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Path in CML
Tomek Szczudlo, MD
Executive Medical Director
Novartis Oncology
Path in CML
A Long-Term Partnership Between Novartis and the CML Community
Better Understanding
CML
Improving Detection
& Monitoring
Optimizing
Treatment Strategies
Achieving a durable response to treatment that can lead to a
sustained treatment-free remission
CML GOLS Meeting - Clinical Survey
What is your current treatment goal for CML
patients in CP?
1. Controlling minimal residual disease with chronic TKI treatment (overall
survival)
65%
82%
2. Eradicating leukemia and discontinuing treatment (definitive cure)
35%
18%
2013
2012
Approximately 900 attendees. Helsinki, February 23, 2013
CML GOLS Meeting - Clinical Survey
What will be your treatment goal for CML
patients in the future?
1. Controlling minimal residual disease with chronic TKI treatment (overall
survival)
8%
10%
2. Eradicating leukemia and discontinuing treatment (definitive cure)
92%
90%
2013
2012
Approximately 900 attendees. Helsinki, February 23, 2013
Prior experiences with stopping TKI
Attempts to stop TKI were not successful when patients
were <CMR or in CMR for short period
Response at the time
of TKI discontinuation
% of patients with
molecular and/or
cytogenetic relapse
CCyR (Korean)
100%
At least MMR (Nordic)
100%
MMR, CCyR, MCyR (Hammersmith)
100%
CMR with imatinib (STIM, TWISTER)
(maintained for a minimum of 2 years)
> 50%
Goh HG, et al. Leuk Lymphoma. 2009 Jun;50(6):944-51.
Koskenvesa et al. Blood. 2008;112 (11):738.
Kuwabara A, et al. Blood 2010;116 (6):1014-1016.
Mahon FX, et al, Lancet Oncol. 2010; 11:1029-35
Prior experiences with stopping TKI
 Approximately 40% of patients remained treatment-free in
Survival Without Molecular Relapse
STIM study
• Median 50 month duration of prior
imatinib
• Median 36 months in prior CMR on
imatinib
• Median time to CMR < 2 years
100
90
80
70
60
50
40
30
20
10
0
0
3
6
9
12
15
18
21
Months Since Discontinuation of Imatinib
Patients with ≥ 12 months
follow-up (n = 69)
Mahon FX, et al, Lancet Oncol. 2010; 11:1029-35
24
27
Rationale and benefits of TFR
PATIENT BENEFITS
MEDICAL RATIONALE
 Molecular responses from ENESTnd
and ENESTcmr
 NME (eg. Hh inhibitors)
targeting LSC
 Discontinuation studies
 “Operational” cure
 Alleviate chronic low grade AEs
 Reduce risk of developing long-term
AEs
 Pregnancy
demonstrating proof of concept
regarding successfully stopping
imatinib therapy
 Patient & Investigator interest
 Minimize drug-drug interactions
 Health economic advantages vs.
chronic lifelong TKI therapy
ENESTnd Cumulative Incidence of MR4.5
Nilotinib 300 mg BID
Nilotinib 400 mg BID
100
Patients With MR4.5, %
Imatinib 400 mg QD
80
By 4 Years
By 1 Year
60
40%, P < .0001
40
37%, P = .0002
Δ 14%-17%
Δ 6%-10%
20
11%, P < .0001
23%
7%, P < .0001
1%
0
0
6
12
18
24
30
36
42
48
54
60
Time Since Randomization, Months

No patient who achieved MR4.5 on any arm progressed to AP/BC
Data cutoff: July 27 2012.
MR4.5,
molecular response of
BCR-ABLIS
≤ 0.0032%.
Kantarjian HM, et al. Blood. 2012;120(21):[abstract 1676].
ENESTnd Overall Survival by BCR-ABL
Levels at 3 Months
100
97.2%
96.5%
90
P = .6348
P = .0219
86.7%
80
% Alive
70
OS rates at 4 years for ≤10% vs >10% BCR-ABL at 3 months:
96.7% vs 86.7%; P = .0116
60
50
40
Pat
Evt
Cen
≤1%
145
5
140
>1% – ≤10%
89
2
87
>10%
24
3
21
30
20
10
Censored observations
0
0
3
6
9
12 15 18 21 24 27 30 33 36 39 42 45 48 51 54 57 60
Time Since Randomization (Months)
Nilotinib 300 mg BID arm data
Data cut-off: 27Jul2012.
Hochhaus A, et al. Blood. 2012;120(21):[abstract 0167].
ENESTnd Cumulative Incidence of MR4.5 by
BCR-ABL Levels at 3 Months
≤1%
>1% – ≤10%
>10%
100
90
Pat
144
89
24
MR4.5 by 3 years
MR4.5 by 4 years
% With MR4.5
80
MR4.5 by 4 years for ≤10% vs >10% BCR-ABL
(47% vs 4%; P <.0001)
70
60
58% (32% overall†)
50%
50
P = .0001
40
28%
30
18%
20
10
P = .0135
4%
4%
0
0
3
6
9
12 15 18 21 24 27 30 33 36 39 42 45 48 51 54 57 60
Time Since Randomization (Months)
* These data exclude 1 patient in the nilotinib arm who achieved MR4.5 at or before 3 months.
† 83
patients with ≤1% BCR-ABL levels at 3 months who later achieved MR4.5 represents 32% of the 257 patients with
BCR-ABL levels available at 3 months.
Data cut-off: 27Jul2012.
Nilotinib 300 mg BID arm data
Hochhaus A, et al. Blood. 2012;120(21):[abstract 0167].
ENESTnd
BCR-ABL Categories at 3 Months*
BCR-ABL ≤10%
100
90.7%
Nilotinib 300 mg BID (n=258)
Imatinib (n=264)
Patients, %
80
>1- ≤10%
(34.5%)
66.7%
60
BCR-ABL >10%
>1- ≤10%
(50.4%)
40
33.3%
≤1%
(56.2%)
20
≤1%
(16.3%)
0
n
234
176
9.3%
24
88
BCR-ABL Level at 3 Months

Reasons for unevaluable samples included:
•
Atypical transcripts: 5 patients on nilotinib, 2 patients on imatinib
•
Missing samples: 4 patients on nilotinib, 5 patients on imatinib
•
Discontinuation: 15 patients (including 1 progression) on nilotinib, 12 patients (including 1 progression) on
imatinib
Data cut-off: 27Jul2012.
*Calculated from total number of evaluable patients with PCR
assessments at 3 months.
Hochhaus A, et al. Blood. 2012;120(21):[abstract 0167].
ENESTcmr study
Median BCR-ABL RatioIS (%)
Enrollment in
ENESTcmr
Predicted Imatinib
Undetectable BCR-ABL
0
1
2
Years on Therapy
Cervantes F, et al. Haematologica. 2012;97(s1):239 [abstract 0586].
Predicted Nilotinib
ENESTcmr Study Design and Endpoints
Patients
treated with
imatinib for ≥ 2
years who
achieved CCyR
but have
detectable
BCR-ABL*
Nilotinib 400 mg BID
R
A
N
D
O
M
I
Z
E
N = 207
1:1 randomization stratified by:
•Prior imatinib (≤ 36 months, > 36 months) AND
•Prior interferon (None, ≤ 12 months, > 12 months)
END POINTS
Imatinib continue same dose
4-year study
Primary
 Confirmed undetectable BCR-ABL by 12 months
Secondary
 Molecular response (MR4.5, undetectable BCR-ABL) in patients without the response in question at
baseline
• RQ-PCR for primary and secondary endpoints was performed every 3 months and assessed at a
central laboratory in Adelaide, Australia
 Event-free survival
 Safety profile
* By RQ-PCR with sensitivity of ≥ 4.5 logs.
RQ-PCR, real-time quantitative polymerase chain reaction..
Hughes TP, et al. Blood. 2012;120(21):[abstract 0694].
Patients with
Undetectable BCR-ABL, %
ENESTcmr Confirmed Undetectable BCR-ABL*
by 24 Months (ITT)†
35
Nilotinib 400 mg BID
P = .0087
30
25
22.1
P = .108
20
15
Δ 13.4%
12.5
Δ 6.7%
10
8.7
5.8
5
0
n=
104
103
Confirmed Undetectable BCR-ABL
by 12 months (Primary Endpoint)

Imatinib 400-600 mg QD
104
103
Confirmed Undetectable BCR-ABL
by 24 months
Increase in rate of undetectable BCR-ABL was 3 times higher on nilotinib (9.6%
increase) vs imatinib (2.9%) from month 12 to 24
* With ≥ 4.5-log assay sensitivity.
† Intention-to-treat (ITT) analyses included all patients randomized to the study, whether or not they received
24-month follow-up
study drug (n = 3 pts on nilotinib did not) or had CMR at baseline (n = 2 on nilotinib; n = 2 on imatinib).
Hughes TP, et al. Blood. 2012;120(21):[abstract 0694].
ENESTcmr Cumulative Incidence of MR4.5
(in patients without MR4.5 at baseline)
Nilotinib
n = 94
Imatinib
n = 91
Censored observations
Patients With MR4.5, %
100
90
80
70
P = .0006
60
42.9%
50
P = .0020
40
Δ 22.1%
32.7%
30
Δ 19.2%
20
10
20.8%
13.5%
0
0
3
6
9
12
15
18
21
24
Time Since Randomization, Months
Hughes TP, et al. Blood. 2012;120(21):[abstract 0694].
ENESTcmr Rates of MR
(in patients without MMR at baseline)
Nilotinib 400 mg BID
Imatinib 400-600 mg QD
P = .0342
Patients with MR4.5, %
90
83.3
80
70
60
53.6
50
P = .0163
P = .0323
40
29.2
30
25.0
20
10
0
3.6
n=
24
MMR
28
24
28
MR4.5
3.6
24
28
Undetectable
BCR-ABL
24-month follow-up
Treatment-Free Remission studies
MR4.5
induction
MR4.5
consolidation
ENESTcmr
PCR monitoring PCR monitoring
Sustained
MR offtherapy
ENESTop
PCR monitoring
Reintroduce TKI at
relapse
Treatment-Free Remission studies
Eligibility
Consolidation
Phase
Treatment-free
Remission
Study period
ENESTfreedom
De Novo
Patients
> 3 years on Nilotinib
CMR4.5 with > 2
years Nilotinib
ENESTop
Imatinib > 1 yr
not achieved
CMR4.5
Nilotinib
1 year
sustain CMR4.5
> 3 years on Nilotinib
CMR4.5 with > 2
years Nilotinib
SWITCH
Nilotinib
1 year
sustain CMR4.5
BCR-ABL Monitoring
Treatment-free
Maintain ≤ MR3.0
BCR-ABL Monitoring
Treatment-free
Maintain ≤ MR4.0
Factors associated with successful TFR
Mahon et al
Ross et al
Lee et al
Age
Not significant
Not significant
Not reported
Sex
Significant
Not significant
Not reported
Sokal score
Significant
Significant
Not reported
Imatinib duration
Significant
Not significant
Not reported
IFN duration
Not significant
Significant
Not reported
Time to CMR
Not significant
NR
Significant
Duration of CMR
before d/c
Not significant
NR
Significant
Mahon FX, et al, Lancet Oncol. 2010; 11:1029-35
Ross D, et al. Haematologica. 2012;97(s1):[abstract 0189]
Lee MD, et al Haematologica. 2012;97(s1):[abstract 0200]
ENESTop correlative science program
Sub-study 1:
•Cytokine measurements
Patient demographics
Clinical endpoints
•BCR-ABL levels
•Cytogenic response
•Hematological response
Sub-study 2:
• Flow cytometry of immune
cells
• KIR genotyping
Gene expression profiling
data
BCR-ABL Mutation data
Sub-study 3:
• Digital DNA PCR and digital
RQ-PCR comparison to
conventional RQ-PCR
One common
database for
data analysis
Path in CML program
Patient
populations
Induce
MR4.5
Maintain
MR4.5
Sustain MR
off Therapy
Nilotinib
frontline
Clinical practice or
clinical trial
Discontinuation study
Imatinib
patients not
in MR4.5
ENESTcmr
ENESTop
Nilotinib
patients not
in MR4.5
Nilotinib combination
trial
Discontinuation study
All
patients
ENESTpcr
CML GOLS Meeting - Clinical Survey
Can CML be cured?
1. Yes, by TKI alone
14%
11%
2. Yes, by SCT alone
13%
20%
3. Yes, by SCT or TKI in combination with other agents
61%
61%
2013
4. No
11%
8%
Approximately 900 attendees. Helsinki, February 23, 2013
2012
Nilotinib combination candidates
 IFN-alpha
Trials ongoing
 New molecular entities targeting
different pathways (examples):
Hedgehog pathway: LDE-225
MEK-162
CXCR4 pathway
Investigational agents
Long term side effects
unknown
Phase I combination of nilotinib and LDE225
•
•
•
CML-CP patients who failed prior therapy with other BCR-ABL inhibitors
Primary outcomes:
• Incidence rate and category of DLTs
• Determination of MTD and/or recommended Phase II dose
combinations of nilotinib with LDE225
Secondary outcomes:
• Rate of MMR, CMR, MCyR, CCyR
• PK
Summary
 Molecular responses from ENESTnd
and ENESTcmr
 NME targeting LSC
 Discontinuation studies demonstrating
ability to successfully stop IM (STIM,
CML8)
 Patient & Investigator interest
 8 studies ongoing in 40 countries
 2,500 patients to be enrolled
 1,000 patients expected to enter TFR