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Patient Deaths, Efficacy Data May Sink Myeloma Drug at FDA Panel

WASHINGTON — The novel XPO1 inhibitor selinexor for heavily pretreated multiple myeloma garnered little enthusiasm from FDA staff ahead of a Tuesday advisory committee meeting, with serious concerns over the drug’s safety and a lack of clarity on its activity highlighted in a briefing document.

The FDA Oncologic Drugs Advisory Committee (ODAC) will discuss whether data from Karyopharm Therapeutics’ STORM trial allow for an “adequate assessment” of the drug’s safety, efficacy, and risk-benefit ratio in this patient population.

STORM part 2 was a single-arm study that tested selinexor plus low-dose dexamethasone in “penta-exposed” myeloma patients — those that had already received at least five prior therapies — and the proposed indication would be for those with triple-class refractory disease: meaning they failed an anti-CD38 monoclonal antibody such as daratumumab (Darzalex); a proteasome inhibitor such as bortezomib (Velcade), ixazomib (Ninlaro), or carfilzomib (Kyprolis); and an immunomodulatory agent such as lenalidomide (Revlimid) or pomalidomide (Pomalyst).

In Karyopharm’s own briefing documents, the company said there is an unmet need for multiple myeloma patients with triple-refractory disease, and said selinexor — a first-in-class, selective inhibitor of nuclear export that blocks the XPO1 protein, which is overexpressed on multiple myeloma cells — “offers a new pathway for treating” these patients.

But FDA staff noted that in this phase II study, the combination demonstrated “limited efficacy and significant toxicity.” In the 122-patient study, the overall response rate (ORR) was 25.4%, which included two complete responses (CRs) and six very good partial responses (PRs). Median duration of response was 4.4 months.

They noted that it’s “difficult to isolate the treatment effect of selinexor” given that response rates with high-dose dexamethasone alone range from 10% to 27% in this patient population.

Tested alone, the activity of the drug appeared far more limited. Of 81 myeloma patients treated with single-agent selinexor, only seven patients responded (8.6%), including one CR and six PRs. And the briefing documents noted that in a randomized study of selinexor or physician’s choice of therapy in advanced acute myeloid leukemia (AML), overall survival was worse in the selinexor arm.

Safety with selinexor at the proposed 80-mg dose is likely to play a large role in the meeting, as more than a quarter of patients in STORM part 2 discontinued treatment due to toxicity (28.5%) and almost all required a dose reduction (88.6%). More concerning were the 10 therapy-related deaths (8.2% of the total study population) within 30 days of starting treatment.

At least one grade 3/4 treatment-emergent adverse event (AE) occurred in 95.1% of patients, the most common of which were thrombocytopenia (58.5%), anemia (42.3%), neutropenia (22.0%), hyponatremia (20.3%), and fatigue (19.5%). And over 60% experienced at least one serious AE, with pneumonia (11.4%), sepsis (8.9%), and mental status changes (4.1%) being the most common.

“It is unclear whether treatment with selinexor-dexamethasone provides a clinically meaningful benefit that outweighs the risks of treatment,” FDA staff concluded. “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 relapsed/refractory multiple myeloma, add to the challenges in interpreting the results of the pivotal study in support of the proposed indication.”

Karyopharm said there are precedents for accelerated approval in myeloma based on phase II studies, pointing to the approvals of carfilzomib in 2012, pomalidomide in 2013, and daratumumab in 2015, which were all approved after showing similar response rates.

But in the phase II study of carfilzomib, for example, while the ORR in penta-exposed patients was similar (22.9%), the median duration of response was 7.8 months and only five of 266 patients deaths were considered to be treatment-related (2.0%).

At the meeting, ODAC will vote on whether an approval decision of selinexor should be delayed until results of the phase III BOSTON trial are available, a study evaluating bortezomib and dexamethasone with or without selinexor in relapsed and refractory multiple myeloma.

Outside of myeloma and AML, selinexor is also being investigated in several other malignancies, including a phase II trial in diffuse large B-cell lymphoma and phase III trials in liposarcoma and endometrial cancer.