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Selinexor for R/R DLBCL: Latest updates and data

Jul 17, 2020

Selinexor, an oral first-in-class selective inhibitor of nuclear export (SINE), received accelerated approvalfrom 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. 1It 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-Mycand Bcl-2oncogene expression . 1Preclinical 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 ³18 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. 2The 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. 2In 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. 4Secondary 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 trial 2

ASCT, autologous stem cell transplantation; DLBCL, diffuse large B-cell lymphoma; ECOG, Eastern Cooperative Oncology Group; GCB, germinal center B-cell; mITT,modified intention-to-treat; R/R, relapsed/refractory

Baseline characteristic

mITT cohort (n = 127)

Age, years

Median (range)

³70 years, %

 

67 (35 -87)

45

Male patients, %

59

ECOG, %

0

1

2

3

 

43

46

10

1

Time since DLBCL diagnosis, years

2.7 (1.38 -4.92)

DLBCL type, %

De novo

Transformed

 

74

24

DLBCL molecular subtype, %

GCB

Non-GCB

Unclassified

 

47

50

4

Double- or triple-hit DLBCL, %

Missing data

4

30

Prior ASCT therapy, %

30

Relapse within 1 year of DLBCL diagnosis, %

33

R/R DLBCL < 1 year after last ASCT therapy, %

17

Refractory to most recent systemic line, %

72

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, 2are 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 trial 2

CI, confidence interval; CR, complete response; GCB, germinal center B-cell; mITT, modified intention-to-treat; ORR, overall response rate; PD, progressive disease; PR, partial response; SD, stable disease

% (95% CI)

ORR

CR

PR

SD

PD or no response

mITT cohort (n = 127)

28.0

(20.7 -37.0)

12.0

(6.8 -18.7)

17.0

(10.5 -24.2)

9.0

(4.4 -15.0)

63.0

(54.0 -71.4)

GCB subtype

(n = 59)

34.0 (22.1 -47.4)

14.0

(6.0 -25.0)

20.0

(11.0 -32.8)

12.0

(4.9 -22.9)

54.0

(40.8 -67.3)

Non-GCB subtype

(n = 63)

21.0

(11.5 -32.7)

10.0

(3.6 -19.6)

11.0

(4.6 -21.6)

5.0

(1.0 -13.3)

75.0

(62.1 -84.7)

Unclassified

(n = 5)

60.0

(14.7 -94.7)

20.0

(0.5 -71.6)

40.0

(5.3 -85.3)

20.0

(0.5 -71.6)

20.0

(0.5 -71.6)

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 ³3 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 trial 2

AE, adverse event

Most common Grade 3 -4 AEs

%N

Thrombocytopenia

46

Neutropenia

24

Anemia

22

Fatigue

11

Hyponatremia

8

Nausea

6

 

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 SADAL 5

At EHA 2020, Maerevoet et al. 5reported 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 2020 5

ASCT, autologous stem cell transplantation; CI, confidence interval; CR, complete response; GCB, germinal center B-cell; HR, hazard ratio; mITT, modified intention-to-treat; NR, not reached; OS, overall survival; PD, progressive disease; PR, partial response; SD, stable disease

Data shown in months (95% CI)

Median OS

HR (95% CI)

mITT cohort (n = 127) 2

9.0 (6.2 -13.7)

Responding patients (CR; n = 18)

NR (29.7 -NR)

Responding patients (PR; n = 21)

NR (12.6 -NR)

Patients with SD (n = 11)

18.3 (11.1 -28.0)

Patients with PD or not evaluable (n = 84)

4.3 (3.0 -5.4)

Patients < 70 years (n = 74)

Patients ³ 70 years (n = 60)

11.1 (5.4 -28.0)

7.8 (6.1 -13.7)

0.72

(0.5 -1.1)

Patients with GCB (n = 63)

Patients with non-GCB (n = 66)

9.0 (5.0 -15.5)

8.3 (5.4 -16.9)

0.95

(0.6 -1.5)

Patients with prior ASCT (n = 40)

Patients without ASCT (n = 94)

10.9 (7.0 -NR)

7.8 (4.9 -13.7)

0.72

(0.4 -1.2)

Patients not refractory to last therapy (n = 30)

Patients refractory to last therapy (n = 96)

13.7 (6.6 -NR)

8.3 (5.2 -13.7)

0.8

(0.5 -1.4)

Safety and efficacy in primary refractory patients with DLBCL—SADAL post-hocanalysis 6

At EHA 2020, Ziljlstra et al. 6presented a post-hocanalysis 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). 6The efficacy and safety post-hocdata for patients with primary refractory DLBCL are shown below in Table 5and 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 SADAL 6

CR, complete response; DLBCL, diffuse large B-cell lymphoma; DoR, duration of response; GCB, germinal center B-cell; NR, not reached; ORR, overall response rate; OS, overall survival

 

ORR, %

DoR, months

OS, months

Primary refractory (n = 71)

25.4%

(CR, 10%)

4.8

(CR, 10.4)

7.8

(CR, NR)

DLBCL subtype

GCB (n = 30)

Non-GCB (n = 37)

Unclassified (n = 4)

 

30.0%

16.2%

75.0%

 

4.4

NR

1.9

 

7.0

7.8

28.0

Table 6. Treatment-related AEs ( ≥ 5%) of Grade ≥ 3 in patients with primary refractory DLBCL in the SADAL study 7

AE, adverse event; DLBCL, diffuse large B-cell lymphoma; mITT, modified intention-to-treat

 

mITT cohort, %

(n = 134)

Primary refractory DLBCL, %

(n = 71)

Thrombocytopenia

40.3

39.4

Neutropenia

24.6

29.6

Anemia

14.9

15.5

Fatigue

10.4

11.3

Hyponatremia

5.2

8.5

Leukopenia

5.2

8.5

Nausea

6.0

5.6

Serious AEs

20.9

18.3

Effect of prior therapy on safety and efficacy of selinexor—SADAL subanalysis 7

In this post-hocanalysis of the SADAL trial, presented at EHA 2020, Follows et al. 7evaluated 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 vsthose without ASCT treatment. The efficacy data from these subanalyses are shown below in Table 7and 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 efficacy 7

CR, complete response; DoR, duration of response; ORR, overall response rate; OS, overall survival

 

2 prior lines

(n = 79)

> 2 prior lines

(n = 55)

p value

mITT cohort 2

(n = 127)

ORR

27.8%

30.9%

0.85

28.0%

CR

15.2%

10.9%

0.65

12.0%

Median DoR (months)

10.4

8.4

0.40

9.3

Median OS (months)

9.1

8.2

0.77

9.1

Table 8. Effect of type of prior line on selinexor's efficacy 7

ASCT, autologous stem cell transplantation; CR, complete response; DoR, duration of response; mITT, modified intention-to-treat; ORR, overall response rate; OS, overall survival

Statistical significance is indicated by bold font.

 

Prior ASCT

(n = 40)

No prior ASCT

(n = 94)

p value

mITT cohort 2

(n = 127)

ORR

42.5%

23.4%

0.04

28.0%

CR

15.0%

12.8%

0.94

12.0%

Median DoR (months)

8.4

9.7

0.93

9.3

Median OS (months)

10.9

7.8

0.19

9.1

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 lines 7

AEs, adverse events; ASCT, autologous stem cell transplant; mITT, modified intention-to-treat

 

mITT cohort

(n = 134)

2 prior lines

(n = 79)

> 2 prior lines

(n = 55)

Prior ASCT

(n = 40)

No prior ASCT

(n = 94)

Thrombocytopenia, %

40.3

36.7

45.5

62.5

30.9

Neutropenia, %

24.6

22.8

27.3

27.5

23.4

Anemia, %

14.9

16.5

12.7

12.5

16.0

Fatigue, %

10.4

10.1

10.9

7.5

11.7

Nausea, %

6.0

6.3

5.5

7.5

5.3

Hyponatremia, %

5.2

5.1

5.5

0.0

7.4

Leukopenia, %

5.2

6.3

3.6

10.0

3.2

Serious AEs, %

20.9

22.8

18.2

22.5

20.2

Dose reduction, %

38.8

34.2

45.5

50.0

34.0

Discontinuation, %

9.0

8.9

9.1

10.0

8.5

Molecular markers of selinexor response—SADAL molecular analysis 8

During EHA 2020, Walker et al. 8presented 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 KTM2Dand the kinase gene PIM1, indicating that such mutations may be linked to selinexor resistance. Mutation frequencies in responders vsnon-responders are shown below in Table 10.

Table 10. Mutation analysis in selinexor responders and non-responders 8

Gene

Mutation frequency, %

Responders with mutations, % (n = 21)

Non-responders with mutations, % (n = 34)

KMT2D

27

14

35

SPEN

15

19

12

PIM1

11

5

15

CREBBP

11

14

9

BCL2

9

5

12

CARD11

7

10

6

TNFRSF14

7

10

6

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.

  1. Kalakonda N, Cavallo F, Follows G, et al. A Phase 2b study of selinexor in patients with relapsed/refractory (R/R) diffuse large B‐cell lymphoma (DLBCL). Hematol Oncol. 2019;37(S2):62-64. DOI: 10.1002/hon.31_2629
  2. 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
  3. Karyopharm Theurapeutics. Karyopharm announces FDA approval of XPOVIO® (selinexor) for the treatment of patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL). https://investors.karyopharm.com/news-releases/news-release-details/karyopharm-announces-fda-approval-xpovior-selinexor-treatment. Published June 22, 2020. Accessed July 09, 2020.
  4. Cheson BD, Fisher RI, Barrington SF, et al. Recommendations for initial evaluation, staging, and response assessment of Hodgkin and non-Hodgkin lymphoma: The Lugano classification. J Clin Oncol. 2014;32(37):3059-3068. DOI: 10.1200/JCO.2013.54.8800
  5. Maerevoet M, Zijlstra JM, Follows G, et al. Survival among patients with relapsed/refractory (R/R) diffuse large B-cell lymphoma (DLBCL) treated with single agent oral selinexor in the SADAL study. Poster #EP1260. 25th EHA Annual Congress; Jun 12, 2020; virtual.
  6. Zijlstra JM, Follows G, Casasnovas R, et al. Efficacy and Safety of Single Agent Oral Selinexor in Patients with Primary Refractory Diffuse Large B-cell Lymphoma (DLBCL): A Post-hoc Analysis of the SADAL Study. Poster #EP1226. 25th EHA Annual Congress; Jun 12, 2020; virtual.
  7. Follows G, Casasnovas R, Vermaat J.S.P, et al. Effect of prior therapy on the efficacy and safety of oral selinexor in patients with relapsed/refractory (R/R) diffuse large B-cell lymphoma (DLBCL): A post-hoc analysis of the SADAL study. Poster #EP1244. 25th EHA Annual Congress; Jun 12, 2020; virtual.
  8. Walker C, Shen Y, Alvarez MJ, et al. Comprehensive assessment of molecular markers of selinexor response in patients with diffuse large B-cell lymphoma (DLBCL). Poster #EP1328. 25th EHA Annual Congress; Jun 12, 2020; virtual.