Xpovio (selinexor)

We previously identified MDM2 as a therapeutic vulnerability in RTs and showed that treatment with the MDM2 inhibitor idasanutlin (IDA) increased survival in mice bearing MRT xenografts...We hypothesized that combining IDA with selinexor (SEL), a CNS penetrant XPO1 inhibitor, would potentiate p53-mediated activation and increase therapeutic response in vivo...The BCL-2 family of proteins was identified as key modulators of intrinsic and acquired resistance. Combining MDM2 inhibitors and XPO1 inhibitors is a promising therapeutic strategy for treating children with ATRT.

The combination strategy provides a novel potential approach for improving the therapeutic efficacy of sorafenib and overcoming both intrinsic and acquired sorafenib resistance in HCC. The main limitations of this study are the lack of RT-PCR verification and further detection of downstream apoptotic effector molecules, which need to be explored in future research.

P1, N=20, Recruiting, Washington University School of Medicine | Not yet recruiting --> Recruiting

P1/2, N=62, Not yet recruiting, Natalie Callander

Selinexor, the first-in-class, orally bioavailable selective inhibitor of exportin 1 (XPO1), has shown encouraging results in combination with other agents, and selinexor-based therapy has been approved for the treatment of relapsed/refractory MM, with selinexor-bortezomib-dexamethasone approved for patients with at least one prior line of therapy and selinexor-dexamethasone approved in the later-relapse setting. Overall, selinexor continues to represent a valuable option, especially for patients who are ineligible to receive T-cell-redirecting therapies, or difficult-to-treat patient subgroups, where alternative strategies remain limited. Meanwhile, further data on the use of selinexor-based combinations in different settings are eagerly awaited, to help clarify its role and address persistent unmet clinical needs.

Finally, both in vitro and in vivo experiments revealed that IVM and selinexor exhibited synergistic anti-MM activities. Overall, our study reveals the role of KPNA3 in MM and suggests that targeting its nuclear import is a promising MM treatment.

Preclinical studies showed a synergistic antileukemia activity with combination of selective XPO1 inhibitor selinexor (SEL) and venetoclax (VEN), with potential to overcome VEN resistance by reducing the anti-apoptotic protein MCL1. In conclusion, SEL-VEN was feasible and active in a heavily pretreated AML cohort, with no new toxicity signal, but survival outcomes remained poor. The second-generation XPO1-inhibitor eltanexor, combined with VEN may further improve outcomes in VEN resistant AML in an ongoing study (NCT06399640).

P2, N=57, Active, not recruiting, Wake Forest University Health Sciences | Trial completion date: Mar 2026 --> Feb 2027 | Trial primary completion date: Mar 2026 --> Feb 2027

These findings demonstrate O-GlcNAcylation-driven enhancement of nuclear export as a therapeutically actionable vulnerability in mesothelioma with inactivation of the Hippo pathway.

A greater proportion of patients achieved spleen volume reduction equal to or greater than 35% (SVR35) and total symptom score reduction equal to or greater than 50% (TSS50) at Week 24 in the 60-mg selinexor group (79% and 58%) compared with the 40-mg group (38% and 25%). Among evaluable patients who received suboptimal ruxolitinib ≤5 mg twice-daily in the selinexor 60-mg group, SVR35 was observed in 100% (6/6) of patients and TSS50 was observed in 75% (3/4) of patients.

P3, N=228, Recruiting, Qilu Pharmaceutical Co., Ltd. | Not yet recruiting --> Recruiting

P2, N=10, Active, not recruiting, The Children's Hospital of Zhejiang University School of Medicine