Pre-clinical Modeling of Navtemadlin Pharmacokinetics, Pharmacodynamics, and Efficacy in IDH-wildtype Glioblastoma Open Access

Background: Navtemadlin is a potent small molecule inhibitor of MDM2, which has completed a Phase 0 window of opportunity study in glioblastoma (GBM). To optimally interpret the clinical data, a detailed analysis of navtemadlin pharmacokinetics (PK), pharmacodynamics, and efficacy was performed in GBM patient derived xenografts (PDXs). Methods: Response to navtemadlin was characterized in vitro and in vivo in GBM PDXs with and without MDM2 amplification. Efficacy in vivo was integrated with measured plasma and intra-tumoral drug levels to develop a translational PK/efficacy model comparing exposure effective in PDX to exposure achieved in phase 0 patient samples. Results: In vitro, navtemadlin showed robust on-target activity in TP53 wild-typeGBM. In vivo efficacy strongly correlated with MDM2 amplification status. In subcutaneous PDXs, navtemadlin significantly extended survival when dosed at 25 mg/kg in an MDM2-amplified PDX, compared to 100 mg/kg in a non-amplified PDX. CNS distribution was limited by blood-brain barrier efflux (K_{p_brain}=0.009). In an MDM2-amplified orthotopic PDX model, navtemadlin was ineffective at 100 mg/kg; when established in mice with deficient blood-brain barrier efflux (Rag^-/-Abcb1a^-/- Abcg2^-/-), 25 mg/kg doubled survival. A tumor PK/efficacy model was built to define target exposure for efficacy in GBM, using the effective 25 mg/kg dose. Modeled exposures exceeded this threshold in 3 (of 16) tumor samples from phase 0 study patients at the 240 mg dose level. Conclusion: Navtemadlin efficacy was highly dependent on adequate brain penetration. Our translational PK/efficacy model suggests that the minimum effective tumor exposures were achieved only in a minority of GBM patients.