Subsequent treatments beyond progression on osimertinib in EGFR-mutated NSCLC and leptomeningeal metastases

Abstract

Background Despite the reported efficacy of osimertinib, central nervous system (CNS) progression is still frequent in EGFR-mutated NSCLC. This study aimed to reveal site-specific resistant mechanisms to osimertinib and investigate subsequent treatments for leptomeningeal metastases (LM). Methods EGFR-mutated NSCLC with LM who progressed on osimertinib were included. Molecular analysis of cerebrospinal fluid (CSF) at osimertinib progression was performed. Subsequent treatments of LM were collected and analyzed. Results A total of 246 patients were identified. Only those with LM as a progression site on osimertinib were included (n=81). In 58 CSF-plasma pairs, more alterations were uniquely detected in CSF (77%) than in plasma (7%). These mechanisms led to 22 patients receiving matched targeted therapy. Among them, 16 (72.7%) had a clinical response. The median overall survival was 7.2 months. For non-matched therapy (n=59), the osimertinib combination had a longer median overall survival than the regimen switch in CNS-only progression (15.3 vs. 7 months, p=0.03). Finally, serial monitoring by CSF revealed the potential evolution of LM. Conclusions Private resistant mechanisms in CSF might match osimertinib-resistant LM for targeted therapy. Besides, continuing osimertinib with intensification strategy might prolong survival, especially for those with CNS-only progression. Prospective exploration is needed.

Research progress on meningeal metastasis of lung cancer

“…However, due to the relative difficulty in accessing LMC tissues, the lack of cells in CSF during the sampling process, and the rapid death of patients, the development of diagnostic techniques for LMC patients is facing numerous challenges [29][30].The recent research results combining liquid biopsy methods with next-generation sequencing techniques have made it possible to analyze circulating tumor cells, circulating tumor DNA (ctDNA), and cell free RNA derived from CSF [31].Other diagnostic techniques include meningeal biopsy, CSF liquid biopsy, CSF circulating tumor cells (CTC), and CSF biomarkers. CtDNA refers to extracellular DNA released by cancer cells through various mechanisms, such as active secretion and/or passive release during cancer cell death.In 2015, Pan and colleagues reported the first use of next-generation sequencing technology to analyze ctDNA derived from CSF in LMC.In 2015, De Mattos Arruda and his colleagues confirmed that CSF derived ctDNA captured the mutation landscape of various central nervous system tumors, including LMC, with higher sensitivity compared to plasma derived ctDNA [33][34].Cerebrospinal fluid analysis has great potential for the diagnosis of LMC, the genetic and epigenetic characteristics of the disease, and the determination of treatment resistance mechanisms.Multiple ctDNA analyses targeting nonsmall cell lung cancer are used to detect driving genes in cerebrospinal fluid and assist in the treatment of patients [35][36][37].The 2021 WCLC conference reported that Professor Wu Yilong's team used ctDNA testing in cerebrospinal fluid to guide targeted treatment for patients with meningeal metastases and achieved good results.Therefore, dynamic monitoring of cerebrospinal fluid ctDNA to identify the unique gene profile of brain metastases can better predict intracranial tumor remission in NSCLC patients with brain metastases [38].…”

Novel systemic therapies in the management of tyrosine kinase inhibitor-pretreated patients with epidermal growth factor receptor-mutant non-small-cell lung cancer

“…A recent retrospective study indicated that 72.7% of patients (16/22) with matched targeted therapy had a clinical response based on the resistance mechanisms of LM, and showed that continuing osimertinib combined with intensification therapy could prolong survival in patients without matched therapies. 125 Local treatments such as radiotherapy, neurosurgery, and intrathecal injection have effectively relieved patients’ neurological symptoms. A recent phase I/II clinical trial involving 30 patients with LM showed that the clinical response rate of intrathecal pemetrexed was 84.6%, the median OS was 9 months (95% CI, 6.6–11.4), and the safety profile was tolerable.…”