FDA Panel Votes Against Accelerated Approval of Selinexor for Myeloma

The FDA’s Oncologic Drugs Advisory Committee (ODAC) voted 8 to 5 against accelerated approval of a new drug application (NDA) for selinexor for the treatment of patients with penta-refractory multiple myeloma, recommending delaying a decision on the drug until results are available from the pivotal phase III BOSTON trial.

UPDATE 3/15/2019: FDA Extends Review Period for Selinexor in Myeloma

Karyopharm Therapeutics, Inc, the manufacturer of the XPO1 (CRM1) inhibitor, submitted the NDA for an accelerated approval of selinexor for patients with myeloma 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 NDA is based on Part 2 of the phase IIb STORM study. Findings from the trial presented at the 2018 ASH annual meeting showed that the combination of selinexor and dexamethasone elicited a 26.2% overall response rate (ORR) and an 8.6-month median overall survival (OS).¹

However, several questions arose during the ODAC meeting. First, STORM was a single-arm combination trial and a previous phase I study had not demonstrated strong single-agent activity with selinexor. Thus, isolating the specific impact of selinexor is difficult. Additionally, there was significant toxicity with selinexor in the STORM trial, including treatment-emergent adverse events (TEAEs), serious adverse events (SAEs), and TEAEs that resulted in patient deaths.

The NDA for the accelerated approval of selinexor is being reviewed under the FDA’s priority review program. The FDA now has until April 6, 2019, to consider ODAC’s recommendation and make a final decision on whether or not to grant selinexor an accelerated approval.

“I believe there is a probable benefit of selinexor and dexamethasone for some triple-class refractory myeloma patients, and of course, I completely understand the urgent need to develop novel agents with novel mechanisms of action for these patients who have exhausted standard options. But as we’ve heard, there are real toxicities with this combination, and this may not be the right dose. I find it really challenging to fairly evaluate these toxicities given the single-arm study,” said ODAC panel member Alice T. Shaw, MD, PhD, in explaining her vote against accelerated approval.

“I do fully acknowledge that it may be that the high rate of AEs, SAEs, and deaths from TEAEs may reflect the very heavily pretreated patient population of patients. But without having that comparator population in STORM, I can’t say that for certain. Hence, I can’t definitively say that the clinical benefit outweighs the significant toxicity. So, in the interest of patient safety, I do favor waiting for the randomized trial,” added Shaw, who is director, Center for Thoracic Cancers, Massachusetts General Hospital, and Paula O’Keeffe Endowed Chair in Thoracic Oncology and professor of Medicine at Harvard Medical School.

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.

The safety population included 123 patients from Part 2 of the STORM trial.² TEAEs occurring in ≥20% of patients included anemia (65.9%), leukopenia (30.9%), neutropenia (38.2%), thrombocytopenia (71.5%), constipation (22%), diarrhea (42.3%), nausea (69.9%), vomiting (37.4%), fatigue (72.4%), weight decreased (48.8%), decreased appetite (53.7%), hyponatremia (35%), and dyspnea (21.1%).

Almost a third (28.5%) of patients discontinued study treatment due to a TEAE and 88.6% of patients needed ≥1 dose modification due to a TEAE. There were 23 patient deaths that occurred within 30 days of study treatment. Of these deaths, 10 were due to a fatal TEAE and 13 were due to disease progression.

Of the 23 deaths that occurred on or within 30 days of study treatment in Part 2 of STORM, 13 (10.6%) were due to disease progression, and 10 (8.1%) were due to a fatal TEAE.

References

1. 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.
2. FDA. Draft Questions for the February 26, 2019 Meeting of the Oncologic Drugs Advisory Committee (ODAC). Accessed February 26, 2019. https://bit.ly/2XnqwpW.

It is hoped that the phase III BOSTON trial (NCT03110562) will allow the FDA to make a more informed decision on selinexor. The open-label trial is evaluating the addition of selinexor to bortezomib (Velcade) and low-dose dexamethasone versus bortezomib and low-dose dexamethasone alone in patients with relapsed/refractory multiple myeloma who have received 1 to 3 prior anti—multiple myeloma regimens.