Selinexor as a not only hematological drug but also with potential use in liposarcoma

What is it about?

Selinexor is a new compound studied for the treatment of liposarcoma, particularly dedifferentiated liposarcoma (DDLPS), where treatment options remain limited. As a first-in-class oral exportin-1 (XPO1) inhibitor, selinexor has shown anti-tumour activity in preclinical models, particularly in MDM2- and CDK4-amplified DDLPS, where it induces apoptosis, inhibits tumour growth and promotes nuclear retention of p53. Preclinical studies have also suggested potential synergy with doxorubicin and eribulin, although these findings have yet to be validated in randomised clinical trials. The phase II/III SEAL trial (NCT02606461) evaluated selinexor versus placebo in patients with advanced, previously treated DDLPS. While the study demonstrated a statistically significant, albeit modest, improvement in median progression-free survival (PFS) from 2.1 to 2.8 months, no overall survival benefit was observed. In addition, selinexor was associated with significant toxicity, including fatigue, nausea and weight loss. Similarly, a phase Ib/II study (NCT03042819) evaluating selinexor in combination with doxorubicin reported a 21% response rate and a median PFS of 5.5 months, although this regimen was also associated with high rates of neutropenia and fatigue. Despite these results, selinexor is not currently approved for the treatment of liposarcoma and its clinical utility remains under investigation. Ongoing studies, such as the SeliSarc trial (NCT04595994) evaluating selinexor in combination with gemcitabine and the NRSTS2021 trial (NCT06239272) evaluating selinexor in paediatric soft tissue sarcoma, aim to further define its role. The results of these studies will be critical in determining whether selinexor can be incorporated into standard sarcoma treatment.

Featured Image

Photo by Europeana on Unsplash

Photo by Europeana on Unsplash

Why is it important?

Selinexor is a new compound studied for the treatment of liposarcoma, particularly dedifferentiated liposarcoma (DDLPS), where treatment options remain limited. As a first-in-class oral exportin-1 (XPO1) inhibitor, selinexor has shown anti-tumour activity in preclinical models, particularly in MDM2- and CDK4-amplified DDLPS, where it induces apoptosis, inhibits tumour growth and promotes nuclear retention of p53. Preclinical studies have also suggested potential synergy with doxorubicin and eribulin, although these findings have yet to be validated in randomised clinical trials. The phase II/III SEAL trial (NCT02606461) evaluated selinexor versus placebo in patients with advanced, previously treated DDLPS. While the study demonstrated a statistically significant, albeit modest, improvement in median progression-free survival (PFS) from 2.1 to 2.8 months, no overall survival benefit was observed. In addition, selinexor was associated with significant toxicity, including fatigue, nausea and weight loss. Similarly, a phase Ib/II study (NCT03042819) evaluating selinexor in combination with doxorubicin reported a 21% response rate and a median PFS of 5.5 months, although this regimen was also associated with high rates of neutropenia and fatigue. Despite these results, selinexor is not currently approved for the treatment of liposarcoma and its clinical utility remains under investigation. Ongoing studies, such as the SeliSarc trial (NCT04595994) evaluating selinexor in combination with gemcitabine and the NRSTS2021 trial (NCT06239272) evaluating selinexor in paediatric soft tissue sarcoma, aim to further define its role. The results of these studies will be critical in determining whether selinexor can be incorporated into standard sarcoma treatment.

Perspectives