Intrathecal pemetrexed efficacy and cerebrospinal fluid tumor marker response in refractory leptomeningeal metastasis of non-small-cell lung cancer: a single-arm phase II trial.

Background: The treatments for refractory leptomeningeal metastasis (RLM) of non-small cell lung cancer (NSCLC) are limited, and response assessment is complex and challenging. This clinical trial aimed to evaluate the efficacy of intrathecal pemetrexed (IP) and response assessment using cerebrospinal fluid (CSF) tumor marker in RLM.

Methods: This was a single-center, single-arm, phase II adaptive clinical trial. Patients with RLM of NSCLC were eligible for inclusion. Patients were assigned to receive 30 mg of IP every 3 weeks for a total of 6 cycles. The primary endpoint was overall survival (OS). The secondary endpoints included progression-free survival (PFS) evaluated according to EANO-ESMO response assessment, disease control rate, the concordance of CSF tumor marker response with EANO-ESMO response assessment, and safety.

Results: A total of 29 patients were enrolled in the trial. The median PFS was 10.03 months (95% CI, 6.42-13.64), and the median OS was 20.37 months (95% CI, 14.86-25.88), respectively. A ± 35% threshold for CSF tumor marker level change (TML) yielded the optimal predictive performance, with AUCs of 0.890 (95% CI, 0.833-0.947), 0.911 (95% CI, 0.870-0.951), and 0.784 (95% CI, 0.717-0.850) for EANO-ESMO response, progression, and stable, respectively. Most patients (93.1%) experienced grade 1-2 treatment-related adverse events.

Conclusions: Our therapeutic regimen of IP provided a practical, survival-extending, and tolerant option for RLM patients. CSF tumor marker response was correlated with EANO-ESMO response assessment, offering an effective tool for response monitoring of RLM.

Trial registration: Chinese Clinical Trial Register (ChiCTR) ChiCTR2200057235. Registered on March 1, 2022. Date of the first patient enrollment: April 29, 2022.