Dr Vachhani on the Potential Disease-Modifying Benefits of Navtemadlin in Myelofibrosis

“So far, we have seen disease-modifying benefits from navtemadlin, in addition to the important, clinically useful improvements in the form of spleen volume responses as well as total symptom score reduction, both when used as monotherapy, as well as when used in combination with a JAK inhibitor for patients with a suboptimal response.”

Pankit Vachhani, MD, an associate professor of medicine and associate scientist of experimental therapeutics at the University of Alabama at Birmingham, discusses the potential disease-modifying benefits of treatment with the novel oral MDM2 inhibitor navtemadlin (KRT-232) either alone or as an add-on to ruxolitinib (Jakafi) in myelofibrosis.

Navtemadlin is an oral, potent inhibitor of MDM2, which functions by restoring TP53 activity in malignant cells, Vachhani explained. Through reactivation of TP53, navtemadlin promotes pro-apoptotic signaling in CD34-positive myeloblasts, leading to a reduction in CD34 cell burden, Vachhani noted.

Early clinical investigations have demonstrated disease-modifying activity with navtemadlin, including reductions in bone marrow fibrosis and mutant allele burden, alongside clinically meaningful improvements in spleen volume reduction and total symptom score (TSS) decreases, Vachhani reported. These benefits have been observed when navtemadlin is used as monotherapy and in combination with JAK inhibitors in patients with suboptimal responses, Vachhani added.

The ongoing phase 3 POIESIS trial (NCT06479135) is evaluating navtemadlin in combination with ruxolitinib in patients with myelofibrosis who exhibit a suboptimal response to ruxolitinib monotherapy, Vachhani stated. In the trial, patients with JAK inhibitor–naive myelofibrosis initially receive ruxolitinib during a run-in period, Vachhani clarified. Those demonstrating a suboptimal response are then randomized to receive either navtemadlin or placebo added to their stable ruxolitinib dose, Vachhani explained.

The trial aims to confirm both the disease-modifying benefits of navtemadlin and its clinical efficacy in terms of spleen volume reduction and TSS improvement, Vachhani said. Improvements in spleen volume and symptom burden have previously been correlated with enhanced quality of life and have been associated with overall survival benefits in prior myelofibrosis studies, Vachhani observed. Results from POIESIS are anticipated to further clarify the role of navtemadlin in the therapeutic landscape for myelofibrosis and its potential to alter disease course when combined with JAK inhibition, Vachhani concluded.