Next Generation TKIs and Small Molecule Inhibitors

Jennifer R Brown, MD PhDDirector, CLL Center

Dana-Farber Cancer InstituteAssociate Professor of Medicine

Harvard Medical School

October 24, 2014

Targeting Kinases in the BCR Pathway

Idelalisib (GS-1101; CAL-101)Ibrutinib (PCI-32765)

Dasatinib FostamatinibEverolimus

Agent Sponsor ORR Development Phase

BTK inhibitors Ibrutinib CC-292 ONO-4059 ACP-196

Pharmacyclics, Inc.Celgene CorporationOno Pharmaceutical

Acerta

71 – 88%31-67% (PR)

89% (PR)—

Registration Phase III Phase IbPhase IPhase I

PI3KΥ/δ inhibitors Idelalisib GS-9820 IPI-145 AMG 319 TGR-1202 SAR245408 (XL147)

Gilead SciencesGilead Sciences

Infinity PharmaceuticalsAmgen

TG Therapeutics

Sanofi

72-100%—

89% nodal33% nodal

—

40% PR

Registration Phase IIIPending Phase I

Phase IIIPhase IPhase I

Phase I

Syk inhibitors GS-9973 Fostamatinib PRT-2070

Gilead SciencesRigel Pharmaceuticals

Portola

—55% nodal

—

Phase IIPhase I/II

Pending Phase I

BCR-Directed Agents in Development for CLL

Targeting Kinases in the BCR Pathway

IPI-145TGR-1202

CC-292 (AVL-292)ONO-4059

Kinase IC50, nM Btk selectivity, fold

BTK 0.5 --BLK* 0.5 1BMX* 0.8 1.6CSK 2.3 4.6FGR 2.3 4.6BRK 3.3 6.6HCK 3.7 7.4

EGFR* 5.6 11.2YES 6.5 13

ErbB2* 9.4 18.8ITK* 10.7 21.4

JAK3* 16.1 32.2FRK 29.2 58.4LCK 33.2 66.4RET 36.5 73FLT3 73 146TEC* 78 156ABL 86 172FYN 96 192

RIPK2 152 304c-SRC 171 342LYN 200 400

Ibrutinib is not a very specific BTK inhibitor

Patient AgeNo.

Prior Ther.

Cytogenetics Study Treatment

Duration on

Ibrutinib

Best Response

Identified Mutation

1 59 5del(17p13.1),

+12560 mg qd 621 days PR C481S BTK

2 75 2del(17p13.1),

complex karyotype

420 mg qd 673 days PRR665W PLCγ2

3 59 3 del(11q22.3)BR x 6 cycles,

420 mg qd388 days CR C481S BTK

4 51 2complex

karyotype

Ofatumumab x 24 weeks, 420

mg qd674 days CR C481S BTK

5 69 9del(17p13.1),

complex karyotype

840 mg qd 868 days PR C481S BTK

6 61 4del(17p13.1),

complex karyotype

Ofatumumab, x 24 weeks, 420

mg qd505 days PR

L845F PLCγ2,

C481S BTK

Mechanisms of Resistance to Ibrutinib

Chang et al., ASCO 2013; Stilgenbauer et al., IWCLL 2013; Woyach NEJM 2014

CC-292 Specificity

Kinase Cell Line CC-292Cellular

EC50

Btk Ramos 8 nM

EGFR A431 >4000 nM

Jak-3 CTLL-2 500-1000 nM

Itk Jurkat 1000 nM

Kinase CC-292 (IC50)

Btk <0.5

Brk 2430

c-Src 1729

Csk >10000

Fyn 7146

Hck 14460

Lck 9079

Syk 1134

Lyn 4401

Yes 723

Uncoupling PK PD with CC-292:Normal Volunteers, 2 mg/kg dose

Study Design

iNHLDose TBD

PART 1: Identify RP2D PART 2

CLL/SLL 500 mg BID

Cohort Dose (mg)

Once dailyDL 1DL 2DL 3DL 4DL 5DL 6a

125 QD250 QD400 QD625 QD750 QD

1000 QD

Twice dailyDL 6bDL7

375 BID500 BID

• Continuous 28-day oral dosing until PD or intolerable toxicity

– 3 + 3 design for cohorts 1-5

– 12 patients per cohort 6a, 6b, and 7 (6 CLL/SLL, 6 NHL/WM)

•Reported analyses focused on patients with CLL or SLL

Ongoing phase 1, multicenter, open-label, dose-escalation study (NCT01351935)

CLL/SLL 750 mg QD

RP2DCLL Expansion

Cohort

Dose Escalation

DLBCLDose TBD

Brown et al, EHA 2013

Baseline Characteristics (84 CLL/SLL patients enrolled from Aug 1, 2011 to July 1, 2013)

Median age, yrs (range) 66.5 (34-89)

Gender, male 58.8%

Rai stage 3-4 disease 53.6%

Median prior therapies, n (range) 3 (1-12)

Refractory 34.5%

Poor-risk factors11q del17p delUnmutated IgVH

56 (66.7%)18 (21.4%)20 (23.8%)45 (53.6%)

Study Population

Time on Study – All Patients

BTK Occupancy 4 Hrs Post Dose

BTK Occupancy 24 Hrs Post Dose

CC-292 Lymph Node Response by Dose and Time

Efficacy Assessment by Dose Level

Efficacy Assessment (N = 66)

Response Based on Prognostic Factors Efficacy Evaluable Patients at Active Doses

(N = 60)

ONO-4059

• ONO-4059 is a highly potent and selective, orally available Btk inhibitor that covalently binds to Cys-481 in Btk.

• Very high selectivity towards BTK (IC50 = 2.2 nm/L).• Bio-availability 40-50% with half-life of 5-7 hours and ∼ ∼ > 90% BTK

inhibition at 12 hours in CLL cells in vivo.

SykLyn

BtkPLCg2

PI3

K

P

PIP3CD

79A

CD

79B

PP

P

PP

ONO-4059

Y223

PDK

AKT

BLNK

PI3K/Aktpathway

MAPK/NF-kBpathway

B cell receptor

B-cell activation and proliferation

P

Yoshizawa T, et al (ICML, 2013)

Study ONO-4059POE001

3 months 6 months

TUMOR ASSESSMENT

• 3+3 phase 1 design• Once daily dosing (QD)• Initial 6 month treatment, with

option of additional 18 months,

+/- dose escalation• No restrictions on growth factor,

anticoagulant use• 6 sites (UK & France)

1 month

# 1 patient experienced Rash (Grade 2) resulting in 1 week drug interruption during Cycle 1 and another patient enrolled to ensure 3 patients completed the required 28 days drug administration in Cycle 1.

ONO-4059Dose

Number of patients(N=25)

20mg 3

40mg 3

80mg 4#

160mg 3

320mg 3

400mg 3

500mg 3

600mg 3

N = 25Age, median (range) 67 yr (40–79)Baseline SPD, median (range) 5,125 mm2 (461-19,750)Lymphocytes, median (range) 30.93 x 109/L (0.7-305)Platelets, median (range) 118 x 109/L (12-177)

Prior Therapies, Median (range) 4 (2-9)Prior rituximab 23 (92%)Prior fludarabine 23 (92%)

Refractory (last therapy) 12 (48%)

Prognostic factors (n =24*)

Cytogenetics 11q– (n = 6; 25%) 17p– (n = 9; 36%)

TP53 Mutated (n=13; 54%)

IgVH Unmutated (n =21; 87.5%)

Patient Demographics

0 4 8 12 16 20 240

50

100

150

200

250

0

20

40

60

80

100

120

Plasma concentration Btk inhibition

Time (hours)

Pla

sm

a C

on

ce

ntr

ati

on

of

ON

O-4

05

9(n

g/m

L)

Btk

In

hib

itio

n (

%)

40mg (QD) ONO-4059 Leads to Durable Btk Inhibition (pBtk/PBMCs)

Relapsed patient with 17p del; tumour reduction by CT-Scan: 64% (C3); 79% (C6); 86% (C10), 89% (C13); Haematology parameters normal at 3 month time-point

Related Grade 1-2 Adverse Events(in ≥ 2 Patients)

Adverse Event

Patient (N=25)

*CTC Grades 1-2

AEs

CTC Grade 1N

(Dose Level)

CTC Grade 2N

(Dose Level)

Haematoma 4 2 (500mg, 600mg) 2 (160mg, 400mg)

Rash 43 (40mg, 400mg,

600mg)1 (80mg)

Acne 33 (40mg, 80mg,

160mg)-

Asthenia 2 1 (160mg) 1 (20mg)

Diarrhea 2 1 (160mg) 1 (40mg)

Fatigue 2 2 (40mg, 80mg) -

Petechiae 2 1 (160mg) 1 (400mg)

Shingles 2 1 (500mg) 1 (40mg)

*Common Toxicity Criteria Adverse Events Version 4.0 (CTCAEV4.0)

Related Grade 3-4 Adverse Events (in ≥ 2 Patients)

Adverse Event

Patient (N=25)

*CTC Grade 3-4N

CTC Grade 3N

(Dose Level)

CTC Grade 4N

(Dose Level)

Neutropenia 5 2 (20mg, 40mg ) 3 (20mg, 80mg, 320mg)

• No DLTs observed• Two events of neutropenia (G3 at 20mg/G4 at 320mg) were

reversed rapidly using G-CSF• Patient who experienced neutropenia at dose 20mg (Grade 4),

also experienced an event of febrile neutropenia which was reported as an SAE. Patient’s neutrophil value at study entry was 0.1 x109/L (CTC Grade 4)

*Common Toxicity Criteria Adverse Events Version 4.0 (CTCAE V4.0)

Efficacy: Best Overall Response 84%

CR/CRi PRPR with

Lymphocytosis SD PDWithdrawn due to AE

2 12 7 1 1* 2#

Best Overall Response is 84% (21/25) based on CT-Scan and Hematological Parameters (IWCLL)

17p Deleted patients: Best Overall Response Rate of 89% (8/9)

Refractory patients: Best Overall Response rate of 92% (11/12)

* Patient ID 101-202 showed initial response to 20mg ONO-4059 with marked reduction of all palpable disease between D15/28 (based on physical examination). PD on D31 (suspected Richter’s Syndrome).# Patients ID 103-228 and 203-222 by investigator decision by experience of AE during cycle 1.

Screen-ing

Cycle 1 Cycle 3 Cycle 7 Cycle 10 Cycle 13 Cycle 19-100%

-50%

0% 20mg

40mg

80mg

160mg

320mg

600mg

400mg

500mg

% C

ha

ng

e f

rom

Ba

se

lin

e S

PD

Treatment Cycles (1 Cycle = 28 Days)

Rapid Lymph Node Reduction Observed

Change in Tumor Burden

-100%

-50%

0%

Ma

x %

Ch

an

ge

in

Tu

mo

r B

urd

en

Patient with17p deletionPatient with11q deletion

Patient without 17p or 11q deletion2 patients have no efficacy data as they withdrew after cycle 1

Absolute Lymphocyte Count over Time

Scree

ning

Cycle

1 D

ay 1

Cycle

1 D

ay 2

Cycle

1 D

ay 8

Cycle

1 D

ay 1

5

Cycle

1 D

ay 2

8

Cycle

3

Cycle

4

Cycle

5

Cycle

6

Cycle

7

Cycle

8

Cycle

9

Cycle

10

Cycle

11

Cycle

12

Cycle

13

Cycle

14

Cycle

15

Cycle

16

Cycle

17

Cycle

18

Cycle

19

0

50

100

150

200

250

300

350

400

450

20mg

40mg

80mg

160mg

320mg

600mg

400mg

500mg

Ab

so

lute

Ly

mp

ho

cy

te C

ou

nt

(10

9/L

)

Treatment Cycles (1 Cycle = 28 Days)

Scree

ning

Cycle

1 D

ay 1

Cycle

1 D

ay 2

Cycle

1 D

ay 8

Cycle

1 D

ay 1

5

Cycle

1 D

ay 2

8

Cycle

3 D

ay 1

Cycle

4 D

ay 1

Cycle

5 D

ay 1

Cycle

6 D

ay 1

Cycle

7 D

ay 1

Cycle

8 D

ay 1

Cycle

9 D

ay 1

Cycle

10

Day 1

Cycle

11

Day 1

Cycle

12

Day 1

Cycle

13

Day 1

Cycle

14

Day 1

Cycle

15

Day 1

Cycle

16

Day 1

Cycle

17

Day 1

Cycle

18

Day 1

Cycle

19

Day 1

Cycle

20

Day 1

Cycle

21

Day 1

Cycle

22

Day 1

60.00

80.00

100.00

120.00

140.00

160.00

Improvement in Hematological Parameters from 3 Months on Treatment

Mea

n H

aem

og

lob

in (

g/d

L)

Mea

n P

late

lets

(x1

09/L

)

Haemoglobin Platelets

N 25 22 16 12 3 2

10.00

11.00

12.00

13.00

14.00

15.00

Durable Responses Observed with ONO-4059 (QD)

20mg

40mg

80mg

320mg

600mg

160mg

500mg

400mg

0 10 20 30 40 50 60 70 80 90

Duration of Treatment (Weeks)

Withdrawn due to PD

Withdrawn due to AE

Continuing ONO-4059 Treatment

Median duration of treatment is 11.5 cycles (min 1/max 22)

Conclusion• ONO-4059

– Was safe with mostly grade 1 and 2 AEs and no DLTs.

– Achieved sustained Btk inhibition at doses of ≥ 40mg and has a half-life of 5-7 hours.

– Showed good efficacy over a range of doses with a best overall response of 84% in phase I with 21/25 patients.

– Showed particularly good efficacy in refractory and in 17p Del patients.

PI3K Signaling Pathway as a Target in B Cells

PI3K Delta: Target for B Cell Diseases

Tyrosine Phosphorylation

Class I PI3K Isoforms

Isoform Alpha Beta Delta Gamma

Expression Broad Broad Leukocytes Leukocytes

Gene KO effect on development Lethal Lethal Benign Benign

Primary physiological role

Insulin signalingAngiogenesis unknown

B-cell signaling, development & survival

Neutrophil &T-cell function

Phase 1 Trial of IPI-145 in Hematologic MalignanciesPreliminary Outcomes in CLL

Dose Escalation 8 mg BID 100 mg BID

MTD = 75 mg BIDCLL cohort 3

Tx Naïve 25 mg BIDn = 15

• R/R CLL (n=52) − Enrolled in dose-escalation and expansion cohorts (25 mg and 75 mg BID)

− Treatment Naïve CLL (n=15)− ≥ 65 years or 17p(del) / p53 mutation

• No restriction on cytopenias in CLL expansion cohorts− 40% ≥ Grade 3 cytopenias at baseline in R/R CLL

CLL cohort 1R/R ≤ 25 mg BID

n = 28

CLL cohort 2R/R 75 mg BID

n = 24

 R/R CLL

N=52Tx-Naïve CLL

N=15

Age (years), median (range) 66 (51-82) 74 (49-83)

Females, n (%) 11 (21) 4 (27)

Prior Systemic Therapies, median (range) 4.5 (1-12) n/a

< 6 Months Since Last Therapy 61% n/a

≥ Stage 3 (High-Risk) 73% 53%

Bulky Lymphadenopathy (> 5 cm lesion) 49% (23/47) 0

17p(del) or p53 mutation 53% (21/40) 54% (7/13)

Prior BTK-inhibitor Therapy, n 4 n/a

CLL Patient Characteristics

AEs ≥ Grade 3 in CLL Patients (All Causality, ≥ 5%)IPI-145 at <=25 mg BID

, g d Inhibition: IPI-145 Nodal Responses in CLL

R/R CLL• 98% (42/43) of patients had a reduction in adenopathy by CT

assessment • 89% (24/27) dosed ≤ 25 mg BID had a nodal response (≥ 50%

reduction)• ORR 47%, including in 17p deletion (ORR 50%)

Population

Patients (n)

Best Response (n) ORR

by IWCLL(CR + PR)

Evaluable CR PR SD PD

Overall R/R CLL 47 1 21 24 1 47%

≤ 25 mg BID 27 1 12 13 1 48%

17p(del) or p53mut 12 0 6 5 1 50%

75 mg BID

20 0 9 11 0 45%

17p(del) or p53mut 7 0 2 5 0 29%

Clinical Responses in R/R CLL, Including Patients with 17p(del) or p53 Mutation

• Median time to response in R/R CLL was < 2 months

Time on Study: R/R CLL Patients Receiving ≤ 25 mg BID IPI-145

Long-term progression free

Recently enrolled, data maturing

Discontinued

Potential to optimize future patient management

• 75% (6/8) patients treated for ≥ 1 year remain progression-free on treatment

• 8 recently enrolled patients (< 6 months) in early follow-up for PFS

TGR-1202

Savona et al., ASH 2013

Second-generation PI3K-delta inhibitor in early clinical development

Preliminary Safety/Efficacy

Savona et al., ASH 2013

Definite, Probable or Possibly Related AEs (N=22)

Adverse Event, nGrade 1 & 2

(>5% of patients)Grade 3

(all events)

Diarrhea 4 -

Neutropenia - 1

Rash - 1

Thrombocytopenia - 1

BCR Pathway Inhibitors In Relapsed CLL

DRUG NNodal Resp

Rate of Incr ALC ORR PFS

LYN (?BTK)

Dasatinib 15 47% NR 20% TTF 6.7m

SYK Fostamatinib 11 55% 69% NR 6.4m

mTOR Everolimus 22 45% 36% 18% 5.1m

PI3K Delta: GS1101 55 83% 58% 39% (72%)

16 m (32 m)

Pan-PI3K: S08 10 60% 50% 40% NR

Gamma Delta: IPI-145

52* 98% 64-73% 47% Too early

BTK Ibrutinib: PCI-32765

85 88% 78% 71% 75% @ 26m

CC-292:AVL-292

64* 60% 55% 45% Too early

ONO-4059 25* 84% 67% (28%) Too early

Summary

• Great enthusiasm for additional BTK and PI3K inhibitors– How will they differentiate?

• BTK: –Greater specificity –? Alternative binding site to overcome

resistance• PI3K:

–Different isoform specificity • Other BCR targets: SYK, mTOR, LYN• Other targets: BCL2 et al.

Acknowledgments

DFCI BiostatisticsDonna NeubergLillian WernerHaesook Kim Kristen Stevenson

Brown Lab, DFCIBethany TesarStacey FernandesSasha VartanovReina ImprogoJosephine Klitgaard

NIH, NHGRICLL Research Consortium

Okonow-Lipton FundMelton Fund Rosenbach Fund

Lymphoma Program, DFCIArnold S FreedmanDavid C FisherAnn S LaCasceEric Jacobsen Philippe ArmandMatthew Davids

Clinical ResearchKaren FrancoeurKaren CampbellShannon MililloHazel Reynolds

Center for CancerGenome Discovery, DFCIMegan HannaLaura Macconaill

Ian Flinn; Stephan Stilgenbauer; Gilles Salles; Matthew Davids; David Johnson

Wu Lab, DFCICatherine WuDan-Avi LandauLili WangYouzhong Wan

Broad Institute Eric LanderGaddy GetzCarrie SougnezNir HacohenStacey GabrielMike LawrencePetar StojanovAndrey SivachenkoKristian CibulskisDavid Deluca