Selinexor for R/R DLBCL: Latest updates and data

Selinexor, an oral first-in-class selective inhibitor of nuclear export (SINE), received accelerated approval from the U.S. Food and Drug Administration (FDA) on June 22, 2020, for the treatment of patients with relapsed/refractory (R/R) diffuse large B-cell lymphoma (DLBCL). Selinexor has a novel mechanism of action, targeting cancer cells differently from the common cytotoxic therapies.¹ It acts as a selective inhibitor of the nuclear export protein, exportin 1 (XPO1), leading to nuclear accumulation and activation of various tumor suppressing genes (p53, p21, IkB) and concomitantly to a reduction in c-Myc and Bcl-2 oncogene expression.¹ Preclinical studies have shown that, due to these actions, selinexor induces cell cycle arrest and substantial apoptosis selectively in cancer cells, leading to tumor growth suppression.²

Selinexor is indicated for adult patients with R/R DLBCL, not otherwise specified or DLBCL transforming from follicular lymphoma, after at least two lines of systemic therapy, including progression after autologous stem cell transplantation (ASCT) for those who were candidates for ASCT. For more information on selinexor’s FDA approval, please read here. Submission for marketing authorization to the European Medicines Agency (EMA) is planned for 2021.³

The SADAL trial

Selinexor’s approval was granted following the results of the multicenter, open-label, phase IIb trial, SADAL (NCT02227251). The trial evaluated patients, aged ³ 18 with pathologically confirmed DLBCL, an Eastern Cooperative Oncology Group (ECOG) performance status of £ 2, who had received 2-5 prior lines of therapy, and had progressed following ASCT or were not eligible for ASCT.² The key patient baseline characteristics are shown below in Table 1.

Initially, the trial was designed to compare two doses of selinexor (60 mg and 100 mg twice weekly) but the 100 mg dose was discontinued after a protocol change in March 2017 due to similar response rates and fewer adverse events (AEs) observed with the 60 mg dose.² In total, 267 patients were randomized (175 patients to the 60 mg group and 92 to the 100 mg group). Then 48 patients were excluded from the 60 mg group, mainly due to the protocol amendment, resulting in 127 patients in the modified intention-to-treat (mITT) and safety populations for this group. Thus, patients received 60 mg of selinexor twice weekly (on Days 1 and 3 in 28-day cycles) until disease progression or intolerable toxicity. All patients received 8 mg of ondansetron, or equivalent, before the first dose of selinexor and continued two to three times daily, as needed.

The primary endpoint of SADAL was overall response rate (ORR) as assessed by Independent Central Radiological Review and based on the 2014 Lugano criteria.⁴ Secondary endpoints included duration of response (DoR) and disease control rate, and exploratory endpoints included progression-free survival and overall survival (OS).

Table 1. Key baseline patient characteristics from the phase IIb SADAL trial²

In total, 118/127 patients (93%) discontinued treatment with selinexor, mainly due to disease progression:

• Disease progression (n = 80)
• Death (n = 9)
• Physician decision (n = 7)
• AEs (n = 9)
• Withdrawal by patient (n = 13)

The reported efficacy results from the analysis of SADAL, published in Lancet Haematology,² are shown below in Table 2. The primary endpoint of ORR was 28% (95% CI, 20.7–37.0). Responses were similar across many different subgroups, independent of age, gender, previous lines, DLBCL subtype, refractory status, previous ASCT, or time since last therapy.

Table 2. Efficacy results reported from the SADAL trial²

At a median follow-up of 11.1 months, the median DoR was 9.3 months (95% CI, 4.8–23.0). The median DoR was 23.0 months (95% CI, 10.4–23.0) for patients with a CR and 4.4 months (95% CI, 2.0–not evaluable) for patients with a PR. The disease control rate was 37% (95% CI, 28.6–46.0). At a median follow-up of 14.7 months, median progression-free survival was 2.6 months (95% CI, 1.9–4.0) and median OS was 9.1 months (95% CI, 6.6–15.1).

In terms of safety, 98% of patients in the SADAL trial had at least one treatment-emergent AE, with the most common being thrombocytopenia (61%), nausea (58%), fatigue (47%), anemia (43%), decreased appetite (37%), diarrhea (35%), constipation (31%), neutropenia (30%), weight loss (30%), vomiting (29%), pyrexia (22%), and asthenia (21%). The most common AEs of Grade 3-4 are shown below in Table 3. These typically resolved with supportive care or dose modification. Dose modification due to treatment-emergent AEs occurred in 70% of patients. No Grade ³ 3 bleeding events were reported in patients with thrombocytopenia, and febrile neutropenia typically resolved following growth factor and antibiotic therapy. In general, selinexor side effects were reversible and manageable, with no specific organ toxicities.

Table 3. Most common Grade 3–4 AEs reported in the SADAL trial²

Post-hoc analyses of SADAL presented at EHA 2020

During the 2020 European Hematology Association (EHA) Annual Congress, multiple analyses of the SADAL trial were presented. We hereby summarize the key points and results from these subanalyses.

Survival outcomes from SADAL⁵

At EHA 2020, Maerevoet et al.⁵ reported analyses of the SADAL study investigating whether there were differences in OS among patients stratified by disease status, age, DLBCL subtype, ASCT, and response to last prior therapy. These are shown below in Table 4. At a median follow-up of 14.8 months, the OS was 9.0 months (95% CI, 6.2-13.7). Death occurred in 59% (n = 79) of patients. OS was similar across patients, irrespective of their age, DLBCL subtype, prior ASCT therapy, or refractory status to last therapy. Responding patients (≥ PR) did not reach a median OS.⁵

Table 4. Exploratory survival data from the SADAL trial reported at EHA 2020⁵

Safety and efficacy in primary refractory patients with DLBCL—SADAL post-hoc analysis⁶

At EHA 2020, Ziljlstra et al.⁶ presented a post-hoc analysis of the SADAL trial, evaluating the safety and efficacy of selinexor in a subgroup of patients with primary refractory DLBCL, defined as progression at or within one year of initial therapy. Seventy-one patients (52%) from the total cohort (N = 134) met these criteria for primary refractory DLBCL upon enrollment to SADAL. Of those, 30 were of the GCB subtype, 37 of non-GCB subtype, and four were unclassified. The median age of those patients was 65 years (range, 35-83).⁶ The efficacy and safety post-hoc data for patients with primary refractory DLBCL are shown below in Table 5 and Table 6, respectively. The ORR rates between patients with primary refractory DLBCL (25.4%) and the total cohort (see Table 2; 28%) were similar, with CR rates of 10% and 12%, respectively. Treatment-related AEs and the incidence of serious AEs were also comparable between primary refractory patients and the total cohort, as indicated in Table 6.

Table 5. Efficacy data in patients with primary refractory DLBCL from SADAL⁶

Table 6. Treatment-related AEs (≥ 5%) of Grade ≥ 3 in patients with primary refractory DLBCL in the SADAL study⁷

Effect of prior therapy on safety and efficacy of selinexor—SADAL subanalysis⁷

In this post-hoc analysis of the SADAL trial, presented at EHA 2020, Follows et al.⁷ evaluated the role of the number and type of prior therapies on the efficacy and safety of selinexor. Patients were subgrouped into those having received 2 vs > 2 prior lines or those with prior ASCT therapy vs those without ASCT treatment. The efficacy data from these subanalyses are shown below in Table 7 and Table 8, respectively. The data indicate that the number of prior lines does not affect the rate or durability of the responses to selinexor. However, patients who received prior ASCT had a significantly higher ORR compared with those without previous ASCT treatment (p = 0.04; Table 7).

Table 7. Effect of prior number of therapies on selinexor's efficacy⁷

Table 8. Effect of type of prior line on selinexor's efficacy⁷

The effect of the number and type of prior lines on selinexor’s safety are shown in Table 9. In summary, the frequency of observed toxicities was similar between all analyzed subgroups and irrelevant to the number or type of prior lines.

Table 9. Treatment-related AEs (≥ 5%) of Grade ≥ 3 in patients with different numbers or types of prior lines⁷

Molecular markers of selinexor response—SADAL molecular analysis⁸

During EHA 2020, Walker et al.⁸ presented a molecular analysis of the SADAL trial in an attempt to identify prognostic markers of selinexor response. The authors performed exome and RNA sequencing from tumor samples of 55 and 44 patients, respectively. Protein expression levels were inferred using RNA sequencing data. Mutation analysis for the most commonly mutated genes in DLBCL was also performed, and patterns were compared between responders and non-responders.

The mutation analysis showed that non-responders more frequently had mutations in the histone methyltransferase gene KTM2D and the kinase gene PIM1, indicating that such mutations may be linked to selinexor resistance. Mutation frequencies in responders vs non-responders are shown below in Table 10.

Table 10. Mutation analysis in selinexor responders and non-responders⁸

Gene expression analysis showed that, in total, 238 genes were differentially expressed between responders and non-responders to selinexor. These were mainly overexpressed genes in non-responders, which were mostly involved with extracellular matrix formation and adhesion proteins (DSC3, KRT10, KRT1, KRT6A, FLG, COL17A1).⁸

In terms of differences in protein expression levels between responders (n = 12) and non-responders (n = 21), the authors identified three protein activities that were associated with response to selinexor: (1) the inhibin subunit βA (INHBA), (2) the RNA polymerase I transcription factor RRN3 homolog, and (3) vestigial-like member 3 (VGLL3) proteins. In patients with the GCB molecular DLBCL subtype (n = 12), predictors of selinexor response seemed to be the three following protein activities: (1) collagen type I αI chain (COL1A1), (2) INHBA, and (3) CCR4-NOT transcription complex subunit 2 (CNOT2).⁸

Future trials

One upcoming trial that will provide further insights into the efficacy of selinexor in R/R DLBCL is the phase II/III XPORT-DLBCL-030 study (NCT04442022). This study will compare the efficacy of rituximab, gemcitabine, dexamethasone, and cisplatin (R-GDP) with or without selinexor in patients with R/R DLBCL who are not intended for ASCT or chimeric antigen receptor (CAR) T-cell therapy.

Additional resources

For more information on the current status of selinexor for the treatment of R/R multiple myeloma, click here.