2nd Generation TKI… Frontline Therapy in CMLimedex.com/hematologic-malignancies-debate... · 2nd Generation TKI… Frontline Therapy in CML Elias Jabbour, M.D. A il 2012April 2012

4/23/2012

1

2nd Generation TKI… Frontline Therapy in CMLpy

Elias Jabbour, M.D.A il 2012April 2012New York

Therapy of CML in 2012•Frontline- imatinib 400 mg daily- nilotinib 300 mg BID- dasatinib 100 mg daily

•Second / third line- nilotinib, dasatinib, bosutiinib, ponatinib- allogeneic SCT

•Other- omacetaxine, decitabine, peginterferon

alfa-2a- hydrea, cytarabine, combos of TKIs and

with TKIs- investigational: hedgehog inhibitors,

JAK2 inhibitors, IL3-DT

4/23/2012

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Results with Imatinib in Early CP CML – The IRIS Trial at 8-Years

• 304 (55%) patients on imatinib on study• Projected results at 8 years:j y

- CCyR 83%- 82 (18%) lost CCyR, 15 (3%) progressed to AP/BP

- Event-free survival 81%- Transformation-free survival 92%

If MMR t 12 100%- If MMR at 12 mo: 100%- Survival 85% (93% CML-related)

• Annual rate of transformation: 1.5%, 2.8%, 1.8%, 0.9%, 0.5%, 0%, 0%, & 0.4%

Deininger. Blood 114: abst 1126, 2009

Long-Term Outcome With Imatinib in ECP CML (ITT)

1.0

0.8

0.9

Pro

bab

ility

0.6

0.4

0.2

0 1

0.7

0.5

0.3

SurvivalPFS

EFSCHR

Loss of MCyR

63%

(88% per IRIS definition)

0.1

6054481260

Time From Start of Imatinib Therapy (months)

4236302418

de Lavallade. J Clin Oncol. 26: 3358; 2008

• EFS: death, progression to AP/BP, loss of CHR, loss of MCyR, or WBC, failure to achieve MCyR, intolerance

4/23/2012

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Frontline Rx with Dasatinib or Nilotinib at MDACC

•Parallel studies with nilotinib (400 mg BID) or dasatinib (100 mg QD or 50 mg BID)

Nil ti ib D ti ibNilotinib Dasatinib

% Response N=100 N=93

CGCR by 12 mos 93 99

MMR by 12 mos 73 83

3-yr Survival 100 99

3 yr TFS 97 1003-yr TFS 97 100

3-yr EFS 91 91

3-yr FFS 78 80

Rx discontinuation 11 9

Quintas-Cardama. Blood 118: abst 454, 2011. Pemmaraju. Blood 118; abst 1700; 2011

Event-Free Survival by Treatment in ECP CML

1.0

bab

ility

Eve

nt-

Fre

e

0.4

0.6

0.8

Im atinib 400 m gIm atinib 800 m g

Total73

208

Ev e nts1522

Cortes. Blood 2009; abst 338 & 341; Updated October 2010Months

Pro

b

0 12 24 36 48 60 72 84 96 108 1200.0

0.2

Im atinib 800 m g Dasatin ib N ilotin ib

2087678

2221 p = 0.01

4/23/2012

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Nilotinib 300 mg BID (n = 282)RA

Nilotinib vs. Imatinib in CML (ENEST-nd). Study Design

NDOMIZED*

Nilotinib 400 mg BID (n = 281)• N = 846

• 217 centers

• 35 countries

*Stratification by Sokal risk score

Imatinib 400 mg QD (n = 283)

Follow-up 5 years

Saglio. Blood 118: abst 452, 2011

Nilotinib vs Imatinib in Newly Diagnosed Chronic Phase CML

• 846 pts randomized to nilotinib 300 mg BID (n=282), nilotinib 400 mg BID (n=281), or imatinib 400 mg QD (n=283)( )

• Minimum follow-up 36 mo

Outcome Nil 300 Nil 400 IM 400% CCyR* 87 85 77% MMR** 73 70 53% BCR-ABL ≤0.0032%** 32 28 15% BCR ABL ≤0.0032% 32 28 15% Discontinued treatment 29 26 38

% Entered extension study 7 1 12% Survival at 36 months 95 97 94

Saglio et al. ASH 2011; Abstract #452

* by 24 months, ** by 36 months

4/23/2012

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By 3 Years

100

90

Nilotinib 300 mg BID


Imatinib 400 mg QD

282

281

283

n

Nilotinib vs. Imatinib in CML (ENEST-nd). Cumulative Incidence of MMR

% W

ith

MM

R

73%, P < .0001

70%, P < .0001

53%

80

70

60

50

40

30

55%, P < .0001

51%, P < .0001

By 1 Year

∆ 24%-28%

∆ 17%-20%

33

Months Since Randomization

20

10

0

0 3 6 9 12 15 18 21 24 27 30

27%

36

Saglio. Blood 118; abst 452, 2011

77 756770

80

P = .0264 P = .0020P = .0004

Nilotinib vs. Imatinib in CML (ENEST-nd). MMR by 3 Years According to Sokal Risk

6763

54

39

10

20

30

40

50

60

70

% W

ith

MM

R

0

10

Low Intermediate High

Nilotinib 300 mg BID Imatinib 400 mg QD

n = 103 104 101 101 78 78


4/23/2012

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282

281

n

40By 3 Years

Nilotinib vs. Imatinib in CML (ENEST-nd). Cumulative Incidence of MR 4.5


Imatinib 400 mg QD

281

283

% W

ith

MR

4.5

30

20

10

11%, P < .0001

7%, P < .0001

By 1 Year

∆ 6%-10%

32%, P < .0001

28%, P = .0003

15%

y

∆ 13%-17%

0

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

1%

∆ 6% 10%

36

Months Since Randomization


40404550

P = .0003

P = .0468

Nilotinib vs. Imatinib in CML (ENEST-nd). MR 4.5 by 3 Years According to Sokal Risk

30

24

18 17

910152025303540

% W

ith

MR

4.5

P = .0099

05

Low Intermediate High

Nilotinib 300 mg BID Imatinib 400 mg QD

n = 103 104 101 101 78 78


4/23/2012

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s, n 17P = .0059

P 0185

P = .0003

P = .0085

Nilotinib vs. Imatinib in CML (ENEST-nd). Progression to AP/BP on Core Rx

Nu

mb

er o

f P

atie

nts

23

12

0.7% 0.7%1.1% 4.2% 1.8% 6.0%

2

5

P = .0185

Including Clonal Evolution0.7% 0.7%1.1% 4.2% 1.8% 6.0%

No new progressions on core Rx since 2-year analysis

Nilotinib 300 mg BID Nilotinib 400 mg BID Imatinib 400 mg QD


100

90

Progressed = 34Died = 23Ali 11

Nilotinib vs. Imatinib in CML (ENEST-nd). Survival After Progression to AP/BP

% A

live

90

80

70

60

50

40

30

Median survival 10.5 months

Alive = 11

Months Since Progression

20

10

0

0 6 12 18 24 30 36 42


4/23/2012

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Nilotinib vs. Imatinib in CML-CP. Adverse Events and Grade 3/4 Myelosuppression

Fluid retention

Di h

Rate difference (imatinib - nilotinib) with 95% CI

Favors imatinib Favors nilotinib (300 mg BID)

Diarrhea

Headache

Muscle cramps

Nausea

Pruritus

Rash

Vomiting

Any grade

Vomiting

Anemia

Neutropenia

ThrombocytopeniaGrade 3/4

0.10 0.2 0.3 0.4 0.5-0.1-0.2-0.3-0.4-0.5

Hochhaus. Haematologica. 2010;95(s2):459 [abst 1113]

Dasatinib Versus Imatinib Study In Treatment-naïve CML (DASISION). Trial Design

Follow up

Dasatinib 100 mg QD (n=259)• N=519

● Primary endpoint: Confirmed CCyR by 12 months

Follow-up

5 yearsRandomized*

Imatinib 400 mg QD (n=260)

• 108 centers

• 26 countries

*Stratified by Hasford risk score

● Secondary/other endpoints: Rates of CCyR and MMR; times to confirmed CCyR, CCyR and MMR; time in confirmed CCyR and CCyR; PFS; overall survival

Kantarjian. JCO. 29:abst 6510; 2011

4/23/2012

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Dasatinib vs Imatinib in Newly Diagnosed Chronic Phase CML

• 519 pts randomized to dasatinib 100 mg QD (n=259) or imatinib 400 mg QD (n=260)( ) g ( )

• Median follow-up 28 mo

Outcome Das 100 IM 400

% CCyR 86 82

% MMR 64 46

% BCR-ABL ≤0.0032% 17 8

% discontinued therapy 23 25

New mutations (No.) 10 10* by 24 months


DASISION. Cumulative Incidence of CCyR100

80

By 12 months85%

By 24 months86%

82%

60

40

20

0

% Dasatinib 100 mg QD

Imatinib 400 mg QD

73%

0 10 20 30 40

Months

0

• cCCyR rate by 24 months for dasatinib vs imatinib was 80% vs 74%


4/23/2012

10

100

80 By 24 months

Dasatinib 100 mg QD

Imatinib 400 mg QD

DASISION. Cumulative Incidence of MMR

%60

40

20

By 12 months46%

28%

By 24 months64%

46%

P<0.0001

0 10 20 30 400

Months

• Median time to MMR in all patients calculated by competing risk analysis was 15 months for dasatinib and 36 months for imatinib


DASISION. Cumulative Incidence of BCR-ABL ≤0.0032% (MR4.5; ≥4.5-log reduction)*

Dasatinib 100 mg QD100

Dasatinib 100 mg QD

Imatinib 400 mg QD80

60

40

20

By 24 months17%

%

0 3 6 9 12 15 18 21 24 27

20

0

17%

9%

Months

Hochhaus. ASH 2011

4/23/2012

11

100

DASISION: Transformation To AP/BP CML (ITT)

Dasatinib 100 mg QD Imatinib 400 mg QD

%

n/N 6/259 13/260 9/259 15/260

On study Including follow-up beyond discontinuation


DASISION. Forest Plot Comparing Differences in AE Rates for Dasatinib and Imatinib

Superficial edema Pleural effusion

Fluid retention

Any grade

Diarrhea

Nausea

Neutropenia

Vomiting

Pleural effusion Myalgia

Fatigue Headache Rash

Rate Difference (dasatinib-imatinib) with 95% CI

Grade 3/4Neutropenia Thrombocytopenia Anemia

Favors dasatinib Favors imatinib

–40 0 20 40–20


4/23/2012

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DASISION: Outcome by Response at 3 Months

•519 pts randomized to dasatinib 100 mg QD vs imatinib 400 mg QD

•PCR in central lab by IS at 3, 6, 12, 18 and 24 monthsy , , ,

3 month transcripts

Percentage

CCyR MMR AP/BP

Dasatinib ≤1 98 88 1.8

>1-10% 98 59 1.2

≥10% 38 16 8.1

Imatinib ≤1 100 88 0

>1-10% 94 60 3.3

≥10% 64 19 9.4* By 24 months

Hochhaus et al. ASH 2011; Abstract #2767

DASISION: BCR-ABL Levels at 3 Months*

80

100

84% Dasatinib 100 mg QD

Imatinib 400 mg QD

20

40

60

64%

16%

36%

% o

f P

atie

nts

Imatinib 400 mg QD

>1-10%

≤1%

>1-10%

0

BCR-ABL Level at 3 Months

n/N 198/235 154/239 37/235 85/239

≤10% >10%

*Calculated from total number of evaluable patients with PCR assessments at 3 months

≤1%


4/23/2012

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Probability of CMR at 12 Months by Response at 3 Months and By Therapy

3-mo Percentage3 oTranscript

LevelIM 400 IM 800 Dasatinib Nilotinib

>10 0 0 0 0*

>1-10 0 8 0 0>1 10 0 8 0 0

≤1 22 40 47 60

* Only one patient evaluable in cohort

Naqvi et al. ASH 2011; Abstract #3784

Kaplan-Meier Plots of PFS According To BCR-ABL Level at 3 months


100

80

60

40

20

no

t p

rog

ress

ed

no

t p

rog

ress

ed

≤1%>1–10%

BCR-ABL level at 3 months

≤1%>1–10%

BCR-ABL level at 3 months


100

80

60

40

2020

0

%

0 6 12 18 24 30 36 42

%

Months Months

>10% >10%20

00 6 12 18 24 30 36 42

For ≤10% vs >10% comparison: P<0.0001 For ≤10% vs >10% comparison: P=0.0004


4/23/2012

14

Kaplan-Meier Plots of OS According To BCR-ABL level at 3-month


% a

live

% a

live

≤1%>1–10%

BCR-ABL Level at 3 months

≤1%>1–10%

BCR-ABL Level at 3 months


100

80

60

40

20

100

80

60

40

20>10%

Months

>10%20

00 6 12 18 24 30 36 42

Months0 6 12 18 24 30 36 42

20

0

For ≤10% vs >10% comparison: P=0.0137 For ≤10% vs >10% comparison: P=0.0081


Phase 3 open-label trial in newly diagnosed CP CML

N = 502

Bosutinib 500 mg/day

n = 2508-year follow-up

RANDO

Bosutinib Efficacy and Safely in Newly Diagnosed CML (BELA): Study Design

● Key eligibility criteria: cytogenetic diagnosis of Philadelphia chromosome–positive (Ph+) CP CML 6 mo prior no prior therapy other than hydroxyurea or anagrelide

N 502

139 sites

31 countries Imatinib 400 mg/day

n = 2528-year follow-up

OMIZE

1-year analysisRandomization is stratified based on Sokal risk score and geographical regions.

(Ph+) CP CML 6 mo prior, no prior therapy other than hydroxyurea or anagrelide

● Primary endpoint: complete cytogenetic response (CCyR) at 12 months

● Key secondary and exploratory endpoints:– MMR at 12 months, time to and duration of CCyR and MMR, time to

transformation to AP/BP CML, event-free survival (EFS), and overall survival (OS)– Safety and tolerability

Cortes et al. ASH 2011; abstract #455

4/23/2012

15

Bosutinib vs Imatinib in Newly Diagnosed Chronic Phase CML

• 502 pts randomized to bosutinib 500 mg QD (n=250) or imatinib 400 mg QD (n=252)Mi i f ll 24• Minimum follow-up 24 mo

% Outcome Bos 500 IM 400CCyR* 79 80MMR* 61 50CMR* 23 16CMR 23 16Failure 4 13AP/BP 2 5Death 3 5

Cortes et al. ASH 2011; abstract #455* by 24months

CML Frontline Rx. Toxicities of TKIs

• Bothersome chronic side-effects less frequent with nilotinib than with imatinib: nausea, cramps, aches, weight gain, fluid retention, periorbital edema

• Rashes, headaches more frequent qwith nilotinib

• Pleural effusions; cytopenias more frequent with dasatinib

4/23/2012

16

Suboptimal Response to Imatinib 400 mg/d in CP CML: GIMEMA CML WP Analysis of 423 Consecutive Patients

98% 98%98% 98%

55% 63%

85%

p<0.0001p<0.0001

55% 63%

85%

p<0.0001p<0.0001

79%

33%

85%

51%

p<0.0001 p<0.0001

79%

33%

85%

51%

p<0.0001 p<0.0001

Castagnetti. Hematologica 2009;94 abstract 0528

EFS by Response to IM at 6 and 12 Mos

•281 pts; imatinib frontline (400mg in 73, 800mg in 208)•Suboptimal response at 6-12 months: 12-17% with

0.5

0.6

0.7

0.8

0.9

1.0

0.5

0.6

0.7

0.8

0.9

1.0

6 month response 12 month response

400mg, 1-4% with 800mg (p=0.002)

0 12 24 36 48 60 72

Months

0.0

0.1

0.2

0.3

0.4

Failure Suboptimal Optimal

p<0.0001

No.9

10240

Events (%)6 (67)5 (50)14 (6)

0 12 24 36 48 60 72

Months

0.0

0.1

0.2

0.3

0.4

Failure Suboptimal

Optimal

p<0.0001

No.1419

213

Evaluable (%)8 (57)3 (16)8 (4)

Alvarado. Cancer. 2009;115:3709-18.

4/23/2012

17

Outcome by 12-Month Response in CML CP

• 848 pts randomized to IM 400mg, IM 800mg, or IM 400 + IFN

• Median FU: 40 months• Median FU: 40 months

12-month BCR-ABL/ABL (IS)

NPercentage

PFS OS

<0.1% 341 99 990 1 1% 240 97 98

CCyR0.1-1% 240 97 98>1% 267 94 93

P value 0.0023 0.0011• Outcome independent of treatment arm

Hehlman et al. JCO 2011;29:1634-42

MDACC Retrospective Analysis: MCyR at 6 Months Associated With OS

Landmark analysis at 6 mos

1.0

Cytogenetic response at 6 mos Total Dead P-value

Complete 201 5

Partial 39 10.85

0 01

0.8

0.6

0.4

0 2

Pro

po

rtio

n a

live

Patients with MCyR have better OS than patients that do not

0 12 24 36 48 60 72

Minor 10 3

Othersa 9 3

0.01

0.62

0.2

0

Months

Kantarjian H. Cancer. 2008;112:837–845.

4/23/2012

18

MDACC Retrospective Analysis: CCyR at 12 Months Associated With PFS


1.0

Pro

po

rtio

n P

FS

0.8

0.6

0.4

0 2

Cytogenetic response at 12 mos Total Failure P-value

Complete 214 7

P ti l 19 30.02

Patients with CCyR have better PFS than patients that do not. Similar results were observed in patients achieving CCyR at 18 and 24 mos.

0.2

00 12 24 36 48 60 72

Months

Partial 19 3

Minor 5 2

Others 8 5

0.2

0.22

Kantarjian H. Cancer. 2008;112:837–845.

Hammersmith Experience. CCyR at 12 Months Associated With PFS

1.0 96%


bab

ility

of

PF

Sa

0.4

0.6

0.8

1.0 96%

74%

P = .007

de Lavallade. J Clin Oncol. 2008;26(20):3358-3363.

Pro

CCyR at 12 mos (n = 121)No CCyR at 12 mos (n = 72)

0

0.2

12 24 48 600 36

Months

4/23/2012

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Survival After Imatinib Therapy by Molecular Response Achieved at 3 Months

• Optimal PCR value determined by Receiver operating characteristic (ROC) curve

bab

ility

of

surv

ival

BCR-ABL/ABL<9.8% OS= 93.3%

BCR-ABL/ABL>9.8% OS= 54%

Pro

b

Time from onset of imatinib therapy (years)

p<0.0001

Marin et al, JCO 2011; [Epub ahead of print]

CML IV: Long-Term Impact of Response at 3 Months

•1223 pts randomized to imatinib 400, imatinib + IFN, imatinib + ara-C, imatinib 8003 th l i PCR i 692 t t ti i•3 month analysis: PCR in 692 pts, cytogenetics in 460

•3 mo transcript levels predictive of achievement of CCyR and MMR

% 5-year Cytogenetics

(% Ph+)Molecular

[BCR-ABL/ABL (IS)]outcome

(% Ph ) [BCR ABL/ABL (IS)]

≤35% >35% ≤10% >10%

PFS 94 87 93 87

OS 95 87 95 87

Hanfstein et al. ASH 2011; Abstract #783

4/23/2012

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TKI Frontline Therapy in CMLCCyR AT Time Periods (ITT)

IM400100

• 465 patients with CML frontline therapy− Imatinib 400 mg (n=71), imatinib 800 mg (n=201),

nilotinib (n=100), and dasatinib (n=93)IM400

IM800

NILOT

DASAT

40

50

60

70

80

90

on

se R

ate

(%)

0

10

20

30

3 6 12 18 24 36

Res

p

MonthsAlattar . Blood 118; abst 745, 2011

TKI Frontline Therapy in CMLResponse AT Time Periods (ITT)

80

90

100 CMR MMR

IM400

IM800

40

50

60

70

80

Res

po

nse

Rat

e (%

)

NILOT

DASAT

0

10

20

30

3 6 12 18 24 36

R

MonthsAlattar . Blood 118; abst 745, 2011

4/23/2012

21

TKI Frontline Therapy in CML Long-Term Outcome By Response Time

Event-Free Survival Transformation-Free Survival

p<0.001

Alattar . Blood 118; abst 745, 2011

EFS and Survival by 12-month Response-CCyR vs Others with TKI Frontline Rx

Jabbour E et al. Blood. 2011.

4/23/2012

22

Months on therapy Response Total (%)

3 (N=160)Optimal 160 (100)

Sub-optimal 0

Optimal Response To 2nd TKIs-Frontline. Response (N=167)

Failure 0

6 (N=155)Optimal 152 (98)

Sub-optimal 3 (2)

Failure 0

12 (N=129)Optimal 128 (99)

Sub-optimal 1 (1)

Failure 0

18 (n=119)Optimal 99 (84)

Sub-optimal 14 (12)

Failure 5 (4)

• Median follow-up 33 months (range, 3 to 66 months)

Jabbour E et al. JCO. 2011.

Optimal Response To 2nd TKIs-Frontline. Event-free by 3 mo Response


4/23/2012

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Optimal Response To 2nd TKIs-Frontline. Event-free by 6 mo Response


TKI Frontline Therapy in CML

• Earlier Responses with dasatinib or nilotinib compared to imatinibor nilotinib compared to imatinib 400 mg

• Superior outcome with newer agent

• Improved long-term outcome due to higher rate of early responses

4/23/2012

24

CML 2012. New Proposed Algorithm• Second generation• Check CG at 3 and 6 mos:• At 3 moAt 3 mo

- CCyR → Home free - PCyR → Recheck at 6 mo- Less than MCyR → Careful monitoring; ? third generation TKIs

• At 6• At 6 mo- CCyR → Home free - Less than CCyR → Careful monitoring; ? third generation TKIs

Jabbour. J Clin Oncol. 2011;29:4260-5.

My Desk On A Good Day!

JC

48

4/23/2012

25

Leukemia Questions?

•Pager 713 606 1307•Pager 713-606-1307

•[email protected]

Eli J bb M DElias Jabbour, M.D.

Documents

2nd Generation TKI… Frontline Therapy in CMLimedex.com/hematologic-malignancies-debate... · 2nd Generation TKI… Frontline Therapy in CML Elias Jabbour, M.D. A il 2012April 2012