Single Agent Oral Selinexor in Relapsed/Refractory
Diffuse Large B-Cell Lymphoma (DLBCL):
Phase 2b SADAL Study
M. Maerevoet, J. Westin, C. Thieblemont, J. Zijlstra, BT. Hill, F. De La Cruz Vicente, S. Choquet, P.
Caimi, J. Kaplan, M. A. Canales, J. Kuruvilla, G. Follows, E. Van den Neste, J. Meade, B. Wrigley, M.
Devlin, J.R Saint-Martin, C. Nippgen, H. Gardner, S. Shacham, M. Kauffman, R.O Casasnovas
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EHA 22 Congress European Hematology Association
Madrid, Spain June 22 – 25, 2017
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Disclosures
Research Support
Bayer, Karyopharm, Celgen, Roche, ARGNx
Consultant
N/A
Honoraria
Travel grant: Amgen, Roche, Takeda, Karyopharm
Scientific Advisory Board
Gilead, Takeda, Roche
Major Stockholder
N/A
Employee, Speakers Bureau
N/A
Selinexor is an investigational therapy not approved by EMA or FDA
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EHA 22 Congress European Hematology Association
Madrid, Spain June 22 – 25, 2017
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Background – Relapsed DLBCL
§ Diffuse large B-cell lymphoma (DLBCL) is the most
common type of non-Hodgkin lymphoma
§ ~60%
of
patients
are
cured
with
frontline
combination chemotherapy + anti-CD20 antibodies
§ Relapsed or refractory DLBCL can be cured by
platinum-based chemoregimens followed by high
dose chemotherapy and stem cell transplantation
(Gisselbrecht, CORAL study, JCO 2010)
§ The patients that have failed second line therapy or are not candidates for transplantation have a very
poor outcome (Crump, SCHOLAR study, ASCO 2016)
Ø Overall Response Rate: ~25% with available agents
Ø Median Overall Survival: < 6 months
§ R/R DLBCL represents a significant unmet medical need
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EHA 22 Congress European Hematology Association
Madrid, Spain June 22 – 25, 2017
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Xenograft
Toledo
Double hit DLBCL
DoHH2
XPO1 amplification
SUDHL-4
Stage IVb
OCI-Ly1
XPO1 is the major
nuclear export
IPI:4 protein
OCI-Ly10
Chemo-refractory
SUDHL-6
cytoplasm including:
(relapse within 3
HBL-1
months)
Ø Tumor Suppressor
SC-1 Proteins (TSPs)
K422
proteins by affectin
Viability: fluorescent assay based on the reduction of
resazurin into resorufin (Cell Titer Blue)
Background – Exportin 1 (XPO1)
§
Ø
§
Oncoprotein mRNAs (e.g., c-Myc,
Cell Cycle Profile: Propidium Iodide Staining and
subsequent
Flow Cytometry
analysiscertain proteins
for which
transports
Exposure to KPT330 results in nuclear ent
from the nucleus to the
Protein expression: SDS-PAGE and Western Blot Analysis
mRNA expression in nuclear vs. cytoplasm: cellular
fractionation by differential centrifugation followed by RNA
isolation
and RT-qPCR
Bcl-xL,
MDM2
and cyclins)
DNA damage repair kinetic: Alkaline Comet Assay
XPO1 in cancer cells:
Ø Inactivates TSPs by nuclear exclusion
Results
Ø Contributes to cell proliferation
XPO1 is highly expressed in DLBCL preferentially
in chemorefractory
cases >70% XPO1 positive cells
§ XPO1 is overexpressed in DLBCL; 60%
of R/R DLBCL having
XPO1 expression in chemosensitive and
XPO1 Expression
in Chemo-sensitive
and Chemochemorefractory
DLBCL patients
XPO1 expression in DLBCL
in tissues
DLBCL
A XPO1 Expression
by IHC
Tissues (by IHC)
41.3%
Sustained Response
SustainedResponse(CR2years)
>5% <30%
>30% <70%
46.5%
Exposure to KPT-330 for 24h reduce
refractory DLBCL Patient Cells
% of XPO1-positive cells
12.3%
Cells were exposed to KPT330 (0.5 µM) for 2
centrifugation. mRNA transcript for each gene
vs. untreated cells was computed
Relapsed/refractory
Relapsed/Refractory
KPT330
(0.5 µM)
-
LY1
Toledo
+
-
-
+
XPO1
MYC
40%
36.3
BCL2
60%
>70%
EHA
DoHH2
18.1%
45.4%
β-AC
Marullo AACR 2015
n=58
+
22nd
Congress European
n=23 Hematology Association
n=20
Madrid, Spain June 22 – 25, 2017
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Selinexor – Mechanism of Action
§ Selinexor:
Ø Oral small molecule, first-in-class inhibitor of XPO1,
inhibits cell growth and tumor apoptosis
Ø Reactivates
multiple
TSPs
and
reduces
oncoproteins known to play critical roles in NHL
Ø Blocks NF-kB activation
§ Phase I study of selinexor, monotherapy demonstrated
activity in heavily pretreated lymphomas including
GC/nonGC subtypes and DH DLBCL (Kuruvilla, Blood
2017). Responses were durable
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EHA 22 Congress European Hematology Association
Madrid, Spain June 22 – 25, 2017
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SADAL Study Design – NCT 02227251
§ A randomized Phase 2B study comparing 60 mg vs. 100 mg single agent oral selinexor in patients with relapsed/refractory
diffuse large B-Cell lymphoma (DLBCL)
Ø
Stratified by cell-of-origin subtype (GCB or non-GCB)
Ø
Twice Weekly / 28 Day Cycle
§ Endpoints:
Ø
Primary: Overall Response Rate (ORR), according Lugano Criteria 2014 (Cheson, JCO, 2014)
Ø
Secondary: Duration of Response (DOR), OS, and safety
§ Main Inclusion/Exclusion Criteria:
Ø
Patients ≥18 years with clinical or radiographic evidence of progressive DLBCL
Ø
Received at least 2 to maximum 5 previous systemic therapies (including anthracycline and mabthera)
Ø
≥14 weeks from last treatment
Ø
Excluded, any significant organ failure or ANC <1,000/mm3 or platelets <75,000/mm3,
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EHA 22 Congress European Hematology Association
Madrid, Spain June 22 – 25, 2017
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Baseline Patient Characteristics
60 mg
100 mg
46
44
Median Age, Years (range)
68 (44 – 87)
66 (30 – 83)
Males : Females
29 M : 17 F
28 M : 16 F
74% de novo : 26% trans
70% de novo : 30% trans
GCB Subtype
22 (48%)
23 (52%)
Non-GCB Subtype
Median Prior Regimens (range)
24 (52%)
3 (2 – 5)
21 (48%)
3 (2 – 5)
13 (28%)
18 (41%)
- High Risk
7 (15%)
7 (16%)
- High Intermediate Risk
18 (39%)
15 (34%)
- Low Intermediate Risk
14 (31%)
15 (34%)
- Low Risk
6 (13%)
5 (11%)
- Unknown
1 (2%)
2 (5%)
Patients Enrolled as of May 15, 2017 (N=90)
de novo DLBCL : Transformed DLBCL
- Prior Stem Cell Transplant
R-IPI Risk (Sehn 2007)
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EHA 22 Congress European Hematology Association
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Safety – Related Adverse Events Occurring in ≥10% of Patients (N=90)
60 mg
N=46
AE Term
Gastrointestinal
Nausea
Anorexia
Vomiting
Diarrhea
Altered Taste
Constipation
Constitutional
Fatigue/Asthenia
Weight Loss
Hematologic
Thrombocytopenia
Anemia
Neutropenia
Other
Hyponatremia
Dizziness
G 3/4 Total Grade 1/2
3 (6.5%) 19 (43.2%)
1 (2.2%) 19 (43.2%)
-11 (25%)
1 (2.2%) 13 (29.5%)
-2 (4.5%)
-4 (9.1%)
100 mg
N=44
Grade 3
Grade 4 G 3/4 Total
3 (6.8%)
-3 (6.8%)
6 (13.6%)
-6 (13.6%)
1 (2.3%)
-1 (2.3%)
3 (6.8%)
-3 (6.8%)
-------
Grade 1/2
21 (45.7%)
18 (39.1%)
16 (34.8%)
14 (30.4%)
6 (13%)
6 (13%)
Grade 3
3 (6.5%)
1 (2.2%)
-1 (2.2%)
---
Grade 4
-------
22 (47.8%)
12 (26.1%)
5 (10.9%)
--
---
5 (10.9%)
--
17 (38.6%) 11 (25%)
17 (38.6%) 1 (2.3%)
6 (13%)
8 (17.4%)
4 (8.7%)
8 (17.4%)
7 (15.2%)
5 (10.9%)
5 (10.9%)
-3 (6.5%)
13 (28.2%)
7 (15.2%)
8 (17.4%)
8 (18.2%)
8 (18.2%)
2 (4.5%)
1 (2.2%)
2 (4.3%)
3 (6.5%)
--
---
3 (6.5%)
--
1 (2.3%)
7 (15.9%)
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EHA 22 Congress European Hematology Association
Madrid, Spain June 22 – 25, 2017
---
11 (25%)
1 (2.3%)
9 (20.5%)
4 (9.1%)
6 (13.6%)
9 (20.5%)
-2 (4.5%)
18 (41%)
4 (9.1%)
8 (18.2%)
4 (9.1%)
--
---
4 (9.1%)
-8
8
Causes of Treatment Discontinuation (N=69)
60 mg (N=44)
100 mg (N=46)
Patients Off Treatment
34 (74%)
35 (80%)
Progressive Disease
21 (62%)
17 (49%)
Toxicity
6 (18%)
11 (31%)
Death
4 (12%)
3 (9%)
Other
3 (9%)
4 (11%)
Median Dose Received
51 mg
71 mg
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EHA 22 Congress European Hematology Association
Madrid, Spain June 22 – 25, 2017
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Efficacy – Pre-Specified Interim Analysis First 63 Patients
Best Responses† in the First 63 Patients as of May 15, 2017
Category
All Patients
(N=63)
60 mg (N=32)
100 mg (N=31)
GCB (N=32)
Non-GCB (N=31)
ORR (%)
21 (33.3%)
11 (34.4%)
10 (32.2%)
9 (28.1%)
12 (38.7%)
CR (%)
9 (14.3%)
4 (12.5%)
5 (16.1%)
4 (12.5%)
5 (16.1%)
PR (%)
12 (19.0%)
7 (21.9%)
5 (16.1%)
5 (15.6%)
7 (22.6%)
SD (%)
6 (9.5%)
1 (3.1%)
5 (16.1%)
3 (9.4%)
3 (9.7%)
PD/NE (%)
36 (57.1%)
20 (62.5%)
16 (51.6%)
20 (62.5%)
16 (51.6%)
†Responses
were adjudicated according to the Lugano Classification (Cheson, 2014) by an independent central radiological review committee.
ORR=Overall Response Rate (CR+PR), CR=Complete Response, PR=Partial Response, SD=Stable Disease, PD=Progressive Disease, NE=Nonevaluable. Responses are based on interim unaudited data as of May 15, 2017 for the first 63 patients (of 90 total patients).
Overall response rate as determined by an independent central radiological review
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EHA 22 Congress European Hematology Association
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Efficacy – ORR Subgroups
60%
CR
PR
50%
ORR 43.3%
ORR 40%
40%
ORR 33.3%
30%
ORR 33.3%
ORR 35.7%
7.1%
20%
14.3%
ORR 24.2%
28.6%
0%
26.7%
3%
14.3%
14.3%
19%
19%
9.1%
20%
10%
ORR 27.3%
19%
AllPatients
Double/Triple
HitPatients
(N=63)
(N=14)
23.3%
Relapsed
Disease
(N=30)
24.2%
15.2%
13.3%
Refractory
Disease
(N=33)
3rdLine
Patients
(N=30)
4th- 6thLine
Patients
(N=33)
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EHA 22 Congress European Hematology Association
Madrid, Spain June 22 – 25, 2017
denovo
TransDLBCL
DLBCL(N=42)
(N=21)
11
11
60_GCB
Responders (N=21) – Response Onset & Time on Treatment
60_NON-GCB
60_GCB
60_NON-GCB
60_NON-GCB
60_GCB
60_NON-GCB
60_GCB
60_NON-GCB
60_GCB
60_NON-GCB
60_GCB
Death
60_GCB
60_NON-GCB
60_NON-GCB
60_NON-GCB
PD
Response Censored
Response Censored
Response Censored
60_GCB
60_GCB
60_NON-GCB
60_NON-GCB
100_GCB
60_GCB
100_NON-GCB
60_NON-GCB
60 mg Patients
(median time on treatment: >10 months )
100_NON-GCB
100_GCB
Tox
100_GCB
100_NON-GCB
60_GCB
CR
100_NON-GCB
100_NON-GCB
60_NON-GCB
PR
Tox
100_NON-GCB
100_GCB
60_NON-GCB
100_NON-GCB
60_GCB
100_NON-GCB
100_GCB
60_NON-GCB
100_NON-GCB
100_GCB
60_NON-GCB
100_NON-GCB
0.00
60_GCB
100_GCB
60_NON-GCB
100_GCB
60_GCB 0
0
60_NON-GCB
100_GCB
Response Onset
Response Censored
100_NON-GCB
60_GCB
100_NON-GCB
2.00
PI Decision
Response Censored
4.00
6.00
Response Censored
Response Censored
2
2
4
4
8.00
6
6
On Treatment
100 mg Patients
(median
time14.00on treatment:
6.718.00
months )
12.00
16.00
10.00
8
8
10
10
12
12
14
14
Off Treatment
Off Treatment
16
18
16
18
Months on Treatment
100_NON-GCB
Among 21 responders, the median time on treatment was 9 months (median DOR >7 months, with a FUP of 13
months) 9 responders remain on treatment including 6 patients in CR
100_NON-GCB
100_GCB
100_NON-GCB
100_NON-GCB
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EHA 22 Congress European Hematology Association
Madrid, Spain June 22 – 25, 2017
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SADAL Efficacy – Overall Survival
SADAL - Overall Survival
All Patients (N=63)
Responders (N=21)
Non-Resp (N=42)
Percent survival
100
Not Reached
50
8 Months
4.5 Months
0
0
3
6
9
12
15
18
Months Following Randomization of Selinexor
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EHA 22 Congress European Hematology Association
Madrid, Spain June 22 – 25, 2017
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Summary and Conclusions
§ Selinexor, a first in class XPO1 inhibitor, has demonstrated activity in R/R DLBCL
§ Overall Response Rate of 33.3%
Ø Response rates were similar across subgroups (60 mg, 100 mg, GCB, non-GCB, DH/TH patients)
Ø Median of DOR >7 months including prolonged CRs
Ø The median overall survival is 8 months (median not reached in responding patients)
§
Most common adverse events:
Ø Fatigue, nausea, anorexia, vomiting (mainly grade 1/2), and thrombocytopenia (mainly grade 3/4)
Ø AEs can be managed with supportive care, dose reductions / interruptions
Ø 60 mg was better tolerated than 100 mg with less dose reductions or discontinuations
§
Based on AE profiles, discontinuation rates, efficacy signals:
Ø The 100 mg arm was discontinued
Ø Enrollment is ongoing with an additional 90 patients to be enrolled on the 60 mg arm
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EHA 22 Congress European Hematology Association
Madrid, Spain June 22 – 25, 2017
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Acknowledgements
Patients and their families
Investigators, co-investigators and study teams at each participating center
§
§
§
§
§
§
§
Institute Jules Bordet, Brussels, Belgium
MD Anderson, Houston, Texas, USA
APHP, Hopital Saint-Louis, Hemato-Oncology,
Paris, France
VU University Medical Center Amsterdam; on
behalf of Lunenburg Lymphoma Phase-I
Consortium, Amsterdam, Netherlands
Cleveland Clinic Taussig Cancer Institute,
Cleveland, Ohio, USA
Hospital University Virgen del Rocio, Sevilla Spain
Hospital Pitie Salpetriere, Paris, France
§
§
§
§
§
§
§
Northwestern University Feinberg School of
Medicine, Chicago, Illinois, USA
Hospital Universitario La Paz, Madrid, Spain
Princess Margaret Cancer Centre, Toronto, ON
Cambridge University Teaching Hospitals NHS
Foundation Trust, Cambridge, UK
University Hospital Seidman Cancer Center,
Cleveland, Ohio, USA
Cliniques Universitaires UCL Saint-Luc, Brussels
Belgium
CHU Dijon, Dijon, France
This study was sponsored by Karyopharm Therapeutics
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EHA 22 Congress European Hematology Association
Madrid, Spain June 22 – 25, 2017
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