Myelofibrosis: Novel Combination Strategies

Transcript:
Stephen T. Oh, MD, PhD:Looking at some of the other novel agents in development, you have, for instance, navitoclax, which is a BCL-2 and BCL-XL inhibitor. The recent phase 2 study was recently published in Journal Of Clinical Oncology, which looked quite promising, also suggesting the possibility that the drug—either alone or in combination with ruxolitinib—may be able to provide, not just symptom benefit, but also molecular response, suggesting the possibility of disease modification. I’m looking ahead with excitement to the ongoing phase 3 studies with that drug. [I would also like to] mention 1 other drug in phase 3, which is pelabresib, or CPI-610, which is a BET [bromodomain and extraterminal domain] inhibitor. In the initial results from initial studies with this drug, it appears to provide—again—some degree of symptom and spleen benefit, but also some degree of anemia benefits. In some ways it’s a little bit analogous to momelotinib in that it can provide multiple means of benefits. You have all of these agents now, which are in phase 3. If you fast forward a couple of years, and at least a few of these have made it to the finish line, it will be, I think, a welcome addition to our available options to treat patients with myelofibrosis.

Ruben Mesa, MD: It is an exciting time for new therapies for myelofibrosis. Indeed, more clinical trials are ongoing now than we've really ever had in the past. I view them in several different categories. We've already discussed numerous agents that are single agents that are now approved. The more recently approved pacritinib as an example, and momelotinib as a single agent JAK inhibitor, which may become approved in the near future. Now there are multiple different agents with distinct mechanisms of action that are being tested in a variety of strategies, either (1) as traditional second-line therapy as single agents; (2) as an add-on strategy for individuals with a suboptimal response to ruxolitinib; or (3) as combination from the beginning. These include everything from navitoclax, a BCL-XL inhibitor; parsaclisib, a PI3 kinase inhibitor; MDM2 inhibitors with multiple agents being looked at in the single line setting such as the telomerase inhibitor, imetelstat, or bomedemstat, an LSD1 inhibitor.

Now, 1 agent in combination that has created a great interest is the agent pelabresib. This is a BET inhibitor and a parallel armed study, the MANIFEST study, was done looking at it in combination in the frontline therapy setting as an add-on or in the second line as a single agent. It is probably the frontline data that has created the most interest in seemingly in a noncontrolled way, having quite a bit higher rate of response for spleen and symptoms than single-agent ruxolitinib, and some potential evidence of disease modification in terms of chain disease and fibrosis or cytopenias. Currently, there's the MANIFEST-2 study that is active and recruiting—active at my site as well as many others, where it is ruxolitinib versus ruxolitinib plus pelabresib, again, to look at this difference both in overall response rate but also in deeper evidence of response or broader response. I'm very excited that there's such a robust pipeline. I think the data from these phase 3 trials are going to be critical.

Pankit Vachhani, MD: It has been known that PI3 kinase and NKT [natural killer T (cell)] developmental pathways can be activated in patients with myelofibrosis, and that this may contribute to a loss of response or a suboptimal response in those patients who are on ruxolitinib therapy for myelofibrosis. There is an ongoing, large phase 3 clinical trial, LIMBER-313, which is looking at the efficacy of parsaclisib and ruxolitinib in patients with myelofibrosis. Parsaclisib is a highly selective next-generation PI3 kinase delta inhibitor. It was previously looked at in a phase 2 trial and that data was presented before. LIMBER-313, which is the phase 3 clinical trial of the combination of parsaclisib and ruxolitinib is a large phase 3 study that is taking in patients with DIPSS [Dynamic International Prognostic Scoring System] intermediate-1, intermediate-2 or high-risk myelofibrosis with no prior JAK inhibitor or PI3 kinase inhibitor therapy. The randomization is to ruxolitinib monotherapy with placebo or ruxolitinib with parsaclisib 5 milligrams daily. Crossover is permitted. The primary objective of this study is evaluation and comparison of spleen volume at 24 weeks between the 2 groups, while secondary objective items include a measurement and comparison of this symptom burden reduction as well as overall survival, amongst other things. Important to note that this clinical study is taking patients who have platelet counts of 50 or more.

Now, correspondingly, there is also another phase 3 study that is very similar to the one that I just mentioned. That's the LIMBER-304 study that is looking at parsaclisib as an add-on drug to patients who were already on ruxolitinib monotherapy prior to that but had suboptimal response. That study is taking in patients who were on ruxolitinib for a minimum of 3 months and had suboptimal response as defined by a palpable spleen of 5 centimeters or more below the left subcostal margin and a total symptom score of 10 or more at screening. Now, this study, too, takes patients who have platelets of 50 or more at baseline, takes patients who have DIPSS intermediate-1, -2, or high-risk myelofibrosis and randomizes them to ruxolitinib plus parsaclisib 5 milligrams daily or ruxolitinib with placebo. Here, once again, much like LIMBER-313, there is crossover, and a defined time point.

Stephen T. Oh, MD, PhD: As far as potential combination therapies, it is, I think, honestly, confusing in sort of a good way, in the sense that until recently, really to date, most of the combination studies have utilized ruxolitinib as a backbone. Ruxolitinib plus or minus an oral therapy or a novel therapy plus or minus ruxolitinib. Now, we have 3 JAK inhibitors that are approved, a fourth that may be soon approved, and that opens that question of, even if you just think about the combination of a JAK inhibitor with another agent, which of those agents do you choose? I don't think there's a clear right answer there, but you could certainly make an argument, for instance, maybe you say pacritinib, because it doesn't really cause so much thrombocytopenia. That's a drug you compare with another drug that causes thrombocytopenia. That might be sort of a safer option in that sense. Maybe momelotinib with its ability to induce an immune response, you pair that with, say, a BET inhibitor, so that you might have combinatorial, or synergistic improvement in anemia. I think there are all kinds of strategies that can be considered. There's not necessarily one right answer. And you've got, historically, plenty of rationale to use ruxolitinib in combination with some of these agents as well. In fact, with some of the ongoing studies, there's even been a hint that there has been more impressive responses when combined with ruxolitinib. I think, again, that there's no one right way to do this, and many of these different combinations are going to be explored going forward.

Transcript edited for clarity.