Activity of EGFR Tyrosine Kinase Inhibitors in NSCLC With Refractory Leptomeningeal Metastases

Flippot, Ronan; Biondani, Pamela; Auclin, Édouard; Xiao, Dingyu; Hendriks, Lizza; Rhun, Émilie Le; Leduc, Charlotte; Beau‐Faller, Michèle; Gervais, Radj; Remón, Jordi; Adam, Julien; Planchard, David; Lavaud, Pernelle; Naltet, Charles; Caramella, Caroline; Péchoux, C. Le; Lacroix, Ludovic; Gazzah, Anas; Mezquita, Laura; Besse, Benjamin

doi:10.1016/j.jtho.2019.05.007

Cited by 24 publications

(25 citation statements)

References 24 publications

(34 reference statements)

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“…We observed a prolongation of PFS to 9.6 months (95% CI: 3.4-15.8 months) in treated patients, while OS is currently immature. This survival result is superior to a previous study of TKI rechallenging in rLM patients with EGFR mutations, which showed a median survival time of 6.1 months (13). This is primarily due to the fact that our study used a combination of intrathecal therapy coupled with targeted therapy and a more complex chemotherapy and/or antivascular treatment paradigm.…”

Section: Discussioncontrasting

confidence: 58%

Multiple combination therapy based on intrathecal pemetrexed in non-small cell lung cancer patients with refractory leptomeningeal metastasis

et al. 2020

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Background: Leptomeningeal metastasis (LM) is a fatal complication, and its incidence is increasing in non-small cell lung cancer (NSCLC). Refractory LM (rLM) has become problematic due to the lack of uniform definition and standardized treatment guidelines. In this study, we assessed the efficacy and safety of multiple therapy based on intrathecal pemetrexed (IP) in patients with rLM in NSCLC. Methods: From March 2019 to June 2020, patients with cytologically confirmed rLM who received IP and systemic salvage therapy were retrospectively analyzed. Our objectives were to assess progressionfree survival (PFS), overall survival (OS), clinical response, and safety. Clinical response was assessed by an investigator according to the Response Assessment in Neuro-Oncology (RANO) proposal criteria. We performed next generation sequencing (NGS) of cerebrospinal fluid (CSF) to explore the gene profile of rLM.Results: A total of 23 patients were enrolled, and the genetic status of the primary tissue was 16 epidermal growth factor receptor (EGFR) mutations (69.6%), two anaplastic lymphoma kinase (ALK) fusions (8.7%), one ROS proto-oncogene 1 (ROS1) fusion (4.3%), one Erb-B2 receptor tyrosine kinase 2 (ERBB2) mutation (4.3%), and three wild-type (13.0%). On the basis of IP therapy, 19 patients were rechallenged with tyrosine-kinase inhibitors (TKIs), 10 patients were treated with systemic chemotherapy, 10 patients were treated with antivascular therapy, one patient was treated with immunotherapy, and one patient was treated with whole-brain radiotherapy (WBRT). Thirteen patients received two or more of the aforementioned combination treatment modes. The median PFS (mPFS) was 9.6 months [95% confidence interval (CI): 3.4-15.8 months]. OS was not mature at the final follow-up. The clinical assessment was: response in eight patients (34.8%), stable in 11 patients (47.8%), worse in two patients (8.7%), and non-evaluable in two patients (8.7%). Adverse events (AEs) related to any component occurred in 14 patients (60.9%). The driver mutation status was highly consistent between the CSF and primary tumor samples (14/14), but we detected EGFR mutations in the CSF of two patients whose primary tumor samples tested wild-type.Conclusions: IP-based multimodal therapy has significant efficacy and a controlled safety profile in patients with rLM in NCSLC.

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Section: Discussioncontrasting

confidence: 58%

Multiple combination therapy based on intrathecal pemetrexed in non-small cell lung cancer patients with refractory leptomeningeal metastasis

et al. 2020

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“…35 Another retrospective study reported an LM OS of 7.6 months in patients rechallenged with EGFR-TKIs after EGFR-TKI failure (n ¼ 50). 36 In a prospective study of patients treated with afatinib (n ¼ 11), ORR was 27.3%; median PFS and OS were 2.0 and 3.8 months, respectively. 37 Given the limitations of the existing treatments for LM and the poor OS reported for firstand second-generation EGFR-TKIs, the encouraging efficacy reported here suggests that osimertinib is the most promising treatment option for patients with LMs of EGFR T790M-positive NSCLC.…”

Section: Discussionmentioning

confidence: 98%

Osimertinib for Patients With Leptomeningeal Metastases Associated With EGFR T790M-Positive Advanced NSCLC: The AURA Leptomeningeal Metastases Analysis

Ahn

Chiu

Cheng

et al. 2020

Journal of Thoracic Oncology

105

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Introduction: Osimertinib has shown promising activity in patients with leptomeningeal metastases (LMs) of EGFRpositive NSCLC at 160 mg once daily (qd) (BLOOM; NCT02228369). We report LM activity with osimertinib (80 mg qd) in a retrospective analysis of studies across the AURA program (AURA extension, AURA2, AURA17, and AURA3). Methods: Patients with EGFR T790M-positive advanced NSCLC and progression after previous EGFR-tyrosine kinase inhibitor therapy received osimertinib (80 mg qd). Patients with central nervous system (CNS) metastases (including LMs) were eligible if the lesions were neurologically asymptomatic and stable. Patients with evidence of LMs at the study entry were retrospectively included for the analysis; brain scans were assessed for radiologic LM response by neuroradiologically blinded, independent central review per the modified Response Assessment in Neuro-Oncology LM criteria. LM objective response rate, duration of response, progression-free survival, and overall survival were assessed. A longitudinal analysis was performed to investigate the relationship between changes from the baseline in non-CNS tumor sizes and LM responses at each visit of patients in AURA LM and BLOOM studies. Results: For the 22 patients included in the analysis, LM objective response rate was 55% (95% confidence interval [CI]: 32-76). Median LM duration of response was not reached (95% CI: 2.8-not calculable [NC]). Median LM progression-free survival and overall survival were 11.1 months (95% CI: 4.6-NC) and 18.8 months (95% CI: 6.3-NC), respectively. The longitudinal analysis revealed similar non-CNS and LM responses between the patients in AURA LM and BLOOM programs. Conclusions: Patients with EGFR T790M-positive NSCLC and radiologically detected LM obtained clinical benefit from osimertinib (80 mg qd).

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“…The OS after LM was remarkably improved in the TKI therapy group versus non-TKI treatment (10.0 vs. 3.3 months) [2]. Another multicenter retrospective analysis from Europe consisting of 92 EGFR-mutated NSCLC patients with LM showed that the median OS from diagnosis of LM was 6.1 months; re-challenging with TKI in TKI-failed patients showed a better prognosis versus patients without further therapy (7.6 vs. 4.2 months) [19].…”

Section: Discussionmentioning

confidence: 99%

Whole brain radiotherapy (WBRT) for leptomeningeal metastasis from NSCLC in the era of targeted therapy: a retrospective study

et al. 2020

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Background and purpose: Leptomeningeal metastasis (LM) is a rare but detrimental complication in patients with non-small cell lung cancer (NSCLC). Although whole brain radiotherapy (WBRT) is used to eliminating cancer cells or microscopic foci, it is becoming less favorable due to the concerns over neurocognitive toxicity. This study aimed to re-evaluate the role of WBRT in the setting of modern targeted therapy. Materials and methods: From December 2014 to March 2019, 80 NSCLC patients with cytologically and/or radiologically proven LM diagnosis were retrospectively analyzed. Results: The median OS (mOS) after diagnosis of LM was 8.0 (95%CI: 4.4 to 11.6) months, and the one-year OS was 39.4%. The mOS for EGFR-mutated LM patients was 12.6 (3.0 to 22.2) months versus only 4.1 (2.8 to 5.4) for patients with wild-type EGFR (P < 0.001). Younger patients (< 53.5 yrs.) appeared to have a better OS than older patients (≥53.5 yrs.) (12.6 vs. 6.1, P = 0.041). No survival benefits were found in EGFR-mutated patients who received WBRT (P = 0.490). In contrast, mOS was significantly prolonged in wild-type EGFR patients with WBRT versus non-WBRT (mOS: 8.0 vs. 2.1, P = 0.002). Multivariate analysis indicated that WBRT (P = 0.025) and younger age (P = 0.048) were independent prognostic factors that predicted prolonged survival for wild-type EGFR LM patients from NSCLC. Conclusion: Our study demonstrated that WBRT has clear survival advantages for patients with wild-type EGFR, and molecular biological stratification of LM patients for WBRT is highly recommended.

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Activity of EGFR Tyrosine Kinase Inhibitors in NSCLC With Refractory Leptomeningeal Metastases

Cited by 24 publications

References 24 publications

Multiple combination therapy based on intrathecal pemetrexed in non-small cell lung cancer patients with refractory leptomeningeal metastasis

Multiple combination therapy based on intrathecal pemetrexed in non-small cell lung cancer patients with refractory leptomeningeal metastasis

Osimertinib for Patients With Leptomeningeal Metastases Associated With EGFR T790M-Positive Advanced NSCLC: The AURA Leptomeningeal Metastases Analysis

Whole brain radiotherapy (WBRT) for leptomeningeal metastasis from NSCLC in the era of targeted therapy: a retrospective study

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