Navtemadlin monotherapy demonstrated improved clinical outcomes and disease burden biomarkers among patients with JAK inhibitor relapsed/refractory (R/R) myelofibrosis (MF), according to results from a phase 3 clinical trial.

Results from the phase 3 BOREAS study were presented by John Mascarenhas, MD, Tisch Cancer Institute, New York, New York, at the 66^th ASH Annual Meeting in San Diego, California.

“BOREAS is the first randomized, global phase 3 study conducted solely in MF [patients] R/R to JAK [inhibitor] to report results. In this phase 3 study, navtemadlin monotherapy was safe and effective, demonstrating clinically relevant efficacy with disease-modifying potential,” Mascarenhas and colleagues concluded.

Transcript:

My name is John Mascarenhas. I'm from the Icahn School of Medicine at Mount Sinai New York. Today we'll be talking about the BOREAS trial, which will present 2 abstracts at ASH 2024, 1 on the clinical outcomes and then 1 on the correlative science that's associated with the trial.

The BOREAS trial is a global randomized phase 3 study comparing navtemadlin, the first in class MDM2 inhibitor versus BAT in patients with TP53 wild-type (TP53WT) myelofibrosis who are relapsed/refractory to a JAK inhibitor. What I'll do is I'll highlight the clinical outcomes first, which were notable. Spleen volume reduction of 35% or greater was more frequent with navtemadlin, and 15% of patients met that endpoint. But there were many patients who had very deep responses versus about 5% with BAT, which excluded a JAK inhibitor arm. The TSS response at 24 weeks was also superior and was doubled in the navtemadlin-arm versus BAT-arm.

Even looking at absolute mean change in TSS, you can see almost a reduction of 5 points, which is pretty significant in the navtemadlin arm, whereas it was actually worsening in 24 weeks in the BAT arm. Across clinical outcome measures of a spleen and symptom, that was clear superiority of navtemadlin versus BAT.

What was really exciting to see the tie-in of the correlative science to the clinical outcomes is the fact that there was biomarker evidence of disease modification as one would expect and has been seen previously with this drug. Reductions in circulating CD34 cells, reduction in driver mutation bath, reduction in inflammatory cytokine mediators, and reduction in bone marrow fibrosis reduction, all of which also correlated with the clinical outcome measures that I mentioned. Spleen volume response, namely. Tying in very nicely the clinical activity and the correlative biomarkers with this drug, which is a drug that very potently induces P53 pathway activation and induces cell death in CD34 cells from the MF clone.

It is a stem cell directed therapy that has shown clinical activity, and which I didn't mention, acceptable toxicity profile. GI toxicity and myelosuppression, which are class effects of this drug, are very easy to manage, were not a major reason for discontinuation. Because the drug is dosed at 240 milligrams, 7 days on 21 days off, you have opportunity to recover blood counts when there is myelosuppression for the subsequent dosing. With GI prophylaxis, the level of grade 3, 4 events of GI [toxicity] is quite low.

This was a very easy to deliver drug in a very sick, advanced patient population with evidence of clinical outcome and biomarker evidence of disease modification. Where does this all go? 180 patients randomized this study. Now we're moving to the POIESIS study, which is really probably one of the most innovative studies in myelofibrosis right now, actively accruing across the world patients who are JAK inhibitor naive.

Then after 18 weeks of JAK inhibitor assessing for response, patients who are suboptimal are then randomized—suboptimal meaning not having optimal spleen and symptom response are randomized to navtemadlin at the same dose, 240 milligrams, 7 days on 21 days off versus placebo with the targeted TSS and spleen volume reduction as the endpoints. Moving the drug, which has shown clear activity as a single agent to earlier on disease course as an add-on to ruxolitnib to improve upon and deepen the responses.

This is all endorsed by preclinical data showing synergy with JAK inhibitor, but also phase1b data demonstrating both enhanced clinical activity and enhanced tolerability in combination. The POIESIS study is the next study on this saga of developing a very potent disease modifying therapy, MDM2 inhibitor navtemadlin, in myelofibrosis.

Sources:

Mascarenhas JO, Bose P, Hou H, et al. Disease-modifying activity of navtemadlin correlates with clinical responses in a randomized, multicenter, global phase 3 study (BOREAS) in JAK-inhibitor relapsed/refractory myelofibrosis. Dec 7-10, 2024; San Diego, CA. Abstract: 483

Mascarenhas JO, Popov VM, Mohan S, et al. Results from the randomized, multicenter, global phase 3 BOREAS study: navtemadlin versus best available therapy in JAK inhibitor relapsed/refractory myelofibrosis. Dec 7-10, 2024; San Diego, CA. Abstract: 1000