Emerging Era of Combination Therapy in Myelofibrosis Explored in SENTRY Study

John Mascarenhas, MD

The myelofibrosis treatment landscape is moving to one where combination therapy may likely become the standard of care. However, more research is needed as there currently are no approved Janus kinase (JAK) inhibitors with novel agents in this space.

One trial investigating this approach is the ongoing SENTRY study (NCT04562389). The global, multicenter, phase 1/3 study is investigating the safety and efficacy of the combination of selinexor (Xpovio) plus ruxolitinib (Jakafi) for the treatment of patients with JAK inhibitor treatment-naive myelofibrosis.

The study is being conducted in 2 phases, including an open-label portion (phase 1) in which enrollment has completed. In phase 1a,the safety and recommended dose of selinexor plus ruxolitinib was evaluated with a standard 3+3 design was used Phase 1b which consisted of the dose-expansion part of the study. Now, phase 3 is enrolling patients with JAK inhibitor treatment-naive myelofibrosis. These patients will be randomized in a 2:1 fashion to receive selinexor plus ruxolitinib or placebo plus ruxolitinib.

The primary end points of phase 3 include the proportion of patients with spleen volume reduction of greater than or equal to 35% at week 24 (SVR35) and the proportion of patients with a total symptom score reduction of greater than or equal to 50% (TSS50) at week 24, as measured by the myelofibrosis symptom assessment form V4.0.

In an interview with Targeted Oncology^TM, John Mascarenhas, MD, professor, medicine, Icahn School of Medicine, Mount Sinai; director, Center of Excellence for Blood Cancers and Myeloid Disorders; and member, The Tisch Cancer Institute, Mount Sinai, discussed the lead up to this study and its potential impact on the treatment of myelofibrosis.

Targeted Oncology: Can you provide an overview of the SENTRY study?

Mascarenhas: The study we are talking about is a global phase 3 study. It is a randomized, double-blind study evaluating the safety and efficacy of selinexor, which is an XPO1 inhibitor, in combination with ruxolitinib in JAK inhibitor-naive patients with myelofibrosis. It is really capitalizing on data that has already been generated, both as a single agent in the relapsed/refractory setting, but also in combination with ruxolitinib in phase 2, demonstrating synergy of the 2 agents in terms of spleen reduction, symptom improvement, bone marrow fibrosis reduction, and a safety profile that would suggest that durability of response can be maintained. This is now the natural evolution of this agent in myelofibrosis in a phase 3 study in patients who are JAK inhibitor-naive, comparing ruxolitinib, which is the standard of care, plus selinexor, the XPO1 inhibitor, vs ruxolitinib plus placebo.

Close-up of red blood cells flowing through a vein: © catalin - stock.adobe.com

What were the methods, design, and inclusion criteria of the trial?

The study is a phase 3, randomized study that is going to include 306 patients who are JAK inhibitor-naive, and they will be randomized to 2:1 to ruxolitinib plus selinexor, the XPO1 inhibitor which is administered orally once a week at 60 mg weekly in a 28-day cycle vs placebo. And the coprimary end point of this global study is SVR35 at week 24 and TSS50 at week 24. A key secondary end point is an immune response at week 24.

The inclusion criteria are patients with a diagnosis of myelofibrosis, either primary or secondary myelofibrosis, and are JAK inhibitor naive. They have to have a [Dynamic International Prognostic Scoring System (DIPSS)] score of intermediate-1 with symptoms or intermediate-2 or high-risk disease and a platelet count of at least 100,000 or greater. In theory, they should not be candidates for immediate stem cell transplantation. Patients can eventually go to transplant, but if they are being considered for transplant immediately, this would not be an option for those patients.

In terms of exclusion, we do exclude patients with blasts that are greater than 10% in the blood or the bone marrow, as these patients would likely benefit from other types of therapies, or previous JAK inhibitor therapy or previous XPO1 inhibitor therapy.

What have prior studies shown for the combination?

We know preclinically that this combination is active; we know that selinexor hits as an inhibitor of a shuttling protein between the nucleus and the cytoplasm. We know it hits a lot of important pathways that are relevant to the biology of myelofibrosis, including p53. There are a lot of preclinical rationale and preclinical studies supporting the use of selinexor and XPO1 inhibition in general in myelofibrosis. But from clinical data, there is phase 2 data that was presented at [the American Society of Hematology] demonstrating synergy of ruxolitinib plus selinexor in these JAK inhibitor-naive patients where the rates of spleen response and symptom response were some of the highest we have seen so far with combinations in the JAK inhibitor-naive space. The phase 2 data is with a limited number of patients, but it did provide a signal of clinical activity and both safety profiles that would support this phase 3 study design.

How does the combination compare with other available treatments for this patient population?

Right now, the standard of care is single-agent ruxolitinib for this patient population. We believe that these combinations, which would also include drugs like pelabresib [CPI-0610] or even navitoclax, the BCL-2 and BCL-XL inhibitor which has stopped development, all have preclinical and clinical data supporting that there is synergy in terms of spleen reduction. Whether these drugs will benefit patients from a system perspective more so than ruxolitinib alone has been a point of discussion.

We are moving to an era where combination therapy is likely going to be the standard of care, but not yet. We do not have an approved combination of a JAK inhibitor plus a novel agent. I will also mention that ruxolitinib has been explored in combination with interferon alfa-2a and -2b, so that is another approach that has been evaluated in earlier phase studies. This is the natural evolution of therapeutic advancement in this space.

What are your key takeaways?

This study is activated and now enrolling across the globe and will continue to activate across multiple centers. We are looking for patients who are JAK inhibitor-naive who require therapy to address spleen and symptom burden who have at least intermediate-1 risk disease with symptomatology. I think what is attractive about the phase 3 study is that everyone gets at least the minimum standard of care, which is ruxolitinib. Then if 1 gets the study drug, we will see whether that adds benefit over ruxolitinib alone.

It is also important to keep in mind that the regulatory end points for these combinations have been spleen and symptom historically. But likely, the most important end point from a clinical perspective and from a clinician's perspective, when considering using combination therapies in our [patients with] myelofibrosis, is going to be durability of response. It is 1 of the secondary end points. So, can we not only get deeper responses from a spleen and perhaps symptom perspective, but can we maintain that durability longer than single-agent ruxolitinib? I think that is going to be the real benefit to these combinations, while avoiding significant toxicity, both clinical toxicity and financial toxicity.

REFERENCE:
Study of selinexor in combination with ruxolitinib in myelofibrosis. ClinicalTrials.gov. Updated July 24, 2024. Accessed August 1, 2024. https://classic.clinicaltrials.gov/ct2/show/NCT04562389