Pelabresib/Ruxolitinib Data Underscore Need for Novel End Points in Myelofibrosis Trials

Although a 35% reduction in spleen volume (SVR35) and a 50% reduction in total symptom score (TSS50) have been established as key end points in clinical trials evaluating therapies for the treatment of patients with myelofibrosis, integrating end points such as overall survival (OS) and progression-free survival (PFS) as key objectives in future studies could help guide drug development and measure any disease-modifying properties of treatments, according to Aaron Gerds, MD.

“[Findings] from [the phase 3] MANIFEST-2 [NCT04603495] and TRANSFORM-1 [NCT04472598] trials are a wakeup call for the field that we need to move beyond SVR35 and TSS50 [as clinical trial end points in myelofibrosis]. We have drugs that are good at making patients’ symptoms better; however, we need are drugs that truly modify the disease course in a meaningful way,” Gerds explained.

Updated data from the MANIFEST-2 presented at the 2024 ASCO Annual Meeting showed that patients with myelofibrosis who received frontline pelabresib (CPI-0610) plus ruxolitinib (Jakafi; n = 214) experienced an SVR35 rate of 65.9% at week 24 compared with 35.2% for those given ruxolitinib plus placebo (n = 216). Notably, updated data showed that in patients who experienced an SVR35 at any time, 13.4% of patients in the experimental arm lost that response vs 27.8% of patients in the placebo arm.¹

Additionally, the TSS50 rates at week 24 were 52.3% for pelabresib plus ruxolitinib vs 46.3% for placebo plus ruxolitinib, translating to a numerical improvement that was not statistically significant (difference, 6.0%; 95% CI, –3.5% to 15.5%; nominal P = .216).

Notably, 40.2% of patients in the pelabresib arm experienced both SVR35 and TSS50 at week 24 compared with 18.5% of patients in the placebo arm.

In an interview with OncLive^®, Gerds an assistant professor of medicine, Hematology, and Medical Oncology at Cleveland Clinic Taussig Cancer Institute in Ohio, detailed prior data from MANIFEST-2 presented at the 2023 ASH Annual Meeting;² expanded on updated data presented at the 2024 ASCO Annual Meeting; and emphasized the need to look beyond current end points in clinical trials evaluating treatments for patients with myelofibrosis.

OncLive: What data were previously reported from MANIFEST-2?

Gerds: MANIFEST-2 was a prospective, randomized phase 3 trial testing pelabresib plus ruxolitinib vs ruxolitinib alone in the frontline setting for [patients with] myelofibrosis. Up until now, all we've had [for the frontline treatment of myelofibrosis] was single-agent JAK inhibitors. This is the next big step forward. JAK inhibitors are fantastic, and they've revolutionized the care of myelofibrosis; however, they are by no means the end all, be all. We need [new] therapies that have more durable responses and more frequent responses, and that was the goal of this study.

The initial reports for [MANIFEST-2] occurred at the 2023 ASH Annual Meeting, and now we got some of the updates [at the 2024 ASCO Annual Meeting]. At the 2023 ASH Annual Meeting, what we saw is that the combination of pelabresib plus ruxolitinib dramatically improved the proportion of patients who had a spleen volume response. There was a trend toward a better symptom improvement [with pelabresib plus ruxolitinib], but that secondary end point was not met.

However, [the study] still met the primary end point of an increased number of patients achieving SVR35 by week 24. Yet, there's been a dispersal of enthusiasm because [the study] didn't get hit this key secondary end point [of TSS50]. For me, the take-home point from the initial results was not that the combination wasn't successful; ruxolitinib [alone just] does a very good job at treating symptoms, and it's maybe an unreasonable bar to reach [with an experimental therapy].

Ongoing results are important because we want to see more durable responses and perhaps some inclination that deeper responses are happening [beyond] SVR35 responses and symptom burden improvement, [meaning] changes deeply affecting the disease, which we sometimes refer to as disease modification. Seeing a more durable response or other signs of deeper remission would be important in the ongoing [analysis].

What were some of the updated efficacy findings presented at the 2024 ASCO Annual Meeting?

We continued to look at SVR35 and the number of patients who maintained that over a longer period of time to make sure that these responses were durable. A lot of the [ASCO] presentation focused on reiterating the topline results that were presented in December [with the updated data] emphasizing [these findings].

One thing that is helpful in terms [evaluating] at the results of this trial is looking at the proportion of patients who had both a SVR35 and TSS50. If we look at the combination [of pelabresib plus ruxolitinib], 40.2% of patients [achieved] both SVR35 and TSS50. If we look at ruxolitinib alone, only 18.5% of patients hit both of these key end points. [The improvement] in TSS50 may not be as robust with the combination because ruxolitinib by itself does a very good job. However, the proportion of patients hitting both of these key end points is very [large] when you compare the combination vs single-agent ruxolitinib.

What we're seeing in the data past week 24 are continued responses that are durable. With the [initial data presentation at the 2023 ASH Annual Meeting], these responses were anticipated to be durable, but we were going to need more follow-up. With the information we have now, we're not seeing increased adverse effects popping up.

Are there any updated safety findings that are important to note?

There was a concern over an increased risk of leukemic transformation and increased proportion of patients with blast transformation. If we look at pelabresib plus ruxolitinib, 2.4% of patients [in the combination arm] vs 0.5% of patients on placebo plus ruxolitinib [experienced blast phase progression].

What we need to do is look at those individual patients who progressed [to blast phase] and see if there was a misalignment of the risk. Were those patients destined to progress independent of the treatment that they got? Again, the number [of patients who progressed to blast phase] are so tiny, it's not statistically different; however, is there a rational explanation for this finding? Biologically, you wouldn't expect that. You would expect BET inhibition to potentially reduce the risk of progression or at least be risk neutral. We need to dig into that and sort that out as additional information comes along.

[Overall], the safety profile [of pelabresib plus ruxolitinib] was similar to what was previously reported. There were no new safety signals that have emerged with the continued follow-up from the study.

What are the clinical implications of the updated findings for this combination in the treatment of patients with myelofibrosis?

If we look at the proportion of patients at week 24 who hitting that dual response of SVR35 plus TSS50, it went from 18.5% with ruxolitinib alone to 40.2% [with the combination]. That's more than doubling of [the proportion of] patients who hit both of these key end points. That's important, particularly since SVR35 is associated with better survival. Of course, more time is going to be needed to follow these patients to see if the OS curves do in separate. It's still too early to tell [if there will be an OS difference] with the data that we had available at the time of this presentation [at the 2024 ASCO Annual Meeting].

An updated analysis will be presented later in [2024], and we should get our first sense of the OS [data] for this study, which [could] be just as important, if not more important, than the results that we saw with the primary end points at week 24.

How can future clinical trials in myelofibrosis be improved to look beyond SVR35 and TSS50?

As we design trials and develop new therapies going forward, we need to [deemphasize] the importance of TSS50, in particular, when designing these trials. We need to go for end points in terms of OS and PFS. SVR35 and TSS50 are still important and need to be measured; however, they shouldn't be the primary focus of trials going forward. We've [used those end points] and that story has been played out. MANIFEST-2 serves as a wakeup call to move away from those end points going forward.

References

1. Rampal R, Grosicki S, Chraniuk D, et al. Updated safety and efficacy data from the phase 3 MANIFEST-2 study of pelabresib in combination with ruxolitinib for JAK inhibitor treatment-naive patients with myelofibrosis. J Clin Oncol. 2024;42(suppl 16):6502. doi:10.1200/JCO.2024.42.16_suppl.6502
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