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Selinexor (KPT-330) in Combination with Immune Checkpoint Inhibition in Uveal Melanoma: A Phase 1B Trial
Mohamed A Gouda1, Abdulrazzak Zarifa1, Yali Yang1
1Department of Investigational Cancer Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
Introduction:
Uveal melanoma remains a disease with aggressive behavior and poor prognosis despite advances in clinical management. Because monotherapy with immune checkpoint inhibitors has led to limited improvement in response rates, combination with other agents that act on the biological basis of oncogenesis has been proposed as a possible therapeutic strategy.
Methods:
We designed a phase 1b trial to test the safety and tolerability of selinexor in combination with immune checkpoint inhibitors in patients with advanced uveal melanoma. Patients received selinexor 60 mg PO twice weekly with standard of care, commercially available immune checkpoint inhibitor of the investigator's choice. In one patient receiving nivolumab and ipilimumab as the immunotherapy backbone, selinexor 60 mg PO was given once weekly.
Results:
We included 10 patients with uveal melanoma who received treatment with either selinexor plus pembrolizumab (n = 9) or selinexor plus nivolumab and ipilimumab (n = 1). The most common adverse events of any grade were neutropenia, thrombocytopenia, leukopenia, and anemia. Additional common nonhematological toxicities included hyponatremia, nausea, and vomiting. Dose reductions were required in six patients (60%). Among nine patients with evaluable disease, eight had stable disease as the best response. The median progression-free and overall survival were 6 months (95% CI: 4, not reached and 17 months (95% CI: 7, not reached), respectively.
Conclusion:
The combination of selinexor and immunotherapy was safe and showed a side effect profile consistent with previous reports. Clinical benefit was achieved in most patients and should be validated in larger phase 2 trials. ClinicalTrials.gov ID: NCT02419495.
Insights
This phase 1b trial investigated selinexor combined with immune checkpoint inhibitors for advanced uveal melanoma. The combination showed safety and clinical benefit in most patients, warranting further study.
Area of Science:
- Oncology
- Immunotherapy
- Uveal Melanoma Research
Background:
- Uveal melanoma (UM) is an aggressive cancer with poor prognosis.
- Immune checkpoint inhibitors (ICIs) show limited efficacy as monotherapy for UM.
- Combination therapies targeting oncogenesis are being explored for UM treatment.
Purpose of the Study:
- To evaluate the safety and tolerability of selinexor combined with ICIs in advanced UM patients.
- To assess preliminary efficacy signals of this combination therapy.
Main Methods:
- Phase 1b trial design.
- 10 patients with advanced UM received selinexor plus investigator's choice of ICI (pembrolizumab or nivolumab/ipilimumab).
- Safety, tolerability, and clinical response were assessed.
Main Results:
- The combination was generally safe, with manageable toxicities including neutropenia and thrombocytopenia.
- Dose reductions were needed in 60% of patients.
- Eight of nine evaluable patients achieved stable disease, with a median progression-free survival of 6 months.
Conclusions:
- Selinexor combined with immunotherapy is a safe and tolerable option for advanced UM.
- The combination demonstrated clinical benefit in most patients.
- Larger phase 2 trials are needed to validate these findings.
