Intrathecal Pemetrexed: Another Potential Treatment Modality for Tyrosine Kinase Inhibitor-Failed Leptomeningeal Metastases?

Leptomeningeal metastases (LM) is a devastating disease with a higher incidence rate in patients with EGFR-mutated NSCLC. Previous studies have suggested that targeted agent osimertinib was effective for these patients. Nevertheless, treatment option for LM is still limited, especially those who fail targeted therapies and few trials include patients with active LM disease. Thus, Fan et al.1Fan C. Zhao Q. Li L. et al.Efficacy and safety of intrathecal pemetrexed combined with dexamethasone for treating TKI-failed leptomeningeal metastases from EGFR-mutant NSCLC—a prospective open-label single-arm phase I/II clinical trial (unique identifier: ChiCTR1800016615).J Thorac Oncol. 2021; 16: 1359-1368Abstract Full Text Full Text PDF PubMed Scopus (10) Google Scholar should be commended for undertaking this prospective, single-arm, phase I–II clinical trial, focusing on intrathecal (IT) pemetrexed, a local treatment other than radiotherapy for patients with tyrosine kinase inhibitor–failed LM. It took 15 mg as the starting dose and 50 mg as the final recommended dose after dose-escalation stage. A total of 30 patients with LM were enrolled in the phase 2 study, and a clinical response rate of 84.6% was reported. The median overall survival (OS) was 9 months (the starting date was not specified though: from enrollment or diagnosis of LM?). What demands notice were 57% (17 of 30) of the patients at enrollment had poor condition with performance status (PS) score greater than 2; 83% of the patients had history of using osimertinib and only 17% received previous whole-brain radiotherapy, indicating it would be a potential option for those with poor PS score or progressed on EGFR tyrosine kinase inhibitors. IT pemetrexed was tolerable with myelosuppression, the most common adverse event. IT chemotherapy at LM diagnosis has been proposed long ago, but prospective and large-scale studies are lacking on its efficacy and safety. In the absence of strong evidence, IT chemotherapy was recommended on the basis of expert opinion in treatment guidelines. This uncertainty leads to the upmost question: the extent of prolonged survival that IT chemotherapy can achieve? Fan et al.1Fan C. Zhao Q. Li L. et al.Efficacy and safety of intrathecal pemetrexed combined with dexamethasone for treating TKI-failed leptomeningeal metastases from EGFR-mutant NSCLC—a prospective open-label single-arm phase I/II clinical trial (unique identifier: ChiCTR1800016615).J Thorac Oncol. 2021; 16: 1359-1368Abstract Full Text Full Text PDF PubMed Scopus (10) Google Scholar reported a median OS of 9 months (range: 6.6–11.4 mo). Nevertheless, in other studies, median OS was reported to be lower: 3.8 months (range: 0.3–14 mo)2Pan Z. Yang G. Cui J. et al.A pilot phase 1 study of intrathecal pemetrexed for refractory leptomeningeal metastases from non-small-cell lung cancer.Front Oncol. 2019; 9: 838Crossref PubMed Scopus (19) Google Scholar and 3 months (range: 0.5–21.5 mo).3Gwak H.S. Joo J. Kim S. et al.Analysis of treatment outcomes of intraventricular chemotherapy in 105 patients for leptomeningeal carcinomatosis from non-small-cell lung cancer.J Thorac Oncol. 2013; 8: 599-605Abstract Full Text Full Text PDF PubMed Scopus (66) Google Scholar In addition, several clinical factors were declared to affect survival of patients receiving IT chemotherapy, such as Karnofsky PS, age, and intracranial pressure (Fig. 1C). What should be noticed is that Fan et al.1Fan C. Zhao Q. Li L. et al.Efficacy and safety of intrathecal pemetrexed combined with dexamethasone for treating TKI-failed leptomeningeal metastases from EGFR-mutant NSCLC—a prospective open-label single-arm phase I/II clinical trial (unique identifier: ChiCTR1800016615).J Thorac Oncol. 2021; 16: 1359-1368Abstract Full Text Full Text PDF PubMed Scopus (10) Google Scholar reported an 84.6% clinical response and more than 50% had poor condition at baseline. Therefore, it seemed that IT therapy may improve PS score. In a word, although it remains unclear whether the improved PS score can translate to improved survival, IT pemetrexed is worth consideration in those with poor condition because of LM. Second, whether IT chemotherapy should be administered alone or as an addition to systemic therapy remains to be determined. The study of Fan et al.1Fan C. Zhao Q. Li L. et al.Efficacy and safety of intrathecal pemetrexed combined with dexamethasone for treating TKI-failed leptomeningeal metastases from EGFR-mutant NSCLC—a prospective open-label single-arm phase I/II clinical trial (unique identifier: ChiCTR1800016615).J Thorac Oncol. 2021; 16: 1359-1368Abstract Full Text Full Text PDF PubMed Scopus (10) Google Scholar had 43% patients (13 of 30) received IT injection alone, but no information of status of systemic disease was provided (active or not). A previous randomized trial of breast cancer with LM revealed that systemic chemotherapy with IT therapy achieved longer progression-free survival than systemic chemotherapy alone and quality of life did not differ between groups, despite some flaws in the trial design.4Le Rhun E. Wallet J. Mailliez A. et al.Intrathecal liposomal cytarabine plus systemic therapy versus systemic chemotherapy alone for newly diagnosed leptomeningeal metastasis from breast cancer.Neuro Oncol. 2020; 22: 524-538Crossref PubMed Scopus (24) Google Scholar Third, heterogeneity exists as regards to agents, doses, administered routes, and schedules of IT chemotherapy in patients with NSCLC (Fig. 1A). The most often used agents were methotrexate, cytarabine, etoposide, and pemetrexed. Regarding the dosage, the phase I cohort by Fan et al.1Fan C. Zhao Q. Li L. et al.Efficacy and safety of intrathecal pemetrexed combined with dexamethasone for treating TKI-failed leptomeningeal metastases from EGFR-mutant NSCLC—a prospective open-label single-arm phase I/II clinical trial (unique identifier: ChiCTR1800016615).J Thorac Oncol. 2021; 16: 1359-1368Abstract Full Text Full Text PDF PubMed Scopus (10) Google Scholar decided pemetrexed 50 mg as the final recommended dose, which was a bit higher than the previously reported 10 mg from another pilot phase I study.2Pan Z. Yang G. Cui J. et al.A pilot phase 1 study of intrathecal pemetrexed for refractory leptomeningeal metastases from non-small-cell lung cancer.Front Oncol. 2019; 9: 838Crossref PubMed Scopus (19) Google Scholar The administration route is also worth noticing. Fan et al.1Fan C. Zhao Q. Li L. et al.Efficacy and safety of intrathecal pemetrexed combined with dexamethasone for treating TKI-failed leptomeningeal metastases from EGFR-mutant NSCLC—a prospective open-label single-arm phase I/II clinical trial (unique identifier: ChiCTR1800016615).J Thorac Oncol. 2021; 16: 1359-1368Abstract Full Text Full Text PDF PubMed Scopus (10) Google Scholar used lumbar puncture for IT injection. Although no survival benefit was found compared with lumbar puncture, the Ommaya reservoir may be recommended owing to producing adequate cerebrospinal fluid distribution and avoiding leakage. In addition, its convenience in drug delivery may better ensure patient compliance to finish the complicated treatment schedule. What should be noted is that at least three LM response assessment criteria have been reported (Fig. 1A). The Response Assessment in Neuro-Oncology–LM criteria seemed unpractical. Others were specifically defined by individual studies and lack of rigorous validation. As a result, comparisons among these studies and interpretation of their results into clinical practice were difficult.1Fan C. Zhao Q. Li L. et al.Efficacy and safety of intrathecal pemetrexed combined with dexamethasone for treating TKI-failed leptomeningeal metastases from EGFR-mutant NSCLC—a prospective open-label single-arm phase I/II clinical trial (unique identifier: ChiCTR1800016615).J Thorac Oncol. 2021; 16: 1359-1368Abstract Full Text Full Text PDF PubMed Scopus (10) Google Scholar, 2Pan Z. Yang G. Cui J. et al.A pilot phase 1 study of intrathecal pemetrexed for refractory leptomeningeal metastases from non-small-cell lung cancer.Front Oncol. 2019; 9: 838Crossref PubMed Scopus (19) Google Scholar, 3Gwak H.S. Joo J. Kim S. et al.Analysis of treatment outcomes of intraventricular chemotherapy in 105 patients for leptomeningeal carcinomatosis from non-small-cell lung cancer.J Thorac Oncol. 2013; 8: 599-605Abstract Full Text Full Text PDF PubMed Scopus (66) Google Scholar,5Pan Z. Yang G. He H. et al.Concurrent radiotherapy and intrathecal methotrexate for treating leptomeningeal metastasis from solid tumors with adverse prognostic factors: a prospective and single-arm study.Int J Cancer. 2016; 139: 1864-1872Crossref PubMed Scopus (54) Google Scholar, 6Pan Z. Yang G. He H. et al.Intrathecal pemetrexed combined with involved-field radiotherapy as a first-line intra-CSF therapy for leptomeningeal metastases from solid tumors: a phase I/II study.Ther Adv Med Oncol. 2020; 121758835920937953Crossref Scopus (7) Google Scholar, 7Miao Q. Zheng X. Zhang L. Jiang K. Wu B. Lin G. Multiple combination therapy based on intrathecal pemetrexed in non-small cell lung cancer patients with refractory leptomeningeal metastasis.Ann Palliat Med. 2020; 9: 4233-4245Crossref PubMed Scopus (3) Google Scholar (Fig. 1B). Neurotoxicity is common as one of the adverse events of IT pemetrexed. Nevertheless, sometimes, it may be difficult to explain the cause of patients' neurologic symptoms, whether from LM disease or from IT therapy itself. Other adverse events include myelosuppression, leukoencephalopathy, and elevation of aspartate transaminase or aspartate transaminase. All of them can be treated after proper managements, indicating the tolerability of IT pemetrexed. Further studies are needed to decide the most effective IT agents, how to use it properly, optimal treatment duration, and how to assess the response. Furthermore, careful selection of patients with LM should be included in clinical trials. Despite a few unsettled questions, the study by Fan et al.1Fan C. Zhao Q. Li L. et al.Efficacy and safety of intrathecal pemetrexed combined with dexamethasone for treating TKI-failed leptomeningeal metastases from EGFR-mutant NSCLC—a prospective open-label single-arm phase I/II clinical trial (unique identifier: ChiCTR1800016615).J Thorac Oncol. 2021; 16: 1359-1368Abstract Full Text Full Text PDF PubMed Scopus (10) Google Scholar sets an important example in this regard. Mei-Mei Zheng: Conceptualization, Methodology, Visualization; Roles/Writing—original draft. Yang-Si Li: Conceptualization, Methodology, Writing—review and editing. Hao Sun, Hua-Jun Chen: Writing—review and editing. Yi-Long Wu: Supervision, Writing—review and editing. Efficacy and Safety of Intrathecal Pemetrexed Combined With Dexamethasone for Treating Tyrosine Kinase Inhibitor-Failed Leptomeningeal Metastases From EGFR-Mutant NSCLC—a Prospective, Open-Label, Single-Arm Phase 1/2 Clinical Trial (Unique Identifier: ChiCTR1800016615)Journal of Thoracic OncologyVol. 16Issue 8PreviewWe aimed to evaluate the efficacy and safety of intrathecal pemetrexed (IP) for treating EGFR-mutant leptomeningeal metastases (LMs) from EGFR-mutant NSCLC. Full-Text PDF Open ArchiveResponse to Letter to the Editor Titled "Intrathecal Pemetrexed: Another Potential Treatment Modality for TKI-Failed Leptomeningeal Metastases?"Journal of Thoracic OncologyVol. 16Issue 10PreviewWe thank Wu et al. for their interest in and comments on our article "Efficacy and safety of intrathecal pemetrexed combined with dexamethasone for treating TKI-failed leptomeningeal metastases from EGFR-mutant NSCLC—a prospective open-label single-arm phase I/II clinical trial."1 Full-Text PDF