2. Acknowledgements Trial & data management, Newcastle Corinne Hedgley, Lynn Seeley, Caroline Hodgson, Ruth Bescoby, Carrie Page, Angela Fallows, Laura Brown, Wendy Banks, Meg Buckley, Leanne Woolmer, Wendy Osborne, Gemma Gills, Sarah Adams, Andrew Johnston, Helen Gallon Trial Steering Committee NCRI CML WG Jane Apperley, Naumann Butt, Jenny Byrne, Richard Clark, Hugues de Lavallade, Letizia Foroni, Andy Goringe, Tessa Holyoake, Brian Huntley, Adam Mead, Dragana Milojkovic, Wendy Osborne, Graeme Smith, Richard Szydlo, Sameer Tulpule, Mhairi Copeland (Chair of CML WG) Data Monitoring CommitteeCharles Schiffer, Keith Wheatley, Graham Dark SponsorNewcastle Hospitals NHS Foundation Trust FunderAriad Chief InvestigatorStephen O’Brien Sitesn~150 Patientsn=1,000 Sandy Craine, CML support; Nigel Deekes, CML UK Facebook

3. 1,000 patients required Starting Q4, 2014 ~150 sites

4. Imatinib Dasatinib Nilotinib Bosutinib Ponatinib 2000201020152005 Development License NICE approved Off patent 2016 TKIs in CML CDF (radotinib)

5. ⅔

6. Imatinib Dasatinib Nilotinib Bosutinib Ponatinib 2000201020152005 Development License NICE approved Off patent 2016 TKIs in CML CDF (radotinib)

7. riskbenefit

8. BCR-ABL (IS) n 5Y-OS ≤1% 21897% 1-10% 28394% >10% 19187% Overall Survival (OS) BCR-ABL (IS) at 3 months ≤1% vs. 1-10% vs. >10% n.s. 0.012 p-value ≤1% 1-10% >10% Hanfstein et al. Leukemia. 2012 Mar 26. doi: 10.1038/leu.2012.85

9. Time from onset of imatinib therapy (years) Probability of survival Good risk OS= 93.3% Good risk c-CCyRS= 91.1% Poor risk OS= 93.3% Poor risk c-CCyRS= 91.1% OS comparison p<0.0001 c-CCyRS comparison p =0.0002 Overall survival and current leukaemia free survival based on transcript numbers at 3 months Good risk (n=211) OS= 93% Poor risk (n=68) OS= 57% Marin et al JCO 2012

10. Key questions in CML 1.10% at 3 months seems important. Can we improve outcome by switching drugs? 2.Imatinib is going to be around for a while. We need to work out how best to use it. 3.Can we give more CML patients less treatment, minimise toxicity and stop treatment? –Quality of life, toxicity, safety –Economics –Survival not compromised; ‘cure’ 4.What’s the most cost effective way to treat CML? 5.Can we personalise treatment?

11. Stage 1 Compare first line intervention: IM vs NIL Randomised 1:1 Stage 2 Identify poor responders (e.g >10% BCR- ABL) early: Switch to ponatinib Stage 3 Identify ‘best’ responders later Reduce/stop, as in DESTINY Primary endpoint: MR 3 (MMR) at 3 years Secondary: sustained MR 3 on reduced dose/stop EFS, PFS, OS Health Economics, QoL

12. R R Imatinib Nilotinib Group I Group N Imatinib Ponatinib Nilotinib Stage 1 Randomise (500 to each group) Stage 2 Selective switch (3 months or later) Stage 3 Reduce dose, stop (after minimum 3 years) Primary endpoint MR3 at 3 years Imatinib Ponatinib Nilotinib Aim to reduce and stop (if MR3 for at least 1 year) Aim to reduce and stop (if MR3 for at least 1 year) n=500

13. Stage 3 Identify ‘best’ responders later Reduce/stop Minimum of 3 years: Halve dose if MMR for 1 year Minimum of 4 years: Stop if remain in MMR Primary endpoint: MR 3 (MMR) at 3 years Secondary: sustained MR 3, CMR on reduced dose/stop EFS, PFS, OS Health Economics, QoL DESTINY is the pilot for SPIRIT 3

14. How much is enough?

16. ENESTnd (nilotinib) Cardiovascular Events by 5 Years Y, year. a All events, regardless of relationship to study drug. b Data cutoff: July 27, 2012 (minimum follow-up of 48 cycles). c Events reported between the 48-cycle and 60-month data cutoffs. Nilotinib 300 mg BID (n = 279) Nilotinib 400 mg BID (n = 277) Imatinib 400 mg QD (n = 280) Total, n (%) Y1-4, n b Y5, n c Total, n (%) Y1-4, n b Y5, n c Total, n (%) Y1-4, n b Y5, n c Total patients with CVEs 21 (7.5)184 37 (13.4) 2414 6 (2.1) 42 Ischemic heart disease11 (3.9) 110 24 (8.7) 14105 (1.8) 32 Ischemic cerebrovascular events 4 (1.4) 319 (3.2) 541 (0.4) 10 Peripheral artery disease 7 (2.5) 437 (2.5) 52000 16 Data cutoff: September 30, 2013 CVE, cardiovascular event.

17. PACE (ponatinib 45mg) Vascular Occlusive Events Median time to onset of arterial thrombotic events in CP-CML: 281 (8-952) days Median time to onset of venous thromboembolic events in CP-CML: 604 (62-802) days Overall, 5 pts died of a vascular occlusive events considered related to ponatinib Treatment-Emergent CP-CML (N=270) AP-CML (N=85) BP-CML (N=62) Ph+ ALL (N=32) Total (N=449) AE n (%) SAE n (%) AE n (%) SAE n (%) AE n (%) SAE n (%) AE n (%) SAE n (%) AE n (%) SAE n (%) Arterial thrombotic61 (23)44 (16)17 (20)12 (14)6 (10)3 (5)2 (6) 86 (19)61 (14) Cardiovascular 27 (10)20 (7)12 (14)7 (8)3 (5)2 (3)1 (3)0 (0)43 (10)29 (7) Cerebrovascular 27 (10)18 (7)5 (6)4 (5)0 (0) 1 (3) 33 (7)23 (5) Peripheral vascular 23 (9)14 (5)3 (4)2 (2)3 (5)1 (2)2 (6) 31 (7)19 (4) Venous thromboembolic11 (4)7 (3)3 (4)1 (1)6 (10)5 (8)3 (9)1 (3)23 (5)14 (3) Total vascular occlusive events 67 (25)49 (18)19 (22)13 (15)10 (16)7 (11)5 (16)3 (9)101 (23)72 (16) Exposure-Adjusted Incidence (Number of Patients With Events per 100 Patient-Years) by Disease Group Cumulative exposure, patient-years 480.8133.831.812.7 Exposure-adjusted incidence of vascular occlusive events 13.910.214.29.731.422.039.323.6 Data as of 6 Jan 2014 Kantarjian et al, J Clin Oncol 32:5s, 2014 (suppl; abstr 7081).

18. EPIC (ponatinib45mg) Vascular Occlusive Events Time to onset of vascular occlusive events: –Ponatinib 10-233 days; imatinib 2-156 days At the time of termination, prespecified DMC threshold for mandatory risk/benefit analysis had not been crossed: serious grade 3/4 ischemic events in ponatinib vs imatinib arm were 5 and 1, respectively, P=0.2142 Ponatinib N=154 n (%) Imatinib N=152 n (%) AESAEAESAE Arterial thrombotic events11 (7)10 (7)3 (2)1 (0.7) Cardiovascular5 (3)4 (3)1 (0.7)0 Cerebrovascular3 (2) 1 (0.7) Peripheral vascular3 (2) 1 (0.7)0 Venous thromboembolic events1 (0.6) 00 Total vascular occlusive events12 (8)11 (7)3 (2)1 (0.7)

19. Cardiovascular uncertainty… Which events? –IHD, ‘MACE’, PAOD, CVEs, TIAs etc –Arterial/venous Confounding variables, dose, exposure –Diabetes, smoking, lipids etc Incomplete data Poor understanding of the biology But there’s something going on…

20. CV risk & SPIRIT 3 Excluded previous MI & CVA –Previous arterial surgery, CABG More CV screening and monitoring: QRISK2 –Especially glucose, lipids, BP –Intervene if risk identified Ponatinib 30mg, reduce to 15mg at MR3 No aspirin (unless otherwise indicated) No statins (unless otherwise indicated)

21. www.qrisk.org QRISK 2

22. www.qrisk.org

24. CV risk management Collect/monitor additional risk factors –Ethnicity, post code, smoking, diabetes, heart/kidney disease, AF, BP, rheumatoid, lipids, BMI, thyroid function Blood pressure Haematologists monitor, GPs manage –HbA1C, lipids, BP

25. riskbenefit

26. Some practicalities Imatinib and nilotinib via NHS Ponatinib available free for up to 10 years We’ll use generic imatinib in 2016 Home delivery of medication for all Immediate and long term savings for your trust Marrows only on switch Biobank samples (inc. mouthwash)

27. Some practicalities Imatinib and nilotinib via NHS Ponatinib available free for up to 10 years We’ll use generic imatinib in 2016 Home delivery of medication for all Immediate and long term savings for your trust Marrows only on switch Biobank samples (inc. mouthwash)

28. Treatment at home

29. Some practicalities Imatinib and nilotinib via NHS Ponatinib available free for up to 10 years We’ll use generic imatinib in 2016 Home delivery of medication for all Immediate and long term savings Marrows only on switch Biobank samples (inc. mouthwash)

30. Timelines MHRA & REC approval Sept 2013 Voluntary hold October 2013 Consultation, revision of protocol –Q1/2 2014 Return to regulators – now Open Q4, 2014 1,000 patients will take 4-5 years

31. www.spirit-cml.org

33. SPIRIT 2 SPIRIT 3 Stephen O’Brien Professor of Haematology Northern Institute for Cancer Research Newcastle University Medical School Happy to send you my slides, drop me a line: stephen.o’brien@ncl.ac.uk The Newcastle Hospitals NHS Foundation Trust www.spirit-cml.org

34. R R Imatinib Nilotinib Group I Group N Imatinib Ponatinib Nilotinib Stage 1 Randomise (500 to each group) Stage 2 Selective switch (3 months or later) Stage 3 Reduce dose, stop (after minimum 3 years) Primary endpoint MR3 at 3 years Imatinib Ponatinib Nilotinib Aim to reduce and stop (if MR3 for at least 1 year) Aim to reduce and stop (if MR3 for at least 1 year) n=500

35. www.mpdmeetings.org