Navtemadlin, a novel MDM2 inhibitor, lowered biomarkers of illness severity in sufferers with relapsed or refractory myelofibrosis, in response to knowledge introduced on the 2024 ASH Annual Assembly.
Sufferers with relapsed or refractory (R/R) myelofibrosis skilled lowered biomarkers of illness severity following therapy with the novel p53 potentiating anticancer agent best-in-class MDM2 inhibitor navtemadlin (KRT-232), which prompt that the agent might goal disease-driving cells and alter its development, in response to knowledge from the part 3 BOREAS trial that had been introduced on the 2024 ASH Annual Assembly.
“I wish to emphasize the biology that drives this strategy. The MDM2 is a detrimental regulator of wild-type p53, which is a grasp determinant of self-fate, and this turns into very essential when you think about its affect 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,” stated Dr. John O. Mascarenhas throughout a presentation of the info.
Mascarenhas is professor of medication, hematology and medical oncology, director, Middle of Excellence for Blood Cancers and Myeloid Issues and director, Grownup Leukemia Program at Mount Sinai Tisch Most cancers Middle in New York.
Within the randomized, multicenter, international part 3 BOREAS trial, navtemadlin monotherapy was in contrast with finest out there remedy (BAT) that included hydroxyurea, peginterferon, immunomodulatory imide medicine or supportive care. These sufferers included within the trial had TP53 wild-type myelofibrosis and had been R/R to a JAK inhibitor. The information cut-off was Sept. 30, 2024.
Glossary:
CD34-positive MF cell proliferation: the rise of cells that specific the protein CD34 in a affected person with myelofibrosis.
MF driver gene variant allele frequency (VAF): frequency of genetic mutations which can be drivers for myelofibrosis.
Bone marrow fibrosis: when bone marrow is changed with scar tissue.
Professional-inflammatory cytokines: proteins that begin or enhance irritation within the physique.
Within the examine, 183 sufferers had been randomly assigned to obtain navtemadlin (123 sufferers) at 240 milligrams for seven days in a row for a 28-day cycle (with 21 days of drug vacation) or one cycle of BAT (60 sufferers) for 28 days.
“The sufferers who had been on a JAK inhibitor on the time had a 28-day washout interval in order that from a spleen and symptom perspective they had been clear on day 1 of navtemadlin dosing,” Mascarenhas defined.
“What we noticed when it comes to biomarkers was a really important, potent, fast discount in circulating CD34 cells as a trademark of MF even inside 12 weeks and sustained over 24 and 36 weeks,” Mascarenhas said. At 12 weeks, CD34+ cells confirmed a median discount of 68% from baseline in 50 sufferers within the therapy arm and 52% in 25 sufferers within the BAT arm. This pattern continued at 24 weeks (48 sufferers, 70% discount versus 19 sufferers, 38% discount) and at 36 weeks (21 sufferers, 76% discount versus 9 sufferers, 33% discount).
The discount in driver gene VAF by 50% or better was noticed in 21% (17of 82) of sufferers within the therapy arm and 12% (4 of 33) of sufferers within the BAT arm at 24 weeks. “So practically doubling the molecular response at 24 weeks,” Mascarenhas famous.
Mascarenhas additionally defined {that a} discount in driver VAF was noticed to be related to different organic hallmarks or options of the illness, serving as a surrogate biomarker of illness burden. He continued to elucidate that the decreases in circulating CD34+ cells and driver gene VAF are related to a rise in spleen quantity response (SVR) with navtemadlin therapy.
As well as, improved bone marrow fibrosis was noticed with navtemadlin therapy versus BAT at 24 weeks. Within the therapy arm, 2% of sufferers had improved by two grades or better, 45% had improved by one grade, 30% had been secure and 23% worsened. Within the BAT arm, 3% had improved by two grades or better, 21% had improved by one grade, 52% had been secure and 24% worsened.
Professional-inflammatory markers had been additionally assayed, and therapy with navtemadlin confirmed a discount in serum cytokine ranges over a 48-week interval, Mascarenhas famous.
Relating to baseline demographics, within the therapy arm 59% had main MF subtype and 42% had secondary. Within the BAT arm 58% had main MF subtype and 42% had secondary. Relating to driver mutations, JAK2 mutations had been noticed in 72% of the therapy arm and 65% of the BAT arm; CALR mutations in 18% versus 27%; MPL mutations in 4% versus 2% and triple-negative circumstances in 6% versus 7%, respectively.
Excessive molecular threat mutations (at the very least one) had been noticed in 62% of the therapy arm and 68% of the BAT arm, and excessive molecular threat mutations (at the very least two) had been seen in 24% and 23%, respectively. ASXL1 mutations had been current in 56% versus 60%, and EZH2 mutations in 15% versus 7%, every respectively. Bone marrow fibrosis scores for grades 1, 2 and three had been 9% versus 10%, 35% versus 35% and 46% versus 37%, respectively. “So, a really superior affected person inhabitants who had failed JAK inhibitor remedy upfront,” Mascarenhas summarized.
“The first finish level was SVR35 at 24 weeks,” Mascarenhas stated. SVR35 is outlined as an SVR of 35% or extra from baseline after 24 weeks. Exploratory finish factors included discount within the following: CD34+ cell rely in peripheral blood, VAF, cytokines and bone marrow fibrosis. Combos of those had been assessed at pre-dose, weeks 12, 24 after which each 12 weeks.
The randomized, double-blinded add-on part 3 POIESIS examine will discover navtemadlin together with Jakafi (ruxolitinib) in sufferers with JAK inhibitor-naive myelofibrosis. Sufferers will begin by taking Jakafi alone through the preliminary part, and those that present a suboptimal response are randomly assigned to obtain both navtemadlin (120 sufferers) or placebo (60 sufferers) along with ongoing Jakafi therapy.
The coprimary finish factors of this examine are focused SVR and whole syndrome rating discount at 24 weeks after randomization.
“The BOREAS trial is the primary international part 3 trial, performed solely in sufferers with MF who’re really R/R to JAK inhibitor therapy, to report outcomes. Navtemadlin monotherapy has been proven to enhance biomarkers of illness burden on this affected person inhabitants that I might argue is suggestive of anti-clonal exercise and illness modification. This contains discount in CD34 cell, driver mutation burden, serum inflammatory cytokine ranges and importantly correlating with SVR, which is a key medical final result predictive of high quality of life and total survival,” Mascarenhas stated.
Reference:
“Illness-modifying exercise of navtemadlin correlates with medical responses in a randomized, multicenter, international part 3 examine (BOREAS) in JAK-inhibitor relapsed/refractory myelofibrosis” by Dr. John O. Mascarenhas et al., Blood.
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