enestnd: evaluating nilotinib efficacy and safety in clinical trials–newly diagnosed patients

ENESTnd: Nilotinib vs Imatinib in CML-CP

Richard A. Larson, Philipp le Coutre, Josy Reiffers, Timothy Hughes, Giuseppe Saglio, Pascal Edrich, Albert Hoenekopp,

Neil Gallagher, Hagop Kantarjian, Andreas Hochhaus on behalf of the ENESTnd Investigators

Comparison of nilotinib and imatinib in patients with newly

diagnosed chronic myeloid leukemia in chronic phase

(CML-CP): ENESTnd beyond one year

ENESTnd: Evaluating Nilotinib Efficacy and Safety in Clinical Trials–Newly Diagnosed Patients


2

Background• Nilotinib is highly potent and the most selective inhibitor of

BCR-ABL1

• Imatinib is the current standard of care for CML

• ENESTnd is a global, multicenter, randomized phase 3 study of nilotinib 300 mg BID and 400 mg BID vs imatinib

• Results reported at ASH 2009 from the primary analysis were from a median follow-up of 13.8 months2

• Results reported here today are with a median follow-up of approximately 18.5 months

1. Manley P, et al. Biochim Biophys Acta. 2009.2. Saglio G, et al. NEJM. E-pub ahead of print 5 June 2010.


3

Study Design and Endpoints

• Primary endpoint: MMR at 12 months

• Key secondary endpoint: Durable MMR at 24 months

• Other endpoints: CCyR by 12 months, time to MMR and CCyR, EFS, PFS, time to AP/BC on

study treatment, OS including follow-up*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


4

Eligibility Criteria

• Ph+ CML-CP within 6 months from diagnosis

• No prior therapy for CML except:–HU/anagrelide–< 2 weeks of imatinib (9-13% across arms)

• Age ≥ 18 years• ECOG performance 0-2• QTcF <450 msec• Adequate organ function


5

Definitions of Patient Populations

• Intention-to-treat (ITT) population (N=846) used for efficacy analyses–All randomized patients are included and

analyzed by assigned treatment

• Safety population (N=836) used for safety analyses–All randomized patients who received at least

one dose of study medication are included and analyzed by treatment they received


6

Definition of Endpoints• Response assessments are collected during study treatment

• MMR: BCR-ABL ≤ 0.1%IS

– Unavailable sample considered as lack of response

– Atypical transcripts at baseline considered as lack of response (8 patients)

• CCyR: No Ph+ metaphases out of 20

– Unavailable or insufficient sample considered as lack of response

– FISH not used for assessment• Progression to AP/BC on treatment

– Progression defined as per ELN 2006 criteria1

• Overall survival includes data from follow-up after discontinuation of treatment

1. Baccarani M, et al. Blood. 2006;108(6):1809-20.


Patient DispositionNilotinib

300 mg BIDn = 282

Nilotinib400 mg BID

n = 281

Imatinib400 mg QDn = 283

Still on treatment 80% 81% 75%Discontinued, % 20 19 25 Disease progression* <1 <1 4

Suboptimal response/ treatment failure*# 6 2 8

Adverse events 5 10 8

Abnormal lab. values 2 2 1

Death 1 0 0

Protocol violation 2 2 1

Other reason 4 3 3

Data cut-off: 2Jan2010

*Investigator assessment of criteria

#Patients were required to discontinue nilotinib 300 mg BID for suboptimal response but could remain on nilotinib 400 mg BID


8

Treatment Duration and Average Dose


Nilotinib300 mg BID

n = 279

Nilotinib400 mg BID

n = 277


Time on treatment, months (median)

18.6 18.5 18.1

Treatment, ≥ 18 months

53% 53% 51%

Dose intensity, mg/day (median)

593 779 400

• Patients had at least 16 months of treatment or discontinued early

• Dose intensity was close to planned dose across all arms

• Nilotinib dose escalation was not permitted in either arm

• Imatinib dose escalation to 800 mg/day permitted for suboptimal response or treatment failure (24%)


Primary Endpoint - MMR Rate at 12 Months (ITT Population)*

% M

MR

P < .0001

P < .0001

Data cut-off: 2Sept2009

n = 282 n = 281 n = 283

*Saglio G, et al. NEJM. E-pub ahead of print 5 June 2010.


Cumulative Incidence of MMR*

40%

66% (P < .0001)

62% (P < .0001)

Pts

24

55% (P < .0001)

51% (P < .0001)

27%

100

90

80

70

60

50

40

30

20

10

0

3 6 9 12 15 18 21

Pat

ien

ts w

ith

MM

R (

%)

Time Since Randomization (mo)

Nilotinib 300 mg BID Nilotinib 400 mg BIDImatinib 400 mg QD

282281283

0

Best response by 12 mo.

Overall best response

Data cut-off: 2Jan2010*ITT population


11

MMR Rates at 18 and 24 Months (Patients with PCR assessment)

% M

MR


n = 178 n = 175 n = 172 n = 49 n = 48 n = 48


12

Rates of Molecular Response of 0.0032%IS* by 12 Months and Overall

% W

ith

0

.00

32%

IS


P < .0001

P < .0001

P < .0001

P < .0001

*ITT population

11%

21%

7%

17%

10%

20%

30%

Nilotinib 300 mg BID Nilotinib 400 mg BID

n = 282 n = 281 n = 283

1%

0%

Month 12

6%

OverallImatinib 400 mg QD

n = 282 n = 281 n = 283


80%85%

78% 82%

65%74%

0%

20%

40%

60%

80%

100%

Month 12 Overall

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

CCyR Rates* by 12 Months and Overall

P < .0001

P < .001

% C

CyR

13 Data cut-off: 2Jan2010

n = 282 n = 281 n = 283

P < .001

P = .017

• Among patients who had a cytogenetic assessment at 18 months (n = 442/846), the rates of CCyR were:

• 99%, 99%, and 89% for nilotinib 300 mg BID, 400 mg BID, and imatinib*ITT population

n = 282 n = 281 n = 283


14

Progression to AP/BC on Study Treatment*


With a median follow-up of 18.5 months. P-values are based on log-rank test stratified by Sokal risk group vs imatinib for time to AP/BC.

*ITT population

Nu

mb

er

of

Pa

tie

nts P = .006

P = .003

1

12

10

15

20


4.2%

0.4%0.7%

2

0

5


15

Overall Grade 3/4 Myelosuppression Any Time on Study

4

1210

4

1012

5

20

9

0

10

20

30

Anemia Neutropenia Thrombocytopenia


% o

f P

atie

nts



16

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

% of Patients Treated

Nilotinib300 mg BID

n = 279

Nilotinib400 mg BID

n = 277

Imatinib400 mg QD

n = 280All

GradesGrade

3/4All

GradesGrade

3/4All

GradesGrade

3/4Nausea 12 <1 20 1 33 0Muscle spasms 7 0 6 <1 26 <1Diarrhea 8 <1 6 0 24 1

Vomiting 5 0 9 1 16 0

Rash 32 <1 37 3 12 1Headache 14 1 22 1 8 0Pruritus 15 <1 13 <1 5 0Alopecia 8 0 13 0 4 0Myalgia 10 <1 10 0 10 0Fatigue 11 0 9 <1 9 <1



Study Drug-Related Fluid Retention (All Grades)

% of Patients TreatedNilotinib

300 mg BIDn = 279

Nilotinib400 mg BID

n = 277


Peripheral edema 5 6 14 Eyelid edema <1 2 14 Periorbital edema <1 <1 13 Facial edema <1 2 9 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%)

• There was no clinically relevant prolongation in QT interval or decrease in LVEF Data cut-off: 2Jan201017


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Laboratory Abnormalities

% of patients treated

Nilotinib300 mg BID

n = 279

Nilotinib 400 mg BID

n = 277

Imatinib400 mg QD

n = 280

All Grades Grade 3/4 All Grades Grade 3/4 All Grades Grade 3/4

Lipase ↑ 24 7 30 7 11 3Amylase ↑ 16 < 1 20 1 13 1

ALT↑ 67 4 74 9 23 3

AST ↑ 41 1 49 3 25 1Total bilirubin ↑ 54 4 63 8 11 < 1Glucose ↑ 38 6 42 4 22 0Albumin ↓ 4 0 5 0 4 0Cholesterol ↑ 22 0 22 < 1 3 0Phosphorous ↓ 33 5 37 6 49 8Alkaline phos. ↑ 21 0 27 0 33 < 1Creatinine ↑ 5 0 6 0 13 < 1Calcium ↓ 3 < 1 5 < 1 11 0

• One patient in the imatinib arm and one in the nilotinib 400 mg BID arm discontinued the study due to acute pancreatitis



19

Overall Survival* Includes Deaths After Discontinuation

Nilotinib300 mg BID

n = 282

Nilotinib400 mg

BIDn = 281

Imatinib400 mg

QDn = 283

Total number of deaths 5 2 9

CML-unrelated 3 1 1

CML-related

(after BMT)

2

(1)

1

(0)

8

(2)

Estimated 18-month rate of OS

98.5% 99.3% 96.9%

Stratified log-rank test

vs. imatinib0.28 0.03 -



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ENESTnd Beyond 1 Year

• With longer follow-up, rates of MMR and CCyR remain superior for nilotinib vs imatinib

• Molecular responses are continuing to deepen over time

• There continues to be fewer progression events and fewer deaths with nilotinib vs imatinib

• Nilotinib at both doses was generally well-tolerated• Longer follow up supports nilotinib as a new

standard of care in patients with newly diagnosed CML


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, V Hungria, V Colturato, M Conchon, A Nonino; Canada: JH Lipton, D Forrest, M Lalancette, R Delage, M-L Savoie; Colombia: G Quintero, M Gomez; Czech Republic: H Klamova, E Faber; Denmark: H Fredriksen, H Vestergaard, 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, F-E Nicolini, T Facon, J-Y Cahn, A Johnson-Ansah, A Charbonnier; J Reiffers, Germany: N Gattermann, C Scheid, D Niederwieser, OG Ottmann, K Blumenstengel, J Duyster, T Brümmendorf, M Kneba, F Stegelmann, P Schafhausen; Hong Kong: Y-L 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, A Tomita, 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 Imamura, A Matsuda, J Ishikawa; Malaysia: T Chuan 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-Dwozdz, J Holowiecki; 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 Gutierrez, M Sanz Alonso, S del Castillo, R Pérez-López, P Herrera, MJ Rodriguez; Sweden: L Stenke, S Lehmann, B Simonsson, H Wadenvik, B Markevärn, 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; Turkey: B Sahin, B Ulkü, B Undar, R Haznedar; United Kingdom: D Marin, T 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, 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


Back-up


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

373628

373628

373628

Prior Rx, % Hydroxyurea Anagrelide Imatinib (≤ 2 wks)

772

13

7509

711

11



Overall MMR Rates according to Sokal Score*

% M

MR



Confirmed* CCyR Rates by 12 Months**%

CC

yR

P < .0001

P < .0001

* Confirmed by subsequent bone marrow assessment

Data cut-off: 2Jan2010**ITT population


26

Suboptimal Response and Treatment Failure

at 12 Monthsa,b


n = 282 n = 281 n=283 n = 282 n = 281 n=283

aBased on modified ELN 2009 Recommendations; Baccarani et al, JCO. 2009; bITT population

Suboptimal response: PCyR at 12 months

Treatment failure: < PCyR at 12 months or loss of CHR, loss of CCyR, progression to AP/BC, or clonal evolution by 12 months

% o

f p

atie

nts


27

Outcome After Imatinib Dose Escalation

• 68 patients received imatinib 400 mg BID –10 patients achieved MMR after dose escalation

–13 patients achieved CCyR after dose escalation without MMR

–18 patients with CCyR prior to dose escalation did not achieve MMR after dose escalation

–27 patients did not achieve MMR or CCyR after dose escalation



QT Prolongation and LVEF Changes

Nilotinib300 mg BID

n = 279

Nilotinib400 mg BID

n = 277

Imatinib400 mg QD

n = 280

QTc prolongation, % of pts

Absolute QTcF > 500 ms 0 0 0

QTcF increase > 60 ms <1 <1 0

Mean (%) LVEF change

Month 6 1.16 1.77 1.24

Month 12 1.27 1.31 1.31

• There was no clinically relevant prolongation in QT interval or decrease in LVEF


enestnd: evaluating nilotinib efficacy and safety in clinical trials–newly diagnosed patients

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