Karyopharm’s Selinexor: US FDA Unconvinced By Efficacy In Single-Arm Trial
Executive Summary
Oncologic Drugs Advisory Committee will consider whether approval for Karyopharm’s proposed refractory myeloma therapy selinexor should await results from an ongoing Phase III randomized trial.
The US FDA appears to have significant reservations about the clinical profile of Karyopharm’s selinexor heading into a Feb. 26 review of the proposed treatment for relapsed refractory multiple myeloma.
The NDA filing is based on a single-arm Phase II study (STORM) in fourth-line multiple myeloma, in which selinexor 80 mg twice-weekly was administered in conjunction with dexamethasone 20 mg. In the trial, “the combination of selinexor and dexamethasone demonstrated limited efficacy and significant toxicity in patients with RRMM,” FDA says in its pre-meeting briefing documents.
The study showed a 25% response rate in a highly refractory population. FDA, however, suggests that the magnitude of the benefit is not as impressive as it sounds, given that that there were only two “stringent complete responses” and six “very good partial responses,” with 23 more partial responses.
Moreover, “given that historical studies have shown response rates of 10-27% to high-dose dexamethasone for RRMM and selinexor did not demonstrate single agent activity in RRMM in the phase 1 trial KCP-330-001, it is difficult to isolate the treatment effect of selinexor.”
On the other hand, “selinexor-dexamethasone was associated with significant toxicity,” FDA notes. In the pivotal trial, “all patients (100%) experienced at least one [treatment-emergent adverse event], 93.5% experienced at least one severe (Grade 3-4) TEAE, 60.2% experienced at least one [serious adverse event], and 8.1% experienced a fatal TEAE,” FDA states.
“Given the limited efficacy and significant toxicity demonstrated in this population, it is unclear whether treatment with selinexor-dexamethasone provides a clinically meaningful benefit that outweighs the risks of treatment,” FDA concludes. “The limitations of interpreting safety and efficacy from a single arm trial, and lack of single agent activity of selinexor coupled with historical data showing activity of dexamethasone in RRMM, add to the challenges in interpreting the results of the pivotal study in support of the proposed indication.”
For all of that, FDA does acknowledge the unmet medical need in refractory myeloma and is not ready to conclude that the drug should be abandoned in the disease. Instead, the agency appears inclined to wait for randomized trial data from the ongoing BOSTON study. The trial is enrolling 364 patients with less refractory multiple myeloma, and will compare bortezomib and dexamathasone with or without selinexor. According to FDA, results are expected by the end of the year.
The sole voting question, in fact, is unusually phrased to point to that outcome: “Should the approval of selinexor be delayed until results of the randomized phase 3 trial, BOSTON, are available?”
One factor clearly weighing on the agency is the prior failure of selinexor, an oral selective inhibitor of nuclear export (SINE) compound, in a different indication: refractory acute myeloid leukemia. The Phase II SOPRA study was terminated early in 2017 following an interim analysis showing that the drug was unlikely to show a benefit for overall survival. (Also see "Karyopharm Absorbs Selinexor AML Blow, Focuses On Other Cancers" - Scrip, 3 Mar, 2017.)
“Although selinexor resulted in higher rates of remission [compared to the control arm], OS was worse in the selinexor arm,” FDA says. “Disparate response and survival trends can be observed with therapies that have significant toxicity. In this situation, the benefits from anti-tumor activity are abrogated by the toxicity.”
“The results of this study … underscores the importance of randomized controlled trials,” FDA says.
From the editors of the RPM Report