The oral MDM2 inhibitor navtemadlin is the first single agent to demonstrate significant efficacy in JAK (Janus kinase) inhibitor–refractory myelofibrosis, achieving improvements in spleen volume, symptoms, and biomarkers, according to data presented at the 2024 American Society of Hematology (ASH) Annual Meeting & Exposition.¹ Findings from the phase III BOREAS study showed navtemadlin nearly tripled spleen volume reductions and doubled symptom score improvements compared with best available therapy. The use of navtemadlin also demonstrated evidence of disease modification, with nearly one-half of patients (48%) experiencing bone marrow fibrosis reduction and sustained biomarker responses.

“The BOREAS findings mark a critical advance for patients with myelofibrosis who have exhausted JAK inhibitor therapy,” 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. “Navtemadlin’s ability to deliver clinically meaningful outcomes with a manageable safety profile offers new hope for patients in need of effective treatment options.”

As Dr. Mascarenhas explained, myelofibrosis is characterized by increased CD34 cell proliferation, inflammatory cytokine expression, and bone marrow fibrosis, leading to debilitating symptoms and splenomegaly. Overexpression of MDM2 disrupts the p53 pathway, a master regulator of apoptosis and cell survival.

The BOREAS findings mark a critical advance for patients with myelofibrosis who have exhausted JAK inhibitor therapy.

— John O. Mascarenhas, MD

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Study Details

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.

Of note, the trial enrolled a high-risk, heavily pretreated population. Approximately 65% of patients had primary refractory disease, 30% had low platelet counts (< 100,000/µL), and 70% had disease for more than 2 years.

Improvements in Spleen Volume Reduction, Quality of Life

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 = .0815). A clinically relevant spleen reduction of 25% was observed in 27% of navtemadlin-treated patients vs 10% in those given best available therapy.

Further analysis highlighted the durability of spleen responses with navtemadlin. A swimmer plot showed continued spleen volume reductions beyond 48 weeks, with some patients remaining on therapy for more than 2 years, indicating sustained benefit.

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,” Dr. Mascarenhas observed.

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, according to Dr. Mascarenhas.

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.

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, said Dr. Mascarenhas, reinforcing navtemadlin’s activity as a disease-modifying agent.

What Next?

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.

“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 Point of View

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 (Janus kinase) inhibitor–refractory myelofibrosis.

“The BOREAS trial is a very exciting and positive study,” Dr. Schiller told The ASCO Post. “Unlike add-on therapies to ruxolitinib, this trial demonstrates clinically meaningful efficacy as a single agent in patients who have exhausted JAK inhibitors.”

Gary J. Schiller, MD, FACP

Dr. Schiller also highlighted the potential impact of navtemadlin moving forward. “This trial shows durable spleen volume reductions and significant symptom improvements, which is particularly important for this challenging patient population,” he continued. “Since this is a phase III trial, I expect it will be submitted for approval soon, and we could see this drug available as early as 2025.”

Finally, Dr. Schiller noted the broader implications for myelofibrosis treatment. “We’re still not at the point where these therapies drastically reduce disease burden, like we see in chronic myeloid leukemia, but navtemadlin moves us closer,” Dr. Schiller concluded. “It brings a meaningful option to patients with few alternatives.”

DISCLOSURE: Dr. Mascarenhas reported financial relationships with AbbVie, Merck, Blueprint Medicines, PharmaEssentia, Celgene, Karyopharm, Novartis, MorphoSys, Kartos, Geron, Sumitomo, Pfizer, GSK, Keros, Disc, Ajax, Roche, Bristol Myers Squibb, CTI BioPharma/SOBI, and Incyte Corporation. Dr. Schiller owns stock in Amgen, BMS, Janssen (J&J); has served as a consultant or advisor to BMS, Curios Therapeutics, Daiichi Sankyo, and Novartis; has served on a speakers bureau for AbbVie, Agios, Amgen, Astellas Pharma US, Blueprint Medicines, BMS, Celgene, Karyopharm Therapeutics, GSK, Kite (Gilead), Jazz Pharmaceuticals, Rigel Pharmaceuticals, Seattle Genetics, and Stemline Therapeutics; and has received research funding from AbbVie, Actinium Pharmaceuticals, Actuate Therapeutics, Agios, Arog Pharmaceuticals, Astellas Pharma US, AllloVir, and Amgen.

REFERENCE

1. 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. 2024 ASH Annual Meeting & Exposition. Abstract 1000. Presented December 9, 2024.