Transcript ENESTnd 24-Month Update: Continued Superiority of

ENESTnd: Nilotinib vs Imatinib in CML-CP
Chronic Myeloid Leukemia 2010
ENESTnd: Nilotinib vs Imatinib in CML-CP
Summary of CML therapy
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TKI therapy is remarkably effective for CML-CP.
Some patients become resistant and progress.
Imatinib resistance can be treated by “second
generation” TKIs (dasatinib or nilotinib), although
CCyR can only be achieved in 50% of CP
patients with IM resistance.
Monitoring endpoints correlate with long-term
outcomes have been established using
cytogenetic, PCR and mutation testing.
ENESTnd: Nilotinib vs Imatinib in CML-CP
ENESTnd: Nilotinib vs Imatinib in CML-CP
Have We “Optimized” First-line
Therapy?
ENESTnd: Nilotinib vs Imatinib in CML-CP
IRIS 8-Year Update
Results: Overall Survival (Intent-to-Treat) – Imatinib Arm
100
90
% Alive
80
%
,
e
vil
A
70
Estimated overall survival
at 8 years was 85%
(93%, considering only
CML related deaths)
60
50
40
30
20
Survival: deaths associated with CML
Overall Survival
10
0
0
12
24
36
48
60
72
Months Since Randomization
84
96
108
ENESTnd: Nilotinib vs Imatinib in CML-CP
ELN recommendations (2006 and 2009)
Failure
(2006)
Suboptimal response
(2006)
Optimal response
(2009)
3 months
No HR
No CHR
CHR,
and at least minor CyR
6 months
No CHR
and no CyR
No PCyR
and/or>10% Bcr-Abl
(IS)
PCyR
and or<10% Bcr-Abl
(IS)
12 months No PCyR
and/or>10%Bcr-Abl
(IS)
No CCyR
and/or>1% Bcr-Abl
(IS)
CCyR
and or<1% Bcr-Abl
(IS)
18 months No CCyR
and/or>1%Bcr-Abl
(IS)
No MMR
MMR
Any time
Loss of MMR,
KD mutation
Loss of CHR、CCyR,
KD mutation,
insensitive to imatinib
ENESTnd: Nilotinib vs Imatinib in CML-CP
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Using the ELN criteria, 25% of early CP cases
would be declared a “failure” or “suboptimal
response” of imatinib.
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Another small proportion of cases will be
intolerant to imatinib therapy.
ENESTnd: Nilotinib vs Imatinib in CML-CP
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The first approach is to just give more imatinib.
(1) TOPS and other study showed that those patients who can tolerate
higher doses of IM, without interruptions for side effects, have a
better response.
(2) It is not clear whether this will translate into long-term survival
differences and how this strategy will compete with secondgeneration TKIs.
•
Dasatinib and nilotinib are second-generation TKIs
approved for the treatment of patients with CML
resistant or intolerant to imatinib.
(1) CCyR: Resistant 50%; Intolerant 70%
(2) Both drugs have been tried as first-line therapy in newly diagnosed
CML-CP.
ENESTnd: Nilotinib vs Imatinib in CML-CP
Hughes TP, et al. Blood. 2010;116(21):94-95 [abstract 207]
ENESTnd 24-Month Update: Continued
Superiority of Nilotinib Versus Imatinib In
Patients with Newly Diagnosed CML-CP
ENESTnd: Evaluating Nilotinib Efficacy and Safety in
Clinical Trials–Newly Diagnosed Patients
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
*
• Primary endpoint:
• Key secondary endpoint:
• Other endpoints:
Nilotinib 300 mg BID (n = 282)
Nilotinib 400 mg BID (n = 281)
Imatinib 400 mg QD (n = 283)
Follow-up
5 years
MMR at 12 months
Durable MMR at 24 months
CCyR, time to MMR and CCyR, EFS, PFS,
time to AP/BC, OS
Hughes TP, et al. Blood. 2010;116(21):94-95 [abstract 207]
ENESTnd: Nilotinib vs Imatinib in CML-CP
MMR AT 12 and 24 Months*
P < . 0001
70
P < .0001
Percentage
% With MMR
60
50
P < . 0001
P < .0001
44
62
59
43
37
40
30
22
20
10
0
n = 282
n = 281
n = 283
MMR at 12 months1
Nilotinib 300 mg BID
n = 282
n = 281
n = 283
MMR at 24 months
Nilotinib 400 mg BID
Imatinib 400 mg QD
Durable MMR at 24 months: Less than 2% of patients in each treatment arm lost
MMR between 12 and 24 months
*ITT population
1. Saglio G, et al. NEJM. 2010;362:2251-2259.
Data cut-off: 20Aug2010
ENESTnd: Nilotinib vs Imatinib in CML-CP
Cumulative Incidence of MMR*
n
Nilotinib 300 mg BID 282
Nilotinib 400 mg BID 281
Imatinib 400 mg QD 283
100
90
80
By 24 months
71%, P < .0001
% with MMR
By 12 months
70
55%, P < .0001
60
67%, P < .0001
50
Δ 23%-27%
51%, P < .0001
40
44%
Δ 24%-28%
30
27%
20
10
0
0
3
6
9
12
15
18
21
24
27
30
33
Time since randomization (Months)
*ITT population
Data cut-off: 20Aug2010
ENESTnd: Nilotinib vs Imatinib in CML-CP
CCyR Rates by 24 Months*
P = .0018
P = .016
100
87
90
85
77
With CCyR
%Percentage
80
70
60
50
40
30
20
10
n = 282
0
Nilotinib 300 mg BID
*ITT population
n = 281
n = 283
Nilotinib 400 mg BID
Imatinib 400 mg QD
Data cut-off: 20Aug2010
ENESTnd: Nilotinib vs Imatinib in CML-CP
Suboptimal Response and
Treatment Failure by 18 Months*
Percentage
% of Patients
50
45
Nilotinib 400 mg BID
40
Imatinib 400 mg QD
30
30
Nilotinib 300 mg BID
24
16
20
10
0
n = 282
n = 281
n = 283
Suboptimal Response
4
4
n = 282
n = 281
n = 283
Treatment Failure
*ITT population
Suboptimal response: < PCyR at 6 months; < CCyR at 12 months; < MMR at 18 months
Treatment failure: No CyR at 6 months; < PCyR at 12 months; < CCyR at 18 months; at any time within 18
months loss of CHR, loss of CCyR, progression to AP/BC, or clonal evolution
Patients satisfying criteria for both suboptimal response and treatment failure were counted as treatment failure
Data cut-off: 20Aug2010
ENESTnd: Nilotinib vs Imatinib in CML-CP
Progression to AP/BC on
Core Treatment*†
P = .0059
25
P = .0003
Percentage
Number of Patients
P = .0196
P = .0089
20
17
15
12
10
5
5
0
2
0.7%
3
1.1%
2
4.2%
0.7%
1.8%
6.0%
Including Clonal Evolution
Nilotinib 300 mg BID
Nilotinib 400 mg BID
Imatinib 400 mg QD
*ITT population
†Progression to AP/BC or death due to CML while on core treatment
Data cut-off: 20Aug2010
ENESTnd: Nilotinib vs Imatinib in CML-CP
PFS on Core Treatment*†
Nilotinib
300 mg BID
n = 282
Nilotinib
400 mg BID
n = 281
Imatinib
400 mg QD
n = 283
5
4
12
Estimated 24-month
rate of PFS
98.0%
97.7%
95.2%
P value
0.0736
0.0437
–
Number of events
*ITT population
†Progression to AP/BC or death due to any cause while on core treatment
Data cut-off: 20Aug2010
ENESTnd: Nilotinib vs Imatinib in CML-CP
Overall Survival*†
Nilotinib
300 mg BID
n = 282
Nilotinib
400 mg BID
n = 281
Imatinib
400 mg QD
n = 283
9
6
11
Estimated 24-month
rate of OS
97.4%
97.8%
96.3%
P-value (OS)
0.6485
0.2125
–
CML-unrelated
4
3
1
CML-related
5
3
10
Total number of deaths
*ITT population
†Including deaths after discontinuation of core treatment
Data cut-off: 20Aug2010
ENESTnd: Nilotinib vs Imatinib in CML-CP
Grade 3/4 Myelosuppression
25
% of Patients
21
20
15
12
11
10
5
0
4
4
10
12
9
5
Anemia
Nilotinib 300 mg BID
Neutropenia
Nilotinib 400 mg BID
Thrombocytopenia
Imatinib 400 mg QD
Data cut-off: 20Aug2010
ENESTnd: Nilotinib vs Imatinib in CML-CP
Selected Grade 3/4 Biochemical
Abnormalities
% of Patients
10
8
9
8
8
7
6
6
4
5
4
4
3
3
2
0
<1
0
Lipase ↑
Nilotinib 300 mg BID
ALT ↑
Total bilirubin ↑
Nilotinib 400 mg BID
Glucose ↑
Imatinib 400 mg QD
Data cut-off: 20Aug2010
ENESTnd: Nilotinib vs Imatinib in CML-CP
ENESTnd 24-Month Update
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Nilotinib continues to demonstrate:
– Superior CCyR, MMR, and CMR.
– Significantly fewer progressions to AP/BC.
– Lower rates of suboptimal response and treatment failure.
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Nilotinib at both doses was generally well-tolerated,
and fewer adverse events lead to discontinuation in
the nilotinib 300 mg BID arm.
Longer follow-up supports the superiority of nilotinib
for the treatment of patients with newly diagnosed
CML-CP.
ENESTnd: Nilotinib vs Imatinib in CML-CP
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The strategy for the treatment of newly
diagnosed CML may change.
ENESTnd: Nilotinib vs Imatinib in CML-CP
Debating Points
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Whether or not a small benefit in early
cytogenetic response with the secondgeneration TKIs will translate to a long-lasting
survival benefit.
The wisdom of switching to second-generation
drugs without long-term safety data.
Cost issues.
ENESTnd: Nilotinib vs Imatinib in CML-CP
Is Resistance Forever?
ENESTnd: Nilotinib vs Imatinib in CML-CP
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One of the unifying features of the biology of CML is the
genetic instability caused by Bcr-Abl.
• The interval from the acquisition of Bcr-Abl and
diagnosis allows Bcr-Abl signaling, and thus the genetic
instability causing either resistance or progression.
(1) Resistance is lowest in early-phase CP, higher in late CP, and
higher yet in AP and BC.
(2) Progression to CML-AP is associated with the consequences of
instability.
(3) Abl point mutations can be found in late-phase CP and AP CML
even prior to initiation of TKI therapy.
ENESTnd: Nilotinib vs Imatinib in CML-CP
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At the time of resistance, selective pressure
facilitates the outgrowth of multiple-resistant
clonal populations.
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Treatment with second generation TKI caused
new natural selection forcing resistant clones to
outcompete sensitive ones.
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With sequential clonal selection, the proportion
of patients carrying the T315I, which is resistant
to both nilotinib and dasatinib, increases.
ENESTnd: Nilotinib vs Imatinib in CML-CP
ENESTnd: Nilotinib vs Imatinib in CML-CP
Implications of these observations
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Once a patient fails primary TKI therapy, one cannot just
expect treatment with a second-generation drug.
----- Allogeneic transplantation; Clinical trial
(1) It is important to proceed to transplant before
progression occurs.
(2) Two studies have suggested measures of response
to guide second-line TKI therapy, allowing physicians to
declare failure early and expeditiously proceed to
transplant.
ENESTnd: Nilotinib vs Imatinib in CML-CP
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Genetic instability is the rationale for more vigorous
suppression of Bcr-Abl activity at the beginning of
treatment.
(1) A more complete suppression of Bcr-Abl could curtail
genetic instability and thus delay or eliminate the disease
progression and the creation of competing clones.
(2) The contrarian point of view is that there will always be a
significant proportion of CML that had the disease for
years before diagnosis; and add whatever TKI you will,
clonal selection will still proceed.
• We need ways to predict response to therapy.
ENESTnd: Nilotinib vs Imatinib in CML-CP
Can We Predict Response?
ENESTnd: Nilotinib vs Imatinib in CML-CP
Functional Studies
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TKIs are among the class of drugs potentially imported
and exported by drug influx and efflux pumps.
• Imatinib can be imported by OCT-1. OCT-1 activity and
mRNA OCT-1 levels correlate well with response rate
(OS, EFS, molecular response, and mutation rate) .
• Intracellular levels of nilotinib and dasatinib are
influenced by ABC efflux pumps activity.
ENESTnd: Nilotinib vs Imatinib in CML-CP
Early BCR-ABL Response
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Perhaps the best predictor of long term
response is short-term response.
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The Australian group have demonstrated BCRABL PCR response after 3 months of therapy is
strongly associated with treatment outcomes
(CCyR, MMR, and PFS).
ENESTnd: Nilotinib vs Imatinib in CML-CP
Mutation Testing
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Testing for the ABL mutations is not useful in newly
diagnosed CP patients.
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Both ELN and NCCN suggest mutation testing at the
time of increasing Bcr-Abl levels, or at loss of response.
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Rationale for this approach:
(1) Identify patients to have a T315I mutation.
(2) Identify patients has a mutation that is sensitive to
one second-generation TKI, but not to the other.

Recent study concluded that, although T315I mutation
testing was important, there was no clear data that
testing of other mutations mattered, because the
outcomes of patients with any mutation versus those
without mutations were similar.
ENESTnd: Nilotinib vs Imatinib in CML-CP
Problems with mutation test
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How the in vitro sensitivity of mutations are
performed and calculated.
As methods of detecting mutations vary, the
significance of mutation detection may
potentially vary from study to study.
Selection of patients entering studies, as well as
definition of outcomes.
Follow-up is not standard across studies.
ENESTnd: Nilotinib vs Imatinib in CML-CP
What Do We Mean When We Talk
About “Cure”?
ENESTnd: Nilotinib vs Imatinib in CML-CP
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One routinely hears arguments that TKI therapy is not
“curative,” as opposed to transplantation, which
supposedly is “curative.”
Some TKI patients become PCR-. Some patients are
able to come off therapy, and roughly 40% will remain in
CMR.
Following allogeneic transplantation, roughly 10% of
cases will be BCR-ABL+ by PCR after 5 years of followup. Long-term relapses occur, at a rate of approximately
1% per year. The longest relapse took place 18 years
post transplant.
Given that it is likely mathematically improbable that all
leukemia stem cells can be destroyed, perhaps we
should use “cure” as relieving symptoms without
detectable disease, freeing patients and doctors from the
impossible expectation of eliminating all disease.
ENESTnd: Nilotinib vs Imatinib in CML-CP
Conclusions—What Else to Do?
ENESTnd: Nilotinib vs Imatinib in CML-CP
• We need to determine to best use of second-generation
TKIs.
(1) Upfront with imatinib, then switch to more active
agents if aggressive milestones are not reached?
(2) Give more potent second-generation drugs first and
then switch optimal responders to maintenance therapy
with a cheap imatinib?
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We need to conduct trials on how reacting to specific Abl
mutations makes a difference, as well as determine if
treatment of a molecular relapse is useful.
•
We need to determine if complete molecular response is
a relative and useful endpoint.
•
Lastly, we await effective therapy of the T315I mutation,
lest it be the final destination of all resistance.
ENESTnd: Nilotinib vs Imatinib in CML-CP
Thanks!