updates in the management of cll - winship cancer … in the management of cll susan o’brien, md...

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Winship Cancer Institute of Emory University

Updates in the Management of CLL

Susan O’Brien, MDProfessor of Medicine

Department of LeukemiaUniversity of Texas

M. D. Anderson Cancer Center

Disclosures

• Consulting Fees from:

– Amgen, Celgene, Emergent, Genentech, Gilead Sciences, Glaxo Smith Kline, Infinity, Pharmacyclics, Spectrum

• Advisory Board: CLL Global Research Foundation

• Research Support from:

─ Acerta, Emergent, Genentech, Gilead Sciences, Infinity, MorphoSys, Pharmacyclics, Spectrum, TG Therapeutics

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Targeting of BCR Signaling in CLL

• BCR-associated kinases are targets of new drugs in preclinical and clinical development

• Syk (spleen tyrosine kinase) inhibitors: R406, Portola’s Syk inhibitors1

• Btk (Bruton’s tyrosine kinase) inhibitors: ibrutinib, CC-292, ONO-4059, ACP196

• PI3 kinases: Isoform-Selective Inhibitor of PI 3-Kinases2, idelalisib, IPI-145, TGR-1202

1 Quiroga MP, et al. Blood 114(5):1029-37, 07/20092 Niedermeier M, et al. Blood 113(22):5549-57, 5/2009

Agent ORR Poster Abstract #’s

BTK inhibitorsIbrutinibCC-292ONO-4059ACP-196

71 – 88%31-67% (PR)

70% (PR)—

1631; 4163; 4166; 41821630; 4169

Oral—

PI3KΥ/δ inhibitorsIdelalisibGS-9820IPI-145AMG 319TGR-1202SAR245408 (XL147)

72-100%—

52%———

1632; 2878; 4176; 41802881

1633; 4167Oral43734170

Syk inhibitorsGS-9973FostamatinibPRT-2070

—55%—

1634——

Novel BCR-Directed Agents for CLLASH 2013 Therapy - Abstracts

ASH Annual Meeting. 2013. New Orleans, LA.

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Ibrutinib in Refractory CLL With 11q Deletion

Before 4 weeks

Pattern of Response:Blood Lymphocytes vs. Lymph Nodes

SPD

0 1 2 3 4 5 6 7 8 9 10 1

1

550

450

350

250

150

50

‐50

ALC

Month Month

‐100

‐75

‐50

‐25

0

25

0 12 3 4 5 6 7 8 9

10 1

1

SPD = sum of products of lymph node dimension

4

Ibrutinib Inhibits CLL Cell Migration Towards CXCL12 and CXCL13

*(0.059)

*(0.055)

*(0.048)

*(0.072)

Hollenriegel et al. ASH 2012

Ibrutinib Treatment Reduced Plasma CCL3 and CCL4 Levels in

Patients (N=28)

* * ** * *

* * ** * *

Hollenriegel et al. ASH 2012

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American Society of Clinical Oncology 2014, PCYC 1102/1103, O’Brien et al.

0% 2% 2%6% 4% 5%6% 4% 5%

65%80% 77%

3%1%13%

6% 8%

0%

20%

40%

60%

80%

100%

Best Response(Investigator-Assessed)

87%90% 89%

30 Month DOR, % (95% CI)

TN (n = 31)

100 (100 to 100)

R/R (n = 101)

79.1 (64.2 to 88.4)

Total (N = 132)

85.3 (74.4 to 91.8)

Median DOR,months (range)

NR (0 to 35.0+) NR (0 to 35.2+) NR (0 to 35.2+)

nPRCR

PRPR+LSDPD

5/6 patients who received prior idelalisib responded to ibrutinib (4PR, 1 PR+L)

2/5 responders continue treatment with one additional patient moving on to SCT


Mean

Hemoglobin +/‐SEM (g/L)

Months

90 50

100

110

120

130

140

2

Hemoglobin

Platelets

Platelet Counts and Hemoglobin Levels*

0 4 6 8 10 12 14 16 18 20 22 24 26 28 30

60

70

80

90

100

110

120

130

Mean

Plate

lets +/‐SEM

(109/L)

HemoglobinPlatelets

5361

5261

4859

4656

4455

4052

4252

4149

4047

3845

4250

4045

3944

3847

3642

3542

2735

3137

2128

2427

1523

1314

Patients with Results

*All treated patients with baseline anemia or thrombocytopenia

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0

10

20

30

40

50

60

70

80

90

100

Progression‐Free Survival (%)

0 6 12 18 24 30 36 42Months

TN

R/R

+ Censored

11

Progression-Free Survival

TN R/R30-month PFS 96.3% 68.4%

(95% CI) (76.5–99.5) (56.1–77.9)Median PFS Not reached Not reached



0

0.2

0.4

0.6

0.8

1.0

Progression‐Free Su

rvival (Proportion)

0 6 12 18 24 30 36 42

Months From Initiation of Study Treatment

12

Progression‐Free Survival by Cytogenetics (FISH) in Relapsed/Refractory Population

Del17p Del11qNo del17p/

11q

30‐monthPFS

45.9% 74.2% 89.0%

(95% CI) (25.0–64.6) (53.3–86.8) (69.0–96.4)

Median PFS

28.1 months Not reached Not reached

del17p

del11q

No del17p or del11q

+ Censored

7

American Society of Clinical Oncology 2014, PCYC 1102/1103, O’Brien et al. 13

Overall Survival

TN R/R

30-month OS 96.6% 79.9%

(95% CI) (77.9–99.5) (69.0–87.3)

Median OS Not reached Not reached0

10

20

30

40

50

60

70

80

90

100

Ove

rall

Su

rviv

al (

%)

0 6 12 18 24 30 36 42

Months

TN

R/R

+ Censored



Overall Survival by Cytogenetics (FISH) in Relapsed/Refractory Population

Del17p Del11q No del17p/11q

30‐monthOS

65.9% 84.9% 93.9%

(95% CI) (45.5–80.2) (64.5–94.0) (77.8–98.4)

Median OS Not reached Not reached Not reached

0

0.2

0.4

0.6

0.8

1.0

Overall Su

rvival (Proportion)

0 6 12 18 24 30 36 42

Months From Initiation of Study Treatment

+ Censored

del17p

del11q

No del17p or del11q

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Ibrutinib: Common AEs(All Grades, Regardless of Causality)

IWCLL 2013, PCYC 1102, Furman et al.

TN(n = 31)

R/R + HR(n = 85)

0% 20% 40% 60% 80%

Nausea

Dizziness

Hypertension

Muscle spasms

Rash

Arthralgia

Fatigue

Diarrhea

0% 20% 40% 60% 80%

Urinary tract…

URI

Hypertension

Arthralgia

Dyspepsia

Rash

Nausea

Grade 3Grade 1 Grade 2 Grade 4

• Primary Endpoint: PFS

• Stratification according to:– Disease refractory to purine analog chemoimmunotherapy (no response or <12

months)

– Presence or absence of 17p13.1 (17p del)

• At time of interim analysis, median time on study was 9.4 months

RESONATE™ Phase 3 Study Design

RANDOMIZE

Oral ibrutinib 420 mg once daily until PD or

unacceptable toxicityn=195

IV ofatumumab initial dose of 300 mg followed by 2000 mg x 11 doses over 24 weeks

n=196

1:1

Patients with previously treatedCLL/SLL

Protocol amended for cross over with support of Data Monitoring Committee and discussion with health authorities.PD, progressive disease.

Cross over to ibrutinib 420 mg once daily after IRC confirmed PD (n=57)

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Progression-Free Survival

0 3 6 9 12

195 183 116 38 7196 161 83 15 1 0

150

10

20

30

40

50

60

70

80

90

100

Progression‐Free Survival (%)

No. at riskIbrutinib:

Ofatumumab:

Months

Ibrutinib

Ofatumumab

Ofatumumab IbrutinibMedian time (mo)

8.08 NR

Hazard ratio

0.215

(95% CI) (0.146‐0.317)

Log‐rank P value

< 0.0001

• This represents a 78% reduction in the risk of PD or death with ibrutinib compared with ofatumumab

• Richter’s transformation was confirmed in 2 patients on each arm.• Another patient on the ibrutinib arm had transformation to prolymphocytic leukemia

NR, not reached

Overall Survival

Ofatumumab IbrutinibMedian time (mo) NR NRHazard ratio 0.434(95% CI) (0.238‐0.789)Log‐rank P value < 0.0049

Ibrutinib (n=195, 16 events)Ofatumumab (n=196, 33 events)

This represents a 57% reduction in the risk of death for the ibrutinib arm At the time of this analysis, 57 patients initially randomized to

ofatumumab were crossed over to receive ibrutinib following IRC-confirmed PD

NR, not reached

First patient cross over

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• Atrial fibrillation any grade: ibrutinib n=10, ofatumumab n=1– Discontinuation of ibrutinib in only 1 patient

Patients were ≥60 years old (median age 73)

Most had predisposing risk factors (a prior history of atrial

fibrillation or in the setting of a pulmonary infection)

• Bleeding-related AEs of any grade: most commonly petechiae and ecchymosesibrutinib 44%, ofatumumab 12%

– No difference in severe/major bleeding events:

ibrutinib n=2, ofatumumab n=3, 1 SDH with ibrutinib

– One patient discontinued ibrutinib due to a bleeding AE

– Concomitant anti-platelets or anticoagulants

50% ibrutinib and 39% ofatumumab

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Safety: Atrial Fibrillation and Bleeding-related Adverse Events

Month 2 - 6Month 1

Day 1 8 15 21 1 1 1 1 1

Ibrutinib 420 mg/d POonce daily

Ibrutinib and Rituximab (iR) in High-risk CLL

Rituximab (375 mg/m2)

Cycle 1 2 3 4 5 6

Month 7-12

Patients with benefit after 12 cycles continue on ibrutinib

Burger et al. ASH 2013

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Transient lymphocytosis on iR

Ab

solu

te l

ymp

ho

cyte

co

un

t (p

er µ

L)

Start of 1st Month

Week 2 Week 3

2 3 4 5 6 7 8 9 10 11 12 13 14 15 16

n=40

n=40

n=40

n=40

n=40

n=37

n=39

n=38

n=38

n=28n=32

n=11n=17

n=23n=23

n=17 n=25 n=10

Months

Week 1

N %

CR# 4 10

PR 34 85

ORR 37 95

NR 2 5

Best Response* (n=40)

*At 12 months or best response before study discontinuation# MRD-negative: 1/4, MRD level: 0.1, 0.2, 0.1%

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Progression-free Survival (PFS)of iR in Previously Treated CLL

0.00

0.25

0.50

0.75

1.00

Pro

port

ion

with

out

pro

gre

ssio

n/d

eath

0 2 4 6 8 10 12 14 16 18 20 22 24Months

0.00

0.25

0.50

0.75

1.00

Pro

port

ion

Su

rviv

ing

0 2 4 6 8 10 12 14 16 18 20 22 24Months

No: del 17p

del 17p

Median PFS at 18 months: 78%

All patients Del 17p versus others

Median PFS at 18 months: Del17p: 72%Others: 84%

Median follow-up: 17 months

Idelalisib is an Orally Bioavailable Small Molecule that Inhibits PI3K Delta Potently

and Selectively

Class IPI3K Isoform

Cell-

Based

Activity

PDGF-

induced

pAKT

LPA-

induced

pAKT

fMLP-

induced

CD63+

FcR1-

induced

CD63+

EC50 (nM) >20,000 1,900 3,000 8

Alpha Beta Gamma Delta

• Selectivity relative to Class I PI3K isoforms involved in insulin signaling and other physiological functions

• No off-target activity against Class II or III PI3K, mTOR, or DNA-PK• No off-target activity seen in screen of >350 protein kinases (Ambit KINOMEscan™)

Lannutti, Blood, 2011

Idelalisib

13

TSt‐4: IdelalisibTSt‐4: Control

Idelalisib Antagonizes BCR-Triggered CLL Cell Migration (Pseudoemperipolesis) Beneath Bone

Marrow Stroma Cells

Marked Reductions in Peripheral Lymphadenopathy Were Observed

Pretreatment With IdelalisibTreatment

38-year-old patient with refractory CLL and 5 prior therapies

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Idelalisib: Idelalisib Improvementof Baseline Cytopenias

Brown et al. ASCO 2013

Idelalisib: Nodal and Overall Response Rate

0

20

40

60

80

100

Res

po

nse

Rat

e 9

5% C

I

Overall Response

Lymph Node

Response

39%n=21

33%n=18

81%n=44 72%

n=39

Decrease by 50% of nodal SPD PR with lymphocytosis (Cheson 2012) PR by IWCLL criteria (Hallek 2008)

ALC (N=54)SPD (N=51)

ALC and Tumor Burden Over Time

15

Idelalisib: Progression-free Survival by Dose

Brown et al. Blood. 2014; e-publication, March 10, 2014.

0

0

Time from Start of Idelalisib, Months

% Progression‐Free

6 12 18 24 30 36 42 48

25

50

75

100≥150 mg BID (N=28): median PFS 31.9 months

<150 mg BID (N=26): median PFS 6.6 months

Idelalisib: Adverse Events (≥ 15%) and Selected Lab Abnormalities (N = 54)

AE, n (%) Any Grade, (%) Grade 3, (%)

Fatigue 17 (32) 1 (2)

Diarrhea 16 (30) 3 (6)Pyrexia 16 (30) 2 (4)

Cough 13 (24) 2 (4)

Back pain 12 (22) 0

Rash 12 (22) 0URI 12 (22) 0

Pneumonia 11 (20) 10 (19)

Night sweats 10 (19) 0

Chills 9 (17) 0

Laboratory abnormality, n (%)

AST, increased* 13 (24) 1 (2)

ALT, increased* 10 (19) 1 (2)*15 subjects total with transaminase elevations

Brown et al ASCO 2013

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Phase 2 Single Arm, Open Label Study of Idelalisib + Rituximab in Frontline CLL

Study Schema

Primary Study: 101-08

Extension Study: 101-99

Subject accrual

Oct 2010through

Apr 2012

Eligibility • Age ≥ 65 years • Treatment naive CLL requiring therapy (IWCLL

2008)• No exclusions for cytopenias

Disease assessment

• Investigator determined• Weeks 0, 8, 16, 24, 36, 48 and per SOC thereafter

Endpoints • Primary: ORR • Secondary: DOR, PFS, Safety

Rituximab(375 mg/m2)weekly x 8

Therapy continues as long aspatient receives benefit

Idelalisib (150 mg BID) x 48 wks

O’Brien et al ASCO 2013

Idelalisib + Rituximab: Response

All Patients Del(17p) and/or TP53 mutation

N = 64 (%) N = 9 (%)

Complete Response 12 (19) 3 (33)

Partial Response 50 (78) 6 (67)

Stable Disease 0 0

Progressive Disease 0 0

Not Evaluable 2 (3) 0

Overall Response 62 (97) 9 (100)

• Median Time to Response 1.9 months• 24/26 patients with B symptoms resolved by week 16

No on-study progressionO’Brien et al ASCO 2013

17

Deaths (n = 5)• Pneumonia/sepsis (1)• Pneumonia/metastatic melanoma (1)• Pneumonitis (2)• Myocardial infarction (1)

Adverse Event< 24 wks

n = 10*

24-48 wksn = 6

> 48 wksn = 7

Totaln = 23*

(%)

Diarrhea/colitis 0 3 5 8 (13)

Respiratory disorders

5 0 0 5 (8)

Rash 3 0 0 3 (5)

Anemia 1 1 0 2 (3)

ALT/AST 1 0 0 1 (2)

Other 2 4 2 8 (13)

Infections in first 48 weeks • 67% - any Grade• 23% - Grade ≥ 3• Grade ≥ 3 pneumonia in 14%

Idelalisib + Rituximab: Discontinuations

*patients may have > 1 AE

*ITT analysis of primary + extension studyExtension study assessments based on standard of care

Idelalisib + Rituximab in Frontline CLL: Progression-Free Survival*

5 10 15 20 25 300

20

40

60

80

100

All Patients N=64

TP53 mutation/ Del (17p) N=9

BL

Months

Pro

bab

ility

of

PF

S

Idelalisib + R(N = 64)

PFS at 24 months: 93%

Lamana et al. iwCLL 2013

18

Study 116: Randomized, Double‐Blind, Placebo‐Controlled

Extension Single‐Agent Therapy

Extension Study 117

RandomizedCombination Therapy

ContinuingSingle‐Agent Therapy

Primary Study 116

Arm A(N=110)

Arm B(N=110)

Idelalisib (150 mg BID)

Placebo (BID)

Rituximab (6 months)

Rituximab (6 months)

ScreeningIdelalisib

(150 mg BID)

Idelalisib (300 mg BID)

Rituximab administration• 375 mg/m2, then 500 mg/m2 Q2W x 4,then 500 mg/m2 Q4W x 3

Clinical Endpoints• Primary: PFS as assessed by IRC• Events: Disease progression or death • Secondary: ORR, LNR, OS

Dise

aseProgre

ssion

Planned interim analyses at 50% and 75% of events

Criteria RequirementRelapsed CLL • CLL progression <24 months since last therapy

• Treatment warranted according to IWCLL criteria

Lymphadenopathy • Presence of ≥1 measurable nodal lesion

Prior therapies • ≥ 1 anti-CD20 antibody containing therapy or ≥ 2 prior cytotoxic therapies

Appropriate for non-cytotoxictherapy

• CIRS score >6

or creatinine clearance <60 ml/min (≥30 mL/min)or Grade 3/4 neutropenia or thrombocytopenia due to prior myelotoxicity

Bone marrowfunction

• Any grade anemia, neutropenia or thrombocytopenia allowed

Karnofsky score • ≥40

Study 116: Key Eligibility

Furman et al NEJM 2014

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Primary Endpoint: Progression-Free Survival

AE, n (%)IDELA + R (N=110) Placebo + R (N=107)

Any Grade Grade 3 Any Grade Grade 3

Patients with any AE 100 (91) 62 (56) 101 (94) 51 (48)

Pyrexia 32 (29) 3 (3) 17 (16) 1 (1)Fatigue 26 (24) 3 (3) 29 (27) 2 (2)Nausea 26 (24) 0 23 (22) 0Chills 24 (22) 2 (2) 17 (16) 0Diarrhea 21 (19) 4 (4) 15 (14) 0Infusion-related reaction

17 (16) 0 30 (28) 4 (4)

Cough 16 (15) 0 27 (25) 2 (2)Decreased appetite 13 (12) 0 9 (8) 1 (1)Constipation 13 (12) 0 12 (11) 0Vomiting 13 (12) 0 8 (8) 0Dyspnea 12 (11) 2 (2) 20 (19) 3 (3)Rash 11 (10) 2 (2) 6 (6) 0Night sweats 11 (10) 0 8 (8) 0

Adverse Events ≥10% In Either Study Arm

Furman et al NEJM 2014

20

ABT-199: Potent and SelectiveBcl-2 Inhibition

• Small molecule, orally bioavailable

• High affinity for Bcl-2, lower affinity for Bcl-xL, Mcl-1

• >100-fold improved functional selectivity for Bcl-2 over Bcl-xL in assays with tumor cell lines

Souers AJ, et al. Nat Med. 2013;19:202-208.

Affinity Cellular Efficacy, EC50, nM

TR FRETKi, nM

FL5.12, 3% FBSHuman Tumor Cell

Lines, 10% HS

Agents Bcl-2 Bcl-xL Bcl-w Mcl-1 Bcl-2 Bcl-xL

FunctionalSelectivity

RS4;11(Bcl-2)

H146(Bcl-xL)

Navitoclax 0.04 0.05 7 > 224 20 13 0.6 110 75

ABT-199 < 0.01 48 21 > 444 4 261 65 12 3600

Dosing Schedule of ABT-199: Dose Escalation Schematic

*3 patients (1 each in cohorts 2, 3, & 5) received ABT-199 20 mg as initial dose.**Step-up doses range from 100 to 400 mg.DCD = Designated Cohort Dose

c

Lead‐in to Designated Cohort Dose ‐ Expanded Safety Cohort

Dose Escalation Scheme

Seymour et al. ASH 2013

21

Serious AEs*

Possibly/Probably ABT-199 RelatedPatients, n (%)

Febrile neutropenia (G3) 3 (5)

Tumor lysis syndrome (G3) 3 (5)

Sudden Death (G5)** 1 (2)

Viral URTI (G3) 1 (2)

Clostridium difficile infection (G3) 1 (2)

Escherichia sepsis (G3) 1 (2)

Influenza (G3) 1 (2)

Pneumonia (G3) 1 (2)

Sepsis (G3) 1 (2)

URTI (G3) 1 (2)

Fluid overload (G3) 1 (2)

Renal failure acute (G3) 1 (2)

Pulmonary embolism (G4) 1 (2)

*More than one SAE may have occurred in the same person; G = Grade; URTI = Upper respiratory tract infection**In the setting of tumor lysis syndrome. 41

Responses of ABT-199 Treated Patients

Responses

Alln (%) n = 56

del (17p)**n (%) n = 17

FludarabineRefractory**

n (%) n = 27

Overall response rate 47 (84) 14 (82) 24 (89)

Complete response 13 (23) 2 (12) 6 (22)

Partial response* 34 (61) 12 (71) 18 (67)

Stable disease 4 (7) 1 (6) 2 (7)

Disease progression 1 (2) 1 (6) ‐

D/C Prior to first (W6) assessment 4 (7) 1 (6) 1 (4)

42

*3 patients had confirmatory CT imaging assessments at less than an 8 week interval (5, 6, and 7 weeks).**10 patients were both del(17p) and fludarabine refractory.

• As of September 30, 2013, response data is limited for patients in the safety expansion (SE) cohort (n = 11)

• 4 patients in the SE cohort had a PR at their first scan, but were not evaluable• Evaluable patients had 2 CT scans, performed approximately 8 weeks apart• 9/13 in CR assessed for MRD: 5 MRD

22

Conclusions

• Several exciting new agents in clinical trials

• More selective than chemotherapy but not without toxicity

• Ibrutinib FDA approved - 2014

• Idelalisib will likely be approved later this year

• Already 2nd generation P13K and BTK inhibitors in clinical trials as well as SYK inhibitors

updates in the management of cll - winship cancer … in the management of cll susan o’brien, md...

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