Imatinib vs. 2nd gen TKI in newly diagnosed Chronic Myelogenous Leukemia

DONG WOOK KIM, MDSeoul, S. Korea

• Professor, Seoul ST. Mary Hospital, Seoul, S. Korea

• Dr. Kim the Head of Cancer Research Institute at the Catholi

c University of Korea, a chairman of Asia CML Study Allian

ce (ACSA) that is an Asian hematologist network and the pu

rpose is to improve the quality and standardization of CML t

herapy and research in Asian countries on the basis of unders

tanding the current situation. And also ACSA seeks collabor

ation in CML studies and sharing information for new medic

al discoveries in CML and ELN (European Leukemia Net) P

anel for CML recommendation 2013.

Imatinib vs. 2G TKI

in newly diagnosed CP-CML

Prof. Dong-Wook Kim MD, PhD

Seoul St. Mary’s Hospital

The Catholic University of Korea

• ENESTnd: MMR, Nil vs IM, approved

• DASISION: cCCyR, Das vs IM, approved

• BELA: cCCyR, Bos vs IM, fail to achieve primary endpoint

• EPIC: MMR, Pon vs IM, suspended due to serious VEs

• RE-RISE: MMR, Rad vs IM, ongoing in Asian countries

• BFORE: MMR, Bos vs IM, ongoing in Global

Clinical trials with IM vs 2 or 3 G TKI

in new CML patients

Treatment strategy recommendation,

chronic phase, firstline

Baseline (firstline treatment)

- Imatinib 400 mg once daily, or

- Nilotinib 300 mg twice daily, or

- Dasatinib 100 mg once daily

In case of intolerance, switch to another TKI

In case of failure, switch to another TKI

In case of warning, do not switch, until the warning is confirmed or

becomes a failure

Baccarani M., et al. Blood 2013, 122(6):872-884

Characteristics of registered patients (n=3,717)

- Type of 1st TKI -

by 1-DEC-2014 7th ACSA-ASH 2014 in San Francisco

Asia Collaboration of CML Research

IM3420 (92%)

Nil92 (3%)

Das120 (3%)

Bos20 (1%)

Rad54 (1%)

Pon11 (0%)

Asia CML Registry (ACR)

- 10 Asian countries

- 17 major hospitals

DASISION (CA180-056) Study Design

Primary end point: confirmed CCyR by 12 months

– 77% dasatinib vs. 66% imatinib (P=0.007)1

Database lock of 24-Mar-2014

5-year

final resultsRandomizeda

Imatinib 400 mg QD (n=260)

Dasatinib 100 mg QD (n=259)

Treatment-naïve

CML-CP patients

(N=519)

108 centers

26 countries

Enrollment:

September 2007–

December 2008

aStratified by EURO (Hasford) risk score.1. Kantarjian H et al. N Engl J Med 2010;362:2260–70.

ENESTnd 5-Year Update

Data cutoff: May 22, 2013

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ENESTnd Study Design

N = 846

217 centers

35 countries

Imatinib 400 mg QD (n = 283)

Nilotinib 300 mg BID (n = 282)

RANDOMIZE


Follow-up: 5 years; extended to 10 years

after protocol amendment

Primary end point: MMR at 12 months

Patients were stratified according to Sokal risk score at diagnosis

BID, twice daily; QD, once daily. Saglio G, et al. Blood. 2013:[abstract 92].

Patient Disposition at 5 Years

At 5 years (study end), 61% and 63% in dasatinib and imatinib are still on

initial therapy

Treated Patients, n (%)

Dasatinib 100 mg QD

(n=258)

Imatinib 400 mg QD

(n=258)

On initial therapy at study end 158 (61) 162 (63)

Discontinued

Progression or treatment failure 28 (11) 36 (14)

AE related to study treatmenta 42 (16) 17 (7)

AE unrelated to study treatmenta 12 (5) 4 (2)

Poor/nonadherence 1 (<1) 7 (3)

Other 17 (7)b 31 (12)c

aAEs defined by investigator.

bIncludes withdrawal of consent and patient request (4 each), insufficient molecular response (3), pregnancy (2), and lost to follow-up, loss of CCyR, increased BCR-ABL, and relocation to the US (1 each).

cIncludes patient request (10), no molecular response/loss of molecular response (4), withdrawal of consent and suboptimal response (3 each), lost to follow-up, insufficient cytogenetic response, and investigator request (2 each), and pregnancy, recurrence of blasts in bone marrow,no CMR, no MMR, and appearance of mutation (1 each).



KR1401170300

Patient Disposition at 5 Years

Few patients have discontinued treatment since the 4-year data cutoff

• 3.5% (n = 10) on nilotinib 300 mg BID; 4.3% (n = 12) on nilotinib 400 mg BID; 6.0% (n = 17) on imatinib

– Of 17 imatinib discontinuations, 5 (vs 0 nilotinib discontinuations) were due to suboptimal response/treatment failure

Median time on core treatment comparable and median dose intensity close to intended dose for all

treatment armsa Patients are either on study drug or in post-treatment follow-up after discontinuation of study drug.b Patients with suboptimal response or treatment failure on nilotinib 300 mg BID or imatinib core treatment were eligible to

discontinue the core study and enter an extension study to receive nilotinib 400 mg BID.

Nilotinib

300 mg BID

(n = 282)

Nilotinib

400 mg BID

(n = 281)

Imatinib

400 mg QD

(n = 283)

Still on study, %a 85.5 87.9 83.4

Still on core treatment, % 62.4 65.1 51.2

Discontinued core treatment and entered extension study, %b 8.5 1.1 15.2

Still on extension treatment, % 5.3 0.7 8.8

Discontinued core treatment without entering extension study, % 29.1 33.8 33.6

Adverse events/laboratory abnormalities 11.0 18.1 12.7

Suboptimal response/treatment failure 3.2 3.6 6.4

Disease progression 0.7 1.4 3.5

Death 2.1 0.4 0.4

Other reason 12.1 10.3 10.6

Saglio G, et al. Blood. 2013:[abstract 92].

Cumulative MMR Rates Over Time

Months Since Randomization

% W

ith

MM

R

Dasatinib 100 mg QD

N

Imatinib 400 mg QD 260259

By 1 year

By 2 years

By 3 years

By 4 years

By 5 years

28%

46%

55%

60%64%

46%

64% 67%

73% 76%

0 6 12 18 24 30 36 42 48 54 60

100

90

80

70

60

50

40

30

20

10

0

p=0.0022

MMR rates have significantly increased in dasatinib arm



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Cumulative Incidence of MMR

MMR, major molecular response (BCR-ABLIS ≤ 0.1%).a Cumulative response rates reported consider each year to consist of twelve 28-day cycles.

By 1 Yeara By 5 Yearsa

55%, P < .0001

51%, P < .0001

27%

Δ 24% to 28%

60%

77%, P < .0001

77%, P < .0001

Δ 17%

By 4 Yearsa

76%, P < .0001

73%, P < .0001

56%

Δ 17% to 20%

100

0 2 6

90

80

70

60

50

40

30

20

10

0

Pati

en

ts W

ith

MM

R,

%

Time Since Randomization, Calendar Years31




4 5


MMR rates were also significantly higher in both nilotinib arms

0 6 12 18 24 30 36 42 48 54 60

100

90

80

70

60

50

40

30

20

10

0

Cumulative MR4.5 Rates Over Time

By 1 year

By 2 years

By 3 years

By 4 years

By 5 years

3%

8%

13%

23%

33%

5%

19%

24%

34%

42%

p=0.0251

Months Since Randomization

% W

ith

MR

4.5

Dasatinib 100 mg QD

N

Imatinib 400 mg QD 260259

MR4.5, BCR-ABL (IS) ≤0.0032% (for subjects with B2a2 and B3A2 transcripts).

Cumulative rate of MR4.5 was also significantly higher in dasatinib arm



KR1401170300

Cumulative Incidence of MR4.5

MR4.5, molecular response ≥ 4.5-logs (BCR-ABLIS ≤ 0.0032%).a Cumulative response rates reported consider each year to consist of twelve 28-day cycles.

By 5 Yearsa

11%, P < .0001

7%, P < .0001

1%

Δ 6% to 10%

31%

52%, P < .0001

54%, P < .0001

Δ 21% to 23%

By 4 Yearsa

40%, P < .0001

37%, P = .0002

23%

Δ 14% to 17%

100

0 2 6

90

80

70

60

50

40

30

20

10

0

Pati

en

ts W

ith

MR

4.5

, %

Time Since Randomization, Calendar Years

31




4 5

By 1 Yeara


By 5 yrs, more than half of nilotinib-treated patients had achieved MR4.5

Dasatinib 100 mg QD

(n=259)

Imatinib 400 mg QD

(n=260)

BCR-ABL at 3 Monthsa≤10%

n=198

>10%

n=37

≤10%

n=154

>10%

n=85

Transformation to AP/BPb, n (%) 6 (3) 5 (14) 5 (3) 13 (15)

0

5

10

15

20

Pati

en

ts,

n12

(4.6%)

19

(7.3%)

Dasatinib

n=259

Imatinib

n=260

On study During follow-up beyond discontinuation

Transformation to AP/BP CML by 5 Years

One imatinib patient and no dasatinib patients transformed between 4 and 5 yearsaOne dasatinib and one imatinib patient transformed but did not have 3-month molecular assessments.

bIncluding follow-up beyond discontinuation (intent to treat).

4.6% (12 pts) progressed to AP/BC in dasatinib arm comparing with 7.3% in IM arm

An achievement of EMR at 3 mos was able to decrease dis. progression by 5 yrs.



KR1401170300

20

10

0

5

10

15

20

25

Progressions on Study

Pati

en

ts,

nProgression to AP/BC on Studya

(Including After Treatment Discontinuation)

a Includes progression to AP/BC (excluding clonal evolution) or deaths in patients with advanced CML occurring on study (on

core or extension treatment or during follow-up after treatment discontinuation).

P = .0588

P = .0047

6

Nilotinib 300 mg BID (n = 282) Nilotinib 400 mg BID (n = 281)

The progression rates were lower in both nilotinib arms and two new progressions on study in year 5

(1 in the nilotinib 300 mg BID arm and 1 in the imatinib arm)

Both patients had BCR-ABL > 10% at 3 months

New events

in year 5

7.1% 3.5% 2.1%



Progression-Free Survival

and Overall Survival

However, no difference of survivals demonstrated between dasatinib and imatinib arm

Causes of death were cardiovascular disease (2 dasatinib, 1 imatinib); disease

progression (9 dasatinib, 17 imatinib); infection (11 dasatinib, 1 imatinib); other

malignancy, septic shock and cardiac failure, multi-organ failure, and whole body swelling

(1 each dasatinib); stem cell transplantation complications and unknown (2 each

imatinib); severe chest pain, clinical deterioration and decrease in performance status,

and fatal bleeding (1 each imatinib)

Dasatinib100 mg QD

(n=259)

Imatinib400 mg QD

(n=260)

Hazard ratio

(95% CI)

Total number of deaths, n 26 26 –

Estimated 5-year OS, % (95% CI) 91 (87–94) 90 (85–93) 1.01 (0.58–1.73)

Estimated 5-year PFS, % (95% CI) 85 (80–89) 86 (80–89) 1.06 (0.68–1.66)

On-study treatment and in follow-up after discontinuation of randomized treatment.

CI, confidence interval; OS, overall survival; PFS, progression-free survival.



KR1401170300

PFS and OS on Study

(Including After Treatment Discontinuation)a

a Includes events occurring on core or extension treatment or during follow-up after treatment discontinuation.b Patients for whom the principle cause of death was either “study indication” or “unknown” or not reported but occurred

subsequent to a documented progression to AP/BC.

Imatinib

400 mg QD

(n = 283)

Nilotinib

300 mg BID

(n = 282)

Nilotinib

400 mg BID

(n = 281)

Estimated 5-year PFS, % 91.1 92.0 95.3

Progressions and deaths, n 23 22 11

Hazard ratio (95% CI) — 0.92 (0.51-1.65) 0.46 (0.23-0.95)

P value .77 .03

Estimated 5-year OS, % 91.6 93.6 96.0

Total deaths, n 21 18 10

Deaths in patients with

advanced CML, nb 15 6 4

Hazard ratio (95% CI) — 0.84 (0.45-1.58) 0.46 (0.22-0.98)

P value — .58 .04

At 5 yrs of FU, PFS and OS were higher in patients treated with nilotinib 400mg BID than with IM

There were 6 newly reported deaths in year 5

Imatinib (n = 2): both due to study indication

Nilotinib 300 mg BID (n = 3): study indication, rectal cancer, and pneumonia

Nilotinib 400 mg BID (n = 1): sepsis


Treated patients, n (%)

Dasatinib 100 mg QD (n=258) Imatinib 400 mg QD (n=258)

Any grade Grade 3/4 Grade 5 Any grade Grade 3/4 Grade 5

Any ischemic event 12 (5) 7 (3) 2 (1) 6 (2) 3 (1) 1 (<1)

Cardiovasculara 10 (4) 5 (2) 2 (1) 4 (2) 2 (1) 1 (<1)

TIA 2 (1) 2 (1) 0 0 0 0

PAD 0 0 0 2 (1) 1 (<1) 0

Total24

(9.3%)14 (5.4) 4 (1.6)

12

(4.7%) 6 (2.3) 2 (<1)

Arterial Ischemic Events Regardless

of Relationship to Study Therapy

All grades of VEs developed twice higher in dasatinib arm and 7 of 10 cardiovascular

ischemic events occurred within 1 year of dasatinib initiation

However, most dasatinib patients restarted therapy without a recurrent event

aIncludes myocardial infarction, angina pectoris, coronary artery disease, and acute coronary syndrome.



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Selected Cardiovascular Events by 5 Years

(All Cause*, All Grades)

All grades of VEs were 3-6 times higher in both nilotinib arms

Approximately 85% of patients with a cardiovascular event had at least 1 risk factor

and were not optimally managed for hyperglycemia and hypercholesterolemia

suggesting importance of treatment of risk factors

*All cause indicates all events, not only those deemed study drug-related by the investigator.

IHD, ischemic heart disease; ICVE, ischemic cerebrovascular events; PAD, peripheral arterial disease.

Patients With an Event, n

Nilotinib

300 mg BID

n = 279

Nilotinib

400 mg BID

n = 277

Imatinib

400 mg QD

n = 280

Total, n

Y1-4, n

Y5, n

Total, n

Y1-4, n

Y5, n

Total, n

Y1-4, n

Y5, n

IHD 11 11 0 21 14 7 5 3 2

ICVE 4 3 1 8 5 3 1 1 0

PAD 4 4 0 6 5 1 0 0 0

Total19

(6.8%) 18 1 35(12.6%) 24 11 6

(2.1%) 4 2


Dasatinib n (%)

TotalGrade 1–2Grade 3–4

73 (28)66 (26)

7 (3)

Discontinuation due to pleural effusion 15 (6)

Dose interruptions due to pleural effusionMedian duration of dose interruption, d (range)

45 (62)14 (2–63)

Dose reductions due to pleural effusionMedian duration of dose reduction, d (range)

30 (41)50 (7–751)

Median time to first grade 1–2 pleural effusion, wk (range) 114 (4–299)

Characteristics and Management

of Pleural Effusion

At 5 years, 28% (73 pts) of dasatinib treated patients had PE and 46 out of 73 patients

had recurrent pleural effusions

Although 62% of patients with pleural effusion had dose interruption (median, 14 d),

this did not impair the ability of patients to obtain a response

• Of patients with pleural effusion, 96% had cCCyR, 82% had MMR,

and 50% had MR4.5

cCCyR, confirmed complete cytogenetic response.

EMR (< 10%) of Bcr-Abl1) at 3 months

91%

67%

84%

64%

0

10

20

30

40

50

60

70

80

90

100

Nilotinib Imatinib Dasatinib Imatinib

ENESTnd DASISION

P<0.0001

At 3 months, both 2 G TKIs achieved higher EMR rates than imatinib arm

Landmark Analysis: Improved Rates of

BCR-ABLIS ≤ 10% at 3 Months Regardless of Sokal Risk Score

79

70

44

93 9286

0

10

20

30

40

50

60

70

80

90

100

Low Risk Intermediate Risk High Risk

Pati

en

ts,

%

Imatinib 400 mg QD Nilotinib 300 mg BID

n = 102 97 92 91 70 70


In high risk Sokal group, an achievement of EMR was higher in nilotinib

300mg BID than imatinib arm suggesting upfront 2G TKIs therapy may be

more beneficial in these patients

PFS (AP/BC or Death) on Study

by BCR-ABL Levels at 3 Months

Nilotinib 300 mg BID Imatinib 400 mg QD

BCR-ABL Level

≤ 1%

> 1% to ≤ 10%

> 10%

Censored

Observations

Pts Evt Cen

145 7 138

89 4 85

24 6 18

P = .9814

P = .0010

PFS by 5 Yearsa

94.6%95.3%

78.3%

100

90

80

70

60

50

40

30

20

10

00 1 2 3 4 5 6

Pa

tie

nts

Witho

ut P

rog

ressio

n, %


100

90

80

70

60

50

40

30

20

10

00 1 2 3 4 5 6

Pa

tie

nts

Witho

ut P

rog

ressio

n, %


PFS by 5 Yearsa

P = .2338P < .0001

98.5%95.3%

80.1%

BCR-ABL Level

≤ 1%

> 1% to ≤ 10%

> 10%

Censored

Observations

Pts Evt Cen

43 2 41

133 2 131

88 16 72

EMR Failure EMR Failure

Cen, censored; EMR, early molecular response; Evt, events; Pts, patients.a PFS rates reported consider each year to consist of twelve 28-day cycles.

Patients with EMR failure (BCR-ABL > 10% at 3 months) have

significantly worse 5-year PFS

Rates of EMR failure are lower on nilotinib 300 mg BID vs imatinib


OS by BCR-ABL Levels at 3 Months


P = .4871

P = .0007

OS by 5 Yearsa

BCR-ABL Level

≤ 1%

> 1% to ≤ 10%

> 10%

Censored

Observations

Pts Evt Cen

145 6 139

89 2 87

24 5 19

100

90

80

70

60

50

40

30

20

10

0

0 1 2 3 4 5 6

Pa

tie

nts

Aliv

e,

%


100

90

80

70

60

50

40

30

20

10

0

0 1 2 3 4 5 6


OS by 5 Yearsa

P < .0001

P = .087399.2%95.3%

BCR-ABL Level

≤ 1%

> 1% to ≤ 10%

> 10%

Censored

Observations

Pts Evt Cen

43 2 41

133 1 132

88 16 72

Cen, censored; EMR, early molecular response; Evt, events; Pts, patients.a OS rates reported consider each year to consist of twelve 28-day cycles.

Patients with EMR failure (BCR-ABL > 10% at 3 months) have

significantly worse 5-year OS

Rates of EMR failure are lower on nilotinib 300 mg BID vs imatinib

79.5%

95.7%97.6%

81.9%

Pa

tie

nts

Aliv

e,

%

EMR Failure:

9% of pts

EMR Failure:

33% of pts


Proportion of Patients With MR4.5

by BCR-ABL Levels at 3 Months

58%

28%

4%

P = .0001

P = .0135

70%

52%

8%

P = .0046

P = .0001

MR4.5 by 4 Yearsa

MR4.5 by 5 YearsaBCR-ABL Level

≤ 1%

> 1% to ≤ 10%

> 10%

Pts

144

89

24

100

90

80

70

60

50

40

30

20

10

0

0 1 2 3 4 5 6

Pa

tie

nts

With M

R4

.5,

%


MR4.5 by 4 Yearsa

MR4.5 by 5 Yearsa

65%

24%

5%

P < .0001

P =

.0001

67%

34%

15%

P = .0001

P = .0016

BCR-ABL Level

≤ 1%

> 1% to ≤ 10%

> 10%

Pts

43

133

88

100

90

80

70

60

50

40

30

20

10

0

0 1 2 3 4 5 6P

atie

nts

With M

R4

.5,

%


a Cumulative response rates reported consider each year to consist of twelve 28-day cycles.

BCR-ABLIS ≤ 1%:

16% of ptsBCR-ABLIS ≤ 1%:

56% of pts


Patients with BCR-ABL ≤ 1% at 3 months have significantly higher rates of MR4.5 by 5 years

More patients achieve BCR-ABL ≤ 1% at 3 months on nilotinib 300 mg BID vs imatinib


Parameters deciding EMR

• Recently, patient and treatment characteristics associated with EMR

in ENESTnd study (Blood 2014:123:1353)

– High Sokal risk score was associated with a high rate of EMR

failure on imatinib, but not on nilotinib

– In contrast, reduced dose intensity and dose interruptions were

strongly associated with EMR failure in nilotinib-treated, but not

imatinib-treated, patients

• Our study with 286 new CP-CML patients treated with imtinib found

various clinical parameters on achieving EMR

Hughes TM et al., Blood 2014:123:1353

Lee SE et al., Leukemia Research 2015 (in press; http://dx.doi.org/10.1016/j.leukres.2015.01.011)

http://dx.doi.org/10.1016/j.leukres.2015.01.011

0

10

20

30

40

50

60

70

80

1 2

0

20

40

60

80

100

120

140

160

180

1 2 Q1

(≤ 958.2 ng/mL)

Q2, Q3, Q4

(> 958.2 ng/mL)

No

of p

atie

nts

with

ava

ilable

data

No

of p

atie

nts

with

ava

ilable

data

Blast ≤ 1% Blast > 1%

Percentage of blast at diagnosis Plasma IM level on day 29

> 10% at 3 months

≤ 10% at 3 months

BCR-ABL1

135/160

(84.4%)

25/160

(15.6%)

22/78

(28.2%)

56/78

(71.8%) 16/24

(66.7%)

8/24

(33.3%)

8/71

(11.3%)

63/71

(88.7%)

P=0.052 P=0.015

Predictive factors for an achievement of 3mo EMR

Blast count at diagnosis and IM trough level on day 29 were significantly

associated with an achievement of 3-month EMR.



7/35

(20.0%)

Predictive factors for an achievement of 6mo EMR

0

20

40

60

80

100

120

140

160

180

1 20

20

40

60

80

100

120

140

160

180

200

220

240

1 2

0

20

40

60

80

100

120

140

1 2

No

of p

atie

nts

with

ava

ilable

data

Low Intermediate/High> 350 mg/day≤ 350 mg/day

Log reduction from

individual baseline to 3 mos

≥ 1-log reduction< 1-log reduction

Mean daily dose by 6 mosSokal risk

> 1% at 6 months

≤ 1% at 6 months

BCR-ABL1

74/101

(73.3%)

27/101

(26.7%)

72/155

(46.5%)

83/155

(53.5%)

13/34

(38.2%)

21/34

(61.8%)

81/229

(35.4%)

148/229

(64.6%)

37/130

(28.5%)

93/130

(71.5%)28/35

(80.0%)


P=0.013 P=0.076 P<0.001

Early decline of BCR-ABL1 transcript, low Sokal risk, and mean daily dose (≥350

mg/day) by 6 months were associated with an achievement of 6-month EMR


Summary and Conclusion

At 5 years of follow-up, rates of PFS and OS were higher in patients

treated with nilotinib 400mg BID than with imatinib

2G TKIs demonstrated higher rates of early and deeper molecular

response, including MR4.5, and a reduced risk of progression

More cardiovascular events were reported in 2G TKIs, especially nilotinib

than in the imatinib

An achievement of EMR was higher in frontline 2 G TKIs suggesting better

long-term responses and survival than with imatinib

Some biological factors were associated with achievement of EMR and can be

modifiable

Continuing the optimal dose intensity is important for better outcomes

These long-term data confirm 2 G TKIs as a standard-of-care in patients

with newly diagnosed CML-CP

Acknowledgement

KCIA members

CCRI colleagues

Education

Imatinib vs. 2nd gen TKI in newly diagnosed Chronic Myelogenous Leukemia