Window of opportunity trial reveals mechanisms of response and resistance to navtemadlin in patients with recurrent glioblastoma
To investigate the effectiveness of p53 reactivation in treating glioblastoma, we conducted a surgical window-of-opportunity trial (NCT03107780) of the MDM2 inhibitor navtemadlin (KRT-232) on 21 patients and determined achievable drug concentrations within tumor tissue and biological mechanisms of response and resistance. Both 120 mg and 240 mg daily dosing achieved a pharmacodynamic impact, but patient relapse was observed. Sequencing of three recurrent tumors revealed an absence of TP53-inactivating mutations, indicating alternative mechanisms of resistance. To understand the mechanisms of response and resistance associated with navtemadlin, we conducted functional and spatial analyses of human tissue and patient-derived glioblastoma (GBM) models. Navtemadlin induced partial tumor cell death as monotherapy, but combination with temozolomide enhanced apoptosis while sparing normal bone marrow cells in vitro. We additionally report upregulation of oligodendrocyte differentiation genes as an unexplored mechanism of navtemadlin tolerance in GBM. Overall, these results indicate that clinically achievable doses of navtemadlin exert pharmacodynamic effects and suggest that combined treatment with standard-of-care DNA damaging chemotherapy may be a route to more durable survival benefits. Overall design: We performed RNAseq of two patient-derived in vitro neurosphere models (BT145 and BT286), both pre- and post-treatment with navtemadlin at an equivalent dose and time point to the clinical trial. We detected altered expression of 390 and 132 genes in BT145 and BT286, respectively, with 125 genes common to both (P < 0.0001). We used these 125 genes to construct sets of genes expected to be upregulated (n=31) and downregulated (n = 94) by treatment, and applied these gene sets to the RNAseq data from our clinical trial samples.