Imatinib & Ponatinib. Two ends of the spectrum in 2016s reality

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Julie Stevenson
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1 Imatinib & Ponatinib Two ends of the spectrum in 2016s reality

2 CML 2016 Benefits & risks Steve O Brien CML Horizons, May 2016

3 Disclosures Research funding, participation in company trial, speaker, consultant, meeting assistance (last 3 years): Ariad, BMS, Novartis, Pfizer, Gilead, Sanofi Aventis Member: NCRI Clinical Studies Group NCRI CML Working Group NICE Technology Appraisal Committee C NHS Cancer Drug Fund Panel Co-Chair Employer: Newcastle University Stock: none

4 Benefits

5 Risks

6 Where next?

7 Imatinib Development License TKIs in CML NICE approved (UK) Off patent 2016 Dasatinib Nilotinib Bosutinib (radotinib) Ponatinib Cancer Drug Fund CDF: Cancer drug fund; CML: Chronic myeloid leukaemia; NICE: National Institute for Health and Care Excellence The following websites were last accessed in April 2015: 1) NICE Imatinib: 2) EMA Sprycel: 3) NICE nilotinib: 4) NICE bosutinib: 5) NICE ponatinib:

8 Benefits

9 Imatinib 1999 Safe Effective Cost effective

10 814 patients in total Recruitment closed Feb hospitals set up,145 recruited patients

5 Response 58/406 (14.3%) Total Cohort n=812 Dasatinib n=406 Off treatment 116/406 (28.

11 SPIRIT 2: PCR data at 24 months Imatinib n=406 On treatment 246/406 (60.6%) Off treatment 160/406 (39.4%) Achieved MR3 Response 187/406 (46.0%) Achieved MR4.5 Response 58/406 (14.3%) Total Cohort n=812 Dasatinib n=406 Off treatment 116/406 (28.6%) On treatment 290/406 (71.4%) Δ = 11.5% p<0.001 Achieved MR3 Response 234/406 (57.5%) Δ = 5.9% P=0.026 Achieved MR4.5 Response 82/406 (20.2%) April 2015

12 DASISION: OS & PFS Dasatinib 100 mg OD (n=259) Imatinib 400 mg OD (n=260) Hazard ratio (95% CI) Total number of deaths, n Estimated 5-year OS, % (95% CI) 91 (87 94) 90 (85 93) 1.01 ( ) Estimated 5-year PFS, % (95% CI) 85 (80 89) 86 (80 89) 1.06 ( ) Causes of death were cardiovascular disease (2 dasatinib, 1 imatinib); disease progression (9 dasatinib, 17 imatinib); infection (11 dasatinib, 1 imatinib); other malignancy, septic shock and cardiac failure, multi-organ failure, and whole body swelling (1 each dasatinib); stem cell transplantation complications and unknown (2 each imatinib); severe chest pain, clinical deterioration and decrease in performance status, and fatal bleeding (1 each imatinib) On-study treatment and in follow-up after discontinuation of randomized treatment. CI, confidence interval; OS, overall survival; PFS, progression-free survival. Cortes J, et al. Presented at: 2014 Annual Meeting of ASH; San Francisco, CA. Oral presentation.

13 ENESTnd: OS and CML-Related Deaths Nilotinib 300 mg BID (n = 282) Nilotinib 400 mg BID (n = 281) Imatinib 400 mg OD (n = 283) Total deaths, n a KM-estimated 5-year OS, % Hazard ratio vs imatinib (95% CI) 0.80 ( ) 0.44 ( ) P value vs imatinib Deaths in patients with advanced CML, n b KM-estimated 5-year freedom from death due to advanced CML, % Hazard ratio vs imatinib (95% CI) 0.37 ( ) 0.24 ( ) P value vs imatinib a OS events included death from any cause at any time (on core or extension treatment or during follow-up after treatment discontinuation). b Patients for whom the principal cause of death was either study indication or unknown or not reported but occurred subsequent to a documented progression to AP/BC. Hughes T, et al. Oral presentation at the Annual Meeting of EHA 2014, Abstract S677. Data cutoff: September 30,

Active against T315I mutant Unique approach

residue Potent activity against an array of

14 Ponatinib: A Pan-BCR-ABL Inhibitor Rationally designed inhibitor of BCR- ABL Active against T315I mutant Unique approach to accommodating gatekeeper isolucine residue Potent activity against an array of BCR-ABL variants Once-daily oral activity Half-life 22 hours Also targets other therapeutically relevant kinases: Inhibits FLT3, FGFR, VEGFR and PDGFR, and c-kit T315I gatekeeper residue O Hare T, et al. Cancer Cell. 2009;16:

15 Ponatinib: PACE study

16 Duration of Response to Ponatinib in CP-CML 83% of responders estimated to remain in MCyR at 36 months a Failed to meet criteria for MCyR in 2 consecutive assessments 28 days apart, or discontinued after a single assessment in which the criteria for MCyR were not met b Kaplan-Meier estimate

17 Risks

19 Treatment-Emergent AE n (%) CP-CML (N=270) SAE n (%) AE n (%) PACE (ponatinib 45mg) Vascular Occlusive Events AP-CML (N=85) SAE n (%) AE n (%) BP-CML (N=62) SAE n (%) AE n (%) Ph+ ALL (N=32) SAE n (%) AE n (%) Total (N=449) Arterial thrombotic 61 (23) 44 (16) 17 (20) 12 (14) 6 (10) 3 (5) 2 (6) 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) 0 (0) 1 (3) 1 (3) 33 (7) 23 (5) Peripheral vascular 23 (9) 14 (5) 3 (4) 2 (2) 3 (5) 1 (2) 2 (6) 2 (6) 31 (7) 19 (4) Venous thromboembolic 11 (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 Exposure-adjusted incidence of vascular occlusive events SAE n (%) 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 Kantarjian et al, J Clin Oncol 32:5s, 2014 (suppl; abstr 7081). Data as of 6 Jan 2014

20 ENESTnd (nilotinib) Cardiovascular Events by 5 Years Nilotinib 300 mg BID (n = 279) Nilotinib 400 mg BID (n = 277) Imatinib 400 mg QD (n = 280) Total, n (%) Y1-4, Y5, n b n c Total, n (%) Y1-4, Y5, n b n c Total, n (%) Y1-4, Y5, n b n c Total patients with CVEs 21 (7.5) (13.4) (2.1) 4 2 Ischemic heart disease 11 (3.9) (8.7) (1.8) 3 2 Ischemic cerebrovascular events 4 (1.4) (3.2) (0.4) 1 0 Peripheral artery disease 7 (2.5) (2.5) 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. CVE, cardiovascular event.

PACE: Probability of Arterial Thrombotic Events Risk factors significantly associated with arterial thrombotic AEs: - Older age (p<0.0001) - History of diabetes (p=0.

21 PACE: Probability of Arterial Thrombotic Events Risk factors significantly associated with arterial thrombotic AEs: - Older age (p<0.0001) - History of diabetes (p=0.0003) - Higher dose intensity to time of first event (p=0.0009) - History of ischemia (p=0.0087) - Longer time since diagnosis (p=0.0228) - Higher baseline neutrophils (p=0.0466) - Higher baseline platelets (p=0.0276) Each 15-mg reduction in average daily dose intensity is predicted to lead to approximately 33% reduction in the risk of an arterial thrombotic event Includes all patients with baseline data available (N=441); the area shaded in orange represents the 95% CI. Hochhaus, et al. J Clin Oncol ,5s: 7084.

22 Where next?

24 5-Year Outcomes by Molecular Response at 3 Months Dasatinib 100 mg OD (n=259) Imatinib 400 mg OD (n=260) BCR-ABL at 3 Months 10% (84%) >10% (16%) P value 10% (64%) >10% (36%) P value Estimated 5-year OS, % Estimated 5-year PFS, % Estimated 5-year TFS, % < < On-study treatment and in follow-up after discontinuation of randomized treatment. TFS, transformation-free survival. Cortes J, et al. Presented at: 2014 Annual Meeting of ASH; San Francisco, CA. Oral presentation.

25 risk benefit drug? dose?

26 Stage 1 Compare first line intervention: Imatinib vs 2 nd generation Stage 2 Identify partial 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

Selective switch for poor response (3, 12, 18 months) Safety optimisation

Imatinib 400 Hi Lo Ponatinib 30 Intolerance: Clinical Review Panel

Other Nilotinib 600 Ponatinib 15 if MR3 Aim to reduce and stop (if MR3 for

27 Selective switch for poor response (3, 12, 18 months) Safety optimisation Primary endpoint: 3 years n=500 Imatinib 400 Imatinib 400 QRISK2 R Imatinib 400 Hi Lo Ponatinib 30 Intolerance: Clinical Review Panel Nilotinib 600 Lo Hi Nilotinib 600 Ponatinib 30 Ponatinib 15 if MR3 Other Other Nilotinib 600 Ponatinib 15 if MR3 Aim to reduce and stop (if MR3 for at least 1 year) 1G Group 2G Group n=500 Dasatinib 100 Hi Lo Dasatinib 100 Dasatinib 100

29 SPIRIT 3 & CV risk QRISK2 at entry Drug stratification 20% 10yr risk threshold for intervention Lipids HbA1C BP Haematologists pick up, GP manages

30 Selective switch for poor response (3, 12, 18 months) Safety optimisation Primary endpoint: 3 years n=500 Imatinib 400 Imatinib 400 QRISK2 R Imatinib 400 Hi Lo Ponatinib 30 Intolerance: Clinical Review Panel Nilotinib 600 Lo Hi Nilotinib 600 Ponatinib 30 Ponatinib 15 if MR3 Other Other Nilotinib 600 Ponatinib 15 if MR3 Aim to reduce and stop (if MR3 for at least 1 year) 1G Group 2G Group n=500 Dasatinib 100 Hi Lo Dasatinib 100 Dasatinib 100

32 CML 2016: benefits & risks Imatinib vs 2 nd generation: Higher rates of PCR response with 2 nd gen No difference in overall survival Marginal difference in progression-free survival Newer TKIs have more/different toxicity Poor understanding of mechanism Balance of risk and benefit; optimal dose? Most (but not all) patients do well on imatinib Who should switch to 2 nd /3 rd line drugs? SPIRIT 3 2 nd gen: maybe more patients can stop or dose reduce? Increasingly cost, risk/benefit will drive choice

33 CML 2016 Risks & benefits Steve O Brien CML Horizons, May 2016

SESSION III: Chronic myeloid leukemia PONATINIB. Gianantonio Rosti, MD, Department of Hematology, University of Bologna, Italy

SESSION III: Chronic myeloid leukemia PONATINIB Gianantonio Rosti, MD, Department of Hematology, University of Bologna, Italy Ponatinib A Pan-BCR-ABL Inhibitor Rationally designed inhibitor of BCR- ABL