Navtemadlin Will Be Evaluated as Add-On Therapy to Ruxolitinib in Myelofibrosis

Building upon encouraging data with navtemadlin as a single agent in JAK inhibitor relapsed/refractory myelofibrosis and as add-on therapy in patients with myelofibrosis who had a suboptimal response to ruxolitinib (Jakafi), investigators have initiated the phase 3 POIESIS trial (NCT06479135) to evaluate add-on navtemadlin to ruxolitinib in JAK inhibitor-naive patients who have a suboptimal response to ruxolitinib.1,2

Navtemadlin is an oral, selective inhibitor of MDM2 that has been shown to restore p53 function.3 Preclinical data have demonstrated that the agent drives apoptosis of TP53 wild-type, CD34-positive myelofibrosis cells via the modulation of the BCL-2 family of proteins.

“By inhibiting MDM2, we are increasing levels of functional TP53,” Pankit Vachhani, MD, said in an interview with OncologyLive. “In preclinical studies, we have seen that MDM2 levels are elevated in samples taken from patients with myelofibrosis, so MDM2 level suppression would be optimal in myelofibrosis. Additionally, the use of navtemadlin and ruxolitinib also has a synergistic role in driving cellular function more toward apoptosis than cellular arrest. When the drugs are used together, we not only get the cell-killing function derived through TP53, we also get the JAK inhibitor–derived JAK-STAT pathway downregulation and the typical spleen volume responses and symptom improvements that we see with JAK inhibitors.”

Vachhani is an associate professor of hematology/oncology at the University of Alabama at Birmingham O’Neal Comprehensive Cancer Center.

Prior Data Provide Rationale for Navtemadlin in Myelofibrosis

During the 66th American Society of Hematology Annual Meeting and Exposition in December 2024, investigators presented findings from the phase 2/3 BOREAS trial (NCT03662126). BOREAS compared navtemadlin monotherapy with best available therapy in patients with TP53 wild-type primary or secondary myelofibrosis whose disease relapsed or was refractory to JAK inhibitor therapy. The primary end point was the rate of spleen volume reduction (SVR) of at least 35% (SVR35) by week 24 by MRI/CT scan per blinded independent central review. The rate of total symptom score reduction of at least 50% (TSS50) at week 24 per the Myelofibrosis Symptom Assessment Form (MFSAF) v4.0 represented the key secondary end point.

Data from BOREAS demonstrated that patients who received navtemadlin (n = 123) achieved an SVR35 rate at week 24 of 15% compared with 5% among those treated with best available therapy (n = 60). The TSS50 rates at week 24 were 24% and 12%, respectively. The mean absolute change in total symptom score from baseline to week 24 was –4.6 (SE, 1.3) in the investigational arm vs 0.9 (SE, 1.8) in the control arm (P = .0078).

“One must remember that [these data] are [in the] second line, a setting where patients had previously been refractory to or had relapsed from their prior JAK inhibitor–related responses,” Vachhani said. “A remarkable feature that was noted was the significantly longer period of time that patients were on navtemadlin compared with best available therapy: [Approximately] 1.5 years with navtemadlin in this ongoing study vs [approximately] 6 months with best available therapy.”

Additional findings from BOREAS showed that the disease-modifying activity of navtemadlin was correlated with clinical responses.4 At week 12, evaluable patients in the navtemadlin arm (n = 50) experienced a –68% median change in CD34-positive cells from baseline compared with –52% in the best available therapy arm (n = 25). At week 24, these rates were –70% and –38% in the investigational (n = 48) and control (n = 19) arms, respectively. At week 36, these rates were –76% and –33% in the investigational (n = 21) and control (n = 9) arms, respectively.

At week 24, evaluable patients in the navtemadlin arm (n = 82) achieved a reduction of driver gene variant allele frequency (VAF) of at least 50% vs baseline at a rate of 21% compared with 12% among those who received best available therapy (n = 33). The study authors noted that the changes in CD34-positive cells and VAF correlated with SVR.

Moreover, during the 28th European Hematology Association Congress in 2023, investigators presented findings from the phase 1b/2 KRT-232-109 study (NCT04485260). KRT-232-109 examined the addition of navtemadlin to ruxolitinib in patients with TP53 wild-type primary or secondary myelofibrosis who experienced a suboptimal response to ruxolitinib.5 The primary end point was determining the recommended phase 2 dose (RP2D) of navtemadlin and SVR35 per central review at week 24. Key secondary end points included TSS50 by MFSAF v4.0 at week 24.

Findings from KRT-232-109 showed that evaluable patients who received navtemadlin (n = 19) achieved an SVR of at least 25% at week 24 at a rate of 42% and an SVR35 rate of 32% at the same time point. The TSS50 rate was 32%. The RP2D of navtemadlin as add-on therapy to ruxolitinib was determined to be 240 mg once daily on days 1 to 7 of each 28-day cycle.

“[We saw] fibrosis reduction as well as [reduction of] VAF of driver gene mutations, which came down over time,” Vachhani added. “[These findings] formed the basis of the launch of the additional investigation of navtemadlin in the form of an add-on therapy [to ruxolitinib] in those who have derived a suboptimal response to JAK inhibitor therapy.”

POIESIS Employs Unique Design to Examine Navtemadlin Add-On

POIESIS is a double-blind, placebo-controlled, global study of navtemadlin as an add-on therapy to ruxolitinib in JAK inhibitor–naive patients with myelofibrosis who experience a suboptimal response to ruxolitinib. Key inclusion criteria include having International Prognosis System Score of intermediate 1–, intermediate 2–, or high-risk disease; and an ECOG performance status of 0 to 2. Patients who are included in the randomization period must also haveTP53 wild-type disease (Figure).1,2

“POIESIS incorporates a novel design, which aligns with the clinical practice for treating JAK inhibitor–naive patients with myelofibrosis, comprised of 2 main periods,” Vachhani explained. “First, there is a run-in period where patients are treated with ruxolitinib monotherapy for at least 18 weeks, up to 25 weeks. At the end of the run-in period, there is an assessment of disease response, and those with a suboptimal response proceed to the add-on period. A suboptimal response is defined as both a suboptimal spleen volume response and a [suboptimal] total symptom score reduction response. A suboptimal spleen volume response is [a response that] is short of the 35% threshold that we hold myelofibrosis clinical trials to, and [in terms of] total symptom score, [it’s] any improvement short of a 50% reduction.”

Following the run-in period, patients who experience an optimal response to ruxolitinib and those who are primary refractory to the agent will be discontinued from the study.2 Eligible patients who experience a suboptimal response to ruxolitinib will then be randomly assigned 2:1 to receive add-on navtemadlin at a dose of 240 mg once daily on days 1 to 7 of each 28-day cycle or placebo, both in combination with a stable dose of oral ruxolitinib given twice daily. Ruxolitinib dose escalation before the primary efficacy assessment and crossover between the 2 arms will not be permitted. Treatment in both arms will continue until unacceptable toxicity or disease progression.

The coprimary end points are the proportion of patients achieving SVR35 by MRI/CT scan and the proportion of patients with a TSS50 by the MFSAF, both assessed at 24 weeks after random assignment between the 2 arms.1 Secondary end points include progression-free survival and overall survival.

POIESIS is currently enrolling patients, and the estimated primary completion of the study is December 2026.1 “If anyone has patients with intermediate 1–, intermediate 2–, or high-risk myelofibrosis, consider this study for your patients [and] make sure that they have not previously [been treated with] JAK inhibitors. If they are patients with a new diagnosis, please refer [them] for enrollment. This will help us move the field forward toward bringing combination therapies [further up] for those with suboptimal responses down the line,” Vachhani concluded.

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. Updated December 24, 2024. Accessed February 11, 2025. https://clinicaltrials.gov/study/NCT06479135
2. Vachhani 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. Blood. 2024;144(suppl 1):1808.2. doi:10.1182/blood-2024-200966
3. Mascarenhas JO, Popov VM, Mohan S, et al. Results from the randomized, multicenter, global phase 3 BOREAS study: navtemadlin versus best available therapy in JAK inhibitor relapsed/refractory myelofibrosis. Blood. 2024;144(suppl 1):1000. doi:10.1182/blood-2024-201642
4. Mascarenhas JO, Bose P, Hou HA, et al. Disease-modifying activity of navtemadlin correlates with clinical responses in a randomized, multicenter, global phase 3 study (BOREAS) in JAK-inhibitor relapsed/refractory myelofibrosis.Blood. 2024;144(suppl 1):483. doi:10.1182/blood-2024-205937
5. Mascarenhas J, Jain T, Otoukesh S, et al. An open-label, global, phase (Ph) 1b/2 study adding navtemadlin (NVTM) to ruxolitinib (RUX) in patients (Pts) with primary or secondary myelofibrosis (MF) who have a suboptimal response to RUX. HemaSphere. 2023;7(suppl):e72578ff. doi:10.1097/01.HS9.0000967752.72578.ff