Results from the Randomized, Multicenter, Global Phase 3 BOREAS Study: Navtemadlin Versus Best Available Therapy in JAK Inhibitor Relapsed<i>/</i>Refractory Myelofibrosis

Background: Myelofibrosis (MF) patients (pts) who are relapsed or refractory (R/R) to JAK inhibitor (JAKi) treatment have a poor prognosis with a median overall survival of 11-13 months (Mascarenhas 2020; Palandri 2020). MF is characterized by excessive production of mouse double minute 2 (MDM2), a key negative regulator of the tumor suppressor protein p53, in CD34+ progenitor cells. Navtemadlin is a potent, selective, orally available MDM2 inhibitor that restores p53 function. Preclinically, navtemadlin drives apoptosis of TP53 wild-type (TP53WT) CD34+ MF cells through modulation of B cell lymphoma (BCL-2) family proteins. In a phase 2 study, navtemadlin showed clinically meaningful activity with disease-modifying potential in MF pts who were R/R to JAKi (Al-Ali 2020; Verstovsek 2022; Vachhani 2023). Aim: To evaluate the efficacy and safety of navtemadlin monotherapy vs best available therapy (BAT) in the phase 3 BOREAS study (NCT03662126). Methods: The BOREAS study enrolled TP53WT adults with primary or secondary MF who were R/R to JAKi treatment (JAKi-intolerant or JAKi-ineligible pts were excluded); ECOG 0-2, intermediate- (int-) or high-risk MF per DIPSS, platelets ≥50x109/L, and peripheral blasts &amp;lt;10%. Pts were randomized 2:1 to receive navtemadlin monotherapy 240 mg once-daily (Day 1-7/28-day cycle) or BAT (monotherapy or combinations: hydroxyurea, chemotherapy, IMiDs, and supportive care; JAKi were excluded). Pts were required to have a 28-day JAKi “wash-out” period prior to baseline MRI/CT. Crossover to navtemadlin was allowed at Week 24 or at time of disease progression. Anti-diarrhea prophylaxis was administered for the first two cycles and anti-nausea prophylaxis was given with every cycle for the seven days of navtemadlin treatment. The primary endpoint was rate of spleen volume reduction ≥35% (SVR35) at Week 24 by MRI/CT (blinded central review). The key secondary endpoint was the rate of total symptom score reduction ≥50% (TSS50) at Week 24 by MFSAF v4.0. Results: As of March 11, 2024 (enrollment stopped in August 2023), 183 pts were randomized (123 pts on navtemadlin and 60 pts on BAT; intention-to-treat population [ITT]) in 23 countries at 181 sites. Baseline characteristics were well balanced between the arms and included: int-1/int-2/high-risk MF per DIPSS (34%/50%/15%), median spleen volume of 2310 cm3, median TSS of 20.8, prior therapy range of 1-6 (99% had ruxolitinib [rux]), median time from initial MF diagnosis was 47.6 months, 34% of pts had platelets &amp;lt;100x109/L, 48% had a bone marrow fibrosis of grade 3, 70% had the JAK2V617F driver mutation, and 77% had ≥1 high molecular risk mutation (≥2 in 23%). At Week 24 (ITT), 15% (18/123) of pts vs 5% (3/60) achieved SVR35 (p=0.08) and 24% (30/123) vs 12% (7/60) achieved TSS50 (p=0.05) with navtemadlin vs BAT, respectively. Forty percent (24/60) of pts on BAT crossed over to navtemadlin. Marked reductions in disease biomarkers (ie, bone marrow fibrosis, driver mutation allele burden, and blood CD34+ progenitors) were greater with navtemadlin, suggesting potential disease modification. At the time of data cut, transformation to AML occurred in 1.6% (2/123) of pts on navtemadlin vs 3.3% (2/60) on BAT; all four pts were TP53WT. At a median follow-up of 10.7 months, the most common hematologic (heme) grade 3/4 treatment-emergent adverse events (TEAEs) were thrombocytopenia (37% vs 21%), anemia (29% vs 25%), and neutropenia (24% vs 12%) with navtemadlin vs BAT, respectively. Gastrointestinal (GI) grade 3/4 TEAEs were diarrhea (5% vs 2%), nausea (3% vs 0%), and vomiting (2% vs 0%) with navtemadlin vs BAT, respectively. Mean platelet and hemoglobin levels remained stable over the course of study treatment. Dose reductions and discontinuations for heme TEAEs were 26% and 3%, and for GI TEAEs were 8% and 0%. Conclusion: BOREAS is the first randomized, global phase 3 study conducted solely in MF pts R/R to JAKi to report results. In this phase 3 study, navtemadlin monotherapy was safe and effective, demonstrating clinically relevant efficacy with disease-modifying potential. The rate of SVR35 and TSS50 at Week 24 was three-fold and two-fold higher with navtemadlin vs BAT, validating the novel approach of MDM2 inhibition in pts with MF. Further studies of navtemadlin in MF are warranted, including as add-on therapy to rux treatment in JAKi-naive pts who have a suboptimal response to rux (POIESIS; NCT06479135).