Choosing wisely – Is there a best TKI for CML?

1. Choosing wisely –Is there a best TKI for CML? Richard A. Larson, MD University of Chicago March 2014

2. Disclosures • Research support to the University of Chicago • Ariad • Bristol Myers Squibb • Novartis • Pfizer • Consultancies & Honoraria • Bristol Myers Squibb • Novartis • Pfizer

3. Case History 49-year-old man with mild fatigue Mild splenomegaly (2 cm) on exam WBC 52,000/uL (1% blasts, 2% basophils) Hemoglobin 11 g/dL Platelets 520,000/uL RT-PCR for BCR-ABL: positive Bone marrow: 95% cellular with with granulocytic hyperplasia Cytogenetics: 46 XY, t(9;22)(q34;q11) Diagnosis: chronic myeloid leukemia in chronic phase Sokal risk score = 0.8 (Low) 3

4. Is there a best TKI for this patient?Is a complete cytogenetic response (CCyR) sufficient, or should CML patients try to achieve a Major Molecular Response (MMR) or better?

5. Survival is the most important endpoint.What are the best surrogates? “It may very well bring about immortality . . . but it will take forever to test . . .”

6. Treatment Objectives Favorable outcomes: • CHR (complete hematologic remission) • CCyR (complete cytogenetic remission) • MMR (major molecular remission) • MR4.0 (4-log reduction) • MR4.5(4.5-log reduction) • Low toxicity (adherence) • Low cost (both for the drug and for monitoring) • Cure (discontinuation) Unfavorable outcomes: • Loss of CHR • Loss of CCyR • ?Loss of MR? • Progression (AP/BC) • High toxicity • Early • Late complications • High cost • Death

7. Randomized Clinical Trials • Best available evidence • “the gold standard” • Even better is agreement between multiple studies

8. First-line Randomized Trials

9. Randomized Clinical Trials • Best available evidence • Even better is agreement between multiple studies • Limitations • Highly selected patients with minimal co-morbidities • Large trials include smaller subsets with various risk characteristics • Rigorous follow-up on study emphasizes adherence (both to treatment and monitoring) • Early endpoints (CCyR, MMR)

10. IRIS: Cumulative Best Response at 60 Months on First-line Imatinib 96% 98% 92% 85% 84% 87% 80% 69% Druker BJ, et al. N Engl J Med. 2006;355(23):2408-2417.

11. IRIS: CML patients with a major molecular response after 12 months of imatinib had an excellent outcome over 5 years Estimated rate at 60 months Response at 12 months  n=136 100% n= 94 95%n=138 88%  CCyR with >=3 log red. p=0.007 p<0.001 CCyR with <3 log red. No CCyR

12. IRIS trial with imatinib:Event-free Survival at 7 years by BCR/ABL levels at 6 and 12 months 6 Months 12 Months ~ MMR ~ CCyR ~ MMR ~ CCyR EFS included loss of CHR, loss of MCyR, progression to AP/BC, and death on study. Hughes T P et al. Blood 2010;116:3758-3765

13. Rate of major molecular response (MMR; 3-log reduction) and the depth of molecular response increase over time 100 90 80 ≤0.1% (MMR) 70 ≤0.01% (MR4.0) 60 % of available samples 50 40 30 20 10 0 0 3 6 9 12 15 18 21 24 30 36 42 48 54 60 66 72 78 84 IRIS: Molecular Response Rates BCR-ABL% (International Scale) Sample analysis time points (months) S. O’Brien et al. ASH 2008; IRIS 7 year update

14. Cumulative Incidence of MMR* Nilotinib 300 mg BID (n = 282) Nilotinib 400 mg BID (n = 281) Imatinib 400 mg QD (n = 283) 100 By 1 Year† By 4 Years† By 5 Years† 90 77%, P < .0001 80 76%, P < .0001 55%, P < .0001 77%, P < .0001 70 73%, P < .0001 Δ 17% 60 Δ 17%-20% 60% 56% Patients With MMR, % 50 51%, P < .0001 40 Δ 24%-28% 30 27% 20 10 0 0 1 2 3 4 5 6 Time Since Randomization, Calendar Years * Major molecular response; BCR-ABLIS ≤ 0.1%. † Cumulative response rates reported consider each year to consist of 12, 28-day cycles.

15. MR4.5 by 5 Years* According to Sokal Risk Score P = .0004 P = .008 P < .0001 P = .01 P = .01 P = .004 n = 104 103 103 101 101 100 78 78 78 (n = 283) (n = 282) (n = 281) *By Cycle 60 (28 days per cycle).

16. ENESTnd: More rapid early responses occur with nilotinib than imatinib in all 3 Sokal risk groups T Hughes et al. 2013, in press

17. ENESTnd: Overall Survival by BCR-ABL Levels at 3 Months (Nilotinib 300 mg BID) 100 97.2% P = .63 96.5% P = .02 90 86.7% 80 70 OS rates at 4 years for ≤10% vs >10% BCR-ABL at 3 months: 97% vs 87%; P = .01 60 % Alive 50 40 Pat Evt Cen 30 ≤1% 145 5 140 20 >1% – ≤10% 89 2 87 >10% 24 3 21 10 Censored observations 0 57 60 0 3 6 9 12 15 18 21 24 27 30 33 36 39 42 45 48 51 54 Time Since Randomization (Months) G Saglio et al. ASCO 2013 Data cut-off: 27Jul2012.

18. ENESTnd: Overall Survival by BCR-ABL Levels at 3 Months (Imatinib) 100 100% P = .10 95.3% 90 P < .0001 83.6% 80 70 OS rates at 4 years for ≤10% vs >10% BCR-ABL at 3 months: 99% vs 84%; P < .0001 60 % Alive 50 40 Pat Evt Cen 30 ≤1% 43 2 41 20 >1% – ≤10% 133 1 132 >10% 88 14 74 10 Censored observations 0 57 60 0 3 6 9 12 15 18 21 24 27 30 33 36 39 42 45 48 51 54 Time Since Randomization (Months) G Saglio et al. ASCO 2013 Data cut-off: 27Jul2012.

19. DASISION: Cumulative Incidence of MMR(BCR-ABL/ABL ≤ 0.1%) Hochhaus A, et al. J Clin Oncol 2012; 30(15 Suppl): Abstract 6504.

20. DASISION: OS According to BCR-ABL Level at 6 Months Dasatinib 100 mg QD 89% had ≤10% BCR-ABL Imatinib 400 mg QD 83% had ≤10% BCR-ABL 100 100 80 80 60 60 Patients not progressed (%) 40 40 20 20 0 0 0 6 12 18 24 30 36 42 0 6 12 18 24 30 36 42 Months Months G Saglio et al. ASH 2012. Abstract #1675

21. DASISION and ENESTnd, 3 Year Follow Up *vs imatinib, P < 0.0001; vs imatinib, P < 0.003; ‡vs imatinib, P = 0.05; §vs imatinib, P = 0.007. Hochhaus et al. J Clin Oncol 2012; 30 (15 Suppl): Abstract 6504 Kantarjian H, et al. J Clin Oncol 2012; 30 (15 Suppl): Abstract 6509. Larson RA, et al. Leukemia 2012; 26(10): 2197-2203

22. 2013 European LeukemiaNet Recommendations for newly diagnosed CML Baccarani et al. Blood 2013

23. Adverse Events / Management Nuances Initial Grade 3/4 Myelosuppression

24. Ponatinib • WARNING: ARTERIAL THROMBOSIS and HEPATOTOXICITY • See full Prescribing Information for complete boxed warning • Arterial Thrombosis: • Cardiovascular, cerebrovascular, and peripheral vascular thrombosis, including fatal myocardial infarction and stroke have occurred in ponatinib-treated patients. In clinical trials, serious arterial thrombosis occurred in 8% of ponatinib-treated patients. Interrupt and consider discontinuation of ponatinib in patients who develop arterial thrombotic events • Hepatotoxicity: • Hepatotoxicity, liver failure and death have occurred in ponatinib-treated patients. Monitor hepatic function prior to and during treatment. Interrupt and then reduce or discontinue ponatinib for hepatotoxicity

25. SAEs of arterial thromboembolism, including arterial stenosis, were observed typically in patients with cardiovascular risk factors.

26. Is there a best TKI for CML? Safety Efficacy CCyR MMR or better Guidelines Expert Recommendations Individual patient characteristics Co-morbidities Concomitant medications Convenience Cost Monitor response

27. What are the remaining questions in CML? • Is there a best TKI for initial therapy? • Can early response assessment be used to optimize long-term outcomes? Probably YES, but it has not yet been proven that switching therapies helps the slow early responders. • Is life-long treatment required? Probably NO (but this remains to be proven in prospective discontinuation trials)