CMLTKIs – where are we up

to?

Steve O’BrienNorthern Institute for Cancer Research Newcastle University Medical

School

Newcastle, March 2013

Second generation TKIs are just better…

… no brainer?

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 2010 2007

Early data suggest a small advantage over

Imatinib

40-50% CCyR

Bosutinib 2012

Not yet clear, maybe slightly

better than imatinib

40-50% CCyR

Ponatinib 2013? EPIC10-30% of

responses in 3rd line (T315I active)

TKIs in CML, the gold rush

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

• 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

Imatinib 400 mg QD (n = 283)

Nilotinib 300 mg BID (n = 282)

* Nilotinib 400 mg BID (n = 281)• N = 846

• 217 centers

• 35 countries

Follow-up 5 years

Dasatinib Versus Imatinib Study In Treatment-naïve CML: DASISION (CA180-056). Design

• 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

Follow-up

5 yearsRandomized*

Imatinib 400 mg QD (n=260)

Dasatinib 100 mg QD (n=259)• N=519

• 108 centers

• 26 countries

*Stratified by Hasford risk score

BELA Study Design

• 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

Phase 3 open-label trial in newly diagnosed CP CML

N = 502

139 sites

31 countries

Bosutinib 500 mg/day

n = 250

Imatinib 400 mg/day

n = 252

8-year follow-up

8-year follow-up

RANDOMIZE

1-year analysisRandomization is stratified based on Sokal risk score and geographical regions.

Nilotinib Leads to Faster / Deeper Responses

% M

MR

p<0.0001

p<0.0001

Dasatinib is Superior to Imatinib in CML-CP: MMR Rates

P<0.0001

MMR(%)

Mo 3 Mo 6 Mo 9 Mo 12 Any time

P<0.00003

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 differenceRed indicates a non significant difference

Early efficacy of nilotinib and dasatinib in comparison to imatinib

Saglio et al, NEJM 2010Kantarjian et al, NEJM 2010Kantarjian et al, Lancet Onc 2011Kantarjian et al, Blood 2012

First-Line Dasatinib is Associated with a Lower Rate of Progression to AP/BP

• 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)

Progressedto AP/BP

(n)

3.5%

1.9%

Dasatinib 100 mg QD

Imatinib 400 mg QD

Reduced Overall Progression to AP/BC nu

mbe

r of p

atien

ts

• No patients who achieved MMR progressed to AP/BC• 3 patients who achieved CCyR on imatinib progressed to AP/BC

p=0.0095* p=0.0037*

*p-values are based on log-rank test stratified by Sokal risk group vs imatinib for time to AP/BC

0.7% 0.4%

3.9%

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

Imatinib vs ‘2nd gen’-inibCost

Duration of therapy

Imatinib

TKI2-inib

‘new-inib’

2015/16

Better/deeper responsePossible to stop

Shorter duration of therapyCheaper cost of treatment ‘package’?

More cost effective??

off patent

Imatinib

Dasatinib

Nilotinib

Bosutinib

Ponatinib

2000 2010 20152005

Development License NICE approved

Off patent

??

??

TKIs in CML

(European license)

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

Kantarjian et al. Lancet Oncology 2011: 12: 841

Imatinib 4001 n=283: 12 events (4.2%) Nilotinib 3002 n=282: 2 events (0.7%)

ENEST nd (nilotinib trial)All deaths at 24 months

Kantarjian et al. Lancet Oncology 2011: 12: 841

Imatinib 4001 n=283: 11 events (3.8%) Nilotinib 3002 n=282: 9 events (3.2%)

How many patients with CML?

£290Mper year

£464Mper year

£????

Huang et al. Cancer 2011: doi: 10.1002/cncr.26679USA: 311, 591,917UK: 62,218,761USA: 311, 591,917UK: 62,218,761

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???

• 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

Modern medicines – amazing!

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

CMLTKIs – where are we up

to?

Steve O’BrienNorthern Institute for Cancer Research Newcastle University Medical

School

Newcastle, March 2013