Selinexor Shows Meaningful, Durable Responses Linked With Improved OS in DLBCL

Single-agent selinexor (Xpovio) was found to induce durable responses with a manageable safety profile in patients with relapsed/refractory diffuse large B-cell lymphoma who had received at least 2 prior lines of chemoimmunotherapy, according to findings from the phase 2b SADAL trial.¹

Results showed an overall response rate (ORR) of 28% (n = 36/127; 95% CI, 20.7-37.0), which was the primary end point of the trial; this included a 12% complete response (CR) rate (n = 15) and a 17% partial response (PR) rate (n = 21; 95% CI, 10.5-24.2). The disease control rate (DCR) reported with the agent was 37% (95% CI, 28.6-46.0). Additionally, the median duration of response (DOR) was 9.3 months at a median follow-up of 11.1 months. For those with a CR, the median DOR was even higher, at 23.0 months; it was 4.4 months in those with a PR.

Moreover, at a median follow-up of 14.7 months, the median progression-free survival (PFS) reported with single-agent selinexor was 2.6 months; the median overall survival (OS) was 9.1 months. Median OS was not yet reached in patients who responded to the agent, and it was 18.3 months in those who achieved stable disease. Patients who experienced disease progression or unevaluable response experienced a median OS of 4.3 months. Notably, more than half of the patients, or 65%, who had a target lesion at baseline and at least 1 following baseline assessment experienced a reduction in tumor burden with the treatment.

“The clinical outcomes for patients with heavily pretreated relapsed or refractory DLBCL are typically very poor, and hence results from the multinational phase 2b SADAL study are noteworthy,” lead author Prof Nagesh Kalakonda, MBBS, MRCP, FRCPath, PhD, of the University of Liverpool, said in a recent press release.² “In this population, single-agent oral selinexor demonstrated an ORR of 28%, including a CR of 12%. Responses were seen in all subgroups, regardless of age, gender, prior therapy, DLBCL subtype or prior stem cell transplant therapy…Responses were associated with longer survival, underscoring the potential of oral XPO1 inhibition as an oral, non-chemotherapeutic option for patients with R/R DLBCL.”

Patients with DLBCL who relapse following salvage treatment regimens are known to have a notably poor prognosis, which leaves a need for improved treatment options. Selinexor, a selective inhibitor of XPO1, which mediates the functional inactivation tumor suppressor proteins, can activate the growth-regulating effects of these proteins and reverse resistance to chemotherapy. Previously, selinexor monotherapy induced a promising ORR of 32%, with a CR of 10% in a phase 1 study.^3,4

The open-label, multicenter, phase 2b SADAL trial, which was conducted in 59 sites spanning 19 countries, was initially designed to evaluate the safety and efficacy of twice weekly selinexor at both a 60-mg dose and a 100-mg dose. Investigators observed that a 60-mg dose yielded an improved therapeutic window in a prespecified interim analysis, this resulting in the discontinuation of the 100-mg cohort.

Patients aged 18 years and older with pathologically confirmed de novo DLBCL or DLBCL that transformed from previously diagnosed indolent lymphoma were permitted to enroll on the trial. Patients also needed to have an ECOG performance score of 0-2 and have experienced progression following 2-5 lines of prior therapy or not be ineligible for autologous stem-cell transplant to participate. Those with primary mediastinal B-cell lymphoma were not included.

Patients who experienced PR or CR during a recent systemic anti-DLBCL therapy needed to wait 60 days before starting selinexor; all others began treatment 14 weeks after their last systemic anti-DLBCL therapy. Patients were given 60 mg of selinexor on day 1 and day 3 of each week until progressive disease, intolerable toxicities, or death. Patients were evaluated via PET and CT scans every 8 weeks to determine DLBCL status.

The primary end point of the trial was OR, and secondary end points included DOR and DCR. Exploratory end points included PFS, OS, time to progression, pharmacokinetic and pharmacodynamic end points, and subgroup analyses.

A total of 267 patients were randomized to either the 60-mg selinexor arm (n = 175) or the 100-mg selinexor arm (n = 92). During the course of the study, 48 patients were excluded, resulting in 127 patients included in the modified intention-to-treat and safety populations. The study saw a high rate of treatment discontinuation in patients who were given selinexor; 93% discontinued because of disease progression, 9 patients died, 7 were discontinued per physician decision, 9 stopped treatment due to adverse effects, and 13 withdrew of their own volition.

Additional results from subgroup analyses revealed a ORR of 34% in patients with germinal center B-cell subtype; this included a 14% CR rate and a 20% PR rate. Seven percent of patients were still responding to treatment at the last disease assessment prior to the data cutoff.

Additionally, the predictive or prognostic biomarker analysis showed that patients who had high c-Myc levels experienced a ORR of 13% and those with low levels had an ORR of 42% (P = .0024). Moreover, patients with a double- or triple-negative expressor status had an ORR of 9.7% versus 40.3% in those without either expressor status (P = .0056). “These differences were largely a reflection of c-Myc overexpression because expression levels of neither Bcl-2 nor Bcl-6 affected the ORR,” the authors wrote.

With regard to safety, nearly all patients (98%) experienced at least 1 treatment-emergent adverse effect (TEAE). The most common TEAEs reported with the agent included thrombocytopenia (61%), nausea (58%), fatigue (47%), anemia (43%), and decreased appetite (37%), among others. Most TEAEs were grade 1 or 2 in severity. The most common grade 3/4 toxicities included thrombocytopenia (46%), neutropenia (24%), anemia (22%), fatigue (11%), hyponatremia (8%), and nausea (6%). Most of the toxicities were found to be reversible with either the use of standard supportive care or through dose modifications.

“Because of the poor prognosis of patients with relapsed or refractory DLBCL after at least 2 previous regimens, the limitations of available therapeutic interventions, and the aging population, single-drug selinexor administered in the outpatient setting showed meaningful durable anti-DLBCL activity,” the authors concluded. “Responses were associated with substantially improved survival, underscoring the potential of oral XPO1 inhibition as an oral, non-chemotherapeutic option for patients with relapsed or refractory DLBCL.”

In June 2020, the FDA approved selinexor for use in adult patients with relapsed/refractory DLBCL, not otherwise specified, including DLBCL arising from follicular lymphoma, following at least 2 lines of systemic therapy. The regulatory decision was based on earlier findings from SADAL, in which the drug showed an ORR of 29%, including a CR of 13%.⁵

References

1. Kalakonda N, Maerevoet M, Cavallo F, et al. Selinexor in patients with relapsed or refractory diffuse large B-cell lymphoma (SADAL): a single-arm, multinational, multicentre, open-label, phase 2 trial. Lancet Haematol. 2020;7(7):e511–e522 doi: 10.1016/S2352-3026(20)30120-4
2. Karyopharm announces publication of Xpovio (selinexor) phase 2b SADAL study results in The Lancet Haematology. News release. Karyopharm Therapeutics Inc. June 24, 2020. Accessed July 21, 2020. https://bit.ly/32E1eZP.
3. Kuruvilla J, Savona M, Baz R, et al. Selective inhibition of nuclear export with selinexor in patients with non-Hodgkin lymphoma. Blood. 2017;129(24):3175-3183. doi:10.1182/blood-2016-11-750174
4. Ben-Barouch S, Kuruvilla J. Selinexor (KTP-330) – a selective inhibitor of nuclear export (SINE): anti-tumor activity in diffuse large B-cell lymphoma (DLBCL). Expert Opin Investig Drugs. 2020;29(1):15-21. doi:10.1080/13543784.2020.1706087
5. FDA approves selinexor for relapsed/refractory diffuse large B-cell lymphoma. News release. FDA. June 22, 2020. Accessed July 21, 2020. bit.ly/37VnEXd.