The phase 1/2 MANIFEST and phase 3 MANIFEST-2 trials are examining a complement to JAK inhibition that could improve responses and disease management up front in patients with myelofibrosis.
Srdan Verstovsek, MD, PhD
The phase 1/2 MANIFEST (NCT02158858) and phase 3 MANIFEST-2 (NCT04603495) trials are examining a complement to JAK inhibition that could improve responses and disease management up front in patients with myelofibrosis, according to Srdan Verstovsek, MD, PhD.
Results from the 2 studies show that the BET inhibitor pelabresib (formerly CPI-0610), in combination with the JAK inhibitor ruxolitinib (Jakafi), has yielded promising efficacy. Moreover, the addition of BET inhibition to JAK inhibition can help manage symptoms, such as anemia, that ruxolitinib, the current standard of care, does not mitigate, Verstovsek noted.
“[It is not] often that we can talk about enhancing the standard of care. We are often, with good reason, preoccupied with helping patients in the second-line setting where there is nothing to offer, Verstovcek said. “Here, we have an opportunity to do a better job from the very beginning, from day 1, and it appears pelabresib does provide safety and efficacy that is clinically relevant and significant.”
In an interview with OncLive, Verstovsek, the United Energy Resources, Inc. professor of medicine, and director of the Hanns A. Pielenz Clinical Research Center for Myeloproliferative Neoplasms at The University of Texas MD Anderson Cancer Center, discussed findings from the MANIFEST studies and the clinical implications of pelabresib in the treatment of patients with myelofibrosis.
Verstovsek: Pelabresib is a BET inhibitor, and this class of drugs is part of a larger group of drugs that are epigenetic modifiers. [These agents] modify genetic expression from outside of the DNA, and there are multiple ways to do that. Epigenetic modifiers have been studied in myeloproliferative neoplasms, such as myelofibrosis, and we have evidence that hypomethylating agents, and LSD1 inhibitors, which are all different classes of epigenetic modifiers, can provide clinical benefit. [As such,] it is not surprising that pelabresib, a BET inhibitor, also has activity in patients with myelofibrosis.
Compared with [other agents], this drug appears to be safer. We have always known about epigenetic modifiers as active drugs, but they were limited by myelosuppression, gastrointestinal toxicities, and all kinds of other adverse effects [AEs].
It appears, from the phase 2, multi-arm MANIFEST study that is underway with pelabresib in different clinical settings in patients with myelofibrosis, that you can deliver the drug in a safe way. Therefore, the benefit we see is enhanced, and can be durable and benefit the patients. We can envision that this drug has a potential role in the future management of patients with myelofibrosis, [because it has] efficacy and safety.
This is a phase 2, open label study where pelabresib is given to patients in different clinical settings, and there are 3 arms. Currently, standard practice for most of the patients with myelofibrosis is to give them the JAK inhibitor ruxolitinib, because it improves the quality of life, patients gain weight, walk more, have less AEs—such as itching, night sweats, bone aches, fevers—and it decreases symptomatic splenomegaly, which is seen in approximately 80% of patients.
This [makes ruxolitinib the] standard first-line therapy for most patients. These patients benefit on average, for approximately 3 years, [based on] clinical studies. [As such, this is] where we have [an unmet need]. What do we do after ruxolitinib? No drug has been approved in the United States as a second-line drug, so this is where the pelabresib is being studied.
The second option is to give pelabresib to patients who are [currently on] ruxolitinib but have suboptimal responses. Finally, the third option is to combine the drugs together from day 1. [These are the 3 study arms.]
[Then, we are looking] at the different types of benefits. As we said, ruxolitinib improves the spleen and symptoms. We want to see if the pelabresib can do the same, can enhance the [efficacy of] JAK inhibitors if they are combined, or [determine whether] this can improve [these] symptoms [when treatment with ruxolitinib fails].
Another main problem in myelofibrosis is anemia. JAK inhibitors do not do anything for anemia; [in fact,] they can worsen it. One of the possible benefits of pelabresib is to improve anemia, which is unexpected, but appears to be evident in these clinical settings.
[In the cohort of patients] who are on the stable dose of ruxolitinib and have a suboptimal response, and then get the addition of pelabresib, approximately 25% have significant improvement in the spleen. [Additionally,] 30% of patients have improvement in symptoms; approximately 25% have improvement in anemia. There are [still questions that remain, such as] the time to response, how long responses last, how long patients are benefiting, and whether patients are benefitting without reaching the official response criteria. The time to response varies for different benefits, and the durability of response is still unknown. [However,] the initial knowledge about the benefits is encouraging.
The most exciting part is the combination [of ruxolitinib and pelabresib] from the very beginning. The preliminary results suggest that the combination has a much better response in the spleen and symptoms over what we would expect from ruxolitinib alone. There is approximately a 25% increase in response [with the combination] vs ruxolitinib alone, and there is perhaps more symptom control.
This is where [there are] plans to do a phase 3 study, and where [Constellation Pharmaceuticals] plans to pursue a possible approval of pelabresib in the frontline setting, comparing the combination vs ruxolitinib alone in a randomized study. Ruxolitinib will not be blinded, but pelabresib and placebo will be blinded to see if there really is benefit over ruxolitinib alone.
Preclinical models of epigenetic modifiers, both in patient samples and mouse models, show enhancement of the JAK inhibitor through changing the genetic expression, as well as the bone marrow environment. Therefore, it is not unheard of, in fact, to see some benefit. This is evident in the frontline setting with ruxolitinib and pelabresib. It is also known that epigenetic abnormalities do exist, and that is why the epigenetic modifiers work in patients with myelofibrosis. Many have a splicing mutation, for example, and there is an underlying biological reason why the drugs would be working.
Some of the preliminary correlative studies that were presented from the ongoing, phase 2 study on the mechanism of action of pelabresib suggest that the drug has an effect on megakaryocytes, and maturational peripheral cells in the bone marrow as well. This is good to know to expand the understanding of possible different mechanism of actions, not just in modifying a genetic expression, but affecting the megakaryocytes that occur in this disease.
Additionally, the maturation of red blood cells possibly explains why this drug would have an anemia benefit on top of the control of the spleen and symptoms. This is all not conclusive, just hypothesis driven research, and obviously the assessment of the correlative studies will be valuable to understanding the clinical benefit.
The study follows the design of the prior studies that lead to the approval of ruxolitinib. The cutoff for participation is platelets above 100,000, which is for safety reasons. There is a possibility of pelabresib lowering the platelet counts, which is why the drug is given on a 2- week-on/1-week-off schedule. That will require a more hands-on approach to make sure it is safely delivered, but so far, that has not appeared to be a major problem in the open-label study.
The design also calls for ruxolitinib to be under-dosed in the beginning. Whether patients are randomized to 1 arm or the other, everyone starts with the lower dose of ruxolitinib for safety reasons. After 1 month, patients will have the ruxolitinib dose increased to what the standard starting dose should have been.
The standard of care might be changed for a particular group of patients for whom there is a need to control the spleen, symptoms, and anemia. Anemia is one problem that contributes significantly to difficulties in disease management, because it can be enhanced by ruxolitinib. If you have a combination that can interrupt the anemia and improve the spleen and the symptoms over ruxolitinib alone, the management would be very much improved. [This is particularly true] in patients that are more advanced, who have problems with anemia and other symptoms. [For these patients,] the combination might be preferred as a frontline treatment over ruxolitinib alone.
Other possibilities are to start with ruxolitinib, see what [benefit is achieved], and then add pelabresib after a few months. There are multiple possibilities, and we are looking forward to understanding the benefit [and superiority of this agent] and how easy it is to deliver.