Download Presentation - Chronice Myeloid Leukemia

Second and Third
Generation Tyrosine
Kinase Inhibitors: How do
we Choose?
Dr Jenny Byrne
Nottingham
Imatinib is a wonderful
drug!
IRIS 8-Year Update
Overall Survival (Intent-to-Treat) – Imatinib Arm
100
% Alive
90
80
70
i sur ivaa
Estimaa
ted
il l
m overall
at 8 years was 85%
E
(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
IRIS 8 year Results

Imatinib is a great drug ……
BUT


Not all patients respond well to Imatinib
IRIS data excludes patients who discontinued
‘study’ Imatinib
Outcome for Patients Discontinuing IRIS Trial
All randomized to imatinib
(n= 553; 100%)
Discontinued study imatinib*
(n = 221; 40%)
Still receiving study imatinib
(n = 332; 60%)
In CCR
(n = 317;
57%)
No CCR
(n = 15;
3%)
Safety
(n = 43;
8%)
Alive
(n = 17;
40%)
Dead**
(n = 26;
60%)
Efficacy
Other
(n = 82; 15%)
(n = 96
17%)
Alive
(n = 52;
63%)
Dead
(n = 30;
37%)
;
Alive
(n = 81;
84%)
**Including primary discontinuation reason ‘Death’ (n=13)
*Patients may have continued imatinib off study.
Dead
(n = 15;
16%)
Up to 40% of patients may ‘fail’ Imatinib
Imatinib Resistance and Intolerance

Some patients do not do well on imatinib...

Imatinib resistance may be defined as:
 Lack/loss of satisfactory response during imatinib therapy
or progression from chronic to accelerated phase or from
chronic or accelerated to blast phase

Imatinib intolerance may be defined as:
 Side effects requiring either a dose reduction of imatinib to
≤400 mg/day or discontinuation of imatinib due to drugrelated toxicity
(Poor adherence / missed doses may also be an
issue)
Resistance has been defined as primary
or acquired (also known as secondary)
Primary resistance
Acquired resistance
Failure to achieve a response Loss of a confirmed response
• Primary haematological
resistance
• failure to achieve a CHR
• In chronic phase
• failure to return to CP
• In advanced disease
• Primary cytogenetic
resistance
• failure to achieve a CCyR or
MCyR
• Haematological resistance
• confirmed loss of a CHR
• Cytogenetic resistance
• confirmed loss of a MCyR or
CCyR
• Molecular resistance
• increase in BCR-ABL
transcripts of more than 1 log
• Often assoc with emergence
of a bcr-abl mutation
Hochhaus et al., Hematol Oncol Clin N Am 2004;18:641–56
BCR/ABL mutations are the most frequently
reported mechanism of acquired resistance
T315I/A/D
F311L/I/V F317L
C305S
V299L
L248V
L298V
G250E/A/F
Q252H/R
P296H
M237I
L324Q
G383D
M343T K357R
K285N
E281A
E279K
T277A
L384M
L387F/M
S348L
A350V
B
M244V
D241G
F382L
A344V
E292V
Y253H/F
E255K/V V289A/I
P
G321E
M388L
C
M351T/L
E355G/D
A397P
H396R/P
E453G/K/A/V
E450G/
Q/K
Q447R
F486S
A
S438C
V379I
L3641
F359V/C/D/I
5417Y
E459K/Q
Adapted from Melo et al (2006)
E276G
E275K
• Kinase domain mutations occur in 50-90% of cases of acquired resistance
• Resistance manifests itself through different mechanisms causing
• Changes to the stability of the Bcr-Abl conformation
• Reduction in binding efficiency of imatinib
Branford et al., Blood 2003;102:276–83; Shah et al., Hematol 2005;183–7; Melo et al., Cancer Lett 2006 (in press)
There is a Clear Need to Monitor Response to
Therapy Carefully: ELN Guidelines 2013
Time
Optimal Response
Warning
Failure
Baseline
n/a
High risk or
CCA/Ph+, major
route
n/a
3 months
BCR-ABL1 ≤ 10%
and/or Ph+ ≤ 35%
BCR-ABL1 >10%
and/or Ph+ 36-95%
No CHR
and/or Ph+ >95%
6 months
BCR-ABL1 <1%
BCR-ABL1 1-10%
and/or Ph+ 0 (CCyR) and/or Ph+ 1-35%
BCR-ABL1 >10%
and/or Ph+ >35%
12 months
BCR-ABL1 ≤ 0.1%
(MMR)
BCR-ABL1 >1%
and/or Ph+ >0
BCR-ABL1 >0.11%
Stable or improving ACA/Ph- (-7 or 7q-) Loss of CHR,
MMR
loss of CCyR,
confirmed loss of
MMR, mutations,
ACA in Ph+ cells
Baccarani M, et al. Blood 2013: 122: 872–884
Anytime
Importance of achieving optimal response
of ≤ 10% BCR-ABLIS at 3 months
Early response is predictive of survival

Significant difference in 8-year overall survival (OS) rates in a real-world s
P < 0.001
• Achieving ≤ 10% BCR-ABL at 3 months correlates with significantly higher rates of improved PFS and OS 1
7
Marin et al. 2012
Important to ‘Get the Drugs in’ to Achieve
Optimal responses: Missed Doses Do
Matter!
Imatinib
Dasatinib
Dosing in 1st
12 months
Achievement of MMR
at 12 months (ITT)
Achievement of MMR
at 12 months (ITT)
100%
125/227 (55.1%)
129/187 (69.0%)
95-99.9%
14/27 (51.9%)
20/29 (69.0%)
80-95%
3/10 (30.0%)
17/37 (45.9%)
<80%
6/18 (33.3%)
13/29 (44.8%)
Chance of achievement of RQ-PCR <0.1% at 12 months
decreases with decreased average dosing
nd
2
Which
line drug should
we choose for our
patients?
Up to 40% of patients may ‘fail’ 1st line Imatinib
Up to 20% may ‘fail’ Nilotinib / dasatinib 1st line
TKIs in CML
Off patent
2016
Imatinib
Development License
NICE approved
Dasatinib
-1st and 2nd line
Nilotinib
- 1st and 2nd line
Bosutinib
- 2nd/3rd line if other TKIs not appropriate
Ponatinib
- T315I or if no other TKI indicated
2000
2005
2010
CDF
2015
Licensed Drugs in CML
Dasatinib
- More potent
- 100 mg once daily
- 400 mg twice a day
N
N
NC
O
Cl
O
N
O
NH
Cl
Bosutinib
- 500 mg once a
day
Ponatinib
- Most potent
- 30 mg once daily
Treating CML is Not Easy!

PATIENT FACTORS




DISEASE FACTORS




Patients are not all the same!
Different ages, comorbidities, sensitivity to side effects
Compliance
CML is not a homogeneous disease!
Different biological properties affecting sensitivity to different
drugs
Different mutations
DRUG FACTORS



The different drugs are not all equal!
Different toxicities
Varying efficacy against different mutations
Aim is to match the correct
patient with the correct drug
for their CML!
Not that easy as in the UK we are not
able to access all the drugs freely
What do the Guidelines Say?
ELN Guidelines 2013 – 2nd Line Treatment
 A change of therapy is mandatory for resistance or toxicity
 If there is intolerance, any other available TKI can be used, including
imatinib second-line after a second-generation TKI first-line.
 For resistance, the logic sequence is: [1] from imatinib to any other
available and approved TKI (dasatinib, nilotinib, bosutinib,
ponatinib), [2] from nilotinib to other TKIs (dasatinib, bosutinib,
ponatinib), and [3] from dasatinib to other TKIs (nilotinib, bosutinib,
ponatinib).
 Regrettably, there are no studies comparing different TKIs in
second-line. Therefore, the choice of the second-line TKI is guided
by some patient characteristics, mainly age and comorbidities, by
the type of side effects with the first TKI, and by the presence of
BCR-ABL1 kinase mutations, and also by drug availability and cost,
and by doctor experience.
No Clear Winner with Respect to
Efficacy
No trials have directly compared the drugs
Factors that need to be
borne in mind when choosing
2nd line treatments
Any known mutations
Known toxicities of the drugs
Patient related comorbidities
What drugs are funded by the NHS!
Efficacy against Different Mutations
Efficacy against Double Mutations
Even more difficult when there are 2 mutations
Side Effects due to the TKIs are
caused by their ‘Off-Target’ Effects
Most of the drugs have unwanted effects on other
cellular proteins leading to their side effects
Imatinib
(Phos. IC50)
PDGFR
72 nM
Nilotinib
(Phos. IC50)
BcrAbl
20 nM
Dasatinib
(Phos. IC50)
Src
0.1 nM
Bosutinib
(Phos. IC50)
Src
3 nM
1. Manley PW, et al. Proc Am Assoc Cancer Res 2007;48:772.
2. Weisberg E, et al. Cancer Cell 2005;7:1129.
3. Remsing Rix LL, et al. Leukemia 2009;23:477.
4. O’Hare T. et al (2009) Cancer Cell. 16: 401-412
>
Kit
99 nM
>
PDGFR
75 nM
>
BcrAbl
1.8 nM
>
BcrAbl
85 nM
>
BcrAbl
221 nM
>
Kit
209 nM
>
PDGFR
2.9 nM
>
PDGFR
>3000
>
Src
>1000 nM
>
Src
>1000 nM
>
Kit
18 nM
>
Kit
>10000 nM
Choice of Drug: Relative Toxicities
Imatinib
Nilotinib
Dasatinib
Bosutinib
Oedema
++
+
+
-
Diarrhoea
++
+
+
+++(transient)
Rash
+
++
+
+
Headache
+
++
++
+
Glucose
-
++
-
+
Lipase
-
+
-
+
QT prolongation
-
+
+
+
Hepatotoxicity
+
+
-
+
Haem toxicity
+
++
++
+
Pleural effusions
-
-
++ (20%)
+ (3%)
Pulm hypertension
-
-
+ (0.5%)
?+
PAOD and IHD
-
+ (6%)
-
-
Need to balance
risk
benefit
Choice of Drug - Comorbidities
Drug
Nilotinib
- Worsens blood glucose levels
- Cardiovascular risk factors
Dasatinib
- Pleural effusions
- Pulmonary hypertension
Try to Avoid in
Diabetics
Patients with history of cardiovascular
problems eg angina, stroke
Chronic lung diseases
Difficult times…
We may not be able
to use the drugs we
want to due to funding
issues
NICE & the CDF
- Recent changes
Currently approved 2nd Line Treatments
NICE
• Second-line therapy for
SMC
• Second-line therapy for
adults with CP/AP Ph+ CML who
are resistant to treatment with
standard-dose imatinib or who
have imatinib intolerance2
adults with CP Ph+ CML who are
resistant to or intolerant of at
least one prior treatment
including imatinib
 Nilotinib*
 Nilotinib5
*If the manufacturer makes nilotinib available with the discount agreed as part of
the patient access scheme
Dasatinib and high dose Imatinib not approved (2012)
NB: Can still get other drugs for certain patients via the Cancer Drugs Fund
1. NICE. Technology appraisal 251.
2. NICE. Technology appraisal 241.
3. SMC. No. 709/11.
4. SMC. No. 01/02.
5. SMC. No. 440/08.
Cancer Drugs Fund (CDF)








New drugs have to prove their safety, quality and efficacy
NICE: clinical effectiveness – how well does something work in
comparison with what we already use? AND cost effectiveness – how
much more life or quality of life do we get for the extra money spent?
A positive NICE appraisal has to be funded by the NHS: as the budget
is fixed, something else has to be axed or delayed
Main issue with NICE - too slow, so in 2007 government set up CDF
to improve access to cancer drugs in the UK
Each drug is scored for impact on survival, quality of life, toxicity and
‘unmet need’ (is it the only systemic therapy for that disease?)
14/15 expenditure on November list £390m and £420m in 15/16
84 separate drug indications in the CDF in November 14 and as
overspent the lowest scoring 45 indications assessed in this recent
prioritisation process and 18 removed (including CML drugs)
Due to finish April 2016 – not quite sure what next!
Available TKIs: NICE and National CDF
1st Line CP
2nd Line CP
3rd / 4th Line CP
Imatinib
 (NICE)
 (after IFN)
X
Nilotinib
 (NICE)
 (NICE)
X
Dasatinib
X
x

If IM intol / ref AND
NIL intol (but not
refractory)
Bosutinib
X
X

If NIL AND DAS intol
(but not refractory)
Ponatinib
X
X
Unless T315I
X
Unless T315I
Not all patients will respond to 2nd line drugs
Nilotinib 2nd Line Responses
CHR



MCyR
CCyR
40- 50% of patients requiring a 2nd line treatment will ‘fail’
There is some evidence for 3rd line treatment using an alternative drug
but funding is an issue
Other option is a stem cell transplant (which is funded)
Bosutinib 3rd Line Results
IM + D
Resistant
(n = 36)
IM + D
Intolerant
(n = 51)
IM + NI
Resistant
(n = 27)
14.8
(2.7–47.3)
28.7
(0.3–49.7)
12.2
(2.0–48.0)
36
50
27
22 (61)
40 (80)
21 (78)
34
38
24
10 (29)
14 (37)
7 (29)
Complete
3 (9)
13 (34)
4 (17)
Partial
7 (21)
1 (3)
3 (13)
25
47
16
2 (8)
17 (36)
1 (6)
Response, n (%)
Median follow-up (range), mo
Hematologic response
Evaluable patients
Complete
Cytogenetic response
Evaluable patients
Major
Molecular response
Evaluable patients
Major
Khoury et al. Oral presentation 892, ASH 2010.
Ponatinib Results
Licensed post 1st line if other drugs not suitable
Efficacy of 3rd Line Drugs
Evidence suggests ponatinib more effective than bostunib
Lipton et al (Ariad sponsored)
What do the Guidelines Say re 3rd Line?
• There are no evidence-based, reliable,
specific recommendations for the patients
who fail two or even three TKIs.
• These patients form a heterogeneous group
• Can try any of the remaining TKIs
• Consider SCT in eligible patients.
• Ponatinib is likely to be more efficient than
any other TKI, but there are no comparative
studies
Summary










The second generation drugs are effective for many patients
who are resistant to or intolerant of Imatinib
Not clear which one is the best
Responses may be durable
Side effect profiles of the drugs differ and rarely overlap
Generally safer than transplants
Should be offered to patients who fail / can’t take Imatinib
Choice of drug should depend on mutation analysis, side
effects & patient comorbidities BUT not all drugs are funded
Not a cure all! Some patients won’t respond
Limited choice for 3rd line treatment in the UK
Transplantation remains an alternative option