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Michael J. Mauro MD

Michael J. Mauro MD. Updates from ASH 2010: Second and Third Generation TKIs for CML Compound -Specific Toxicities of TKIs in CML. IRIS 8-Year Update – 37%* Unacceptable Outcome. Main Causes of Treatment Failure With Imatinib Primary resistance Secondary resistance

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Michael J. Mauro MD

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  1. Michael J. Mauro MD Updates from ASH 2010: Second and Third Generation TKIs for CML Compound-Specific Toxicities of TKIs in CML

  2. IRIS 8-Year Update – 37%* Unacceptable Outcome • Main Causes of Treatment Failure With Imatinib • Primary resistance • Secondary resistance • Progression to AP/BC • Toxicities/chronic AEs Deininger M et al. Blood.2009;114(22):462. Abstract # 1126. 2

  3. Annual Event Rates: Imatinib Arm Event: Loss of CHR Loss of MCyR AP/BC Death during treatment AP/BC Estimated EFS at 8 years = 81% 1 progression to AP/BC and 2 non–CML-related deaths occurred in year 8 Deininger M et al. ASH 2009, Poster 1126.

  4. Study Design and Endpoints in ENESTnd Randomized* N=846 217 centers 35 countries Nilotinib 300 mg BID, n=282 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/BCon study treatment, OS including follow-up *Stratification by Sokal risk score. Hughes T et al. ASH 2010, Abstract #207.

  5. Patient Disposition in ENESTnd *Investigator assessment of criteria. †Patients with suboptimal response were required to discontinue nilotinib 300 mg BID, while those receiving nilotinib 400 mg BID could remain on study Data cut-off: 20Aug2010. Hughes T et al. ASH 2010, Abstract #207.

  6. Cumulative Incidence of MMR* in ENESTnd n Nilotinib 300 mg BID 282 Nilotinib 400 mg BID 281 Imatinib 400 mg QD 283 100 90 By 24 months 71%, P<0.0001 80 By 12 months 55%, P<0.0001 70 60 67%, P<0.0001 % With MMR Δ23%-27% 50 51%, P<0.0001 40 Δ24%-28% 44% 30 20 27% 10 0 0 3 6 9 12 15 18 21 24 27 30 33 Time Since Randomization (Months) Data cut-off: 20Aug2010. *ITT population. Hughes T et al. ASH 2010, Abstract #207.

  7. CCyR Rates* by 24 Months in ENESTnd P=0.0018 P=0.016 n=282 n=281 n=283 Data cut-off: 20Aug2010. *ITT population. Hughes T et al. ASH 2010, Abstract #207.

  8. Progression to AP/BC* in ENESTnd P=0.0059 P=0.0196 0.7% 1.1% 4.2% n=282 n=281 n=283 • Progression-free survival: 98.0% with nilotinib 300 mg BID, 97.7% with nilotinib 400 mg BID, and 95.2% with imatinib 400 mg QD (NS) Data cut-off: 20Aug2010. *ITT population. Hughes T et al. ASH 2010, Abstract #207. 8

  9. Overall Grade 3/4 Myelosuppression Any Time on Study in ENESTnd n=279 n=277 n=280 Data cut-off: 20Aug2010. Hughes T et al. ASH 2010, Abstract #207.

  10. Study Drug-Related Nonhematologic Adverse Events (≥10% in Any Group) in ENESTnd Data cut-off: 20Aug2010. Hughes T et al. ASH 2010, Abstract #207. 10

  11. QTcF Changes in ENESTnd • All maximum changes occurred within 6 months of therapy initiation • 3 drug-related events of syncope: 1 patient in each arm; not attributed to QT prolongation • No episode of torsades de pointes or sudden death • At the 24-month data cut-off, 1 patient in the imatinib arm had a QTcF >500 msec, but no patient in any of the nilotinib arms had QTcF >500 msec • No patient had a decrease in LVEF <45% WARNING: QT PROLONGATION AND SUDDEN DEATHS TASIGNA prolongs the QT interval. Sudden deaths have been reported in patients receiving TASIGNA. TASIGNA should not be used in patients with hypokalemia, hypomagnesemia, or long QT syndrome. Hypokalemia or hypomagnesemia must be corrected prior to TASIGNA administration and should be periodically monitored. Drugs known to prolong the QT interval and strong CYP3A4 inhibitors should be avoided. Patients should avoid food 2 hours before and 1 hour after taking dose. A dose reduction is recommended in patients with hepatic impairment. ECGs should be obtained to monitor the QTc at baseline, 7 days after initiation, and periodically thereafter, as well as following any dose adjustments. *Not associated with clinical signs or symptoms of arrhythmia. Larson RA et al. ASH 2010, Abstract 2291. Hughes T et al. ASH 2010, Abstract 207. TASIGNA PI 2010. 11

  12. GIMEMA* (CML0307): Study Design RostiG et al. ASH 2010, Abstract 359. • Open-label, multicenter, phase 2 • Nilotinib 400 mg twice daily • Endpoints • Primary • CCyR rate at 1 year • Secondary • Molecular response

  13. GIMEMA* 3-Year Update: Complete Cytogenetic Response Rates Only 1 patient had a confirmed loss of CCyR N=73 (ITT) Months RostiG et al. ASH 2010, Abstract 359.

  14. GIMEMA 3-Year Update: Survival Rates Overall Survival Progression-Free Survival 97% 97% 100 100 100 100 80 80 80 80 60 60 60 60 40 40 40 40 20 20 20 20 0 0 0 0 0 0 0 0 12 12 12 12 24 24 24 24 36 36 36 36 Failure-Free Survival Event-Free Survival 97% 91% Failures: 2009 ELN criteria. Events: failure, or treatment discontinuation for any reason. RostiG et al. ASH 2010, Abstract 359. 14

  15. Summary of GIMEMA 3-Year Update Rosti G et al. Haematologica. 2010;95(s2):459 [abstract 1114] (oral). Only 1 patient with a progression at 3 years Molecular responses are stable after a median follow-up of 3 years CMR (≤0.01%) by 36 months is 57% Nilotinib (400 mg BID) safety profile unchanged with longer follow-up Tolerability with nilotinib 400 mg BID improves over time; 92% of patients remain on nilotinib Supports importance of maintaining planned starting dose 15

  16. Dasatinib Clinical Updates: DASISION 18 month and SWOG-S0325 16

  17. DASISION Study • Treatment-naïve Ph+ CML*(N=519) • 108 centers • 26 countries Dasatinib 100 mg QD, n=259 Randomize 1:1 Imatinib 400 mg QD, n=260 *Stratified by Hasford score. Follow-up 5 years • Primary endpoint: confirmed CCyR by 12 months • Secondary endpoints: MMR at any time, time to confirmed CCyR, time to MMR, rates of CCyR (observed at least once in at least 20 metaphase cells) and MMR by 12 months, progression-free survival, and overall survival Shah et al. ASH 2010, Abstract 206.

  18. DASISION Differences Definition of EFS in ENESTnd: The time between randomization and the earliest of the following events on study treatment in the core phase of the study: death due to any cause, progression to AP or BC, loss of PCyR, loss of CCyR, loss of CHR. Kantarjian H et al. N Engl J Med. 2010;362:2260-2270. • Endpoint was confirmed CCyR • Stratified by Hasford score • Exclusion criteria included pleural effusions at baseline • Progression if any of the following occurred: • A doubling of the white-cell count to more than 20×109 per liter in the absence of complete hematologic response (CHR) • A loss of CHR • An increase in Ph-positive bone marrow metaphase cells to more than 35% • Progression to accelerated phase or blastic-phase CML, OR • Death from any cause • Dose reductions or escalations allowed on both treatment arms • Routine chest x-ray at 6 month

  19. Patient Disposition and Treatment Discontinuations in DASISION • *Increasing WBC count; loss of CHR; loss of MCyR including 30% rise in Ph+ metaphase cells and additional chromosomal abnormalities; progression to AP/BC. • PFS rates at 18 months were 94.9% and 93.7% for dasatinib and imatinib, respectively • OS rates were 96.0% for dasatinib and 97.9% for imatinib Shah et al. ASH 2010, Abstract 206.

  20. Confirmed CCyR in DASISION* n=259 n=260 P=0.0086 P=0.0366 • * ITT population • Shah et al. ASH 2010, Abstract 206.

  21. MMR Rates (ITT) by Month of Treatment n=259 n=260 P<0.0001 Molecular Response (%) MMR, BCR-ABL <0.1% Shah et al. ASH 2010, Abstract 206.

  22. Transformation to Advanced-Phase CML in DASISION • 5 patients who achieved CCyR transformed to AP/BP (2 dasatinib) • No patient who achieved MMR transformed to AP/BP to date • Patients were followed for transformation for up to 60 days after last dose of study drug; clonal evolution without additional criteria for AP was NOT counted as transformation to AP/BC Shah et al. ASH 2010, Abstract 206.

  23. Grade 3/4 Myelosuppression Any Time on Study: DASISION • Nearly 75% of cytopenia occurred during the first 4 months of treatment • Grade 3/4 bleeding occurred in 2 dasatinib-treated patients and 3 imatinib-treated patients Shah et al. ASH 2010, Abstract 206.

  24. Drug-Related Nonhematologic AEs (≥10%) in DASISION • Grade 3/4 AEs were infrequent (≤1%) with either treatment Shah et al. ASH 2010, Abstract 206. 24

  25. SWOG-S0325 Dasatinib vs Imatinib in Newly Diagnosed CML Patients: 12-Month Efficacy *Derived ITT = responders/total patients randomized in each arm. †Unclear duration of follow-up, missing cytogenetic samples in ~1/3 of patients. Radich et al. ASH 2010, Abstract LBA-6.

  26. SWOG-S0325 Dasatinib vs Imatinib in Newly Diagnosed CML Patients: 12-Month Safety *Discontinuation due to pericardial effusion noted in at least 2 patients. †Grade 3/4 = QTc prolongation >500 msec. Radich et al. ASH 2010, Abstract LBA-6.

  27. Phase 1 Study of Ponatinib: Best Response to Therapy Median follow-up: • Acceptable safety profile at therapeutic dose levels • Pancreatic DLTs at 60 mg *Includes only those with T315I status confirmed at study entry. Cortes et al. ASH 2010, Abstract 210.

  28. Bosutinib: Response Rates at 12 Months (ITT) Newly Diagnosed Ph+ CML-CP Patients CCyR, Primary Endpoint P=0.601 P=0.002 Gambacorti-Passerini et al. ASH 2010, Abstract 208.

  29. TIDEL-II: Selective Escalation of Imatinib Therapy and Early Switching to Nilotinib 67% TIDEL -II PK TIDEL-I TIDEL -II NIL ü ü 47% Start Rx with imatinib 600 mg TIDEL -I Dose adjust to imatinib 800 mg for failing target ü ü MMR rates at 12 months Dose escalate if imatinib <1000 mg, D22 û ü û ü Allow switch to nilotinib Yeung DT et al. ASH 2010, Abstract #209.

  30. Rates of CCyR and MMR From ENESTnd and DASISION ENESTnd DASISION These data are from separate studies • ENESTnd (18 months) • 24% of imatinib patients were dose escalated • Dose escalation was not permitted in nilotinib arms • DASISION (18 months) • 15% of imatinib patients were dose escalated • 6% of dasatinib patients were dose escalated Larson RA et al. ASH 2010, Abstract 2291 Kantarjian et al. NEJM. 2010:362;2260. 30

  31. Rates of Progression From ENESTnd and DASISION ENESTnd DASISION These data are from separate studies • ENESTnd (18 months) • No patient who achieved MMR progressed to AP/BC • 4 patients who achieved CCyR on imatinib progressed to AP/BC • DASISION (18 months) • No patient who achieved MMR progressed to AP/BC • 5 patients who achieved CCyR on imatinib/dasatinib progressed to AP/BC (2 dasatinib) Larson RA et al. ASH 2010, Abstract 2291 Kantarjian et al. NEJM. 2010:362;2260. 31

  32. generally accepted conclusions regarding CP CML therapy Nilotinib and Dasatinib both engender more rapid and greater numbers of cytogenetic complete remissions; Bosutinib may as well with less conviction from available data Molecular response (MMR, CMR) follows thereafter and is greater with 2G TKIs Much more time is needed to understand ability to permit treatment interruption but optimism runs high Each drug has a degree of ‘class effect toxicity’ as well as ‘specific toxicities’ of minimal morbidity; some related to response (lymphocytosis)? Current modus operandi may be to ‘fit the TKI to the patient’- most potent TKI suitable for the patient based on comorbidities and risks, and then tolerable over at least the medium-term

  33. The toxicity spectrum of TKIs

  34. ENESTnd: Selected Grade 3/4 Biochemical Abnormalities Additional events between 12 and 24 months 9 8 8 7 6 5 % of Patients 4 4 3 3 < 1 0 Lipase ↑ ALT ↑ Total bilirubin ↑ Glucose ↑ Nilotinib 300 mg BID Nilotinib 400 mg BID Imatinib 400 mg QD Hughes TP, et al. Blood. 2010;116(21):94-95 [abstract 207]

  35. Nilotinib in CML-CP 2ndline: Cminand hyperbilirubinemia Giles F et al, ASH 2010 Abstract #890 100 80 TA(7)/TA(7) (n = 48) TA(6)/TA(6) or TA(6)/TA(7) ( n = 18) 60 % With Grade 3/4 Bilirubin Elevation 40 20 0 300 400 500 600 700 800 900 1000 Median NilotinibCmin (ng/mL) • NIL induced biliassociated with the TA(7)/TA(7) repeat in the UGT1A1 gene • UGT1A1 gene TA promoter repeat polymorphism: ‘Gilbert’s (syndrome) gene’

  36. Nilotinib in CML-CP 2nd line: Cmin and lipase elevation 100 All grade incidence 80 P = 0.001 53 50 60 33 34 40 % With Lipase Elevation 20 59/118 63/119 39/119 40/118 n/N = 0 (620,859) ≥ 859 < 451 (451,620) Nilotinib Cmin Quartile (ng/mL) 50 Grade 3/4 incidence 40 23 30 P = 0.193 15 % With Lipase Elevation 14 13 20 10 18/119 27/119 16/119 17/119 n/N = 0 (620,859) ≥ 859 < 451 (451,620) Nilotinib Cmin Quartile (ng/mL) Giles F et al, ASH 2010 Abstract #890

  37. Phase 1 Study of Ponatinib Dose Escalation Cortes J, ASH 2010 Abstract #210

  38. 100 80 60 % Patients with MMR 40 20 0 6 12 0 24 36 18 Time (months) Nilotinib in CP-CML 2nd line: Dose Interruption and time to response (n = 229) Time to CCyR vs. dose interruption Time to MMR vs. dose interruption Cumulative dose interruption: No interruption <7 days 7-14 days 14- 28 days ≥ 28 days 100 P = .00091* P = .0000993* 80 60 % Patients with CCyR 40 20 0 0 6 12 18 24 36 Time (months) *Log-rank test Dose interruptions were 4% of total days of exposure1

  39. ENESTndSubstudy:Adverse events in Patients with Type 2 Diabetes Ischemic heart disease (1) None for ‘diabetes’ Intestinal obstruction (1) and suicide (1) Saglio G et al, ASH 2010 Abstract #3430

  40. Changes in Parameters related to Glucose Metabolism in ENESTnd Insulin levels increased in nilotinib arms more than imatinib control arm No change in HGA1c values Saglio G et al, ASH 2010 Abstract #3430

  41. Hyperglycemia AEs, ENESTnd Saglio G et al, ASH 2010 Abstract #3430 • In Type II Diabetes population (n=57): • change in diabetic regimen on study: 14% in NIL 300 BID, 8% in NIL 400 BID, 4% in IM • no DKA/hyperosmolar events; one gr2 hyperglycemia->hospitalized in NIL 300 BID

  42. CCyRby 12 mo: Type II DM versus overall, ENESTnd Saglio G et al, ASH 2010 Abstract #3430

  43. Lymphocytosis with Dasatinib Therapy Schiffer C et al, ASH 2010 Abstract #358 • Persistent expansion of clonal cytotoxic T cells or NK cells has been described in patients with chronic myeloid leukemia (CML) and Ph+ acute lymphoblastic leukemia (ALL) receiving dasatinib1 • Other small studies have also suggested a relationship between the development of T/NK lymphocytosis with both improved response and some toxicity • A recent analysis of ~1100 CML patients who were resistant to or intolerant of imatinib indicated that lymphocytosis occurred in ~30% of patients in all stages of CML after treatment with dasatinib2 • In that analysis, lymphocytosis was associated with improved cytogenetic response and an increased incidence of pleural effusions 1. Porkka K, et al. Cancer 2010;116:377–86. Kruetzman A, et al. Blood 2010;116:772-782. 2. Schiffer C, et al. 2010 ASCO abstract #6553.

  44. Lymphocytosis with Dasatinib Therapy Schiffer C et al, ASH 2010 Abstract #358 • Patients enrolled in the DASISION study were retrospectively evaluated for lymphocytosis (N=516) • Lymphocytosis was defined as lymphocytes >3.6 x 109/L on ≥2 occasions after 28 days of treatment • The interval between blood counts was usually between 1-3 months • Immunophenotyping was not done as part of these studies • Rates of complete cytogenetic response (CCyR), major molecular response (MMR), progression-free survival (PFS), and adverse events (AEs) were measured in those with and without lymphocytosis • Statistical comparisons were retrospective and not adjusted for multiple comparisons • Median follow-up was 18 months (Range 0−30)

  45. Cumulative Incidence of Lymphocytosis, DAS vs IM Schiffer C et al, ASH 2010 Abstract #358 100 90 80 70 60 Lymphocytosis (%) 50 40 30 20 10 0 0 3 6 9 12 15 18 21 24 27 30 33 Months SUBJECTS AT RISKDASATINIBIMATINIB 190 229 210 201 195 194 192 190 190 190 0 258 258 254 248 244 243 243 243 243 243 0 246 243

  46. Cumulative response rates according to presence of lymphocytosis (minimum follow-up 15 months) Schiffer C et al, ASH 2010 Abstract #358 CCyR=complete cytogenetic response; cCCyR=confirmed CCyR; MMR=major molecular response

  47. Landmark analysis of response at 12 months by presence of lymphocytosis Schiffer C et al, ASH 2010 Abstract #358 cCCyR=confirmed complete cytogenetic response; MMR=major molecular response

  48. Fluid-related adverse events * * * 22% vs 9 %, 95% CI 4-24% • No significant difference in other AEs • In dasatinib-treated patients, the incidence of grade 3-4 pleural effusion was 1.5% with lymphocytosis and 0% without

  49. QTc prolongation with 2G TKIs in front-line ENESTndDASISION Nilotinib 300 mg BID Nilotinib 400 mg BID Imatinib 400 mg QD Imatinib 400 mg QD Dasatinib 100 mg QD • No patients with QTc >500ms • <1% QTc>60ms • No patients with QTc >500ms • <1% QTc>60ms • No patients with QTc >500ms • No patients with QTc>60ms • QTc >500ms in 0.4% • 5% QTc>60ms • QTc >500ms in 0.4% • 5% QTc>60ms Nilotinib phase II data

  50. QTc and relationship to nilotinib trough concentration 5000 4000 NilotinibCmin (ng/mL)* Larson R et al, ASH 2010 Abstract #2291 3000 2000 1165 1190 998.5 1000 Nilotinib in CML-CP 2nd Line: Cmin(steady state) by disease phases 0 CP n = 200 AP n = 81 BP n = 88 Disease Phase Giles F et al, ASH 2010 Abstract #890

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