KRT-232-109: Navtemadlin plus ruxolitinib in MF with a suboptimal ruxolitinib response

Myelofibrosis (MF) is a myeloproliferative neoplasm characterized by splenomegaly and significant symptom burden.¹ Although the Janus kinase inhibitor ruxolitinib has improved splenomegaly and MF-related symptoms in patients with MF, the majority achieve suboptimal responses.¹

Navtemadlin is a potent, selective, oral, mouse double minute 2 inhibitor (MDM2i) that restores p53 activity and modulates the expression of pro-apoptotic Bcl-2 family proteins to induce apoptosis of TP53^wt CD34⁺ myeloblasts.¹ In a phase II study, single-agent navtemadlin demonstrated promising clinical and disease-modifying activity in patients with relapsed/refractory MF. Preclinical studies have demonstrated the synergistic effects of navtemadlin plus ruxolitinib in mediating p53-dependent apoptosis of myeloblasts by inhibiting checkpoint p21-mediated cell-cycle arrest, providing the rationale for investigation of the combination in the clinical setting.¹

Below, we summarize one of our European Hematology Association (EHA) 2023 top abstracts reporting the efficacy and safety of navtemadlin combined with ruxolitinib in patients with primary or secondary MF who have a suboptimal response to ruxolitinib, presented by John Mascarenhas.¹

Study design

KRT-232-109 (NCT04485260), is a global, open-label, multicenter, phase IIb/II study, which included patients with:

• Primary, post-polycythemia vera, or post-essential thrombocythemia MF
• Suboptimal response to ruxolitinib after ≥18 weeks
• No evidence of response or progression on ruxolitinib
• Platelet count >100 × 10⁹/L
• Wild-type p53

The phase I dose escalation evaluated three doses of navtemadlin (120 mg, 180 mg, and 240 mg) added to a pre-study ruxolitinib dose (≥8 weeks) to identify the recommended phase II expansion dose (RP2D). In the phase II dose expansion, navtemadlin at 240 mg was administered for 7 days, with 21 days off in a 28-day cycle.

Primary endpoints:

• To determine the recommended phase II dose (RP2D) of navtemadlin at phase I
• Spleen response rate at Week 24, defined as spleen volume reduction by central review at phase II

Key secondary endpoints:

• Symptom improvement from ≥50% at Week 24
• Spleen response duration
• Red blood cell transfusion independence
• Spleen response rate at any time point from baseline

Results

Overall, 28 patients were treated with navtemadlin at the RP2D of 240 mg. Baseline characteristics are summarized in Table 1.

Table 1. Baseline characteristics*

DIPPS, Dynamic International Prognostic Scoring System; MF, myelofibrosis; TSS, total symptom score. *Data from Mascarenhas.1 †Ruxolitinib was administered twice daily.
Characteristic, % (unless otherwise stated)	Navtemadlin 240 mg + ruxolitinib (N = 28)
Median age at diagnosis (range), years	63 (40–85)
DIPPS	27
Intermediate 1	43
Intermediate 2	32
High	25
MF subtype
Primary	36
Secondary	64
Median spleen volume at baseline (range), cm3	2,039 (650–3,549)
Median platelets (range), 106/L	165 (100–636)
Transfusion dependence, n	25
Median prior lines of therapy (range), n	1 (1–5)
Median TSS (range)	15 (3.2–49.1)
Median duration of prior ruxolitinib therapy (range), months	21.6 (7–129)
Ruxolitinib dose at entry†
5 mg	14
10 mg	25
15 mg	18
20–25 mg	39

Efficacy

Among evaluable patients (n = 19) at the May 2, 2023, data cut off:

• Spleen volume reduction of 35% and 25% at Week 24 was achieved in 42% and 32% of patients, respectively.
• Total symptom score improvements of ≥50% was attained in 32% of patients at Week 24.
• The median time on treatment was 6 months and ongoing.
• There was a reduction in the CD34⁺ myeloblasts from baseline until Week 24.

Among seven evaluable patients, 71% achieved a ≥20% reduction of driver VAF, and 57% had improved bone marrow fibrosis of Grade >1 by central review.

Safety

Overall, treatment emergent adverse events (TEAEs) were mostly Grade 1–2. Any grade and Grade 3–4 TEAEs were reported in 96% and 46% of patients, respectively.

• The most common gastrointestinal toxicities were Grade 1–2 nausea, diarrhea, and vomiting.
  • These were mostly seen in the first two cycles and within the 7-day treatment period.
• Grade 3/4 TEAEs included thrombocytopenia (29%), anemia (18%), nausea (7%), diarrhea (4%), vomiting (4%), and asthenia (4%).
• The most common any grade TEAEs were nausea, diarrhea, thrombocytopenia, constipation, vomiting, asthenia, anemia, and fatigue (Figure 1).
• There was no progressive decline in the mean platelet and hemoglobin count over time.

*Data from Mascarenhas.¹

Presenter’s conclusion

This phase II study demonstrated the clinically meaningful benefit and safety of navtemadlin plus ruxolitinib in patients with primary or secondary MF who had a suboptimal response to ruxolitinib. This combination resulted in reduced spleen volume, reduced symptom burden, reduced percentage of CD34⁺ cells, as well as driver VAF and bone marrow fibrosis reductions, with low incidences of high-grade adverse events. These data support the evaluation of this novel combination in a phase III study.