July 7, 2023
Kyle Doherty
The addition of the MDM2 inhibitor navtemadlin (formerly KRT-232) to ruxolitinib (Jakafi) led to clinically meaningful improvements in spleen volume reduction (SVR) among patients with primary or secondary TP53 wild-type myelofibrosis who had a suboptimal response to ruxolitinib, according to findings from the phase 1/2 KRT-232-109 study (NCT04485260) presented during the 2023 European Hematology Association (EHA) Congress.
Results from the trial showed that at 24 weeks among efficacy-evaluable patients (n = 19) adding navtemadlin to ruxolitinib conferred a minimum SVR of 25% in 42% of patients and an SVR of at least 35% in 32%. Additionally, a minimum total symptom score (TSS) improvement of at least 50% was observed in 32% of patients.
“This therapeutic approach is clearly active,” John O. Mascarenhas, MD, said. “The combination of navtemadlin and ruxolitinib achieves two things: synergy in terms of cell kill directed at the CD34 myeloblasts population, which is really what we’re trying to accomplish, and an improved toxicity profile [compared with] monotherapy. This is a combination that could potentially even be used upfront in the JAL inhibitor-naïve patient population. MDM2 inhibition is here and likely is going to be a component in the future. Navtemadlin is poised to be at the forefront as a first-in-class agent to deliver that kind of clinical activity.”
In an interview with OncLive®, Mascarenhas, professor of medicine at the Icahn School of Medicine at Mount Sinai, director of the Center of Excellence for Blood Cancers and Myeloid Disorders, and a member of Tisch Cancer Institute in New York, New York, discussed the design and rationale of KRT-232-109, more key findings from the trial, and potential future directions of the study.
OncLive: What is the mechanism of action of navtemadlin and what was the rationale for evaluating it in KRT-232-109?
Mascarenhas: Myelofibrosis is predominantly a TP53 wild-type disease. MDM2 negatively regulates TP53. [The] p53 pathway is important for regulating cell fate and balancing prosurvival and prodeath signals.
In myelofibrosis, MDM2 is overexpressed in CD34 cells, and this negatively regulates TP53 activity. It’s an alternative mechanism for cancer cells to increase the threshold for induction of apoptosis. Navtemadlin interrupts that interaction between MDM2 and wild-type TP53, thereby activating TP53 and inducing apoptosis.
What’s exciting about the phase 1b/2 study adding navtemadlin to patients receiving ruxolitinib with a suboptimal response is [the fact that] ruxolitinib works synergistically with navtemadlin in reducing p21. [This] essentially lowers the threshold to induce apoptosis in the setting of navtemadlin, so the two work well together to induce apoptosis in myelofibrosis CD34 cells—there’s great preclinical data that justify this concept.
What were the goals of the KRT-232-109 study?
The goal of the phase 1 was to determine the recommended phase 2 dose of navtemadlin in combination with ruxolitinib in these suboptimal ruxolitinib-[responding] myelofibrosis patients.
We evaluated 3 different dose levels and different dose schedules, and the recommended phase 2 dose based [not only] on the clinical results, but also on some of the pharmacokinetic results that were that were conducted is 240 mg of navtemadlin 7 days in a row of a 28-day cycle. [It’s a] 1-week-on-3-week-off [schedule of] 1-month cycles with the stable dose of ruxolitinib that the patient is on. So, you don’t adjust the dose of ruxolitinib, you simply add navtemadlin.
The ongoing purpose of the phase 2 [study] is to document the efficacy as measured by SVR and symptom improvement at 24 weeks.
What were some of the key inclusion criteria?
Patients had to have a platelet count greater than 100,000 because we often use platelet counts in these trials to determine eligibility. Patients had to have TP53 wild-type disease. Importantly, this approach is probably not effective in patients who have mutant disease because MBM2 doesn’t regulate mutant TP53. [Patients also needed to be] on ruxolitinib for at least 18 weeks, which is the minimal amount of time needed to determine whether someone has an optimal [response], suboptimal [response], or progressive disease, and at a stable dose of ruxolitinib for 8 weeks.
What were the key efficacy findings from KRT-232-109 presented during the 2023 EHA Congress?
We looked [what] we would normally look at in myelofibrosis, [such as] spleen response. The SVR [of] at least 35% at 24 weeks in evaluable patients was 32%. If you look at SVR [of at least] 25%, which is also considered by regulatory agencies a meaningful spleen response at 24 weeks, it was 42%. There was clear spleen reduction, and most patients [experienced] some degree of spleen response.
Symptom improvement was also seen; 32% of patients at week 24 had a 50% or greater TSS score and some of these patients had very significant spleen symptom burden at baseline. The drug was effective in addressing those 2 clinical end points.
What was really interesting was that patients, in some cases, had ruxolitinib doses of 5 mg twice daily going into the study, meaning they were coming in at low doses. And despite low doses of ruxolitinib, there was synergistic activity with navtemadlin[and] we were seeing very deep spleen and symptom responses. This speaks to the fact that biologically there is a priming almost of the diseased cells for TP53 induction of apoptosis with ruxolitinib. The preclinical data supported and translated very nicely into the clinical findings.
Are there any safety concerns clinicians should be aware of when using navtemadlin plus ruxolitinib?
[This was a] well-tolerated drug. We know that, as a class of agents, there is a degree of gastrointestinal [GI] toxicity with MDM2 inhibitors, [including] nausea, vomiting and diarrhea. [These events were] rarely grade 3/4 [in severity]; 70% of were grade 1. [Approximately] 60% of patients experienced some GI toxicity, usually in the first 2 cycles. Preemptively, we give antiemetic and an antidiarrheal. That is a very effective way of managing those nausea and diarrhea type toxicities.
The [inclusion] of ruxolitinib it seems to offset some of that toxicity. There may be some biologic reasons why there’s synergy with ruxolitinib, not just an efficacy, but also in improving the safety profile with navtemadlin. The deep responses that we see are also complemented by a well-tolerated combination.
What are the next steps for this research?
We want to finish the follow-up of patients enrolled in phase 2. We still have ongoing correlatives to look at. We presented correlatives that were very encouraging [showing] that we were having on-target stem cell–directed therapeutic effects, [such as] reduction of CD34 cell burden, reduction in bone marrow fibrosis, and reduction in driver RAF level in these patients that were treated.
We were clearly having disease-modifying effect, biologic response modification. We want to see that in a greater number of patients [and] I’d love to see some of the cytokine results. There’s still more to be done from a correlative science aspect and patient follow-up to be conducted.
Ultimately, where this will go is to a phase 3 study, which will be entitled BOREAS-2, where we’ll be [enrolling patients with] suboptimal ruxolitinib response and adding navtemadlin [and evaluating this treatment] vs placebo to improve responses.
Reference
Mascarenhas J, Jain T, Otoukesh S, et al. An open-label, global, phase (Ph) 1b/2 study adding navtemadlin (NVTM) to ruxolitinib (RUX) in patients (Pts) with primary or secondary myelofibrosis (MF) who have a suboptimal response to RUX. HemaSphere. 2023;7(suppl 3):S210.