Karyopharm Therapeutics is set to present novel clinical data on its lead product candidate selinexor, an oral selective inhibitor of nuclear export compound that is being developed for a variety of advanced hematologic and solid tumors.
The data, to be presented at the upcoming American Society of Hematology (ASH) 2016 annual meeting Dec. 3-6, in San Diego, Calif., will include updates from the Phase 2 STORM and Phase 1b/2 STOMP trials. Both studies are evaluating selinexor in refractory multiple myeloma patients, and have demonstrated promising results.
“The STORM and STOMP studies continue to demonstrate robust response rates, with selinexor showing tolerability, both as a single-agent and in combination with other widely used therapies in heavily pretreated patients with MM,” Sharon Shacham, PhD, president and chief scientific officer of Karyopharm, said in a press release. “Collectively, the MM data being presented at ASH this year continue to support the efficacy and safety of oral selinexor, as well as our planned development path in MM, and we look forward to presenting even more mature data at the meeting in December,” she said.
Selinexor is a selective inhibitor of the XPO1 protein, a nuclear export protein. Usually, cancer cells get rid of tumor suppressor proteins, which activate the apoptotic pathways of defective cells. But by inhibiting their transport, selinexor leads to the accumulation of these proteins in the nucleus, leading to the selective induction of cell death in the cancer cells.
The multi-center, single-arm Phase 2b STORM trial (NCT02336815) was designed to evaluate selinexor in combination with low-dose dexamethasone in heavily treated multiple myeloma patients. The study, which is still recruiting participants, enrolled 78 patients, 48 of whom had quad-refractory disease, and 30 of whom had penta-refractory disease.
Patients with quad-refractory disease are those who previously received two proteasome inhibitors (Velcade (bortezomib) and Kyprolis (carfilzomib)) and two immunomodulatory agents (Revlimid (lenalidomine) and Pomalyst (pomalidomide)) and who are refractory (do not respond) to at least one treatment of each category, and whose disease progressed after their most recent treatment.
Those with penta-refractory disease are similar to patients with quad-refractory disease, but also are refractory to an anti-CD38 monoclonal antibody, such as Darzalex (daratumumab) or isatuximab.
In an oral presentation, titled “Selinexor and Low Dose Dexamethasone in Patients with Lenalidomide, Pomalidomide, Bortezomib, Carfilzomib and Anti-CD38 Ab Refractory MM STORM Study,” Dan T. Vogl, MD, assistant professor of medicine at the Perelman School of Medicine, University of Pennsylvania, will be presenting updated data from this study.
Selinex induced an overall response rate of 21% and 20% in the quad-refractory and penta-refractory groups, respectively. Median overall survival (OS) was 9.3 months for all patients, with those who had partial or complete responses showing a median OS of 11 months, and those who did not respond showing a median OS of 5.7 months. Progression-free survival (PFS) in this heavily treated population was 2.1 months, and the grade 3 adverse events were mainly reversible cytopenias.
Since no other agent had previously shown activity in penta-refractory multiple myeloma patients, Karyopharm has now expanded the STORM study to include 120 additional penta-refractory myeloma patients. Results are expected by early 2018. Assuming positive results, the company will submit an application to the U.S. Food and Drug Administration requesting accelerated approval for selinexor in multiple myeloma.
In addition to the STORM study, Karyopharm also will present an update on the Phase 1b/2 STOMP multi-arm clinical trial (NCT02343042, and also recruiting participants), designed to evaluate selinexor and low-dose dexamethasone in combination with currently existing therapies for the multiple myeloma population, including Velcade, Pomalyst or Revlimid.
In an oral presentation, titled “Selinexor in Combination with Bortezomib and Dexamethasone Demonstrates Significant Activity in Patients with Refractory Multiple Myeloma Including Proteasome-Inhibitor Refractory Patients,” Nizar Bahlis, MD, associate professor of hematology, Southern Alberta Cancer Research Institute, will present data from the study arm evaluating selinexor and dexamethasone in combination with Velcade.
Among the 22 patients enrolled in this combination arm, 17 responded to the treatment, including one complete response and 11 very good partial responses, accounting for an overall response rate of 77 percent.
In detail, all 10 patients with non-refractory disease responded to the combination therapy, accounting for an ORR of 100%, while seven of the 12 patients with proteasome refractory myeloma responded, with an ORR of 58%.
Importantly, dexamethasone plus Velcade combination in myeloma patients who are not refractory to proteasome inhibitor leads to an ORR of only 50%, and in patients who are refractory to a proteasome inhibitor, the ORR is lower than 10%.
The most commonly reported adverse events included fatigue, nausea, diarrhea and anorexia, most of which were grade 1 or 2 and reversible. Six patients experienced grade 3 or grade 4 thrombocytopenia (low platelet levels), and one experienced grade 1 peripheral neuropathy.
Based on the promising clinical results obtained in the Velcade arm of the STOMP study, Karyopharm is planning to initiate the BOSTON Phase 3 randomized trial, assessing dexamethasone plus Velcade with or without selinexor in multiple myeloma patients who received one to three prior lines of therapy. The study, which is awaiting feedback from the FDA, will be conducted worldwide and is expected to enrol 360 patients.