Previously Untreated CLL

DEBATE: Do we have enough data to eliminate chemotherapy from initial CLL

therapy? Can kinase inhibitors and IMiDs replace chemotherapy?

Jennifer R Brown, MD PhDDirector, CLL Center

Dana-Farber Cancer InstituteOctober 25, 2013

1960s 1970s 1980s 1990s 2000s

Chemo-immunotherapy (CIT) 45% CR; better PFS & OSAlemtuzumab monotherapy 24% CRBendamustine 30% CR

Alkylating agents- Chlorambucil - Cyclophosphamide

5% CR

Purine nucleosides- Fludarabine- Pentostatin- Cladribine

5% - 20% CRBetter PFS in younger pts

Purine nucleosidesand alkylators

30% CRBetter PFS

Previously Untreated CLL

P<0.001

CLL8: Progression-Free Survival

Median PFS:FCR: 51.8 moFC: 32.8 mo(N=790Hazard ratio 0.563, p<0.001)

PFS rate 3 yrs post randomization:FCR: 64.9%FC: 44.7%

Incidence of Refractory Disease • 20-35% to single agent fludarabine• In GCLLSG CLL8:

PFS % pts OS 17p deln

TP53 mutn

< 6 mos (refractory)

11% (14.5 FC,

7.6 FCR)

21.9 mos 34% 44%

6 - <12 5.6% 21.2 mos 28% 24%

12 - < 24 14.3% 47.3 mos 11% 18%

30.9% of patients progressed within two years

CLL: Problems with Chemotherapy• Continuous relapse at progressively shorter

intervals and progressive resistance to therapy– Patients with 17p and/or complex cytogenetics respond

poorly from the start• Elderly patients (most!) tolerate chemotherapy

poorly– Myelosuppression, often persistent

• Risk of tMDS / AML– Immunosuppression, often persistent

• Increased infection risks• ? Increased risk of second malignancies• Clonal evolution:

– ? Selection for pre-existing adverse clones vs induction of new clones

What are the Alternatives?

• Mature data in previously untreated patients: (+/- rituximab)– Lenalidomide– Idelalisib (GS1101, CAL101)– Ibrutinib

• Evolving data:– Obinutuzumab

• Highly effective novel agents not yet tested upfront: IPI-145, ABT199

What about Lenalidomide?

• Immunomodulatory agent– Promotes CLL cell activation but is not

cytotoxic– Promotes T cell function

• Effective in relapsed refractory CLL with ORR 35-50%– BUT can be difficult to tolerate, with tumor flare,

tumor lysis, myelosuppression– Often better tolerated with antibody given first

• Mechanism of action still unclear

Lenalidomide for Upfront Therapy in Elderly CLL Patients

88%

60%

Median F/U 24 mos

Blood 2011; 118:3489

Lenalidomide for Upfront Therapy in Elderly CLL Patients

At 4 yr follow-up: TTF NR OS 82%

N=35 (58%) had DOR >36 mos:

71% CRs 29% PRs

Blood 2013; 122:734

Immune Parameters Improved on Lenalidomide

T cells Immunoglobulins

Lenalidomide: Best Response (n=25)

Median follow-up 20.7 months - n (%)

Median follow-up 53.2 months - n (%)

CR 0 5 (20%)

PR 14 (56%) 13 (52%)

SD 10 (40%) 6 (24%)

PD 1 (4%) 1 (4%)

ORR 56% 72%

Median DOR 16.6 mos 40.4 mos

Median time to best response 18.1 months (1.8-63.4)

Chen C, et al: ASH 2012

PFS and OS Outcomes (n=25)

7 patients have progressed 2 developed Richter’s transformation after discontinuation,

2 skin cancer, 1 recurrence of remote lung cancer

3 year PFS 64.6% (95% CI: 47.5-87.8%)

3 year OS 85.3% (95% CI: 71.1-100%)

Summary: Status of Lenalidomide

• Mature data in previously untreated elderly patients looks very promising

• BUT pivotal phase 3 study LEN vs chlorambucil closed early due to excess of deaths on LEN arm, plus many patients dropped out early on that arm – Especially in patients >80

Targeting Kinases in the BCR Pathway

Idelalisib (GS-1101; CAL-101)

Ibrutinib (PCI-32765)

Idelalisib: Highly Selective for PI3K Delta

PI3KαAlpha

PI3KBeta

PI3KδDelta

PI3KγGamma

Assay System

PDGF induced pAKT in

fibroblasts

LPA induced pAKT in

fibroblastsFceR1-induced

CD63 in basophils

fMLP-induced CD63 in

basophils

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

0.0001 0.001 0.01 0.1 1 10 1000

25

50

75

100

Whole Blood (n=20)

PMBC (n=9)

CAL-101 (mM)

% +

CD

63

Ce

lls

(no

rma

lize

d(c

on

tro

l)

EC50=65 nMWhole Blood

Basophil Activation FceR1

Less than 10-fold shift in EC50 in whole blood

Idelalisib + Rituximab in Frontline CLL

Phase 2 Single Arm, Open Label Study

Study Schema

Primary Study: 101-08 Extension Study: 101-99

Rituximab(375 mg/m2)weekly x 8

Therapy continues as long aspatient receives benefit

Subject Accrual

Oct 2010

ThroughApr 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

Idelalisib (150 mg BID) x 48 wks


Demographics and Baseline CharacteristicsIdelalisib + R

N = 64 (%)

Age (yrs), median [range] 71 [65-90]

Rai Stage III-IV 27 42

β2 Microglobulin, mg/L, median [range] 4.0 (1.9-15.8)

Hematology Parameters

Hemoglobin < 11 g/dl 17 27

Platelets < 100 x103/µl 17 27

B-symptoms 26 41

Bulky adenopathy (≥ 5 cm) 7 11

IGHV unmutated (n = 60) 37 58

Either Del(17p) or TP53 mutation (n = 61) 9 14

Baseline Characteristics


-100

-75

-50

-25

0

+25

+50

+75

+100

% C

han

ge

in S

PD

Nodal Response at 8 Weeks

Not evaluable N = 14• Patients without adenopathy at baseline, N =

12• Early withdrawal, N = 2

-100

-75

-50

-25

0

+25

+50

+75

+100

% C

han

ge

in S

PD

Not evaluable N = 16• Patients without adenopathy at baseline, N =

12• Early withdrawal, N = 2• No assessment, N = 2

Idelalisib + R Best Nodal Response

* Assessed by Physical Exam or CT


Response Assessment

All Subjects 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 progression


Improvement in Cytopenias

• Hematologic response rate– 17/17 with Anemia– 16/17 with Thrombocytopenia– 5/5 with Neutropenia

0 2 4 6 8 10 12 16 20 24 32 40 480

1

2

3

49

10

11

12

13

14

0

1

2

3

450

100

150

200

Platelets N=17

Neutrophil N=5Hemoglobin N=17

Time from Start of Idelalisib, Weeks

Hem

oglo

bin

x g/

dl M

ed, Q

1,Q

3P

late le ts x 1 0

3

/ lM

ed Q1,Q

3

AN

C x

10

3 / l

Med

, Q1,

Q3


Adverse Event n (%) with any Grade n (%) with Grade ≥ 3

Diarrhea** 35 (55) 15 (23)

Pyrexia 27 (42) 2 (3)

Nausea 24 (38) 1 (2)

Rash 24 (38) 5 (8)

Chills 23 (36) 0

Cough 21 (33) 1 (2)

Fatigue 20 (31) 0

Pneumonia 17 (27) 11 (17)**10 patients reported as Gr 3 colitis, including 6 lacking any AE report of Gr ≥ 3 diarrhea Med time to Gr 3 diarrhea/colitis = 9 mos

Lab Abnormality* n (%) with Increase to Grade ≥ 3

Transaminase elevations 15 (23)Neutropenia 18 (28)Anemia 2 (3)Thrombocytopenia 1 (2)

All Cause AEs ≥25% in Primary and Extension Studies; On-Study Lab Abnormalities


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

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

Progression-Free Survival

PFS at 24 months: 93%

Ibrutinib (PCI-32765): BTK Inhibitor

• Forms a specific and irreversible bond with cysteine-481 in Btk

• Potent Btk inhibition • IC50 = 0.5 nM

• Orally available

• Once daily dosing results in 24-hr sustained target inhibition

N

N

NN

NH 2

O

N

O

PCYC-1102-CA: Phase Ib/II in CLL/SLL (Treatment Naïve ≥ 65 yrs population)

PCYC-1102-CA

117 patients

Dates enrolled20th May 10 – 27th Jul 11

Relapsed/Refractory420 mg/d (n=27)

Median follow-up 12.6monthsTreatment Naïve ≥ 65 yrs420 mg/d (n=26)

Median follow-up 14.4 months


Median follow-up 9.3 monthsHigh-risk


Median follow-up 2.8 monthsTreatment Naïve ≥ 65 yrs840 mg/d (n=5)*

Median follow-up 7.4 months

24

*The 840mg TN cohort was terminated after comparable activity and safety between doses was shown in R/R patients. One patient in this cohort received only 420 mg daily.

Patient Characteristics

TN ≥65 yrs (N=31)

Age, years Median (Range) ≥ 70 years, (%)

71 (65 – 84)74%

β2 Microglobulin > 3mg/L, % 26%

Rai Stage III/IV at Baseline

48%

Prognostic Markers, % IgVH unmutated del 17p13.1 del 11q22.3

55% 7%3%

PCYC-1102-CA: Patient Disposition(Treatment Naïve ≥ 65 yrs)

420 mg/d (N=26)

840 mg/d(N=5)

Median time on treatment, months 21.3 (0.3, 26.6)

Subjects Discontinued, # (%) 4 (15) 1 (20)

Primary Reasons for Discontinuation, # (%)

Disease Progression

Adverse event Unrelated: viral syndrome Unrelated: Worsening GI hemorrhage Possibly related: fatigue

Subject withdrew consent “desired faster response”

1 (4)a

2 (8)b,c

1 (4)d

0 (0)

1 (20)e

Death on study, # (%) 0 0

# days on ibrutinib: a) 280 days; b) 41 days; c) 115 days; d) 41 days; e) 9 days

Common AEs (>20%) Regardless of Relationship

Grade 1 Grade 2 Grade 3 Grade 4

Vomiting

Hypertension

Dizziness

Contusion/Ecchymosis

Rash

Dyspepsia

Fatigue

Nausea

Diarrhea

0% 10% 20% 30% 40% 50% 60% 70%

any

≥ g

3 in

fect

ion

0%10%20%30%40%50%

SafetyAdverse Events ≥ Grade 3

Ne

utr

op

en

ia

Th

rom

bo

cy

top

en

ia

An

em

ia

0%

10%

20%

30%

40%

50%

InfectiousHematologic

Grade 3 Grade 4 Grade 5

Best Response

0%

20%

40%

60%

80%

0%

Treatment Naïve(n=31)

2 not evaluable

CR

PR

SD

PD

71%

10%

13%

58%

3/31

18/31

3/314/31

PR w/ lymphocytosis

13%

4/31

PCYC 1102: Best Overall Response by Risk Features

aOverall response rate and 95% exact binomial CI

Immunoglobulin Levels Remain Stable or Increased (IgA)

Durable Remissions with Ibrutinib Monotherapy as Initial CLL Therapy

Summary • Mature follow-up data with lenalidomide,

idelalisib-R, and ibrutinib demonstrate at least comparable and possibly improved PFS vs chemoimmunotherapy

• Oral agents are preferred by patients and toxicities are manageable

• Can we improve further on these outcomes?

34

Lower CDCType II versus Type I antibody

Effectorcell

Increased Direct Cell DeathType II versus Type I antibody

Enhanced ADCCGlycoengineering for

increased affinity to FcγRIIIa

CD20 FcγRIIIa

ComplementGA101

B cell

GA101: Mechanisms of Action

• GA101: 1,000 mg days 1, 8, and 15 cycle 1; day 1 cycles 2–6, every 28 days• Rituximab: 375 mg/m2 day 1 cycle 1, 500 mg/m2 day 1 cycles 2–6, every 28 days• Clb: 0.5 mg/kg day 1 and day 15 cycle 1–6, every 28 days• Patients with progressive disease in the Clb arm were allowed to cross over to G-Clb

RANDOMI

ZE 1:2:2

Rituximab + chlorambucil x 6 cycles

GA101 + chlorambucil x 6 cycles

Chlorambucil x 6 cyclesPreviously untreated CLL with comorbiditiesTotal CIRS* score > 6 and/or creatinine clearance < 70 ml/min

Age ≥ 18 years

N = 780 (planned)

Stage I, n = 590Additional 190 patients

to complete stage II

Stage IIG-Clb vs R-Clb

Stage IaG-Clb vs Clb

Stage IbR-Clb vs Clb

CLL11: Study Design

*Cumulative Illness Rating Scale

Summary • Kinase inhibitors and IMiDs (+/- anti-

CD20 antibody) show durable remissions in previously untreated patients– Randomized comparisons to CIT ongoing

• ECOG FCR vs IR age < 70• Alliance BR vs IR vs I age 65+

– Additional drugs (IPI-145, ABT199) are poised to add to this landscape

• How do we best combine these agents, i.e. how much does the antibody add?– Is rapid remission induction important?

Open Questions

• How durable are the remissions in 17p patients?

• How do we best sequence different novel agents?

• Are more relapses occurring as Richter’s transformation, even in previously untreated patients?

• What are the long-term side effects of continued therapy?

• Where do SCT or CAR T cell therapy fit?

1960s 1970s 1980s 1990s 2000s

Chemo-immunotherapy (CIT) 45% CR; better PFS & OSAlemtuzumab monotherapy 24% CRBendamustine 30% CR

Alkylating agents- Chlorambucil - Cyclophosphamide

5% CR

Purine nucleosides- Fludarabine- Pentostatin- Cladribine

5% - 20% CRBetter PFS in younger pts

Purine nucleosidesand alkylators

30% CRBetter PFS

Previously Untreated CLL

2010s

Novel Targeted Therapies

(BCR, BCL2, IMiDs, ?)

+Monoclonal Antibodies

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 FrancoeurCaitlin Tesmer-BrierKaren CampbellShannon MililloHazel Reynolds

Center for CancerGenome Discovery, DFCIMegan HannaLaura Macconaill

Richard Furman, Susan O’Brien, John Byrd, John Seymour, Valentin Goede

Wu Lab, DFCICatherine WuDan-Avi LandauLili WangYouzhong Wan

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

Documents

Previously Untreated CLL