Dr Mascarenhas on Prior Data Showing the Efficacy of Navtemadlin in R/R Myelofibrosis

“There’s a ton of preclinical data that indicate a role for MDM2 inhibition in myeloid neoplasms like polycythemia vera and myelofibrosis. Navtemadlin, without a doubt, [has] the best clinical data at this point demonstrating activity as a single agent in the relapsed/refractory setting.”

John Mascarenhas, MD, professor of medicine, Icahn School of Medicine, Mount Sinai, director, Center of Excellence for Blood Cancers and Myeloid Disorders, member, the Tisch Cancer Institute, Mount Sinai, discusses prior preclinical and clinical data indicating that symptom improvement and spleen response can be achieved with navtemadlin in myelofibrosis.

Preclinical data have shown the potential for MDM2 inhibitors, including navtemadlin, to serve as an effective treatment option in myeloid neoplasms like polycythemia vera and myelofibrosis, Mascarenhas begins. Navtemadlin stands out among other options in this drug class due to its more robust clinical profile, particularly in the relapsed/refractory settings, where it has demonstrated activity as a monotherapy, he states, adding that this has been especially evident in patients with advanced disease.

Notably, findings from the randomized, multicenter, global phase 3 BOREAS study (NCT03662126), which evaluated navtemadlin against best available therapy (BAT), were presented at the 2024 ASH Annual Meeting, Mascarenhas reports. In the study, navtemadlin demonstrated clinical efficacy among patients with myelofibrosis who were relapsed or refractory to prior JAK inhibition and have limited treatment options, he details.

Additionally, early clinical studies suggest synergy between navtemadlin and ruxolitinib (Jakafi) in patients with suboptimal responses to ruxolitinib, Mascarenhas continues. This led to its evaluation as an add-on therapy to ruxolitinib in the randomized phase 3 POIESIS trial (NCT06479135). In this study, patients who had a suboptimal response to ruxolitinib will be randomly assigned 2:1 to receive either navtemadlin at 240 mg for 7 days of a 28-day cycle or a matching placebo, both in combination with a stable dose of ruxolitinib. This intermittent dosing schedule contrasts with continuous treatment regimens, Mascarenhas notes. The goal of this trial is to capture significant spleen and symptom benefits, while also demonstrating stability in blood counts, Mascarenhas explains.

Early biomarker changes, such as reductions in bone marrow fibrosis, decreased driver mutation levels, and a profound reduction in circulating CD34 cells, which are indicative of the disease, further suggest that navtemadlin may have disease-modifying potential, he states. Moreover, navtemadlin appears to work by upregulating p53 and inducing apoptosis in the malignant cells that drive the pathology of myelofibrosis, Mascarenhas adds. This mechanism of action is enhanced when combined with ruxolitinib, which addresses the inflammatory and proliferative aspects of the disease, he concludes.