Improved OS Seen With Momelotinib-Associated Transfusion Independence at 24 Weeks in Myelofibrosis

Data presented from the phase 3 SIMPLIFY 1 and SIMPLIFY 2 trials at 2021 EHA indicate success of momelotinib in extending overall survival in patients with myelofibrosis who achieve transfusion independence.

Patients with myelofibrosis who were randomized to momelotinib in the phase 3 SIMPLIFY 1 (NCT01969838) experienced better overall survival (OS) results with transfusion independence at 24 weeks vs those who were transfusion dependent at the same time point, according to data that were presented at the 2021 European Hematology Association (EHA) Congress.

In SIMPLIFY 1, week 24 transfusion independent responders randomized to momelotinib had an OS advantage, with a median OS that was not reached and a 3-year OS rate of 80% (HR, 0.32; P <.0006) vs a median OS of 3 years and a 3-year OS rate of 50% in momelotinib transfusion independent non-responders.

In SIMPLIFY 2, week 24 transfusion independent responders randomized to momelotinib showed a trend toward improved OS vs momelotinib transfusion independent non-responders (HR, 0.52; P = .0652).

The comparison between OS from week 24 and OS from randomization demonstrated comparable results.

“Momelotinib has previously been shown to provide an anemia benefit for [patients with myelofibrosis], resulting in higher rates of transfusion independence. The data presented at EHA are particularly exciting because they suggest [that] patients randomized to momelotinib who achieve or maintain transfusion independence at week 24 achieve a clinically relevant improvement in overall survival, the gold standard measurement of oncology treatment,” Barbara Klencke, MD, Chief Medical Officer at Sierra Oncology, said in a press release.

In SIMPLIFY 1, week 24 transfusion independent responders randomized to momelotinib had an OS advantage, with a median OS that was not reached and a 3-year OS rate of 80% (HR, 0.30; P <.0001) vs a median OS of 3 years and a 3-year OS rate of 50% in momelotinib transfusion independent non-responders.

In SIMPLIFY 2, week 24 transfusion independent responders randomized to momelotinib showed a trend toward improved OS vs momelotinib transfusion independent non-responders (HR, 0.57; P = .0652).

The comparison between OS from week 24 and OS from randomization demonstrated comparable results.

“The correlation between Week 24 transfusion independence response and overall survival observed with momelotinib is unique among JAK inhibitors. This suggests that the likelihood of achieving or maintaining transfusion independence may become an important consideration for physicians when recommending myelofibrosis treatment options,” Klencke said. “With this in mind, we wanted to understand which patients were most likely to maintain or achieve transfusion independence by Week 24. In other data presented at EHA, we report observing higher rates of transfusion independence with momelotinib relative to ruxolitinib [Jakafi], regardless of a patient's baseline degree of anemia, platelet count or transfusion status.”

Approximately 60% of patients with myelofibrosis are anemic and 45% require red blood cell transfusions within 1 year of diagnosis, with the majority progressing to transfusion dependency. Transfusion dependence and anemia are negative prognostic factors in myelofibrosis and confer poor quality of life.

Approved JAK inhibitors provide spleen and symptom improvements but are typically myelosuppressive and do not treat transfusion dependence.

Momelotinib is a potent JAK1/2 and ACVR1/ALK2 inhibitor that is effective against anemia, constitutional symptoms, and splenomegaly in myelofibrosis. Additionally, preclinical and clinical studies support the use of momelotinib as an effective agent against anemia and transfusion dependence through inhibition of ACVR1/ALK2.

Prior data demonstrated that rates of week 24 transfusion independence were higher in the momelotinib arms of SIMPLIFY 1 and SIMPLIFY 2, which compared momelotinib with ruxolitinib (Jakafi) in JAK inhibitor–naïve patients and momelotinib with best available therapy in ruxolitinib pretreated patients, respectively.

Moreover, momelotinib has been shown to provide higher rates of transfusion independence vs ruxolitinib irrespective of the degree of baseline anemia, baseline platelet count, or transfusion status.

To evaluate the relationship between efficacy outcomes and OS, subgroup analyses were performed for patients randomized to momelotinib in SIMPLIFY 1 and SIMPLIFY 2. The subgroups were defined as follows:

  • Week 24 transfusion independence response: No red blood cell transfusion for at least 12 weeks, with a hemoglobin level of at least 8 g/dL
  • Week 24 spleen response: At least a 35% reduction in spleen volume vs baseline
  • Week 24 symptom response: At least a 50% reduction in Myelofibrosis Symptom Assessment Form total symptom score vs baseline

Additional analyses of patients with spleen and symptom response at week 24 in SIMPLIFY 1 indicated that the hazard ratios for spleen and symptoms among responders vs non-responders were 0.59 (P = .0904) and 0.66 (P = .1657), respectively. Although these findings were not statistically significant, they suggest a trend toward improved OS in responders for spleen and symptom response.

Similarly, in SIMPLIFY 2, no statistically significant difference in OS was observed between spleen and symptom responders vs nonresponders.


References

1. Momelotinib Oral Presentation at European Hematology Association Demonstrates Association Between Transfusion Independence and Improved Overall Survival. News release. Sierra Oncology, Inc. June 11, 2021. Accessed June 16, 2021. https://prn.to/35qkSIP


2. Mesa RA, Oh ST, Gerds AT, et al. Association of transfusion independence with improved overall survival in myelofibrosis patients receiving momelotinib. J Clin Oncol. 2021;39(suppl 15):7046. doi:10.1200/JCO.2021.39.15_suppl.7046