Efficacy and Safety of Selinexor (KPT-330) inRecurrent ... · Selinexor: First-in-Class, Oral...
Transcript of Efficacy and Safety of Selinexor (KPT-330) inRecurrent ... · Selinexor: First-in-Class, Oral...
Efficacy and Safety of Selinexor(KPT-330) in Recurrent Glioblastoma
(KING)Andrew B. Lassman1, Patrick Y. Wen2, Martin van den Bent3, Scott R. Plotkin4, Annemiek Walenkamp5, Adam Green2,6, Xiu Huang7, Karla Rodriguez-Lopez7,
Michael G. Kauffman7, Sharon Shacham7, Morten Mau-Soerensen8
1
1Columbia University Irving Medical Center, New York, NY, USA; 2Dana Farber Cancer Institute, Boston, MA, USA;3Erasmus MC Cancer Center, Rotterdam, The Netherlands; 4Massachusetts General Hospital, Boston, MA, USA;
5University of Groningen, Groningen, The Netherlands; 6Currently: University of Colorado, School of Medicine, Aurora, CO 7Karyopharm Therapeutics Inc, Newton MA, USA; 8Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark
Department of Neurology &Herbert Irving Comprehensive Cancer Center
Andrew B. Lassman, MS, MDRhodes GBM Center
Selinexor: First-in-Class, Oral Selective Inhibitor of Nuclear Export (SINE)1-4
1Green et al., Neuro-Oncology, 2014, 2Argueta et al., Oncotarget, 2018, 3Shang et al., Sci Rep, 2018, 4Wahba et al, MCT 2018
2Department of Neurology &Herbert Irving Comprehensive Cancer Center
Andrew B. Lassman, MS, MDRhodes GBM Center
• Exportin 1 (XPO1) is a major nuclear exporter.
• Increased XPO1 inactivates tumors suppressor proteins by mislocalization
• Selinexor: selective XPO1 inhibitor
KING (KPT-330 in Recurrent Glioblastoma) Study Design
3
Primary Objectives: • ARM A: Surgical arm to explore intra-tumoral pharmacokinetics (PK) • ARMs B-D: 6mPFS rate
Patient Population:• Recurrent/Progressive GBM (after RT and Temozolomide), no prior bev/VEGFRi• Age ≥18 years, KPS ≥60, measurable disease (arms B-D)
Cycle = 4 w, treat until PD (RANO by local MD, MRI q 8 w)
Selinexor: 50 mg/m2 BIW↓
Resection↓
Resume Selinexor
ARM A (n=8)
Selinexor: 50 mg/m2 BIW
ARM B (n=24)
Selinexor: 60 mg BIW
ARM C (n=14)
Selinexor: 80 mg QW
ARM D (n=30)
Surgical Arm – PK Analysis Medical Arms: Safety & Efficacy
Department of Neurology &Herbert Irving Comprehensive Cancer Center
Andrew B. Lassman, MS, MDRhodes GBM Center
KING Study Results
4
Pharmacokinetic results have demonstrated reasonable intra-tumor penetration with tumor concentration of SEL averaging 136nM (~2h post dose, n =6) in a range of the mean
in vitro IC50 of 133 nM.
Surgical Arm A – PK Analysis (WFNOS 2017 Results)
Modified Intent to Treat (mITT) Population – Safety & Efficacy Analyses (ARMs B, C, D)
ARM B ARM C ARM D
Selinexor 60 mg BIWTolerable but efficacy
limited
Selinexor 80 mg QW WFNOS 2017: Tolerable and responses observed
(WFNOS 2017) à Expanded
Selinexor 50 mg/m2 BIW 2 more arms added to explore dose/schedule
Department of Neurology &Herbert Irving Comprehensive Cancer Center
Andrew B. Lassman, MS, MDRhodes GBM Center
Randomized to ARM C or D (1:1)
Patient Characteristics
5
ARM A ARM B ARM C ARM D
Patients Enrolled as of 1-May-2019 8 24 14 30
Age: Years median (range) 58 (43-65) 50 (29-69) 52 (27-65) 56 (21-78)
Men (%) : Women (%) 88% : 12% 79% : 21% 64% : 36% 63% : 37%
Median Prior Therapies 2 (1-3) 1 (1-3) 1 (1-3) 2 (1-7)
Karnofsky Performance Score (KPS): Median
Patients KPS – 60%
Patients KPS – 70% – 80%
Patients KPS – ≥90%
80%
--
5 (63%)
3 (37%)
90%
2 (8%)
8 (33%)
14 (58%)
90%
1 (7%)
4 (29%)
9 (64%)
80%
2 (6%)
14 (47%)
14 (47%)
Department of Neurology &Herbert Irving Comprehensive Cancer Center
Andrew B. Lassman, MS, MDRhodes GBM Center
Treatment-Related non-Hematological Adverse Events in ≥10% of Patients (mITT)
6
AE Term Arm B – 50 mg/m2 BIW (n=24) Arm C – 60 mg BIW (n=14) Arm D – 80 mg QW (n=30)Gastrointestinal Grade 1/2 Grade 3 Grade 1/2 Grade 3 Grade 1/2 Grade 3
Nausea 9 (37.5%) 1 (4.2%) 9 (64.3%) -- 19 (63.3%) --Anorexia 11 (45.8%) -- 10 ( 71.4%) -- 8 (26.7%) --Vomiting 8 (33.3%) -- 5 (35.7%) -- 10 (33.3%) --Diarrhea 3 (12.5%) -- -- -- 4 (13.3%) --Altered Taste 9 ( 37.5%) -- 6 (42.9%) -- 7 (23.3%) --Constipation 2 (8.3%) -- 4 (28.6%) -- 5 (16.7%) --
Constitutional Fatigue 10 (41.7%) 7 (29.2%) 8 (57.1%) 2 (14.3%) 14 (46.7%) --Weight Loss 5 (20.8%) -- 5 (35.7%) 1 (7.1%) 2 (6.7%) --Confusional State 1 (4.2%) -- -- -- 4 (13.3%) --Malaise -- -- 3 (21.4%) -- 3 (10.0%) --
OtherHyponatremia 9 (37.5%) 1 (4.2%) 2 (14.3%) -- 1 (3.3%) --Vision Blurred 5 (20.8%) 1 (7.1%) 2 (14.3%) -- 2 (6.7%) --
Data cutoff 01-May-2019;
• No Grade 4 treatment-related AEs were reported in ≥10% patients • No Grade 5 treatment-related AEs were reported
Department of Neurology &Herbert Irving Comprehensive Cancer Center
Andrew B. Lassman, MS, MDRhodes GBM Center
Treatment-Related Hematological Adverse Events in ≥10% of Patients (mITT)
7
AE Term Arm B – 50 mg/m2 BIW (n=24) Arm C – 60 mg BIW (n=14) Arm D – 80 mg QW (n=30)
Hematological Grade 1/2 Grade 3 Grade 1/2 Grade 3 Grade 1/2 Grade 3 Grade 4
Leukopenia 8 (33.3%) 1 (4.2%) -- 1 (7.1%) 12 (40.0%) 1 (3.3%) --
Neutropenia 4 (16.7%) 3 (12.5%) -- 2 (14.3%) 7 (23.3%) 3 (10.0%) --
Anemia 5 (20.8%) -- 1 (7.1%) -- 7 (23.3%) -- --
Thrombocytopenia 14 (58.3%) 2 (8.3%) 4 (28.6%) -- 7 (23.3%) -- --
Lymphopenia 2 (8.3%) 1 (4.2%) -- -- 3 (10.0%) 1 (3.3%) 1 (3.3%)
Data cutoff 01-May-2019
• No Grade 5 treatment-related AEs were reported
Department of Neurology &Herbert Irving Comprehensive Cancer Center
Andrew B. Lassman, MS, MDRhodes GBM Center
KING Efficacy
8
• 19% of patients on ARM D achieved 6 month PFS rate (180 days)
• 30% of patients on ARM D achieved 6 cycle PFS rate (180 – 14 days)
ARM B – 50 mg/m2 BIW ARM C – 60 mg BIW ARM D – 80 mg QW
N 24 14 30
6mPFS rate (95% CI) 10% (3 – 35) NE 19% (9 – 41)
6 cycle PFS rate (95% CI) 15% (5 – 40) 11% (2 – 68) 30% (17 – 54)
Overall Response Rate (PR + CR) 8% 7% 10%
Median OS (95% CI) months 9.0 (4.9 – 16.4) 8.5 (7.8 – NE) 9.4 (7.0-NE)
Data cutoff as of May 1, 2019, response by local investigators per Response Assessment in Neuro-Oncology (RANO).CR=Complete Response, PR=Partial Response, OS=Overall Survival, PFS=Progression Free Survival
Department of Neurology &Herbert Irving Comprehensive Cancer Center
Andrew B. Lassman, MS, MDRhodes GBM Center
0 3 6 9 12 18 27 360
25
50
75
100
Months
Percent S
urvival
0 3 6 9 12 18 27 360
25
50
75
100
Months
Percent S
urvival
ARM D Results – PFS and OS
9
Progression Free Survival Overall Survival
n=30n=30
Median OS – 9.4 Months
Median PFS – 1.9 Months 95% CI (9 – 41)
Months 0 1.5 3.0 5.6 9.0 18.0 34.9
Patients at Risk 30 22 9 6 4 2 1
Months 0 2.8 6.1 9.0 12.0 17.7 29.9 30.0 34.9
Patients at Risk 30 24 20 10 5 4 3 2 1
Department of Neurology &Herbert Irving Comprehensive Cancer Center
Andrew B. Lassman, MS, MDRhodes GBM Center
Selinexor Tumor Effect
10
18
1
16
2
15
5
12
3
11
3
74
70
68
51
27
18
17
8 8
3 2
-16
-31
-32
-40
-78
-98
-10
0
21
6
94
79
54
49
21
0
-1
-13
-21
-24
-71
-10
0
75
8
29
7
16
7
14
3
10
6
97
76
66
60
41
33
29
26
22
15
9
6
0
-7
-11
-18
-55
-76
-96
-10
0
00
03
-03
60
30
1-0
25
00
03
-03
10
00
3-0
16
00
02
-02
60
00
2-0
30
00
03
-03
40
00
2-0
21
03
01
-02
20
00
2-0
14
00
02
-01
10
00
3-0
19
03
01
-00
30
30
1-0
12
03
01
-00
40
00
3-0
23
00
03
-02
40
00
2-0
17
03
01
-00
10
00
2-0
18
03
01
-01
30
00
3-0
29
03
01
-00
50
50
2-0
63
00
01
-03
70
30
1-0
44
05
01
-05
80
50
1-0
48
03
01
-04
50
30
1-0
51
05
01
-06
10
00
1-0
41
05
01
-04
90
50
1-0
54
05
01
-05
70
30
1-0
39
00
02
-07
40
00
1-0
38
00
02
-06
40
00
2-0
66
03
01
-03
30
00
2-0
70
05
01
-05
60
00
1-0
43
00
01
-04
60
50
1-0
53
00
02
-04
20
00
1-0
76
00
01
-04
00
00
2-0
75
00
01
-05
50
00
1-0
78
00
02
-06
90
50
2-0
52
05
01
-05
90
00
2-0
67
00
01
-07
10
30
1-0
28
00
01
-04
70
50
2-0
62
00
01
-06
4
-100
-50
0
50
100
cha
ng
e f
rom
ba
seli
ne
(%
)M
ax
imu
m r
ed
uct
ion
- s
um
of
dia
me
ters Arm D
Arm CArm B
Max
imal
tum
or v
olum
e △
(%)
Arms B-D pooled
↓ tumor size in 29%
>
Department of Neurology &Herbert Irving Comprehensive Cancer Center
Andrew B. Lassman, MS, MDRhodes GBM Center
* Denotes patient with increases beyond 100%
ARM B – 50 mg/m2
BIWARM C – 60 mg
BIWARM D – 80 mg
QW
ARM D – Survival
11Department of Neurology &Herbert Irving Comprehensive Cancer Center
Andrew B. Lassman, MS, MDRhodes GBM Center
TMZ x 5
PD #2 (post-op)
RT + TMZ AKTi+mTORi
PD #1
Selinexor • Durable PR (↓72%)• 80 mg QW ongoing > 3y
Patient 1: Durable PR 3L Therapy in Recurrent GBM
64 yo manuMGMT IDHwt (IHC & PCR)
rGBM(Subtotal resection)
Ongoing PR
Department of Neurology &Herbert Irving Comprehensive Cancer Center
Andrew B. Lassman, MS, MDRhodes GBM Center
13
Patient 2: Complete Response Patient Profile
36 year old man, RT+TMZ+/-Deptux-m x 7 m
IDHwt (IHC & PCR), mMGMT
Durable CR80 mg QW ongoing >15 m
Department of Neurology &Herbert Irving Comprehensive Cancer Center
Andrew B. Lassman, MS, MDRhodes GBM Center
Selinexor
80 mg/w
Ongoing CR, on treatment > 1y
14
• Selinexor achieves adequate intra-tumor penetration
• 80 mg po QW is recommended dose for further evaluation
• Side effects expected and manageable
• Anti-tumor activity, supporting further development
• Molecular correlative analyses ongoing to identify enrichment biomarker(s)
KING Conclusions
Department of Neurology &Herbert Irving Comprehensive Cancer Center
Andrew B. Lassman, MS, MDRhodes GBM Center
15
AcknowledgmentsPatients, their families, and caregivers
Investigators, co-investigators and study teams at each participating center
• Columbia University Irving Medical Center, New York, NY
• Dana Farber Cancer Institute, Boston, MA
• Erasmus MC Cancer Center, Rotterdam, The Netherlands
• Massachusetts General Hospital, Boston, MA
• University of Groningen, Groningen, The Netherlands
• Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark
This study was sponsored by Karyopharm Therapeutics
Department of Neurology &Herbert Irving Comprehensive Cancer Center
Andrew B. Lassman, MS, MDRhodes GBM Center