Selinexor's Endometrial Cancer Bet: Biological Signal Validated, but Statistical Failure Shuts Regulatory Door

No FDA-approved second-line standard of care exists, leaving clinicians to rely on agents with variable and often limited success once adjuvant chemotherapy fails.

Poor response rates to conventional systemic therapy (chemotherapy, targeted agents, hormonal therapy) in metastatic/recurrent disease highlight the need for novel mechanisms of action, including maintenance strategies such as the XPO1 inhibitor selinexor, which has shown potential benefit specifically in p53-wildtype endometrial cancer and is under prospective investigation.

Immune checkpoint inhibitors remain largely restricted by molecular subtype: pembrolizumab and dostarlimab are approved for previously treated dMMR/MSI-H disease, while pembrolizumab plus lenvatinib is approved for mismatch repair-proficient/microsatellite-stable tumours (including CN-high/p53abn and CN-low/NSMP subgroups)—leaving open questions about optimal immunotherapy sequencing and combinations for TP53 wild-type tumours outside these categories.

Targeted and antiangiogenic therapies (e.g., mTOR inhibitors, tyrosine kinase inhibitors such as anlotinib) show promise but are not yet standard, with efficacy signals (e.g., ORR 24.14%, DCR 55.17% for anlotinib monotherapy) often improved when combined with immunotherapy (DCR 75.00% vs. 30.76%; OS not reached vs. 12.5 months, HR 0.32), pointing to a need for further validation in TP53 wild-type populations specifically.

Molecular stratification is still evolving: real-world genomic testing reveals frequent PI3K (35.8%), TP53 (34.7%), and PTEN (26.5%) alterations, yet only a subset of patients (233 of 902 tested) currently receive matched biologic therapies, and while these show improved PFS (6.9 months) and OS (20.5 months) versus chemotherapy, broader integration of molecular tools into treatment algorithms for TP53 wild-type disease remains a work in progress.

Antibody-drug conjugates (e.g., trastuzumab deruxtecan) and combination immunotherapy-antiangiogenic approaches are being explored, but clinical trials are still needed to define how best to incorporate these novel agents into existing treatment paradigms for this molecularly distinct patient population.

Multiple Myeloma (MM): Selinexor is well-established in relapsed/refractory MM (RRMM). The pivotal Phase 3 BOSTON trial demonstrated that adding selinexor to bortezomib and dexamethasone resulted in a significantly longer median progression-free survival (PFS) compared to bortezomib and dexamethasone alone in patients with one to three prior lines of therapy. This led to approvals for this triplet regimen, which followed an earlier accelerated approval for selinexor plus dexamethasone in heavily pretreated, penta-refractory patients based on the Phase 2 STORM trial.

Other Hematologic Malignancies: In diffuse large B-cell lymphoma (DLBCL), the SADAL trial led to regulatory approval for selinexor. For high-risk myelodysplastic syndromes (MDS) or oligoblastic acute myeloid leukaemia (AML) refractory to hypomethylating agents, a Phase 2 trial showed an overall response rate of 26% with an additional 52% of patients achieving stable disease.

Sarcomas: The Phase 2/3 SEAL study evaluated selinexor in advanced dedifferentiated liposarcoma (DD-LPS). The trial met its primary endpoint, demonstrating a statistically significant improvement in PFS for selinexor versus placebo (HR 0.70; p=0.011). In advanced soft tissue sarcoma (STS), the Phase 1b METSSAR trial found that a split-dosing schedule (40 mg, 20 mg, 20 mg on days 1, 8, 15, and 22 of a 28-day cycle) was well-tolerated and resulted in a median PFS of 4.0 months.

Gynecologic Cancers: In a Phase 2 trial enrolling heavily pretreated patients with recurrent gynecologic malignancies, selinexor demonstrated clinical activity. For the 66 patients with ovarian cancer (median 6 prior regimens), the disease control rate (DCR) was 30% with a median PFS of 2.6 months. In the 25 patients with cervical cancer (median 3 prior regimens), the DCR was 24% with a median PFS of 1.4 months.

Other Solid Tumors: Selinexor has been investigated in thymic epithelial tumors, though two parallel Phase 2 trials were halted due to low overall response rates. Preclinical and early clinical studies have also suggested efficacy in a variety of other solid tumors, including glioblastoma multiforme (GBM), lung cancer, and triple-negative breast cancer, warranting further clinical investigation in these areas.