1. Dr Jenny Byrne Nottingham
Second and Third Generation Tyrosine Kinase Inhibitors: How do we Choose?
Dr Jenny Byrne
Nottingham

2. Imatinib is a wonderful drug!

3. IRIS 8-Year Update Overall Survival (Intent-to-Treat) – Imatinib ArmEs t i m
imaa e d o v r a l s u
ivaa 8 y w 5 %
(93%, considering only CML related deaths) 1 2 3 4 6 7 9 M n h S c R z : C L O
% Alive 3

4. IRIS 8 year Results BUT Imatinib is a great drug ……
Not all patients respond well to Imatinib
IRIS data excludes patients who discontinued ‘study’ Imatinib

5. Outcome for Patients Discontinuing IRIS Trial
All randomized to imatinib (n= 553; 100%)
Still receiving study imatinib (n = 332; 60%)
Discontinued study imatinib* (n = 221; 40%)
In CCR (n = 317; 57%)
No CCR (n = 15; 3%)
Safety (n = 43; 8%)
Efficacy
(n = 82; 15%)
Other (n = 96; 17%)
Still on drug
317 in CCyR (298 never lost CCyR, 19 had re-gained after initial loss CCyR)
15 not in CCyR (6 had lost CCyR but are still in MCyR, 9 never achieved CCyR, mostly not documented BMA)
Discontinuations
Safety = 26 discontinuations + 4 cross-over for intolerance + 13 deaths (all CML unrelated on study treatment, except the 1 case in CMR with UNK reason suspected to be CML)
Efficacy = 72 discontinuatios + 10 cross-over (including progressions to AP/BC, loss of responses but also Unsatisfactory Therapeutic Effect, e.g. Lack of response)
Other = 16 BMT + 80 Other (incl. Withdrew consent, Lost to follow-up, PV etc)
Alive (n = 17; 40%)
Dead** (n = 26; 60%)
Alive (n = 52; 63%)
Dead (n = 30; 37%)
Alive (n = 81; 84%)
Dead (n = 15; 16%)
**Including primary discontinuation reason ‘Death’ (n=13)
*Patients may have continued imatinib off study. 5

6. Up to 40% of patients may ‘fail’ Imatinib

7. 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 drug-related toxicity
(Poor adherence / missed doses may also be an issue)

8. Primary resistance
Acquired resistance
Resistance has been defined as primary or acquired (also known as secondary)
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
Resistance can be defined as decreased effectiveness of a drug in treating a disease.1 Imatinib resistance can be categorized as primary or secondary. Primary resistance is also known as intrinsic resistance, and secondary resistance is also known as acquired resistance. Molecular resistance can also be indicated as a trend (at least three points).
Primary resistance is defined as failure to achieve and/or sustain a significant haematological response (i.e complete haematological response [CHR]) or cytogenetic response (i.e. complete cytogenetic response [CHR])
Secondary resistance is defined as the progressive reappearance of the leukaemic clone after an intial response to the drug. This includes:
Haematological resistance (loss of normalisation of peripheral blood counts and spleen size)
Cytogenetic resistance (loss of a major cytogenitc response [MCR])
Molecular resistance (loss of a complete or major molecular response [MMR]).
Baccarani and the Leukaemia Net recent guidance would class all of these patients as Imatinib failures (see next slide).
1. Melo JV, Chuah C. Cancer Lett 2006 (in press).
Hochhaus et al., Hematol Oncol Clin N Am 2004;18:641–56

9. BCR/ABL mutations are the most frequently reported mechanism of acquired resistance
F486S P B C A
Q252H/R
E255K/V
Y253H/F
G250E/A/F
L248V
D241G
M237I
M244V
E279K
E281A
T277A
E276G
K285N
E275K
E355G/D
F359V/C/D/I
V379I
L3641
M351T/L
F382L
G383D
L384M
L387F/M
M388L
H396R/P
A397P
E453G/K/A/V
E450G/Q/K
Q447R
S438C
E459K/Q
A350V
T315I/A/D
A344V
M343T
F317L
S348L
L324Q
G321E
F311L/I/V
C305S
V299L
E292V
L298V
V289A/I
P296H
Adapted from Melo et al (2006)
K357R
5417Y
Acquired point mutations in the ABL kinase domain are the most frequently reported mechanism for acquired resistance.1
These mutations shift the loop into the ‘active’ or ‘open’ conformation of the BCR-ABL protein, as well as interrupt critical contact points necessary for imatinib to bind.
Imatinib binds to BCR-ABL in the ‘inactive’ or ‘closed’ conformation of the kinase only.
Mutations are grouped into four main sites/types:
-Imatinib binding site (B)
-P-loop (P; ATP binding site)
-A-loop (A; activation loop)
-Catalytic site (C)
1. Deininger M, Buchdunger E, Druker BJ. Blood. 2005;105:2640–53.
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)

10. 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
3 months
BCR-ABL1 ≤ 10%
and/or Ph+ ≤ 35%
BCR-ABL1 >10%
and/or Ph %
No CHR
and/or Ph+ >95%
6 months
BCR-ABL1 <1%
and/or Ph+ 0 (CCyR)
BCR-ABL1 1-10% and/or Ph+ 1-35%
and/or Ph+ >35%
12 months
BCR-ABL1 ≤ 0.1% (MMR)
BCR-ABL1 >0.1-1%
BCR-ABL1 >1%
and/or Ph+ >0
Anytime
Stable or improving MMR
ACA/Ph- (-7 or 7q-)
Loss of CHR, loss of CCyR, confirmed loss of MMR, mutations, ACA in Ph+ cells
Baccarani M, et al. Blood 2013: 122: 872–884

11. 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 OS1 7
Marin et al. 2012

12. Achievement of MMR at 12 months (ITT)
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)
100%
125/227 (55.1%)
129/187 (69.0%) %
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

13. Which 2nd 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

14. TKIs in CML Imatinib CDF Dasatinib Nilotinib Bosutinib Ponatinib 2000
Off patent
2016
Imatinib
Development
License
NICE approved
CDF
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
2015

15. Licensed Drugs in CML Dasatinib More potent 100 mg once daily
- 400 mg twice a day
Bosutinib
mg once a day
Ponatinib
Most potent
30 mg once daily

16. Treating CML is Not Easy!
PATIENT FACTORS
Patients are not all the same!
Different ages, comorbidities, sensitivity to side effects
Compliance
DISEASE FACTORS
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

17. 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

18. 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.

19. No Clear Winner with Respect to Efficacy
No trials have directly compared the drugs

20. 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!

21. Efficacy against Different Mutations

22. Efficacy against Double Mutations
Even more difficult when there are 2 mutations

23. 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
>
Kit
99 nM
BcrAbl
221 nM
Src
>1000 nM
Nilotinib
20 nM
75 nM
209 nM
Dasatinib
0.1 nM
1.8 nM
2.9 nM
18 nM
Bosutinib
3 nM
85 nM
>3000
>10000 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:

24. 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%)

25. Need to balance
risk
benefit

26. Choice of Drug - Comorbidities
Try to Avoid in
Nilotinib
Worsens blood glucose levels
Cardiovascular risk factors
Diabetics
Patients with history of cardiovascular problems eg angina, stroke
Dasatinib
Pleural effusions
Pulmonary hypertension
Chronic lung diseases

27. NICE & the CDF Difficult times…
We may not be able to use the drugs we want to due to funding issues
NICE & the CDF
- Recent changes

28. Currently approved 2nd Line Treatments
NICE
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
Nilotinib*
Second-line therapy for adults with CP Ph+ CML who are resistant to or intolerant of at least one prior treatment including imatinib
Nilotinib5
NICE. Technology appraisal 251. Dasatinib, nilotinib and standard-dose imatinib for the first-line treatment of chronic myeloid leukaemia (part review of technology appraisal guidance 70)
NICE. Technology appraisal 241: Leukaemia (chronic myeloid) – dasatinib, nilotinib, imatinib (intolerant, resistant)
Scottish Medicines Consortium. Nilotinib 150 mg hard capsules (Tasigna®) no. 709/
Scottish Medicines Consortium. Imatinib Mesylate (Glivec®) no. 01/
Scottish Medicines Consortium. Nilotinib, 200 mg capsules (Tasigna®) no. 440/
*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 NICE. Technology appraisal SMC. No. 709/ SMC. No. 01/ SMC. No. 440/08.

29. 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!

30. Available TKIs: NICE and National CDF
1st Line CP
2nd Line CP
3rd / 4th Line CP
Imatinib
 (NICE)
 (after IFN) X
Nilotinib
Dasatinib x 
If IM intol / ref AND
NIL intol (but not refractory)
Bosutinib
If NIL AND DAS intol (but not refractory)
Ponatinib
Unless T315I

31. Not all patients will respond to 2nd line drugs
CHR
MCyR
CCyR
Nilotinib 2nd Line Responses
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)

32. Bosutinib 3rd Line Results
Response, n (%)
IM + D
Resistant
(n = 36)
Intolerant
(n = 51)
IM + NI
(n = 27)
Median follow-up (range), mo
14.8
(2.7–47.3)
28.7
(0.3–49.7)
12.2
(2.0–48.0)
Hematologic response
Evaluable patients 36 50 27
Complete
22 (61)
40 (80)
21 (78)
Cytogenetic response 34 38 24
Major
10 (29)
14 (37)
7 (29)
3 (9)
13 (34)
4 (17)
Partial
7 (21)
1 (3)
3 (13)
Molecular response 25 47 16
2 (8)
17 (36)
1 (6)
IM, imatinib; D, dasatinib; NI, nilotinib.
aEvaluable patients had a baseline and 1 post-baseline disease assessment for the corresponding endpoint or had died or discontinued the study due to disease progression.
bOf the 13 patients in this cohort excluded from the analyses, 6 had no post-baseline assessment, 5 had no baseline assessment, and 2 had no valid assessments at baseline or post-baseline. [20 metaphases]
Khoury et al. Oral presentation 892, ASH 2010. 32

33. Ponatinib Results
Licensed post 1st line if other drugs not suitable

34. Efficacy of 3rd Line Drugs
Evidence suggests ponatinib more effective than bostunib
Lipton et al (Ariad sponsored)

35. 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

36. 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