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Selinexor induces response among certain patients with recurrent glioblastoma
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CHICAGO — Selinexor induced antitumor activity with durable responses and disease stabilization among patients with recurrent glioblastoma, according to phase 2 study results presented at ASCO Annual Meeting.
“Recurrent glioblastoma is very much so an area of unmet medical need,” Andrew B. Lassman, MD, the John Harris associate professor of neurology and chief of neuro-oncology at Columbia University, told HemOnc Today. “Glioblastoma — the most common kind of brain tumor in adults — is disproportionately mortal, representing about 1.5% of cancers, but about 2.5% of cancer deaths. It is a highly malignant tumor. And, because it affects the brain, it can be a disproportionally morbid tumor compared with other cancers.”
Most patients with glioblastoma fail frontline therapy and require treatment for recurrent or progressive disease in the second- or third-line setting.
“But, there is no proven therapy that prolongs survival in the second-line setting, and we clearly need new and better therapies for that patient population,” Lassman said.
Selinexor (Karyopharm Therapeutics) is a selective inhibitor of nuclear export that works by forcing nuclear retention of tumor suppressor proteins, including p53 and p27, leading to apoptosis.
“This drug is a new avenue of exploration,” Lassman said. “An exportin inhibitor, it reduces the ability of the cell to have its normal intracellular trafficking of molecules from inside to outside the cell. So, it forces intracellular retention of various proteins that would otherwise be exported. By being retained inside the cell, those proteins contribute to the drug effect because, when those proteins are normally exported, they are associated with various cancer-like properties.”
Researchers previously presented data from arm A of the trial, in which eight patients received 50 mg/m2 selinexor biweekly prior to and following resection. Analyses conducted among those patients led the researchers to determine that selinexor penetrates the blood-brain barrier and was worthy of additional exploration.
Due to toxicity in arm B, researchers amended the trial to include arms C and D at different doses. Based on the favorable safety and early signs of efficacy in arm D — for which patients were treated at an 80-mg dose once weekly — researchers expanded enrollment for that cohort.
Lassman presented updated data from 30 patients (median age, 56 years; range, 21-78; 63% men) treated on arm D. Patients had received a median two (range, 1-7) prior therapies.
Nineteen percent (95% CI, 9-41) of patients achieved 6-month PFS; median PFS was 1.9 months (95% CI, 9-41). The six-cycle PFS rate was 30% (95% CI, 17-54).
“Our goal for 6-month PFS was higher than 19%, so we didn’t quite reach that goal,” Lassman said. “There is nothing magic about a 30% 6-month PFS rate, we just use that generally to say there is a signal. Even though it didn’t quite reach that point, the fact that we saw bona fide responses in patients with biopsy-proven recurrent disease, despite presence of negative biomarkers, such as absence of IDH mutation — patients who really should have rapidly progressing disease and did not — is encouraging enough to be in our minds worthy of further study.”
Overall response rate was 10% and median OS was 9.4 months (95% CI, 7-not estimable).
For arms B through D combined, researchers observed a decrease in tumor size among 29% of patients.
The most common adverse events observed in arm D included grade 1 to grade 2 nausea (63.3%), fatigue (46.7%), anorexia (26.7%) and thrombocytopenia (23.3%).
“The drug clearly induces response in a subset of patients,” Lassman said. “There are patients with stable disease, and with durable responses. I have one patient who has been on trial for 3 years now, for example. We have other patients with complete responses that are durable. We are very interested in pursuing that further to identify what it is about those patients who seemed to benefit through molecular characterization of their tumor tissue, to potentially perform a follow-up study that might enrich for benefit.”
Potential combinations are another area worthy of additional research, Lassman said.
“Preclinical data demonstrates combinations with alkylator therapies are at least additive, which is another potential strategy that is being considered,” he said. – by Alexandra Todak
Reference:
Lassman AB, et al. Abstract 2005. Presented at: ASCO Annual Meeting; May 31-June 4, 2019; Chicago.
Disclosures: Lassman reports honoraria from AbbVie and WebMD; consultant/advisory roles with AbbVie, Agios, BioClinica, Celgene, Cortice, Kadmon, Karyopharm Therapeutics, Northwest Biotherapeutics, Orbus Therapeutics and Sapience Therapeutics; research funding to his institution from AbbVie, Aeterna Zentaris, Amgen, BeiGene, Celldex, Genentech/Roche, Kadmon, Karyopharm Therapeutics, Millennium, Novartis, Oncoceutics, Pfizer and VBI Vaccines; and travel expenses from Agios, Karyopharm Therapeutics and Novocure. Please see the abstract for all other authors’ relevant financial disclosures.
Perspective
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Manmeet Ahluwalia, MD, FACP
The results of this study by Lassman and colleagues evaluating the safety and efficacy of selinexor showed that the 80-mg dose cohort had a 6-month PFS rate of 19%. Our benchmarks of PFS in recurrent glioblastoma have usually been described in the ballpark of 10% to 15%. So, this is on the higher end of what has been described previously.
What was most interesting to me was that among the 30 evaluable patients receiving this dose, there was one complete response and two partial responses, for a 10% response rate. This compares favorably with the 5% response rate that we are used to seeing.
However, this is a small data set, and the CIs are going to be large. Obviously, more data would help us put this in perspective, and we need additional patients treated. Patients who receive selinexor could be evaluated post-surgery to see if there is any pharmacodynamic impact of the drug and to better understand its mechanism of action.
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