Navtemadlin Reduces Markers of Disease Burden in Relapsed/Refractory Myelofibrosis

Navtemadlin in Relapsed/Refractory

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Treatment with navtemadlin (KRT-232) lowered the levels of biomarkers of disease burden in patients with relapsed/refractory myelofibrosis, according to findings from the phase 3 BOREAS trial (NCT03930732) that were presented at the 2024 ASH Annual Meeting.¹

“I want to emphasize the biology that drives this approach. MDM2 is a negative regulator of wild-type p53, which is a master determinant of cell fate, and this becomes very critical when you consider its influence over the 4 hallmarks of myelofibrosis: CD34-positive myelofibrosis cell proliferation, myelofibrosis driver gene variant allele frequency (VAF), bone marrow fibrosis, and pro-inflammatory cytokines,” said John O. Mascarenhas, MD, during a presentation of the data.

Mascarenhas is professor of medicine, hematology and medical oncology, director of the Center of Excellence for Blood Cancers and Myeloid Disorders, and director of the Adult Leukemia Program at the Mount Sinai Tisch Cancer Center in New York, New York.

In the randomized, multicenter, global phase 3 BOREAS trial, navtemadlin monotherapy was compared with best available therapy (BAT) that included hydroxyurea, peginterferon, immunomodulatory drugs, or supportive care. Patients included in the trial had TP53 wild-type myelofibrosis and were refractory or had relapsed on prior therapy with a JAK inhibitor. The data cutoff date was September 30, 2024.

In the study, 183 patients were randomly assigned 2:1 to receive navtemadlin (n =1 23) at 240 mg 7 days in a row for a 28-day cycle (with 21 days of drug holiday) or 1 cycle of BAT (n = 60) for 28 days. “The patients who were on a JAK inhibitor at the time had a 28-day washout period so that from a spleen and symptom perspective they were clear on day 1 of navtemadlin dosing,” Mascarenhas explained.

“What we saw in terms of biomarkers was a very significant potent, rapid reduction in circulating CD34 cells as a hallmark of myelofibrosis even within 12 weeks and sustained over 24 and 36 weeks,” Mascarenhas stated. At 12 weeks, CD34-positive cells showed a median reduction of 68% from baseline in 50 patients in the navtemadlin arm and 52% in 25 patients in the BAT arm. This trend continued at 24 weeks (n = 48, 70% reduction vs n = 19, 38% reduction) and at 36 weeks (n = 21, 76% reduction vs n = 9, 33% reduction).

The reduction in driver gene VAF by 50% or greater was observed in 21% (n = 17/82) of patients in the navtemadlin arm and 12% (n = 4/33) of patients in the BAT arm at 24 weeks, “nearly doubling the molecular response at 24 weeks,” Mascarenhas noted.

Mascarenhas also explained that a reduction in driver VAF was observed to be associated with other biological hallmarks or features of the disease, serving as a surrogate biomarker of disease burden. He continued to explain that the decreases in circulating CD34-positive cells and driver gene VAF are associated with an increase in spleen volume response (SVR) with navtemadlin treatment.

In addition, improved bone marrow fibrosis was observed with navtemadlin treatment vs BAT at 24 weeks. In the navtemadlin arm, 2% of patients had improved by 2 grades or greater, 45% of patients had improved by 1 grade, 30% of patients were stable, and 23% of patients had worsened. In the BAT arm, 3% of patients had improved by 2 grades or greater, 21% of patients had improved by 1 grade, 52% of patients were stable, and 24% of patients had worsened.

Pro-inflammatory markers were also assayed, and treatment with navtemadlin generated a reduction in serum cytokine levels over a 48-week period, including TNFα, IL-6, CRP, IL-8, and TGF-β levels, Mascarenhas noted.

Regarding baseline demographics, in the navtemadlin arm, 59% of patients had primary myelofibrosis, and 42% of patients had secondary myelofibrosis. In the BAT arm, 58% of patients had primary myelofibrosis, and 42% of patients had secondary myelofibrosis. Regarding driver mutations, JAK2 mutations were observed in 72% of patients in the navtemadlin arm and 65% of those in the BAT arm; CALR mutations were seen in in 18% vs 27% of patients, respectively; MPL mutations were observed in in 4% vs 2% of patients, respectively; and triple-negative cases were seen in in 6% vs 7% of patients, respectively.

High molecular risk mutations (≥1) were observed in 62% of patients in the navtemadlin arm and 68% of those in the BAT arm, and high molecular risk mutations (≥ 2) were seen in 24% and 23% of patients, respectively. ASXL1 mutations were present in 56% vs 60% of patients, respectively, and EZH2 mutations were observed in in 15% vs 7% of patients, respectively. Respective bone marrow fibrosis scores for grades 1, 2, and 3 were 9%, 10%, and 35% in the navtemadlin arm vs 35%, 46%, and 37% of those in the BAT arm, respectively. “[This was] a very advanced patient population who had [progressed on] JAK inhibitor therapy upfront,” Mascarenhas summarized.

“The primary end point was SVR35 at 24 weeks,” Mascarenhas said. SVR35 is defined as a SVR of 35% or greater from baseline after 24 weeks. Exploratory end points included reductions in the following: CD34-positive cell counts in the peripheral blood, VAF, cytokines, and bone marrow fibrosis. Combinations of these were assessed at pre-dose, week 12, week 24, and then every 12 weeks.

The randomized, double-blinded, add-on phase 3 POIESIS study (NCT06479135) will explore navtemadlin in combination with ruxolitinib (Jakafi) in patients with JAK inhibitor–naive myelofibrosis. Patients will receive ruxolitinib alone during the initial phase, and those who have a suboptimal response will be randomly assigned 2:1 to receive either navtemadlin (n = 120) or placebo (n = 60) in addition to ongoing ruxolitinib treatment.²

The coprimary end points of this study are targeted SVR and total syndrome score reduction at 24 weeks after randomization.

“The BOREAS trial is the first global phase 3 trial, conducted solely in patients with myelofibrosis who are truly relapsed/refractory to JAK inhibitor treatment, to report results. Navtemadlin monotherapy has been shown to improve biomarkers of disease burden in this patient population that I would argue is suggestive of anti-clonal activity and disease modification. This includes reductions in CD34[-positive] cells, driver mutation burden, serum inflammatory cytokine levels, [as well as important correlations with] SVR, which is a key clinical outcome predictive of quality of life and overall survival,” Mascarenhas said.

References

1. 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
2. Study of navtemadlin add-on to ruxolitinib in JAK inhibitor-naïve patients with myelofibrosis who have a suboptimal response to ruxolitinib. National Cancer Institute. Accessed November 8, 2024. https://www.cancer.gov/research/participate/clinical-trials-search/v?id=NCI-2024-05880&r=1