FDA Approves Xpovio Combo for Heavily Treated RRMM Patients

The U.S. Food and Drug Administration (FDA) has approved — with conditions — Xpovio (selinexor) tablets, in combination with the corticosteroid dexamethasone, for the treatment of adults with relapsed or refractory multiple myeloma who received at least four prior therapies and failed to respond to treatment.  The combo is designed for patients whose disease is resistant to several other forms of treatment, including at least two proteasome inhibitors, two immunomodulatory agents, and an anti-CD38 monoclonal antibody.

The endorsement — called accelerated approval by the FDA — allows a medication addressing an unmet need in a serious condition to be used if it shows benefit on surrogate or interim measures made in a clinical trial. But its continued use, and full approval, requires a further showing of efficacy in a confirmatory study.

Xpovio, Karyopharm Therapeutics‘ lead compound, is a first-in-class oral inhibitor of the XPO1 protein that prevents tumor suppressor proteins from exiting the cell nucleus. This leads to cancer cell death while leaving healthy cells unharmed.

After designating Xpovio an orphan drug, the FDA granted it fast track status, and now has given the therapy accelerated approval.

“Today we approved a treatment under our accelerated approval program that provides a treatment option for patients with multiple myeloma with no available therapy,” Richard Pazdur, MD, director of the FDA’s Oncology Center of Excellence, said in a press release.

“While there is no cure for multiple myeloma, there are FDA-approved treatments to target the cancer and slow down the spread of the disease. Sadly, often over time, patients can exhaust all available treatments and still see their disease progress,” said Pazdur, the acting director of the Office of Hematology and Oncology Products in the FDA’s Center for Drug Evaluation and Research (CDER).

“With today’s accelerated approval of Xpovio by the FDA, patients with heavily pretreated multiple myeloma will now have a new therapeutic option to treat their disease,” Sharon Shacham, PhD, MBA, founder, president, and chief scientific officer of Karyopharm, said in a company-issued press release.

“Discovering, developing and securing FDA approval for Xpovio with its novel mechanism of action over the past decade required the dedication of many people, including the patients, caregivers and physicians involved in our clinical trials, along with the many employees at Karyopharm. We are tremendously grateful for everyone’s contributions to this important milestone, and we look forward to the next stage in our pursuit of improving the lives of patients with cancer,” Shacham added.

The FDA’s accelerated approval was based on findings from the multicenter, single-arm, open-label, STORM Phase 2b trial (NCT02336815).

The study assessed the safety and efficacy of Xpovio (80mg), in combination with dexamethasone (20mg), in relapsed or refractory multiple myeloma patients who had received at least three prior therapies. The treatment was given twice per week until disease progression, death, or unacceptable toxicity.

In Part 2 of STORM, treatment efficacy and safety were assessed in a group of 83 people who failed to respond to therapy with two proteasome inhibitors, Velcade (bortezomib) and Kyprolis (carfilzomib), two immunomodulatory agents, Revlimid (lenalidomide) and Pomalyst (pomalidomide), and the anti-CD38 monoclonal antibody Darzalex (daratumumab).

Study findings showed that 25.3% of patients responded to the Xpovio-dexamethasone combination, with a median duration of response of 3.8 months and a median time to first response of 4 weeks.

The most common side effects of treatment reported in the 202 patients who participated in Part 1 and 2 of STORM were low platelet count (thrombocytopenia), low white blood cell count (neutropenia), and low red blood cell counts (anemia). Other common side effects included fatigue, nausea, vomiting, diarrhea, decreased appetite, weight loss, constipation, upper respiratory tract infections, and low blood sodium levels (hyponatremia).

Treatment was discontinued due to side effects in 27% of the participants. More than half of the patients (53%) required a reduction in the dose of Xpovio during the trial, and 65.3% had to interrupt treatment with Xpovio. Fatal adverse reactions were reported in 8.9% of patients.

Xpovio’s effectiveness, in combination with Velcade and low-dose dexamethasone, will be confirmed in the ongoing, randomized, BOSTON Phase 3 trial (NCT03110562). If proven effective, Xpovio will receive FDA’s full approval to be used together with dexamethasone as a therapy for heavily treated patients.

According to Karyopharm, Xpovio should become available to patients living in the U.S. no later than July 10, 2019. The full prescribing information, including dosing, scheduling and side effects, can be found here.

The company, meanwhile, is waiting for feedback from the European Medicines Agency (EMA) regarding its marketing authorization application (MAA). That MAA seeks the approval of Xpovio for the same indication in the E.U.