ENESTnd: Nilotinib vs Imatinib in CML-CP
Comparison of nilotinib and
imatinib in patients with newly
diagnosed chronic myeloid
leukemia in chronic phase
(CML-CP): ENESTnd beyond
one year
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
ENESTnd: Evaluating Nilotinib Efficacy and Safety in
Clinical Trials–Newly Diagnosed Patients
ENESTnd: Nilotinib vs Imatinib in CML-CP
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 followup of approximately 18.5 months
1.
2.
Manley P, et al. Biochim Biophys Acta. 2009.
Saglio G, et al. NEJM. E-pub ahead of print 5 June 2010.
2
ENESTnd: Nilotinib vs Imatinib in CML-CP
Study Design and Endpoints
• N = 846
• 217 centers
• 35 countries
R
A
N
D
O
M
I
Z
E
D
*
Nilotinib 300 mg BID (n = 282)
Nilotinib 400 mg BID (n = 281)
Imatinib 400 mg QD (n = 283)
Follow-up
5 years
• Primary endpoint:
• Key secondary endpoint:
• Other endpoints:
*Stratification by Sokal risk score
MMR at 12 months
Durable MMR at 24 months
CCyR by 12 months, time to MMR
and CCyR, EFS, PFS, time to AP/BC on
study treatment, OS including follow-up
3
ENESTnd: Nilotinib vs Imatinib in CML-CP
Eligibility Criteria
• Ph+ CML-CP within 6 months from
•
diagnosis
No prior therapy for CML except:
•
•
•
•
Age ≥ 18 years
ECOG performance 0-2
QTcF <450 msec
Adequate organ function
– HU/anagrelide
– < 2 weeks of imatinib (9-13% across arms)
4
ENESTnd: Nilotinib vs Imatinib in CML-CP
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
5
ENESTnd: Nilotinib vs Imatinib in CML-CP
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.
6
ENESTnd: Nilotinib vs Imatinib in CML-CP
Patient Disposition
Nilotinib
300 mg BID
Still on treatment
Discontinued, %
Disease progression*
Suboptimal response/
treatment failure*#
Adverse events
Abnormal lab. values
Death
Protocol violation
Other reason
Nilotinib
Imatinib
400 mg BID 400 mg QD
n = 282
80%
20
n = 281
81%
19
n = 283
75%
25
<1
<1
4
6
2
8
5
2
1
2
4
10
2
0
2
3
8
1
0
1
3
*Investigator assessment of criteria
#Patients
were required to discontinue nilotinib 300 mg BID for suboptimal response
but could remain on nilotinib 400 mg BID
Data cut-off: 2Jan2010
ENESTnd: Nilotinib vs Imatinib in CML-CP
Treatment Duration and Average Dose
Nilotinib
Nilotinib
300 mg BID 400 mg BID
Imatinib
400 mg QD
n = 279
n = 277
n = 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%)
8
Data cut-off: 2Jan2010
ENESTnd: Nilotinib vs Imatinib in CML-CP
Primary Endpoint - MMR Rate at 12 Months
(ITT Population)*
P < .0001
60
Percentage
% MMR
50
P < .0001
44
43
40
30
22
20
10
n = 282
n = 281
n = 283
0
Nilotinib 300 mg BID
Nilotinib 400 mg BID
*Saglio G, et al. NEJM. E-pub ahead of print 5 June 2010.
Imatinib 400 mg QD
Data cut-off: 2Sept2009
ENESTnd: Nilotinib vs Imatinib in CML-CP
Cumulative Incidence of MMR*
Pts
Nilotinib 300 mg BID 282
Nilotinib 400 mg BID 281
Imatinib 400 mg QD 283
Patients with MMR (%)
100
90
80
Best response
by 12 mo.
Overall
best response
66% (P < .0001)
70
55% (P < .0001)
60
62% (P < .0001)
50
51% (P < .0001)
40
40%
30
27%
20
10
0
0
3
6
9
12
15
18
21
24
Time Since Randomization (mo)
*ITT population
Data cut-off: 2Jan2010
ENESTnd: Nilotinib vs Imatinib in CML-CP
MMR Rates at 18 and 24 Months
(Patients with PCR assessment)
86%
69%
Percentage
% MMR
100%
90%
80%
70%
60%
50%
40%
30%
20%
10%
0%
88%
63%
48%
36%
n = 178
n = 175
n = 172
18 Months (N = 525/846)
Nilotinib 300 mg BID
n = 49
n = 48
24 Months (N = 145/846)
Nilotinib 400 mg BID
11
n = 48
Imatinib 400 mg QD
Data cut-off: 2Jan2010
ENESTnd: Nilotinib vs Imatinib in CML-CP
Rates of Molecular Response of
 0.0032%IS* by 12 Months and Overall
30%
P < .0001
% With  0.0032% IS
P < .0001
21%
P < .0001
20%
17%
P < .0001
11%
10%
7%
6%
1%
n = 282
n = 281
n = 283
n = 282
n = 281
n = 283
0%
Month 12
Nilotinib 300 mg BID
*ITT population
Overall
Nilotinib 400 mg BID
12
Imatinib 400 mg QD
Data cut-off: 2Jan2010
ENESTnd: Nilotinib vs Imatinib in CML-CP
CCyR Rates* by 12 Months and Overall
Nilotinib 300 mg BID
Nilotinib 400 mg BID
Imatinib 400 mg QD
P < .001
P < .0001
100%
80%
% CCyR
80%
P = .017
P < .001
85%
78%
82%
74%
65%
60%
40%
20%
n = 282 n = 281
n = 283
n = 282
n = 281 n = 283
0%
•
Month 12
Overall
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
13
Data cut-off: 2Jan2010
ENESTnd: Nilotinib vs Imatinib in CML-CP
Progression to AP/BC
on Study Treatment*
Number of Patients
Nilotinib 300 mg BID
20
Nilotinib 400 mg BID
P = .006
P = .003
15
12
10
5
0
Imatinib 400 mg QD
4.2%
2
1
0.4%
0.7%
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
14
Data cut-off: 2Jan2010
ENESTnd: Nilotinib vs Imatinib in CML-CP
Overall Grade 3/4 Myelosuppression
Any Time on Study
% of Patients
30
20
20
12
12
10
10
4
4
10
9
5
0
Anemia
Nilotinib 300 mg BID
Neutropenia
Nilotinib 400 mg BID
15
Thrombocytopenia
Imatinib 400 mg QD
Data cut-off: 2Jan2010
ENESTnd: Nilotinib vs Imatinib in CML-CP
Study Drug-Related Non-laboratory
Adverse Events (≥ 10% in Any Group)
% of Patients
Treated
Nausea
Muscle spasms
Diarrhea
Vomiting
Rash
Headache
Pruritus
Alopecia
Myalgia
Fatigue
Nilotinib
300 mg BID
n = 279
All
Grade
Grades
3/4
12
7
8
5
32
14
15
8
10
11
<1
0
<1
0
<1
1
<1
0
<1
0
Nilotinib
400 mg BID
n = 277
All
Grade
Grades
3/4
20
6
6
9
37
22
13
13
10
9
16
1
<1
0
1
3
1
<1
0
0
<1
Imatinib
400 mg QD
n = 280
All
Grade
Grades
3/4
33
26
24
16
12
8
5
4
10
9
0
<1
1
0
1
0
0
0
0
<1
Data cut-off: 2Jan2010
ENESTnd: Nilotinib vs Imatinib in CML-CP
Study Drug-Related Fluid Retention
(All Grades)
% of Patients Treated
Nilotinib
Nilotinib
Imatinib
300 mg BID 400 mg BID 400 mg QD
n = 279
n = 277
n = 280
Peripheral edema
Eyelid edema
Periorbital edema
Facial edema
Weight gain
5
<1
<1
<1
3
6
2
<1
2
1
14
14
13
9
6
Pericardial effusion
Pleural effusion
<1
<1
0
0
<1
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
17
Data cut-off: 2Jan2010
ENESTnd: Nilotinib vs Imatinib in CML-CP
Laboratory Abnormalities
% of patients
treated
Lipase ↑
Amylase ↑
ALT↑
AST ↑
Total bilirubin ↑
Glucose ↑
Albumin ↓
Cholesterol ↑
Phosphorous ↓
Alkaline phos. ↑
Creatinine ↑
Calcium ↓
Nilotinib
300 mg BID
n = 279
Nilotinib
400 mg BID
n = 277
Imatinib
400 mg QD
n = 280
All Grades
Grade 3/4
All Grades
Grade 3/4
All Grades
Grade 3/4
24
16
67
41
54
38
4
22
33
21
5
3
7
<1
4
1
4
6
0
0
5
0
0
<1
30
20
74
49
63
42
5
22
37
27
6
5
7
1
9
3
8
4
0
<1
6
0
0
<1
11
13
23
25
11
22
4
3
49
33
13
11
3
1
3
1
<1
0
0
0
8
<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
18
Data cut-off: 2Jan2010
ENESTnd: Nilotinib vs Imatinib in CML-CP
Overall Survival*
Includes Deaths After Discontinuation
Nilotinib
300 mg BID
n = 282
Nilotinib
400 mg
BID
n = 281
Imatinib
400 mg
QD
n = 283
Total number of deaths
5
2
9
CML-unrelated
3
1
1
CML-related
(after BMT)
2
(1)
1
(0)
8
(2)
98.5%
99.3%
96.9%
0.28
0.03
-
Estimated 18-month
rate of OS
Stratified log-rank test
vs. imatinib
*ITT population
19
Data cut-off: 2Jan2010
ENESTnd: Nilotinib vs Imatinib in CML-CP
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
20
ENESTnd: Nilotinib vs Imatinib in CML-CP
ENESTnd Contributing Investigators
Argentina: 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 Characteristics
Nilotinib
300 mg BID
N = 282
Nilotinib
400 mg BID
N = 281
Imatinib
400 mg QD
N = 283
47 (18–85)
47 (18–81)
46 (18–80)
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
Age, median (range)
Time since Dx, median
(days)
Data cut-off: 2Sept2009
ENESTnd: Nilotinib vs Imatinib in CML-CP
Overall MMR Rates
according to Sokal Score*
80
70
70
69
Percentage
% MMR
60
67
63
59
51
51
50
39
40
28
30
20
10
0
Low
Nilotinib 300 mg BID
*ITT population
Intermediate
Nilotinib 400 mg BID
High
Imatinib 400 mg QD
Data cut-off: 2Jan2010
ENESTnd: Nilotinib vs Imatinib in CML-CP
Confirmed* CCyR Rates by 12 Months**
P < .0001
P < .0001
80
70
69
68
Percentage
% CCyR
60
51
50
40
30
20
10
0
Nilotinib 300 mg BID
Nilotinib 400 mg BID
* Confirmed by subsequent bone marrow assessment
**ITT population
Imatinib 400 mg QD
Data cut-off: 2Jan2010
ENESTnd: Nilotinib vs Imatinib in CML-CP
Suboptimal Response and Treatment Failure
at 12 Monthsa,b Nilotinib 300 mg BID
Nilotinib 400 mg BID
Imatinib 400 mg QD
14
11
Percentage
% of patients
12
10
8
8
6
4
2
2
n = 282
n = 281
3
2
2
0
n=283
n = 282
Suboptimal Response
aBased
n = 281
n=283
Treatment Failure
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
26
Data cut-off: 2Sept2009
ENESTnd: Nilotinib vs Imatinib in CML-CP
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
27
Data cut-off: 2Jan2010
ENESTnd: Nilotinib vs Imatinib in CML-CP
QT Prolongation and LVEF Changes
Nilotinib
Nilotinib
Imatinib
300 mg BID 400 mg BID 400 mg QD
n = 279
n = 277
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
Month 12
1.16
1.27
1.77
1.31
1.24
1.31
• There was no clinically relevant prolongation in QT
interval or decrease in LVEF
28
Data cut-off: 2Jan2010