nilotinib demonstrates superior efficacy compared with ... · *p-values are based on log-rank test...

Giuseppe Saglio, Dong-Wook Kim, Surapol Issaragrisil, Philipp le Coutre, Josy Reiffers, Clarisse Lobo, Ricardo

Pasquini, Richard Clark, Timothy Hughes, Andreas Hochhaus, Neil Gallagher, Albert Hoenekopp, Mei Dong,

Ariful Haque, Hagop Kantarjian, and Richard Larson

on behalf of the ENESTnd Investigators

Nilotinib Demonstrates Superior Efficacy Compared With Imatinib in

Patients With Newly Diagnosed CML-CP: Results From the

International Randomized Phase III ENESTnd Trial

Slid

e-

ResultsOverall survival （intent-to-treat）：imatinib Arm

100

60

20

Alive, ％

40

80

10

0 1080

90

50

30

70

96726048362412

Months since randomization

84

Overall survival

Survival: deaths associated with CML

Estimated overall survival

at 8 years was 85％（93％, considering only

CML-related deaths）

These results are not only due to imatinib!

% S

urv

ival

(all d

eath

s)

0

10

20

30

40

50

60

70

80

90

100

Months after stopping imatinib study therapy

0 12 24 36 48 60 72 84 96

Safety (n=30)

Efficacy (n=82)

Bone marrow transplant (n=16)

Other reason (n=80)

Survival 85% at 5 years after

discontinuing study

Survival approximately 50%

at 5 years after stopping

imatinib study drug

IRIS 7 year update

Survival of Patients Who

Discontinued Imatinib Study Therapy

Nilotinib

Held in place by lipophilic

interactions in place of hydrogen-

bonds, making it less susceptible to

point mutations

Specifically designed to

bind more efficiently to

the ATP binding site

Imatinib

ATP binding

site

Hydrogen bonds form with

specific amino acids lining

the binding site

• Differences in drug binding account for nilotinib’s activity in BCR-ABL mutations that are resistant to imatinib

Nilotinib designed for a better fit to inactivate

conformation of the ABL kinase domain

O'Hare T, Walters DK, Deininger MW, Druker BJ. AMN107: tightening the grip of imatinib. Cancer Cell. 2005;7:117.

Nilotinib:Increased potency and selectivity for Abl

Nilotinib

(Cell prolif. IC50)

Abl

(25 nM)

> PDGFR

(53 nM)

> KIT

(158 nM)

Imatinib

(cell prolif IC50)

PDGFR

(39 nM)

> KIT

(98 nM)

> Abl

(669 nM)

Nilotinib has no significant effect on other kinases evaluated

(including Src, FLT3, VEGFR, EGFR, InsR, RET, MET , IGFR, etc)

at concentration <3000 nM.

Mestan. Blood 2004;104(546a): Abstract 1978

Weisberg. Cancer Cell 2005;7(129)

0

500

1,000

1,500

IC50

Ce

ll P

rolife

rati

on

(n

M)

Nilotinib sensitive:

Range 19–791 nM

Nilotinib resistant:

>10,000 nM

Trough levels at 400 mg nilotinib BID (1,700 nM)

exceed IC50 for 32/33 mutations.

Hochhaus et al. Blood 2006;108(11):Abstract 749 Oral presentation

Nilotinib Against Imatinib-resistant

Bcr-Abl Mutants

T315I

Figure 1. Hematologic and Cytogenetic Response in

Patients With a Minimum Follow-Up of 24 Months (N = 321)

• Median time to CHR was 1.0 month in patients without CHR at baseline

• Median time to MCyR was 2.8 months

• MCyR was achieved in 59% of patients, 74% of which were CCyR

n 321 155 55 321 226 95 321 226 95

* Patients who achieved (without baseline CHR) or maintained CHR (had CHR at study entry).

† Patients with no CHR at baseline.

‡ See definition of imatinib-intolerant with resistance in the Methods sections.

MCyR CCyRCHR

41%44%

56%59%

85%72%

66%

51%

0

10

20

30

40

50

60

70

80

90

100

% P

ati

en

ts

Overall* OverallImatinib

Resistant

Imatinib

Intolerant w/

Resistance ‡Overall

Imatinib

Resistant

Imatinib

Intolerant w/

Resistance ‡

CCyR, complete cytogenetic response; CHR, complete hematologic response; MCyR, major cytogenetic response.

RESULTS

Imatinib

Resistant †Imatinib

Intolerant w/

Resistance † ‡

90%

Kantarjian HM et al., ASH 2009

RESULTS

CCyR, complete cytogenetic response.

Figure 4. Duration of CCyR

Kantarjian HM et al., ASH 2009

2 Phase II clinical trials performed at MDAnderson and in Italy

testing nilotinib 400 mg BID as front line treatment of newly

diagnosed CML patients

showed very good results

Rosti G, et al. Blood. 2009 ; 114:4933.

Molecular responses (GIMEMA)

11

ENESTnd StudyStudy Design and Endpoints

• Primary endpoint: MMR at 12 months

• Secondary endpoint: CCyR by 12 months

• Other endpoints: time to and duration of MMR and

CCyR, EFS, PFS, time to AP/BC, OS

*Stratification by Sokal risk score

Imatinib 400 mg QD (n=283)

Nilotinib 300 mg BID (n=282)RANDOMIZED*

Nilotinib 400 mg BID (n=281)

• N = 846

• 217 centers

• 35 countries

Follow-up 5 years

1212

Definition of Endpoints

• MMR: BCR-ABL ≤ 0.1%IS

– Unavailable sample considered as lack of response

– Atypical transcripts at baseline considered as lack of response

• CCyR: No Ph+ metaphases out of 20

– Insufficient metaphases considered as lack of response

– Unavailable sample considered as lack of response

– FISH not allowed

13

Baseline Patient CharacteristicsNilotinib

300 mg BIDN = 282

Nilotinib400 mg BID

N = 281

Imatinib400 mg QD

N = 283

Age, median (range) 47 (18–85) 47 (18–81) 46 (18–80)

Time since Dx,

median (days)

31 31 28

Sokal risk, %

Low

Intermediate

High

37

36

28

37

36

28

37

36

28

Prior Rx, %

Hydroxyurea

Anagrelide

Imatinib (< 2 wks)

77

2

13

75

0

9

71

1

11

14

Patient DispositionNilotinib

300 mg BID

N = 282

Nilotinib400 mg BID

N = 281

Imatinib400 mg QD

N = 283

Still on treatment, % 84 82 79

Discontinued, % 16 18 21

Disease progression <1 <1 4

Treatment failure <1 2 4

Suboptimal response 3 0 2

Adverse events 5 9 7

Abnormal lab. values 2 2 1

Death <1 0 0

Protocol violation 1 2 1

Other reason 3 3 2

15

Suboptimal Response/Treatment Failure

5

1

5

2

13

8

0

5

10

15

20

25

Suboptimal response Treatment failure

Pe

rce

nta

ge

Nilotinib 300 mg BID


Imatinib 400 mg QD

% o

f p

ati

en

ts

16

K-M Estimate of EFS

Imatinib 400 mg QD



283

282

281

93

47

51

190

235

230

Pat Evt Cen

Censored observations

p < 0.0001p < 0.0001

17

MMR Rates Over Time (ITT)

9

33

43 44

5

30

3843

1

12

1822

0

10

20

30

40

50

60

Month 3 Month 6 Month 9 Month 12

Pe

rce

nta

ge

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

% M

MR

p<0.0001

p<0.0001

18

Deeper Molecular Responses at Any Time (ITT)(4- and 4.5-log* Reduction)

24

13

21

1210

4

0

5

10

15

20

25

4-log reduction (< 0.01%) 4.5-log* reduction (< 0.0032%)

Pe

rce

nta

ge



Imatinib 400 mg QD

% r

esp

on

der

BCR-ABL Transcript Level Reduction

- -

*Most sensitive measure of leukemic burden available

19

CCyR Rates (ITT)

67

80

63

78

45

65

0

20

40

60

80

100

Month 6 Month 12


p<0.0001

p=0.0005

% C

CyR

20

CCyR Rates by 12 Months by Sokal Score

8678

74

8780

63

77

65

49

0

10

20

30

40

50

60

70

80

90

100

Low Intermediate High

Pe

rce

nta

ge


% C

CyR

21

Overall Progression to AP/BC (ITT)

21

11

0

5

10

15Nilotinib 300 mg BID


Imatinib 400 mg QD

nu

mb

er

of

pa

tie

nts

• No patients who achieved MMR progressed to AP/BC

• 3 patients who achieved CCyR on imatinib progressed to AP/BC

p=0.0095* p=0.0037*

*p-values are based on log-rank test stratified by Sokal risk group vs imatinib for time to AP/BC

0.7% 0.4%

3.9%

22

Grade 3/4 Myelosuppression

3

1210

3

1012

5

20

9

0

10

20

30

Anemia Neutropenia Thrombocytopenia


% o

f p

ati

en

ts

2323

Study Drug-Related Adverse Events (≥ 10% in Any Group)

% of patients treated

Nilotinib300 mg BID

N = 279

Nilotinib400 mg BID

N = 277

Imatinib400 mg QD

N = 280

All Grades

Grade 3/4

All Grades

Grade 3/4

AllGrades

Grade 3/4

Nausea 12 <1 20 1 31 0

Muscle spasms 7 0 6 <1 24 <1

Diarrhea 8 <1 7 0 21 1

Vomiting 5 0 9 1 14 0

Rash 31 <1 36 3 11 1

Myalgia 10 <1 10 0 10 0

Headache 14 1 21 1 8 0

Fatigue 11 0 9 <1 8 <1

Pruritus 15 <1 13 <1 5 0

Alopecia 8 0 13 0 4 0

24

Study Drug-Related Fluid Retention (All Grades)

% of patients treatedNilotinib

300 mg BID

N = 279

Nilotinib400 mg BID

N = 277

Imatinib400 mg QD

N = 280

Peripheral edema 5 5 14

Eyelid edema <1 2 13

Periorbital edema <1 <1 12

Facial edema <1 2 8

Weight Gain 3 <1 6

Pericardial effusion <1 0 <1

Pleural effusion <1 0 0

•Grade 3/4 AEs were rarely observed in any treatment arm (<1%)

25

Laboratory Abnormalities (Grade 3/4)

% of pts treated Nilotinib300 mg BID

N = 279


N = 277

Imatinib400 mg QD

N = 280

Lipase ↑ 6 6 3

Amylase ↑ <1 1 1

ALT ↑ 4 9 3

AST ↑ 1 3 1

Total bilirubin ↑ 4 8 <1

Glucose ↑ 6 4 0

Albumin ↓ 0 0 0

Cholesterol ↑ 0 <1 0

Phosphorous ↓ 5 5 8

Alkaline phos. ↑ 0 0 <1

Cholesterol ↑ 0 <1 0

Creatinine ↑ 0 0 <1

Calcium ↓ <1 <1 0

• One patient in the imatinib arm and one in the nilotinib 400 mg BID arm

discontinued the study due to acute pancreatitis

2626

QTcF Prolongation

% of patients treatedNilotinib

300 mg BIDN = 279

Nilotinib400 mg BID

N = 277

Imatinib400 mg QD

N = 280

Absolute QTcF >480 ms 0 <1 0

Absolute QTcF >500 ms 0 0 0

QTcF increase >30 ms 26 26 18

QTcF increase >60 ms <1 <1 0

•There was no decrease from baseline in mean LVEF

anytime during treatment in any arm

27

Conclusions• Nilotinib is superior to imatinib with significantly higher

rates of MMR and CCyR, at both 300 mg BID and 400 mg BID

• Significantly fewer patients on nilotinib progressed compared with imatinib

• Nilotinib is superior to imatinib across all Sokal risk groups

• Nilotinib is generally well-tolerated

• Incidence of AEs leading to discontinuation was lowest in the nilotinib 300 mg BID arm

• Based on these results nilotinib may become the new standard of care in newly diagnosed CML

The available data with nilotinib used as first-

line therapy for CP-CML show:

1) A high percentage of responses (CCyR, MMR) (less primary resistance)

2) A lower rate of progression (less secondary resistance)

Why?

Possible explanations

• Higher potency in inhibiting BCR-ABL1 TK

• Lower dependence of intra/extracellular mechanisms of drug influx/efflux

• Higher capability in suppressing “permissive situations” for the development of resistance

– Mutations of BCR-ABL1

– Activation of alternative TK activities

30

ENESTnd Contributing InvestigatorsArgentina: B Moiraghi, M Perez; Austria: R Greil, P Valent; Belgium: L Noens, A Bosly, G Verhoef, M André,

P Martiat; Brazil: MA Zanichelli, C Souza, M Mello, V Hungria, V Colturato, A Nonino; Canada:

J Lipton, D Forrest, M Lalancette, R Delage, M-L Savoie; Colombia: G Quintero, M Gomez; Czech Republic:

H Klamova, E Faber; Denmark: H Frederiksen, H Vestergaard, C Marcher, O Weis Bjerrum, C Marcher; Egypt:

H Kamel, H Elzawam; Finland: K Porkka, K Remes; France: J-L Harousseau, A-P Guerci-Bresler, F Rigal-

Huguet, M Tulliez, D Guyotat, M Gardembas, M Escoffre, L Legros, F Guilhot, D Rea, FE Nicolini, T Facon, J-Y Cahn,

A Johnson-Ansah, A Charbonnier; Germany: N Gatterman, C Scheid, D Niederwieser, O Ottmann,

K Blumenstengel, J Duyster, T Bruemmendorf, M Kneba, F Stegelmann, P Schathausen; Hong Kong:

Y-I Kwong; Hungary: T Masszi; Italy: G Fioritoni, G Alimena, F Nobile, E Pungolino, G Rosti, M Gobbi, E Abruzzese,

M Petrini, A Bosi, AM Carella, EM Orlandi, F Ferrara, F Lauria, S Amadori, F Di Raimondo, A Levis, M Tiribelli, P Leoni,

A Rambaldi, M Martelli, B Rotoli, F Pane; Japan: M Hino, I Matsumura, M Kurokawa, Y Kanda, C Nakaseko, O Miura,

I Jinnai, Y Maeda, K Ohnishi, T Nagai, S Miyawaki, K Imai, K Ohishi, K Usuki, M Okada, Y Miyazaki, A Kimura,

K Miyamura, S Nakao, K Toba, S Okamoto, S Chiba, N Tsukamoto, N Takahashi, Y Kobayashi, K Ohyashiki,

T Kawaguchi, M Hino, M Imamura, I Jinnai, A Matsuda, I Matsumura, J Ishikawa; Malaysia: TC Ong; Mexico:

J Kassack, D Gómez Almaguer; Netherlands: GJ Ossenkoppele; Norway: T Gedde-Dahl, H Hjorth-Hansen;

Poland: K Kuliczkowski, S Kyrcz-Krzemieñ, W Jedrzejczak, A Dmoszynska, J Starzak-Gwozdz; Russia: A Turkina,

T Pospelova, A Zaritsky; Singapore: LP Koh, YT Goh; Slovakia: L Demitrovicova, M Mistrik; South Africa: G Cohen,

LM Dreosti, V Louw, P Ruff, N Novitzky; South Korea: S-K Sohn, H-J Kim, C-W Jung, K-H Lee, S-Y Park;

Spain: F Cervantes, F Marin, J Hernandez Boluda, C Boque, R De paz, J Batlle, RF Rodriguez, E Conde, J Odriozola,

M Perez Encinas, C Cañizo, A Julia Font, B Heredia, P Giraldo, P Lopez, JL Steegman, MA Echeveste, M Sanz Alonso,

S del Castillo, F Martin, R Perez, P Herrera, R Rogriguez, MJ Rodriguez; Sweden: L Stenke, S Lehmann,

B Simonsson, H Wadenvik, B Markevarn, K Myhr Eriksson, M Bjoreman, J Richter, ASjälander; Switzerland:

Y Chalandon; Taiwan: M-C Wang, M Yao, L-Y Shih; Thailand: S Jootar, U Bunworasate; United Kingdom: D Marin,

Holyoake, J Byrne, G Smith; United States: I Flinn, S Goldberg, M Kalaycio, R Gingrich, J Burke, T Ervin, T Shea,

B Powell, C Alemany, K Kolibaba, G Guzley, M Guerra, L Fehrenbacher, WG Harker, J Davis, W Edenfield, E

Arrowsmith, H Koh, L Fehrenbacher, R Paquette, A Al-Janadi, L Akard, G Robbins, M Savin, D Schlossman, D

Richards, W Berry, M Woodson, C Siegrist, J Glass, M Heaney, H Wallach; Venezuela: J Lopez

nilotinib demonstrates superior efficacy compared with ... · *p-values are based on log-rank test...

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