ASH 2021 | MDM2 inhibitor navtemadlin: clinical activity correlates with improvements in disease burden markers

Navtemadlin is a potent, selective MDM2 inhibitor, shown preclinically to reduce leukemic burden and prolong survival in in myeloproliferative neoplasm-blast phase (MPN-BP) patient-derived xenograft models. A Phase II trial (NCT03662126) was conducted in which 113 patients with relapsed/refractory myelofibrosis were treated with navtemadlin. Previously reported findings demonstrated a best spleen volume reduction (SVR) ≥35% in 16% of patients and best total symptom score (TSS) response over 50% in 30% of patients using once daily navtemadlin at 240 mg. Ronald Hoffman, MD, Icahn School of Medicine at Mount Sinai, New York, NY, describes the findings of an investigation into the correlations between these clinical benefits and changes in biomarkers of disease burden. It was demonstrated that 34% of evaluable patients showed driver gene reduction ≥20% after navtemadlin and 29% showed a complete variant allele frequency (VAF) reduction. Additionally, spleen responses correlated with reductions in MPN-driver mutation burden, decreased peripheral CD34+ cell counts, and improvements in bone marrow fibrosis. These data suggest navtemadlin may have disease-modifying effects in myelofibrosis, which will be further explored in the global Phase III BOREAS trial (NCT03662126). This interview took place at the 63rd ASH Annual Meeting and Exposition congress in Atlanta, GA..