All content on this site is intended for healthcare professionals only. By acknowledging this message and accessing the information on this website you are confirming that you are a Healthcare Professional. If you are a patient or carer, please visit the MPN Advocates Network.
Introducing
Now you can personalise
your MPN Hub experience!
Bookmark content to read later
Select your specific areas of interest
View content recommended for you
Find out moreThe MPN Hub website uses a third-party service provided by Google that dynamically translates web content. Translations are machine generated, so may not be an exact or complete translation, and the MPN Hub cannot guarantee the accuracy of translated content. The MPN Hub and its employees will not be liable for any direct, indirect, or consequential damages (even if foreseeable) resulting from use of the Google Translate feature. For further support with Google Translate, visit Google Translate Help.
The MPN Hub is an independent medical education platform, sponsored by AOP Health and GSK, and supported through an educational grant from Bristol Myers Squibb. The funders are allowed no direct influence on our content. The levels of sponsorship listed are reflective of the amount of funding given. View funders.
Bookmark this article
Momelotinib is a potent inhibitor of Janus kinase 1 and 2 (JAK1/2) and activin A receptor type I (ACVR1), also known as activin receptor-like kinase-2 (ALK-2), and is currently under evaluation for approval by the U.S. Food and Drug Administration (FDA) for the treatment of patients with myelofibrosis (MF) and anemia.1
To date, results from phase III studies have demonstrated that momelotinib leads to reduced severity of anemia and subsequent transfusion independence (TI) relative to ruxolitinib, and is associated with an increased splenic response.
In Leukemia, Ruben Mesa, et al.,2 recently published longer-term overall survival (OS), leukemia-free survival (LFS), and safety data following extended momelotinib treatment of patients with MF in the phase III SIMPLIFY-1 (NCT01969838) and SIMPLIFY-2 (NCT02101268) trials, including those enrolled in an ongoing open-label, extended access clinical trial (NCT03441113).2 We are pleased to provide a summary of this publication here.
The SIMPLIFY-1 and SIMPLIFY-2 trials compared momelotinib to ruxolitinib in JAK inhibitor-naïve patients with MF and to ruxolitinib/best available therapy (BAT) in the relapsed/refractory MF setting, respectively. The study designs of these two trials can be found here. In both trials, patients who were initially randomized to ruxolitinib or ruxolitinib/BAT could cross over to momelotinib at Week 24. Patients who tolerated momelotinib and who did not have disease progression during the SIMPLIFY trials could continue momelotinib in the open-label extended access trial.
The analysis by Mesa, et al. included patients from the three trials to investigate the following parameters:
In the SIMPLIFY-1 trial, the median follow-up was 3.43 years and 3.47 years in the momelotinib arm and ruxolitinib (crossover to momelotinib) arm, respectively:
In the SIMPLIFY-2 trial, the median follow-up was 3.07 years and 3.22 years in the momelotinib arm and ruxolitinib/BAT (crossover to momelotinib) arm, respectively:
The 2-year OS and LFS were similar for both studies (Figure 1).
Figure 1. 2-year OS and LFS in A SIMPLIFY-1 and B SIMPLIFY-2*
BAT, best available therapy; LFS, leukemia-free survival; OS, overall survival.
*Adapted from Mesa, et al.2
The baseline patient characteristics found to be associated with OS are shown in Table 1 (univariate analysis) and Table 2 (multivariate analysis).
Table 1. Univariate analysis of baseline characteristics in the SIMPLIFY-1 and SIMPLIFY-2 trials*
Characteristic |
Prevalence, |
Median OS, |
2-year OS, |
HR (95% CI) |
p value |
---|---|---|---|---|---|
SIMPLIFY-1 (n = 432) |
|||||
TI |
24.9 |
NR |
86.0 |
0.373 |
<0.0001 |
Hb, ≥10 g/dL |
27.3 |
NR |
83.3 |
0.351 |
<0.0001 |
Spleen volume, >2,000 cm3 |
35.6 |
NR |
74.2 |
1.448 |
0.0288 |
Platelets, >200 × 109/L |
28.1 |
NR |
84.5 |
0.466 |
0.0035 |
IPSS, high risk |
44.0 |
3.76 |
72.2 |
5.494 |
<0.0001 |
IPSS, Int-2 |
28.0 |
NR |
85.7 |
2.792 |
<0.0001 |
WBC, ≥10 × 109/L |
36.1 |
5.31 |
76.4 |
1.466 |
0.0258 |
SIMPLIFY-2 (n = 156) |
|||||
TI |
23.5 |
NR |
80.7 |
0.319 |
0.0002 |
Hb, ≥10 g/dL |
35.3 |
NR |
67.9 |
0.335 |
0.0003 |
Spleen volume, >2,000 cm3 |
54.8 |
2.19 |
53.2 |
2.329 |
0.0006 |
DIPSS, high-risk |
70.4 |
1.18 |
24.0 |
5.043 |
<0.0001 |
DIPSS, Int-2 |
44.4 |
5.31 |
70.9 |
1.651 |
<0.0001 |
WBC, ≥10 × 109/L |
62.7 |
1.33 |
38.4 |
3.335 |
<0.0001 |
CI, confidence interval; DIPSS, Dynamic International Prognostic Scoring System; Hb, hemoglobin; Int-2, intermediate-2; IPSS, International Prognostic Scoring System; NR, not reached; OS, overall survival; TI, transfusion independence; WBC, white blood cells. |
Table 2. Multivariate analysis of baseline characteristics from the SIMPLIFY trials*
Characteristic |
Hazard ratio (95% CI) |
p value |
---|---|---|
SIMPLIFY-1 (n = 432) |
||
IPSS risk |
||
High vs Int-1 |
4.293 (2.160–8.532) |
<0.0001 |
Int-2 vs Int-1 |
2.759 (1.373–5.546) |
0.0044 |
TI vs non-TI |
0.474 (0.325–0.691) |
0.0001 |
WBC, ≥10 × 109/L vs <10 × 109/L |
1.648 (1.160–2.342) |
0.0054 |
SIMPLIFY-2 (n = 156) |
||
TI vs non-TI |
0.226 (0.097–0.524) |
0.0005 |
Spleen volume, >2,000 cm3 vs ≤2,000 cm3 |
1.905 (1.128–3.216) |
0.0159 |
Hb, 8 g/dL to <10 g/dL vs <8 g/dL |
0.427 (0.239–0.762) |
0.0040 |
WBC, ≥10 × 109/L vs <10 × 109/L |
4.498 (2.655–7.621) |
<0.0001 |
CI, confidence interval; Hb, hemoglobin; Int, intermediate; IPSS, International Prognostic Scoring System; TI, transfusion independence; WBC, white blood cells. |
In the SIMPLIFY-1 trial, TI responders at Week 24 had significantly improved OS compared with TI non-responders in the momelotinib arm (3-year OS: 77.2% vs 51.6%; HR, 0.323; p < 0.0001), which was then confirmed in the multivariate analysis (HR, 0.311; 95% CI, 0.173–0.559; p < 0.0001). The difference between TI responders and TI non-responders in the SIMPLIFY-2 trial was not statistically significant (2-year OS: 66.1% vs 57.0%; p = 0.4193) in the momelotinib arm. In the ruxolitinib (SIMPLIFY-1) and ruxolitinib/BAT (SIMPLIFY-2) crossover arms, there was a trend towards improved OS; however, it was not statistically significant (p = 0.0954 and p = 0.2326, respectively).
In the context of total symptom score, there were no significant differences between arms in both studies. In the SIMPLIFY-1 trial, patients who achieved splenic volume reduction response at Week 24 had significantly better OS compared with non-responders in the ruxolitinib arm (p = 0.0078); the improvement in OS was significant in the momelotinib arm.
The median duration of momelotinib treatment in the SIMPLIFY-1 and SIMPLIFY-2 trials was 17.7 months and 9.2 months, respectively. The safety profile of momelotinib was similar to ruxolitinib during the randomized treatment period of the SIMPLIFY-1 trial when considering treatment-emergent adverse events (TEAEs). The frequency of Grade 3/4 anemia was lower with momelotinib than ruxolitinib in the SIMPLIFY-1 trial (6.1% vs 22.7%, respectively) and the SIMPLIFY-2 trial (13.5% vs 17.3%, respectively). The prevalence of any grade TEAEs was similar in both studies across all treatment groups (Table 3).
The most common any grade TEAEs in the SIMPLIFY-1 trial were thrombocytopenia (18.7%) and anemia (25.8%) in patients receiving momelotinib, and anemia in patients receiving ruxolitinib (37.5%). The most common any grade TEAEs in the SIMPLIFY-2 trial were diarrhea (32.7%) in patients receiving momelotinib, and anemia (19.2%) and fatigue (19.2%) in patients receiving ruxolitinib/BAT.
Table 3. Most common Grade 3/4 TEAEs in each treatment group in SIMPLIFY-1 and SIMPLIFY-2*
SIMPLIFY-1 |
MMB (n = 214) |
Rux (n = 216) |
Extended duration MMB (n = 411) |
---|---|---|---|
Any grade TEAEs, % |
92.5 |
95.4 |
97.3 |
Grade 3/4 TEAEs, %† |
34.6 |
43.5 |
64.0 |
Thrombocytopenia |
7.0 |
4.6 |
14.6 |
Anemia |
6.1 |
22.7 |
13.1 |
Pneumonia |
2.3 |
1.4 |
7.8 |
SIMPLIFY-2 |
MMB (n = 104) |
Rux/BAT (n = 52) |
Extended duration MMB (n = 144) |
Any grade TEAEs, % |
97.1 |
88.5 |
98.6 |
Grade 3/4 TEAEs, %† |
54.8 |
42.3 |
72.9 |
Anemia |
13.5 |
17.3 |
23.6 |
Thrombocytopenia |
10.6 |
5.8 |
16.0 |
BAT, best alternative treatment; MMB, momelotinib; Rux, ruxolitinib; TEAE, treatment-emergent adverse event. |
Of the 118 patients who entered the momelotinib extended access protocol following the completion of SIMPLIFY-1 or SIMPLIFY-2, 88 continued treatment for more than 5 years. No new safety concerns were raised, suggesting long-term tolerance.
During the 24-week randomization period and the extended duration, the momelotinib dose intensity was maintained, whereas induced or worsening myelosuppression required lower starting doses or dose reductions in patients treated with ruxolitinib.
The study by Mesa, et al. reports for the first time, the longer-term survival data from the two phase III SIMPLIFY trials with extended protocol. The results suggest that JAK inhibitor-naïve patients receiving momelotinib or ruxolitinib followed by momelotinib (SIMPLIFY-1) or ruxolitinib-pretreated patients receiving momelotinib or ruxolitinib/BAT followed by momelotinib (SIMPLIFY-2) may achieve a good OS and LFS with extended momelotinib treatment, which may be attributed to improvements in anemia and TI.
The prevalence of adverse events was similar in both treatment groups, but with patients on momelotinib receiving full doses for longer periods than those on ruxolitinib, with a more favorable hematologic safety profile.
Your opinion matters
Subscribe to get the best content related to MPN delivered to your inbox