Selinexor Paves the Way for More Affordable, Effective Treatment Options in 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.^1,2

In July 2023, the FDA granted 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.³

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.⁴

“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.”

In an interview with OncLive^®, 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.

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

Scandura: 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.

References

1. 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. J Clin Oncol. 2024;42(suppl 16):TPS6594. doi:10.1200/JCO.2024.42.16_suppl.TPS6594
2. 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
3. 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
4. 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