Potential Combination Therapy Approaches with Ruxolitinib in Myelofibrosis

Transcript:

Naveen Pemmaraju, MD: Among the novel agents, and there are many out there that are being studied, there are 3 now in the later stages of phase 3 development, which really have tried to combine with the JAK inhibitor. But one of those agents that I've been particularly involved in is that of BCLXL inhibition with the oral agent Navitoclax [ABT-263]. And Navitoclax is not yet FDA-approved for any indication but it's an oral pill drug that's been available for targeting dual BCLXL and BCL2. The cousin drug venetoclax [Venclexta] is more focused on targeting the BCL2 pathway. And so, for many reasons of interest, it appears that in MPN [myeloproliferative neoplasms] such as myelofibrosis, it's the BCLXL pathway rather than the BCL2 that is over-expressed or amenable to targeted inhibition.

The Navitoclax agent we have studied in a series of cohorts under the phase 2 designation, the REFINE trial. One of those cohorts was the add-on addition of ruxolitinib to the Navitoclax in the so-called cohort 1A of the REFINE study. And we recently published those studies by me and Claire Harrison, MD, FRCP, FRCPath in the JCO [Journal of Clinical Oncology] in 2022. And among the first 30 patients treated, we observed that there was a spleen and symptom decrease after the addition of the Navitoclax. These are patients who remain on their JAK inhibitor ruxolitinib, but we're having a failing or suboptimal response. And in addition to that, we showed the potential for disease modification with some patients experiencing bone marrow fibrosis reduction, variant allele fraction [VAF] reduction, and even an improvement in overall survival. And so that approach continues to be evaluated in the long-term setting. Also in the phase 2 setting was Navitoclax alone. So, testing the BCLXL agent by itself in the relapse setting.

And then also another arm included was in testing the combination of ruxolitinib Navitoclax in the frontline setting. And in that phase 2 experience, our colleague Peter Passamani, MD, recently showed those data at ASCO [American Society of Clinical Oncology] and ASH [American Society of Hematology Annual Meetings], showing very encouraging results, including spleen size reduction in more than 60% of patients, and symptom burden improvement. And again, this modulation of VAF and bone marrow fibrosis in several of the patients. So now building on those phase 2 results in the multiple cohorts I described to you, it's the combination of ruxolitinib and Navitoclax that's moving forward. And that's in 2 separate phase 3 studies. One is known as the TRANSFORM-1 study, which is a frontline, upfront JAK inhibitor naive study, randomizing ruxolitinib plus Navitoclax vs ruxolitinib plus placebo. In this randomized controlled study, the endpoints again are to assess patients by spleen and symptoms. It's a global study that's actively enrolling. And so, we hope to have those results in the coming 1 to 2 years.

The additional study is the TRANSFORM-2 study, which is again, another globally enrolling phase 3 randomized study. And this is focusing on the Navitoclax-ruxolitinib combination beyond the frontline setting. I think you have the TRANSFORM-1, and TRANSFORM-2 data. We have the refined data. And so, we can see that Navitoclax clearly has what you would consider encouraging activity and beyond or in addition to the Ruxolitinib-JAK-affine. It's found to be a fairly safe, well-managed drug with the expected signals that have been seen in prior Navitoclax studies, mainly the most common hematologic is that of thrombocytopenia and expected side effect given the BCLXL target, which is present in the vast majority of patients, 80% or more of the patients in these earlier studies. And then a GI [gastrointestinal] signal, which includes diarrhea, would be one of the most common nonhematologic side effects again, well-managed, well-tolerated, and expected.

I think the last aspect of this is the concept of disease modification. Can the addition of a second agent such as Navitoclax do deeper, more durable responses in terms of the biochemical parameters, such as cytokines, variant allele fraction, glomerular fibrosis, the clinical factors that we already know about, spleen, and symptoms? And then finally, can it translate into an overall survival benefit for the patient, many of whom are high-risk patients with molecular markers that portend a higher risk of transformation in AML [acute myeloid leukemia]. So, these are the factors that we await in the remaining studies that are pending, which feature the Navitoclax agent.

Aaron Gerds, MD: One of the combination therapies that we're really interested in the field is a combination of pelabresib [CPI-0610] and ruxolitinib. So, pelabresib is a BET inhibitor, and the MANIFEST study was a phase 2 trial looking at pelabresib with ruxolitinib in the frontline setting as well as in the second-line setting both by itself and in combination with ruxolitinib, so a catch-all phase 2 trial. But really impressive results across the board. And this spurred on the development and launching of the MANIFEST-2 trial. So, the MANIFEST-2 trial is a prospective randomized phase 3 trial in patients with myelofibrosis, a frontline setting, so for patients who have not previously received a JAK inhibitor comparing ruxolitinib plus a placebo vs ruxolitinib plus pelabresib. And the trial has completed enrollment, so that's very exciting that all the patients that are on it and have been randomized are going along in their treatment. So hopefully, we'll get some top-line data from this study very soon.

While we wait with that top-line data from the MANIFEST-2 trial, Dr Joseph Michael Scandura, MD, PhD at the most recent ASH Annual Meeting in 2022 presented really interesting data from the phase 2 MANIFEST study. And we're always looking for deeper effects on the disease. We think ruxolitinib can affect the disease somewhat, and it certainly led to better outcomes, but we want more. We want patients to have a deeper response where maybe scar tissue is being reversed or allele burden's going down, or things that can directly translate into better disease-free survival, or even reverse the effects of the disease.

Dr Scandura presented a really interesting abstract where they looked at megakaryocytes in the bone marrow and definitely saw some of these effects of the megakaryocyte that the cell of the disease being lessened in its density and appearance in the bone marrow. And he's a world expert on this topic and really made a convincing case that the combination can lead to deeper effects, perhaps getting for this mythical goal of disease modification for this combination, which ultimately, I think it's going to be incredibly important as this moves forward because the combination of ruxolitinib and pelabresib may have an increased number of responses in terms of spleen volumes and symptom burden in the frontline setting. And I think to really argue for using a combination upfront where you may have increased toxicity is showing a deeper effect on disease whether we're delaying progression and having more durable responses or perhaps reversing pathology we see in the bone marrow. So, I think we're going to need more to justify using this in the frontline and Dr Scandura's abstract 630 was really a first step in that direction.

Pankit Vachhani, MD: At ASH 2022, we heard and got the final results of the Ruxopeg study. This is a phase 1 study to adapt to a randomized trial of ruxolitinib and PEGylated interferon Alpha-2A in patients with myelofibrosis. A total of 37 patients with myelofibrosis from 6 centers participated. These were patients with intermediate or high-risk myelofibrosis by IPSS [the International Prognostic Scoring System] risk stratification. The primary endpoint, which was that of 50% or more spleen length reduction at week 24, was achieved in 70% of patients at 24 weeks in the intent-to-treat population. Importantly, by the use of combination therapy of both ruxolitinib and PEGylated interferon, committed as well as immature and enriched progenitor cells, which were carrying Homozygous or heterozygous JAK2 V617F mutant clones, were decreased in this clinical trial. In addition to that, the JAK2 V617F allele burden decreased from a median of 84% at baseline to about 65% and 53% at 6 and 12 months. Impressive results in terms of spleen length reductions, as well as JAK2 V617F allele burden reductions, and those results, came about through selective targeting of mutated progenitor cells.

Transcript edited for clarity.