Join editorial board member Dr John Mascarenhas (Icahn School of Medicine at Mount Sinai, New York, NY, USA) as he explores the potential of navtemadlin, an oral MDM2 inhibitor, as a treatment option for myelofibrosis. He discusses thehey take-aways from the BOREAS study, including its disease-modifying impact in patients relapsed or refractory to JAK inhibitors, and the POIESIS trial, investigating navtemadlin in combination with ruxolitinib for suboptimal responders.
The Oral Abstract, ‘Results from the Randomized, Multicenter, Global Phase 3 BOREAS Study: Navtemadlin Versus Best Available Therapy in JAK Inhibitor Relapsed/Refractory Myelofibrosis’ (https://ash.confex.com/ash/2024/webprogram/Paper201642.html) was presented at the 66th ASH Annual Meeting & Exposition on 7–10 December 2024 in San Diego, CA, USA.
The Oral Abstract, ‘POIESIS: A Randomized, Double-Blind, Placebo-Controlled, Multicenter, Global Phase 3 Study of Navtemadlin As Add-on to Ruxolitinib in JAK Inhibitor-Naïve Patients with Myelofibrosis Who Have a Suboptimal Response to Ruxolitinib’ (https://ash.confex.com/ash/2024/webprogram/Paper200966.html) was presented at the 66th ASH Annual Meeting & Exposition on 7–10 December 2024 in San Diego, CA, USA.
Disclosures: Dr Mascarenhas is a consultant for Incyte, Novartis, Geron, Keros, BMS, Sobi, karyopharm, GSK, Merck, Pfizer, Roche, PharmaEssentia, Morphosys, Keros. He has received grant/research support from Incyte, Novartis, BMS, SOBI, AbbVie, PharmaEssentia, Ajax, Geron, Kartos, Karyopharm, Disc.
Transcript
My Name is John Mascarenhas. I’m from the Icahn School of Medicine at Mount Sinai in New York City.
Q1. What is the mechanism of action of navtemadlin and how could it be used for patients with myelofibrosis
So navtemadlin is an oral MDM2 inhibitor. So this is a drug that binds a protein MDM2 that’s over-expressed in CD34myelofibrosis cells and inhibits its ability to negatively regulate P53. So it essentially turns on the P53 pathway, which is an essential pathway for cell survival and cell vitality. So this drug induces cells, to undergo apoptosis and almost selectively so in those cells that overexpressed this MDM2 protein, which is found in patients with, MF CD34 cells versus normal CD34. So there’s a nice therapeutic window to capitalize on this difference, and that is really where navtemadlin has an advantage. And this was seen with, a number of different MDM2 inhibitors, in in this setting preclinically, but also validate with navtemadlin. And then now we are talking about phase 3 data, and we can get into what that looks like. But if there’s clear preclinical rationale, mechanistic understanding of why navtemadlin as a best in class MDM2 inhibitor is effective in this setting.
Q2. Please summarize the key findings of the BOREAS study, and how might they influence treatment guidelines for patients with myelofibrosis relapsed or refractory to JAK inhibitors?
So the BOREA study is a global randomized phase 3 study in the JAK inhibitor relapsed refractory setting of patients with intermediate-1 to high risk randomized to , the oral MDM 2 inhibitor, seven days on at 240mg, 21 days off, so 28-day cycle with GI prophylaxis, so antiemetics and anti diarrheals to to reduce that toxicity that’s a class effect, versus BAT. And BAT can include hydroxyurea, lenalidomide, interferon, danosol, but it excludes JAK inhibitors. So the primary endpoint of the BOREAS study is SVR 35% at week 24, and the key secondary endpoint is TSS 50 at 24. We also looked at a lot of correlative studies. What happens to circling CD34, which are hallmarks of disease. CD34 cell number circulating in the peripheral blood, JAK2 V617f BAF, bone marrow fibrosis, and cytokine expression. What we saw was that at 24 weeks, we had tripling of SVR 35%, 15% versus 5%, navtemadlin superior than BAT.
In the symptom department, it was doubling of symptoms score, 24% versus 12%. And then depending on how you look at the symptomatology and there’s different ways of assessing symptom reduction, TSS 50 is one way. It’s probably not the best way. Looking at the mean absolute change in symptom scores, another way. Modified TSS taking out the symptom score the the symptom of fatigue is another different angle at looking at symptom improvement. You saw benefit of navtemadlin over BAT. We also saw doubling of bone marrow fibrosis reduction and doubling of driver mutation BAFF reduction with navtemadlin, tying in nicely that there’s a disease modifying aspect. In fact, we did correlation analysis demonstrating that reductions in these biomarkers, CD34 cell reduction, JAK2 V617f reduction, correlated with spleen volume reduction, which is a tangible clinical outcome measure that in other studies has also been linked to better survival.
So this is really the first, randomized phase 3 study, after JAK inhibitor failure of a nongenic inhibitor treatment option to result demonstrating that navtemadlin is very effective in the setting. It was also well tolerated. When used correctly with antiemetics upfront, and antidiarrheal for diarrhea, you can mitigate that risk factor or that that toxicity and make it a much more manageable drug with very infrequent grade 3, 4 events. Even thrombocytopenia that was seen, at grade 3, 4, 37% didn’t really compromise the ability to continuously dose navtemadlin each cycle. So we had a nice graph showing that there was stability in both the hemoglobin platelet count over time with navtemadlin. So we didn’t see significant hematologic or non-hematologic that drove discontinuation of the drug, particularly if you optimize the patient from that perspective. And I will point out one third of the patients even went on the study with platelet counts less than a hundred thousand, cytopenic, and we were still able to deliver this drug in an effective manner. So it really was a reassuring look in a very large patient population; 183 patients, 2:1 randomization. So we had a really good feel over a 15-month median duration of exposure of the benefits of and the ability to deliver it in an effective and safe manner.
Q3. What was the methodology, study design and inclusion criteria for the POIESIS trial?
The POIESIS trial is the next iteration, the next trial, being, executed in with . What POIESIS is doing is building upon that and using earlier on in the disease course for the suboptimal responders before they become relapsed refractory. And this is built off of preclinical data demonstrating synergy between and ruxolitinib, as well as early phase 1b study, results that we’ve, reported that demonstrate, not just synergistic clinical activity, but but likely better tolerability when you add the 2 together. So the POIESIS study is a large study enrolling patients who are JAK inhibitor naive that are TP53 wild type and have intermediate 1, 2, or high risk MF, and they’re treated with ruxolitinib, a standard of care upfront. But they’re they’re assessed for spleen and symptom burden, centrally. After at least 18 weeks of therapy on ruxolitinib, they are then reassessed for response on ruxolitinib. If they are responders, meaning SVR and TSS 50 at that point, they just stay on ruxolitinib and they come off the study. If they have no response to therapy, they’re considered primary refractory and they come off the study. Everyone in between would be a suboptimal responder.
Those patients, are randomized to navtemadlin 240mg, 7 days in a row out of a 28 day cycle or placebo in the POIESIS study. So it’s comparing navtemadlin to placebo in patients who have suboptimal response to ruxolitinib to demonstrate after 24 weeks of the of the combination that one can hit a targeted TSS and and SVR. So this is really a strategy of treating patients who don’t fully respond to ruxolitinib as a combination approach, which is differs from the BOREAS study, which is single agent navtemadlin patients who fully failed ruxolitinib and have discontinued.
Q4. What potential does navtemadlin have as part of combination therapy and how could this change the myelofibrosis treatment landscape?
Depending on how the drug moves forward, it could move forward as a single agent in the relapsed/refractory setting. The study is evaluating its ability to synergize with ruxolitinib, which we saw really good evidence for in the phase 1b study. So I could see a world where it could be used either as a combination earlier on with ruxolitinib or in the relapsed refractory setting for those patients who are just on single agent ruxolitinib. So really get a a breadth of experience and opportunity to incorporate this, drug, which is very rational and mechanism based, in our treatment of myelofibrosis. I think patients who likely get these types of treatments that are anticlonal are also likely over time to, benefit from a survival and a progression-free survival aspect. Of course, you have to follow these patients longer out to get that kind of information.
But the the fact that we’re even seeing these these, changes in in biomarkers of disease modification would suggest that we’re likely to see that kind of a phenomena. There’s really an interest, across both patient and physician community, and regulatory bodies to see this data. And and I think that, you know, the next step is is, you know, does the drug start to move forward as a single agent? Do we wait for the combo agent?What will the label look like?
And then maybe, you know, there there are strategies I think are exciting, for example. I you know, they’re not I don’t think they’re yet in the works in terms of clinical studies, but navtemadlin can really synergize with a lot of other mechanism based relevant drugs, for example, like BET inhibitors that are very popular, like palabrasin. So work that Ron Hoffman’s done at at Mount Sinai has really validated and credentialed the synergy of these two classes of drugs together in depleting and eliminating MF stem and progenitor cells, which is really the goal of what we’re trying to accomplish here, is to really develop the next generation of therapies that able to remit the disease, maybe even cure the disease in patients.
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Interviewer/Editor: Sophie Nickelson
Cite: Mascarenhas J. Navtemadlin in myelofibrosis: Advancing treatment with MDM2 inhibition. touchHAEMATOLOGY. 19 December 2024.
