Efficacy and safety of intrathecal pemetrexed for TKI-failed leptomeningeal metastases from EGFR+ NSCLC: an expanded, single-arm, phase II clinical trial

Abstract

Background: This study aimed to evaluate the efficacy and safety of intrathecal pemetrexed (IP) for treating patients with leptomeningeal metastases (LM) from non-small-cell lung cancer (NSCLC) who progressed from epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor (TKI) treatment in an expanded, prospective, single-arm, phase II clinical study (ChiCTR1800016615).

Patients and methods: Patients with confirmed NSCLC-LM who progressed from TKI received IP (50 mg, day 1/day 5 for 1 week, then every 3 weeks for four cycles, and then once monthly) until disease progression or intolerance. Objectives were to assess overall survival (OS), response rate, and safety. Measurable lesions were assessed by investigator according to RECIST version 1.1. LM were assessed according to the Response Assessment in Neuro-Oncology (RANO) criteria.

Results: The study included 132 patients; 68% were female and median age was 52 years (31-74 years). The median OS was 12 months (95% confidence interval 10.4-13.6 months), RANO-assessed response rate was 80.3% (106/132), and the most common adverse event was myelosuppression (n = 42; 31.8%), which reversed after symptomatic treatment. The results of subgroup analysis showed that absence of brain parenchymal metastasis, good Eastern Cooperative Oncology Group score, good response to IP treatment, negative cytology after treatment, and patients without neck/back pain/difficult defecation had longer survival. Gender, age, previous intrathecal methotrexate/cytarabine, and whole-brain radiotherapy had no significant influence on OS.

Conclusions: This study further showed that IP is an effective and safe treatment method for the EGFR-TKI-failed NSCLC-LM, and should be recommended for these patients in clinical practice and guidelines.

Keywords: epidermal growth factor receptor; intrathecal pemetrexed; leptomeningeal metastasis; non-small-cell lung cancer.

Figure 1

Flow diagram. ^aReasons for screening failure: epidermal growth factor receptor (EGFR) status negative or not assessed (n = 1), screening failure as results of other inclusion/exclusion criteria (n = 13). d, day.

Figure 2

OS of all patients with NSCLC-LM and subgroup analysis. (A) The OS of all the patients. (B) Subgroup analysis for patients with and without brain parenchymal metastases. (C) Subgroup analysis for patients with good and bad ECOG scores. (D) Subgroup analysis for patients with and without clinical response for IP treatment. (E) With and without CSF cytological transformation to negative subgroup. (F) With and without neck pain, back pain, or defecation difficulty subgroup. BM, brain parenchymal metastasis; CI, confidence interval; ECOG, Eastern Cooperative Oncology Group; NBM, no brain parenchymal metastasis; OS, overall survival.