In an emotional discussion on Tuesday, February 26 at the FDA’s Oncologic Drugs Advisory Committee (ODAC) meeting, committee members voted 8 to 5 to await the results of an ongoing randomized trial (BOSTON phase III trial) comparing bortezomib and dexamethasone with and without selinexor, instead of approving selinexor now based on the single-arm STORM trial results of selinexor plus dexamethasone.
This opinion did not come out of the blue. Late last week, the FDA posted preliminary assessments in background material that outlined significant concerns about serious toxicities with the use of selinexor. The Karyopharm Therapeutics drug is a first-in-class, oral Selective Inhibitor of Nuclear Export (SINE) compound.
The four-and-a-half-hour meeting included testimonies from Karyopharm representatives, the FDA staff, and myeloma experts, such as Drs. Paul Richardson, Sundar Jagannath, Philip McCarthy, and Saad Usmani—all supportive of approving selinexor right now. Likewise, Diane Moran, IMF’s Senior Vice President for Strategic Planning, spoke in support of selinexor, as did Robin Tuohy, IMF’s Senior Director of Support Groups, and Michael Tuohy, myeloma patient survivor, giving the patient and caregiver perspectives. They also incorporated the story of Aldo Del Col, Co-Founder and Chief Scientific Advisor of Myeloma Canada—and a long-time myeloma patient--who has achieved a very important ongoing remission with selinexor therapy. These positive recommendations and patient stories clearly resonated with panel members.
However, when it came time to vote, the clear evidence of efficacy was counterbalanced by emphasis on dose-related serious toxicities. It was particularly unfortunate that the starting dose in the STORM trial was extremely poorly tolerated and required almost immediate dose reductions in a majority of patients. This was linked to serious toxicities and deaths in a separate leukemia trial with selinexor, which underscored the potential for serious and life-threating toxicities, including infections, which the FDA panel attributed to the active treatment.
Nonetheless, a key concept about efficacy emerged—outlined by Dr. Jagannath and illustrated by the very positive experience of Aldo del Col—and that is the notion of a “bridging therapy” for relapsed patients who have exhausted all other options. Although toxicities of selinexor can be difficult to manage, especially in the longer term, a lifesaving response can be achieved which allows patients to move forward to a next therapy or become eligible for a trial previously out of reach. This is an important niche in the myeloma therapy armamentarium.
All in all, it was a difficult day, with some panel members questioning how patients will be able to access selinexor, since current “compassionate use” is very difficult and cumbersome. There may be an option to submit additional data prior to the outcomes of the BOSTON trial, due in 2020. The FDA can overturn ODAC recommendations if compelling data are submitted which resolves open questions or concerns. So, there are several potential paths forward.
It was a disappointing day with potential approval of selinexor on hold. We must now wait for further developments to see what the future holds for access to an agent which can be an important bridging therapy.
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