Navtemadlin-Based Therapy Could Drive Change in the Myelofibrosis Treatment Paradigm

Supplements and Featured Publications, Integrating MDM2 Inhibition Into Myelofibrosis Management, Volume 1, Issue 1

John Mascarenhas, MD, discusses navtemadlin's mechanism of action and its potential to shift the myelofibrosis treatment landscape

Along with the efficacy displayed by the novel MDM2 inhibitor navtemadlin (KRT-232) as a single agent in patients with relapsed/refractory myelofibrosis, its use as part of combination therapies could alter the treatment paradigm for patients who experience a suboptimal response to ruxolitinib (Jakafi) alone in the up-front setting, according to John Mascarenhas, MD.

Data from the phase 3 BOREAS trial (NCT03930732) presented at the 2024 ASH Annual Meeting showed that navtemadlin reduced levels of biomarkers of disease burden in patients with myelofibrosis who were relapsed/refractory to a JAK inhibitor. Now, the agent is being evaluated in combination with ruxolitinib vs placebo plus ruxolitinib in the phase 3 POIESIS trial (NCT06479135). The study is enrolling patients with JAK inhibitor–naive myelofibrosis, and those with a suboptimal response to ruxolitinib monotherapy will be randomly assigned to the navtemadlin or placebo combinations.

“Navtemadlin has, without a doubt, the best clinical data at this point as a single agent in the relapsed/refractory setting,” Mascarenhas explained. “The drug has already demonstrated the potential to enhance spleen and symptom improvement in patients with myelofibrosis. This is a profoundly active compound with a tremendous amount of mechanistic rationale.”

In an interview with OncLive®, Mascarenhas highlighted navtemadlin’s mechanism of action; touched on preclinical and clinical data with navtemadlin both as monotherapy and in combination with ruxolitinib; and discussed the potential for the combination therapy to shift the myelofibrosis treatment landscape.

Mascarenhas is a professor of medicine at the Icahn School of Medicine, director of the Center of Excellence for Blood Cancers and Myeloid Disorders, and a member of The Tisch Cancer Institute. He also serves as a clinical investigator in malignant hematology, director of the Adult Leukemia Program, and lead of clinical investigation within the Myeloproliferative Disorders Program at Mount Sinai in New York, New York.

OncLive: What is the unique mechanism of action of navtemadlin?

Mascarenhas: Navtemadlin is a first-in-class, [potentially] best-in-class, MDM2 inhibitor. This is a small molecule, orally delivered drug that binds MDM2, which is a protein that negatively regulates TP53 wild-type. This drug ultimately activates the P53 pathway, and in doing so, it induces senescence and cell death.

In the [context of] myelofibrosis, this drug selectively targets the malignant stem and progenitor cell population. That's critical because this is a drug that can have an anti-clonal effect and the potential to profoundly affect the disease at its core.

What prior preclinical and clinical data exist that support navtemadlin’s ability to improve symptoms and spleen response in patients with myelofibrosis?

There is a ton of preclinical data for this class of agents, indicating a role for MDM2 inhibition in myeloproliferative neoplasms, whether it's polycythemia vera or myelofibrosis. [We presented] mature data from the randomized phase 3 BOREAS study at the 2024 ASH Annual Meeting in December, characterizing the safety profile and the clinical efficacy in this advanced patient population. [The majority of these patients were] refractory to JAK inhibitors, and there are a limited number of treatments to improve [these patients’] outcomes.

There's substantial data that's driven [this agent] as monotherapy, particularly in the advanced patient population, and now we have early clinical data demonstrating synergy with ruxolitinib in patients who have a suboptimal response [to ruxolitinib alone] from a phase 1/2 study [NCT04485260]. That [combination] is now being advanced into the registrational, randomized phase 3 [POIESIS] study in patients who have had a suboptimal response to ruxolitinib, where they are being randomly assigned to navtemadlin at 240 mg once daily or placebo for 7 days out of a 28-day cycle [in combination with ruxolitinib]. That's an important point to make: this is not continuous dosing with the drug. It's intermittent.

We want to try to capture substantial spleen and symptom benefits [with the combination]. Beyond that, we want to see stability in the blood counts and biomarker changes suggesting the potential for disease modification. [This accounts for] reduction in bone marrow fibrosis, reduction in driver gene mutation levels, and profound reduction in circulating CD34 cells, which is a hallmark of this disease.

There are a lot of preclinical data, and the preclinical data look the best—as the clinical data also suggest—for synergy between ruxolitinib and navtemadlin, addressing biological aspects that drive the pathology of this disease by upregulating P53 and inducing apoptosis in these cells. That effect is exaggerated and improved upon in combination with ruxolitinib [vs navtemadlin alone].

How have single-agent data from BOREAS supported the investigation of this agent into an earlier setting as part of combination therapy?

We know the drug is active as a single agent in patients who have very advanced disease. Now the concept is to not wait for patients to [progress on] ruxolitinib before introducing an active agent. [The idea is] to try to salvage patients who remain on ruxolitinib and are experiencing an inadequate response. [We are] trying to capitalize on the synergy between ruxolitinib and navtemadlin, both from an efficacy and a safety [standpoint]. Giving ruxolitinib [as part of a combination] likely offsets some of the toxicity that one can see with MDM2 inhibition. This improves upon the tolerability and the efficacy of navtemadlin by [preventing] patients from [progressing on] ruxolitinib and trying to get the deepest responses, rather than waiting for their disease to [progress].

Importantly, the POIESIS trial is not asking the question, 'Is ruxolitinib plus navtemadlin better than ruxolitinib alone in the JAK inhibitor–naive setting?' [The study is enrolling] patients to receive first-line JAK inhibitor monotherapy, allowing them to experience either optimal or suboptimal benefits [to ruxolitinib alone]. If they're not fully succeeding on [ruxolitinib alone], then they get the opportunity to add navtemadlin to get a sense of what [the combination] brings to the table in terms of improved spleen size, symptoms, cytopenias, and impact on biomarkers of disease modification. Can we improve upon the responses and prolong the duration of the benefit of ruxolitinib in that setting?

[POIESIS] is an incredibly important study in this field, and in an extremely innovative manner, it is asking an important question: can we salvage patients and do better by synergizing navtemadlin with ruxolitinib, not necessarily in the up-front setting, but in the suboptimal response setting?

The primary end points of the POIESIS study will be the classic spleen volume response of 35% or greater [SVR35] at 24 weeks. Additionally, can we significantly reduce the symptom burden to push them through the threshold of 50% or better [TSS 50] at 24 weeks? This is being done innovatively.

[POIESIS] has a study design that we've not seen before, which Kartos Therapeutics has pioneered in this setting. It is exciting because it allows us as a field to move forward in terms of study design and drug development, and that's sorely needed in this area.This innovation will likely lead the field forward in terms of study design, drug development, and the measurement of end points, which can be challenging in this area. This study is important for the development of navtemadlin, but it could also change the paradigm for the registrational studies conducted in the future [in myelofibrosis], which have been stymied as of late.

This is an ambitious study, enrolling patients up-front before randomly assigning them after 18 to 24 weeks of ruxolitinib monotherapy to [receive] either navtemadlin or placebo [plus ruxolitinib] in those patients who are suboptimal responders. [The goal is] to take patients who've not enjoyed what we are labeling as the optimal response from a spleen and symptom perspective, with the goal of improving upon and deepening that response with the addition of navtemadlin, which has already demonstrated significant synergy in combination with ruxolitinib in the phase 1/2 study.

[POIESIS] is a pivotal study and [represents] a pivotal moment in myelofibrosis clinical development. It is an ambitious study design and an innovative schema.

How are suboptimal responses to ruxolitinib being defined in the trial?

A suboptimal response is not hitting those SVR35 and TSS 50 [end points with ruxolitinib alone], which has been the regulatory benchmark for success with a JAK inhibitor. Patients must also not be refractory to ruxolitinib. If you enjoy spleen and symptom benefits to that degree, then you're a responder, and those are not the patients who will get randomly assigned to navtemadlin or placebo. Patients who have no response to or even [have] progressive spleen or symptom burden with ruxolitinib [alone] also would not be considered suboptimal responders, although that's a minority of patients. These patients would be considered non-responders and refractory, [excluding them from being randomly assigned].

[The randomized portion of the trial] is focusing on the patients in between [responders and non-responders]. This includes the patients who've had some degree of response [to ruxolitinib alone], but an inadequate response. Can we do better for these patients? Can we deepen that response in a meaningful way with the addition of navtemadlin?

Do you anticipate any barriers to enrollment?

Not particularly. It's an ambitious trial that has a global reach, so it will be accruing across many centers in many countries around the world. It will accrue patients who are JAK inhibitor–naive, but not for the purpose of administering [navtemadlin plus ruxolitinib] up-front. A lot of questions will be answered prospectively with this trial. I don't see a lot of barriers [to enrollment]. The community at large and the patient community in general are looking for effective therapies. There's something attractive about starting a standard-of-care therapy with the option to add on the experimental drug if one does not have an optimal response.

The trial is not committing patients to combination therapies up-front; rather, we are allowing some period of time to determine whether that need is there if they're suboptimally responding. That [strategy] better mimics what incorporating a new therapy in a combination strategy will look like in the community setting. In the community setting—even if any new drug is approved—it is likely that patients will continue to use ruxolitinib [alone] up-front. We will then add on the new combination partner at some later point if there's a lack of substantial, significant, or adequate clinical response. This strategy is clinically relevant in the community setting and one that could be adopted very readily and eagerly by clinicians and patients in practice.

How does navtemadlin’s adverse effect profile lend itself to use in combination therapies?

Navtemadlin and MDM2 inhibitors in general are known to have 2 notable toxicity profiles. One of them is gastrointestinal [GI], like nausea or diarrhea, and the other is myelosuppression. Navtemadlin dosed at 240 mg once daily for 7 consecutive days with a 21-day holiday in a 28-day cycle allows for adequate dosing so that you can hit MDM2, turn on the P53 pathway adequately, and not incur significant myelosuppression, as there is an opportunity for counts to recover during that [21-day] period [off treatment]. Additionally, prophylaxis significantly reduces GI toxicity, which is predictably experienced in patients around day 2 to day 8 of the week that they're treated [with navtemadlin].

[Toxicities] are further improved upon with the addition of ruxolitinib. Ruxolitinib also seems to synergize in an efficacious manner, but it also offsets some of the toxicity that you can see with MDM2 inhibition. It makes the combination very attractive.

What is one thing you hope your colleagues take away from this interview and apply to their practice or research?

You have to have persistence in your objectives and learn from history to develop alternative strategies and overcome obstacles. This is a great example of a paradigm that's shifting because of the investigators who believe in and have embraced this concept and worked closely with the FDA to develop meaningful alternative pathways to develop therapeutics for our patients with myelofibrosis. It is a lesson for all of us on how to remain committed and continue to drive these therapies and potentially shift the paradigms of treatment forward. It's important for the field in general.

At the end of the day, the real benefit of navtemadlin could be the ability to fundamentally change the dynamics of the disease. This drug has the potential to provide spleen and symptom benefits, which is significant, but it also has the potential to change the disease burden and course positively. I'm excited to see the study’s rollout and the follow-up that will ensue.

Reference

Mascarenhas JO, Bose P, Hou HA, 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. Blood. 2024;144(suppl 1):483-483. doi.org/10.1182/blood-2024-205937