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


• 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



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



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%)



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



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



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



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



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%

>



* 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


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



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



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



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



efficacy and safety of selinexor (kpt-330) inrecurrent ... · selinexor: first-in-class, oral...

Documents