SILVER SPRING, Md. — Approval of selinexor for multiple myeloma may have to await further data, after an FDA advisory committee couldn’t agree that the benefits outweigh the risks.
The FDA Oncologic Drugs Advisory Committee (ODAC), discussing the drug for patients with triple class-refractory disease on Tuesday, split on the key question. Eight panelists recommended the agency wait on results of the phase III BOSTON trial versus five who recommended accelerated approval.
Alice Shaw, MD, PhD, of Harvard Medical School in Boston, said it was a tough call but, in the interest of patient safety, the FDA should wait on the BOSTON results.
“I believe there is a probable benefit of selinexor-dexamethasone for some triple class-refractory myeloma patients, and of course I completely understand the urgent need to develop novel agents with novel mechanisms of action for these patients,” she said. “But as we heard, there are real toxicities with this combination.”
Topline results of the BOSTON study are expected in the first half of 2020. The trial is evaluating bortezomib and dexamethasone with or without selinexor in relapsed and refractory multiple myeloma.
Committee chair Brian Rini, MD, of the Cleveland Clinic Taussig Cancer Institute in Ohio, agreed with Shaw, and also voted to await more data. “I think this is probably one of the most difficult votes I’ve had in many years now on this committee.”
“I think there’s benefit here — what I’m struggling with is benefit and risk,” said Rini.
David Harrington, PhD, of Dana-Farber Cancer Institute, voted to recommend immediate approval, and told FDA staff that for him the BOSTON study “doesn’t really solve anything,” noting that it includes myeloma patients with a different clinical profile and both the dosing and combination are different.
“It doesn’t actually isolate the single-arm activity of selinexor,” Harrington said, one of the FDA’s chief concerns with selinexor.
Richard Pazdur, MD, acting director of the FDA’s Office of Hematology & Oncology Products, responded that this would not be unique, and emphasized that, unlike with prior accelerated approvals, single-agent activity with selinexor was “missing.” If the BOSTON study yields positive results, it would give the agency “the knowledge that at least there was a benefit with the addition of this drug to a regimen in multiple myeloma.”
Drugmaker Karyopharm Therapeutics presented data from STORM part 2, a single-arm study that tested selinexor plus low-dose dexamethasone in “penta-exposed” myeloma patients — those who had already received at least five prior therapies — and the proposed indication would be for those with triple-class refractory disease, that is, those failing an anti-CD38 monoclonal antibody, a proteasome inhibitor, and an immunomodulatory agent.
In the 122-patient study, the overall response rate (ORR) was 26.2%, according to updated results presented at the meeting, which included two complete responses (CRs) and six very good partial responses (PRs). But while the median duration of response was just 4.4 months, one study investigator called the results “clinically meaningful” during the presentation.
Massimo Cristofanilli, MD, of Robert H. Lurie Comprehensive Cancer Center in Chicago, who voted in favor of accelerated approval based on the data said that this patient population cannot be studied in a randomized fashion, which the FDA had recommended. “They’re terminal phase, essentially pre-hospice,” he said. “Essentially, the study met the primary objective.”
As Pazdur alluded to, the drug’s activity appeared far more limited, if not non-existent. In a phase I dose-escalation study of 81 myeloma patients treated with selinexor, only seven responded (8.6%), including one complete response (CR) and six partial responses (PR). And of the 56 patients on selinexor monotherapy, there was only one response, and even this patient had apparently received dexamethasone as a concomitant medication.
FDA staff highlighted that in a randomized study of selinexor or physician’s choice of therapy in advanced acute myeloid leukemia (AML), selinexor was associated with worse overall survival compared with physician’s choice (94 vs 170 days, HR 1.18, 95% CI 0.79-1.75). Also, objective responses with the drug did not correlate with survival in this study.
Karyopharm argued that selinexor — a first-in-class, selective inhibitor of nuclear export that blocks the XPO1 protein, which is overexpressed on multiple myeloma cells — works synergistically with dexamethasone by increasing expression of the glucocorticoid receptor and its transitional activity, which increases the effect of the investigational drug, and that preclinical studies confirmed this synergy.
The FDA pointed to response rates with high-dose dexamethasone alone ranging from 10% to 27%, but one STORM investigator noted that these higher rates were not achieved in the modern era of novel agents in multiple myeloma, and that more recent data from 2013 put the efficacy for single-agent dexamethasone at 4%, as assessed by an independent review committee. The investigators in that study reported a 10% ORR.
At the meeting, Karyopharm presented updated median overall survival from STORM part 2 (8.6 months), and compared this with an expected survival of 3.5 to 5.6 months. But FDA staff pointed out that patients with an expected survival of less than 4 months had been excluded from the trial.
Karyopharm said there are precedents for accelerated approval in myeloma based on phase II studies, pointing to several agents that were approved after showing similar ORRs: carfilzomib in 2012 (22.9%), pomalidomide in 2013 (29.2%), and daratumumab in 2015 (29.2%).
But FDA staff noted that, in those studies, deaths from treatment-emergent adverse events (AEs) occurred in 4%, 5%, and 2%, respectively. With selinexor, 10% of patient deaths were due to treatment-emergent AEs. In all, almost 30% of patients in STORM part 2 discontinued treatment due to toxicity and nearly 90% required a dose reduction.
At least one grade 3/4 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.
Although the FDA is not required to follow its advisory committees’ recommendations, it typically does.