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CML TKIs – where are we up to? Steve O ’ Brien

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. Thanks to David Marin. 2G drug trials.

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CML TKIs – where are we up to? Steve O ’ Brien

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  1. CML TKIs – where are we up to? Steve O’Brien Northern Institute for Cancer Research Newcastle University Medical School Newcastle, March 2013

  2. Second generation TKIs are just better… … no brainer?

  3. TKIs in CML, the gold rush Thanks to David Marin

  4. 2G drug trials • DASISION, SPIRIT 2 • Dasatinib • ENESTnd • nilotinib • BELA • Bosutinib • EPIC • Ponatinib (3G??)

  5. www.spirit-cml.org www.spirit-cml.org

  6. ENESTnd * 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

  7. Dasatinib 100 mg QD (n=259) Imatinib 400 mg QD (n=260) 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 • N=519 • 108 centers • 26 countries Follow-up 5 years Randomized* *Stratified by Hasford risk score

  8. 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 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

  9. Nilotinib Leads to Faster / Deeper Responses p<0.0001 p<0.0001 % MMR

  10. Dasatinib is Superior to Imatinib in CML-CP: MMR Rates P<0.00003 P<0.0001 MMR (%) Mo 3 Mo 6 Mo 9 Mo 12 Any time

  11. Early efficacy of nilotinib and dasatinib in comparison to imatinib 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

  12. 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) Dasatinib 100 mg QD Imatinib 400 mg QD Progressed to AP/BP (n) 3.5% 1.9%

  13. Reduced Overall Progression to AP/BC number of patients 3.9% p=0.0037* p=0.0095* 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

  14. Side effects

  15. PFS is similar in patients with CCyR regardless of depth of molecular response Druker BJ, et al. NEJM, 2006;355(25):2408-17.

  16. CML @ ASH • ‘Even better’ responses • 2 possible strategies • Give more, give less! • Stopping (reducing) • From CMR not MMR • 2nd gen data – early days

  17. 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

  18. TKIs in CML Off patent Imatinib Development NICE approved License Dasatinib Nilotinib ?? Bosutinib ?? Ponatinib 2000 2005 2010 2015 (European license)

  19. 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

  20. 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

  21. NICE • Bosutinib • considered June 2013 • FAD approx Oct 2013 • Ponatinib • no time frame as yet

  22. 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

  23. ENESTnd study. Kantarjian et al. Lancet Oncology 2011: 12: 841

  24. ‘Isotypes’ of Otto Neurath and Gerd Arntz Thanks to David Spiegelhalter

  25. ENEST nd (nilotinib trial)Progression to AP/BC at 24 months Imatinib 4001 n=283: 12 events (4.2%) Nilotinib 3002 n=282: 2 events (0.7%) Kantarjian et al. Lancet Oncology 2011: 12: 841

  26. ENEST nd (nilotinib trial)All deaths at 24 months Imatinib 4001 n=283: 11 events (3.8%) Nilotinib 3002 n=282: 9 events (3.2%) Kantarjian et al. Lancet Oncology 2011: 12: 841

  27. How many patients with CML? £290M per year £464M per year £???? USA: 311, 591,917 UK: 62,218,761 Huang et al. Cancer 2011: doi: 10.1002/cncr.26679

  28. NHS spending on CML • In next 10 years… • Between £290M - £460M per annum • Over next ten years… £2-3 billion?

  29. Difficult times… So can we afford all these great new developments in CML?

  30. Second generation TKIs are just better… … no brainer?

  31. Will there be any more???

  32. 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

  33. So what about generics?2016 in UK

  34. 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

  35. So what about generics?2016 in UK

  36. CML TKIs – where are we up to? Steve O’Brien Northern Institute for Cancer Research Newcastle University Medical School Newcastle, March 2013

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