Dr Vachhani on the Rationale for Evaluating Navtemadlin as a Ruxolitinib Add-On in Myelofibrosis

"When these 2 drugs are used together, we…get the cell killing function that we derive through TP53 [and] downregulation of the JAK/STAT pathway, [as well as] the typical spleen volume responses and symptom improvements that we see with JAK inhibitor use."

Pankit Vachhani, MD, associate professor, medicine; associate scientist, experimental therapeutics, University of Alabama at Birmingham, discusses the rationale for evaluating the novel oral MDM2 inhibitor navtemadlin (KRT-232) as an add-on to ruxolitinib (Jakafi) for patients with myelofibrosis who achieve a suboptimal response to ruxolitinib alone.

The ongoing phase 3 POIESIS trial (NCT06479135) is evaluating the 2 agents in patients with myelofibrosis who have a suboptimal response to ruxolitinib monotherapy. The trial is enrolling patients with JAK inhibitor–naive myelofibrosis, and they are first receiving ruxolitinib alone during the trial’s run-in period; those with a suboptimal response are being randomly assigned to navtemadlin or placebo as an add-on to their stable dose of ruxolitinib.

Previously, data from the phase 3 BOREAS trial (NCT03930732) showed that navtemadlin monotherapy reduced biomarkers of disease burden compared with best available therapy in patients with relapsed/refractory myelofibrosis.

The TP53 pathway plays a critical role in apoptosis, particularly in myelofibrosis, Vachhani begins. However, this apoptotic pathway is often impaired due to the overexpression of MDM2, a key negative regulator of TP53, he says. MDM2 suppresses TP53 activity through multiple mechanisms, including direct inhibition of its transcriptional activity, nuclear export, and proteasomal degradation, Vachhani details. This dysregulation creates an environment where malignant cells evade apoptosis, contributing to disease progression, he explains. He adds that the upregulation of MDM2 in myelofibrosis provides a strong rationale for targeting this pathway therapeutically.

Navtemadlin is a potent oral MDM2 inhibitor designed to restore TP53 function, thereby promoting apoptosis in malignant cells, Vachhani states. Preclinical studies have demonstrated elevated MDM2 levels in samples taken from patients with myelofibrosis, suggesting that MDM2 inhibition [by navtemadlin] could be beneficial in this disease setting, he notes.