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.
| Original language | English |
|---|---|
| Pages (from-to) | 452-460 |
| Number of pages | 9 |
| Journal | Clinical Cancer Research |
| Volume | 28 |
| Issue number | 3 |
| DOIs | |
| Publication status | Published - 1 Feb 2022 |
Bibliographical note
Funding Information:A.B. Lassman reports grants, personal fees, and non-financial support from Karyopharm, Orbus, NW Biotherapeutics, AbbVie, Novocure, and QED; grants and non-financial support from Agios, Celgene, Kadmon, VBI, Beigene, Oncoceutics/ Chimerix, Pfizer, Genentech/Roche, Millennium, Celldex, Novartis, Global Coalition for Adaptive Research (GCAR), BMS, Sumitomo Dainippon, and RTOG Foundation; and grants from NIH/NCI during the conduct of the study. A.B. Lassman also reports non-financial support from Aeterna Zentaris, American Society of Clinical Oncology (ASCO), Matheson Foundation, National Brain Tumor Society, NRGOncology Foundation, NextSource, DelMar, Corden, and Kazia; grants from Accelerate Brain Cancer Cure (ABC2); personal fees from Forma, Sapience, Vivacitas, and Fondazion AIRC (Italian Foundation for Cancer Research); and personal fees and non-financial support from PER/MJH Holdings, Bioclinica (as an expert blinded independent reviewer of clinical and imaging data for a BMS-sponsored trial), Abbott Molecular, Bayer, and Society for Neuro-Oncology (SNO) outside the submitted work. P.Y. Wen reports other support from Agios, AstraZeneca/Medimmune, Beigene, Bayer, Celgene, Boston Pharmaceuticals, CNS Pharmaceuticals, Eli Lily, Genentech/Roche, Elevate Bio Immunomic Therapeutics, Imvax, Kazia, MediciNova, Karyopharm, Merck, Novartis, Nuvation Bio, Oncoceutics, Vascular Biogenics, VBI Vaccines, Voyager, QED, Celularity, and Sapience outside the submitted work. M.J. van den Bent reports personal fees from Karyopharm during the conduct of the study, as well as personal fees from AbbVie outside the submitted work. S.R. Plotkin reports other support from Karyopharm during the conduct of the study. K. Li reports personal fees from Karyopharm Therapeutics outside the submitted work. C.J. Walker reports personal fees and other support from Karyopharm Therapeutics, Inc. during the conduct of the study, as well as a patent for Biomarkers for Selinexor pending. S. Tamir is an employee of Karyopharm Therapeutics. L. Henegar is an employee and stockholder of Karyopharm Therapeutics Inc. M.J. Alvarez reports other support from Karyopharm during the conduct of the study, as well as other support from DarwinHealth, Inc outside the submitted work; in addition, M.J. Alvarez has a patent for WO2017/040315-A1 issued to Columbia University. A. Califano reports personal fees and other support from DarwinHealth Inc. outside the submitted work; in addition, A. Califano has a patent for VIPER algorithm issued, licensed, and with royalties paid from DarwinHealth. Y. Landesman reports personal fees and other support from Karyopharm Therapeutics during the conduct of the study. M.G. Kauffman reports personal fees from Karyopharm Therapeutics Inc. during the conduct of the study and outside the submitted work. S. Shacham reports personal fees from Karyopharm Therapeutics during the conduct of the study, personal fees from Karyopharm Therapeutics outside the submitted work, and a patent for selinexor composition of matter issued. M. Mau-Sørensen reports grants from Karyopharm Therapeutics Inc during the conduct of the study, as well as personal fees and grants from Karyopharm Therapeutics Inc outside the submitted work. No disclosures were reported by the other authors.
Funding Information:
Karyopharm funded the study and provided selinexor supply. Tamar Apraha-mian, PhD, of JetPub Scientific Communications, LLC, supported by funding from Karyopharm, provided drafts and editorial assistance to the authors during preparation of this manuscript. The authors were also supported in part by The William Rhodes and Louise Tilzer-Rhodes Center for Glioblastoma at New York-Presbyterian Hospital (to A.B. Lassman and A. Califano) and by NIH/NCI grants U01 CA217858 (to A. Califano), P30CA013696 (to A.B. Lassman and A. Califano), UG1CA189960 (to A.B. Lassman), S10 OD012351 (to A. Califano), and S10 OD021764 (to A. Califano).
Publisher Copyright:
© 2021 The Authors.
