POIESIS: a phase III study of add-on navtemadlin in JAK inhibitor-naïve myelofibrosis patients with a suboptimal response to ruxolitinib

Most myelofibrosis (MF) patients treated with ruxolitinib fail to achieve optimal response (i.e., spleen volume reduction ≥35% SVR35 and improvement in total symptom score ≥50% TSS50, and instead experience suboptimal reductions in spleen volume and constitutional symptoms. Maximizing SVR and TSS is critical for MF patients, as both are associated with improved quality of life (QoL) and overall survival (OS). Navtemadlin is a potent, selective, oral MDM2 inhibitor that restores p53 activity, inducing apoptosis of malignant TP53 wild-type (TP53WT) CD34+ MF progenitor cells. In vitro and clinical data demonstrated navtemadlin's synergy with ruxolitinib and disease-modifying potential. POIESIS is a global, randomized, double-blind phase III trial (NCT06479135) evaluating navtemadlin versus placebo as add-on to ruxolitinib in JAK inhibitor-naïve TP53WT MF patients with suboptimal response to ruxolitinib. The study includes a ruxolitinib monotherapy run-in period, followed by randomization of suboptimal responders to add-on navtemadlin or placebo to their stable ruxolitinib dose. Study objectives are to isolate the contribution of add-on navtemadlin by assessing SVR and TSS 24-weeks after randomization from the pre-randomization baseline and to demonstrate that this contribution is clinically meaningful using established SVR and TSS endpoints from the pre-ruxolitinib treatment baseline. Secondary endpoints include progression-free survival, leukemia-free survival, and OS.Clinical Trial Registration: NCT06479135 (ClinicalTrials.gov); EUCT 2023-504724-25-00 (EUClinicalTrials.EU).