Ruxolitinib (Jakafi)-based combinations continue to demonstrate promising ability to address splenomegaly and a signal toward improvement of tumor-related symptoms in myelofibrosis. As novel targets for development are unearthed and considered for evaluation in combination with standard JAK inhibition, the assessment of other meaningful end points is necessary to confirm the true benefit of such agents alone or in combination across myeloproliferative neoplasms (MPNs), according to Gabriela Hobbs, MD.

Results from the phase 3 TRANSFORM-1 study (NCT04472598)were presented at the 2023 ASH Annual Meeting and demonstrated that up-front navitoclax and ruxolitinib (Jakafi) significantly reduced spleen volume by 35% or more at week 24 vs ruxolitinib plus placebo in patients with myelofibrosis.¹ Despite this, no significant difference in total symptom score (TSS) was observed between the arms.

Additionally, data from the phase 3 MANIFEST-2 trial (NCT04603495) showed that pelabresib (CPI-0610) plus ruxolitinib reduced spleen volume by 35% or more in 65.9% of patients with JAK inhibitor–naive myelofibrosis vs 35.2% in those who received placebo/ruxolitinib (95% CI, 21.6-39.3; P < .001). The agent also trended toward improving TSS reduction by 50% (TSS50) at 24 weeks.²

“One of the things we must answer as a field is: What is the benefit of using combination therapy for this disease?” Hobbs, who is clinical director of the Leukemia Service at Massachusetts General Cancer Center, and an assistant in medicine at Massachusetts General Hospital in Boston, Massachusetts, stressed in an interview with OncLive®News Network: On Location during the 2023 ASH Annual Meeting. “We need to have end points that are meaningful, [as well as] therapies that are well tolerated and affordable for patients.”

In the interview, Hobbs discussed the significance of key data from the TRANSFORM-1 and MANIFEST-2 trials for patients with myelofibrosis, expanded on the ongoing or future development of novel targets and potential combination regimens across MPNs, and spotlighted the phase 1/2 SAVE study (NCT05360160) and other key research efforts being made in leukemia.

OncLive: What key data on novel ruxolitinib-based combination regimens were reported at the 2023 ASH Annual Meeting?

Hobbs: I primarily treat MPN, and this is probably the first ASH Meeting where 2 different phase 3 studies [in this space] were presented at the same time. The navitoclax data are impressive, specifically when it comes to the improvement that we see with the combination of navitoclax and ruxolitinib for improving spleen volume response [SVR]. That can be very meaningful for patients—especially those with myelofibrosis who have very large spleens. We saw a very similar SVR with the combination of pelabresib and ruxolitinib as up-front therapy in patients who had not received a JAK inhibitor before.

How do you distinguish between these 2 agents in clinical practice?

In addition to showing an impressive improvement in SVR, neither study showed a dramatic improvement in symptoms [with the combinations] compared with ruxolitinib alone. That’s something that we need to consider. Pelabresib probably did a better job at improving symptoms than navitoclax. However, we need to start thinking about whether there are more meaningful end points other than expecting agents to improve SVR and symptoms. For example, could they potentially delay progression to leukemia, improve overall survival, or improve treatment outcomes in general or after transplant? Those are difficult end points to demonstrate, so they weren’t the primary objectives of the studies.

What other emerging agents of interest were discussed during the meeting?

There were lots of interesting novel agents presented at the meeting. There is a single-agent study [examining] a selective PIM kinase inhibitor and [we saw] some updated results in approximately 30 patients who have received the agent. [The agent appears to be] incredibly well tolerated, with very little impact on blood counts in a group of heavily pretreated patients. We’re also seeing a variety of other agents that are being developed. We’re seeing results from [the phase 2 VALENTINE-PTCL01 (NCT04703192)] study with the LSD1 inhibitor valemetostat tosylate [DS-3201b], an agent that also helps to prevent the development of fibrosis.

Are any of these agents viable options for further investigation as part of combination regimens?

That is the question to answer in [the] MPN [field]. Many studies have focused on combining a novel agent with a JAK inhibitor, primarily with ruxolitinib since it’s the one that has been around for the longest. I wouldn’t be surprised if the future of myelofibrosis [will be] to utilize combinations. [However,] we must remember that there’s a difference between treating patients in clinical trials vs treating patients in real life.

At this year’s meeting, findings from the phase 1/2 SAVE study of revumenib (SNDX-5613) plus decitabine/cedazuridine, (ASTX727) and venetoclax (Venclexta) were also presented. How did the results live up to expectations surrounding the use of menin inhibitors, and what are the next steps for the regimen?

That was an exciting study [done in] a group of patients with heavily pretreated AML. Some of these patients had undergone allogeneic stem cell transplantation and had received several lines of [prior] therapy. Patients who have refractory AML must go to clinic very frequently. Being able to offer them a regimen that’s all oral is very meaningful because [they do not] have to come to clinic as frequently to receive an IV hypomethylating agent. Most patients had at least some response [to the combination], and many had impressive responses. [Notably,] many patients had been previously treated with venetoclax. Menin inhibitors have been practice-changing in AML, and we’ve seen some responses [with this approach] in patients who have previously not responded to anything else. I look forward to seeing [more about] this combination, and hopefully [we can] bring it into earlier lines of therapy.

What were the biggest updates in chronic myeloid leukemia (CML) according to data presented at the meeting?

CML is very interesting. We all think that CML is a disease that we’ve conquered. We [see] great outcomes and almost normal life expectancy in most patients who are responding to therapy. [However], there is still a lot of development in the field. Several studies are investigating asciminib [Scemblix] in several different ways. The first study that we see is the [phase 3] ASCEMBL study [NCT03106779] comparing asciminib with bosutinib [Bosulif]. Updated [data presented at this year’s meeting] showed that asciminib is still outperforming bosutinib in terms of molecular remissions. [Investigators are] also studying asciminib in different, more creative ways in CML. They’re combining asciminib with other TKIs either in the up-front setting or in a later-line setting because of its slightly different mechanism of action. We’re also seeing the development of other TKIs that are either similar to asciminib or similar to ponatinib [Iclusig] in their mechanisms of action. There is still a lot of drug development in a disease where we thankfully have [achieved] a lot of great outcomes.

[It will be interesting to see how this next generation of agents impact current practice,] especially if they improve tolerability. For a disease where [a patient has] to be on life-long therapy, it’s important to have agents that are well tolerated.

Editor’s note: This interview was conducted prior to the conclusion of the 2023 ASCO Annual Meeting.

References

1. Pemmaraju N, Mead AJ, Somervaille T, et al. Transform-1: a randomized, double-blind, placebo-controlled, multicenter, international phase 3 study of navitoclax in combination with ruxolitinib versus ruxolitinib plus placebo in patients with untreated myelofibrosis. Blood. 2023;142(suppl 1):620. doi:10.1182/blood-2023-173509
2. Rampal R, Grosicki S, Chraniuk D, et al. Pelabresib in combination with ruxolitinib for Janus Kinase Inhibitor treatment-naïve patients with myelofibrosis: results of the MANIFEST-2 randomized, double-blind, phase 3 study. Blood. 2023;142(suppl 1):628. doi:10.1182/blood-2023-179141

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