Treatment with navtemadlin, a potent, selective, orally available mouse double minute 2 (MDM2) inhibitor that restores p53 function, appeared to be safe and clinically effective for patients with myelofibrosis that is relapsed or refractory (R/R) to JAK inhibitors, according to results of the BOREAS trial presented at the 66th American Society of Hematology Annual Meeting and Exposition.
“There is clinically relevant efficacy and safety with nearly tripling of [spleen volume reduction of at least 35%] and doubling of [total symptom score reduction of at least 50%],” said lead author John O. Mascarenhas, MD, of Tisch Cancer Institute at the Icahn School of Medicine in Mount Sinai, New York, who presented the results.
According to Dr. Mascarenhas, in a preclinical setting, navtemadlin was shown to drive apoptosis of TP53 wild-type CD34-positive myelofibrosis cells through modulation of BCL2-family proteins.
In BOREAS, researchers tested navtemadlin against best available therapy in 183 patients with primary or secondary myelofibrosis R/R to JAK inhibitors; best available therapy could include monotherapy or combinations of hydroxyurea, chemotherapy, immunomodulatory drugs, and supportive care.
Patients were randomly assigned 2:1 to navtemadlin monotherapy or best available therapy. All patients had a JAK inhibitor wash-out period prior to therapy, and crossover was allowed at week 24 or disease progression. Forty percent of patients who were assigned best available therapy crossed over to treatment with navtemadlin.
At week 24, 15% of patients assigned to navtemadlin achieved the primary endpoint of spleen volume reduction of at least 35% (SVR35) compared with 5% of patients assigned best available therapy (p=0.08). Total symptom score reduction of at least 50% (TSS50), a secondary endpoint, was doubled in patients assigned to navtemadlin (24% vs. 12%; p=0.05).
Median time on study was 15.6 months for navtemadlin and 6.5 months for best available therapy. Common grade 3-4 treatment-emergent adverse events (TEAEs) of navtemadlin included thrombocytopenia (37%), anemia (29%), and neutropenia (24%). According to the researchers, the mean platelet and hemoglobin levels were “relatively” stable with navtemadlin. Gastrointestinal adverse events were mostly grade 1 or 2, and Dr. Mascarenhas described them as “predictable in their occurrence and fleeting in their duration.”
“[BOREAS] demonstrated efficacy and maintained safety of the drug from a hematologic and non-hematologic perspective,” Dr. Mascarenhas told ASH Clinical News. “The emphasis on developing this drug is focused on moving it up earlier in the treatment algorithm to patients with suboptimal response [to ruxolitinib].”
Indeed, Dr. Mascarenhas said the BOREAS study was stopped before accrual solely for the purpose of focusing attention and resources on the POESIS trial (NCT06479135), a phase III study of navtemadlin that will evaluate the safety and efficacy of navtemadlin and ruxolitinib compared with placebo and ruxolitinib in JAK inhibitor-naïve patients with myelofibrosis with suboptimal response to ruxolitinib.
Any conflicts of interest declared by the authors can be found in the original abstract.
Reference
Mascarenhas JO, Popov VM, Mohan S, et al. Results from the randomized, multicenter, global phase 3 BOREAS study: navtemadlin versus best available therapy in JAK inhibitor relapsed/refractory myelofibrosis. Abstract 1000. Presented at the 66th American Society of Hematology Annual Meeting and Exposition; December 9, 2024; San Diego, California.
