Dr Scandura on the SENTRY-2 Trial of Single-Agent Selinexor in JAK Inhibitor–Naive Myelofibrosis

Joseph M. Scandura, MD, PhD, associate attending physician, NewYork-Presbyterian Hospital; associate professor, medicine, Weill Cornell Medical College, Cornell University, discusses the phase 2 SENTRY-2 study (XPORT-MF-044; NCT05980806) evaluating single-agent selinexor (Xpovio) in JAK inhibitor–naive myelofibrosis.

fast track designation to single-agent selinexor

 for the treatment of patients with primary myelofibrosis, post-essential thrombocythemia myelofibrosis, and post-polycythemia vera myelofibrosis in July 2023. Notably, selinexor will be assessed in combination with ruxolitinib (Jakafi) in the phase 3 portion of the SENTRY trial (NCT04562389) and as a monotherapy in the phase 2 SENTRY-2 study for JAK inhibitor–naive patients.

The primary aim of the SENTRY-2 study is to evaluate the efficacy of selinexor as a standalone treatment for patients with myelofibrosis who have not previously been treated with a JAK inhibitor, Scandura begins. Currently, JAK inhibitors are the only FDA-approved class of drugs for this condition, complicating the ability to test alternative treatments like selinexor independently, he states. However, evidence suggests that selinexor demonstrates activity, prompting the FDA to permit the study’s initiation, Scandura says. In SENTRY-2, patients will start treatment with selinexor, and responses will be measured based on spleen volume reduction and symptom improvement, particularly anemia, he details.

An innovative aspect of the study is its flexibility, Scandura notes. If a patient shows some degree of response but it is not deemed significant, they may have a JAK inhibitor added to their treatment regimen, he explains. This could include ruxolitinib or newer agents such as pacritinib (Vonjoy), which does not suppress platelet counts, making it suitable for patients with low platelets. Momelotinib (Ojjaara), known for its efficacy in improving anemia, will be added if patients are anemic and maintain adequate platelet counts.

The importance of safety and rigorous science is emphasized in clinical trials, especially when evaluating new treatments, Scandura continues. If selinexor gains FDA approval for myelofibrosis, it could play a significant role in a more nuanced treatment approach, reflecting the complexities of managing this condition amidst financial considerations and the availability of multiple JAK inhibitors, Scandura concludes.

Videos

Joseph M. Scandura, MD, PhD, discusses the phase 2 SENTRY-2 study evaluating single-agent selinexor in JAK inhibitor–naive myelofibrosis.

Attempts to leverage drugs that are effective in combination, such as selinexor (Xpovio), as single agents for the management JAK inhibitor–naive myelofibrosis reflects the need for improved personalization of therapy according to individual factors, and mitigation of financial toxicities associated with standard JAK inhibitor–based regimens, according to Joseph M. Scandura, MD, PhD.

Selinexor, an oral exportin 1 inhibitor potentially targeting both JAK/STAT and non-JAK/STAT pathways, has previously demonstrated efficacy when used in combination with ruxolitinib (Jakafi) in the phase 1/3 SENTRY trial (XPORT-MF-034; NCT04562389). Results from the phase 1 portion of the trial showed a 35% or greater reduction in spleen volume (SVR35) at weeks 12 and 24 in 71% and 79% of patients treated with 60 mg of selinexor plus ruxolitinib in the intention-to-treat (ITT) population (n = 14), respectively. Moreover, 58% of patients who achieved symptom improvement of at least 50% (TSS50) at week 24 in the ITT population (n = 12) remained in response at the data cutoff of August 1, 2023.

fast track designation to single-agent selinexor 

for the treatment of patients with myelofibrosis, including primary myelofibrosis, post-essential thrombocythemia myelofibrosis, and post-polycythemia vera myelofibrosis.

Selinexor will be evaluated in combination with ruxolitinib in the phase 3 portion of SENTRY and as monotherapy in the phase 2 SENTRY-2 study (XPORT-MF-044; NCT05980806) in JAK inhibitor–naive patients with myelofibrosis.

“The big thing that differentiates the [SENTRY-2] study is that it’s testing selinexor [alone] and only adding the JAK inhibitor [to selinexor] when it is needed, and it matches the patients’ characteristics. It’s not a one-size-fits-all study,” said Scandura, who is an associate attending physician at NewYork-Presbyterian Hospital and an associate professor of medicine at Weill Cornell Medical College, Cornell University, in New York. “This allows patients to be treated similarly to clinical practice in the context of a clinical trial…and allows us to [learn whether] one of these drugs works much better with selinexor than the other.”

, Scandura discussed selinexor’s mechanism of action, reviewed clinical data supporting its potential use both alone and in combination with JAK inhibitors in myelofibrosis, and highlighted how approval of this agent as monotherapy could help alleviate financial burdens associated with JAK inhibitor–based regimens.

: What is unique about selinexor’s mechanism of action?

: Selinexor is an exportin-1 inhibitor. This is a class of proteins that [function as] gatekeepers of the nucleus, and what gets into or out of the nucleus of a cell. Many signaling factors ultimately have to communicate from the cell surface to the nucleus to decide what genes to turn on or turn off. The exportin-1...prevents some of that signaling from getting to the nucleus where it can act. [This mechanism of action] is not just restricted to myelofibrosis, but to all cancer cells. There’s often a lot more signaling going on, and these cells are a bit messed up, so they require certain signals to survive or have their cancerous phenotype. [Accordingly], they’re a bit more dependent on this than normal cells.

Exactly which signals are being blocked by a drug like selinexor is only partially known. We do think that the JAK/STAT pathway is quite important in [the pathogenesis] of myeloproliferative neoplasms [MPNs]. That pathway requires STAT proteins to get into the nucleus and interact with other regulatory factors that switch genes on and off. [With agents like selinexor], that gets blocked, along with a lot of other things that can be abnormally elevated. The consequence of that is turning off some of the cytokine signaling which leads to the inflammatory phenotype in myelofibrosis. Some of the cellular proliferation going on there leads to abnormal blood cell production.

What previously reported data have been seen with selinexor?

The drug has been around for a while. It was originally developed [based on] the general idea that it should do something against cancer cells that are dependent upon this abnormal signaling going in and out of the nucleus. [Therefore], it was developed in a couple of different diseases, including acute myeloid leukemia [AML]. As is often the case, we thought [the drug] might work in clinical practice, but it didn’t work that well in AML, at least in the way those original studies were done. However, [selinexor] was subsequently found to have potent activity in multiple myeloma. The drug was then developed and approved [by the FDA] for treatment of [patients with] multiple myeloma. Based on some of its activity and understanding of its mechanism of action, we thought that it could work in myelofibrosis as well.

A couple of studies were conducted in myelofibrosis. One of them was for people who had been on ruxolitinib but did not achieve an optimal response. In that instance, the idea was to add selinexor to ruxolitinib. Most of those people were [given] a low dose of ruxolitinib. What was surprising to everybody was [that this combination] seemed to work quite well. There was a very strong symptom response in these patients as well as SVR which is, for better or for worse, a primary end point in a lot of these clinical trials. [Between] 50% and 80% of patients were meeting these benchmarks for response in a group of patients that were not responding adequately to a lower dose of ruxolitinib by itself. Then there was a single-agent study. Both studies have smaller [study populations], but when you have big numbers in terms of response, [the efficacy outcomes] are more believable. As a single agent, approximately 40% of patients had objective evidence of response, which is in line with what we see with JAK inhibitors by themselves. [Selinexor] looked like it had good activity both in combination with a JAK inhibitor like ruxolitinib even at a very low dose, and by itself. 

Why is it important for clinical trials to consider and attempt to address financial burdens associated with therapy?

Cancer drugs are expensive, and many patients already have a hard time with getting insurance approval for JAK inhibitors, or they get approval, and the copay is too high. Because these drugs have high costs, there’s scrutiny over the [insurance] approval, and depending on the insurance, it can become prohibitively expensive from a copay standpoint. When you’re looking at combinations of drugs it can be worrisome, because now you don’t have just 1 expensive drug, you have 2 expensive drugs. It can reach a point where, although this is a great combination, it’s not available to patients for financial reasons. When you have a single agent [with] activity you can avoid that additional complication. The single-agent activity of selinexor is interesting and [serves as] the motivation for the SENTRY-2 study.

What is the study design and methodology of SENTRY-2? How does the study account for the use of JAK inhibitors in current clinical practice?

This is an early-phase study, and the goal is to test how well selinexor works as monotherapy in patients with myelofibrosis who have not already been treated with a JAK inhibitor. From the FDA standpoint, JAK inhibitors are the only approved class of drugs in myelofibrosis. If patients require therapy, the FDA feels that they should be treated with a JAK inhibitor as the approved class before a clinical trial. That makes it hard to learn whether these [other] drugs can work by themselves. There’s now enough evidence that selinexor has some activity, so the FDA allowed this study to be developed. Patients will be started on this trial with selinexor. If they achieve a response based upon SVR and symptom improvement, [particularly] whether anemia improves, that’s all they would get.

The clever thing about this study is that, for example, [if a patient experiences] some degree of response, but it’s not very strong, this study allows you to add a JAK inhibitor to selinexor. This is not just ruxolitinib, which is our oldest and most familiar friend from the JAK inhibitor [family], but also the newer agents that are approved [for] slightly different indications. For instance, pacritinib [Vonjo] is known to not suppress platelet count, so that’s a great drug to use for patients who have low platelet count. Momelotinib [Ojjaara] is good [at] improving anemia in many patients. In this study, if patients are anemic and have adequate platelet counts] above 50,000 [platelets/mcL], they would have momelotinib added [to selinexor]. If they didn’t have an adequate response to selinexor itself, or if they had a platelet count under 50,000 [platelets/mcL] then they would get pacritinib. If they had very good counts, and did not have anemic platelets above 50,000 [platelets/mcL], then they would receive ruxolitinib.

Ultimately, the FDA is concerned is about toxicity in clinical trials. They want rigorous science. To convince them that a new drug is going to potentially be better [than the current standard] we need the early-phase studies to show some preliminary signals, but we mostly have to show that the drug is safe. Now that selinexor is an [FDA-]approved drug, there’s a lot of [evidence showing that it] is a safe drug to use. The question is: how can we use this drug most effectively? This study is very forward-looking, because it’s not just married to ruxolitinib or what is potentially a cost prohibitive combination therapy. It [reflects] the reality [of myelofibrosis treatment] now. If [single-agent] selinexor is eventually approved [by the FDA] for myelofibrosis, given that we have multiple JAK inhibitors and also have these financial considerations, we might be able to find a place for selinexor in a much more complicated environment than what existed when ruxolitinib was approved.

Given the agent’s FDA fast track status, could a potential approval prior to full accrual affect timelines for the SENTRY and SENTRY-2 trials? How might these trials inform the agent’s use in clinical practice if approved?

I don’t think so. There are 2 studies that Karyopharm, the company that makes selinexor, is developing in myelofibrosis. After these early-phase studies, they spoke to the FDA. Given the high response rates [achieved with selinexor in these studies], the FDA allowed them to move to the large phase 3 [SENTRY] study, which is a combination study. Ruxolitinib is a standard of care, at least for certain patients. What [the trial is] going to do is [randomly assign] one-third of the patients onto the ruxolitinib arm and have the remainder [treated with] the combination of selinexor plus ruxolitinib. The hope there is that we will learn [whether] selinexor plus ruxolitinib improves response rates while being safe compared with ruxolitinib by itself. This is a strategy that’s been used by a couple other companies that have also been trying to develop combination therapy.

If [SENTRY] hits both of its end points of symptom improvement and SVR35 and TSS50, the FDA would likely look favorably on that. [However], the [question is] who’s going to pay for it in the end, and is there enough of a benefit for insurers to pay for 2 expensive drugs instead of 1? We will only learn that once one of these combinations is approved. I personally believe that even if selinexor were approved, it’s likely to be more heavily used as a single agent. That’s where the SENTRY-2 study comes in. We’re going to get more information about how to use it as a single agent, what dose to use, and whether it combines well with a JAK inhibitor other than ruxolitinib. This study is going to be very helpful [for navigating the] real-world use of selinexor, if it proves to be effective.

What is your main message for colleagues regarding current and future research directions in myelofibrosis?

There’s still often a belief in the community that some of these diseases are junior cancers; for example, myelofibrosis is an MPN, and MPNs are the mild cancers that [have generally good prognosis]. That’s a misunderstanding when it comes to myelofibrosis. If you look at myelofibrosis and you compare it to what everybody would agree are cancers of concern, the [duration of] survival for myelofibrosis is much shorter than it is for early-stage breast cancer, early-stage colorectal cancer [CRC], early-stage prostate cancer, and so on. There’s a need to recognize the morbidity and, frankly, mortality of these diseases for many patients. Right now, the FDA struggles with how to evaluate these drugs. The thought is—though I’m not personally convinced it’s correct—that, at least in myelofibrosis, we can’t run studies looking at survival because it’s too hard to get enough patients to evaluate that rigorously and statistically. That’s why we have these proxy end points, which are SVR and symptom reduction. One of those [end points] is important, as it makes patients feel better. To me, SVR is more debatable. The overall point is that these are real cancers that are taking people’s lives, and we would very much like to find drugs that can prolong life. [Our goal is to improve overall survival] as we search for drugs in prostate, breast, CRC, and lung cancer, and we need to have that same mindset in myelofibrosis.

Mascarenhas J, Maher KR, Rampal R, et al. Phase 3 randomized double-blind study evaluating selinexor, an XPO1 inhibitor, plus ruxolitinib in JAKi-naïve myelofibrosis. 

2024;42(suppl 16):TPS6594. doi:10.1200/JCO.2024.42.16_suppl.TPS6594

Karyopharm reports fourth quarter and full year 2023 financial results and highlights recent company progress. News Release. Karyopharm Therapeutics. February 29, 2024. Accessed October 10, 2024. https://www.prnewswire.com/news-releases/karyopharm-reports-fourth-quarter-and-full-year-2023-financial-results-and-highlights-recent-company-progress-302074918.html

Karyopharm receives FDA fast track designation for selinexor for the treatment of myelofibrosis. News release. Karyopharm Therapeutics. July 17, 2023. Accessed October 10, 2024. https://investors.karyopharm.com/2023-07-17-Karyopharm-Receives-FDA-Fast-Track-Designation-for-Selinexor-for-the-Treatment-of-Myelofibrosis

SENTRY-2 (XPORT-MF-044): a phase 2 study to evaluate the efficacy and safety of selinexor monotherapy in patients with JAKi-naïve myelofibrosis and moderate thrombocytopenia (NCT05980806). Karyopharm Therapeutics. Accessed October 10, 2024. https://www.karyopharm.com/wp-content/uploads/2024/05/09_US-PIPE-11-23-00003_SENTRY-2_Trial_Card_Digital.pdf

Articles

Joseph M. Scandura, MD, PhD, discusses the importance of research with single-agent selinexor in JAK inhibitor–naive myelofibrosis. 

Selinexor Paves the Way for More Affordable, Effective Treatment Options in Myelofibrosis

John Mascarenhas, MD, discusses the use of selinexor with ruxolitinib in JAK inhibitor–naive myelofibrosis, highlighting the phase 2 XPORT-MF-044 trial

Dr Mascarenhas on the Use of Selinexor in Myelofibrosis

John Mascarenhas, MD, professor, medicine, Icahn School of Medicine, Mount Sinai, director, Center of Excellence for Blood Cancers and Myeloid Disorders, member, The Tisch Cancer Institute, Mount Sinai, discusses the use of selinexor in patients with JAK inhibitor–naive myelofibrosis, highlighting the phase 2 XPORT-MF-044 trial (NCT05980806) evaluating the safety and efficacy of selinexor monotherapy in this patient population.

Selinexor is indicated for use in patients with various hematologic malignancies, 

, Mascarenhas begins. In the context of myelofibrosis, however, the agent has been developed at a lower dose administered less frequently, once a week rather than the twice-weekly dosing schedule for patients with multiple myeloma, he says. Initial phase 1 data from the XPORT-MF-034 trial (NCT04562389) of selinexor plus ruxolitinib (Jakafi) in patients with myelofibrosis, especially in the JAK inhibitor–naive setting in combination regimens, 

 of the agent, particularly regarding spleen and symptom improvement, Mascarenhas emphasizes. Although the patient population was relatively small in this trial, the outcomes are still impressive, and show benefits with selinexor in the form of deep responses, safety, and tolerability, he adds.

The agent is now advancing into the phase 3 portion of the XPORT-MF-034 study, which is currently recruiting and builds upon the combination approach that has shown efficacy with other drugs, Mascarenhas expands. Despite the encouraging aspects of this combination and trial design, it is essential to acknowledge the expected toxicities associated with selinexor, notably potential gastrointestinal issues, dysgeusia, and myelosuppression, he emphasizes. Monitoring these potential AEs will be crucial as the drug progresses through development. Mechanistically, selinexor aligns with relevant pathways in myelofibrosis, including XPO1 inhibition and activation of proteins within the JAK/STAT signaling pathways, along with non-signaling pathways like p53, which play a pivotal role in mediating NSC-34 cell survivability, Mascarenhas says.

Selinexor has also been evaluated as a monotherapy in in patients with JAK inhibitor–naive myelofibrosis and moderate thrombocytopenia in the XPORT-MF-044 trial. Although the agent exhibits activity as a monotherapy, the preferred strategy for its development involves combination approaches, he continues. Combining selinexor with other drugs, whether upfront or as a salvage therapy for suboptimal responders, seems to offer a balanced approach between efficacy and safety, Mascarenhas imparts. Different treatment strategies, such as starting with one approach and potentially pivoting to salvage therapy with another drug, can be complementary, he notes. The ongoing XPORT-MF-034 study and the exploration of various combination approaches highlight the promising trajectory of selinexor in myelofibrosis management, Mascarenhas concludes.

The XPO1 inhibitor selinexor is under investigation as monotherapy in patients with JAK inhibitor–naive myelofibrosis and moderate thrombocytopenia in the phase 2 XPORT-MF-044 (NCT05980806) and in combination with the JAK inhibitor ruxolitinib (Jakafi) in the phase 3 XPORT-MF-034 (NCT04562389) trials, respectively.

Myelofibrosis is associated with underlying biological characteristics including cytokine production and inflammation; aberrant bone marrow and blood differentiation; extramedullary hematopoiesis; and bone marrow fibrosis.

 JAK inhibitors provide limited efficacy against the underlying drivers of myelofibrosis, and often do not prevent disease progression or induce disease modification, such as alterations in bone marrow fibrosis or inflammation.2 Furthermore, treatment options are limited for patients with thrombocytopenia who often receive suboptimal doses of ruxolitinib that results in suboptimal spleen and/or symptom reduction.

Selinexor is an oral XPO1 inhibitor with anti-inflammatory and pro-apoptotic properties that may affect JAK and non-JAK pathways.3 “Mechanistically, [the drug] makes a lot of sense,” John O. Mascarenhas, MD, said in an interview with 

. “[Selinexor] hits a lot of the pathways that are relevant to the disease, including XPO1 inhibition and the proteins that exist within the JAK/STAT signaling pathways. Related pathways are activated, [as well as] non-signaling pathways, such as p53, which are important players in mediating myelofibrosis CD34-positive cell survivability.” Mascarenhas is a professor of medicine at the Icahn School of Medicine at Mount Sinai, director of the Center of Excellence for Blood Cancers and Myeloid Disorders, and a member of the Tisch Cancer Institute, where he directs the Adult Leukemia Program and leads clinical investigations within the Myeloproliferative Disorders Program.

The phase 1 analysis of the XPORT-MF-034 trial showed that 79% of patients (n = 11/14) with JAK inhibitor–naive myelofibrosis who received selinexor at 60 mg plus ruxolitinib achieved spleen volume reduction of at least 35% (SVR35) from baseline, and 58% of patients (n = 7/12) achieved total symptom score reduction of at least 50% (TSS50) from baseline at week 24.4 The most common adverse effects (AEs) observed in the study were nausea (78.6%), fatigue (57.1%), anemia (64.3%), and thrombocytopenia (64.3%), most of which were grade 1/2. Two patients experienced treatment-related AEs leading to treatment discontinuation, 1 with thrombocytopenia and 1 with neuropathy.

“There is expected toxicity with this drug, potential gastrointestinal [GI] toxicity, dysgeusia, asthenia, and myelosuppression,” Mascarenhas noted. “Those are things we’ll have to keep an eye on that could be vulnerabilities of the drug. But the initial data look encouraging from a balancing act of deep responses, safety, and tolerability.”

The 2-arm, sequential, multicenter, open-label, phase 2 XPORT-MF-044 trial is evaluating the efficacy and safety of selinexor monotherapy followed by an optional JAK inhibitor add-on medication in 58 to 118 patients with JAK inhibitor–naive myelofibrosis with moderate thrombocytopenia.3 The multicenter, randomized, double-blind, placebo-controlled, global phase 3 component of XPORT-MF-034 is evaluating the efficacy of selinexor plus ruxolitinib in 300 to 450 patients with JAK inhibitor–naive myelofibrosis.

“[Selinexor] has activity as a monotherapy, [but] I don’t think that’s the best strategy for the drug to be developed,” Mascarenhas emphasized. “For most drugs on the near horizon that are being developed, [they need to be developed] in combinations. That’s where you get the best balance between efficacy and safety…Different strategies can be complementary, where you might start with 1 [drug], then you might pivot to salvage with another drug. Ruxolitinib might end up being the backbone of these combination approaches.”

Across both trials, patients at least 18 years of age will be included if they have primary myelofibrosis, post-essential thrombocythemia myelofibrosis, or post-polycythemia vera myelofibrosis; measurable splenomegaly, defined as spleen volume of at least 450 cm3 by MRI or CT scan; active myelofibrosis symptoms, defined as the presence of 2 or more symptoms with a score of at least 3 or a total score of at least 10 using the Myelofibrosis Symptom Assessment Form v4.0 at screening; a Dynamic International Prognostic Scoring System (DIPSS) score of intermediate-1 with symptoms, intermediate-2, or high-risk; and an ECOG performance status of 0 to 2.

In XPORT-MF-044, patients must have platelet counts of 50 to less than 100 x 109/L without platelet transfusion, whereas in XPORT-MF-034, platelet counts must be at least 100 x 109/L without platelet transfusion.

Patients will be excluded if they are a candidate for stem cell transplantation; have greater than 10% blasts in the peripheral blood or bone marrow; have received previous treatment with JAK inhibitors for myelofibrosis; have previously received selinexor or other XPO1 inhibitors; have impaired GI function or GI disease that could significantly alter selinexor absorption; have undergone major surgery less than 28 days before day 1 of cycle 1; have undergone prior splenectomy or splenic radiation within 6 months before day 1 of cycle 1; or are unable to tolerate 2 forms of antiemetics.

In XPORT-MF-044, patients will initiate selinexor treatment at either 60 mg once weekly (n = 29) or 40 mg once weekly (n = 29) and will be required to receive supportive care in the form of dual antiemetics for nausea prophylaxis during the first 2 cycles.3 Patients who do not reach an SVR of over 10% at week 12 or over 35% at week 24 will receive an optional JAK inhibitor add-on medication. These patients will receive ruxolitinib if their platelet counts are at least 50 x 109/L and their hemoglobin levels are greater than 10 g/dL or less; pacritinib (Vonjo) if their platelet counts are less than 50 x 109/L; or momelotinib (Ojjaara) if their platelet counts are at least 50 x 109/L and their hemoglobin levels are less than 10 g/dL.

The primary end point of XPORT-MF-044 will be SVR35 at week 24. Secondary end points include safety; TSS50 at week 24; anemia response at week 24; overall survival (OS); overall response rate (ORR); SVR35 and TSS50 at any time; SVR35 and TSS50 by prespecified subgroups; SVR35, TSS50, and safety with add-on treatment; pharmacokinetics and pharmacodynamics; and bone marrow fibrosis. Exploratory end points include duration of response (DOR), progression-free survival (PFS), platelet counts, variant allele frequency changes (VAF) changes, patient-reported outcomes (PROs) in the form of patient global impression of change (PGIC), selected biomarker changes, and transfusion independence.

In XPORT-MF-034, patients will be randomly assigned 2:1 to receive either ruxolitinib twice daily plus selinexor at 60 mg once weekly in 28-day cycles or twice-daily ruxolitinib plus placebo.5 Both arms will be required to receive supportive care in the form of dual antiemetics for nausea prophylaxis during the first 2 cycles. The ruxolitinib doses will be based on patient platelet counts per the ruxolitinib prescribing information. Patients will also be stratified by DIPSS risk category (intermediate-1 vs intermediate-2 vs high-risk), spleen volume (< 1800 cm3 vs > 1800 cm3), and baseline platelet counts (100-200 x 109/L vs >200 x 109/L).

“You don’t need full doses of ruxolitinib to potentiate the effect of this combination approach,” Mascarenhas added. “You can offset toxicity with the JAK inhibitor and synergize, even at low doses, with some [other] agents.”

SVR35 at week 24 and TSS50 at week 24 will serve as the coprimary end points of XPORT-MF-034 phase 3 trial. Anemia response at week 24 will be a key secondary end point. Additional secondary end points will include safety, OS, ORR, SVR35 and TSS50 at any time, SVR35 and TSS50 by prespecified subgroups, pharmacokinetics, and bone marrow fibrosis. Exploratory end points will include DOR, PFS, VAF changes, PROs in the form of PGIC and EuroQoL 5-dimensional instrument 5 levels (ED-5D-5L), selected biomarker changes, transfusion independence, and ruxolitinib pharmacokinetics.

“We’re trying to figure out a lot of the biology and mechanism [of selinexor] and whether there are certain patient populations that are better served in this regard,” Mascarenhas concluded.

Both XPORT-MF-044 phase 2 trial and XPORT-MF-034 phase 3 trial are open for enrollment.

O'Sullivan JM, Harrison CN. Myelofibrosis: clinicopathologic features, prognosis, and management. 

Levavi H, Hoffman R, Marcellino BK, et al. JAK inhibitors in the treatment of myelofibrosis. 

Scandura JM, Gerds AT, Ritchie EK, et al. A phase 2 study to evaluate the efficacy and safety of selinexor monotherapy in patients with JAK inhibitor-naïve myelofibrosis and moderate thrombocytopenia (XPORT-MF-044). 

. 2023;142(suppl 1):3211. doi:10.1182/blood-2023-181720

Ali H, Kishtagari A, Maher KR, et al. Selinexor (SEL) plus ruxolitinib (RUX) in JAK inhibitor (JAKi) treatment-naïve patients with myelofibrosis: updated results from XPORT-MF-034. 

. 2023;41(suppl 16):7063. doi:10.1200/JCO.2023.41.16_suppl.7063

Maher K, Rampal RK, Bose P, et al. A global, phase 3, randomized, double-blind study to evaluate safety and efficacy of selinexor, an XPO-1 inhibitor, in combination with ruxolitinib in JAK inhibitor-naïve myelofibrosis (XPORT-MF-034). 

. 2023;142(suppl 1):3209. doi:10.1182/blood-2023-180695

Selinexor is under investigation as monotherapy and in combination with the JAK inhibitor ruxolitinib in patients with JAK inhibitor–naive myelofibrosis.

Investigators Set to Explore Selinexor Monotherapy or Plus Ruxolitinib in JAK Inhibitor–Naive Myelofibrosis 

Dr Tantravahi on the Efficacy of Selinexor Plus Ruxolitinib in JAK Inhibitor–Naive Myelofibrosis  

Srinivas K. Tantravahi, MBBS, MRCP, hematologist, the University of Utah Huntsman Cancer Institute, discusses the preliminary efficacy of selinexor (Xpovio) in combination with ruxolitinib (Jakafi) in patients with JAK inhibitor–naive myelofibrosis, as evaluated in the phase 1/3 XPORT-MF-034 trial (NCT04562389).

The open-label XPORT-MF-034 study assessed the safety and efficacy of the oral, highly selective XPO1 inhibitor selinexor at 40 mg and 60 mg in combination with ruxolitinib, Tantravahi begins. Among the 14 patients who received the 60 mg dose of weekly selinexor, the majority had intermediate-2 to high-risk disease, he notes.

Findings from the 60 mg selinexor cohort which were presented at the 2023 ASH Annual Meeting showed that the combination had a manageable safety profile and produced encouraging signals of both durable spleen volume reduction (SVR) and symptom improvement in patients with JAK inhibitor–naive myelofibrosis, Tantravahi reports. The median time to both spleen and symptom response was 12.1 weeks, and the probability that patients would have achieved an SVR was 100% at a median follow-up duration of 32 weeks (range, 12-78). Furthermore, it was anticipated that 100% of these patients will maintain a total symptom score (TSS) response at a median follow-up of 51 weeks (range, 12-64).

SVR of 35% or greater (SVR35) and TSS improvement of 50% or more improvement (TSS50) with selinexor plus ruxolitinib was also evaluated in the study. At week 24, the SVR35 rate was 92% in the efficacy-evaluable population and 79% in the intent-to-treat patient population, Tantravahi states. The TSS50 was also favorable, with rates of 78% and 58% in these respective populations.

These responses were found to be encouraging compared with historical response rates seen with single-agent JAK inhibitors, Tantravahi notes. In turn, these data support further investigation of the 60 mg dose of selinexor plus ruxolitinib vs placebo with ruxolitinib in the ongoing, randomized phase 3 portion of XPORT-MF-034, Tantravahi concludes.

Srinivas K. Tantravahi, MBBS, MRCP, discusses the preliminary efficacy of selinexor in combination with ruxolitinib in patients with JAK inhibitor–naive myelofibrosis, as seen in the phase 1 XPORT-MF-034 trial.

Dr Tantravahi on the Efficacy of Selinexor Plus Ruxolitinib in JAK Inhibitor–Naive Myelofibrosis

Dr Mascarenhas on the Potential Utility of Selinexor Plus Ruxolitinib in Myelofibrosis

John Mascarenhas, MD, professor of medicine, Icahn School of Medicine, Mount Sinai, director, Center of Excellence for Blood Cancers and Myeloid Disorders, member, the Tisch Cancer Institute, Mount Sinai, discusses the potential advantages of utilizing selinexor (Xpovio) with ruxolitinib (Jakafi) in patients with JAK inhibitor–naive myelofibrosis.

The rationale behind combining the investigational oral XPO1 inhibitor selinexor with the JAK inhibitor ruxolitinib lies in the potential synergy between the 2 drugs, which is achieved through leveraging their overlapping pathways, Mascarenhas begins.

Preclinical data have indicated the potential synergy between selinexor and ruxolitinib, Mascarenhas states. Additionally, data from a phase 1 trial (NCT04562389), which were presented at the 2023 ASH Annual Meeting, demonstrated early signals of clinical activity with selinexor and ruxolitinib in JAK inhibitor–naive patients, including promising spleen volume reduction rates and total symptom score reduction. Furthermore, early data have also shown that patients receiving low-dose ruxolitinib still experience significant spleen and symptom responses, Mascarenhas adds. This suggests that full doses of ruxolitinib may not be necessary to enhance the effectiveness of the combination approach, he explains.

Similar findings have been observed with other ruxolitinib-based combination therapies, Mascarenhas continues. For example, treatment with the second-generation MDM2 inhibitor navtemadlin (KRT-232) plus low doses of ruxolitinib produced deep responses while mitigating toxicity, he details. This indicates the potential to achieve meaningful therapeutic effects with lower doses of JAK inhibitors in combination with certain agents, Mascarenhas says.

These positive outcomes supported the initiation of the phase 3 XPORT-MF-034 (NCT04562389) trial. In this global, randomized, placebo-controlled study, patients with JAK inhibitor–naive myelofibrosis will be randomly assigned in a 2:1 ratio to receive either oral selinexor at 60 mg or placebo once a week alongside twice-daily ruxolitinib. The study will further elucidate the combination’s therapeutic benefit in this patient population. XPORT-MF-034 phase 3 trial is currently open for enrollment.

Although knowledge and understanding of the underlying biology, mechanisms, and optimal patient populations for such combinations is still evolving, these early signals highlight the potential to enhance efficacy while managing toxicity through strategic drug combinations, Mascarenhas emphasizes. Further research is needed to unravel the complexities of these interactions and identify specific patient subsets that may benefit most from ruxolitinib-based approaches, he concludes.

John Mascarenhas, MD, discusses the potential advantages of utilizing selinexor with ruxolitinib in patients with JAK inhibitor–naive myelofibrosis.

The Importance of Evaluating Selinexor in JAK Inhibitor–Naive Myelofibrosis

Dr Gerds on the Importance of Evaluating Selinexor in JAK Inhibitor–Naive Myelofibrosis

Aaron Gerds, MD, assistant professor in medicine, Hematology and Medical Oncology, Cleveland Clinic Taussig Cancer Institute, discusses the importance of evaluating the efficacy and safety of selinexor (Xpovio) in patients with JAK inhibitor–naive myelofibrosis, as assessed in the phase 1/3 XPORT-MF-034 trial (NCT04562389).

Selinexor, a selective inhibitor of nuclear export, is an active agent that has already been studied in the treatment of various hematologic malignancies, Gerds begins. Due to the agent’s adverse effect profile, it is believed to synergize well with ruxolitinib (Jakafi) in this context, he states. Several trials are ongoing in myelofibrosis evaluating selinexor that have produced promising phase 1 and phase 2 data that have since been shared at various international congresses, Gerds emphasizes. Notably, the dosing schedule for the novel agent in myelofibrosis differs from that inmultiple myeloma and is intended to mitigate the cytopenias and associated toxicities that can limit the agent’s use.

Numerous prospective trials are underway, such as the XPORT-MF-034 study, which was discussed at the 

, Gerds expands. The study, which is investigating the combination of ruxolitinib plus selinexor vs ruxolitinib and placebo,aims to extend the activity of frontline treatment strategies to more patients with myelofibrosis, he states. Data from the phase 1 portion of the study showed that selinexor when combined with ruxolitinib had encouraging signals of durable spleen volume response.

Notably, the concept of combination therapy in the upfront setting has become a reality. Recent findings presented at the 2023 ASH Annual Meeting showcase positive results from studies exploring various agents in the frontline setting, marking a pivotal moment in the transition from JAK inhibitor monotherapy to combination therapies, Gerds explains.

Although JAK inhibitors have revolutionized myelofibrosis care, significant strides are needed to enhance patients’ quality and duration of life, he states. The rapid integration of combination therapy into the frontline setting, bypassing the second-line and relapsed/refractory disease stages, represents an advancement for the field and a strategic move likely to benefit patients in the long term, Gerds concludes.

Aaron Gerds, MD, discusses the importance of evaluating the efficacy and safety of selinexor in patients with JAK inhibitor–naive myelofibrosis, as assessed in the phase 1/3 XPORT-MF-034 trial.


The oral XPO1 inhibitor selinexor in combination with ruxolitinib (Jakafi) was associated with a tolerable and manageable adverse effect (AE) profile and elicited signals of clinical efficacy in patients with JAK inhibitor–naive myelofibrosis, according to data from the phase 1/3 XPORT-MF-034 trial (NCT04562389) presented at the 

In an evaluation of 14 patients, the median time to both spleen and symptom response was 12.1 weeks on the study. At a median duration follow-up of 32 weeks (range, 12-78), it is a 100% probability that these patients will have achieved a spleen volume response (SVR). At a median follow-up of 51 weeks (range, 12-64), 100% of these patients are expected to maintain total symptom score (TSS) response.

Investigators also evaluated SVR at 35% or greater (SVR35) and TSS at a 50% or more improvement (TSS50) with selinexor plus ruxolitinib. The SVR35 at week 24 was 92% in the efficacy-evaluable population and 79% in the intent-to-treat patient population; the TSS50 was 78% and 58%, respectively.

“Encouraging signals of durable SVR and symptom improvement were observed with selinexor at 60 mg weekly plus ruxolitinib,” Srinivas K. Tantravahi, MBBS, MRCP, of the University of Utah Huntsman Cancer Institute, said in an interview with 

Myelofibrosis is an advanced myeloproliferative neoplasm that, despite currently present treatment options, still has various unmet needs due to the overactive JAK/STAT pathway and activating mutations. Treatment options, such as JAK inhibitors including ruxolitinib (Jakafi), may present with limitations such as low response rates and non-durable responses, leading to worsening cases of cytopenia. Based on these unmet needs, further investigations into aggressive upfront treatment may enhance disease modification.

Selinexor is highly selective as it targets XPO1, which has the ability to target both the JAK/STAT and non-JAK/STAT pathways in myelofibrosis.

Based on preliminary evidence, as well as mouse model investigations, investigators have shown that selinexor decreases phosphorylation and other key downstream proteins, as well as increases 

-driven cell death, causing cell cycle arrest. These outcomes led to the investigation of this combination in JAK-naive patients with myelofibrosis.

Patients were eligible for enrollment if they presented with a spleen volume of 450 cm

 or greater by magnetic resonance imaging or computed tomography; a Dynamic International Prognostic Scoring System (DIPSS) score of intermediate-1 and symptomatic, as well as intermediate-2, or high risk; an ECOG performance statues of no more than 2; and a platelet count of 100 x 10

The investigation began with the phase 1a dose-escalation phase, wherein patients were treated with selinexor at 40 mg (n = 3) or 60 mg (n = 3) once weekly and ruxolitinib given at 15 or 20 mg twice daily. This then led to the phase 1b dose-expansion portion of the study of selinexor at 40 or 60 mg once weekly given with ruxolitinib (n = 18).

This has led to the ongoing, randomized phase 1/3 trial of 306 patients who will be randomly assigned 2:1 fashion to receive oral selinexor 60 mg once weekly with ruxolitinib vs placebo with ruxolitinib.

The data cutoff date was August 1, 2023, and investigators evaluated patients for safety, durability of the agent, and disease modification, as assessed by biomarkers.

The primary end points included establishing a maximum-tolerated dose or recommended phase 3 dose, as well as safety. Secondary end points included SVR35, TSS50, anemia response, and AEs.

Regarding baseline characteristics, the median age was 64.5 years (range, 58-77), 35.7% of patients were female, and the median weight of patients was 77.5 kg (range, 54.7-141.9). Furthermore, 92.9% of patients were transfusion independent and 7.1% were transfusion dependent; 50% of patients had primary myelofibrosis; 28.6% had post-essential thrombocythemia myelofibrosis; and 21.4% had post polycythemia vera myelofibrosis.

Regarding mutational statuses, 78.6%, 14.3%, 7.1%, and 35.7% of patients had 

, and high molecular risk mutations, respectively. A total 21.4% of patients had a DIPSS score of intermediate-1, while 57.1% and 21.4% had a DIPSS score of intermediate-2 or high risk.

Looking to hemoglobin at baseline, 57.1% of patients had a baseline hemoglobin of less than 10 g/dL and 85.7% of patients had a platelet count (10

/L) of 150 or greater. The median baseline spleen volume of patients was 1961.6 cm

 (range, 650.1-3657.0) and the mean baseline TSS was 21.6.

Investigators noted that in patients who received 5 mg or less twice daily of ruxolitinib in combination with 60 mg selinexor for at least 5 out of the first 6 cycles, spleen volume and symptom score reduction still occurred.

Investigators examined cytokine changes, as well, which showed that early decreases in proinflammatory cytokines observed by week 4 after selinexor plus ruxolitinib in evaluable patients were associated with SVR at week 24. Variant allele frequency was also measured at week 24 with both doses of selinexor plus ruxolitinib, which showed that reduced allele burden was observed in 13 evaluable patients, regardless of driver gene mutations.

A 20% or greater decrease in variant allele frequency was observed in 5 patients, 3 of which had a 50% or greater variant allele frequency at baseline and were high molecular risk. Notably, 13 of 24 patients had variant allele frequency values at baseline, and 11 of these 13 patients achieved SVR35 at any time.

Looking to safety, any-grade treatment-emergent adverse effects (TEAEs) to occur in patients treated with 60 mg of selinexor included nausea (78.6%), anemia (64.3%), thrombocytopenia (64.3%), fatigue (57.1%), constipation (50.0%), vomiting (50.0%), dyspnea (35.7%), headache (35.7%), hyponatremia (35.7%), leukopenia (35.7%), and neutropenia (35.7%). Nausea was transient with a median duration of 2 cycles. Sixty-four percent of patients received 1 prophylactic anti-emetic. In the subgroup that received 1 prophylactic anti-emetic, 67% of patients experienced nausea (grade 1 only) vs 100% of those without prophylactic anti-emetics who had nausea (grades 1-3).

Grade 3 or greater TEAEs reported were anemia (42.9%), thrombocytopenia (28.6%), back pain (14.3%), neutropenia (7.1%), atrial fibrillation (7.1%), and leukopenia (7.1%). Furthermore, treatment-related AEs that led to treatment discontinuations included 1 patient with grade 3 thrombocytopenia and 1 patient with grade 3 peripheral neuropathy.

“This is really encouraging and indicate that the combination treatment can be well tolerated, and patients can stay on treatment,” Tantravahi concluded.

Tantravahi SK, Kishtagari A, Maher K, et al. Selinexor plus ruxolitinib in JAK inhibitor (JAKi) treatment-naïve patients with myelofibrosis: long term follow up from XPORT-MF-034 suggestive of disease modification. 

. 2023;142(suppl 1):622. doi:10.1182/blood-2023-180844 

The oral XPO1 inhibitor selinexor in combination with ruxolitinib was associated with a tolerable and manageable adverse effect profile and elicited signals of clinical efficacy in patients with JAK inhibitor–naive myelofibrosis. 

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