An ongoing phase 3 study is exploring the use of oral navtemadlin (KRT-232) therapy for patients with myelofibrosis (MF) that is relapsed/refractory (R/R) to Janus kinase (JAK)-inhibitor therapy. A description of the study was recently published in the journal Future Medicine.

Because of their potential effects on symptom control and reduction in spleen volume, JAK inhibitors have been the standard of care in treatment of MF. However, poor prognosis has been seen in patients with MF who have received JAK-inhibitor therapy, but who have discontinued this treatment owing to disease progression or resistance.

Navtemadlin is thought to act as a murine double minute 2 (MDM2) inhibitor. In circulating CD34+ malignant MF cells, MDM2 shows overexpression, and this protein is considered a negative regulator of p53 protein, the study investigators explained in their report.

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Navtemadlin is thought to have potential to restore the activity of p53 and promote apoptosis in malignancies with wild-type TP53. Navtemadlin is an oral agent being tested in the global, randomized phase 3 BOREAS study ( Identifier: NCT03662126) in patients with MF that is R/R to JAK-inhibitor therapy.

Among eligibility criteria for the BOREAS study, patients must be adults with a confirmed diagnosis of TP53-wild-type primary or secondary MF and a disease risk status of intermediate-1, intermediate-2, or high risk, based on Dynamic International Prognostic Scoring System criteria. They must also have an Eastern Cooperative Oncology Group performance status of ≤2 and adequate hematologic function.

Patients may not have had prior MDM2 inhibitor therapy, p53-directed therapy, allogeneic stem cell transplant therapy, JAK-inhibitor intolerance, or JAK-inhibitor treatment in the 28 days prior to screening by magnetic resonance imaging (MRI)/computed tomography (CT).

Patients in this study are randomly assigned 2:1 into 2 study arms. One arm is assigned to receive navtemadlin, while the other arm is assigned to best available therapy. In the navtemadlin arm, in each treatment cycle, patients receive 240 mg of this agent daily for 7 days, with 21 days off therapy. In the arm receiving best available therapy, treatment cycles are also 28 days. The target study population size is approximately 282 patients, with 188 patients in the navtemadlin arm and 94 patients in the arm receiving best available therapy.

The primary study end point is the proportion of participants with a spleen volume reduction of ≥35% at week 24, based on central review of MRI/CT results. Several key secondary end points related to efficacy and safety are also being evaluated.

“The BOREAS study has the potential to establish navtemadlin as a novel therapeutic approach for MF patients who are R/R to JAK inhibitor treatment and would otherwise have limited treatment options,” the study investigators wrote in their report.

Disclosures: Some authors have declared affiliations with or received grant support from the pharmaceutical industry. Please refer to the original study for a full list of disclosures.


Verstovsek S, Al-Ali HF, Mascarenhas J, et al. BOREAS: a global, phase III study of the MDM2 inhibitor navtemadlin (KRT-232) in relapsed/refractory myelofibrosis. Future Oncol. Published online November 23, 2022. doi:10.2217/fon-2022-0901