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
ENESTnd: Nilotinib vs Imatinib in CML-CP
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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.
ENESTnd: Nilotinib vs Imatinib in CML-CP
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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
ENESTnd: Nilotinib vs Imatinib in CML-CP
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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
ENESTnd: Nilotinib vs Imatinib in CML-CP
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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
ENESTnd: Nilotinib vs Imatinib in CML-CP
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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.
ENESTnd: Nilotinib vs Imatinib in CML-CP
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
ENESTnd: Nilotinib vs Imatinib in CML-CP
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Treatment Duration and Average Dose
Data cut-off: 2Jan2010
Nilotinib300 mg BID
n = 279
Nilotinib400 mg BID
n = 277
Imatinib400 mg QDn = 280
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%)
ENESTnd: Nilotinib vs Imatinib in CML-CP
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.
ENESTnd: Nilotinib vs Imatinib in CML-CP
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
ENESTnd: Nilotinib vs Imatinib in CML-CP
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MMR Rates at 18 and 24 Months (Patients with PCR assessment)
% M
MR
Data cut-off: 2Jan2010
n = 178 n = 175 n = 172 n = 49 n = 48 n = 48
ENESTnd: Nilotinib vs Imatinib in CML-CP
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Rates of Molecular Response of 0.0032%IS* by 12 Months and Overall
% W
ith
0
.00
32%
IS
Data cut-off: 2Jan2010
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
ENESTnd: Nilotinib vs Imatinib in CML-CP
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
ENESTnd: Nilotinib vs Imatinib in CML-CP
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Progression to AP/BC on Study Treatment*
Data cut-off: 2Jan2010
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
Nilotinib 300 mg BID Nilotinib 400 mg BID Imatinib 400 mg QD
4.2%
0.4%0.7%
2
0
5
ENESTnd: Nilotinib vs Imatinib in CML-CP
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Overall Grade 3/4 Myelosuppression Any Time on Study
4
1210
4
1012
5
20
9
0
10
20
30
Anemia Neutropenia Thrombocytopenia
Nilotinib 300 mg BID Nilotinib 400 mg BID Imatinib 400 mg QD
% o
f P
atie
nts
Data cut-off: 2Jan2010
ENESTnd: Nilotinib vs Imatinib in CML-CP
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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
Data cut-off: 2Jan2010
ENESTnd: Nilotinib vs Imatinib in CML-CP
Study Drug-Related Fluid Retention (All Grades)
% of Patients TreatedNilotinib
300 mg BIDn = 279
Nilotinib400 mg BID
n = 277
Imatinib400 mg QDn = 280
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
ENESTnd: Nilotinib vs Imatinib in CML-CP
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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
Data cut-off: 2Jan2010
ENESTnd: Nilotinib vs Imatinib in CML-CP
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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 -
Data cut-off: 2Jan2010*ITT population
ENESTnd: Nilotinib vs Imatinib in CML-CP
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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: Nilotinib vs Imatinib in CML-CP
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
ENESTnd: Nilotinib vs Imatinib in CML-CP
Back-up
ENESTnd: Nilotinib vs Imatinib in CML-CP
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
Data cut-off: 2Sept2009
ENESTnd: Nilotinib vs Imatinib in CML-CP
Overall MMR Rates according to Sokal Score*
% M
MR
Data cut-off: 2Jan2010*ITT population
ENESTnd: Nilotinib vs Imatinib in CML-CP
Confirmed* CCyR Rates by 12 Months**%
CC
yR
P < .0001
P < .0001
* Confirmed by subsequent bone marrow assessment
Data cut-off: 2Jan2010**ITT population
ENESTnd: Nilotinib vs Imatinib in CML-CP
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Suboptimal Response and Treatment Failure
at 12 Monthsa,b
Data cut-off: 2Sept2009
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
ENESTnd: Nilotinib vs Imatinib in CML-CP
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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
Data cut-off: 2Jan2010
ENESTnd: Nilotinib vs Imatinib in CML-CP
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
Data cut-off: 2Jan201028