Disease-Modifying Activity of Navtemadlin Correlates with Clinical Responses in a Randomized, Multicenter, Global Phase 3 Study (BOREAS) in JAK-Inhibitor Relapsed/Refractory Myelofibrosis

Introduction: Mouse double minute 2 (MDM2) is a key negative regulator of the tumor suppressor protein p53. Myelofibrosis (MF) is characterized by excessive production of MDM2 in CD34⁺ progenitor cells. Navtemadlin is a potent, selective, orally available MDM2 inhibitor that restores p53 function and drives apoptosis of TP53 wild-type (TP53^WT) MF cells through the modulation of B cell lymphoma (BCL-2) family proteins.

Maximizing spleen volume reduction (SVR) and total symptom score (TSS) in MF is critical for patient (pt) care since both are correlated with quality of life (QoL) and overall survival (Vannucchi 2015; Maffioli 2022; Mesa 2013). Approved therapies have shown SVR and TSS reduction, with modest impact on the biological markers of disease modification (ie, peripheral blood [PB] CD34⁺ progenitors, bone marrow fibrosis grade, and driver mutation allele burden; Pemmaraju 2023). In the phase 2 study KRT-232-101 Part A, navtemadlin demonstrated clinically meaningful activity with disease-modifying potential in pts with MF who were relapsed or refractory (R/R) to JAK inhibitor (JAKi) treatment (Al-Ali 2020; Verstovsek 2022; Vachhani 2023). Navtemadlin markedly decreased PB CD34⁺ cell counts and driver mutation burden, which correlated with SVR (p=0.0048; Vachhani 2021, 2023).

Aim: To assess changes in biomarkers of disease burden and correlations with SVR in the global, randomized phase 3 BOREAS study (NCT03662126), navtemadlin monotherapy vs best available therapy (BAT: hydroxyurea, chemotherapy, IMiDs, and supportive care) for pts with TP53^WT MF who were R/R to JAKi.

Methods: CD34⁺ cell counts, variant allele frequencies (VAFs) of driver mutations (JAK2^V617F, CALR, MPL), and serum cytokine levels (TNFα, IL-6, CRP) were analyzed by central laboratory from PB of pts receiving navtemadlin 240 mg once daily (Day 1-7/28-day cycle) or BAT using flow cytometry, next generation sequencing, and ELISA at baseline, Week 12, and Week 24. Changes in bone marrow fibrosis grade from baseline to Week 24 and Week 48 were assessed by central pathology review.

Results: As of March 11, 2024, samples were collected and analyzed from 180 treated pts (123 with navtemadlin and 57 with BAT).

Decrease in Peripheral Blood CD34⁺ Cells: Navtemadlin demonstrated on-target biological activity, reflected by substantial decreases in PB CD34⁺ cell counts. Median PB CD34⁺ cell counts decreased from baseline by -62% at Week 12 (n=30) and -82% at Week 24 (n=24) vs -52% (n=19) and -42% (n=12) with BAT, respectively. Notably, 40% (6/15) of navtemadlin treated pts who had a >50% reduction in CD34⁺ counts from baseline to Week 24 achieved SVR ≥35% vs 1/5 pts with BAT. Reductions in CD34⁺ cells with navtemadlin treatment were significantly correlated with SVR at Week 24 (p=0.001).

Improvement of Bone Marrow Fibrosis: Of the evaluable pts who had paired bone marrow biopsies at baseline and Week 24, bone marrow fibrosis grade improved by one or more in 47% (31/66) of navtemadlin treated pts vs 24% with BAT (7/29). Of the 16 navtemadlin treated pts with paired evaluable samples at both Week 24 and Week 48, 56% (9/16) had a one grade improvement at Week 24, while 44% (7/16) maintained this improvement or improved further at Week 48 (13% [2/16]; two or more grades).

Decrease in Driver VAFs: At Week 24, reductions in driver mutation VAF ≥50% were noted in 18% (14/80) of evaluable navtemadlin treated pts vs 12% (4/33) for BAT. Decreases in driver mutation VAF with navtemadlin were significantly correlated with SVR at Week 24 (p<0.001).

Decrease in Serum Cytokines: At Week 24, the percent change in selected inflammatory cytokines TNFα, IL-6, and CRP were significantly correlated with SVR (p<0.001 for all).

Conclusions: Navtemadlin treatment improved biomarkers of disease burden in pts with R/R MF, suggestive of anti-clonal activity and disease modification. Changes in CD34⁺ counts, driver mutation burden, and serum inflammatory cytokine levels with navtemadlin treatment were significantly correlated with magnitude of SVR; demonstrating an effect between navtemadlin-induced disease modification and SVR, a key clinical outcome predictive of QoL and overall survival. Biomarkers of disease modification and associated clinical correlations will be further explored with navtemadlin as add-on therapy to ruxolitinib treatment in JAKi-naïve MF pts who have a suboptimal response to ruxolitinib in the global phase 3 POIESIS study (NCT06479135).