William G. Wierda, Prof., M.D., Ph.D. - Oslo Cancer Clusteroslocancercluster.no/wp-content/uploads/2017/02/WWierda_CC2017… · William G. Wierda, Prof., M.D., Ph.D. Current position:

William G. Wierda, Prof., M.D., Ph.D.

Current position:

• Professor and Center Medical Director, Department of

Leukemia, Division of Cancer Medicine, The University of Texas

MD Anderson Cancer Center, Houston, TX

• Director of clinical core and clinical research at CLL

Consortium (CRC, multicenter P01 project)

Focus of work:

• Directing clinical and translational efforts in CLL and low-

grade lymphoproliferative diseases also as part of his role in

the CRC

• NCCN guidelines: CLL treatment recommendations

Specific expertise / current research interest:

• Prognostic factors and developing prognostic models in CLL

• Immune and Gene therapies for patients with CLL

• Developing Chemoimmunotherapy regimens and treatment

strategies for relapsed and refractory patients with CLL

Chronic Lymphocytic Leukemia:

Individualizing Therapy

26 January 2017

William G. Wierda M.D.,Ph.D.

Professor of Medicine

Department of Leukemia

Division of Cancer Medicine

U.T. M.D. Anderson Cancer Center

Houston, TX USA

Chronic Lymphocytic Leukemia

Chronic Lymphocytic Leukemia• Most common adult leukemia (~ 15,000 cases per year)

– 30% of adult leukemias

• Median age at diagnosis 72 years

• Median survival 9 yrs– Causes ~ 4400 deaths per year

• Absolute survival has increased over last 2 decades

• Advanced CLL has increased morbidity and mortality related to infections

American Cancer Society. Cancer Facts & Figures 2008; Rai K, et al. Blood. 1975;46:219-234;

Brenner H, et al. Blood. 2008;111:4916-4921.

1980-1984 2000-2004 P

5-year 54.2% 60.2% < .0001

10-year 27.8% 34.8% < .0001

CLL Diagnosis

ALC: > 5,000 /L – mature appearing lymphocytes

PLL = > 55% prolymphocytes or > 15,000 /L

Immunophenotype:

CD5+ / CD19+ / CD23+ / surface Ig light chain restricted ( or )

BM Bx: not required for diagnosis

> 30% lymphocytes on aspirate

Additional testing for prognosis:

Cytogenetics, FISH, CD38, ZAP70, IgVH mutations, serum B2M

Clinical Course of CLL

• Asymptomatic at diagnosis and for prolonged periods

• Diagnosis often incidental

• Initial symptoms: lymph node / anemia

• Progression: bone marrow impairment, susceptibility to infection

• Progressive hypogammaglobulinemia with advancing disease

• Long-term complications:autoimmune phenomena, Richter’s transformation

“Clinical and Classical” Prognostic Factors Associated With Inferior Survival in CLL

Advanced stage

Short lymphocyte doubling time

Diffuse pattern of bone marrow infiltration

Advanced age / male

-2 microglobulin and circulating CD23

Newer Prognostic Factors Associated With Inferior Survival in CLL

FISH cytogenetic abnormalities

17p deletion

11q deletion

Complex abnormalities

Unmutated (<2% homology with germline) immunoglobulin heavy chain variable gene (IGHV)

Expression of ZAP-70 ( 20% positive)

Expression of CD38 ( 30% positive)

Genomic Aberrations in CLLInterphase FISH Results—82% Abnormal

Abnormality No. Patients (%)

13q deletion 178 (55)

11q deletion 58 (18)

trisomy 12 53 (16)

17p deletion 23 (7)

6q deletion 21 (6)

Dohner et al. N Engl J Med. 2000;343:1910.

Dohner et al. N Engl J Med. 2000;343:1910-1916.

Probability of Survival100

80

60

40

20

00 12 24 36 48 60 72 84 96 108 120 132 144 156 168 180

Pa

tie

nts

Su

rviv

ing

(%

)

Months

17p deletion

11q deletion

12q trisomy

Normal

13q deletion as

sole abnormality

Su

rviv

ing

(%

)

Survival of CLL Patients With Mutated vs Unmutated IgVH Gene

All patients (N=84)Stage-A CLL patients

(n=62)

Su

rviv

ing

(%

)

0 50100 150 200 250 3000

20

40

60

80

100

Months

P=0.0008

Months

P=0.001

0 50 100 150 200 250 3000

20

40

60

80

100

Mutated

UnmutatedUnmutated

Mutated

Hamblin TJ et al. Blood. 1999;94:1848-1854.

Hallek et al Blood 2008;111:5446-5456

IWCLL-NCI: Indications to

Initiate Treatment for CLL• Constitutional symptoms referable to CLL

• Progressive marrow failure

• Autoimmune anemia +/- thrombocytopenia poorly

responsive to steroids or other

• Massive (>6 cm) or progressive splenomegaly

• Massive (>10 cm) or progressive lymphadenopathy

• Progressive lymphocytosis, >50% increase over 2 months

or LDT < 6 months

• NO EARLY TREATMENT, EVEN FOR HIGH-RISK

1960s

1970s

Alkylating agents

- Chlorambucil

- Cyclophosphamide

2000s

Chemoimmunotherapy (FCR)

Alemtuzumab

CD20 mAbs

Bendamustine

1990s

Combination

chemotherapy

First-line Treatments for CLLTreatment Evolution

1980s

Purine nucleosides

- Fludarabine

- Pentostatin

- Cladribine

2010s

Small molecule

inhibitors

- BCR pathway

- Bcl-2

CLL Patient Populations and Community “Standards of Care”

Untreated, high-risk - watch and wait

First-line therapyDel(17p) - Ibrutinib

“Elderly” – chlorambucil+CD20 mAb

Fit CIT-eligible – FCR / BR

Salvage treatments for active disease, incl del(17p)BTK-inhibitor (ibrutinib)

PI3-K-inhibitor (idelalisib) + rituximab

Rel / Ref del(17p) - venetoclax

Richter’s transformation – intensive CIT the allo-SCT

ibrutinib

Treatment comparisons

R

A

N

D

O

M

I

Z

E

2:1:2

G-Clb vs. Clb

Obinutuzumab + chlorambucilx 6 cycles

R-Clb vs. Clb

Rituximab + chlorambucilx 6 cycles

Chlorambucil x 6 cycles (control arm)

R

A

N

D

O

M

I

Z

E

2:1:2

Chlorambucil x 6 cycles (control arm)

G-Clb vs. R-Clb

Obinutuzumab + chlorambucilx 6 cycles

Rituximab + chlorambucilx 6 cycles Goede V et al. ASH 2013; Plenary Abstract 6;

Goede V et al. N Engl J Med 2014;370:1101-1111

Median observation time: G-Clb, 18.8 months; R-Clb, 18.6 months

Type 1 error controlled through closed test procedure; P value of the global test was <0.0001

Independent Review Committee-assessed progression-free survival (PFS) was consistent with investigator-assessed PFS

0 3 6 9 12 15 18 21 24 27 30 33 36 39

330 317 309 259 163 114 72 49 31 14 5 2 0 0

330 307 302 278 213 156 122 93 60 34 12 4 1 0

1.0

0.9

0.8

0.7

0.6

0.5

0.4

0.3

0.2

0.1

0.0

Pro

gre

ssio

n-f

ree

su

rviv

al

Time (months)

G-Clb:

R-Clb:

No. at risk

Progression-free survival (Head-to-Head)

Goede V et al. ASH 2013; Plenary Abstract 6; Goede V et al. N Engl J Med 2014;370:1101-1111

Currently no significant difference in overall survival

Median observation time: G-Clb, 23.2 months; Clb, 20.4 months

No multiplicity adjustment was done for secondary endpoints

Total number of deaths: G-Clb, 22 (9%); Clb, 24 (20%)

0 3 6 9 12 15 18 21 24 27 30 33 36 39

118 109 105 103 102 94 70 56 44 29 15 5 0 0

238 226 223 221 215 211 170 144 115 71 34 14 2 0

1.0

0.9

0.8

0.7

0.6

0.5

0.4

0.3

0.2

0.1

0.0

Ove

rall

su

rviv

al

Time (months)

G-Clb:

Clb:

No. at risk

Overall survival (Obinutuzumab)

Goede V et al. ASH 2013; Plenary Abstract 6; Goede V et al. N Engl J Med 2014;370:1101-1111

ran

do

mis

e 1

:1

Minimum 3 cycles, until best response or PD , maximum 12 cycles

- No cross over allowed -

Ofatumumab +

Chlorambucil (O+CHL)

Chlorambucil (CHL)

Follow up:

1 Month post

last dose,

Month 3, q3mo

thereafter

COMPLEMENT 1: Study Design

O: cycle 1 d1 300 mg, d8 1000 mg, Cycle 2-12 d1 1000 mg every 28 days

CHL: 10 mg/m2 d1-7 every 28 days

Dose rationale: evidence of highest ORR and longest PFS with low toxicity

compared to any other CHL monotherapy regimen

Patients with

previously

untreated CLL

• considered

inappropriate for

F-based therapy

• Active disease (NCI-WG IWCLL 2008)

• ≥18 years

• ECOG ≤ 2

• N=444 (planned)

Hillmen et al. ASH 2013, Abstract 528.

Subjects at risk

C 226 173 130 92 67 52 33 17 6 1 1

O+CHL 221 192 169 148 125 104 70 46 28 15 9 3 1

Progression-free Survivalas assessed by an Independent Review Committee

(median [months])

CHL

mPFS: 13.1(95% CI: 10.6,13.8)

O+CHL

mPFS: 22.4(95% CI: 19.0,25.2)

HR 0.57, p<0.001

Pro

ba

bil

ity o

f P

rog

res

sio

n-f

ree S

urv

iva

l

Median follow-up: 28.9 months

Time since randomization (months)

Hillmen et al. ASH 2013, Abstract 528. Currently no difference in overall survival

CLL8 STUDY: FCR VS FC IN FRONTLINE

Rationale

Fischer K et al.

ASH 2012

FCR 69.4% alive

Median not reached

FC 62.3% alive

Median 86 months

HR 0.68,

95% CI 0.535-0.858

p=0.001

FCR300: PFS by IGHV Mutation Status

Thompson PA, et al. Blood 2016; 127:303–309

P<0.0001Perc

en

tag

e P

rog

ressio

n-f

ree

Time (Years)

0

25

50

75

100

0 1 2 3 4 8 9 105 6 7 11 12 13 14 15 16

N Prog-free

IGHV mutated 88 49

IGHV unmutated 126 12

CLL10 STUDY: FCR VS BR IN FRONT-LINE

Design

Non-Inferiority of BR in comparison to FCR for PFS:

HR (λ BR/FCR) less than 1.388

Randomization

Patients with untreated, active CLL without del(17p) and good physical fitness

(CIRS ≤ 6, creatinine clearance ≥ 70 ml/min)

FCR Fludarabine 25 mg/m² i.v., days 1-3

Cyclophosphamide 250 mg/m², days 1-3,

Rituximab 375 mg/ m2 i.v. day 0, cycle 1

Rituximab 500 mg/m² i.v. day 1, cycle 2-6

BR

Bendamustine 90mg/m² day 1-2

Rituximab 375 mg/m² day 0, cycle 1

Rituximab 500 mg/m² day 1, cycle 2-6

Eichhorst et al., ASH 2014, Abstract 19


PFS in IGHV matched population (n=398: FCR= 201; BR =197)

P = 0.005

HR = 1.565 =

> 1.388

Median PFS

FCR NR

BR 43.1 months


NO difference in overall survival


Progression-free survival by age group

Patients ≤ 65 years: P < 0.001

FCR 53.6 months BR 38.5 months

Patients > 65 years: P = 0.170

FCR not reached BR 48.5 months



Infections CTC 3-4 in detail

Adverse event FCR

(% of pt)

BR

(% of pt)

p value

All Infections 39.1 26.8 <0.001

Infections during therapy

only

22.6 17.3 0.1

Infections during first 5

months after therapy

11.8 3.6 <0.001

All infections in patients ≤ 65years

35.2 27.5 0.1

All infections in patients > 65years

47.7 20.6 <0.001


Targeting of BCR signaling in CLL

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

• Btk (Bruton’s tyrosine kinase) inhibitors: Ibrutinib, CC-292, ACP-196

• PI3 kinase inhibitors: Isoform-Selective Inhibitor of PI3-Kinases1, Idelalisib, IPI-145, TGR-1202

• Syk (spleen tyrosine kinase) inhibitors: GS-9973, Fostamatinib, PRT-20702

1 Niedermeier M, et al. Blood 113(22):5549-57, 5/20092 Quiroga MP, et al. Blood 114(5):1029-37, 07/2009From: Nat Rev Immunol 2:945

RESONATE-2 (PCYC-1115/1116) Study Design

Patients (N=269)• Treatment-naïve CLL/SLL

with active disease• Age ≥65 years• For patients 65-69 years,

comorbidity that may preclude FCR

• del17p excluded

ibrutinib 420 mg once daily until progression

chlorambucil 0.5 mg/kg (to maximum 0.8 mg/kg) days 1 and 15 of 28-day cycle up to

12 cycles

CLL progression or

1115 study closure

PCYC-1116 Extension

Study*

In clb arm, n=55 crossed

over to ibrutinib

following PD

Stratification factors• ECOG status (0-1 vs. 2)• Rai stage (III-IV vs. ≤II)

RANDOMIZE

1:1

Efficacy (PFS, OS, ORR) determined by investigator-assessment.

*Patients could enroll in separate extension study PCYC-1116 after independent review committee-confirmed PD or at study PCYC-1115 closure for continuing treatment and follow-up.

Barr et al. ASH 2016, Abstract 234

RESONATE-2: Ibrutinib Prolonged PFS Over Chlorambucil

88% reduction in the risk of progression or death for patients randomized to ibrutinib Subgroup analysis of PFS revealed benefit was observed across all sub-groups

(n=136)

(n=133)

Median PFS not reached

Median PFS 15 mo


RESONATE-2: Ibrutinib Significantly Improved PFS in Patients with Del11q

In del11q subgroup, Ibrutinib led to 99% reduction in risk of progression or death and 82% reduction in those without del11q, compared to chemotherapy

(n=101)

(n=29)

(n=96)

(n=25)

(n=101)

(n=29)

(n=96)

(n=25)

ibrutinibdel11q yes (n=29)

del11q no (n=101)

del11q yes (n=25)

chlorambucil del11q no (n=96)


RESONATE-2: Ibrutinib Significantly Improved PFS in Patients Regardless of IGHV Status

Ibrutinib led to 83% and 92% reduction in the risk of progression or death in patients with mutated and unmutated IGHV, respectively, compared to chemotherapy

(n=40)

(n=58)

(n=42)

(n=60)


RESONATE-2: Ibrutinib Continues to Demonstrate OS Benefit Over Chlorambucil With Longer Follow-Up and Cross-Over

(n=136)

(n=133)


RESONATE-2: ORR in the Ibrutinib* Arm

Ibrutinib CR rates continue to improve over time: increasing from 7% at 12 months to 15% at 24 months to 18% with median follow-up of 29 months.

CR, complete response; CRi, CR with incomplete blood count recovery.

71%86%

67% 74%65%

18%

14%

20%21%

20%

0%10%20%30%40%50%60%70%80%90%

100%

All Patients(N=136)

With Del11q(n=29)

Without Del11q(n=101)

Unmutated IGHV(n=58)

Mutated IGHV(n=40)

PR-L PR nPR CR/CRi

1%

1%

1%

2%

3%

95%88%

100%92% 90%

0

6070

9080

100

40302010

50

Be

st R

esp

on

se (

%)

*Response rates with chlorambucil are the same as in the original report (Burger NEJM 2015)


Emerging Concepts in

First-line Therapy for CLL

del(17p) = no chemo

Older adults = move away from chemo

Mutated IGHV = role for FCR

MRD-negative = longer PFS, OS

Combination approaches

MDACC First-line Therapy

Individualizing treatment

Younger, fit, IGHV-M – 20% Ibrutinib + FC + Obinutuzumab (GA101) (iFCG) (2015-0281)

IGHV-UM, del(11q), ≥65yr – 75% Ibrutinib + Venetoclax (2015-0860)

Del(17p) – 5% Ibrutinib + Venetoclax (2015-0860)

FCR300: PFS by IGHV Mutation Status

Thompson PA, et al. Blood 2016; 127:303–309

P<0.0001Perc

en

tag

e P

rog

ressio

n-f

ree

Time (Years)

0

25

50

75

100

0 1 2 3 4 8 9 105 6 7 11 12 13 14 15 16

N Prog-free

IGHV mutated 88 49

IGHV unmutated 126 12

iFCG Regimen

2015-0281

•Obinutuzumab: more effective CD20 mAb than rituximab

•Addition of ibrutinib to CIT may be synergistic

•Reducing chemotherapy exposure may reduce risk of secondary MDS/AML

•Higher MRD-negativity will result in better PFS, OS

iFCG

First-line, Fit, IGHV-M

2015-0281

Courses 1-3Course 1 Course 2-3

D1 D2 D3 D4 D8 D15 D1 D2 D3

Obinutuzumab (mg) 100 900 - - 1000 1000 1000 - -

Fludarabine (mg/m2) - 25 25 25 - - 25 25 25

Cyclophosphamide

(mg/m2)- 250 250 250 - - 250 250 250

Ibrutinib 420 mg once daily continuous

iFCG

2015-0281

Treatment Schema

Ibrutinib

CR, MRD-negative @ C3

Ibrutinib+obinutuzumab

<CR or MRD-positive @ C3

iFCG iFCG iFCG

C3 Response

CT

BM

iG iG iG

C6 Response

CT

BM

C12 Response

CT

BM

MRD-positive

@ 1yr

Continue

Ibrutinib

Statistical Considerations

•Primary endpoint: CR/CRi and bone marrow MRD-negativity after 3 courses of iFCG

For mutated IGHV, the bone marrow MRD(-) rate was 26% (16/62) after 3 courses of FCR

Strati et al. Blood 2014

Simon’s optimal two-stage design

Null hypothesis 26%; target response rate 45%

Sample size = 45

Clinical Responses

n=18 BM MRD n=18 BM MRD

ORR 18/18 14/18 neg 18/18 16/18 neg

CR/CRi

PR

6

12

6/6 neg

8/12 neg

7

11

7/7 neg

9/11 neg

78% (14/18) BM MRD neg at 3 mos

Comparison: FCR 3 cycles, 26% marrow MRD-

3 mos Best

• 31 consented

• 24 started treatment

BCR vs. BCL-2 Inhibitors

B-cell Receptor Inhibitors

(Ibrutinib, Idelalisib)

Bcl-2

Antagonists

(ABT-199)

Response Blood +++

LN +++

Marrow +

Blood +++

LN ++

Marrow +++

Lymphocytosis +++ -

Complete Responses CR <10% CR 20-25%

S/E profile Ibrutinib (A. fib, bleeding)

Idelalisib (colitis, pneumonitis)

TLS

Ibrutinib + Venetoclax (2015-0860)

• Investigator-initiated Phase II trial

•Rationale

Non-overlapping mechanism of action

Non-overlapping toxicity profile

Synergy in preclinical models (Dr. Gandhi, MDACC)

• Cervantes-Gomez et al. Clin Cancer Res. 2015;21(16):3705-15.

5-Year Experience With Ibrutinib MonotherapyPCYC-1102/1103 Phase 2 Study Design

Patients with CLL/SLL treated with

oral, once-daily ibrutinib (420 or 840 mg/day)

Long-Term Follow-Up

≥SD

*R/R includes patients with high-risk CLL/SLL, defined as progression of disease <24 months after initiation of a chemoimmunotherapy regimen or failure to respond

Relapsed/Refractory*

(R/R)n=101

Treatment Naïve (TN) ≥65 years

n=31

Phase 2 (PCYC-1102)N=132

Extension Study (PCYC-1103)

O’Brien et al. ASH 2016, Abstract 233

5-Year Experience With Ibrutinib MonotherapyBaseline Characteristics

CharacteristicTN

(n=31)R/R

(n=101)

Cytogenetic abnormalitiesDel17pDel11qTrisomy 12Del13qComplex karyotype

Unmutated IGHV

6%3%

26%55%13%

48%

34%35%12%47%37%

78%

Median lines of prior therapies, n (range)1–23≥4

———

4 (1–12)27%14%59%


DispositionTN

(n=31)R/R

(n=101)

Median time on study, months (range)62

(1–67)49

(1–67)

Duration of study treatment, n (%)≤1 year>1–2 years>2–3 years>3–4 years≥4 years

5 (16%)0

1 (3%)1 (3%)

24 (77%)

24 (24%)14 (14%)

9 (9%)19 (19%)35 (35%)

Patients remaining on ibrutinib therapy, n (%) 20 (65%) 30 (30%)

Primary reason for discontinuation, n (%)Progressive diseaseAdverse eventConsent withdrawalInvestigator decisionLost to follow-up

1 (3%)6 (19%)3 (10%)

01 (3%)

33 (33%)21 (21%)

5 (5%)11 (11%)

1 (1%)

Ibrutinib Treatment Continued in 65% of TN and 30% of R/R Patients

• After ~5 years of follow-up, 65% of TN and 30% of R/R patients continue treatment on study.


3% 3% 3%

55%

76% 71%

29%

10% 14%

0%

20%

40%

60%

80%

100%

5-Year Experience With Ibrutinib MonotherapyBest Response

47

87% 89% 89%

Median DOR, months (range)

NR (0.0+ to 65.5+) 56.8 (0.0+ to 65.5+) NR (0.0+ to 65.5+)

Median follow-up, months (range)

62 (1–67) 49 (1+–67) 56 (1+–67)

CR

PRPR-L

TN (n=31) R/R (n=101) Total (N=132)


5-Year Experience With Ibrutinib MonotherapySurvival Outcomes: Overall Population

Median PFS 5-year PFS

TN (n=31) NR 92%R/R (n=101) 52 mo 43%

Progression-Free Survival Overall Survival

Median OS 5-year OS

TN (n=31) NR 92%R/R (n=101) NR 57%


5-Year Experience With Ibrutinib MonotherapySurvival by IGHV-MS in R/R Patients*

*Only 2 patients in the TN group showed disease progression. Subgroup analyses, therefore, focused on the R/R population.


Median OS 5-year OS

Mutated IGHV (n=16) 63 mo 66%

Unmutated IGHV (n=79) NR 55%


Mutated IGHV (n=16) 63 mo 53%

Unmutated IGHV (n=79) 43 mo 38%


5-Year Experience With Ibrutinib MonotherapySurvival by FISH in R/R Patients*

**No del17p, del11q, del13q, or trisomy 12; in hierarchical order for del17p, and then del11q.


*Only 2 patients in the TN group showed PD or death. Subgroup analyses, therefore, focused on the R/R population.

Median OS 5-year OS

Del17p (n=34) 57 mo 32%

Del11q (n=28) NR 61%

Trisomy 12 (n=5) NR 80%

Del13q (n=13) NR 91%

No abnormality** (n=16) NR 83%


Del17p (n=34) 26 mo 19%

Del11q (n=28) 55 mo 33%

Trisomy 12 (n=5) NR 80%

Del13q (n=13) NR 91%

No abnormality** (n=16) NR 66%


5-Year Experience With Ibrutinib MonotherapySurvival by Complex Karyotype


• The majority (90%) of patients with complex karyotype had R/R disease (median 4 prior therapies).

Median PFS

5-year PFS

Complex karyotype (n=41) 33 mo 36%

No complex karyotype (n=71) NR 69%

Median OS

5-year OS

Complex karyotype (n=41) 57 mo 46%

No complex karyotype (n=71) NR 84%


Factors considered

Del17p

Del11q

Trisomy 12

Del13q

Lines of prior therapy (1-2, 3, and ≥4 lines vs 0 lines)

Bulky disease (≥5cm vs <5 cm)

IGHV mutation status

Complex karyotype

Del17p was identified as a significant predictor of PFS and OS

5-Year Experience With Ibrutinib MonotherapyMultivariate Analysis* for PFS and OS

*Multivariate regression analysis using Cox Proportional Hazard model and stepwise selection. There might be confounding effectsbetween covariates considered.


Ibrutinib Refractory/Intolerant:Cumulative Incidence of Discontinuation

Woyach et al. ASH 2016, Abstract 55

Ibrutinib Refractory/Intolerant:Baseline Characteristics Associated with IbrutinibDiscontinuationVariable Transformation CLL Progression Other Event

HR (95% CI) P HR (95% CI) P HR (95% CI) P

Complex Karyotype

(y vs. n)

5.00

(1.51-16.52)0.008

2.81

(1.34-5.88)0.006 --- ---

MYC abnormality

(y vs. n)

2.15

(1.00-4.65)0.051 --- --- --- ---

Del(17p13.1) on FISH (y

vs n) --- ---2.14

(1.15-3.96)0.016 --- ---

Age, years

(≥65 vs <65) --- ---0.49

(0.27-0.91)0.023

2.02

(1.25-3.28) 0.004

Prior therapies >3 (yes

vs no) --- ---

1.99

(1.23-3.23) 0.005

All models adjusted for monotherapy with ibrutinib versus combination therapy with ibrutinib and ofatumumab, regardless of

statistical significance.


Ion Torrent for BTK and PLCγ2 performed on blood or marrow on 46 patients

87% have mutations in BTK or PLCG2 acquired at relapse

31 had BTK C481 as sole mutations

3 had PLCG2 hotspot mutations only

6 have both BTK C481S and PLCG2 hotspot mutations

6 have neither mutation

Association of CLL Progression with BTK and PLCγ2 Mutations



Ibrutinib Refractory/Intolerant:Resistance Mutations Appear Over Time

Ibrutinib Refractory/Intolerant:Resistance Mutations Persist After Salvage Therapy

Venetoclax Therapy Non-Venetoclax Therapy


Ibrutinib FDA approved: relapsed CLL; first-line; del(17p)

Monotherapy @ 420 mg once daily-continuous

Lymphocytosis on start, resolves with Tx

Potent LN shrinkage, most responses partial,

residual disease in blood and marrow

GI toxicity most common; <5% a. fib. / bleeding

90% prog-free @30 mo (non-del(17p)-del(11q)

Median PFS for relapsed CLL with del(17p) is

32 months

Improved OS vs. ofatumumab in relapsed CLL

Class IPI3K Isoform

Cell TypeMouse embryonic

fibroblasts

Mouse embryonic

fibroblastsHuman basophils

Human

basophils

Cell-Based

Activity

PDGF-induced

pAKT

LPA-induced

pAKT

fMLP-induced

CD63+

FceR1-induced

CD63+

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

a g d

Idelalisib/

GS-1101

Idelalisib: Potent and Selective Inhibitor of PI3Kd

Lannutti, et al. Blood, 2011

• 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™)

Idelalisib

FDA approved for relapsed CLL appropriate for

rituximab monotherapy

Twice daily dosing, continuous + rituximab

Toxicities: elevated LFTs, GI / diarrhea;

less common colitis and pulmonary

Most responses are partial, residual disease

Median PFS was 19.4 months

Efficacy in relapsed CLL with del(17p) & del(11q)

Improved OS vs. rituximab + placebo

Infection concerns in first-line

Venetoclax is a BCL-2 Selective Inhibitor

BCL-2 overexpression allows cancer cells to evade apoptosis by

sequestering pro-apoptotic proteins

Venetoclax binds selectively to BCL-2, freeing pro-apoptotic proteins that initiate

programmed cell death (apoptosis)

Cancer Cell DeathCancer Cell Survival

Restoration of apoptosis through BCL-2 inhibition

Pro-apoptoticprotein

BCL-2

Activation of caspases

Venetoclax

Apoptosis initiation

Pro-apoptoticprotein

BCL-2

BIM

BAX

BAK

BAX

Cytochrome c

Venetoclax oral once daily continuous dosing

Step-wise weekly ramp-up with risk-based prophylaxis to mitigate against tumor

lysis syndrome (TLS)

Response assessment (per iwCLL 2008 criteria):

• Monthly physical exam and blood counts

• CT scan

– To confirm clinical response

– Prespecified at week 36

• Bone marrow biopsy to confirm CR

Venetoclax (ABT-199) for Rel / Ref del(17p) CLL

Dosing Schedule and Assessments

*20mg dose for 1 week in patients with electrolyte abnormalities after first dose

Venetoclax 20 mg test 50 mg 100 mg 200 mg 400 mg

Week 1

D1

Week 1

D2-7

Week 2 Week 3 Week 4 and following*

Stilgenbauer et al. ASH 2015, Abstract LBA-6.

N=107a n (%)

Median age (years), range 67, 37–85

Male 70 (65)

Prior therapies: median, range 2, 1–10

Prior bendamustine / refractory 54 (50) / 38 (70)

Prior fludarabine / refractory 78 (73) / 34 (44)

Prior CD20 mAb 90 (84)

ECOG grade 1/2 56 (52) / 9 (8)

One or more nodes ≥ 5 cm 57 (53)

ALC ≥25 x 109/L 54 (51)

TLS risk category

Low 19 (18)

Medium 43 (40)

High 45 (42)

Rai stage III or IV 51(48)

IGHV unmutated 30 (81)aIncludes 1 patient without 17p–; bLow defined as ALC<25 and nodes <5cm, medium defined as ALC>20 OR nodes

≥5 and < 10cm), high defined as (ALC>25 nodes ≥5 and < 10cm OR nodes > 10cm


Baseline Characteristics


IRC,

n (%)

Investigator, n

(%)

Overall Response 85 (79.4) 79 (73.8)

CR or CRi 8 (7.5) 17 (15.9)

nPR 3 (2.8) 4 (3.7)

PR 74 (69.2) 58 (54.2)

No response 22 (20.6) 28 (26.2)

Stable disease NA 24 (22.4)

Disease progression NA 2 (1.9)

Incomplete data NA 2 (1.9)

• 25 of 48 patients with no CLL in the bone marrow

• 18 of 45 patients assessed were MRD-negative in PB


Best Response


Of 45 patients tested, 18 achieved

MRD-negativity in peripheral blood

MRD-Negativity

Median time-to-first response: 0.8

months (0.1–8.1)

Median time to CR/CRi:

8.2 months (3.0–16.3)


Cumulative Incidence of Response

iwCLL Response



Durability of Venetoclax Activity

PFS and OS (N=107)Duration of Response (N=85)

• 12-month estimates (95% CI):

– PFS: 72.0% (61.8, 79.8)

– OS: 86.7% (78.6, 91.9)

• 12-month estimates:

– All responders: 84.7%

– CR/CRi/nPR: 100%

– MRD-negative: 94.4%



Treatment-Emergent Adverse Events

Any grade

n (%)a

Grade 3/4

n (%)

Any treatment-emergent adverse event 103 (96) 81 (76)

Neutropenia 46 (43) 43 (40)

Diarrhea 31 (29) 0

Nausea 31 (29) 1 (1)

Anemia 29 (27) 19 (18)

Fatigue 23 (22) 0

Pyrexia 21 (20) 1 (1)

Thrombocytopenia 20 (19) 16 (15)

Hyperphosphatemia 17 (16) 1 (1)

Vomiting 16 (15) 1 (1)

Upper respiratory tract infectionb 16 (15) 2 (2)

aTable shows all-grade events occurring in 15% of patients or more; bInfections occurred in a total of 77 (72%) patients


M14-032: Efficacy

Arm A

n=43

Arm B

n=21

Best response, n

(%)

Assessed by Assessed by

IRC Investigator IRC Investigator

ORR 30 (70) 29 (67) 13 (62) 12 (57)

CR/CRi 0/1 (2) 2 (5)/1 (2) 0/0 2 (10)/1 (5)

nPR 0 2 (5) 0 0

PR 29 (67) 24 (56) 13 (62) 9 (43)

Non-responder*

SD

PD

D/C‡

13 (30)

–

–

–

14 (23)

9 (21)

1† (2)

4 (9)

8 (38)

–

–

–

9 (43)

8 (38)

1† (5)

0*Non-responder category for IRC includes both SD or PD, which were not identified as separate categories

per IRC.†CLL progression and discontinued due to progression.‡D/C, patient discontinued the study prior to assessment.

Data as of 10June2016Jones et al. ASH 2016, Abstract 637

Median DoR, PFS, and OS had not been reached after 11.8 months of follow up

Estimated 12 month PFS for all patients: 80% (95% CI: 67%, 89%)

M14-032: Efficacy Per Independent Review

0 2 4 6 8 1 0 1 2 1 4

0

2 5

5 0

7 5

1 0 0

D u ra tio n o f R e s p o n s e

M o n th s s in c e f irs t d o s e

Pa

tie

nts

wit

h R

es

po

ns

e (

%)

N o . a t r is k 3 0 2 9 2 3 1 8 1 0 1

1 0 8 6 5 2

4 0 3 7 2 9 2 3 1 2 1

A rm A (R /R ib ru t in ib )

A rm B (R /R id e la l is ib )

A ll p a t ie n ts

0 2 4 6 8 1 0 1 2 1 4

0

2 5

5 0

7 5

1 0 0

P ro g re s s io n -F re e S u rv iv a l

M o n th s s in c e f irs t d o s e

Pro

gre

ss

ion

-fre

e s

urv

iva

l (%

)

4 3 3 7 3 6 2 8 2 7 1 5 3

2 1 1 7 1 5 6 5 2

6 4 5 4 5 1 3 4 3 2 1 7 3

A rm A (R /R ib ru t in ib )

A rm B (R /R id e la l is ib )

A ll p a t ie n ts

Data as of 10June2016Jones et al. ASH 2016, Abstract 637

Multivariate Analysis of R/R CLL/SLL in Phase 1 Studies of

Venetoclax ± Rituximab - Design

Final Escalation Strategy:

100 mg

Month 7 and ongoing

Cohort DoseCohort Dose200 mg

50 mg20 mg

Cohort Dose

Months 2 – 6Month 1Week 4Week 3

Week 2Week 1D2 – 7

Week 1D1 Venetoclax monotherapy

Rituximab: D1375 mg/m2

D1 of Months 2 - 6500 mg/m2

Dose escalation phase: 200, 300, 400, 500, 600mg/day cohorts (n = 41)

Safety expansion phase: 400mg/day cohort (n = 8)

Data pooled for these safety and efficacy analyses

Protocol-defined option to stop venetoclax after achieving CR or MRD-negative PR

Ma et al. ASH 2015, Abstract 830

Multivariate Analysis of R/R CLL/SLL in Phase 1 Studies of Venetoclax ± Rituximab – Baseline and Disposition

71

Characteristics Ven + R (n=49) Ven (n=116)

Median age, (range) 68 (50-88) 66 (36-86)

Male, n (%) 30 (61) 89 (77)

CLL, n (%)SLL, n (%)

48 (98)1 (2)

102 (88)14 (12)

ALC > 5 × 109/L, n (%)Median (range)*

32 (65)58 (5-207)

66 (57)28 (5-260)

Node size, n (%)>5 cm>10 cm

22 (25)1 (2)

67 (58)22 (19)

Prior therapies, median (range) 2 (1-5) 3 (1-11)

Del17p, n/N (%) 9/47 (19) 31/102 (30)

Del11q, n/N (%) 20/46 (44) 28/102 (28)

Unmutated IGHV, n/N (%) 19/27 (70) 46/63 (73)

Disposition Ven + R (n=49) Ven (n=116)

Months on venetoclax, median (range) 22 (<1-42) 17 (<1-44)

Discontinuation, n (%)Disease progressionAE/toxicityWithdrew consentManagement of comorbiditiesAllogeneic SCT

15 (31)9 (18)3 (6)3 (6)

00

65 (56)41 (35)13 (11)

2 (2)2 (2)7 (6)

*For patients with ALC > 5 × 109/L

Roberts et al. EHA 2016. Abstract P209

Multivariate Analysis of R/R CLL/SLL in Phase 1 Studies of Venetoclax ± Rituximab – Outcomes

72

Response, n/N (%)

ORR CR/CRi

Ven + R Ven Ven + R Ven

Best objective response 42/49 (86) 92/116 (79) 25/49 (51) 23/116 (20)

SubgroupsPrior therapies ≥3Lymph node size >5 cmDel17pDel11qAge ≥70 yearsDose ≥400 mg

16/21 (76)18/22 (82)

8/9 (89)17/20 (85)17/22 (77)28/33 (85)

52/72 (72)52/67 (78)22/31 (77)23/28 (82)24/34 (71)72/87 (83)

9/21 (43)9/22 (41)6/9 (67)

5/20 (25)11/22 (50)18/33 (55)

13/72 (18)5/70 (7)

5/31 (16)3/28 (11)7/34 (21)

18/87 (21)

Multivariate Analysis

ORR Odds Ratio* (95% CI); P Value

(n=157)

CR Odds Ratio†

(95% CI); P Value (n=129)

DOR HR for Relapse (95% CI); P Value (n=105)

Ven + R vs. Ven 1.14 (.43-3.02); .796.13 (2.44-15.44);

.0001.37 (.15-.89); .03

Prior therapies <3 vs ≥3 4.58 (1.62-12.91); .004 NS NS

Lymph node size ≤5 cm vs >5 cm NS 3.50 (1.39-8.84); .008 .36 (.15-.84); .02

11q, not deleted vs deleted NS 2.96 (1.04-8.43); .04 NS

17p, not deleted vs deleted NS NS .42 (.18-.95); .04

Age, continuous variable NS NS NS

Dose of Ven, >400 mg vs 400 mg NS NS 1.72 (.62-4.76); .29*Responders vs non-responders; †CR/CRi vs all other patients.

Roberts et al. EHA 2016. Abstract P209

Phase Ib - IBR+VEN+OBIN:Treatment Schema

C1 C2 C3 C4 C5 C6 C7 C8 C9 C10 C11 C12 C13 C14

Obinutuzumab 1000 mg IV

Ibrutinib 420 mg daily PO

Venetoclax (cohort dose) mg daily PO

Response assessed (CT + BMBx) –After Cycle 8– 2 months beyond end Cycle 14

Drugs initiated sequentially to limit risk for tumor lysis syndrome (TLS) All patients discontinue treatment after Cycle 14 Sequential cohorts of 3 underwent dose escalation to target venetoclax dose in Cycle 3 to

establish MTD of venetoclax in combination

Cycle = 28 days

Jones et al. ASH 2016, Abstract 639

Phase Ib - IBR+VEN+OBIN:Cycle 9 Treatment Response (N=12)

Patient ID Cycle 9 Response† Peripheral Blood MRDⱡ (%) Bone Marrow MRDⱡ (%)

Dose Level 1(venetoclax 100)

PR 0.00 0.40

PR 0.00 0.00

PR 1.70 0.50


PR 1.00 8.00

PR 0.00 4.00

CR 0.00 0.20


PR 0.00 0.00

PR 0.00 0.00

CR 0.10 0.05

PR 0.00 0.00

NR* -- --

NR* -- --

†IWCLL (2008) response; PR = partial response; CR = complete response; NR = not reachedⱡMeasured by four-color flow cytometry, reported as percentage (%) of events*All remain on therapy but had not yet completed 9 cycles of therapy

Jones et al. ASH 2016, Abstract 639

Venetoclax (ABT-199)

FDA approved: relapsed del(17p) CLL

Oral Bcl-2 inhibitor, potent monotherapy activity

Complete remissions in rel/ref CLL

MRD-negative CRs

Active in high-risk CLL: rel/ref CLL with del(17p) &

fludarabine-refractory CLL

TLS and neutropenia AE’s to monitor

Safely combined with rituximab and obinutuzumab

Phase III trial initiated in first-line

Management for “High-risk” Rel / Ref CLL

BTK-I-refractory / BTK/PLCG2-Mut / complex karyotypeVenetoclax (± CD20 mAb)

PI3K-inhibitor

Chemoimmunotherapy to de-bulk [non-del(17p)]

Allo-SCT

Del(17p) / TP53-Mut (BTK-I first-line)Venetoclax (± CD20 mAb)

Alternative BCR-inhibitor

Allo-SCT

BTK-inhibitor- or PI3K-inhibitor-intolerantAlternative BCR-inhibitor

Venetoclax (± CD20 mAb)

New Agents Changing Treatment for Patients with CLL

Agent Development Phase Sponsor

BTK inhibitorsIbrutinibONO-4059ACP-196BGB-3111

ApprovedPhase I

Phase IIIPhase I

AbbVieGilead / Ono

AcertaBeiGene

PI3KΥ/δ inhibitorsIdelalisibIPI-145AMG/ACP-319TGR-1202SAR245408 (XL147)

ApprovedRegistration Phase III

Phase IPhase IIIPhase I

Gilead SciencesInfinity Pharmaceuticals

AcertaTG Therapeutics

Sanofi

Syk inhibitorsEntospletinibFostamatinibPRT-2070

Phase IIPhase I/IIPhase I

Gilead SciencesRigel Pharmaceuticals

Portola

BCL-2 inhibitorVenetoclax (ABT-199) Approved AbbVie/Roche

CLL Treatment Directions

Untreated, high-risk – early intervention

First-line therapy

Fit CIT-eligible – IGHV-MutatedFCR-based with maintenance or Tx for MRD

Fit-IGHV-Unmutated & ElderlyBCR- / Bcl-2-inhibitor – sequencing and combinations

Second-line Therapy for active disease

Treatment (consolidation) for persistent disease on BTK-inhibitor (1st and later)

Richter’s transformation work-up and “novel treatments” program

THANK YOU!

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William G. Wierda, Prof., M.D., Ph.D. - Oslo Cancer Clusteroslocancercluster.no/wp-content/uploads/2017/02/WWierda_CC2017… · William G. Wierda, Prof., M.D., Ph.D. Current position: