Novel MDM2 Inhibitor Shows Disease-Modifying Activity in R/R Myelofibrosis

"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 reduction in CD34 cell, driver mutation burden, serum inflammatory cytokine levels, and importantly correlating with SVR, which is a key clinical outcome predictive of quality of life and overall survival," according to study author John O. Mascarenhas, MD.

Disease-driving cells in patients with relapsed/refractory (R/R) myelofibrosis (MF) may be targetable with the investigational p53-potentiating, best-in-class MDM2 inhibitor navtemadlin (KRT-232), according to findings from the phase 3 BOREAS trial (NCT03930732) presented at the 2024 American Society of Hematology Annual Meeting & Exposition (ASH).¹

“I want to emphasize the biology that drives this approach. The MDM2 is a negative regulator of wild type p53, which is a master determinant of self-fate, and this becomes very critical when you consider its influence over the 4-hallmarks of myelofibrosis: CD34-positive MF cell proliferation, MF 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, Center of Excellence for Blood Cancers and Myeloid Disorders, director, Adult Leukemia Program at Mount Sinai Tisch Cancer Center, 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 imide drugs, or supportive care. Those patients included in the trial had TP53^WT myelofibrosis and were R/R to a JAK inhibitor. The data cut-off was September 30, 2024.

In the study, 183 patients were randomly assigned 2:1 to receive navtemadlin (n=123) 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 MF even within 12 weeks and sustained over 24 and 36 weeks,” Mascarenhas stated. At 12 weeks, CD34+ cells showed a median reduction of 68% from baseline in 50 patients in the treatment arm and 52% in 25 patients in the BAT arm. This trend continued at 24 weeks (48 patients, 70% reduction vs 19 patients, 38% reduction) and at 36 weeks (21 patients, 76% reduction vs 9 patients, 33% reduction).

The reduction in driver gene VAF by 50% or greater was observed in 21% (17/82) of patients in the treatment arm and 12% (4/33) of patients in the BAT arm at 24 weeks. “So 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 treatment arm, 2% of patients had improved by 2 grades or greater, 45% had improved by 1 grade, 30% were stable, and 23% worsened. In the BAT arm, 3% had improved by 2 grades or greater, 21% had improved by 1 grade, 52% were stable, and 24% worsened.

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

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

High molecular risk mutations (≥1) were observed in 62% of the treatment arm and 68% of the BAT arm, and high molecular risk mutations (≥2) were seen in 24% and 23%, respectively. ASXL1 mutations were present in 56% vs 60%, and EZH2 mutations in 15% vs 7%, each respectively. Bone marrow fibrosis scores for grades 1, 2, and 3 were 9% vs vs 10%, 35% vs 35%, and 46% vs 37%, respectively. “So, a very advanced patient population who had failed 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 more from baseline after 24 weeks. Exploratory end points included reduction in the following: CD34+ cell count in peripheral blood, VAF, cytokines, and bone marrow fibrosis. Combinations of these were assessed at pre-dose, weeks 12, 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 start by taking ruxolitinib alone during the initial phase, and those who show a suboptimal response are 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 MF who are truly R/R 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 reduction in CD34 cell, driver mutation burden, serum inflammatory cytokine levels, and importantly correlating with SVR, which is a key clinical outcome predictive of quality of life and overall survival,” Mascarenhas said.¹

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