methotrexate + regorafenib

Methotrexate + regorafenib is an investigational combination therapy consisting of two small molecule drugs with distinct mechanisms of action. Methotrexate is a folate antimetabolite that inhibits dihydrofolate reductase, thereby blocking DNA synthesis and cell replication, primarily used in cancer and autoimmune diseases. Regorafenib is an oral multi-kinase inhibitor targeting several protein kinases involved in tumor angiogenesis (such as VEGFR1-3), oncogenesis (including KIT, RET, RAF-1, BRAF), and the tumor microenvironment (PDGFR-β, FGFR). The combination has been studied in phase II clinical trials for patients with advanced KRAS-mutant non-small cell lung cancer (NSCLC) who have progressed after standard therapies. Preclinical models suggested potential synergy between these agents; however, clinical studies found the regimen limited by toxicity and did not meet primary efficacy endpoints[1][4][6][8].