Surgical window of opportunity trial reveals mechanisms of response and resistance to navtemadlin (KRT-232) in patients with recurrent glioblastoma
We evaluated the efficacy of navtemadlin (KRT-232) in treating recurrent glioblastoma through a surgical window-of-opportunity trial (NCT03107780) involving 21 patients. The study aimed to determine achievable drug concentrations in tumor tissue and investigate mechanisms of response and resistance. Daily doses of 120 mg and 240 mg demonstrated pharmacodynamic activity. Sequencing of three recurrent tumors revealed no TP53-inactivating mutations, suggesting alternative resistance mechanisms. In patient-derived GBM models, navtemadlin at clinically relevant concentrations induced partial tumor cell death as a monotherapy. However, combining navtemadlin with temozolomide significantly enhanced apoptotic activity while sparing normal bone marrow cells, which exhibited reversible growth arrest. These findings indicate that clinically achievable doses of navtemadlin produce meaningful pharmacodynamic effects and highlight the potential of combining navtemadlin with standard-of-care DNA-damaging chemotherapy to achieve durable survival benefits.
Statement of significance: This clinical trial leveraged tumor tissue sampling to elucidate mechanisms of response and resistance to navtemadlin in recurrent GBM. The study demonstrates that clinically achievable doses induce pharmacodynamic effects and supports the use of navtemadlin in combination with standard chemotherapy for durable therapeutic outcomes.