FDA Approves Oral Selinexor for R/R DLBCL

The FDA has approved oral selinexor (Xpovio) for the treatment of adult patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL), not otherwise specified, including DLBCL arising from follicular lymphoma, after at least 2 lines of systemic therapy, according to Karyopharm Therapeutics, the developer of the agent.

The indication was approved under accelerated approval based on response rate observed in the multi-center, single-arm phase 2b SADAL (Selinexor Against Diffuse Aggressive Lymphoma) study, though continued approval may be dependent upon verification and description of clinical benefit in a confirmatory trial(s).

Karyopharm indicated that selinexor will be commercially available immediately in this new indication in the US. Even further, a marketing authorization application for selinexor for relapsed or refractory DLBCL is planned for submission to the European Medicines Agency in 2021.

“For the significant number of patients with relapsed or refractory DLBCL, there is an important need for new therapies for this particularly vulnerable patient population,” John P. Leonard, MD, the Richard T. Silver Distinguished Professor of Hematology and Medical Oncology at Weill Cornell Medicine and an oncologist at NewYork-Presbyterian/Weill Cornell Medical Center, said in a press release. “Unfortunately, despite often multiple types of chemotherapy and targeted-drug combination therapy, many patients have disease which continues to progress.”

“The clinical profile and tolerability of oral [selinexor] provides physicians and patients with a new treatment alternative to traditional intravenous chemotherapy regimens,” Leonard continued.

The phase 2b SADAL study evaluated 134 patients with relapsed or refractory DLBCL, including patients with germinal center B-cell (GCB) or non-GCB subtypes of DLBCL. Participants were given a fixed dose of 60 mg of selinexor orally twice weekly for a 4-week cycle.

The primary endpoint of overall response rate (ORR) was met with an ORR of 29%, including 18 (13%) complete responses (CRs) and 21 (16%) partial responses (PRs). Moreover, key secondary endpoints included a median duration of response (DOR) in the responding patients. In the responding patients, 56% maintained a response at 3 months, 38% at 6 months, and 15% at 12 months.

All 134 patients enrolled were included in the safety analyses. The most common treatment-related adverse events (AEs) were cytopenias along with gastrointestinal and constitutional symptoms and were generally reversible and managed with dose modifications, as well as standard supportive care. The most common non-hematologic AEs were fatigue (63%), nausea (57%), decreased appetite (37%), and diarrhea (37%), and were mostly grade 1 and 2 events.

Grade 3 and 4 laboratory abnormalities in ≥15% of patients included thrombocytopenia, lymphopenia, neutropenia, anemia, and hyponatremia. Grade 4 laboratory abnormalities in ≥5% of patients were thrombocytopenia (18%), lymphopenia (5%), and neutropenia (9%).

“The accelerated approval of oral [selinexor] in patients with relapsed or refractory DLBCL is a significant milestone for the patients and families who currently have limited treatment options available for their disease,” Sharon Shacham, PhD, MBA, founder, president, and chief scientific officer of Karyopharm, said in a press release. “This approval marks the first for an oral agent for patients with previously treated DLBCL and the first approval of any single drug for this highly aggressive type of lymphoma.”

“Additionally, this is now the second commercial oncology indication for [selinexor], highlighting its novel mechanism of action, ease of administration and ability to produce rapid and durable responses in patients with heavily pretreated disease,” Shacham added. “We share this tremendous achievement with the patients, employees, caregivers and physicians who have tirelessly contributed to the advancement of [selinexor] from its original discovery and clinical development to today’s second FDA approval.”

In addition, as part of the accelerated approval, the FDA has agreed that the XPORT-DLBCL-030 study may serve as the confirmatory trial for evaluating selinexor in DLBCL. This trial will assess the effect of selinexor or placebo added to a standard backbone immunochemotherapy of rituximab-gemcitabine-dexamethasone-platinum (R-GDP) in patients with 1-3 prior treatments for DLBCL.

The rationale for this study is based on data from the ongoing Phase 1B study being conducted by the French Lymphoma Academic Research Organization (LYSARC). Karyopharm suggested that the XPORT-DLBCL-030 study is anticipated to begin by the end of 2020.

Reference:

Karyopharm Announces FDA Approval of XPOVIO® (selinexor) for the Treatment of Patients with Relapsed or Refractory Diffuse Large B-cell Lymphoma (DLBCL) [news release]. Published June 22, 2020. investors.karyopharm.com/news-releases/news-release-details/karyopharm-announces-fda-approval-xpovior-selinexor-treatment. Accessed June 22, 2020.