S214: disease-modifying activity of navtemadlin (nvtm) correlated with survival outcomes in janus kinase inhibitor (jaki) relapsed or refractory (r/r) myelofibrosis (mf) patients (pts)

Background: MF is characterized by the presence of CD34+ myeloblasts that overexpress MDM2 (Lu 2017). JAKi R/R MF pts have a poor prognosis; 14 months (mos) median overall survival (OS) (Kuykendall 2018). Nvtm is a potent, selective, orally available mouse double minute 2 inhibitor (MDM2i) that induces apoptosis in TP53 wild-type (TP53WT) myeloblasts by overcoming dysregulated MDM2 (Lu 2017). Single agent nvtm demonstrated clinically meaningful and disease-modifying activity in JAKi R/R MF pts, including reduction of MPN driver mutational burden and circulating MF cells (Vachhani 2021). Aims: To evaluate correlations between biomarkers of disease burden and survival outcomes (progression-free survival [PFS] and OS) in JAKi R/R MF pts. Methods: Eligible TP53WT JAKi R/R MF pts were treated with nvtm in a global, multicenter Phase (Ph) 2 trial evaluating four regimens to identify the optimal dose and dose schedule for Ph 3: 120 mg QD (Day 1-7/21-day cycle), 240 mg QD (Day 1-7/21-day cycle), 240 mg QD (Day 1-7/28-day cycle) and 240 mg QD (Day 1-5/28-day cycle). Pts were followed on study until death or withdrawal of consent. Peripheral blood was tested at baseline and Week (Wk) 12/24 for circulating CD34+ cell count (flow cytometry), cytokines (ELISA), and driver gene variant allele frequency (VAF) by next-generation sequencing. Bone marrow biopsies collected at baseline and Wk 24 were assessed by central pathology. Log rank test was used to compare survival distribution in subgroups. Results: At a median follow up of 32.5 mos, a total of 113 pts were treated with nvtm with sixty percent still alive at the 06 Jan 2023 data cutoff; median PFS (mPFS) was 13.8 mos (range 0, 42.1+) and median OS (mOS) was 35.2 mos (range 0.3, 44.9+). Improved PFS and OS correlated with biological markers of disease modification, including reductions in driver gene VAF and circulating CD34+ cell count. Among pts with paired samples (baseline, Wk 12/24) and ≥20% driver gene VAF reductions, mPFS was significantly longer (25.6 mos vs 13.0 mos, p=0.041). In pts with high baseline circulating CD34+ counts (n=59), resolution of cell count to below the upper limit of normal (7 cells/uL) was also associated with longer mPFS (median not reached [mNR] vs 10.7 mos; p=0.018). Likewise, despite a limited number of events, favorable OS trends correlated with ≥20% driver gene VAF reductions (mNR vs 34.4 mos, p=0.12) and normalization of circulating CD34+ cell count (mNR, vs 35.2 mos; p=0.086). At the recommended Ph 3 dose regimen of 240 mg QD (Day 1-7/28-day cycle), 32 pts were treated with nvtm with 66% still alive at a median follow up of 37.6 mos (range 0.3, 41.9); mPFS was 15.1 mos (0, 18+) and mOS was not reached (range 0.3, 41.9+ [Figure 1]). Pts continue to be followed for survival. Treatment emergent adverse events occurred in 98% of pts (n=111/113) and were consistent with those previously reported. The most common (≥20%) TEAEs of any grade, regardless of causality, were diarrhea, nausea, anemia, thrombocytopenia, vomiting and abdominal pain. No evidence of worsening toxicity with prolonged treatment was observed. Summary/Conclusion: In JAKi R/R MF pts treated with nvtm, improved OS and PFS were associated with reductions in driver gene VAF and circulating CD34+ cell counts, highlighting the disease modifying effects of this therapy. BOREAS, a global Phase 3 study investigating single agent nvtm in TP53WT JAKi R/R MF pts, is enrolling (NCT03662126).Keywords: relapsed/refractory, Myelofibrosis, Janus Kinase inhibitor, TP53