Radiopharmaceutical therapy provides superior survival advantage for leptomeningeal metastasis compared to external beam radiotherapy

BACKGROUND: Leptomeningeal metastasis from a solid tumor carries a dismal prognosis with median survival of 3 to 5 months after diagnosis and treatment with external beam radiation therapy. It targets the whole-brain or the entire central nervous system depending on disease extent, and is the current standard therapeutic approach, however, its effectiveness is limited by insufficient cytotoxicity and severe off target radiotoxicity. METHODS: Radiopharmaceutical therapy is a promising strategy to deliver therapeutic radiation doses directly to the leptomeningeal space while minimizing damage to the normal central nervous system tissue. In this study, the tumor targeting alkylphosphocholine (NM600) was radiolabeled with 177Lu for SPECT/CT imaging and 225Ac for therapeutic efficacy in the context of solid tumor leptomeningeal metastasis. RESULTS: In in-vitro experiments 225Ac-NM600 induced significantly greater apoptosis, reduced colony formation, and increased expression of DNA damage markers, compared to 177Lu or external beam radiation. In-vivo therapeutic and toxicity profiles were assessed in leptomeningeal metastasis models of triple negative breast cancer and non-small cell lung cancer in NSG mice. Intrathecal administration of 177Lu- or 225Ac-NM600 demonstrated excellent tumor targeting with minimal off target effect, confirmed by SPECT/CT imaging and ex vivo biodistribution. 225Ac-NM600 was well tolerated, inhibited tumor growth, and significantly improved overall survival in both models. Moreover, central nervous system radiotoxicity was markedly lower with 225Ac-NM600 RPT compared to external beam radiation therapy. CONCLUSIONS: Compared with whole brain external beam radiation therapy, 225Ac-NM600 provides superior anti-tumor efficacy and reduced off target toxicity supporting its further evaluation in clinical trial.