The Food and Drug Administration (FDA)’s Oncologic Drugs Advisory Committee (ODAC) voted 8 to 5 against an accelerated approval of the combination use of selinexor plus dexamethasone for the treatment of patients with penta-refractory multiple myeloma, recommending the action be delayed until further trial data are available.
Moreover, the committee called for further results from the randomized phase 3 BOSTON trial,
from which Karyopharm Therapeutics, Inc – the manufacturer of the first-in-class, oral Selective Inhibitor of Nuclear Export (SINE) compound – submitted data to support its new drug application
of selinexor to treat patients with myeloma who have received three or more prior lines of therapy and whose disease is refractory to at least one proteasome inhibitor, one immunomodulatory agent, one CD38-targeted antibody and to their most recent treatment.
In 2018, Karyopharm reported positive data from the single-arm phase 2b STORM study evaluating selinexor in combination with low-dose dexamethasone in patients with penta-refractory multiple myeloma. Based on these results, the FDA previously granted the agent an orphan drug designation as well as a fast track designation to treat relapsed/refractory multiple myeloma.
However, several questions arose during the ODAC meeting. First, STORM was a single-arm combination trial and a previous phase 1 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.
“I think the data that we have doesn’t meet the FDA standard for evidence on safety and effectiveness,” Natalie Compagni Portis, PsyD, a clinical psychologist working in public mental health and private practice. “We absolutely need more treatment that help patients live longer and/or improve quality of life. The trial leaves us with a lot of incomplete information on both of these issues. Given the fact that there is expanded access for those willing to take on the risk and given the serious side effects and even fatal (side effects), and the real lack of clarity on dosing, it seems vital and responsible to wait for more data.”
Despite this rationale, patients diagnosed with multiple myeloma
implored accelerated approval of selinexor in the treatment of their disease.
“I am invested in my future and I am a candidate for selinexor when my current protocol stops working,” said Deb Graf, a survivor previously diagnosed with the 17p deletion. “The importance of trials and the approval of this drug cannot be measured in just side effects. The time I’ve had with my husband, family and friends, the weddings of children and the birth of grandchildren would not be traded. I am dependent upon research and trials for my future, but more importantly, there are younger people here that have exhausted all their options. They need to have hope and the choice to take the risks for a life ahead.”
Members of panel agreed, noting there is an unmet need for treatment options in these patients. “Efficacy is our number one goal and what we must consider in this context,” committee member Paul G. Richardson, M.D., from Dana Farber Cancer Institute in Boston, said. “It is important to note multiple myeloma is the second most common hematological cancer and incurable. (Almost 13,000) patients will die (from multiple myeloma) in the US in 2019.”
Similarly, Clifton Mo, M.D., a hematologist in Leonardtown, Maryland, voted for the accelerated approval of selinexor. “I invite my colleagues to take a look at all the parameters of concern and look at historical context in drugs that have already been approved by the FDA and have proven to be life-saving, game-changing drugs for thousands of patients. Other than the percentage of patients who required a dose modification, tell me: what was actually worse about (selinexor])?”
The phase 3 BOSTON study is fully enrolled, but approval would not occur for at least another two years, with potential approval in the second half of 2021. The trial will hopefully allow the FDA to make a more informed decision regarding the efficacy of selinexor, as it is evaluating the addition of selinexor to Velcade (bortezomib) and dexamethasone in patients with relapsed or refractory multiple myeloma who have received up to three prior treatments for multiple myeloma.
The FDA’s ODAC is an independent panel of experts that evaluates data concerning the efficacy and safety of marketed and investigational products for use in the treatment of cancer and makes appropriate recommendations to the FDA. While the agency considers these panel recommendations, of note, the FDA solely makes the final decision regarding the approval of agents and the recommendations by the panel are non-binding.