Pacritinib Possesses Unique Potential for Myelofibrosis With Low Platelet Counts

Ruben Mesa, MD

The JAK2 inhibitor pacritinib has proven to be particularly safe and effective in patients with myelofibrosis—particularly those with low platelet counts, making it a welcome addition to the evolving treatment armamentarium, according to Ruben Mesa, MD, who added that next steps with the agent will likely focus on examining its use in novel combinations with BCL-2 and BET inhibitors to further improve outcomes.

“The potential addition of pacritinib to our currently approved armamentarium of ruxolitinib [Jakafi] and fedratinib [Inrebic] – and perhaps at some point momelotinib – as all being positive,” Mesa said. “They all have benefits that they bring to the table, patients that they can help, and subtle differences. Over time, we will learn how to best match the patient to their JAK inhibitor…I certainly hope that we see this soon as an additional agent for patients with myelofibrosis.”

In June 2021, the FDA granted priority review to a new drug application seeking the approval of pacritinib for use in patients with myelofibrosis and severe thrombocytopenia, defined as platelet counts less than 50 x 109/L, based on results from the phase 3 PERSIST-1 (NCT01773187) and PERSIST-2 (NCT02055781) trials, as well as the phase 2 PAC203 trial.

In an interview with OncLive,® Mesa, the director of UT Health San Antonio MD Anderson Cancer Center, discussed what makes pacritinib a unique option in the myelofibrosis landscape, future efforts with the agent, and where the drug might fit into the paradigm if approved.

OncLive®: How does pacritinib differ from other agents utilized in the treatment of patients with myelofibrosis?

Mesa: Pacritinib is a JAK2 inhibitor, and I have been grateful to be involved with a program [that has been examining it] for quite a long time. [The] unique aspect [of the agent] is that it is particularly safe and effective for individuals with low platelet counts; it is [also] effective against splenomegaly, [as well as] against symptoms [experienced by] patients with myelofibrosis.

[However,] many JAK2 inhibitors have thrombocytopenia as a dose-limiting toxicity. [Neither] of the currently approved JAK inhibitors, ruxolitinib or fedratinib, are [indicated] for individuals with a platelet count of less than 50,000. [As such,] the particularly unique aspect [of pacritinib] is that it can be safely administered to that population of patients.

What has been learned from PERSIST-1 and PERSIST-2 about pacritinib, and what how might the phase 3 PACIFICA trial help to provide additional clarity on the agent in this space?

[We have seen] earlier studies with pacritinib, [such as] the frontline PERSIST-1 trial, [which included] individuals with any level of platelets, as well as the PERSIST-2 trial, which focused on

individuals with thrombocytopenia. The phase 3 PACIFICA trial [NCT03165734] is a newer [effort] that is randomizing patients between pacritinib and best available therapy for individuals with marked thrombocytopenia. [The goal of this study is to] further flesh out the level of effectiveness [of the agent in] those individuals with marked thrombocytopenia, as well as to understand the safety [of the agent in] those individuals.

In the earlier studies, as one might imagine by enrolling individuals with very advanced disease and marked thrombocytopenia, there had been some question of whether bleeding events or other events that had been seen were related to patient selection, or [if those] toxicities were related to the agent. Fortunately, it seemed that it had been a bit of adverse patient selection. As such, the PACIFICA study, additionally, is trying to look at a population of individuals who have thrombocytopenia but are otherwise medically stable [enough] to be on an investigational study, so that we get the cleanest picture of the safety and efficacy [of the agent] in that group.

If the data from the trial are positive, how do you foresee pacritinib fitting into the paradigm?

I have confidence that data [from PACIFICA] will really help to support the role of pacritinib in individuals with marked thrombocytopenia, and be a unique [option] for [patients with] myelofibrosis. [It may be beneficial in] the frontline setting, where individuals with marked thrombocytopenia currently do not have many other good options. In the second-line setting, it is not infrequent that individuals who had prior [treatment with a] JAK inhibitor fail, or who have advanced disease, have marked thrombocytopenia; [the agent may benefit these patients].

Have any differences in efficacy been observed between myelosuppressive and myelodepletive patient groups?

In individuals with myelodepletive [disease], or some have called it the cytopenic phase of myelofibrosis, pacritinib is valuable because it has efficacy against splenomegaly and symptoms; [this is] important in terms of both decreasing the burden in myelofibrosis, and potentially in terms of having an impact even on survival for these patients. Individuals can receive a full dose of the drug vs the current state. In the current state, off label, we largely use a modest, very low, or sometimes truly just homeopathic doses of the current available agents for individuals with a platelet count of less than 50. The PERSIST-1 study [demonstrated that] pacritinib is active in individuals who have higher platelet counts as well, so it does not limit that possibility [for improvement, potential combinations, etc.], but the uniqueness of the pacritinib data [can be observed] in that group that are [considered to be] quite cytopenic.

Where will future efforts with pacritinib focus?

In the future, [we may see the agent used] in combination. Many other drugs are being looked at in combination with JAK inhibition; this includes BCL-2 inhibitors like navitoclax and BET inhibitors like [pelabresib [CPI-0610]). Other compounds are also active. Many of these drugs can cause a decrease in platelet count. As we think about combinations with agents that also

might cause thrombocytopenia, pacritinib is going to be a strong consideration to build on some of those experiences.

What is your take-home message regarding the potential for pacritinib in this disease?

As JAK inhibitors evolve, we do realize that there are some important differences [with what has come before]. There has been some good science behind the additional kinases in targets such as IRAK-4, and others, that pacritinib is hitting, along with FLT3, that may be important for some of the differences we are seeing in terms of its safety and efficacy for patients with myelofibrosis.

As I look longer term in the myelofibrosis landscape, I envision patients being optimized in terms of their JAK inhibitor, and then potentially, in certain subsets, having a second agent added in[to the mix], depending upon the quality of the response, or other features, such as risk or molecular phenotype.