1. CML TKIs – where are we up to? Steve O’Brien
Northern Institute for Cancer Research Newcastle University Medical School
Newcastle, March 2013

2. Second generation TKIs are just better… … no brainer?

3. TKIs in CML, the gold rush
Date of FDA approval
First Line
Second Line
1st
2nd
Imatinib
2002
2001
Gold standard
No published experience
Dasatinib
2010
2006
Early data suggest a small advantage over Imatinib
40-50% CCyR
Nilotinib
2007
Bosutinib
2012
Not yet clear, maybe slightly better than imatinib
Ponatinib
2013?
EPIC
10-30% of responses in 3rd line (T315I active)
Thanks to David Marin

4. 2G drug trials DASISION, SPIRIT 2 ENESTnd BELA EPIC Dasatinib
nilotinib
BELA
Bosutinib
EPIC
Ponatinib (3G??)

6. ENESTnd Nilotinib 300 mg BID (n = 282) N = 846 217 centers*
Nilotinib 300 mg BID (n = 282)
N = 846
217 centers
35 countries
Nilotinib 400 mg BID (n = 281)
Imatinib 400 mg QD (n = 283)
Follow-up
5 years
Primary endpoint: MMR at 12 months
Key secondary endpoint: Durable MMR at 24 months
Other endpoints: CCyR by 12 months, time to MMR and CCyR, EFS, PFS, time to AP/BC on study treatment, OS including follow-up 6

7. Primary endpoint: Confirmed CCyR by 12 months
Dasatinib Versus Imatinib Study In Treatment-naïve CML: DASISION (CA ). Design
Imatinib 400 mg QD (n=260)
Dasatinib 100 mg QD (n=259)
N=519
108 centers
26 countries
Follow-up
5 years
Randomized*
*Stratified by Hasford risk score
Primary endpoint: Confirmed CCyR by 12 months
Secondary/other endpoints: Rates of CCyR and MMR; times to confirmed CCyR, CCyR and MMR; time in confirmed CCyR and CCyR; PFS; overall survival

8. Phase 3 open-label trial in newly diagnosed CP CML
BELA Study Design R A N D O M I Z E
Bosutinib
500 mg/day
n = 250
8-year follow-up
Phase 3 open-label trial in newly diagnosed CP CML
N = 502
139 sites
31 countries
Imatinib
400 mg/day
n = 252
8-year follow-up
BELA is an open-label, randomized, phase 3 trial in chronic phase CML within 6 months from diagnosis. Patients were randomized 1:1 to a starting dose of bosutinib 500 mg/day or imatinib 400 mg/day and stratified by Sokal risk group and geographic region. Dose escalation to bosutinib 600 mg/day or imatinib 600 mg/day was permitted for lack of efficacy if no grade 3/4 drug-related adverse event had occurred. The primary endpoint was the rate of complete cytogenetic response at 12 months.
Randomization is stratified based on Sokal risk score and geographical regions.
1-year analysis
Key eligibility criteria: cytogenetic diagnosis of Philadelphia chromosome–positive (Ph+) CP CML 6 mo prior, no prior therapy other than hydroxyurea or anagrelide
Primary endpoint: complete cytogenetic response (CCyR) at 12 months
Key secondary and exploratory endpoints:
MMR at 12 months, time to and duration of CCyR and MMR, time to transformation to AP/BP CML, event-free survival (EFS), and overall survival (OS)
Safety and tolerability 8

9. Nilotinib Leads to Faster / Deeper Responses
% MMR

10. Dasatinib is Superior to Imatinib in CML-CP: MMR Rates
(%)
Mo 3 Mo 6 Mo 9 Mo 12 Any time

11. Early efficacy of nilotinib and dasatinib in comparison to imatinib
ENESTnd
DASISION
imatinib
nilotinib
difference
dasatinib
CCyR at 12 month
65%
80% 15
73%
85% 12
CCyR at 24 month
77%
87% 10
82% 3
PFS at 24 month
95.2%
98.0%
92.1%
93.7% 2
OS at 24 month
96.3
97.4% 1
95.3%
Blue indicates a statistically significant difference
Red indicates a non significant difference
Saglio et al, NEJM 2010
Kantarjian et al, NEJM 2010
Kantarjian et al, Lancet Onc 2011
Kantarjian et al, Blood 2012

12. First-Line Dasatinib is Associated with a Lower Rate of Progression to AP/BP
Dasatinib 100 mg QD
Imatinib 400 mg QD
Progressed
to AP/BP
(n)
3.5%
1.9%
No patient who achieved MMR progressed to accelerated or blast phase
2 patients who achieved CCyR progressed to accelerated or blast phase (1 with dasatinib, 1 with imatinib)

13. Reduced Overall Progression to AP/BC
number of patients
3.9%
p=0.0095*
p=0.0037*
0.7%
0.4%
No patients who achieved MMR progressed to AP/BC
3 patients who achieved CCyR on imatinib progressed to AP/BC
*p-values are based on log-rank test stratified by Sokal risk group vs imatinib for time to AP/BC

14. Side effects

15. PFS is similar in patients with CCyR regardless of depth of molecular response
Druker BJ, et al. NEJM, 2006;355(25):

16. CML @ ASH ‘Even better’ responses Stopping (reducing)
2 possible strategies
Give more, give less!
Stopping (reducing)
From CMR not MMR
2nd gen data – early days

17. Imatinib vs ‘2nd gen’-inib
Cost
Better/deeper response
Possible to stop
Shorter duration of therapy
Cheaper cost of treatment ‘package’?
More cost effective??
‘new-inib’
TKI2-inib
off patent
Imatinib
2015/16
Duration of therapy

18. TKIs in CML Imatinib Dasatinib Nilotinib Bosutinib ?? Ponatinib ??
Off patent
Imatinib
Development
License
NICE approved
Dasatinib
Nilotinib
Bosutinib ??
Ponatinib ??
2000
2005
2010
2015
(European license)

19. NICE TA251: first line treatment TA 241: second line 25 April 2012
Imatinib & nilotinib approved
Subject to Patient Access Scheme (PAS)
Dasatinib not approved (no PAS offered)
TA 241: second line
13 January 2012
Same as above

20. NICE
Dasatinib
“People currently receiving dasatinib that is not recommended according to 1.3 should be able to continue treatment until they and their clinician consider it appropriate to stop”
Minimum free supply in SPIRIT 2 to 2018
NICE rapid review currently in process

21. NICE Bosutinib Ponatinib considered June 2013 FAD approx Oct 2013
no time frame as yet

22. So where are we now? Most CML patients are fine
There are more and more…
Not much difference between TKIs?
Apart from cost and perhaps side effects
Use wisely/selectively
Imatinib off patent 2016
We really need to figure out how to reduce and/or stop treatment for a lot more patients

23. ENESTnd study. Kantarjian et al. Lancet Oncology 2011: 12: 841

24. ‘Isotypes’ of Otto Neurath and Gerd Arntz
Thanks to David Spiegelhalter

25. ENEST nd (nilotinib trial) Progression to AP/BC at 24 months
Progressions (AP/BC); deaths. Lancet Oncology Sept 2011 paper. 24 months minimum follow up
20 deaths if just look at imat and nilot 300
Imat: 12 of 283 (4.2%); of 283 (3.8)
Nilot: 2 of 282 (0.7%); of 282 (3.2)
Imatinib n=283: 12 events (4.2%)
Nilotinib n=282: 2 events (0.7%)
Kantarjian et al. Lancet Oncology 2011: 12: 841

26. ENEST nd (nilotinib trial) All deaths at 24 months
Progressions (AP/BC); deaths. Lancet Oncology Sept 2011 paper. 24 months minimum follow up
20 deaths if just look at imat and nilot 300
Imat: 12 of 283 (4.2%); of 283 (3.8)
Nilot: 2 of 282 (0.7%); of 282 (3.2)
Imatinib n=283: 11 events (3.8%)
Nilotinib n=282: 9 events (3.2%)
Kantarjian et al. Lancet Oncology 2011: 12: 841

28. How many patients with CML?
per year
£464M
per year
£????
USA: 311, 591,917
UK: 62,218,761
Huang et al. Cancer 2011: doi: /cncr.26679

30. £2-3 billion? NHS spending on CML In next 10 years…
Between £290M - £460M per annum
Over next ten years…
£2-3 billion?

31. Difficult times…
So can we afford all these great new developments in CML?

32. Second generation TKIs are just better… … no brainer?

33. Will there be any more???

34. Modern medicines – amazing!
Kinase inhibitors
Imatinib & others
ABL, CML
Sunitinib
PDGF-R, VEGF-R, renal
Afatinib
Her2, EGF-R, breast cancer
Regorafenib
Trametinib
Dabrafenib
Ibrutinib
Vemurafenib
B-RAF, melanoma, hairy cell leukaemia
Ruxolitinib JAK-2
Targeted antibodies
Trastuzumab (Herceptin)
HER2/neu receptor, breast cancer
Rituximab (Rituxan)
CD20, lymphoid disease
Cetuximab (Erbitux)
EGF-R, colorectal
Bevacizumab (Avastin)
VEGF, various

35. So what about generics? 2016 in UK

36. CML @ ASH Drugs jostling for position Imatinib off patent in 2016
At least 10 generics waiting in the wings
Genfatinib, Imatinib Teva, Veenat, Celonib, Imatib, Mesylonib, Mitinab, Shantinib, Zoleta, Spotnib.
Dasatinib, nilotinib (radotinib), bosutinib, ponatinib
Better responses
No difference in survival

38. So what about generics? 2016 in UK

39. CML TKIs – where are we up to? Steve O’Brien
Northern Institute for Cancer Research Newcastle University Medical School
Newcastle, March 2013