CML Drugs and their Availability in the UK. Jane Apperley

Transcription

1 CML Drugs and their Availability in the UK Jane Apperley

2 Drugs used in the treatment of CML Traditional chemotherapy Busulphan Hydoxycarbamide Interferon-alpha Omacetaxine Tyrosine kinase inhibitors Imatinib Others Dasatinib Nilotinib Bosutinib Ponatinib

3 Drugs development Through clinical trials Phase I: safety Phase II: efficacy Phase III: comparison with previous best therapy Licensing European Medicines Agency (EMA): Europe Food and Drug Administration (FDA): USA NICE Cancer Drug Fund

4 Drug availability in the UK Licensed 1 st line: imatinib, dasatinib, nilotinib 2 nd line: imatinib, dasatinib, nilotinib, bosutinib, ponatinib NICE 1 st line : imatinib, nilotinib 2 nd line : nilotinib Cancer Drug Fund Bosutinib, dasatinib, ponatinib Not available Omacetaxine

5 Why might you need another drug? Resistance Primary: failure to achieve MMR and/or CCYR Secondary: loss of MMR and/or CCyR Predictor of probable resistance RQ-PCR level >10% at 3 months Intolerance Grade 3/4 (severe) side effects Chronic grade 2 debilitating side effects Resistance and intolerance

6 Mutations

7 Outcome According to 3 Month PCR: Imatinib Outcome Cut-off (%) Number of patients at risk Eight years outcome probability P value Overall survival 9.84 > p< Progression free survival 9.54 > p< Event free survival 9.84 > p< CCyR 8.58 > p< MMR 2.81 > p< MR > p< Marin et al. JCO. 2011;30:232-38

8 Outcome According to 3 and 6 Month PCR: Dasatinib n CCyR MMR CMR month transcript >10% 11 p< % p< % p< % 10% % 79.8% 45.7% 6 month transcript >1% 23 p< % p< % p< % 1% % 89.1% 52.2% Marin et al. Blood. 2012;120:291-4

9 Drugs used in the treatment of CML Nilotinib

10 ENESTnd 4-Year Update 1 st line Nilotinib - ENESTnd: Cumulative Incidence of MMR Patients With MMR, % By 1 Year 55%, P <.0001 Δ 51%, 24%-28% P < % Nilotinib 300 mg BID Nilotinib 400 mg BID Imatinib 400 mg QD n By 4 Years 76%, P < Time Since Randomisation, Months 73%, P <.0001 Δ 17%-20% 56% 60 *Equivalent to BCR-ABL transcript levels of 0.1% expressed on the International Scale (BCR-ABL IS ) Data cutoff: July Kantarjian HM, et al. Blood. 2012;120(21):[abstract 1676].

11 Nilotinib in CML-CP: Responses (N=321) Kantarjian et al. Haematologica (14th Annual Congress of the EHA). 2009;94(s1): Abstract 0627.

12 Pros and cons: nilotinib Pros 1 st line: faster deeper responses 2 nd line: 40% CCyR in imatinib resistance (also mutations) Approved by NICE Cons Not effective in all imatinib resistance (NB some mutations) Side effects» Low blood counts» Rash» Abnormal liver function tests» Thrombosis Cost

13 Mutations

14 Drugs used in the treatment of CML Dasatinib

15 DASISION 3-Year Update Dasatinib - DASISION Cumulative Incidence of MMR 100 Dasatinib 100 mg QD Imatinib 400 mg QD % With MMR* P< Fold higher likelihood of achieving MMR with dasatinib; HR=1.62 ( ) By 1 year 46% By 2 years 64% 46% By 3 years 68% 55% 20 23% Months *BCR-ABL 0.1% Jabbour J, et al. Haematologica. 2012;97(s1) [abstract 1106].

16 Response to dasatinib in CML-CP Shah et al. JCO. 2008;26:3204.

17 Pros and cons: dasatinib Pros 1 st line: faster deeper responses 2 nd line: 40% CCyR in imatinib resistance (also mutations) Available via Cancer Drugs Fund Cons Not approved by NICE Not effective in all imatinib/nilotinb resistance (NB some mutations) Side effects» Low blood counts» Rash» Fluid retention, particularly in between membranes lining the lungs» Bleeding Cost

18 Mutations

19 Drugs used in the treatment of CML Bosutinib

20 Bosutinib as First-Line Therapy BELA Study Design Phase 3 open-label trial in newly diagnosed CP CML N= sites 31 countries Randomization is stratified based on Sokal risk score and geographical regions. R A N D O M I Z E Bosutinib 500 mg/day n=250 Imatinib 400 mg/day n=252 5-year follow-up 5-year follow-up 1-year analysis Key eligibility criteria: cytogenic diagnosis of Philadelphia chromosome-positive (Ph+) CP CML 6 months prior, no prior therapy other than hydroxyurea or anagrelide Primary endpoint: complete cytogenic 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 Brümmendorf et al, Haematologica. 2012;97(s1) [abstract 0587].

21 Overall Molecular Response in the BELA Trial Probability of molecular response (%) Bosutinib 3-log reduction (MMR) 4-log reduction 4.5-log reduction Imatinib 3-log reduction (MMR) 4-log reduction 4.5-log reduction Time to molecular response (wk) In the BELA trial (ITT population), the rate of molecular response was generally higher at all time points for bosutinib versus imatinib 3-log reduction (MMR) was defined as Bcr-Abl/Abl ratio 0.1% on the International Scale, based on quantitative reverse transcriptase PCR for Bcr-Abl copy number in peripheral blood according to the International Scale and required 3,000 Abl copies; 4-log reduction was defined as Bcr-Abl/Abl ratio 0.01% and required 8,100 Abl copies; and 4.5-log reduction was defined as Bcr-Abl/Abl ratio % and required 25,614 Abl copies. Time to MMR with competing risks of going off treatment (all reasons). Brümmendorf et al. Blood. 2012;120:69

22 Cumulative MMR Rates Over Time by Bcr-Abl/Abl Ratio 10% Versus >10% at Month 3 Probability of MMR (%) Bosutinib Bcr-Abl/Abl ratio 10% at Month 3 Bcr-Abl/Abl ratio > 10% at Month 3 Imatinib Bcr-Abl/Abl ratio 10% at Month 3 Bcr-Abl/Abl ratio > 10% at Month Time since randomization (wk) Evaluable patients had a valid molecular assessment at Month 3. MMR was defined as a Bcr-Abl/Abl ratio 0.1% on the International Scale, based on quantitative reverse transcriptase PCR for Bcr-Abl copy number in peripheral blood according to the International Scale and required 3,000 Abl copies. Time to MMR with competing risks of going off treatment (all reasons). Brümmendorf et al. Blood. 2012;120:69

23 Bosunitib Study 200 Patient Cohort (Total N=570) Patient Group Chronic Phase Second-Line N=288 Chronic Phase Third-Line N=118 Key Efficacy Endpoint Major Cytogenetic Response Major Cytogenetic Response Accelerated Phase 1 prior TKI N=76 Overall Hematologic Response Blast Phase 1 prior TKI N=64 Primary cohort: CP 2nd-Line Imatinib Resistant N=200 CP 2nd-Line Imatinib Intolerant N=88 Ph+ ALL N=24 CP 3rd-Line Dasatinib Resistant N=37 BP CML N=64 CP 3rd-Line Dasatinib Intolerant N=50 CP 3rd-Line Nilotinib Resistant N=27 CP 4th-Line or Nilotinib Intolerant N=4 AP CML N=76

24 Bosutinib for Imatinib Failure Best Cumulative Response to Bosutinib Response, n (%) [95% CI] IM-R (n=195) IM-I (n=91) Total (n=286) Median follow-up (range), mo 41.8 ( ) 39.5 ( ) 41.7 ( ) Hematologic response Evaluable a CHR (86) [80-91] (85) [76-91] (86) [80-91] Cytogenetic response Evaluable a MCyR CCyR PCyR MiCyR (58) [51-66] 88 (48) [41-56] 18 (10) [6-15] 3 (2) [<1-5] (60) [48-70] 42 (51) [40-62] 7 (9) [4-17] 5 (6) [2-14] (59) [53-65] 130 (49) [43-55] 25 (10) [6-14] 8 (3) [1-6] CI, confidence interval; IM-R, imatinib-resistant; IM-I, imatinib-intolerant; CHR, complete hematologic response; MCyR, major cytogenetic response; CCyR, complete cytogenetic response; PCyR, partial cytogenetic response; MiCyR, minor cytogenetic response. a Evaluable patients had received 1 bosutinib dose and had a valid baseline assessment for the corresponding endpoint. Cortes et al. Blood. (ASH Annual Meeting Abstracts), 2012;120:3779

25 Bosutinib for 2GTKI Failure Response I & D (rest) I & D (int) I & N (rest) I & D & N Pt nos CHR 23 (62%) 39 (80%) 19 (76%) 3 (75%) CCyR 7 (19%) 19 (43%) 7 (27%) 2 (50%) PCyR 5 (14%) 2 (5%) 3 (12%) 0 Khoury HJ, et al. Blood. (ASH Annual Meeting Abstracts), Nov 2012; 120: 3785.

26 Pros and cons: bosutinib Pros 1 st line: faster deeper MMR 2 nd line: 40% CCyR in imatinib resistance (also mutations) Available via Cancer Drugs Fund In theory fewer side effects Cons Not approved by NICE Not effective in all imatinib/nilotinb resistance (NB some mutations) Side effects» Low blood counts» Diarrhoea +++ Cost

27 Drugs used in the treatment of CML Ponatinib

28 Ponatinib Phase II: PACE Study Design 449 patients entered between Sep 2010 and Sep 2011 Patients entered into 1 of 6 cohorts No. of Patients Treated CP-CML AP-CML BP-CML Ph+ ALL R/I to dasatinib or nilotinib T315I mutation Total* Primary endpoints: CP-CML: MCyR AP-CML, BP-CML, Ph+ALL: MaHR Secondary endpoints include MMR *Includes 5 patients (3 CP, 2 AP) who were unassigned (post-imatinib, non-t315i) but treated Cortes J, et al. Haematologica. 2012;97(s1):abstract 1104

29 PACE Results Response CP-CML n Response (%) Response Overall # N=267 R/I Cohort N=203 T315I Cohort N=64 CHR* 249 (93) 191 (94) 58 (91) MCyR** 144 (54) 99 (49) 45 (70) CCyR 118 (44) 76 (37) 42 (66) MMR*** 79 (30) 47 (23) 32 (50) *CHR maintained or achieved during study; 103 patients had CHR at baseline **MCyR = primary endpoint ***Patients without a valid baseline MMR assessment, or who meet the criteria for MMR at baseline, counted as non-responders. MMR was assessed on the International Scale using peripheral blood. # Excludes 3 patients who were unassigned (post-imatinib, non-t315i) but treated Cortes J, et al. Haematologica. 2012;97(s1) abstract 1104.

30 Pros and cons: ponatinib Pros Effective in T315I mutations Effective in 40% of patients with nilotinib/dasatinib resistance Cons Not effective in all cases resistance or mutations Side effects» Low blood counts» Rash» Abnormal liver function tests» Thrombosis, seemingly at a higher level than other TKI Cost

31 Anomalies of the Cancer Drug Fund

32 CML Drugs: the future Chronic and accelerated phase Needed in cases of resistance/intolerance to 2-3 TKI?needed to increase likelihood of deep responses/stopping Single agents unlikely TKI in combination with drugs that target other chemical pathways in the cell Blast crisis TKI have short-lasting, if any, efficacy in blast crisis TKI in combination with standard chemotherapy TKI in combination with drugs that target other chemical pathways in the cell

33 Generic tyrosine kinase inhibitors Imatinib Teva Genfatinib Veenat Celonib Imatib Mesylonib Mitinab Shantinib Zoleta Spotnib

34 Mary Alikian, Letizia Foroni, Gareth Gerrard, John Goldman, David Marin, Dragana Milojkovic, George Nteliopoulos, Christos Paliompeis, Alistair Reid, Richard Szydlo, Steve O Brien, Mhairi Copland, and colleagues at Ariad, BMS, Novartis and Pfizer