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. 2024 Dec 5;26(12):2316-2327.
doi: 10.1093/neuonc/noae138.

Osimertinib-induced DNA resistance mutations in cerebrospinal fluid of epidermal growth factor receptor-mutated non-small-cell lung carcinoma patients developing leptomeningeal metastases: Osimertinib Resistance Analysis-leptomeningeal metastases study

Affiliations

Osimertinib-induced DNA resistance mutations in cerebrospinal fluid of epidermal growth factor receptor-mutated non-small-cell lung carcinoma patients developing leptomeningeal metastases: Osimertinib Resistance Analysis-leptomeningeal metastases study

J W Tijmen van der Wel et al. Neuro Oncol. .

Abstract

Background: Diagnosis and treatment of leptomeningeal metastases (LM) in epidermal growth factor receptor mutation-positive (EGFRm +) non-small-cell lung carcinoma (NSCLC) is challenging. We aimed to identify resistance mechanisms (RM) to osimertinib in cerebrospinal fluid (CSF) and plasma.

Methods: EGFRm + patients with new or progressive LM during osimertinib were enrolled. NGS Ampliseq was performed on DNA isolated from CSF. Patients were prescribed osimertinib dose escalation (DE, 160 mg QD) following lumbar puncture. Clinical and radiological response was evaluated 4 weeks after osimertinib DE.

Results: Twenty-eight patients were included. The driver mutation was identified in 93% of CSF samples (n = 26). Seven (27%) harbored ≥1 RM. Twenty-five patients (89%) were prescribed osimertinib DE. Four weeks afterwards, symptoms improved in 5 patients, stabilized in 9 and worsened in 11 patients. Twenty-one (84%) patients underwent MR imaging. Four showed radiological improvement, 14 stabilization, and 3 worsening.

Conclusions: In 27% of patients, an RM was found in CSF ctDNA, none of which are targetable at the time of writing, and the clinical efficacy of osimertinib DE seems limited. There is much to gain in diagnostic as well as therapeutic strategies in EGFRm + NSCLC LM.

Keywords: EGFR; NSCLC; leptomeningeal metastases; osimertinib; resistance.

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Conflict of interest statement

J.W.T.v.d.W., M.C.B., M.J., S.A.S., K.W.M., M.J.A.L., A.C., R.P.B.B., N.S. and D.v.d.B. report no conflict of interest. K.M. reports consulting fees from Lilly, Bayer, and Amgen, all paid to the institution. E.F.S. reports consulting fees from Eli Lilly, AstraZeneca, MSD, Merck, BMS, DSI, Takeda, and Boehringer Ingelheim, all financial compensation paid to the institution, payment or honoraria for lectures, presentations, speaker bureaus, manuscript writing or educational events from BI, and participation on a Data Safety Monitoring Board of Advisory Board with DSI. A.J.L. reports grants from BMS, MSD, AstraZeneca, and Boehringer Ingelheim, all paid to the institution, and nonfinancial support from Merck Serono and Roche. D.B. reports grants from Gilead Sciences, and consultancy fees from Lilly Pharmaceuticals and Boehringer Ingelheim, all paid to the institution.

Figures

Figure 1.
Figure 1.
Flowchart of ORA-LM study inclusion.
Figure 2.
Figure 2.
Progression pattern, biopsy details, and treatment outcome per patient. *Either exon19del or exon19delins, ~, equivocal; CTCs, circulating tumor cells; Osi, osimertinib; DE, dose escalation; carbo, carboplatin; pem, pemetrexed; RTx, radiotherapy.
Figure 3.
Figure 3.
Flowchart of treatment post LP, MTB recommendation and adherence to MTB recommendation. LP, lumbar puncture; MTB, molecular tumor board.
Figure 4.
Figure 4.
Mechanisms leading to osimertinib failure in EGFRm + non-small-cell lung carcinoma leptomeningeal metastases. Germline variations in ABCB1 and ABCG2 decrease intracerebral osimertinib efficacy, complement component 3 allows growth factors to enter the CSF, cancer cells deploy Lipocalin-2 to collect iron, limiting macrophage efficacy, and tumor cells adopt floating and attached forms in CSF in order to spread through and thrive in the CSF. Tumor cell genetic alterations (some examples are provided) also vastly contribute to osimertinib resistance.

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