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 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

2G drug trials DASISION, SPIRIT 2 ENESTnd BELA EPIC Dasatinib 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 * 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

Primary endpoint: Confirmed CCyR by 12 months Dasatinib Versus Imatinib Study In Treatment-naïve CML: DASISION (CA180-056). 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

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

Nilotinib Leads to Faster / Deeper Responses % MMR

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

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)

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

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 Stopping (reducing) 2 possible strategies Give more, give less! Stopping (reducing) From CMR not MMR 2nd gen data – early days

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

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)

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

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 Ponatinib considered June 2013 FAD approx Oct 2013 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 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%); 11 of 283 (3.8) Nilot: 2 of 282 (0.7%); 9 of 282 (3.2) 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 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%); 11 of 283 (3.8) Nilot: 2 of 282 (0.7%); 9 of 282 (3.2) 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? per year £464M per year £???? USA: 311, 591,917 UK: 62,218,761 Huang et al. Cancer 2011: doi: 10.1002/cncr.26679

£2-3 billion? 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 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

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