anlotinib + temozolomide

The combination of anlotinib and temozolomide (TMZ) is a therapeutic approach used primarily for the treatment of high-grade gliomas, including glioblastoma (GBM). This combination leverages anlotinib's anti-angiogenic properties with temozolomide's cytotoxic effects. ## Description Anlotinib is a multi-target tyrosine kinase inhibitor that primarily targets vascular endothelial growth factor receptors (VEGFR1/2/3), platelet-derived growth factor receptors (PDGFRs), fibroblast growth factor receptors (FGFRs), and c-Kit. It effectively penetrates the blood-brain barrier and inhibits tumor angiogenesis[1][5][7]. Temozolomide is an alkylating agent that damages DNA and triggers cell death in rapidly dividing cells, making it effective against glioma cells[2][6]. The combination therapy shows enhanced efficacy compared to either drug alone, with studies demonstrating improved progression-free survival (PFS), overall survival (OS), and objective response rates (ORR) in patients with recurrent high-grade glioma[1][3][5]. ## Clinical Evidence Multiple clinical studies have evaluated this combination: - A phase II trial (ChiCTR2000028957) of anlotinib plus temozolomide in recurrent GBM patients showed an impressive objective response rate of 81.0% and a disease control rate of 95.2%. The median PFS was 13.2 months, with 60.0% of patients progression-free at 6 months[3]. - A retrospective analysis of anlotinib combined with dose-dense temozolomide (7 days on/7 days off regimen) showed good efficacy in recurrent GBM patients[4][10]. - A recent clinical study presented at ESMO Congress 2024 evaluated anlotinib hydrochloride combined with temozolomide in 94 patients with recurrent high-grade glioma, reporting a median OS of 8.97 months, PFS of 6.13 months, and ORR of 32.9%[5]. ## Safety Profile The combination therapy demonstrates a favorable safety profile with manageable adverse events. Common adverse events include elevated liver enzymes (AST/ALT), hypertension, and leukopenia[3][5]. No grade 4 treatment-related adverse events or treatment-related deaths were reported in the studies reviewed[3][5]. ## Mechanism of Action The combination works through complementary mechanisms: 1. Anlotinib inhibits multiple angiogenesis-related kinases (VEGFR, FGFR, PDGFR) and tumor-associated kinases (c-Kit, Ret), reducing tumor vascularization[1][7][8]. 2. Anlotinib has been shown to suppress the JAK2/STAT3/VEGFA signaling pathway in glioma cells, decreasing levels of secretory VEGFA and angiogenesis[2]. 3. Temozolomide exerts cytotoxic effects through DNA alkylation, leading to cell cycle arrest and apoptosis[2][6]. 4. The combination demonstrates enhanced cytotoxicity and anti-angiogenesis effects compared to either agent alone[2]. This combination represents a promising approach for patients with high-grade gliomas, particularly those with recurrent disease who have limited treatment options.