette Cancer Centre, Sunnybrook Health Sciences Centre, Toronto, ON M4N 3M5, Canada
4
Department of Medicine, University of Toronto, Toronto, ON M5S 1A1, Canada
*
Author to whom correspondence should be addressed.
Therapeutics 2025, 2(2), 7; https://doi.org/10.3390/therapeutics2020007
Submission received: 13 February 2025 / Revised: 18 April 2025 / Accepted: 23 April 2025 / Published: 28 April 2025
Browse Figures
Versions Notes

Abstract

Background: In metastatic non-small cell lung cancer (NSCLC) with epidermal growth factor receptor (EGFR) mutation, osimertinib is the cornerstone treatment able to prolong overall survival (OS). Evidence around osimertinib being effective in leptomeningeal metastasis (LM) is scarce. Methods: We conducted a retrospective cohort study of patients with metastatic NSCLC-EGFR mutation treated with osimertinib at Sunnybrook Hospital. Results: We identified a total of 56 patients. Of these, 45 (79.4%) were never smokers, 53 (94.6%) had adenocarcinoma histology, and 26 (46.42%) had either the EGFR exon 21-L858R mutation or exon 19 deletion. The estimated median OS was 51 months (43.5–58.5). All eight patients with LM died during the study period. From the time of NSCLC diagnosis, the OS of patients without LM was 53 months (95% CI 47.2–58.7), and with LM was 21 months (95% CI 3.0–39), p = 0.001. However, the median OS from LM diagnosis was 2 months (95% CI, 1.0–26). Conclusions: In our population of patients with metastatic NSCLC-EGFR mutation who received osimertinib, there was a significant reduction in life expectancy in the group with LM. Patients who had advanced stage at diagnosis and were more likely to develop LM exhibited poorer survival compared to those who had early-stage cancer at diagnosis and developed metastases later on.

1. Introduction

Lung cancer is the cancer that is most responsible for oncologic-related mortality in the world [1]. Approximately 85% of all types of lung cancer are non-small cell lung cancer (NSCLC) [2]. At the time of diagnosis, 40–50% of patients with NSCLC are diagnosed with metastatic disease, and the estimated 5-year survival for stage IV disease is only 6% [3,4]. Previously, platinum-based chemotherapy was the only treatment for metastatic NSCLC. However, due to the better understanding of molecular pathways and the development of novel targeted therapies, the management of metastatic NSCLC has dramatically changed, with improvement in clinical outcomes [5].
Epidermal growth factor receptor (EGFR) mutation is one of the most common driver mutations of NSCLC. It is present in approximately 15–20% of Caucasians and more than 50% of Asians with a diagnosis of NSCLC, and it is more prevalent in non-smokers and women [6,7]. Among the EGFR mutation subtypes, sensitizing mutations in exons 19 or 21 are the most typical EGFR gene abnormality, comprising 45% and 40% of patients, respectively [8]. Targeted treatment for patients harboring classical EGFR mutations (L858R or exon 19 deletions (Ex19del)) using tyrosine kinase inhibitors (TKIs) demonstrated longer overall survival and progression-free survival, higher response rates, better quality of life, and decreased incidence of brain metastases [9,10].
Osimertinib is an oral third-generation EGFR-TKI, which, through irreversible mechanisms, terminates the natural course of EGFR driver mutation down-regulations [11,12]. Unlike its predecessors, osimertinib promotes downstream pathway cascade disruption in the intracellular domain, leading to DNA synthesis interruption and cancer cell apoptosis [12,13]. It selectively inhibits EGFR-TKI sensitizing domains and EGFR-T790M resistance mutations [14,15]. For patients with previously untreated EGFR mutation positivity (exon 19 deletion/L858R), the phase III FLAURA study showed significantly longer disease-free survival (DFS) and overall survival (OS) with osimertinib compared to the first and second generations of EGFR-TKI. The median OS was 38.6 months [95% confidence interval (CI), 34.5–41.8] in the osimertinib group versus 31.8 months (95% CI, 26.6–36.0) in the comparator EGFR-TKIs group, HR 0.80 [(95% CI, 0.64–1.00), p = 0.046] [16]. For previously treated patients with EGFR T790M-positivity, the phase III AURA 3 trial demonstrated an overall response rate (ORR) of 71% to osimertinib [16,17,18].
One of the characteristics of NSCLC-EFGR mutation is tropism for central nervous system (CNS) involvement, which includes brain and leptomeningeal metastases (LM). Brain metastases can occur in up to 70% of the cases, and LM is seen in between 3% and 5% of patients [19,20]. The estimated OS in NSCLC patients with LM ranges from 3 to 10 months [19,20]. Although LM is a rare and severe event, the NSCLC-EGFR population has double the likelihood of developing LM compared to non-EGFR patients [21].
Thankfully, the third-generation EGFR-TKI osimertinib demonstrates greater penetrance across the blood-brain barrier compared to other TKIs. In addition to demonstrating improved CNS activity with a 70% intracranial response rate, osimertinib also showed efficacy in delaying LM progression, with a 55% response rate in EGFR T790M-positive NSCLC [20,22]. Hence, based on superior CNS efficacy, osimertinib is the standard systemic therapy for EGFR-positive NSCLC, including patients with brain and LM involvement [23,24].
This study aimed to carry out a descriptive analysis and evaluate the survival outcomes and risk factors of patients with metastatic NSCLC-EGFR mutation treated with osimertinib.

2. Materials and Methods

2.1. Study Design and Data Sources

We conducted a retrospective observational study using data from electronic medical records at Sunnybrook Health Sciences Centre, Toronto, Ontario, Canada. The Research Ethics Board from Sunnybrook approved this study.

2.2. Study Population

We identified consecutive patients diagnosed with metastatic NSCLC with EGFR mutation between January 2010 and December 2018. All patients had an NSCLC diagnosis through tissue biopsy. The EGFR mutation was detected by tissue sampling or analyzing plasma circulating tumor DNA (ctDNA) using either next-generation sequencing (NGS) or digital polymerase chain reaction (PCR) methods to identify EGFR mutations. The latter utilized the Entrogen EGFR Mutation Analysis Kit for Real-Time PCR. All patients were treated with osimertinib 80 mg daily. Exclusion criteria included (a) history of a second malignancy, (b) missing information regarding patient’s baseline or tumor characteristics and date of cancer diagnosis, (c) received osimertinib for less than 30 days, (d) LM at baseline.

2.3. Outcomes

The primary endpoint was the OS of the study population. The secondary outcomes of interest were (a) OS of patients with a diagnosis of LM vs. without LM; (b) OS stratified by cancer stage at diagnosis; and (c) association between the survival time of patients and the predictor variables of choice.

Statistical Analysis

Survival analysis was used to evaluate the incidence rate of mortality. The non-parametric Kaplan–Meier (KM) estimator and the log rank (Mantel–Cox) test were used to estimate and compare survival distribution over time between two population samples. Due to clinical relevance, a 95% confidence interval (CI) of the survival median was selected. Cox proportional-hazards (PH) models were utilized to investigate whether there was an association between the survival time of patients and the predictive factors identified as their baseline characteristics.
The endpoint OS was calculated in months from the date of NSCLC diagnosis until patients were censored or the date of the event (death). Time-to-event of death was considered the time from the NSCLC diagnosis to death. Patients were censored if they were alive at the end of the data collection period or were lost to follow-up. Two-sided p-values were tested and considered significant at p ≤ 0.05. The data analysis was performed using the software IBM® SPSS® Statistics version 27.

2.4. Covariates

The dichotomous variables were LM, cancer stage at diagnosis, smoking status, and gender. LM was defined as cancer involving the meninges. Early stage was defined as cancer stages I, II, or III, and advanced stage as stage IV or metastasis at diagnosis. LM and cancer stage were classified radiologically. Our study utilized the TNM classification based on the eighth edition of the American Joint Committee on Cancer’s Staging for lung cancer [25]. In this population sample, age was considered a continuous variable.

3. Results

3.1. Patient Characteristics

We identified 56 patients diagnosed with metastatic NSCLC-EGFR mutation. Of those, 45 (79.4%) were never smokers. Among the entire cohort, 53 patients (94.6%) had adenocarcinoma, 2 (3.6%) had squamous cell carcinoma, and 1 (1.8%) had mixed histology of adeno-squamous carcinoma. The largest majority of the study population, 41 patients (73.2%), had advanced stage disease, classified as stage IV at diagnosis (Table 1). A similar proportion of patients, 26 (46.42%), had the EGFR exon 21-L858R mutation and exon 19 deletion, and only 4 had an uncommon type or unknown type of EGFR mutation. The T790M point mutation was detected in 43 (76.7%) patients, of whom 24 (46.4%) received this diagnosis through plasma testing and 19 (28.5%) through biopsy.

3.2. Treatment Characteristics

Most of the study population was treated with osimertinib as second-line therapy and onwards, comprising 47 (84%) patients. A total of 50 (89%) patients received first- or second-generation EGFR-TKI prior to osimertinib (Table 2). A total of eight (14.3%) patients had LM, and all of them had brain metastasis. Among those eight, there was only one who did not receive palliative radiotherapy and seven (87.5%) who received whole-brain radiotherapy (WBRT), specifically to treat LM. A total of 28 (50%) patients had brain metastasis, of whom only 4 (14.3%) had surgical resection of brain metastases. All patients with brain metastasis received CNS radiotherapy. Concerning radiation modalities, 19 (67.9%) received gamma knife radiation, 12 (42.85%) were treated with stereotactic radiosurgery, and 16 (57.1%) underwent WBRT.

3.3. Descriptive Statistics

3.3.1. Survival Comparison to Evaluate Leptomeningeal Metastasis

From NSCLC diagnosis to death, the estimated median OS for the entire study population was 51 months (95% CI, 43.5–58.5) (Figure 1). Of those, 48 patients did not have LM: 24 (50%) died, and 24 (50%) were censored. Of the total 56 patients, 8 had LM, and all 8 died. The estimated median OS for the group without LM was 53 months (95% CI, 47.2–58.7 months), and the median OS for the group with LM was 21 months (95% CI, 3.0–39 months) p = 0.001 (Figure 2).
Among all eight patients diagnosed with LM, there were five who exhibited LM after progression on first-line, second-generation EGFR-TKI. They all received osimertinib in the second-line setting. Their median duration of osimertinib treatment was 6.5 months (95% CI, 1.0–15 months). Amid those, there was one patient who received osimertinib for 15 months, followed by third-line ICI and fourth-line platinum-doublet chemotherapy with taxane, with a progression of 26 months after the initial finding of LM.
There were two patients who had LM after disease progression on second-line osimertinib. None of them received any further systemic therapy after the LM event.
There was one patient diagnosed with LM after disease progression on third-line treatment. This preceded treatment with second-line osimertinib for 9 months, followed by platinum-doublet chemotherapy with taxane for 4 months.
Overall, in the group of patients with NSCLC who had LM, the median duration of osimertinib treatment was 9 months (95% CI, 1.0–15 months). The median OS from the LM diagnosis was 2 months (95% CI, 1.0–26 months).

3.3.2. Survival Comparison to Evaluate LM, Stratified by Cancer Stage at Diagnosis

Among patients who had early-stage cancer at diagnosis, the estimated median OS in those without LM was 86 months (95% CI, 33.7–138.3 months) and in those with LM was 51 months (95% CI, 20.6–81.4 months, p = 0.122) (Figure A1A Appendix A). In the group of patients who had advanced-stage cancer at diagnosis, the estimated median OS in those with no LM was 53 months (95% CI, 44.6–61.4 months) and in those who had LM was 19 months (95% CI, 10.5–27.6 months), p < 0.0001 (Figure A1B, Appendix A).

3.3.3. Association Between the Survival Time of Patients and the Predictor Variables of Choice

In the adjusted analysis containing the predictor variables cancer stage and age at diagnosis, smoking status, and gender, patients with LM had a higher likelihood of death, HR 8.27 (95% CI, 3.10–22.0, p < 0.0001). Patients with advanced-stage cancer at diagnosis had a higher likelihood of death, HR 4.72 (95% CI, 1.75–12.77, p = 0.002) (Table 3).

4. Discussion

4.1. Key Findings and Comparative Analysis with Other Studies

In our NSCLC-EGFR population, all patients who developed LM had received at least one line of systemic therapy, consisting of first-line afatinib or gefitinib, in the metastatic setting. In the analysis of OS from NSCLC diagnosis to death, having LM led to a significant absolute reduction in OS by 32 months compared to those without LM. Nevertheless, with regards to the OS analysis from LM to death, the median OS was 2 months, regardless of the systemic treatment received.
In the cohort of advanced-stage cancer at diagnosis, there was a significant absolute lower OS by 34 months seen in the group with LM. No difference in survival was seen among those who had an initial diagnosis of early-stage cancer and who developed LM over their lifetime developed versus those who did not develop LM. Our results found an association between survival time of NSCLC-EGFR patients and the predictor variables LM and cancer stage at diagnosis, but no association with age at diagnosis, smoking status, or gender. There were no survival differences between patients with versus without brain metastasis (95% CI 43.5–58.5 months), p = 0.409 (Figure A2, Appendix A).
From the time of LM diagnosis, while other studies of NSCLC [19,20] have reported that patients with and without EGFR mutation have OSs ranging from 3 to 10 months, our population exhibited OSs ranging from 1 to 26 months. Many factors could have contributed to that result. First, all our patients had EGFR mutation and were treated with two sequential lines of EGFR-TKI, one being osimertinib. Second, all patients with LM, except one, received whole-brain radiation to treat LM. All of these patients also had brain metastasis and were treated with palliative CNS radiotherapy.
In other studies, the third-generation TKI osimertinib has demonstrated a significant ability to penetrate the blood-brain barrier effectively, with increased rates of controlling brain metastasis, delaying CNS progression, and improving survival, when compared to first or second generations [19,26]. A comprehensive systematic review and meta-analysis evaluating the effectiveness of osimertinib in the treatment of LM revealed a cumulative 1-year OS rate of 59% among 233 patients across five studies (95% CI 53–65%). In this review, the median OS ranged from 11.0 to 18.8 months and the median PFS from 3.7 to 17.3 months. Furthermore, one study indicated that patients treated with osimertinib demonstrated improved OS compared to those not treated with osimertinib (17.0 vs. 5.0 months, HR = 0.36 (95% CI 0.28–0.47) [27].
For decades, the management of LM has been based exclusively on directed local therapies, including WBRT and intrathecal chemotherapy (ITC), providing improvement of neurological symptoms and questionable or discrete survival benefit, at the expense of neurotoxicity [28]. A pooled analysis of four prospective trials and five retrospective observational studies, including a more significant number of NSCLC patients with a diagnosis of LM, showed that the clinical response rates with intrathecal chemotherapy (ITC) ranged from 71% to 79%, leading to a median OS of 7.5 months. Hence, ITC was shown to have a higher relative benefit when compared to WBRT, first- or second-generation TKIs, and chemotherapy. None of these interventions was associated with OS longer than 5 months. Based on these findings, ITC might improve clinical outcomes in NSCLC-LM [29]. Recently, a phase I–II trial evaluated the role of intrathecal pemetrexed in 30 patients with NSCLC-EGFR with LM diagnosis. With a clinical response rate of 84.6%, the median OS reached 9.0 months (95% CI 6.6–11.4 months) [30].
Given the low incidence of metastatic NSCLC with LM events, this topic has limited data. No randomized controlled trials were identified that included patients with NSCLC-EGFR and LM diagnosis, as this condition is commonly an exclusion criterion in clinical trials [22,31]. Furthermore, real-world data, including for patients with NSCLC and patients with LM, are scarce. Most studies carried out have had retrospective cohort designs and small sample sizes [32].
Nevertheless, the phase II, non-randomized, single-arm BLOSSOM study examined a cohort of 73 participants diagnosed with NSCLC-EGFR mutation, who presented with LM following treatment with first- or second-generation EGFR-TKIs. As part of the study protocol, patients were treated with osimertinib, and prior radiotherapy, which included WBRT or intrathecal chemotherapy, was allowed up to 2 weeks before study enrollment. Furthermore, this investigation assessed the pharmacokinetics of osimertinib in both plasma and cerebrospinal fluid (CSF). The results indicated that the median OS was 15.6 months (95% CI, 11.5–20.2) and intracranial PFS was 12.5 months (95% CI, 9.6–16.6). The pharmacokinetic analysis indicated that osimertinib at an 80 mg dose, when analyzed by CSF-to-free plasma ratio, yielded comparable CSF concentrations and OS to those observed with the 160 mg dosage, thereby supporting the effectiveness of osimertinib at an 80 mg daily regimen in patients with LM, irrespective of T790M mutation status [33].
Before the era of third-generation EGFR-TKI, one retrospective study demonstrated that erlotinib elicited a superior response in patients with NSCLC-EGFR-mutated with LM compared to gefitinib, likely due to the higher penetration of erlotinib through the blood-brain barrier [34]. An extensive Chinese retrospective study of 5387 patients showed a higher prevalence of LM in NSCLC-EGFR-mutated when compared to EGFR wild-type (9.4% vs. 1.7%). Among those harboring EGFR mutations with LM diagnosis, the group treated with first- and second-generation TKIs exhibited prolonged survival, compared to those who did not receive TKIs (10.0 months versus 3.3 months). Interestingly, this survival advantage was not seen in patients with NSCLC-EGFR-mutated who received WBRT [35]. One retrospective study included 80 patients with NSCL with a radiological diagnosis of LM. This study revealed an absolute survival benefit of 5.9 months in patients treated with WBRT for LM with NSCLC-EGFR wild-type when compared to EGFR-mutated, HR 0.23 [(OS: 8.0 vs. 2.1 months), p = 0.002] [32].
In TKI failure scenarios, a European retrospective study included 92 patients with EGFR-mutated NSCLC who received LM, and patients rechallenged with a subsequent EGFR-TKI generation had an OS of 7.6 months compared to 4.2 months in those who did not receive additional EGFR-TKI therapy [36]. A prospective pilot study using osimertinib, including 13 patients with LM harboring NSCLC-EGFR and T790M mutations, showed that standard-dose osimertinib led to a median progression-free survival (PFS) of 7.2 months after progression on first- or second-generation EGFR-TKIs [37]. Supporting the hypothesis that higher doses of osimertinib could increase drug penetration and activity in the CNS, the BLOOM study was a phase I non-randomized, single-arm trial that tested the efficacy and safety of osimertinib at 160 mg in 42 patients with LM and NSCLC-EGFR-mutated after failure to EGFR-TKI therapy. This study revealed a remarkable ORR of 62%, PFS of 8.6 months, and median overall treatment duration response of 15.2 months (7.5 to 17.5 months). This trial met the safety profile requirements of osimertinib, which was administered at doubled dosage, demonstrating a potential treatment option for this population with LM disease [21].
Data are scarce regarding the role of immune checkpoint inhibitors (ICIs) in patients with NSCLC with LM diagnosis [38]. One retrospective cohort study included only 19 patients with NSCLC and an LM diagnosis, demonstrating a discrete benefit with the usage of ICIs. In this study, PFS was 2.0 (95% CI, 1.8–2.2) months, and OS was 3.7 months (95% CI, 0.9–6.6) [39]. Phase II trials showed substantial effectiveness of single-agent pembrolizumab and the combination of nivolumab with ipilimumab in patients with different solid tumors, not exclusively NSCLC. However, given the small sample size, some of these studies did not have the statistical power to identify a meaningful difference between the groups under investigation. Perhaps a prospective study focusing on NSCLC with LM would be warranted for achieving robust evidence [40,41,42].
Similarly, there is insufficient evidence about combining ICIs with EGFR-TKIs for treating NSCLC with LM [43]. While there are isolated studies and case reports about transient successful experiences of combinations between both drug classes, in stage IV NSCLC [44], the addition of ICI to EGFR-TKI led to interstitial lung disease/pneumonitis in 22% of patients in the TATTON study, and 71.4% of patients developed grade 3 hepatotoxicity in the phase I/II KEYNOTE-021 trial [45,46]. A case report described life-threatening Stevens–Johnson syndrome leading to severe liver toxicity induced by osimertinib started shortly after the last exposure to pembrolizumab [47]. None of these studies or individual case descriptions tested ICIs with EGFR-TKIs in patients with metastasis involving the leptomeninges.
Nonetheless, it is essential to highlight that our research encompassed individuals who received a diagnosis of NSCLC within the specified timeframe of 2010 and 2018, during which nearly 90% of them received osimertinib only after experiencing failure with first- or second-generation EGFR-TKIs. It should be noted that the vast majority of our patients received osimertinib through compassionate access or a clinical trial before provincial funding was granted. At our institution, a few patients started accessing first-line osimertinib in September 2018 via private insurance.

4.2. EGFR Resistance Mechanisms

Chronic exposure to EGFR-targeted therapy often leads to decreased treatment response duration due to the development of resistance from alterations in EGFR oncogenic drivers [48]. Resistance mechanisms are classified as EGFR-dependent or EGFR-independent. One of the most prevalent acquired resistance mechanisms observed following first-line treatment failure with first- or second-generation EGFR-TKIs is the T790M mutation [49]. Moreover, the third-generation TKI osimertinib has demonstrated efficacy regardless of the T790M mutation in EGFR-TKI naïve patients and those previously treated with earlier generations of EGFR-TKIs [50].
The predominant mechanism of acquired resistance to osimertinib is linked to the development of the C797S mutation arising during osimertinib exposure. The C797S resistance mutation inhibits osimertinib from binding to the EGFR protein, especially during second-line treatment, decreasing treatment efficacy [51,52]. Another factor identified as a predictor of developing resistance to osimertinib is enhanced expression of the epithelial-mesenchymal transition (EMT)-associated gene AXL [53]. It has been hypothesized that the molecular mechanisms underlying this resistance to EGFR-targeted therapy include involvement of stem cell–like properties, downregulation of the pro-apoptotic protein Bcl-2-like protein 11, and chromatin remodeling promoted by EMT transcription factors [54,55,56].
Regarding EGFR-TKI resistance in patients with LM diagnosis, Li et al. demonstrated that CSF, obtained via a mini-invasive procedure, exhibits greater sensitivity than plasma and reflects the distinct genetic profiles associated with LM [57]. Zheng et al. conducted a study involving patients with EGFR-mutated advanced NSCLC diagnosed with LM. CSF genotyping was performed at the time of LM diagnosis, prior to initiating or during treatment with osimertinib. The study concluded that CSF genotyping demonstrated a heterogeneous effect of osimertinib and identified cell cycle alterations, specifically CDK4 and CDKN2A, as being linked to unfavorable outcomes. Furthermore, analysis of CSF may uncover resistance mechanisms contributing to osimertinib failure and LM progression, including the C797S mutation, MET dysregulation, and TP53 and RB1 mutations [58].
To address and overcome treatment resistance mechanisms that hinder the effectiveness of therapies in tumors harboring EGFR mutation, preclinical and early-phase clinical trials are underway, assessing the safety and anti-tumor activity of new treatments, particularly high-affinity reversible EGFR-TKIs. These novel agents are designed to target the C797S and T790M mutations, while also improving the inhibitory mechanisms of oncogenic pathways recognized as predictors of resistance to osimertinib [59].

4.3. Strengths and Limitations

We aimed to perform a retrospective real-world analysis of patients with metastatic NSCLC-EGFR mutation treated with osimertinib through a descriptive and observational cohort study. Regarding the strengths of this work, we developed the Lung Cancer Biomatrix database of highly reliable individual-level data from patients registered at Sunnybrook Hospital. To minimize selection bias, we utilized refined and comprehensive inclusion criteria by excluding NSCLC patients with missing baseline characteristics and treatment information. The adjusted analysis included relevant patients’ prognostic and NSCLC characteristics. On the other hand, these attempts reduced the eligible population. Nonetheless, despite the small sample size, there were enough events included to answer the outlined research questions regarding survival outcomes.
Regarding the weaknesses of this study, it is notable that the small sample size restricted evaluation of the association of survival in the Cox PH multivariate models. Although all patients developed metastasis over their lifetime, there is a potential survival bias, since there were patients who, at the moment of diagnosis, had early-stage cancer and others who had advanced-stage cancer, the latter of which may have a shorter survival time. Other limitations include potential confounding factors due to the heterogeneity of the population and systemic treatment dosages and compliance. Moreover, the radiation treatment modalities and fractions/doses used to treat LM may have differed. There is a possible selection bias for LM diagnosis, which depends on the radiologist’s interpretation of neurological images. Lastly, to avoid multicollinearity concerns between the variables LM and brain metastasis, the latter was neither included in the adjusted analysis nor assessed with regards to the delivered radiation therapy treatment modalities.

5. Conclusions

In our population of patients with metastatic NSCLC-EGFR mutation who received third-generation EGFR-TKI, we found consistent findings of reduced life expectancy in the cohort with leptomeningeal disease, irrespective of the sequence in which osimertinib was administered. We found that patients who had advanced-stage cancer at diagnosis were more likely to develop LM and to have poorer survival when compared to those who had early-stage cancer at diagnosis and developed metastases later on.
Many questions remain unanswered regarding the specific effectiveness of osimertinib in treating NSCLC with EGFR mutation in patients with LM. Thus, in light of the limited number of randomized trials involving participants with LM, prospective studies must be undertaken to enroll a substantial number of patients to support the clinical benefits observed in previous data and establish a standardized treatment approach for this condition.

Author Contributions

Conceptualization, D.G.d.M.M.M. and I.B.M.; methodology, D.G.d.M.M.M. and I.B.M.; software, D.G.d.M.M.M.; validation, D.G.d.M.M.M. and I.B.M.; formal analysis, D.G.d.M.M.M. and T.P.A.V.; investigation, D.G.d.M.M.M., T.P.A.V. and I.B.M.; resources, D.G.d.M.M.M. and I.B.M.; data curation, D.G.d.M.M.M. and T.P.A.V.; writing—original draft preparation, D.G.d.M.M.M. and T.P.A.V.; writing—review and editing, D.G.d.M.M.M., T.P.A.V., C.A.C., A.A.-H., S.G., A.T., M.R., M.K.D. and I.B.M.; visualization, D.G.d.M.M.M., T.P.A.V. and I.B.M.; supervision, D.G.d.M.M.M. and I.B.M.; project administration, D.G.d.M.M.M. and I.B.M.; funding acquisition, I.B.M. All authors have read and agreed to the published version of the manuscript.

Funding

This research received no external funding.

Institutional Review Board Statement

This study was conducted following the Declaration of Helsinki and approved by the Institutional Review Board of Sunnybrook Health Sciences Centre (protocol code: SUN-3683, 29 December 2023).

Informed Consent Statement

Under the legislation of Ontario Health’s privacy information program, patients’ written informed consent was waived.

Data Availability Statement

Data are unavailable due to privacy or ethical restrictions.

Acknowledgments

We would like to thank Rachel Lau for contributing to the revision of this manuscript’s methodology and Mkeila Sowa for formatting and editing the attached tables. All individuals included in this section have consented to the acknowledgement.

Conflicts of Interest

The authors declare no conflicts of interest.

Appendix A

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Figure A1. Kaplan-Meier estimates of survival in patients with LM and NSCLC-EGFR mutation. (A) Early-stage cancer and (B) advanced-stage cancer.
Figure A1. Kaplan-Meier estimates of survival in patients with LM and NSCLC-EGFR mutation. (A) Early-stage cancer and (B) advanced-stage cancer.
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Figure A2. Kaplan-Meier estimates of survival for brain metastasis in patients with NSCLC-EGFR mutation.
Figure A2. Kaplan-Meier estimates of survival for brain metastasis in patients with NSCLC-EGFR mutation.
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Figure 1. Kaplan–Meier estimates of survival in patients with NSCLC-EGFR.
Figure 1. Kaplan–Meier estimates of survival in patients with NSCLC-EGFR.
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Figure 2. Kaplan-Meier estimates of survival in patients with LM and NSCLC-EGFR mutation.
Figure 2. Kaplan-Meier estimates of survival in patients with LM and NSCLC-EGFR mutation.
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Table 1. Baseline characteristics of patients with metastatic NSCLC-EGFR mutation.
Table 1. Baseline characteristics of patients with metastatic NSCLC-EGFR mutation.
CharacteristicStatusTotal
N = 56 (%)
GenderFemale38 (67.8%)
Male18 (32.2%)
Smoking StatusNever Smoker45 (80.3%)
Smoker11 (19.7%)
HistologyAdenocarcinoma53 (94.6%)
Squamous Cell2 (3.6%)
Adeno-squamous1 (1.8%)
Cancer Stage at DiagnosisI1 (1.8%)
II2 (3.6%)
III12 (21.4%)
IV41 (73.2%)
EGFR MutationExon 21-L858R 26 (46.4%)
Exon 19 deletion 26 (46.4%)
Unknown 4 (7.1%)
T790 MutationPositive 43 (76.7%)
Negative 5 (8.9%)
Unknown 8 (14.2%)
T790 Mutation Assay MethodPlasma ctDNA 24 (42.8%)
Biopsy 19 (34%)
Unknown 13 (23.2%)
OsimertinibFirst line 9 (16.0%)
Second line 47 (84.0%)
Brain MetastasisYes 28 (50.0%)
No 28 (50.0%)
Leptomeningeal MetastasisYes 8 (14.3%)
No 48 (85.7%)
Table 2. Treatment characteristics for patients with metastatic NSCLC-EGFR mutation.
Table 2. Treatment characteristics for patients with metastatic NSCLC-EGFR mutation.
Treatment LineDrug ClassPopulation
First Line Total (N = 56)
EGFR-TKI (Gefitinib)27 (48.2%)
EGFR-TKI (Afatinib)14 (25.0%)
EGFR-TKI (Osimertinib)9 (16.1%)
EGFR-TKI (Erlotinib)3 (5.4%)
Platinum Doublet Chemotherapy2 (3.6%)
Immune Checkpoint Inhibitor1 (1.8%)
Second Line Total (N = 41)
EGFR-TKI (Gefitinib)2 (4.9%)
EGFR-TKI (Afatinib)2 (4.9%)
EGFR-TKI (Osimertinib)28 (68.3%)
EGFR-TKI (Erlotinib)1 (2.4%)
Platinum Doublet Chemotherapy7 (17.1%)
Immune Checkpoint Inhibitor1 (2.4%)
Third Line Total (N = 19)
EGFR-TKI (Gefitinib)1 (5.3%)
EGFR-TKI (Afatinib)1 (5.3%)
EGFR-TKI (Osimertinib)5 (26.3%)
EGFR-TKI (Erlotinib)1 (5.3%)
Platinum Doublet Chemotherapy8 (42.1%)
Immune Checkpoint Inhibitor2 (10.5%)
EGFR-TKI (Osimertinib plus Savolitinib)1 (5.3%)
Fourth Line Total (N = 20)
EGFR-TKI (Afatinib)2 (10.0%)
EGFR-TKI (Osimertinib)7 (35.0%)
EGFR-TKI (Erlotinib)1 (5.0%)
Platinum Doublet Chemotherapy7 (35.0%)
Immune Checkpoint Inhibitor2 (10.0%)
EGFR-TKI (Osimertinib plus Savolitinib)1 (5.0%)
Table 3. Cox proportional hazard model—multivariable analysis.
Table 3. Cox proportional hazard model—multivariable analysis.
CovariatesHR95% CIp Value
Leptomeningeal Metastasis8.273.10–22.0<0.001
Cancer Stage at Diagnosis4.721.75–12.770.002
Age at Diagnosis1.010.97–1.050.539
Smoking Status1.060.47–2.390.875
Gender2.110.92–4.820.760
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Giffoni de Mello Morais Mata, D.; Vargas, T.P.A.; Carmona, C.A.; Al-Humiqani, A.; Gehlaut, S.; Thawer, A.; Romero, M.; Doherty, M.K.; Menjak, I.B. The Impact of Leptomeningeal Metastasis in Patients with Non-Small Cell Lung Cancer with EGFR Mutation: Survival Analysis of a Retrospective Cohort Study. Therapeutics 2025, 2, 7. https://doi.org/10.3390/therapeutics2020007

AMA Style

Giffoni de Mello Morais Mata D, Vargas TPA, Carmona CA, Al-Humiqani A, Gehlaut S, Thawer A, Romero M, Doherty MK, Menjak IB. The Impact of Leptomeningeal Metastasis in Patients with Non-Small Cell Lung Cancer with EGFR Mutation: Survival Analysis of a Retrospective Cohort Study. Therapeutics. 2025; 2(2):7. https://doi.org/10.3390/therapeutics2020007

Chicago/Turabian Style

Giffoni de Mello Morais Mata, Danilo, Tatianny P. Araujo Vargas, Carlos Amir Carmona, Abdullah Al-Humiqani, Sara Gehlaut, Alia Thawer, Maria Romero, Mark K. Doherty, and Ines B. Menjak. 2025. "The Impact of Leptomeningeal Metastasis in Patients with Non-Small Cell Lung Cancer with EGFR Mutation: Survival Analysis of a Retrospective Cohort Study" Therapeutics 2, no. 2: 7. https://doi.org/10.3390/therapeutics2020007

APA Style

Giffoni de Mello Morais Mata, D., Vargas, T. P. A., Carmona, C. A., Al-Humiqani, A., Gehlaut, S., Thawer, A., Romero, M., Doherty, M. K., & Menjak, I. B. (2025). The Impact of Leptomeningeal Metastasis in Patients with Non-Small Cell Lung Cancer with EGFR Mutation: Survival Analysis of a Retrospective Cohort Study. Therapeutics, 2(2), 7. https://doi.org/10.3390/therapeutics2020007

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