Selinexor, an oral exportin 1 inhibitor, is emerging as a promising and potentially more affordable treatment option for myelofibrosis, addressing the need for personalized therapy and mitigating the financial toxicities associated with standard JAK inhibitor-based regimens. The agent is being investigated both as a monotherapy and in combination with ruxolitinib.
Selinexor's Mechanism of Action
Selinexor functions by inhibiting exportin-1, a protein that regulates the transport of molecules in and out of the cell nucleus. By blocking this protein, selinexor disrupts signaling pathways crucial for cancer cell survival and proliferation. Joseph M. Scandura, MD, PhD, associate attending physician at NewYork-Presbyterian Hospital, explained that this mechanism isn't restricted to myelofibrosis but affects cancer cells in general, which often rely on abnormal signaling for their survival.
Specifically, selinexor is thought to interfere with the JAK/STAT pathway, which is implicated in the pathogenesis of myeloproliferative neoplasms (MPNs). By preventing STAT proteins from entering the nucleus, selinexor can reduce cytokine signaling and the inflammatory phenotype characteristic of myelofibrosis.
Clinical Data and Ongoing Trials
Previous studies have demonstrated selinexor's efficacy in myelofibrosis, both as a single agent and in combination with ruxolitinib. In the phase 1/3 SENTRY trial (XPORT-MF-034; NCT04562389), the combination of selinexor and ruxolitinib achieved a spleen volume reduction of 35% or greater (SVR35) in 71% and 79% of patients at weeks 12 and 24, respectively. Moreover, 58% of patients experienced a symptom improvement of at least 50% (TSS50) at week 24.
Currently, selinexor is being evaluated in the phase 3 portion of the SENTRY trial in combination with ruxolitinib and as a monotherapy in the phase 2 SENTRY-2 study (XPORT-MF-044; NCT05980806) in JAK inhibitor–naive patients with myelofibrosis.
Addressing Financial Burdens
One of the key advantages of selinexor is its potential to reduce the financial burden associated with myelofibrosis treatment. Cancer drugs are often expensive, and the cost of combination therapies can be prohibitive for many patients. Selinexor's activity as a single agent offers an alternative that could be more accessible and affordable.
SENTRY-2 Study Design
The SENTRY-2 study is designed to evaluate selinexor monotherapy in patients with myelofibrosis who have not previously been treated with a JAK inhibitor. Patients are started on selinexor, and if they achieve a response based on SVR and symptom improvement, they continue with selinexor alone. However, the study also allows for the addition of a JAK inhibitor if the response to selinexor is not sufficient.
The choice of JAK inhibitor is tailored to the patient's individual characteristics. For example, patients with low platelet counts may receive pacritinib, while those with anemia may receive momelotinib. Patients with adequate platelet counts who do not have anemia may receive ruxolitinib.
Future Directions
While current endpoints for myelofibrosis drug evaluation focus on spleen volume reduction and symptom improvement, there is a growing recognition of the need to improve overall survival in patients with myelofibrosis. As Dr. Scandura notes, myelofibrosis survival rates are often shorter than those of early-stage breast, colorectal, or prostate cancer, highlighting the importance of developing therapies that can prolong life.
