Dasatinib: il vantaggio dal multitarget 25 maggio 2013 Drssa Patrizia Pregno S.C. Ematologia

Dasatinib: il vantaggio dal multitarget
25 maggio 2013
Drssa Patrizia Pregno
S.C. Ematologia
Kinase selectivity profiles of nilotinib
and dasatinib
Imatinib
4 targets
AMN107
4 targets
50 X
Dasatinib
15 targets
325 X
IMA
16 X
NILO
IC50
< 10 nM
10-50 nM
50-250 nM
250-1000 nM
After Fabian et al. Nature Biotech. 2005;23:329
Dasatinib inhibits growth of imatinib-resistant
BCR-ABL-expressing Ba/F3 cell lines in vitro
1.2
Parental Ba/F3 cells
BCR-ABL
E255K
1
Relative growth after 48
hours of drug exposure
Ba/F3
T315I
T315I
M351T
0.8
M244V
G250E
0.6
Q252H
E255K
0.4
Q252R
“wt” BCR-ABL
0.2
Y253F
Y253H
M351T
E255V
0
0
1
5
10
50
100
Concentration of Dasatinib (nM)
 attivo su > 100 mutazioni incluse quelle della
regione del p-loop
 poco attivo anche su V299L F317L/V e T315 I
F317L
E355G
F359V
H396R
F486S
Shah et al., Science, 2004
Inibitori delle tirosin‐chinasi: diversa selettività
Imatinib
Nilotinib
ABL
ARG
BCR-ABL
KIT
PDGFR
DDR1
NQO2
ABL
ARG
BCR-ABL
KIT
PDGFR
DDR1
NQO2
7
7
targets
targets
Weisberg E, et al. Br. J. Cancer. 2006; 94:1765-1769.
Weisberg E, et al. Br. J. Cancer. 2006; 94:1765-1769.
Dasatinib
ABL
ARG
BCR-ABL
KIT
PDGFR
SRC
YES
FYN
LYN
HCK
LCK
FGR
BLK
FRK
CSK
BTK
TEC
BMX
TXK
DDR1
DDR2
ACK
ACTR2B
ACVR2
BRAF
EGFR/ERBB1
EPHA2
EPHA3
EPHA4
EPHA5
targets
FAK
GAK
GCK
HH498/TNNI3K
55
ILK
LIMK1
LIMK2
MYT1
NLK
PTK6/Brk
QIK
QSK
RAF1
RET
RIPK2
SLK
SLK36/ULK
SYK
TAO3
TESK2
TYK2
ZAK
Attività di Dasatinib
 E’ in grado di inibire:
* BCR-ABL1 nella conformazione inattiva/attiva del domain
chinasico ABL
* c-KIT, PDGF-R ed EPHA2
* Src chinasi come Lyn, Yes e Src
 E’ in grado di bloccare i «signaling pathways» intracellulari
attivati da BCR-ABL1 in vitro inclusi i segnali di trasduzione
e di attivazione di trascrizione di Stat-5
 Non è substrato di MDR protein-1
 Non è substrato di OCT-1 e la sua attività non è influenzata
da una iper-espressione di OCT-1
Attività di Dasatinib sui progenitori
 L’ espressione di Src chinasi è aumentata nelle cellule
staminali CD34+ e nella frazione CD34+CD38- in tutte le
fasi di LMC.
 E’ più attivo di Imatinib sul compartimento delle cellule
staminali, ma le cellule primitive quiescenti sono resistenti
al farmaco.
 E’ in grado di inibire la P mitogen-activated protein kinase
MAPK9, Akt e STAT5 nei progenitori di LMC, ma non è in
grado di alterare il livello delle proteine che regolano
l’apoptosi nelle cellule CD34+.
Copland m et al, Blood 2006, 107 (11, 4532-9
DASISION (CA180-056): Study Design
 Treatmentnaïve CML-CP
patients
(N=519)
Dasatinib 100 mg QD (N=259)
Long-term
Randomizeda
 108 Centers
follow-up
Imatinib 400 mg QD (N=260)
 26 Countries
aStratified
 Primary endpoint
by EURO (Hasford) risk score
Confirmed CCyR (cCCyR) by 1 year
DASISION (CA180-056):NCT00481247;
CCyR = complete cytogenetic response
PFS was defined as doubling of WBC ; loss of CHR; increase in Ph-positive metaphases to >35%;
transformation; or death from any cause
Jabbour J, et al. Haematologica. 2012;97(s1) [abstract 1106].
DASISION 3-Year Update
Patient Disposition and Discontinuation
Treated patients, n (%)
Dasatinib 100 mg QD
N=258
Imatinib 400 mg QD
N=258
183 (71)
179 (70)
75 (30)
79 (31)
17 (7)
18 (7)
8 (3)
12 (5)
27 (11)
16 (6)
20 (8)
12 (5)
7 (3)
4 (2)
Unrelated AE
6 (2)
2 (<1)
Deathb
4 (2)
1 (<1)
Poor /nonadherence
0 (0)
4 (2)
13 (5)
26 (10)
Still on treatment
Discontinued
Progressiona
Treatment failure
Adverse event (AE)
Nonhematologic
Hematologic
Otherc
aIncreasing
WBC count; loss of CHR; loss of MCyR, including 30% rise in Ph+ metaphases and additional chromosomal abnormalities; or progression to AP/BP
due to death, which represents a subset of total deaths: 17 deaths overall in dasatinib arm, 20 deaths in imatinib arm
CIncludes consent withdrawal, loss to follow-up, pregnancy, patient request, and poor/nonadherence
bnDiscontinuation
Jabbour J, et al. Haematologica. 2012;97(s1) [abstract 1106].
DASISION 3-Year Update
Adverse Events of Clinical Interest (any Grade)
 Overall, most AEs occurred within the first year with minimal increases between 1-2 years
and 2-3 years
 One patient in each arm experienced a QTc interval prolongation ≤1 month from the start
of treatment; no patients between 3 months and 3 years developed a QTc prolongation
Jabbour J, et al. Haematologica. 2012;97(s1) [abstract 1106].
DASISION 3-Year Update
3-Year Rates of Grade 3/4 Lab Abnormalities
Dasatinib 100 mg QD
Imatinib 400 mg QD
AST ↑
Neutropenia
Creatinine ↑
Total bilirubin ↑
ALT ↑
Thrombocytopenia
Potassium ↓
Calcium ↓
Anemia
Phosphorus ↓
%
%
 The majority of Grade 3/4 lab abnormalities occurred within the first year
Jabbour J, et al. Haematologica. 2012;97(s1) [abstract 1106].
DASISION 3-Year Update
Transformation To AP/BP CML by 3 Years
Number of Patients, n
Dasatinib 100 mg QD
Imatinib 400 mg QD
p=ns
16
p=ns
13
11
8
N
ns= non-significant
259
260
On study
259
260
Including follow-up beyond
discontinuation (ITT)a
aYearly
evaluations after discontinuation are currently stipulated per protocol;
additional information on patient status may be provided by investigators at other times
Jabbour J, et al. Haematologica. 2012;97(s1) [abstract 1106].
DASISION 3-Year Update
Overall Survival (OS) and
Progression Free Survival (PFS)
Dasatinib
100 mg QD
N=259
Imatinib
400 mg QD
N=260
Hazard ratio
17
20
-
Estimated 3-year OS, %
93.7
(90.6-96.7)
93.2
(90.1-96.4)
HR=0.86
(0.45-1.65)
Estimated 3-year PFS, %
91.0
(87.4-94.7)
90.9
(87.1-94.6)
HR=1.00
(0.55-1.80)
Total number of deaths,a n
aOn
study treatment and in follow-up after discontinuation of randomized treatment
PFS was defined as doubling of WBC ; loss of CHR; increase in Ph-positive metaphases to >35%; transformation; or death
from any cause
Jabbour J, et al. Haematologica. 2012;97(s1) [abstract 1106].
DASISION: European Subpopulation Analyses
Table 6. Deaths on treatment or after discontinuation
Treated patients, n (%)
European subpopulation
Global population
Dasatinib
100 mg QD
N=74
Imatinib
400 mg QD
N=96
Dasatinib
100 mg QD
N=258
Imatinib
400 mg QD
N=258
3 (4)
8 (8)
17 (7)
20 (8)
CML progression
0
5 (5)
9 (3)
14 (5)
Cardiovascular disease
0
1 (1)
2 (1)
1 (<1)
Infectiona
2 (3)
0
5 (2)
1 (<1)
Bleeding
0
0
0
1 (<1)
1 (1)
0
1 (<1)
0
0
2 (2)
0
3 (1)
Total deaths
Other neoplasm
Other
aFor
the Global population, deaths due to infection in the dasatinib arm included sepsis/infection (no organism
identified), meningoencephalitis (Klebsiella), and pneumonia; in the European population the two deaths due to
infection included sepsis/infection (no organism identified) and meningoencephalitis (Klebsiella).
EHA 2012
16
BMS Confidential - Not for Further Copying or Distribution
DASISION 3-Year Update
Cumulative Incidence of MMR (BCR-ABL ≤0.1%)
Dasatinib 100 mg QD
% With MMR
100
Imatinib 400 mg QD
P<0.0001
1.6-Fold higher
likelihood of achieving
MMR with dasatinib;
HR=1.62 (1.30-2.02)
80
By 3 years
68%
By 2 years
64%
By 1 year
46%
60
55%
40
46%
20
23%
0
0
12
24
36
Months
Hasford Risk Score
MMR 3-y cumulative rates
Low
Intermediate
High
Dasatinib
Imatinib
83%
65%
65%
57%
61%
43%
Jabbour J, et al. Haematologica. 2012;97(s1) [abstract 1106].
DASISION 3-Year Update
Cumulative Incidence of MR4 and MR4.5
Dasatinib 100 mg QD
40
40
35%
28%
P=0.00635
P=0.00069
30
12%
20
18%
22%
10
5%
0
0
12
% with MR4.5
30
% with MR4
Imatinib 400 mg QD
22%
17%
20
3%
10
12%
9%
0
24
Months
36
2%
0
12
24
36
Months
MR4 = BCR-ABL ≤0.01%
MR4.5 = BCR-ABL ≤0.0032%
Hochhaus A, et al. J Clin Oncol 30, 2012 [abstract 6504].
Kaplan-Meier Analyses
Progression-free survival*
(no AP/BP or loss of response)
100
80
% without failure
% not progressed
100
60
24 months
Dasatinib: 93.7%
Imatinib: 92.1%
40
20
Failure-free survival*
(ELN 2006 criteria)
80
60
24 months
Dasatinib: 91.2%
Imatinib: 87.8%
40
20
0
0
0
10
20
Months
30
40
0
10
20
Months
30
40
Overall survival†
100
% alive
80
60
* Patients who discontinued for other
reasons were censored at last
hematologic or cytogenetic evaluation
24 months
Dasatinib: 95.3%
Imatinib: 95.2%
40
20
† Surviving
0
0
10
20
Months
30
40
patients were followed after
discontinuation and were censored on the
last date known to be alive
An exploratory analysis from 3 year DASISION followup examining the impact on patient outcomes of early
complete cytogenetic responses at 3 months and major
molecular responses at 12 months
Elias Jabbour,1 Neil Shah,2 Charles Chuah,3 Carolina Pavlovsky,4 Jiri Mayer,5
M Brigid Bradley-Garelik,6 David Dejardin,7 Hesham Mohamed,8 Andreas
Hochhaus,9 Guiseppe Saglio10
1 MD
Anderson Cancer Center University of Texas, Houston, Texas, 2 Helen Diller Family
Comprehensive Cancer Center, UCSF School of Medicine, San Francisco, CA,
3Singapore General Hospital,Singapore, 4 FUNDALEU,Centro de Internación e
Investigación Clínica Angélica Ocampo, Buenos Aires, Argentina, 5 University Hospital
Brno, Brno Czech Republic, 6 Bristol-Myers Squibb, Wallingford, CT, USA, 7 BristolMyers Squibb, Braine l’Alleud, Belgium, 8 Bristol-Myers Squibb, Plainsboro, NJ, USA
9Universitätsklinikum Jena, Jena, Germany, 10 University of Torino, Ospedale San Luigi
Gonzaga, Orbassano-Torino, Italy
Molecular and Cytogenetic Response at 3 Months
P<0.0001
P<0.0001
100
Dasatinib 100 mg QD
84%
81%
% of patients
80
>1-10%
64%
PCyR
Imatinib 400 mg QD
67%
60
PCyR
>1-10%
40
CCyR
≤1%
20
CCyR
≤1%
0
n//N
198/235
154/239
≤10% BCR-ABL at 3 Months

171/210
148/221
PCyR/CCyR at 3 Months
BCR-ABL of <10% and ≤1% are not fully concordant with ≥PCyR and CCyR, respectively
 96% and 83% of dasatinib and imatinib pts with ≥PCyR had <10% BCR-ABL, respectively
 68% and 26% of dasatinib and imatinib pts with CCyR had ≤1% BCR-ABL, respectively
MR4.5 According to BCR-ABL Level at 3 Months
Dasatinib 100 mg QD
Imatinib 400 mg QD
84% of patients had ≤10% BCR-ABL
48% of patients had ≤1% BCR-ABL
64% of patients had ≤10% BCR-ABL
13% of patients had ≤1% BCR-ABL
BCR-ABL level
at 3 months
≤1%
>1-10%
>10%
≤10% vs >10%
≤1% vs >1%
Patients with MR4.5 (%)
100
80
60
40
MR4.5
3-Year
37.5%
} P<.0001
14.0%
} P=.0380
2.7%
P=.0004
P<.0001
80
60
40
20
20
0
0
0
3
6
9 12 15 18 21 24 27 30 33 36 39 42
Months
BCR-ABL level
at 3 months
≤1%
>1-10%
>10%
≤10% vs >10%
≤1% vs >1%
100
0
3
6
3-Year MR4.5
43.8%
} P<.0001
11.5%
} P=.0204
2.4%
P=.0008
P<.0001
9 12 15 18 21 24 27 30 33 36 39 42
Months
Saglio G, et al., Blood 2012;120:[abstract 1675].
Patients not progressed (%)
PFS According to BCR-ABL Level at 3 Months
Dasatinib 100 mg QD
Imatinib 400 mg QD
84% had ≤10% BCR-ABL
64% had ≤10% BCR-ABL
100
100
80
80
60
BCR-ABL level
at 3 months
≤1%
>1-10%
>10%
≤10% vs >10%
40
20
60
3-Year PFS
92.3%
} P=.9639
94.0%
} P=.0135
68.2%
P=.0003
BCR-ABL level
at 3 months
≤1%
>1-10%
>10%
≤10% vs >10%
40
20
3-Year PFS
100%
} P=.3459
94.9%
} P=.0002
75.2%
P<.0001
0
0
0
6
12
18
24
30
36
42
0
6
12
98
81
22
93
79
19
24
30
36
42
20
76
37
7
25
13
Months
Months
Subjects at risk
≤1%
112
112
105
>1-10% 85
83
81
>10%
36
33
28
18
89
75
16
60
52
11
24
21
6
Subjects at risk
≤1%
32
31
30
>1-10% 121
119
116
>10% 84
81
71
30
112
59
29
108
55
28
106
51
Saglio G, et al., Blood 2012;120:[abstract 1675].
OS According to BCR-ABL Level at 3 Months
Dasatinib 100 mg QD
Imatinib 400 mg QD
84% had ≤10% BCR-ABL
100
Patients alive (%)
64% had ≤10% BCR-ABL
100
80
80
60
BCR-ABL level
at 3 months
≤1%
>1-10%
>10%
≤10% vs >10%
40
20
0
0
6
12
18
60
3-Year OS
95.5%
} P=.7342
96.5%
} P=.0525
85.9%
P=.0348
24
30
36
40
20
0
42
0
BCR-ABL level
at 3 months
≤1%
>1-10%
>10%
≤10% vs >10%
3-Year OS
100%
} P=.3453
95.0%
} P=.0110
87.8%
P=.0036
6
24
12
Months
Subjects at risk
112
112
110
≤1%
85
84
>1-10% 86
37
37
35
>10%
109
83
34
106
83
33
18
30
36
42
30
116
70
28
96
55
11
33
20
Months
104
79
27
85
66
22
29
25
9
Subjects at risk
32
32
32
≤1%
121
120
>1-10% 122
85
85
82
>10%
32
118
80
31
118
76
Saglio G, et al., Blood 2012;120:[abstract 1675].
PFS According To Cytogenetic Response at 3
Months
Dasatinib 100 mg QD
Imatinib 400 mg QD
81% of patients had PCyR/CCyR
67% of patients had PCyR/CCyR
100
% Not Progressed
100
P<0.0001
80
P<0.0026
80
60
60
PCyR
40
CCyR
P=0.2185
CCyR, N=139
20
PCyR
40
CCyR
CCyR, N=79
20
PCyR, N=68
PCyR, N=31
<PCyR, N=39
0
0
6
12
< PCyR, N=73
0
24
Months
For ≥PCyR vs <PCyR at 3 months
3-year PFS rates were 93.9% vs 71.3%
36
42
P=0.8062
0
6
12
24
Months
For ≥PCyR vs <PCyR at 3 months
3-year PFS rates were 93.7% vs 77.3%
36
42
OS According To Cytogenetic Response at 3
Months
Dasatinib 100 mg QD
Imatinib 400 mg QD
81% of patients had PCyR/CCyR
67% of patients had PCyR/CCyR
100
80
80
60
60
% Alive
100
PCyR/CCyR
<PCyR
40
P=0.0115
CCyR, N=140
20
<PCyR, N=39
0
6
12
<PCyR
40
PCyR, N=68
< PCyR, N=73
0
24
Months
For ≥PCyR vs < PCyR at 3 months
3-year OS rates were 96.4% vs 84.2%
36
42
P=0.3681
CCyR, N=80
20
PCyR, N=31
0
PCyR/CCyR
0
6
12
24
Months
For ≥PCyR vs < PCyR at 3 months
3-year OS rates were 93.9% vs 93.1%
36
42
PFS According To Response at 12 Months
% Not Progressed
Dasatinib 100 mg QD
Imatinib 400 mg QD
100
100
80
80
60
MMR and/or CCyR
<CCyR
40
60
MMR and/or CCyR
P<0.0001
<CCyR
40
MMR, N=95
20
P<0.0001
MMR, N=64
20
CCyR (no MMR), N=85
CCyR (no MMR), N=87
<CCyR, N=26
<CCyR, N=50
0
0
0
6
12
24
Months
36
42
0
6
12
24
Months
36
42
OS According To Response at 12 Months
Dasatinib 100 mg QD
100
100
80
80
60
% Alive
Imatinib 400 mg QD
MMR and/or CCyR
<CCyR
40
60
MMR and/or CCyR
P=0.0503
<CCyR
40
MMR, N=64
MMR, N=95
20
20
CCyR (no MMR), N=86
<CCyR, N=28
0
0
6
12
Months
P=0.0041
CCyR (no MMR), N=89
< CCyR, N=52
0
24
36
42
0
6
12
24
Months
36
42
DASISION: European Subpopulation Analyses
Table 8. Mutations identified during treatment: 2-year follow-up
European subpopulation
Global population
Dasatinib
100 mg QD
N=74
Imatinib
400 mg QD
N=96
Dasatinib
100 mg QD
N=259
Imatinib
400 mg QD
N=260
47 (64)
75 (78)
181 (70)
206 (79)
Samples analyzed for mutations, n
25
43
93
128
Patients with newly detected mutations on treatment, n
3
2
14
14
2
–
–
–
1
1
1
–
–
–
6
2
2
3
1
9
3
1
1
–
Patients with eventsa triggering mutation analyses, n (%)
No CCyR at 1 year
No CCyR at 1 year and 5-fold increase in BCR-ABL
No MMR at 1 year
No MMR at 1 year and 5-fold increase in BCR-ABL levels
Loss of CCyR and 5-fold increase in BCR-ABL levels
Mutations
F317L (2)
V299L (1)
T315I (1)
detectedb
M244V (1)
E355G (1)
F317L (1)
F317I (1)
V299L (3)
T315I (9)
G250E (1)
M244V (1)
L248V (1)
G250E (1)
E255K/V (3)
D276G (1)
M351T (3)
E355G (2)
F359C/V (4)
L387M (1)
H396P (1)
E450G (1)
Mutations were detected by direct sequencing
aNo CCyR or MMR within 1 year, loss of CCyR, 5-fold increase in BCR-ABL, off-treatment due to progression,
treatment failure, or other event, including AEs unrelated to study drug, study drug toxicity, consent withdrawal, loss
to follow-up, pregnancy,patient request, and poor/nonadherence
b1 patient in the dasatinib arm and 5 in the imatinib arm had more than one mutation
EHA 2012
30
BMS Confidential - Not for Further Copying or Distribution
Conclusions
 3-year follow-up from DASISION continues to support dasatinib
100 mg QD as first-line treatment for newly diagnosed CML-CP
– Deeper cytogenetic and molecular responses with dasatinib vs
imatinib :
• at 3 mo, ≤10% BCR-ABL (84% vs 64%) & MCyR (81% vs 67%)
• at 12 mo, MMR (46% vs 23%) & CCyR (83% vs 72%)
– Fewer transformations to AP/BP
 3-month <10% BCR-ABL and MCyR and 12-month CCyR associated
with:
– Higher probability of PFS and OS at 36 months

Management of patients with lack of 3-month <10% BCR-ABL or less
than MCyR and 12-month less than CCyR remains to be determined
 Safety profile continues to be well tolerated with minimal changes
from 2 to 3 years
OPTIM study : dose adapted to PK
 Patients > 18 years old in untreated CP
 Dasatinib initiated at 100 mg QD
 PK evaluation (Cmin and Cmax measurements) performed after 7 ‐ 10 days of therapy
 Cmin < 3nM  continue dasatinib 100 mg QD
 Cmin > 3nM  RANDOM  Continue dasa 100 mg daily
 “adaptation” arm: dose adjusted to Cmin less than 3 nM
Rousselot P et al, ASH 2010
Six-year FU of pts with imatinib-resistant or
intolerant CML-CP receiving dasatinib (CA180-034)
Study design
670 Randomized
662 Treated
100 mg QD (n=165)
100 mg
CP-CML with
• Resistance
• Intolerance to
imatinib
• Suboptimal
response
50 mg BID (n=167)
140 mg QD (n=163)
140 mg
70 mg BID (n=167)
BID, twice daily.
Shah N et al, ASCO 2012, abs 6506
Abstract 6506: Shah et al 6-year follow-up of CA180-034
Patient disposition
Treated patients, %
100 mg QD
(n=165)
140 mg QD
(n=163)
50 mg BID
(n=167)
70 mg BID
(n=167)
31
24
30
28
Progressiona
21
26
16
16
Study drug toxicity
21
26
24
29
Request
14
14
12
11
Otherb
6
6
6
8
AE unrelated to drug
4
2
5
4
No responsec
2
2
5
3
Death unrelated to drug
<1
0
0
1
On treatment
Reason for discontinuation
aProgression
(as reported by investigator) was defined as increasing white blood cell count, loss of CHR or MCyR,
≥30% increase in Ph+ metaphases, confirmed AP/BP disease, or death; bcommercial supply and/or travel
requirements, transplant, noncompliance or to avoid toxicity, unknown reason, developed mutation, pregnancy,
other malignancy; cas reported by the investigator.
AE, adverse event; CHR, complete hematologic response; MCyR, major cytogenetic response.
34
Abstract 6506: Shah et al 6-year follow-up of CA180-034
Response rates (dasatinib 100 mg QD)
Best overall response
within 2 years
 CHR: 92%
 MCyR: 63%
 CCyR: 50%
100
% With MMR
80
60
35%
41%
42%
42%
40
20
0
0
12
24
36
48
60
72
Months
CCyR, complete cytogenetic response; MMR, major molecular response.
35
Abstract 6506: Shah et al 6-year follow-up of CA180-034
PFS and OS in imatinib-resistant and -intolerant patients
100 mg QD
(n=165)
140 mg QD
(n=163)
50 mg BID
(n=167)
70 mg BID
(n=167)
Imatinib-resistant, n
124
124
123
126
Rate of PFS, %
46
32
50
45
Rate of OS, %
69
73
72
67
43
44
44
42
Rate of PFS, %
58
66
53
55
Rate of OS, %
78
87
79
81
Imatinib-intolerant, n
36
Abstract 6506: Shah et al 6-year follow-up of CA180-034
Exploratory analysis: PFS by time to BCR-ABL ≤10%
Analysis restricted to imatinib-resistant patients with >10% transcript
level at baseline
% Not progressed
100
80
60
40
0-3 Months
6 Months
12 Months
>12 Months
20
0
0
12
24
36
48
60
72
Months
 Earlier achievement (≤3 months) of BCR-ABL ≤10% is a significantly
(P<.002) better predictor of prolonged PFS than later achievement
37
Abstract 6506: Shah et al 6-year follow-up of CA180-034
% Not progressed
Exploratory analysis: PFS by BCR-ABL level at 3 months
Overall population
100
64%
80
60
40
20
0
P<.0001
≤10%
>10%
0 3
Patients at risk
≤10%
325
>10%
228
12
24
36
289
173
241
109
202
76
Months
48
60
72
172
58
146
36
40
6
≤10%
>10%
Imatinib-resistant, n
222
202
Rate of PFS, %
62
25
Imatinib-intolerant, n
103
26
Rate of PFS, %
68
30
38
26%
Abstract 6506: Shah et al 6-year follow-up of CA180-034
Exploratory analysis: effect of baseline factors on survival
by BCR-ABL level at 3 months
PFS
OS
100
64%
80
60
P<.0001
40
20
0
≤10%
>10%
03
12
Patients at risk
≤10% 225
201
>10% 194
147

36
48
60
59%
40
0
72
P<.0001
60
20
26%
24
83%
80
% Alive
% Not progressed
100
≤10%
>10%
0 3
12
24
Months
167
95
138
67
36
48
60
72
177
121
160
104
54
33
Months
119
50
100
31
26
5
226
199
218
182
202
164
189
139
Patients who achieved BCR-ABL ≤10% at 3 months had a significantly higher rate of PFS,
regardless of the presence or absence of the following baseline factors:
–
Mutationsa
–
PCyRa
–
CHRa
aData
not shown.
PCyR, partial cytogenetic response.
39
Abstract 6506: Shah et al 6-year follow-up of CA180-034
Exploratory analysis: survival by BCR-ABL ≤10% versus CHR
at 3 months
Analysis excludes patients with CHR and BCR-ABL ≤10% at baseline
PFS
OS
CHR + ≤10% vs CHR + >10% comparison
P<.0001
CHR + ≤10% vs CHR + >10% comparison
P<.0001
100
64%
80
60
21%
40
20
0
CHR+≤10%
CHR+>10%
No CHR
03
Patients at risk
CHR+≤10% 124
CHR+>10% 105
No CHR
29
55%
60
40
20
14%
80%
80
% Alive
% Not progressed
100
0
36%
CHR+≤10%
CHR+>10%
No CHR
12
24
36
48
Months
60
72
0 3
12
24
36
48
Months
60
72
112
81
14
94
52
6
76
37
2
59
18
2
18
1
1
124
106
32
121
96
26
112
89
20
105
73
17
88
55
10
32
17
3
69
27
2
40
97
64
13
Abstract 6506: Shah et al 6-year follow-up of CA180-034
Nonhematologic AEs (dasatinib 100 mg QD, n=165)
47.3
Headache
Headache
0.6
Musculoskeletal
Pain
Musculoskeletal Pain
48.5
3.0
46.7
Infection
Infection
6.1
41.3
Diarrhea
Diarrhea
4.3
37.0
Fatigue
Fatigue
4.3
32.8
Rash
Rash
2.4
31.1
Arthralgia
Arthralgia
33.2
Dyspnea
Dyspnoea
2 Years
2.4
23.6
Hemorrhage
Hemorrhage
3.0
Nausea
Nausea
0.6
2 Years
23.7
Abdominal Pain
Abdominal Pain
5 Years
6 Years
Grade 3/4
25.5
Superficial Edema
4 Years
22.4
0.6
Superficial Edema
4 Years
5 Years
6 Years
2.5
17.0
Myalgia
Myalgia
0.0
Pleural Effusion
Pleural Effusion
5.3
25.3
5.3
0

All grades
1.8
10
20
30
40
50
60
70
80
90
Percent
Two cases with the term pulmonary arterial hypertension were reported. Neither case
was confirmed with a diagnostic right heart catheterization and both were considered
to be unrelated to dasatinib by the investigators
41
100
Abstract 6506: Shah et al 6-year follow-up of CA180-034
Grade 3/4 AEs (dasatinib 100 mg QD, n=165)
Cumulative incidence of
hematologic AEs
Two-year chemistry
abnormalities
9,9
Phosphorus ↓
36.4
Neutropenia
Thrombocytopenia
AST ↑
0,6
Total bilirubin ↑
0,6
Potassium ↓
0,6
Calcium ↓
0,6
2 Years
23.6
4 Years
5 Years
Anemia
ALT ↑
6 Years
12.7
0
Creatinine ↑ 0
0
20
40
60
80
100
0
Percent
20
40
60
Percent
42
80
100
Abstract 6506: Shah et al 6-year follow-up of CA180-034
Transformation to AP/BP on study (dasatinib 100 mg QD)
% Transformation
12
100
10
8
6
4
n=2
n=2
n=4
n=1
n=0
n=1
1
2
3
4
5
6
2
0
Years
 Transformation to AP/BP on study by 6 years
– All patients: 10/166 (6%)
– Imatinib-resistant patients: 9/124 (7%)
– Imatinib-intolerant patients: 1/43 (2%)
43
Abstract 6506: Shah et al 6-year follow-up of CA180-034
Conclusions

In the longest reported follow-up of patients treated with a second-generation BCRABL inhibitor, dasatinib was generally well-tolerated
–
No new safety signals identified
 With six years of follow-up of dasatinib in the second-line setting:
–
–
–
–
–

31% of patients randomized to 100 mg daily remain on study
The cumulative CCyR rate is 50%
The cumulative MMR rate is 42%
Six percent of patients have experienced transformation to AP/BP on study in the 100 mg once daily
treatment arm
The estimated overall survival rate is 71% for 100 mg daily
●
12.5% of patients have died due to CML
Exploratory analyses reveal
–
A reduction in BCR-ABL/ABL of ≤ 10% at three months is highly predictive of superior longer
term PFS and OS irrespective of:
●
●
●
Resistance or intolerance to imatinib
Presence or absence of mutations at time of switch
Baseline response level
44
DASISION:
Analysis of Lymphocytosis and Response
 Retrospective analysis of lymphocytosis (> 3.6 x 109/L on ≥ 2
occasions) in patients from DASISION (N = 516)
 Cumulative incidence of lymphocytosis higher on dasatinib:
 Dasatinib, 68/258 (26%)
 Imatinib, 15/258 (6%); P < .0001
 Cumulative responses higher in dasatinib-treated patients with
lymphocytosis at any time, no relationship in imatinib-treated patients
Lymphocytosis
CCyR
cCCyR
MMR
Dasatinib
(n=258)
Yes
93%
85%
68%
No
85%
76%
54%
Imatinib
(n=258)
Yes
53%
53%
27%
No
83%
72%
42%
Schiffer C, et al. Blood. 2010;116(21): [abstract 358].
Dasatinib and Pleural Effusion
Risk factors
Quintas-Cardama A, JCO 2007
 in multivariate analysis
 Arterial hypertension
 History of cardiac disorders
 Twice vs once daily dosage
 AP/BP only in univariate analysis
Shah NP, JCO 2008
• 140 vs 100 mg dosage
De Lavallade et al, BJH 2008
Single Center; 62 pts in I or II line; 27%
 CML advanced phase
 Hypertension
 Cardiac disorders
 Hypercholesterolemia
 Skin rash under imatinib
 History of autoimmune disorders
Dasatinib and PE: a role for age
 Risk factors evaluated: age,, duration of CML,
sex, prior SCT, lymphocytosis
 Lymphocytosis was associated with a 1.7
increased risk of PE
PORKKA K. et al, Cancer Jan 2010
Role of comorbidities in predicting PE Breccia M. et al, Hematologica 2011
Valent P et al, Haematologica 2011
Dasatinib and Pulmonary Hypertension
Mattei D et al
51
Dasatinib and Pulmonary Hypertension
Montani, Circulation 2012
• Evaluation of incident cases of dasatinib‐associated PH reported in the French PH registry
• From November 2006 to September 2010 identified 9 incident cases treated by dasatinib at the time of PH diagnosis
• At diagnosis, patients had moderate to severe precapillary PH with functional and hemodynamic impairment. • Clinical, functional, or hemodynamic improvements were observed within 4 months of dasatinib discontinuation in all but 1 patient
• Only one of these 9 patients had risk factors for cardiac or pulmonary diseaeses or comorbidities: hypertension and coronary artery disease
52
Dasatinib and Pleural Effusion
Mechanism
unknown
Management
 immune-mediated pathogenesis
 combined inhibition of Src (affecting vascular
permeability) and PDGFR (affecting interstitial
fluid pressure and vascular permeability)
 allergen-induced histamine secretion in basophils
 Resolution is rapid after dasatinib discontinuation,
accelerated by adding diuretics or steroids.
 Transient discontinuations of dasatinib have been
reported to be for a median duration of 27 days,
(although this duration was contributed to by some patients
remaining off therapy post pleural effusion resolution ,due to
simultaneous occurrence of other grade 3/4 events).
Conclusions
 Dasatinib is a multitarget TKI , able to inhibit BCR-ABL , c-KIT, PDGFR,
EPHA-2 and Src kinase family (Lyn, Yes e Src)
 It is more active than imatinib on the stem cell compartment, but the
primitive quiescent cells are resistant to the drug.
 Well tolerated safety profile of Dasatinib. The onset of pleural effusion is
favored by known risk factors. Its treatment is usually manageable and
does not affect the outcome
 3-year follow-up from DASISION continues to support dasatinib
100 mg QD as first-line treatment for newly diagnosed CML-CP
 Deeper cytogenetic and molecular responses with dasatinib vs
imatinib :
•
at 3 mo, ≤10% BCR-ABL (84% vs 64%) & MCyR (81% vs 67%)
•
at 12 mo, MMR (46% vs 23%) & CCyR (83% vs 72%)
 Fewer transformations to AP/BP
 3-month <10% BCR-ABL and MCyR and 12-month CCyR associated
with higher probability of PFS and OS at 36 months
Conclusions
 With six years of follow-up of dasatinib in the second-line setting:
 31% of patients randomized to 100 mg daily remain on study
 The cumulative CCyR rate is 50% and the cumulative MMR rate is 42%
 Six percent of patients have experienced transformation to AP/BP on
study in the 100 mg once daily treatment arm
 The estimated overall survival rate is 71% for 100 mg daily with 12.5% of
patients died due to CML
 Exploratory analyses reveal a reduction in BCR-ABL/ABL of ≤ 10% at 3
months is highly predictive of superior long-term PFS and OS irrespective
of:
 Resistance or intolerance to imatinib
 Presence or absence of mutations at time of switch
 Baseline response level
Grazie!
Drssa Patrizia Pregno
S.C. Ematologia
2° generation TKIs in first line therapy of CP‐CML
Results of trials
 Reduced rate of progression to
AP/BC
 Increased and earlier CCyR rate
 Increased and earlier MMR and CMR rate
 No major safety issues
 Data at 36/48 months
 Survival?
 Longstanding CMR?
Open questions
 Dasatinib / Nilotinib to be used as first line treatment in all patients?
 In selected patients?
 Young population
 High/intermediate Sokal risk
 Evaluating comorbidities
 As early shift in patients with suboptimal response?
Novel TKIs and Immunity (2)
DASATINIB
• The Btk tyrosine kinase is a major target of the Bcr-Abl
inhibitor dasatinib
• Dasatinib inhibits T-cell activation and proliferation
• Dasatinib inhibits the proliferation and function of
CD4+CD25+ regulatory T cells
• Dasatinib inhibits recombinant viral antigen-specific
murine CD4+ and CD8+ T-cell responses and NK-cell
cytolytic activity in vitro and in vivo
• Clonal expansion of T/NK-cells during tyrosine kinase
inhibitor dasatinib therapy
Hantschel. PNAS 2007; Schade, Blood 2004; Fei, BJH 2008; Fraser, Exp Hematol 2009; Mustjoki, Leukemia 2009
Altered bone metabolism
Dasatinib
• c‐FMS inhibition and downstream signaling inhibition
(Erk e Akt)
• PDGFR and c‐KIT inhibition
• Inhibition of tumour‐associated macrophages and
osteoclasts
• Abnormalities in bone metabolism may be a general
class effect of TKIs.
Brownlow et al, Leukemia 2008
Clinical implications of differential TK profiles
Dasatinib/Nilotinib Cautions
QTc prolongation: Both – Baseline EKG, close K+
and Mg++ monitoring, drug I/A
Pancreatitis, uncontrolled diabetes, severe liver
disease: Nilotinib
Hypertension, COPD, CCF, chest wall injury,
asthma, pneumonia, GI bleeding, autoimmune
disorders, aspirin: Dasatinib
Modified from Giles et al. Leukemia 2009.
Conclusions…. 2nd generation TKIs reduce the rate of progression in all studies
Possible Explanations
•
Higher potency in inhibiting BCR‐ABL1 TK
•
Lower dependence of intra/extracellular mechanisms of drug influx/efflux
•
Higher capability in suppressing “permissive environment” for the development of resistance
–
Mutations of BCR‐ABL1
–
Activation of alternative TK activities Considerations
• …even if patients respond well to therapy, until the achievement of very low levels of residual disease (at least MMR?) patients may still have some risk of losing response and also of progression. • …it is important also to have a fast response , as for those patients who are late in reducing the leukemic burden the risk of non responding and of progression is higher.
2° generation TKIs in first line therapy of CP‐CML
Results of trials
Open questions
• Reduced rate of progression • Dasatinib / Nilotinib to be to AP/BC
used as first line treatment in all patients?
• Increased and earlier CCyR
rate
• In selected patients?
• Increased and earlier MMR – Young population
and CMR rate
– High/intermediate Sokal risk
• No major safety issues
– Evaluating comorbidities
• Data at 36/48 months
• As early shift in patients • Survival?
with suboptimal response?
• Longstanding CMR?
`