A potential role of pemetrexed (PMTX) for the treatment (Tx) of thymidylate synthase (TS) negative primary brain tumors and systemic malignancies with CNS metastasis.

Abstract

e13519 Background: Fluoropyrimidne analogue Capecitabine, a TS inhibitor, can cross blood brain barrier and has been used for the Tx of breast cancer with brain metastasis (mets). An antifolate Methotrexate (MTX), which also inhibits TS, has been used for the Tx of PCNSL secondary to it's excellent CNS penetration. MTX analogue, PMTX inhibits purine synthesis via TS and DHFR, and pyrimidine synthesis via GARFT, thus, making it a viable Tx option for CNS malignancies. Methods: We have treated 40 pts with previously heavily treated recurrent primary and systemic malignancies with CNS mets based on the molecular profiling. 26/40 pts were found to have TS negative expression (5/12 GBM, 5/5 AA, 1/1 Gr II Astrocytoma (A), 5/7 meningioma, 1/3 PCNSL, 1/2 Esthesioneuroblastoma, 1/1 chordoma, and 7/9 brain mets) and 10/26 TS negative pts were treated with PMTX. MRI was performed every 2-3 mo for tumor response. Results: Total pts: 10. M:F 6:4. Age: 48-88 yo. Median age: 61.9 yo. Tx period: 7/14–1/17. 1/1 GBM pt: stable disease (SD) x 4 mo. 1/2 AA pts: SD x 4 mo, 1/2 pts: tumor progression. 1 Gr. II A pt, SD x 7 mo. 2/2 meningioma pts: SD x 2 and 4 mo. Both pts also received concurrent cisplatin (also ERCC1 negative). 3/3 pts: squamous cell Ca of skin with skull base/brain mets responded x 24 mo, 24 mo and 3 mo respectively (1 PR and 2 SD), 2 pts: still receiving Tx. 1 pt: 26 mo reponder, died of nontumor related issue. 1/1 chordoma pt: SD x 11 mo. Toxicities: very mild except 2 pts (Gr. 3-4) who also received cisplatin. Conclusions: TS negative expression is commonly found in most of secondary malignancies with brain mets and in non-GBM primary brain tumors. PMTX appears to have a favorable efficacy for the Tx of TS negative primary and systemic malignancies with CNS mets. Albeit small cohort, overall response was 90% (PR:1, SD:8). Tx was particularly effective for squamous cell ca with brain mets and responses were durable in all spectrum. Due to favorable tolerance and response, especially in the elderly pts with squamous cell with brain mets, PMTX could be an excellent Tx option for TS negative CNS malignancies. PMTX trial for TS negative CNS malignancies should be considered.