Phase 3 POIESIS Trial Explores Safety, Efficacy of Navtemadlin and Ruxolitinib

Studies evaluating navtemadlin (KRT-232; Kartos Therapeutics) as a monotherapy in patients with myelofibrosis (MF) who are relapsed or refractory to Janus kinase inhibitor (JAKi) therapy provide strong justification for the POIESIS trial (NCT06479135) investigating navtemadlin as an add-on to ruxolitinib (Jakafi; Incyte Corp). The upcoming study was presented at the 66th ASH Annual Meeting and Exposition on December 7, 2024.¹

Blood cells in bone marrow illustration | Image Credit: © Катерина Євтехова

JAKi therapy, namely ruxolitinib, is the first line, standard of care treatment for patients with MF. Approved in 2011, it has demonstrated efficacy in symptoms management and fibrosis reduction. However, many patients become JAKi-naïve and fail to achieve an optimal spleen volume reduction of ≥ 35% (SVR35) and a total symptom score reductions of ≥ 50% (TSS50), underscoring a crucial gap in treatment for this population. Thereby, researchers began investigating use of other agents as monotherapies or add-ons for patients with MF receiving ruxolitinib.^2,3

In various studies, navtemadlin has demonstrated treatment clinically meaningful activity with disease-modifying potential in patients with MF who were R/R to JAKi treatment. Navtemadlin is a potent, selective, oral mouse double minute 2 inhibitor (MDM2i) that induces apoptosis in TP53 wild-type (TP53^WT) CD34⁺ MF cells and restores the tumor suppressor protein p53. According to preclinical study, when added to ruxolitinib, it increases apoptosis through the inhibition of p21-mediated cell-cycle arrest.³

In both the monotherapy and combination settings, navtemadlin has demonstrated notable capabilities in bone marrow fibrosis reduction, driver mutation allele burden, circulating CD34⁺ cell counts, and serum cytokine levels. In the randomized, global, phase 3 BOREAS trial (NCT03662126), researchers reported that navtemadlin monotherapy in JAKi-naïve patients with MF showed meaningful activity with disease-modifying potential in TP53^WT. When navtemadlin was added to ruxolitinib in a phase 1b/2 study (NCT04485260), patients achieved an SVR35 and a TSS50 of 32% at Week 24.^3-5

These promising results have influenced the intitiation of the registrational, randomized double-blind, placebo-controlled, global phase 3 POIESIS trial evaluating the safety and efficacy of navtemadlin and ruxolitinib versus placebo and ruxolitinib in patients with JAKi-naïve MF who have a suboptimal response to ruxolitinib.³

The study will have 2 treatment periods: a ruxolitinib monotherapy period followed by navtemadlin or placebo as an add-on therapy to ruxolitinib (n=180). Patients will be randomized 2:1 to receive either navtemadlin (n=120) or placebo (n=60) at a dose of 240 mg QD (Day 1-7/28-day cycle) added on to a stable dose of ruxolitinib. The primary end points are the rates of SVR35 and TSS50 at 24 weeks after the start of the randomized period.³

The POIESIS trial represents a critical step in addressing the unmet needs of patients with myelofibrosis who fail to achieve optimal responses with JAK inhibitor therapy alone. this study seeks to deliver more effective, disease-modifying treatments that could redefine standard care practices and improve long-term outcomes for patients with MF.

REFERENCES

1. Study of navtemadlin add-on to ruxolitinib in JAK inhibitor-naïve patients with myelofibrosis who have a suboptimal response to ruxolitinib (POIESIS). ClinicalTrials.gov Identifier: NCT06479135. Updated October 30, 2024. Accessed December 9, 2024. https://clinicaltrials.gov/study/NCT06479135

2. Navitoclax and ruxolitinib show potential in treating R/R myelofibrosis. Pharmacy Times^®. November 29, 2024. Accessed December 9, 2024. https://www.pharmacytimes.com/view/navitoclax-and-ruxolitinib-show-potential-in-treating-r-r-myelofibrosis

3. Nachhani P, Rampal R, Bradley T, et al. POIESIS: a randomized, double-blind, placebo-controlled, multicenter, global phase 3 study of navtemadlin as add-on to ruxolitinib in JAK inhibitor-naïve patients with myelofibrosis who have a suboptimal response to ruxolitinib. Presented at: 66th ASH Annual Meeting and Exposition. December 7, 2024. San Diego, CA. Abstract 1801.2.

4. KRT-232 versus best available therapy for the treatment of subjects with myelofibrosis who are relapsed or refractory to JAK inhibitor treatment (boreas). ClinicalTrials.gov Identifier: NCT03662126. Updated April 28, 2023. Accessed December 9, 2024. https://clinicaltrials.gov/study/NCT03662126

5. An open-label, multicenter, phase 1b/​2 study of the safety and efficacy of KRT-232 combined with ruxolitinib in patients with primary myelofibrosis (PMF), post-polycythemia vera MF (post-PV-MF), or post-essential thrombocythemia MF (post ET-MF) who have a suboptimal response to ruxolitinib. ClinicalTrials.gov Identifier: NCT04485260. Updated May 9, 2022. Accessed December 9, 2024. https://clinicaltrials.gov/study/NCT04485260