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Professor Mhairi Copland
Institute of Cancer Sciences
University of Glasgow
Choice of first line therapy: Possible role of generics
[email protected]
CML Landmarks in Biology and Therapy
Ph
Scientific observation
1960
TYROSINE
KINASE
t(9:22)
IM CLINICAL
BCR-ABL
TRIALS
1973 1980
1990
1953
1845 Treatment options
1998
2015
Nilotinib
2005 Bosutinib
Dasatinib
2008
2004
1953
chemotherapy
1979
1982
2000
Allo BMT
IFNα
Imatinib
2010
Ponatinib
Treatment options
Hydroxyurea - palliative (controls counts)
Imatinib
Second generation TKIs – dasatinib/nilotinib/bosutinib
Third generation TKI - ponatinib
Allogeneic bone marrow transplant – curative in 60% in CP
Interferon - prolonged survival in chronic phase (<2 years)
Novel agents in clinical trial, e.g. SMO inhibitors
Druker BJ et al, Nat Med 1996;2:561-6
Imatinib mesylate – an ATP-binding
antagonist of BCR-ABL
Imatinib
(
)
Proliferation
Anti-Apoptotic effect
Adhesion properties modified
Goldman J et al, N Engl J Med 2001;344:1084;
IRIS Study:
Complete Haematological Responses
100
90
97%
96%
87% 93%
p<0.001
% responding
80
70
67%
60
69%
50
58%
40
38%
30
20
Imatinib
IFN+Ara-C
10
0
0
3
6
9
12
15
18
Months since randomisation
21
24
IRIS Study:
Complete cytogenetic responses
100
Imatinib
IFN+Ara-C
90
% responding
80
76%
69%
70
63%
60
51%
50
p<0.001
40
25%
30
20
10
3%
1%
0
0
3
6
9%
9
14%
12%
12
15
18
Months since randomisation
21
24
IRIS Study:
Patients Without Progression
100
% without progression
90
80
70
60
Estimated rate at 18 months
Imatinib
92.3% (p<0.001)
IFN+Ara-C
73.6%
50
40
30
Imatinib
IFN+Ara-C
20
10
0
0
3
6
9
12
15
18
Months since randomisation
21
24
IRIS Study: Quality of Life
95
95
imatinib (n =523 )
90
90
p<0.05
Crossed over to imatinib (n = 209)
80
80
Trial Outcome Index (TOI)
85
85
75
75
65
70
70
IFN + Ara-C, no crossover (n = 310)
60
65
60
0
* p<0.001, IFN no crossover vs. crossed over
55
0 11 2 2 3 3 4 45 56
6
9
9
12
12
18
18
Months Since Randomization
Months after randomisation
Hahn E et al, J Clin Oncol 2003; 21:2138
TKIs in the UK
Off patent
2016
Imatinib
Development
NICE approved
License
Dasatinib
Nilotinib
Bosutinib
Ponatinib
Cancer Drug Fund
2000
2005
2010
2015
Imatinib is a Safe Drug....
IRIS Study: Most Frequently Reported Adverse Events (AEs)
Most Common
Adverse Events (by 5
Years)
•
•
All Grade AEs
Patients, %
Grade 3/4 AE’s
Patients %
Fluid retention
60
2
Nausea
50
1
Muscle cramps
49
2
Musculoskeletal pain
47
5
Diarrhoea
45
3
Rash/skin problems
40
3
Fatigue
39
2
Headache
37
<1
Abdominal pain
37
4
Joint pain
31
3
Only Serious Adverse Events (SAEs) were collected after 2005
Grade 3/4 adverse events decreased in incidence after years 1-2
IRIS 8 year update
Generic TKIs – a growth industry!
• http://www.cmladvocates.net/generics/cml-drugsregister – last updated July 2014
• 54 generic imatinibs and 8 generic dasatinibs to date
• No generic nilotinib, bosutinib, or ponatinib . . . yet
• Several generic imatinibs already approved by EMA
Use of generics
• Usually rapidly adopted in UK practice due to equivalent
efficacy and very significantly reduced costs
• Examples from oncology/haematology where generics not
adopted
– Goserelin (Zoladex®) – very difficult to formulate, only
1 generic, which is seldom used as monthly and not
3-monthly depot
– Tamoxifen – variable severity of side effects dependent
on preparation
– Biosimilar G-CSF NOT used for allo donors for HSCT
– Ciclosporin – levels may vary depending on brand
– Biosimilar monoclonal antibodies will be difficult to deliver
Generic imatinib in Canada
• Canada is first Western society to have access to
generic imatinib
• Significant cost reduction
– Glivec® – Novartis – 100 mg – 120 tabs - $2995
– Imatinib – generic – 100 mg – 120 tabs - $295
– Imatinib – generic – 400 mg – 90 tabs - $795
• CML Society Canada currently running an online
survey for patients converting to generic imatinib
Getting perspective
• Questions about use of generics posed on UK CML support
Website patient forum
http://www.cmlsupport.org.uk/node/8848
– What are your specific concerns about this prospect?
– If you are taking one of the other TKIs – how do you think you
would feel about a possible switch to a generic form of that drug
in the future?
• Answers
– General anxiety about switch and many that replied would want
more frequent monitoring in the first few months after switch
– Acceptance from some that switch is inevitable and should be
OK, as already on generics for other conditions
– Some expressed extreme reluctance to switch
to generic
What are the benefits of giving 2G TKIs
first-line?
First-line dasatinib – DASISION:
Cumulative incidence of MMR
Jabbour E, et al. Haematologica. 2012;97(s1) [abstract 1106]
First-line nilotinib – ENESTnd:
Cumulative incidence of MMR
Despite big differences in MMR rates
(9%–20%), no significant differences
were seen in
overall survival at 2.5 to 3 years in
DASISION, ENESTnd and BELA
Clinical Scenarios in Generic Imatinib Era
• Majority of patients do well with imatinib
• Can we identify patients who benefit from 2G TKIs firstline?
– Sokal/Hasford/EUTOS high risk
– Advanced phase
– Is an early switch to 2G TKI a more appropriate approach?

BUT small number of patients will rapidly progress to AP/BC
• Does 2G TKI first-line increase likelihood of MR4.5/MUL
and thus therapy discontinuation?
– Will be answered in SPIRIT 3 together with assessment of
generic imatinib
– EURO-SKI – 55% remain in MMR at 18 months
– STOP-2G-TKI – 57.4% remain in MMR at 24 months
Concluding remarks
• Generic imatinib is likely to be widely adopted
• There is likely to be significant pressure to start
patients on generic imatinib from health care payers
• Personally . . .
– Less concerned about efficacy and more concerned about
variable side effect profiles with generic products
– Important to involve everyone, including patient groups
and educate about the introduction of generic imatinib
Tell us what
you think?