FDA Approves Selinexor for Relapsed/Refractory DLBCL

The FDA has approved selinexor 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.¹

The regulatory decision was based on the phase 2b SADAL trial (NCT02227251), in which the agent demonstrated a 29% overall response rate (ORR; 95% CI, 22-38), including a complete response (CR) rate of 13%. Thirty-eight percent of the 39 patients who had achieved a partial response or CR had response durations of at least 6 months; 15% experienced response durations that lasted at least 12 months.

Selinexor is an oral selective inhibitor of exportin 1 (XPO1), which is the major nuclear export protein for tumor suppressor proteins and eIF4E-bound oncoprotein RNAs. XPO1 inhibition via selinexor promotes nuclear localization of eIF4E and activation of tumor suppressor proteins relevant to non-Hodgkin lymphoma including p53, p21, and IκBα, along with reductions in c-Myc and Bcl-2 oncogenes.

In the open-label, randomized phase 2b SADAL study, investigators are comparing a 60-mg versus 100-mg dose of twice-weekly selinexor monotherapy administered in 28-day cycles in this patient population. Eligible patients received 2 to 5 prior treatment regimens, and those who achieved a CR or a partial response (PR) to prior therapy required an 8-week washout before enrolling onto the trial.

A total of 129 patients were enrolled as of November 15, 2018. The median age of participants was 67 years (range, 35-87) and the median time from their DLBCL diagnosis was 2.1 years (range, <1-16.2). Patients received a median of 2 prior lines of treatment (range, 1-6), and 31% had prior transplant. Sixty patients had the germinal center B-cell (GCB) histology subtype, 63 had non-GCB, and 5 were unclassified.

Patients were evenly split between good prognosis (45%) and poor prognosis (46%) by the Revised-International Prognostic Index (2% were very good and 7% were unknown). One hundred fifteen patients have been evaluated for response.

Initial data were previously presented at the 2018 ASH Annual Meeting, which showed an ORR of 29.6%, along with a CR rate of 9.6%.3 The response rates were 34.0% in patients with the GCB subtype and 21.1% in those with the non-GCB subtype.² Median overall survival (OS) was 9.1 months in the modified intent-to-treat (mITT) group, improving to 29.7 months in patients who achieved a CR or PR.

The mITT group included patients who discontinued selinexor due to toxicity or disease progression, or who had died. The mITT population formed the primary analysis population and was used for exploratory analyses of efficacy.

In addition to the 11 patients who achieved CR, 23 (20.0%) achieved PR and 8 (7.0%) had stable disease. Among the 34 responders, the median DOR was 9.2 months (95% CI, 4.9-23.0). The median DOR was 23.0 months (95% CI, 4.9-23.0) among those who achieved CR and 7.8 months in those with PR (95% CI, 2.8-NE).

Seven of the 11 patients who achieved a CR are still on treatment. Forty-six patients with a post-baseline response reading had reductions in tumor burden.

Among patients with the GCB subtype, 5 (9.4%) had a CR, 13 (24.5%) had PR, and 5 (9.4%) had stable disease. Among those with the non-GCB subtype, the corresponding rates were 10.5%, 10.5%, and 5.3%, respectively.

The updated SADAL findings were presented at the 2019 International Conference on Malignant Lymphoma. The analysis included 134 evaluable patients who had received a median of 2 (range, 1-6) prior treatment regimens. Results showed that the 28.3% ORR comprised 36 responses, including 13 CRs and 23 PRs; the data submitted in the NDA included an additional 2 CRs.³ The disease control rate was 37%, which included 11 patients with stable disease.

Deep and durable responses occurred in patients, regardless of DLBCL subtype. Among the 59 patients with GCB histology, the ORR was 33.9%, and in the 63 patients with the non-GCB subtype, the ORR was 20.6%. In the remaining 5 patients, in whom the disease subtype was unclassified, there was 1 CR and 2 PRs. Responses were often rapid, and the median DOR was 9.2 months. Across the overall population, the median OS was 9 months. Among responders, the median OS had not yet been reached.

Regarding safety, the most commonly reported adverse events, excluding laboratory abornmalities, included fatigue, nausea, diarrhea, a decrease in appetite and weight, constipation, vomiting, and pyrexia. Grade 3/4 laboratory abnormalities that occurred in ≥15% of patients included thrombocytopenia, lymphopenia, neutropenia, anemia, and hyponatremia.

Serious AEs were observed in just under half of the participants, or 46%, and most of them were from infection. The most common event that led to dose modifications was thrombocytopenia. Furthermore, 80% of patients developed gastrointestinal toxicity, while 61% developed any-grade hyponatremia. Twenty-five percent of patients experienced central neurological AEs, such as dizziness and mental status changes.

References

1. FDA approves selinexor for relapsed/refractory diffuse large B-cell lymphoma. News release. FDA. June 22, 2020. Accessed June 22, 2020. bit.ly/37VnEXd.
2. Karyopharm Reports Updated Data from the Phase 2b SADAL Study at the 2019 International Conference on Malignant Lymphoma. News release. Karyopharm. June 19, 2019. Accessed June 22, 2020. bit.ly/2PO7qrc.
3. Maerevoet M, Vermaat J, Canales MA, et al. Single agent oral selinexor demonstrates deep and durable responses in relapsed/refractory diffuse large B-cell lymphoma (DLBCL) in both GCB and non-GCB subtypes: the phase 2b SADAL study. Blood. 2018;132(suppl 1677):626. doi: 10.1182/blood-2018-99-116868