John O. Mascarenhas, MD, on Relapsed/Refractory Myelofibrosis: Navtemadlin vs Best Available Therapy After JAK Inhibitor Treatment

I am going to be talking about the BOREAS trial, which is a randomized phase three study of navtemadlin and MDM2 inhibitor for patients who have wild-type TP53 relapsed or refractory myelofibrosis. So these are patients who've had a JAK inhibitor who've failed it, have either primary refractory or relapsed from it, and need another next-line therapy. So this trial really enrolled very ill patients and randomized them to navtemadlin versus best available therapy. So this trial really enrolled a very ill patient population and randomized them to navtemadlin versus best available therapy with the idea that a different mechanism of action that's relevant to the biology of disease would be effective in salvaging patients with this type of situation. And what we saw from this study in a very sick patient population of 183 patients enrolled was superior SVR spleen volume response at 24 weeks, reduction in total symptom score by 50% or absolute value at 24 weeks. That was superior in the NADALINE arm, then BAT, as well as biomarkers of disease modification. So reduction in bone marrow fibrosis, reduction in ANC 34 cells, circulating numbers, reduction in inflammatory cytokines, and reduction in driver mutation. And interestingly, maybe very relevant to the disease understanding, as we correlated those changes in biomarkers with outcome measures like spleen volume reduction. So it really tells a very nice story of inhibiting MDM2, which upregulates p53 and induces cell death in the stem and progenitor cells in myelofibrosis, which is really a goal of therapy in myelofibrosis, in a very advanced patient population that have already failed a JAK inhibitor. And this is really an important study, I would say, because it's the first one that I'm aware of, reporting phase three results in the relapsed refractory setting, demonstrating the ability to bring a non-JAK inhibitor therapy to improve outcomes. We'll continue to follow these patients over time to see what happens with progression-free survival, overall survival, correlating other biomarkers with response. But this is an important study credentialing p53 pathway activation in myelofibrosis and really highlights the next study in this program that's underway, which is the POIESIS study, which is ruxolitinib upfront. So people enroll in ruxolitinib upfront after 18 weeks. If you have a suboptimal response, you randomize to the addition of navtemadlin given in the same way, 240 milligrams, seven days in a row out of a 28-day cycle or placebo with a total symptom score, an SVR targeted response at 24 weeks. So we're really seeing this program move forward, and I'm hopeful that we'll continue to see very effective results with navtemadlin, the MDM2 inhibitor, in myelofibrosis, both single-agent relapsed refractory setting, and in the future as an add-on strategy to ruxolitinib.