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MOMENTUM trial: Updates from the 2022 ASCO Annual Meeting

Jun 30, 2022
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Learning objective: After reading this article, learners will be able to cite a new clinical development in myelofibrosis.

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 design1,2

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*

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

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

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*

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

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

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.

MOMENTUM: How might momelotinib change the treatment for cytopenic patients with MF?

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*

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

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

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.

Figure 1. Responses in thrombocytopenic patients*

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, %

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

TEAE, treatment-emergent adverse event.
*Adapted from Gerds et al.2

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

  1. Mesa RA, Gerds AT, Vannucchi A, et al. MOMENTUM: Phase 3 randomized study of momelotinib (MMB) versus danazol (DAN) in symptomatic and anemic myelofibrosis (MF) patients previously treated with a JAK inhibitor. Abstract #7002. 2022 ASCO Annual Meeting; June 3–7, 2022; Chicago, US.
  2. Gerds AT, Verstovsek S, Vannucchi A, et al. Thrombocytopenic myelofibrosis (MF) patients previously treated with a JAK inhibitor in a phase 3 randomized study of momelotinib (MMB) versus danazol (DAN) [MOMENTUM]. Abstract #7061. 2022 ASCO Annual Meeting; June 3–7, 2022; Chicago, US.