Momelotinib Efficacy Propels the Future Development of JAK Inhibitors in Myelofibrosis

Successful research with momelotinib (Ojjaara) as a treatment for patients with myelofibrosis and anemia has established this agent as a standard of care for this patient population and strengthened the foundation for further JAK inhibitor–based combination regimens, according to Joseph G. Jurcic, MD.

In an interview with OncLive^®, Jurcic highlighted findings from the phase 3 SIMPLIFY-1 (NCT01969838) and SIMPLIFY-2 (NCT02101268) trials that led to the further study of momelotinib in patients with myelofibrosis, described key findings from the phase 3 MOMENTUM trial (NCT04173494) that supported the 2023 FDA approval of the agent for patients with myelofibrosis and anemia,¹ and summarized the optimal use of various JAK inhibitors for patients with myelofibrosis. He provided further insights on the use of JAK inhibitors in myelofibrosis in another article.

Jurcic is a professor of medicine at Columbia University Medical Center, as well as the director of the Hematologic Malignancies Section in the Division of Hematology/Oncology at the Columbia University Herbert Irving Comprehensive Cancer Center, both in New York, New York.

OncLive: What were the early findings with momelotinib in patients with myelofibrosis in the SIMPLIFY-1 and SIMPLIFY-2 trials?

Jurcic: SIMPLIFY-1 and SIMPLIFY-2 were early trials with momelotinib, now the fourth JAK inhibitor [available for patients with myelofibrosis]. Interestingly, both those trials were technically negative trials. SIMPLIFY-1 required that patients had no prior JAK inhibitor exposure, and patients were randomly assigned [to receive] either momelotinib or ruxolitinib [Jakafi]. In SIMPLIFY-2, patients could have [received] a prior JAK inhibitor, and momelotinib was randomized against best available therapy [BAT]. However, it’s important to remember that in this [trial’s control arm], almost all the patients—89% of them—had received ruxolitinib [as BAT], so it was almost a replay of SIMPLIFY-1.²

In those 2 trials, [patients experienced] benefit from momelotinib vs BAT; however, the primary end points of superiority were not met. One interesting observation from both these studies was that approximately 35% to 40% of patients receiving momelotinib who were transfusion dependent developed transfusion independence. There may be a unique niche for momelotinib in the treatment of patients with myelofibrosis; namely, those who have severe anemia and are transfusion dependent.

What did the MOMENTUM trial show about the efficacy of momelotinib in patients with myelofibrosis and anemia?

MOMENTUM is the trial that resulted in the licensing of momelotinib, [in which] momelotinib was randomized against danazol. Danazol is a commonly used therapy, a supportive androgen [inhibitor] that can also improve anemia in patients with myelofibrosis. MOMENTUM focused on anemia. We saw improved symptom scores and spleen reduction compared with danazol in this study.

Importantly, there was also an improvement in transfusion independence. Approximately 60% of patients in this trial who received momelotinib became transfusion independent, and that includes the group of patients who crossed over [from the danazol arm to the momelotinib arm] during the trial at week 24.

MOMENTUM was an important trial because showed that momelotinib is perhaps the drug of choice now for patients with anemia associated with myelofibrosis. Subgroup analyses of this trial evaluated the impact of achieving transfusion independence on overall survival [OS]. [These findings were] presented at the 2022 ASH Annual Meeting. Investigators found that even when adjusting for covariates, there was still improvement in OS in the group of patients who became transfusion independent. Therefore, transfusion independence may be an important surrogate end point for OS.

What ongoing myelofibrosis research could alter the treatment paradigm in the future?

The next step in treating patients with myelofibrosis is [investigating] combination therapies. [Several combination therapies] were presented at the 2023 ASH Annual Meeting. Of the 2 that are furthest along, the BET inhibitor pelabresib [CPI-0610] elicited significant improvement in spleen response [when combined with ruxolitinib in the phase 3 MANIFEST-2 trial (NCT04603495)].

The other drug that’s also been reported in the phase 3 [TRANSFORM-1 trial (NCT04472598)] is navitoclax, a BCL-2 inhibitor that also inhibits BCL-xL. The major advantage there was an improvement in spleen response. Those [agents] are coming along probably in the not-too-distant future. Some other interesting partners for JAK inhibitors would be LSD1 inhibitors, XPO1 inhibitors, and PIN1 inhibitors.

What is your main message for colleagues regarding the use of JAK inhibitors for patients with myelofibrosis?

JAK inhibitors are an important part of the management of myelofibrosis. For patients with relatively preserved [platelet] counts who have symptoms and significant splenomegaly, ruxolitinib is still my go-to. Fedratinib [Inrebic] is a useful drug for patients who are progressing on ruxolitinib. I typically use pacritinib [Vonjo] in patients with significant thrombocytopenia, remembering that it also may help the anemia associated with myelofibrosis. [I also use] momelotinib for patients with anemia. The other important point to remember is that transplant is still the only curative modality [for myelofibrosis]. For younger patients who are fit and who have higher-risk disease, we still consider transplant.

References

1. Ojaara (momelotinib) approved in the US as the first and only treatment indicated for myelofibrosis patients with anaemia. News release. GlaxoSmithKline. September 15, 2023. Accessed March 23, 2024. https://www.gsk.com/en-gb/media/press-releases/ojjaara-momelotinib-approved-in-the-us-as-the-first-and-only-treatment-indicated-for-myelofibrosis-patients-with-anaemia
2. Harrison CN, Vannucchi AM, Platzbecker U, et al. Momelotinib versus best available therapy in patients with myelofibrosis previously treated with ruxolitinib (SIMPLIFY 2): a randomised, open-label, phase 3 trial. Lancet Haematol. 2018;5(2):e73-e81. doi:10.1016/S2352-3026(17)30237-5