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

Abstract

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 <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 <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).