CML
TKIs – where are we up to?
Steve O’Brien
Northern Institute for Cancer Research Newcastle University Medical School
Newcastle, March 2013
Second generation TKIs
are just better…
… no brainer?
TKIs in CML, the gold rush
Date of FDA
approval
Imatinib
Dasatinib
Nilotinib
Bosutinib
Ponatinib
First Line
Second Line
1st
2nd
2002
2001
Gold standard
No published
experience
2006
Early data
suggest a small
advantage over
Imatinib
40-50% CCyR
2007
Early data
suggest a small
advantage over
Imatinib
40-50% CCyR
2012
Not yet clear,
maybe slightly
better than
imatinib
2010
2010
2013?
EPIC
40-50% CCyR
10-30% of
responses in 3rd line
(T315I active)
Thanks to David Marin
2G drug trials
• DASISION, SPIRIT 2
– Dasatinib
• ENESTnd
– nilotinib
• BELA
– Bosutinib
• EPIC
– Ponatinib (3G??)
www.spirit-cml.org
www.spirit-cml.org
ENESTnd
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:
• Key secondary endpoint:
• Other endpoints:
MMR at 12 months
Durable MMR at 24 months
CCyR by 12 months, time to MMR
and CCyR, EFS, PFS, time to AP/BC on
study treatment, OS including follow-up
Dasatinib Versus Imatinib Study In Treatment-naïve
CML: DASISION (CA180-056). Design
• N=519
• 108 centers
Dasatinib 100 mg QD (n=259)
Follow-up
Randomized*
• 26 countries
5 years
Imatinib 400 mg QD (n=260)
*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
BELA Study Design
Phase 3 open-label trial in
newly diagnosed CP CML
N = 502
139 sites
31 countries
Randomization is stratified based on Sokal risk score
and geographical regions.
R
A
N
D
O
M
I
Z
E
Bosutinib
500 mg/day
n = 250
8-year follow-up
Imatinib
400 mg/day
n = 252
8-year follow-up
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
Nilotinib Leads to Faster / Deeper
Responses
p<0.0001
p<0.0001
60
% MMR
Percentage
50
43
38
40
33
30
30
18
20
10
44
43
9
22
12
5
1
0
Month 3
Nilotinib 300 mg BID
Month 6
Month 9
Nilotinib 400 mg BID
Month 12
Imatinib 400 mg QD
Dasatinib is Superior to Imatinib in CML-CP:
MMR Rates
P<0.00003
P<0.0001
MMR
(%)
Mo 3
Mo 6
Mo 9
Mo 12
Any time
Early efficacy of nilotinib and dasatinib
in comparison to imatinib
ENESTnd
DASISION
imatinib
nilotinib
difference
imatinib
dasatinib
difference
CCyR at 12 month
65%
80%
15
73%
85%
12
CCyR at 24 month
77%
87%
10
82%
85%
3
PFS at 24 month
95.2%
98.0%
3
92.1%
93.7%
2
OS at 24 month
96.3
97.4%
1
95.2%
95.3%
0
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
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)
number of patients
Reduced Overall Progression to AP/BC
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
Side effects
PFS is similar in patients with CCyR regardless of depth
of molecular response
Druker BJ, et al. NEJM, 2006;355(25):2408-17.
CML @ ASH
• ‘Even better’ responses
– 2 possible strategies
– Give more, give less!
• Stopping (reducing)
– From CMR not MMR
– 2nd gen data – early days
Cost
Imatinib vs ‘2nd gen’-inib
‘new-inib’
TKI2-inib
Better/deeper response
Possible to stop
Shorter duration of therapy
Cheaper cost of treatment ‘package’?
More cost effective??
off patent
Imatinib
2015/16
Duration of therapy
TKIs in CML
Off patent
Imatinib
Development License
NICE approved
Dasatinib
Nilotinib
??
Bosutinib
??
Ponatinib
2000
(European license)
2005
2010
2015
NICE
• TA251: first line treatment
– 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
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
NICE
• Bosutinib
– considered June 2013
– FAD approx Oct 2013
• Ponatinib
– no time frame as yet
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
ENESTnd study. Kantarjian et al. Lancet Oncology 2011: 12: 841
‘Isotypes’ of Otto Neurath and Gerd Arntz
Thanks to David Spiegelhalter
ENEST nd (nilotinib trial)
Progression to AP/BC at 24 months
Imatinib 4001 n=283: 12 events (4.2%)
Nilotinib 3002 n=282: 2 events (0.7%)
Kantarjian et al. Lancet Oncology 2011: 12: 841
ENEST nd (nilotinib trial)
All deaths at 24 months
Imatinib 4001 n=283: 11 events (3.8%)
Nilotinib 3002 n=282: 9 events (3.2%)
Kantarjian et al. Lancet Oncology 2011: 12: 841
How many patients with CML?
USA: 311, 591,917
UK: 62,218,761
£290M
per year
£464M
per year
£????
Huang et al. Cancer 2011: doi: 10.1002/cncr.26679
NHS spending on CML
• In next 10 years…
• Between £290M - £460M per annum
• Over next ten years…
£2-3 billion?
Difficult
times…
So can we afford
all these great new
developments in
CML?
Second generation TKIs
are just better…
… no brainer?
Will there be any more???
Modern medicines – amazing!
•
Kinase inhibitors
–
Imatinib & others
•
–
Sunitinib
•
–
•
Her2, EGF-R, breast cancer
Regorafenib
Trametinib
Dabrafenib
Ibrutinib
Vemurafenib
•
–
PDGF-R, VEGF-R, renal
Afatinib
•
–
–
–
–
–
ABL, CML
B-RAF, melanoma, hairy cell leukaemia
Ruxolitinib JAK-2
Targeted antibodies
–
Trastuzumab (Herceptin)
•
–
Rituximab (Rituxan)
•
–
CD20, lymphoid disease
Cetuximab (Erbitux)
•
–
HER2/neu receptor, breast cancer
EGF-R, colorectal
Bevacizumab (Avastin)
•
VEGF, various
So what about generics?
2016 in UK
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
So what about generics?
2016 in UK
CML
TKIs – where are we up to?
Steve O’Brien
Northern Institute for Cancer Research Newcastle University Medical School
Newcastle, March 2013