A Phase II Study of the Efficacy and Safety of Oral Selinexor in Recurrent Glioblastoma

Abstract

Purpose: Selinexor is an oral selective inhibitor of exportin-1 (XPO1) with efficacy in various solid and hematologic tumors. We assessed intratumoral penetration, safety, and efficacy of selinexor monotherapy for recurrent glioblastoma. Patients and Methods: Seventy-six adults with Karnofsky Performance Status ≥ 60 were enrolled. Patients undergoing cytoreductive surgery received up to three selinexor doses (twice weekly) preoperatively (Arm A; n = 8 patients). Patients not undergoing surgery received 50 mg/m2 (Arm B, n = 24), or 60 mg (Arm C, n = 14) twice weekly, or 80 mg once weekly (Arm D; n = 30). Primary endpoint was 6-month progression-free survival rate (PFS6). Results: Median selinexor concentrations in resected tumors from patients receiving presurgical selinexor was 105.4 nmol/L (range 39.7–291 nmol/L). In Arms B, C, and D, respectively, the PFS6 was 10% [95% confidence interval (CI), 2.79–35.9], 7.7% (95% CI, 1.17–50.6), and 17% (95% CI, 7.78–38.3). Measurable reduction in tumor size was observed in 19 (28%) and RANO-response rate overall was 8.8% [Arm B, 8.3% (95% CI, 1.0–27.0); C: 7.7% (95% CI, 0.2–36.0); D: 10% (95% CI, 2.1–26.5)], with one complete and two durable partial responses in Arm D. Serious adverse events (AEs) occurred in 26 (34%) patients; 1 (1.3%) was fatal. The most common treatment-related AEs were fatigue (61%), nausea (59%), decreased appetite (43%), and thrombocytopenia (43%), and were manageable by supportive care and dose modification. Molecular studies identified a signature predictive of response (AUC = 0.88). Conclusions: At 80 mg weekly, single-agent selinexor induced responses and clinically relevant PFS6 with manageable side effects requiring dose reductions. Ongoing trials are evaluating safety and efficacy of selinexor in combination with other therapies for newly diagnosed or recurrent glioblastoma.

A three gene signature predicts response to selinexor in multiple myeloma

“…To test this hypothesis, we obtained RNA-seq of tumor samples from 57 patients with recurrent glioblastoma who were treated with selinexor monotherapy as part of the phase II KING trial (NCT01986348). 12 Overall, we found that patients with higher expression of the signature experienced improved PFS, although statistical significance was not achieved (log rank P = 0.078, Cox PH P = 0.0734, HR = 0.549, Fig S3A). However, patients who achieved a clinical benefit with a partial response (PR) or better had significantly higher signature expression (Wilcoxon P = 0.0034, Fig S3B ).…”

“…Gene-level read counts were obtained from pretreatment tumors from 57 patients with recurrent glioblastoma that were enrolled in the phase 2 KING study. 12…”

“…KING Gene-level read counts were obtained from pretreatment tumors from 57 patients with recurrent glioblastoma that were enrolled in the phase 2 KING study. 12 Bioinformatics Processing Raw reads were aligned to the GRCh38 human reference genome using STAR. 15 Gene-level counts, obtained through featureCounts, were filtered to remove immunoglobulin and ribosomal transcripts, and to remove genes whose counts across all samples had zero variance.…”

Mechanisms of Cell Cycle Arrest and Apoptosis in Glioblastoma

“…Inhibition of the importin XPO1 or CRM1 via selinexor has reduced proliferation and prolonged survival in GBM animal models [105]. A phase 2 study on efficacy, safety, and intratumoral pharmacokinetics of selinexor monotherapy in recurrent GBM (KING Trial) [124] concluded that there was a clinically relevant response in patients with GBM to a 80 mg weekly dose of selinexor in terms of prolonged progression-free survival [124]. The follow-up study NCT04421378 analyses the effect of selinexor in combination with standard of care therapy for newly diagnosed or recurrent GBM (https://clinicaltrials.gov/ct2/show/NCT04421378, accessed on 30 December 2021).…”

Clinically oriented prediction of patient response to targeted and immunotherapies from the tumor transcriptome

“…We additionally used an unpublished dataset that was obtained as part of a collaboration with Massachusetts General Hospital (MGH). Overall, we identified and set aside 21 datasets 20,24,[42][43][44][45][46][47][48][49][50][51][52][53][54][55][56][57][58][59][60] the evaluation setsas unseen data for evaluation. See Table S1 and Supplementary Note 1 for full details.…”