Novel XPO1 inhibitor shows antitumour activity in recurrent glioblastoma

The oral selective inhibitor of exportin-1 (XPO1) selinexor has therapeutic potential in recurrent glioblastoma, yielding favourable responses and clinically relevant 6-month progression-free survival (PFS) rate with manageable side effects requiring dose reductions, according to the results of a phase II trial.

The trial included 76 adult patients (median age 56 years, 71 percent male) with Karnofsky Performance Status (KPS) ≥60. These patients had received a median of one prior therapy in addition to radiotherapy and temozolomide (range 1–8).

Patients scheduled to undergo cytoreductive surgery received up to three selinexor doses (twice weekly) preoperatively (arm A; n=8). Meanwhile, those who were not undergoing surgery received 50 mg/m² (arm B; n=24), 60 mg flat dose twice weekly (arm C; n=14), or 80 mg flat dose once weekly (arm D; n=30).

The median selinexor concentrations in resected tumours from patients receiving presurgical selinexor was 105.4 nmol/L. The primary endpoint of 6-month PFS was 10 percent (95 percent confidence interval [CI], 2.79–35.9) in arm B, 7.7 percent (95 percent CI, 1.17–50.6) in arm C, and 17 percent (95 percent CI, 7.78–38.3) in arm D.

There was a measurable reduction in tumour size seen in 19 patients (28 percent), and RANO-response rate overall was 8.8 percent (arm B: 8.3 percent; arm C: 7.7 percent; arm D: 10 percent), with one complete and two durable partial responses in arm D.

In terms of safety, serious adverse events (AEs) occurred in 26 patients (34 percent), of whom one (1.3 percent) died. Frequently reported treatment-related AEs were fatigue (61 percent), nausea (59 percent), decreased appetite (43 percent), and thrombocytopenia (43 percent). These AEs were managed by supportive care and dose modification.

Finally, molecular studies identified a signature predictive of response (area under the curve, 0.88).