Navtemadlin, an oral MDM2 inhibitor, has emerged as a potential breakthrough for patients with myelofibrosis who have relapsed or are refractory to JAK inhibitor therapy. Data from the phase III BOREAS trial, presented at the 2024 American Society of Hematology (ASH) Annual Meeting & Exposition, revealed that navtemadlin significantly improved spleen volume, symptoms, and biomarkers in this challenging patient population.
The BOREAS trial enrolled 183 patients with wild-type p53 myelofibrosis who had relapsed or were refractory to prior JAK inhibitor therapy. Patients were randomly assigned 2:1 to receive navtemadlin (240 mg, days 1–7 of a 28-day cycle) or best available therapy. The primary endpoint was spleen volume reduction of at least 35% at week 24, assessed by central review. The key secondary endpoint was total symptom score reduction of at least 50% at week 24.
Spleen Volume and Symptom Improvement
At week 24, 15% of patients receiving navtemadlin achieved a spleen volume reduction of at least 35%, compared with 5% in those given best available therapy (P = .012). A clinically relevant spleen reduction of 25% was observed in 27% of navtemadlin-treated patients vs 10% in those given best available therapy. Navtemadlin also significantly improved symptom burden, with 24% of patients achieving a total symptom score reduction of at least 50%, compared with 12% of those given best available therapy. Mean absolute changes in total symptom score further underscored navtemadlin’s impact, with a reduction of nearly 5 points vs a 1-point increase with best available therapy (P = .0078).
"These findings highlight navtemadlin’s ability to meaningfully reduce the symptoms that affect patients’ quality of life," said lead study author John O. Mascarenhas, MD, Professor of Medicine at the Icahn School of Medicine at Mount Sinai, and Director of the Center of Excellence for Blood Cancers and Myeloid Disorders.
Disease Modification Evidence
Navtemadlin also demonstrated evidence of disease modification, with significant improvements in biomarker responses. Bone marrow fibrosis reduction was observed in 48% of navtemadlin-treated patients vs 24% of those given best available therapy. Partial molecular responses (≥ 50% reduction) occurred in 21% of navtemadlin-treated patients vs 12% of those receiving best available therapy. These biomarker improvements correlated with clinical endpoints, reinforcing navtemadlin’s activity as a disease-modifying agent.
Safety and Tolerability
Navtemadlin’s safety profile was consistent with expectations for MDM2 inhibitors. Gastrointestinal toxicity and thrombocytopenia were the most common adverse events, but both were reported to be reversible and manageable with prophylaxis. Gastrointestinal events occurred predominantly in the first week of treatment, peaking on days 2 to 9, and resolved within a median of 7 to 9 days. Hematologic toxicities, including thrombocytopenia, occurred in 37% of patients, but platelet counts remained stable throughout the treatment period, preserving hematopoiesis.
POIESIS Trial: Navtemadlin in Combination with Ruxolitinib
Looking forward, the POIESIS study will evaluate navtemadlin in patients with suboptimal responses to ruxolitinib, potentially broadening its role earlier in the myelofibrosis treatment paradigm. The study will have 2 treatment periods: a ruxolitinib monotherapy period followed by navtemadlin or placebo as an add-on therapy to ruxolitinib (n=180). Patients will be randomized 2:1 to receive either navtemadlin (n=120) or placebo (n=60) at a dose of 240 mg QD (Day 1-7/28-day cycle) added on to a stable dose of ruxolitinib. The primary end points are the rates of SVR35 and TSS50 at 24 weeks after the start of the randomized period.
"This study will assess navtemadlin in suboptimal responders to determine whether we can move the drug further up the development pathway and provide benefit to patients earlier in their treatment journey," Dr. Mascarenhas concluded.
Expert Commentary
Gary J. Schiller, MD, FACP, Professor of Medicine at UCLA Health, emphasized the significance of the BOREAS trial in addressing an unmet need for patients with JAK inhibitor–refractory myelofibrosis. "The BOREAS trial is a very exciting and positive study. Unlike add-on therapies to ruxolitinib, this trial demonstrates clinically meaningful efficacy as a single agent in patients who have exhausted JAK inhibitors."
