MOMENTUM trial: Updates from the #ASCO22 Annual Meeting

Momelotinib is an inhibitor of Janus kinase 1 and 2 (JAK1/2) with an effect on activin A receptor, type I, a master iron regulator that plays a role in reducing hepcidin levels and inflammation in the bone marrow. The randomized, double blind, phase III MOMENTUM trial (NCT04173494) is investigating momelotinib versus danazol in symptomatic and anemic patients with myelofibrosis (MF), previously treated with an approved JAK inhibitor.¹

During the 2022 American Society of Clinical Oncology (ASCO) Annual Meeting, the studies by Ruben Mesa et al.¹ and Aaron Gerds et al.² were presented, which comprised updated results of the MOMENTUM trial from symptomatic/anemic¹ and thrombocytopenic² patients, respectively. Here, we summarize these results.

Study design^1,2

A total of 195 anemic (hemoglobin <10 g/dL) and symptomatic (total symptom score [TSS] ≥10) patients were stratified by TSS, palpable spleen length, transfused units in the prior 8 weeks, and study site. After a JAK inhibitor taper/washout period for ≥21 days, these patients were randomized at a 2:1 ratio for momelotinib (Mmb) 200 mg daily plus placebo (n = 130), or danazol (Dan) 600 mg daily plus placebo (n = 65) for 24 weeks, followed by an open-label/crossover period. The eligibility criteria for all patients are as follows:

• Primary or post-essential thrombocythemia/polycythemia vera MF
• Dynamic International Prognostic Score (DIPSS) — high risk, Intermediate 2, or Intermediate 1
• MF Symptom Assessment Form TSS ≥10
• Hemoglobin <10 g/dL

Of note, this study included patients with baseline platelet counts of ≥25 × 10⁹/L.

Primary endpoint was a TSS response (≥50% reduction from baseline) at 24 weeks, and key secondary endpoints were transfusion independence and spleen response rate (≥35% reduction in spleen volume reduction [SVR35] from baseline) at 24 weeks. These endpoints were met in January 2022; read more here.

Results

Symptomatic and anemic patients with MF — Intention-to-treat (ITT) analysis

A total of 94 patients (72.3%) treated with momelotinib and 38 patients (58.5%) treated with danazol completed the full 24-week regimen. The baseline characteristics are shown in Table 1.

Table 1. Baseline characteristics of anemic and symptomatic patients*

DIPSS, Dynamic International Prognostic Scoring System; MF, myelofibrosis; PET-MF, post-essential thrombocythemia myelofibrosis; PMF, primary myelofibrosis; PPV-MF, post-polycythemia vera myelofibrosis; TSS, total symptom score. *Adapted from Mesa et al.1
Characteristic	Momelotinib (n = 130)	Danazol (n = 65)
Median age, years	71.0	72.0
MF subtype, %
PMF	60.0	70.8
PPV-MF	20.8	16.9
PET-MF	19.2	12.3
DIPSS risk category, %
Intermediate-2	55.4	61.5
High	38.5	29.2
Mean TSS	28.0	25.7
Mean hemoglobin, g/dL	8.1	7.9
Transfusion independence, %	13.1	15.4
Mean platelet count, × 109/L	151.7	130.7
Mean spleen volume, cm3	2,367	2,288

All the primary and secondary endpoints were met; the results for anemic and symptomatic patients are shown in Table 2.

Table 2. Primary and secondary endpoints for anemic and symptomatic patients*

SVR25, ≥25% reduction in spleen volume from baseline; SVR35, ≥35% reduction in spleen volume from baseline; TSS, total symptom score. *Adapted from Mesa et al.1
Week 24 endpoint	Momelotinib (n = 94)	Danazol (n = 38)	p value
TSS response rate (primary), %	24.6	9.2	0.0095
TSS changes from baseline	−9.36	−3.13	0.0014
SVR35, %	23.1	3.1	0.0006
SVR25, %	40.0	6.2	< 0.0001
Transfusion independence rate, %	31	20	0.0064 (one-sided)
Zero transfusion rate, %	35.4	16.9	0.0012

Grade ≥3 adverse events (AEs) were recorded in 53.8% and 64.6% of patients in the momelotinib and danazol groups, respectively. Grade ≥3 hematologic AEs observed in the momelotinib and danazol groups, respectively, are as follows:

• Anemia: 60.8% vs 75.4%
• Thrombocytopenia: 27.7% vs 26.2%
• Neutropenia: 12.3% vs 9.2%

The trial was not designed to evaluate overall survival (OS); there seemed to be a trend towards improved OS with momelotinib at Week 24 (HR 0.506; 95% CI, 0.238–1.076; p = 0.0719). However, this needs a longer-term follow-up.

Overall, the analysis¹ suggests that momelotinib is associated with significant improvements in disease-related symptoms and splenomegaly, as well as anemia, compared with danazol in symptomatic and anemic patients with MF.

The MPN Hub was pleased to talk to Ruben Mesa on the results of the MOMENTUM trial during the 2022 ASCO Annual Meeting.

Thrombocytopenic patients with MF

A separate subset of 131 patients with moderate and severe thrombocytopenia with a baseline platelet count of <100 × 10⁹/L (n = 100) and <50 × 10⁹/L (n = 34), respectively, were also analyzed. The baseline characteristics for these patients by platelet count and treatment arm are shown in Table 3.

Table 3. Baseline characteristics of thrombocytopenic patients*

BL, baseline; DIPSS, Dynamic International Prognostic Scoring System; JAKi, Janus kinase inhibitor; MF, myelofibrosis; PET-MF; post-essential thrombocythemia myelofibrosis; PMF, primary myelofibrosis; PPV-MF, post-polycythemia vera myelofibrosis; TSS, total symptom score. *Adapted from Gerds et al.2
Characteristic	BL platelet count <100 × 109/L		BL platelet count <50 × 109/L
	Momelotinib (n = 66)	Danazol (n = 34)	Momelotinib (n = 18)	Danazol (n = 13)
Median age, years	70.0	70.6	72.6	70.2
MF subtype, %
PMF	60.6	70.6	66.7	76.9
PPV-MF	28.8	17.6	27.8	7.7
PET-MF	10.6	11.8	5.6	15.4
DIPSS risk category, %
Intermediate-2	59.1	61.8	44.4	46.2
High	36.4	32.4	50.0	38.5
Mean TSS	27.7	24.9	29.4	27.2
Mean hemoglobin, g/dL	8.1	7.8	7.7	8.0
Hemoglobin <8 g/dL, %	51.5	50.0	66.7	46.2
Mean prior JAKi duration, weeks	145.6	137.8	150.7	110.6

Response rates in patients with moderate and severe thrombocytopenia are shown in Figure 1. In patients with platelet counts <50 × 10⁹/L, platelet counts were maintained during the treatment period. A wider thrombocytopenic patient subset with baseline platelet counts of ≤150 × 10⁹/L showed similar efficacy and safety outcomes in the momelotinib and danazol arms; TSS response rate of 29.6% and 11.6%, transfusion independence rate of 32.1% and 18.6%, SVR35 of 22.2% and 4.7%, respectively.

Dan, danazol; Mmb, momelotinib; SVR35, ≥35% reduction is spleen volume from baseline; TI, transfusion independency; TSS50, ≥50% reduction in total symptom score from baseline.
*Adapted from Gerds et al.²

Overall survival rate at Week 24 was also reported for the patients in the Gerds et al.² study, with a trend towards a better survival with momelotinib, consistent with the ITT analysis reported by Mesa et al.¹

• Patients with platelet counts <100 × 10⁹/L in the momelotinib and danazol arms: 86.2% vs 82.1%
• Patients with platelet counts <50 × 10⁹/L in the momelotinib and danazol arms: 94.4% vs 59.8%

The most common Grade ≥3 treatment-emergent adverse events (TEAEs) were thrombocytopenia, anemia, and dyspnea. Table 4 summarizes safety outcomes by platelet counts and treatment arm.

Table 4. Adverse events recorded during 24 weeks of treatment*

TEAE, treatment-emergent adverse event. *Adapted from Gerds et al.2
TEAE, %	Platelet counts <100 × 109/L		Platelet counts <50 × 109/L
	Momelotinib	Danazol	Momelotinib	Danazol
Grade ≥3 TEAEs	60.6	61.8	55.6	69.2
Serious TEAEs	42.4	32.4	44.4	46.2
TEAE-related treatment discontinuations	18.2	14.7	11.1	23.1
Most common Grade ≥3 TEAEs
Thrombocytopenia	33.3	2.06	44.4	15.4
Anemia	9.1	11.8	22.2	23.1
Dyspnea	3.0	2.9	11.1	0
Hemorrhage	6.1	0	5.6	0

The analysis in thrombocytopenic patients² indicates better spleen and symptom responses and transfusion independence rates with momelotinib vs danazol, consistent with the ITT analysis.