The FDA has scheduled an Oncologic Drugs Advisory Committee (ODAC) hearing for February 26, 2019, to discuss a new drug application (NDA) for selinexor in combination with dexamethasone for the treatment of patients with penta-refractory multiple myeloma.1UPDATE 2/26/2019: FDA Panel Votes Against Accelerated Approval of Selinexor for Myeloma
Karyopharm Therapeutics, Inc, the manufacturer of the XPO1 (CRM1) inhibitor, submitted the NDA for an accelerated approval for patients who have received ≥3 prior lines of therapy and whose disease is refractory to at least 1 proteasome inhibitor, 1 immunomodulatory agent, and 1 CD38-targeted antibody, and to their most recent treatment. The FDA granted a priority review designation to the application in October 2018.
The FDA will consider the recommendation of the ODAC panel following the hearing. Under the Prescription Drug User Fee Date, the FDA must make a decision on the approval by April 6, 2019. Karyopharm also submitted a marketing authorization application to the European Medicines Agency (EMA) for conditional approval for the same indication. The application was granted accelerated assessment by the EMA’s Committee for Medicinal Products for Human Use.
The applications are based on findings from the phase IIb STORM study, which demonstrated that the combination of selinexor and dexamethasone elicited a 26.2% overall response rate (ORR) and an 8.6-month median overall survival (OS).2
In the multicenter STORM trial, 122 patients with penta-refractory multiple myeloma were enrolled, 85 of whom were treated per-protocol. The median patient age was 65 years (range, 40-85). Patients were treated with 80 mg of oral selinexor plus 20 mg of oral dexamethasone twice weekly until disease progression. The primary endpoint was ORR; secondary endpoints included duration of response and clinical benefit rate.
To be eligible for enrollment, patients had to have received prior treatment with bortezomib (Velcade), carfilzomib (Kyprolis), lenalidomide (Revlimid), pomalidomide (Pomalyst), daratumumab (Darzalex), an alkylator, and glucocorticoids. Those with smoldering multiple myeloma, plasma cell leukemia, systemic amyloid light chain amyloidosis, and central nervous system myeloma were excluded.
In the study, patients had undergone a median of 7 prior treatments (range, 3-18), and all were refractory to proteasome inhibitor/immunomodulatory drugs/daratumumab/glucocorticoid. Additionally, 96% of patients were refractory to carfilzomib/pomalidomide/daratumumab, 84% had undergone stem cell transplant, and 28% had undergone ≥2 transplants.
Additional updated results of part 2 of the trial, which were presented during the 2018 ASH Annual Meeting, showed that the 26.2% ORR included a 19.7% very good partial response rate (VGPR) and a 6.5% ≥VGPR. This included 2 patients with stringent complete responses, with minimum residual disease (MRD) negativity at a level of 10-6 in 1 patient and 10-4 in the second patient. Additionally, 2 patients who progressed on chimeric antigen receptor T-cell therapy achieved a partial response.
The median time to response was 1 month (range, 1-14 weeks) and the median duration of response was 4.4 months. Of the evaluable patients, 71% experienced a reduction in the M-protein. Response rates were similar, regardless of the patient’s last prior therapy.
Regarding safety, frequently reported any-grade treatment-related non-hematologic adverse events (AEs) included nausea (69.1%), fatigue (56.1%), anorexia (52.0%), weight loss (47.2%), hyponatremia (30.9%), vomiting (35.0%), and diarrhea (33.3%). The most frequent grade 3 AEs were fatigue (18.7%), hyponatremia (16.3%), and nausea (9.8%).
Moreover, any-grade treatment-related hematologic AEs included thrombocytopenia (67.5%), anemia (48.0%), neutropenia (36.6%), leukopenia (29.3%), and lymphopenia (13.8%). The rate of grade 3/4 thrombocytopenia increased as baseline platelet counts also decreased.
The median duration of the combination regimen was 9 weeks (range, 1-60+); a total 79.7% of patients required a dose modification, most of which occurred in the first 2 cycles.
Ajai Chari, MD, highlighted these data in a presentation during the 2018 ASH Annual Meeting.
“STORM Part 2 represents the largest, most heavily pretreated population with MM in a prospective clinical trial to date,” said Chari, director of clinical research, Multiple Myeloma Program, Mount Sinai School of Medicine. “Patients received a median of 7 prior therapies over 6.6 years. These patients have no known available therapies with clinical benefit.”
Selinexor is being investigated in several ongoing phase III trials, including in combination with bortezomib and dexamethasone (BOSTON; NCT03110562), in combination with various backbone treatments (STOMP; NCT02343042), in dedifferentiated liposarcoma (SEAL; NCT02606461), and an investigator-sponsored study in endometrial cancer (SIENDO; NCT03555422).
- Karyopharm Announces FDA Advisory Committee Meeting to Review Selinexor for the Treatment of Patients with Triple Class Refractory Multiple Myeloma Who Have Received At Least Three Prior Therapies. Karyopharm Therapeutics, Inc. Published February 7, 2019. https://yhoo.it/2TE9XE6. Accessed February 7, 2019.
- Chari A, Vogl DT, Dimopoulos MA, et al. Results of the pivotal STORM study (Part 2) in penta-refractory multiple myeloma (MM): deep and durable responses with oral selinexor plus low dose dexamethasone in patients with penta-refractory MM. In: Proceedings from the 2018 ASH Annual Meeting; Dec. 1-4, 2018; San Diego, CA. Abstract 598.