Glioblastoma (GBM) is the most common primary brain tumor in adults and is associated with a poor prognosis. The karyopherin exportin-1 (XPO1) is a nuclear export protein that plays a critical role in the transport of approximately 300 proteins from the nucleus to the cytoplasm. XPO1 is overexpressed in many solid tumors, including gliomas, where its increased expression correlates with poor outcomes.
Selinexor is an oral selective inhibitor of XPO1-mediated nuclear export (SINE) that can cross the blood-brain barrier. Initially designed for the treatment of GBM, selinexor has since been FDA-approved for refractory multiple myeloma and relapsed/refractory diffuse large B-cell lymphoma. The inhibition of XPO1 by selinexor leads to the nuclear retention and reactivation of tumor suppressor proteins, reduced translation of oncogene mRNAs, and modulation of other pathways.
The KING Trial: Design and Methodology
The Efficacy and Safety of Selinexor (KPT-330) in Recurrent Glioblastoma (KING) trial was an open-label, international, phase II study with four arms:
- Surgical Arm (Arm A): This arm explored the intra-tumoral pharmacokinetics and pharmacodynamics of selinexor by administering 1-3 doses before cytoreductive surgery. The goal was to determine if selinexor reached effective concentrations within the tumor.
- Medical Arms (Arms B, C, and D): These arms explored different dosing schedules for patients not undergoing surgery. Initially, only Arm B (50 mg/m² twice weekly) was part of the trial, but it was halted due to frequent adverse events (AEs). The study was amended to include Arm C (60 mg flat dose twice weekly) and Arm D (80 mg flat dose once weekly). Based on an interim analysis, Arm D showed better tolerability and efficacy, leading to its expansion.
Patient Eligibility and Study Protocol
Eligible patients were adults with a diagnosis of GBM and recurrence/progression after radiotherapy and temozolomide. Key inclusion criteria included a Karnofsky Performance Status (KPS) of ≥ 60 and adequate bone marrow, renal, and hepatic function. Patients needed to have recurrent radiographically measurable disease and a minimum interval of 12 weeks from radiation therapy completion.
Efficacy and Safety Assessments
The primary endpoint was the 6-month progression-free survival (PFS6) rate, with secondary objectives including response rate, median PFS, median overall survival (OS), and safety and tolerability evaluation. Pharmacokinetics (PK) were determined by measuring pre- and post-dose blood levels of selinexor in Arm A.
Results: Efficacy
Between March 2014 and January 2020, 76 patients were treated with selinexor across different trial arms (Arm A: 8; Arm B: 24; Arm C: 14; Arm D: 30). These patients had previously undergone a median of one therapy in addition to radiotherapy and temozolomide, with a median Karnofsky Performance Status (KPS) of 90. The median age was 56 years, and 71% of the participants were male.
In the modified intent-to-treat (mITT) population (67 patients in Arms B, C, and D), the median treatment duration was 1.64 months, with disease progression being the most common cause of discontinuation (83.6%).
The progression-free survival at 6 months (PFS6) varied among the arms:
- Arm B: 10% (95% CI, 2.67–35.4)
- Arm C: 7.7% (95% CI, 1.2–50.6)
- Arm D: 17.2% (95% CI, 7.78–38.3)
Median overall survival (OS) was:
- Arm B: 10.5 months (95% CI, 4.9–17.0)
- Arm C: 8.5 months (95% CI, 7.3–not evaluable)
- Arm D: 10.2 months (95% CI, 7.0–15.4)
The overall response rate (partial or complete) was:
- Arm B: 8.3% (95% CI, 1.0–27)
- Arm C: 7.7% (95% CI, 0.2–36.0)
- Arm D: 10% (95% CI, 2.1–26.5)
A measurable reduction in tumor size was observed in 19 patients (28% overall).
Results: Safety
The safety population included all 76 treated patients. Common hematologic treatment-related adverse events (TRAEs) included:
- Thrombocytopenia: 43.4%
- Neutropenia: 26.3%
- Anemia: 17.1%
No febrile neutropenia or bleeding events occurred in patients with grade 3 or 4 thrombocytopenia.
Common non-hematologic TRAEs were:
- Fatigue: 60.5%
- Nausea: 59.2%
- Decreased appetite: 43.4%
- Vomiting: 30.3%
- Dysgeusia: 26.3%
- Hyponatremia: 19.7%
- Decreased weight: 17.1%
- Constipation: 14.5%
- Blurred vision: 10.5%
- Diarrhea: 11.8%
Most AEs were reversible with dose modification and standard supportive care.
Serious AEs (SAEs) were experienced by 34.2% of patients, with the most common being:
- Seizures: 8%
- Syncope: 4%
- Fatigue, headache, pulmonary embolism, and urinary tract infection: 3% each
Eight of the 26 SAEs were considered related to selinexor, including:
- Decreased appetite
- Diarrhea,
- Seizures,
- Pneumonia
- Hyperlipasemia
- Hypophosphatemia
Grade 4 or 5 SAEs unrelated to selinexor included hyperglycemia, cerebral edema, and a fatal pulmonary embolism.
Treatment discontinuation due to AEs occurred in 6.6% of patients, with fatigue being the most common cause of dose reductions.
Intratumoral Pharmacokinetics and Pharmacodynamics
Selinexor concentrations in contrast-enhancing tumors ranged from 39.7 to 291 nmol/L, with plasma concentrations 2 hours post-dosing ranging from 645 nmol/L to 1.62 mmol/L. The tumor/plasma ratio was in the range of the IC50 for patient-derived glioblastoma cell lines treated with selinexor.
Immunohistochemistry showed a marked reduction in proliferation and an increase in apoptosis in post-treatment tumor samples. RNA-seq revealed increased expression of XPO1 and other genes induced by selinexor, indicating successful inhibition of XPO1 nuclear export activity.
Conclusion
The KING trial provides valuable insights into the efficacy and safety of selinexor in treating recurrent glioblastoma. While the treatment shows promise with measurable reductions in tumor size and manageable adverse events without putting patients at risk, continued research is essential to optimize its use and further understand its impact.
Source: AACR