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Oncology Journal Club Addressing Imatinib-resistant CML Frank Giles, MD, FRCPI, FRCPath Chief, Division of Hematology and ...
Historical CML Survival Curve
 
Targets in CML Signaling Pathways CEP701, MLN518 PKC412 Ribosome biogenesis PI3K Raptor mTOR PDK1 IRS Perifosine Triciribi...
Human tyrosine kinases
Human Kinase Dendrogram Manning. Science; 298: 1912, 2002
ASH 2007, Abstract 25 Hochhaus A. et al IRIS 6-Year Follow-Up: Sustained Survival and Declining Annual Rate of Transformat...
IRIS 6-Year Update: Overall Survival  (ITT Principle)   6 year OS is 88%  (95% considering only CML-related deaths) (incl....
IRIS 6-Year Update: Annual Event Rates 3.3 7.5 4.8 1.5 0.8 0.4 1.5 2.8 1.6 0.9 0.5 0 0 1 2 3 4 5 6 7 8 1st 2nd 3rd 4th 5th...
Incidence of CML by Age SEER 2001
Adherence to Imatinib  May Decline Over Time <ul><ul><li>In this US study, persistency* was near 100% at month 4  </li></u...
Radich. PNAS 103: 2794, 2006 Genes Associated with CML Progression
Dasatinib in Blast Phase CML   Overall Survival 0 3 6 9 12 15 18 21 Months Proportion alive 1.0 0.8 0.6 0.4 0.2 0 Martinel...
Clinical Resistance to Imatinib  Mechanisms <ul><li>Primary resistance </li></ul><ul><ul><li>Insufficient inhibition of BC...
After Fabian et al. Nature Biotech. 2005;23:329 Kinase Selectivity Profiles Of  Nilotinib And Dasatinib   Dasatinib 15 tar...
“ Targets” of Imatinib, Nilotinib, and Dasatinib  Imatinib Nilotinib Dasatinib ABL ARG BCR-ABL KIT PDGFR DDR1 NQO2 ABL ARG...
Dasatinib:  SRC/ABL Kinase Inhibitor Shah. Science 305: 399, 2004
Dasatinib 70 mg BID in CP-CML Baccarani. Blood. 2006;108: Abstr 164. Efficacy at 15.2 month Median Follow-up % Complete he...
Progression-Free Survival with Dasatinib 70 mg BID in CP CML *  70 mg BID †   Progression defined as confirmed AP / BC, lo...
Dasatinib 70 mg BID in CP-CML  Dose Adjustment Resistant (N = 288) Intolerant (N = 99) Total (N = 387) Reduction (%) 73 75...
Dasatinib 70 mg BID in CP-CML  Fluid Retention/Cardiac AEs Baccarani. Blood 2006; 108: abst# 164 Percentage Any G3-4 Pleur...
ASCO 2007, Abstract 7004 Shah NP. et al. Dasatinib 50 Mg Or 70 Mg BID Compared  To 100 Mg Or 140 Mg QD In Patients With CM...
Dasatinib  in CP-CML   Study Design 662 treated International, 139-center, Randomized, Open-label, Phase III <ul><li>Accru...
Dasatinib Phase III in CP-CML Failing Imatinib  (N = 662) +  100 QD vs 70 BID Shah,  JCO.  2007;25: Abstract 7004  Paramet...
Dasatinib Phase III in CP-CML Failing Imatinib Progression-free Survival Proportion progression free 1.0 0.8 0.6 0.4 0.2 0...
Dasatinib: Pleural Effusions in CML <ul><li>138 patients:  Phase I (50); Phase II (88) </li></ul><ul><li>Pleural effusion:...
ABL Binding Surfaces  Weisberg. Ca Cell 7:129, 2005 Manley. Biochem Bio Acta 1754:3, 2005 Nilotinib Imatinib
Nilotinib / Imatinib:   Potency and Selectivity Nilotinib has no significant effect on other kinases evaluated, including ...
<ul><li>More potent, more selective, inhibitor of Bcr-Abl auto, substrate phosphorylation than imatinib </li></ul><ul><li>...
Nilotinib Phase I Study CML  Hematologic Responses Kantarjian*, Giles* et al. N Engl J Med. 354:2542, 2006 * Indicates co-...
Nilotinib Phase I Study: PK Kantarjian*, Giles* et al. N Engl J Med. 354:2542, 2006. *Indicates co-first author.   <ul><li...
Clinical Resistance to Imatinib  Mechanisms <ul><li>Primary resistance </li></ul><ul><ul><li>Insufficient inhibition of BC...
BCR-ABL Mutations  Associated With Imatinib Resistance F486S  E255K /V M244V   M351T /L M343T  Y253F /H E279K  F317L E355G...
Nilotinib: Phase I Study Grade 3/4 Possibly Related Laboratory AEs Kantarjian*, Giles* et al. N Engl J Med. 354:2542, 2006...
ASH 2007, Abstract 471 and 735 Le Coutre P. et al.  (471) Kantarjian HM. et al. (735) Nilotinib Is Highly Active and Safe ...
Nilotinib: Phase II Baseline Demographics and Disease Characteristics Kantarjian HM et al. ASH abstract 735, Blood 2007: 1...
Nilotinib  Phase II Studies: Dose Intensity (mg/day) le Coutre et al. ASH 2006; Abst #165 Kantarjian et al. ASH 2006; Abst...
Nilotinib Phase II CML-CP Study  Response Rates Hematologic  Response Cytogenetic  Response ASH'06 Patients with ≥ 6 month...
Nilotinib Phase II CML-AP Study: Response Rates Hematologic  Response Cytogenetic   Response ASH'06 Patients with ≥ 8 mont...
Nilotinib Phase II Study:  CML-CP Overall Survival Post Imatinib Failure Kantarjian et al.  ASH 2007 abstract 735 95% 91% ...
Phase II CML-AP Study Overall Survival Post Imatinib Failure Le Coutre  et al . ASH 2007 abstract 471 Patients = 129  Numb...
Phase II CML-CP Study Grades 3/4 Biochemical Laboratory Abnormalities Kantarjian  et al .  ASH 2007 abstract 735 N = 321 G...
Phase II CML-CP Study   Possibly Related Non-hematologic AEs  (frequency >10%) Kantarjian  et al , ASH 2007 abstract 735 N...
Cross-intolerance Between  Imatinib and Nilotinib Cortes  et al . ASH abstract 29, Blood 2007:110 (11)  CML-CP (N=94) / CM...
Nilotinib Cross Intolerance in Patients with Imatinib Intolerance Nonhematologic AEs Reason for Imatinib Intolerance Imati...
Nilotinib Phase II Study CML-CP Myelosuppresion All Grades Grade 3/4 ASH'06 Patients with ≥ 6 months of follow-up (N = 316...
Nilotinib Phase II Study CML-AP Myelosuppresion All Grades Grade 3/4 ASH'06 Patients with ≥ 8 months of treatment (N = 64)...
<ul><li>Addressing Imatinib-resistant CML </li></ul><ul><li>Future Directions </li></ul>
Young. Ca Res 66;1007, 2006
Giles. Blood. 109, 500 2007 MK-0457 Phase I: Patient with T315I CML BP 1 Cycles of therapy WBC (x10 9 /L) 2 7 6 5 4 3 8 9 ...
Ph Chromosome And BCR-ABL Transcript Numbers As Measures Of ‘Residual’ Leukemia During Treatment 0 Decreasing residual  le...
Dasatinib in ECP CML Non-Hematologic Adverse Events Number of patients Percentage G1 G2 G3 34 20 26 29 40 9 3 26 17 3 37 3...
ASCO 2007, Abstract 7023 Hochhaus A. et al. Efficacy Of Dasatinib In Chronic Phase Chronic Myelogenous Leukemia Patients A...
Dasatinib Response: Cellular IC 50  Of Post-imatinib Mutation (CP-CML) Hochhaus et al. JCO 25; 2007 Abstract # 7023   Cell...
ASCO 2007, Abstract 7024 Mueller MC. et al. Response Dynamics To Nilotinib Depend On The Type Of Bcr-abl Mutations In Pati...
CML: Potential Antigen Targets  <ul><li>Junction Peptides </li></ul><ul><li>b3a2-p210 Bcr/Abl </li></ul><ul><li>b2a2-p210 ...
CML in 2008 <ul><li>Imatinib (IM) optimal frontline therapy: No role for frontline AlloSCT in adults </li></ul><ul><li>Das...
Questions on Patients and/or Studies with/of Hematologic Malignancies or Refractory Solid Tumors? <ul><li>[email_address] ...
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Addressing Imatinib-resistant CML

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Transcript of "Addressing Imatinib-resistant CML"

  1. 1. Oncology Journal Club Addressing Imatinib-resistant CML Frank Giles, MD, FRCPI, FRCPath Chief, Division of Hematology and Medical Oncology Director, Institute for Drug Development Deputy Director, CTRC at University of Texas Health Science Center San Antonio, TX
  2. 2. Historical CML Survival Curve
  3. 4. Targets in CML Signaling Pathways CEP701, MLN518 PKC412 Ribosome biogenesis PI3K Raptor mTOR PDK1 IRS Perifosine Triciribine eIF4E eIF4E eIF3 eIF4G PABP TSC2 TSC1 RHEB 4E-BP1 S6K1 AKT Cap-dependent translation Translation Ribosomal proteins P P P P VEGF PDGF Flt3 Cell membrane Hif-1a ERK RAD001 CCI-779 AP23573 Bcr-Abl Jak2 MK-0457 Dasatinib Nilotinib MK-0457 SKI606 Dasatinib Sunitinib Surafinib PTK787
  4. 5. Human tyrosine kinases
  5. 6. Human Kinase Dendrogram Manning. Science; 298: 1912, 2002
  6. 7. ASH 2007, Abstract 25 Hochhaus A. et al IRIS 6-Year Follow-Up: Sustained Survival and Declining Annual Rate of Transformation in Patients with Newly Diagnosed Chronic Myeloid Leukemia in Chronic Phase (CML-CP) Treated with Imatinib
  7. 8. IRIS 6-Year Update: Overall Survival (ITT Principle) 6 year OS is 88% (95% considering only CML-related deaths) (incl. 3% after BMT, 4% non-CML related) Hochhaus A. et al, Blood. 110, 11. Abstract 25. ASH 2007 38 (7%) patients lost to follow-up by 5 years
  8. 9. IRIS 6-Year Update: Annual Event Rates 3.3 7.5 4.8 1.5 0.8 0.4 1.5 2.8 1.6 0.9 0.5 0 0 1 2 3 4 5 6 7 8 1st 2nd 3rd 4th 5th 6th % Annual Rates Year Event Loss of CHR, Loss of MCyR, AP/BC, Death during treatment AP/BC Hochhaus A. et al, Blood. 110, 11. Abstract 25. ASH 2007
  9. 10. Incidence of CML by Age SEER 2001
  10. 11. Adherence to Imatinib May Decline Over Time <ul><ul><li>In this US study, persistency* was near 100% at month 4 </li></ul></ul><ul><ul><li>Persistency declined from 94% at month 5, to 23% at month 14 </li></ul></ul><ul><ul><li>Imatinib plasma level testing may help identify patients who become less adherent </li></ul></ul>*Time on therapy without significant gaps in refills. Tsang J-P, Rudychev I, Pescatore SL. Poster presented at ASCO 2006. 685 Patients Months 0–1 3500 3000 2500 2000 1500 0 1000 500 1–2 2–3 3–4 4–5 5–6 6–7 7–8 8–9 9–10 10–11 11–12 12–13 13+ 2,921 Patients taking recommended dose of imatinib
  11. 12. Radich. PNAS 103: 2794, 2006 Genes Associated with CML Progression
  12. 13. Dasatinib in Blast Phase CML Overall Survival 0 3 6 9 12 15 18 21 Months Proportion alive 1.0 0.8 0.6 0.4 0.2 0 Martinelli. ASH 2006. Abs 745 N No. of deaths Median (mo) CML-MB 109 49 11.8 CML-LB 48 27 5.3
  13. 14. Clinical Resistance to Imatinib Mechanisms <ul><li>Primary resistance </li></ul><ul><ul><li>Insufficient inhibition of BCR-ABL </li></ul></ul><ul><ul><ul><li>Low plasma levels of imatinib </li></ul></ul></ul><ul><ul><ul><li>Activity of drug pumps </li></ul></ul></ul><ul><li>Secondary resistance </li></ul><ul><ul><li>Imatinib-resistant BCR-ABL kinase-domain mutations </li></ul></ul><ul><ul><li>Overproduction of BCR-ABL </li></ul></ul><ul><ul><li>BCR-ABL-independent mechanisms </li></ul></ul><ul><ul><ul><li>? Activation of other kinases </li></ul></ul></ul><ul><ul><ul><li>? Other molecular events </li></ul></ul></ul>Giles. Hematol Am Soc Hematol Educ Program:2005:183-187; von Bubnoff. Leukemia. 203;17:829 .
  14. 15. After Fabian et al. Nature Biotech. 2005;23:329 Kinase Selectivity Profiles Of Nilotinib And Dasatinib Dasatinib 15 targets Imatinib 4 targets Nilotinib 4 targets IC 50 < 10 nM 10-50 nM 50-250 nM 250-1000 nM
  15. 16. “ Targets” of Imatinib, Nilotinib, and Dasatinib Imatinib Nilotinib Dasatinib ABL ARG BCR-ABL KIT PDGFR DDR1 NQO2 ABL ARG BCR-ABL KIT PDGFR DDR1 NQO2 ABL ARG BCR-ABL KIT PDGFR SRC YES FYN LYN HCK LCK FGR BLK FRK CSK BTK TEC BMX TXK DDR1 DDR2 ACK ACTR2B ACVR2 BRAF EGFR/ERBB1 EPHA2 EPHA3 EPHA4 EPHA5 FAK GAK GCK HH498/TNNI3K ILK LIMK1 LIMK2 MYT1 NLK PTK6/Brk QIK QSK RAF1 RET RIPK2 SLK STK36/ULK SYK TAO3 TESK2 TYK2 ZAK
  16. 17. Dasatinib: SRC/ABL Kinase Inhibitor Shah. Science 305: 399, 2004
  17. 18. Dasatinib 70 mg BID in CP-CML Baccarani. Blood. 2006;108: Abstr 164. Efficacy at 15.2 month Median Follow-up % Complete hematologic response Major cytogenetic response CHR 91 59 11 49 80 5 75 52 13 40 CCyR PCyR Total Total Imatinib intolerant Imatinib resistant
  18. 19. Progression-Free Survival with Dasatinib 70 mg BID in CP CML * 70 mg BID † Progression defined as confirmed AP / BC, loss of CHR / MCyR, ↑ WBC count, or death Proportion progression-free 1.0 0.8 0.6 0.4 0.2 0 Baccarani. Blood 2006; 108: Abstract 164. 0 2 4 6 8 10 12 14 16 18 20 Months N No. progressed Intolerant 99 3 Resistant 287 37 Total 386 40
  19. 20. Dasatinib 70 mg BID in CP-CML Dose Adjustment Resistant (N = 288) Intolerant (N = 99) Total (N = 387) Reduction (%) 73 75 73 Interruption (%) 86 89 87 Escalation (%) 21 9 18 Median daily dose (mg) (range) 101 (18–171) 104 (11–140) 101 (11–171)
  20. 21. Dasatinib 70 mg BID in CP-CML Fluid Retention/Cardiac AEs Baccarani. Blood 2006; 108: abst# 164 Percentage Any G3-4 Pleural effusion 27 6 Peripheral edema 18 0 Pericardial effusion 4 <1 Pulmonary edema 1 <1 Congestive heart failure 5 3 Other cardiac dysfunction 2 1
  21. 22. ASCO 2007, Abstract 7004 Shah NP. et al. Dasatinib 50 Mg Or 70 Mg BID Compared To 100 Mg Or 140 Mg QD In Patients With CML In Chronic Phase (CP) Who Are Resistant Or Intolerant To Imatinib: One-year Results Of CA180034
  22. 23. Dasatinib in CP-CML Study Design 662 treated International, 139-center, Randomized, Open-label, Phase III <ul><li>Accrual period: July 2005–March 2006: Total 662 pts </li></ul><ul><li>Minimum follow-up: 6 months </li></ul><ul><li>Median treatment duration, months (range): 8 (<1–15) </li></ul>670 randomized Shah et al .JCO 25; 2007 Abstract # 7004. 100 mg QD (N = 165) 140 mg QD (N = 163) 50 mg BID (N = 167) 70 mg BID (N = 167) 100 mg 140 mg Imatinib-resistant or -intolerant CP-CML
  23. 24. Dasatinib Phase III in CP-CML Failing Imatinib (N = 662) + 100 QD vs 70 BID Shah, JCO. 2007;25: Abstract 7004 Parameter (%) 100mg QD N = 165 50mg BID N = 167 140mg QD N = 163 70mg BID N = 167 P value MCyR 64 58 62 58 NS CCyR 46 46 47 50 NS Interruption 58 66 69 71 0.047 Reduction 33 45 54 57 <0.001 Neutropenia 34 46 43 43 0.123 Thrombocytopenia 22 34 40 38 0.003 Pleural effusion 10 16 20 18 0.058 +
  24. 25. Dasatinib Phase III in CP-CML Failing Imatinib Progression-free Survival Proportion progression free 1.0 0.8 0.6 0.4 0.2 0 0 2 4 6 8 10 12 14 16 18 20 Months Kantarjiran. Blood . 2006;108: Abstr 746 N No. progressed 100 mg QD 165 16 50 mg BID 167 22 140 mg QD 163 23 70 mg BID 167 30
  25. 26. Dasatinib: Pleural Effusions in CML <ul><li>138 patients: Phase I (50); Phase II (88) </li></ul><ul><li>Pleural effusion: 48 patients (35%; grade 3/4 in 23 [17%]). 29% in CP, 50% in AP, 33% in BP </li></ul><ul><li>MVA risk factors: History of cardiac disease, hypertension, twice-daily schedule </li></ul><ul><li>Exudative in 78% of assessable cases </li></ul><ul><li>Increased RV systolic pressure documented </li></ul><ul><li>Management included: </li></ul><ul><ul><li>Drug interruption - 83% </li></ul></ul><ul><ul><li>Diuretics - 71% </li></ul></ul><ul><ul><li>Corticosteroids - 27% </li></ul></ul><ul><ul><li>Thoracentesis - 19% </li></ul></ul>Quintás-Cardama. JCO 25: 3908, 2007
  26. 27. ABL Binding Surfaces Weisberg. Ca Cell 7:129, 2005 Manley. Biochem Bio Acta 1754:3, 2005 Nilotinib Imatinib
  27. 28. Nilotinib / Imatinib: Potency and Selectivity Nilotinib has no significant effect on other kinases evaluated, including Src, FLT3, VEGFR, EGFR, InsR, RET, MET , IGFR at concentrations <3000 nM . Mestan. Blood 104 546a: Abs 1978, 2004 Weisberg. Cancer Cell 7:129, 2005 Nilotinib (cell prolif. IC 50 ) ABL (25 nM) > PDGFR (53 nM) > KIT (158 nM) Imatinib (cell prolif IC 50 ) PDGFR (39 nM) > KIT (98 nM) > ABL (649 nM)
  28. 29. <ul><li>More potent, more selective, inhibitor of Bcr-Abl auto, substrate phosphorylation than imatinib </li></ul><ul><li>Selectively induces apoptosis, inhibits proliferation of Bcr-Abl transfected and primary leukemia cells </li></ul><ul><li>Increases survival in murine Bcr-Abl MPD models including imatinib-resistant models </li></ul><ul><li>Inhibits PDGFRα,ß and KIT ~ Imatinib </li></ul><ul><li>STAT, CRKL inhibitor </li></ul>Nilotinib: Pre-clinical Activity Verstovsek et al. Cancer. 2005;104:1230 Golemovic et al. Clin Ca Res. 2005;11:4941 Griffin et al. Blood. 2004;104:160a Abs# 551 Le Coutre et al. Blood. 2004;104:218a Abs# 76 Mahon et al. Blood. 2004;104:251b Abs# 4670 Martinelli et al. Blood. 2004;104:255b Abs# 4687 Weisberg et al. Br. J. Cancer 2006, 94, 1765 O’Hare et al. Cancer Res. 2005;65(11):4500-5 Manley et al. Biochim Biophys Acta. 2005 1754(1-2) Scuto et al. Blood. 2004;104:546a Abs# 1977 Weisberg et al. Cancer Cell. 2005;7(2):129-41
  29. 30. Nilotinib Phase I Study CML Hematologic Responses Kantarjian*, Giles* et al. N Engl J Med. 354:2542, 2006 * Indicates co-first author. Diagnosis N Evaluable OR (%) CHR MR RTC CP 12 11 (92) 11 – – AP 46 33 (72) 21 3 9 AP clonal evolution only 5 5 (100) 5 – – Myeloid BP 24 10 (42) 2 2 6 Lymphoid BP 9 3 (33) – 1 2
  30. 31. Nilotinib Phase I Study: PK Kantarjian*, Giles* et al. N Engl J Med. 354:2542, 2006. *Indicates co-first author. <ul><li>Median time to peak concentrations 3 hours post dose </li></ul><ul><li>Mean apparent half-life = 15 hours </li></ul><ul><li>Steady state by day 8 in both QD and BID regimens </li></ul><ul><li>All trough levels > IC 50 for cellular Bcr-Abl phosphorylation </li></ul><ul><li>PK parameters dose proportional to 400 mg QD </li></ul><ul><li>Exposure is greatest in the 600 mg BID group </li></ul>Dose (mg) Daily Twice daily 60,000 20,000 40,000 AUC (ng/ml/hr) 0 50 100 200 400 600 400 600 800 1200
  31. 32. Clinical Resistance to Imatinib Mechanisms <ul><li>Primary resistance </li></ul><ul><ul><li>Insufficient inhibition of BCR-ABL </li></ul></ul><ul><ul><ul><li>Low plasma levels of imatinib </li></ul></ul></ul><ul><ul><ul><li>Activity of drug pumps </li></ul></ul></ul><ul><li>Secondary resistance </li></ul><ul><ul><li>Imatinib-resistant BCR-ABL kinase-domain mutations </li></ul></ul><ul><ul><li>Overproduction of BCR-ABL </li></ul></ul><ul><ul><li>BCR-ABL-independent mechanisms </li></ul></ul><ul><ul><ul><li>? Activation of other kinases </li></ul></ul></ul><ul><ul><ul><li>? Other molecular events </li></ul></ul></ul>Giles. Hematol Am Soc Hematol Educ Program:2005:183-187; von Bubnoff. Leukemia . 203;17:829.
  32. 33. BCR-ABL Mutations Associated With Imatinib Resistance F486S E255K /V M244V M351T /L M343T Y253F /H E279K F317L E355G /D F359V /C/D/I H396R /P Q252H /R S417Y E459K/Q E450G/Q/K M388L G250E /A/F D276G T277A/N L387F/M V379I A397P P-loop Activation loop T315I** F311L/I/V V289A/I L248V F382L E281A V299L L364I G383D L298V E292V E453G/K/A/V Q447R S438C G236E D241G M237I L324Q K357R K285N E275K S348L A344V A350V M472I I418V
  33. 34. Nilotinib: Phase I Study Grade 3/4 Possibly Related Laboratory AEs Kantarjian*, Giles* et al. N Engl J Med. 354:2542, 2006 * Indicates co-first author Overall (N=119) 400 BID (N=32) 600 BID (N=18) 0% 0% 11% 11% 5% 3% 9% 3% 5% 3% 5% 3% Amylase ALT/AST Lipase Bilirubin
  34. 35. ASH 2007, Abstract 471 and 735 Le Coutre P. et al. (471) Kantarjian HM. et al. (735) Nilotinib Is Highly Active and Safe in Chronic Phase Chronic Myelogenous Leukemia (CML-CP) Patients with Imatinib-Resistance or Intolerance
  35. 36. Nilotinib: Phase II Baseline Demographics and Disease Characteristics Kantarjian HM et al. ASH abstract 735, Blood 2007: 110 (11). Le Coutre P et al. ASH abstract 471, Blood 2007: 110 (11). CML-CP (N = 321) CML-AP (N = 127) Median age, years 58 (21-85) 58 (22-82) Additional chromosomal abnormalities, % 24.4 31 Median duration of CML, months 58 (5-75) 71 (2-298) Median duration of prior imatinib use, months 33 29 Imatinib-resistant/intolerant, % 71/29 80/20
  36. 37. Nilotinib Phase II Studies: Dose Intensity (mg/day) le Coutre et al. ASH 2006; Abst #165 Kantarjian et al. ASH 2006; Abst #2169 800 797 787 Planned Delivered (CP) N = 316 Delivered (AP) N = 64
  37. 38. Nilotinib Phase II CML-CP Study Response Rates Hematologic Response Cytogenetic Response ASH'06 Patients with ≥ 6 months of follow-up (N = 279) ASCO'07 Patients with ≥ 6 months of treatment (N = 320) ASH'07 Patients with ≥ 11 months of treatment (N = 321) CHR at baseline / *No CHR at baseline, N 115 / 206 Time to first CHR* 1 month Time to first MCyR (N=178) 2.8 months Median duration of MCyR has not been reached at the time of data cutoff
  38. 39. Nilotinib Phase II CML-AP Study: Response Rates Hematologic Response Cytogenetic Response ASH'06 Patients with ≥ 8 months of treatment (N = 64) ASCO'07 Patients with ≥ 6 months of treatment (N = 119) ASH'07 Patients with ≥ 6 months of treatment (N = 129)
  39. 40. Nilotinib Phase II Study: CML-CP Overall Survival Post Imatinib Failure Kantarjian et al. ASH 2007 abstract 735 95% 91% Months Since Start of Treatment Alive, % Total = 321 Failed = 25 lll = Censored observations
  40. 41. Phase II CML-AP Study Overall Survival Post Imatinib Failure Le Coutre et al . ASH 2007 abstract 471 Patients = 129 Number deaths = 27 92% 81% Alive, % Months Since Start of Treatment
  41. 42. Phase II CML-CP Study Grades 3/4 Biochemical Laboratory Abnormalities Kantarjian et al . ASH 2007 abstract 735 N = 321 Grades 3/4 (%) AST 2 ALT 4 Bilirubin (total) 8 Bilirubin (direct) 5 Creatinine 1 Hypocalcemia 1 Hypomagnesemia <1 Hypophosphatemia 14 Lipase elevation 15 Hyperglycemia 13
  42. 43. Phase II CML-CP Study Possibly Related Non-hematologic AEs (frequency >10%) Kantarjian et al , ASH 2007 abstract 735 N = 321 All Grades (%) Grades 3/4 (%) Rash 30 2 Pruritus 25 <1 Nausea 24 <1 Fatigue 20 1 Headache 18 2 Vomiting 12 <1 Constipation 12 0 Diarrhea 12 2
  43. 44. Cross-intolerance Between Imatinib and Nilotinib Cortes et al . ASH abstract 29, Blood 2007:110 (11) CML-CP (N=94) / CML-AP (N=23) Patients enrolled in nilotinib study 2101 with grade 3/4 imatinib intolerance Patients with cross-intolerance (grade 3/4) after switching to nilotinib Rash / skin toxicity Fluid retention GI intolerance Liver toxicity Myalgias / Arthralgias
  44. 45. Nilotinib Cross Intolerance in Patients with Imatinib Intolerance Nonhematologic AEs Reason for Imatinib Intolerance Imatinib Intolerant* Grade 3/4 AE or persistent Grade 2 AE on nilotinib** Gr. 3/4 AE on Nilotinib*** AE that led to dose reduction of nilotinib D/C nilotinib due to AE N N N N CML-CP N = 95 Non-hematologic 57 4 1 0 0 Rash/Skin 26 0 0 0 0 Fluid Retention 17 0 0 0 0 GI - diarrhea 17 3 1 0 0 Liver Toxicity - ALT - AST 12 3 1 0 0 Myalgia/arthralgia 9 1 0 0 0
  45. 46. Nilotinib Phase II Study CML-CP Myelosuppresion All Grades Grade 3/4 ASH'06 Patients with ≥ 6 months of follow-up (N = 316) ASCO'07 Patients with ≥ 6 months of treatment (N = 320) ASH'07 Patients with ≥ 11 months of treatment (N = 321) Grade 3/4 Median Duration (days) 9 15 23 Median Onset (days) 61 55 42 Most Frequent Newly Occurring or Worsening Hematologic Lab Abnormalities Regardless of Causality
  46. 47. Nilotinib Phase II Study CML-AP Myelosuppresion All Grades Grade 3/4 ASH'06 Patients with ≥ 8 months of treatment (N = 64) ASCO'07 Patients with ≥ 6 months of treatment (N = 127) ASH'07 Patients with ≥ 11 months of treatment (N = 136) Grade 3/4 Median Duration (days) 8 15 27 Median Onset (days) 14 21 21 Most Frequent Newly Occurring or Worsening Hematologic Lab Abnormalities Regardless of Causality
  47. 48. <ul><li>Addressing Imatinib-resistant CML </li></ul><ul><li>Future Directions </li></ul>
  48. 49. Young. Ca Res 66;1007, 2006
  49. 50. Giles. Blood. 109, 500 2007 MK-0457 Phase I: Patient with T315I CML BP 1 Cycles of therapy WBC (x10 9 /L) 2 7 6 5 4 3 8 9 10 12 mg/m 2 /hr 20 mg/m 2 /hr 16 mg/m 2 /hr
  50. 51. Ph Chromosome And BCR-ABL Transcript Numbers As Measures Of ‘Residual’ Leukemia During Treatment 0 Decreasing residual leukemia Number of leukemia cells (log 10 ) 1 2 3 4 5 6 7 8 9 10 11 12 13 0 6.0 5.0 4.0 3.0 1.0 0 Log reduction from baseline Leukocytosis Ph-chromosome pos RQ-PCR <3 log Cure ? 2.0 CCyR MMR RQ-PCR negative (undetectable) RQ-PCR >3 log
  51. 52. Dasatinib in ECP CML Non-Hematologic Adverse Events Number of patients Percentage G1 G2 G3 34 20 26 29 40 9 3 26 17 3 37 3 14 20 23 9 26 6 23 6 11 17 0 11 9
  52. 53. ASCO 2007, Abstract 7023 Hochhaus A. et al. Efficacy Of Dasatinib In Chronic Phase Chronic Myelogenous Leukemia Patients After Imatinib Failure According To Baseline BCR-ABL Mutations
  53. 54. Dasatinib Response: Cellular IC 50 Of Post-imatinib Mutation (CP-CML) Hochhaus et al. JCO 25; 2007 Abstract # 7023 Cellular IC 50 Dasatinib Imatinib N nM nM H396P/R 0.6-1.3 850-4200 7 M351T 1.1 930 8 M244V 1.3 2000 8 G250E 1.8 1350-3900 9 Y253F/H 1.3-10 >10000 5 L387M 2 1000 2 F359V 2.2 1200 2 Q252H 3.4 1300-3900 2 E255K/V 5.6-13 4400-8400 6 F317L 7.4-18 810-1500 3 T315I >1000 >10000 3                                                                                                                       Complete CyR Partial CyR Complete HR No response
  54. 55. ASCO 2007, Abstract 7024 Mueller MC. et al. Response Dynamics To Nilotinib Depend On The Type Of Bcr-abl Mutations In Patients With Chronic Myelogenous Leukemia (CML) After Imatinib Failure
  55. 56. CML: Potential Antigen Targets <ul><li>Junction Peptides </li></ul><ul><li>b3a2-p210 Bcr/Abl </li></ul><ul><li>b2a2-p210 Bcr/Abl </li></ul><ul><li>e1a2-p190 Bcr/Abl </li></ul><ul><li>Non-specific </li></ul><ul><li>Hsp70 </li></ul><ul><li>Tissue-specific Antigens </li></ul><ul><li>Proteinase 3 </li></ul><ul><li>Tryptase </li></ul><ul><li>Cathepsin G </li></ul><ul><li>Leukotriene-B4 omega hydroxylase </li></ul><ul><li>C-pim, C-fes </li></ul><ul><li>MRP14 </li></ul><ul><li>GM-CSF receptor  chain </li></ul>
  56. 57. CML in 2008 <ul><li>Imatinib (IM) optimal frontline therapy: No role for frontline AlloSCT in adults </li></ul><ul><li>Dasatinib / nilotinib are effective in IM-failure in equivalent % patients with approved regimens </li></ul><ul><li>Toxicities should dictate order of use of dasatinib and Nilotinib. Each will generate new patterns of resistance </li></ul><ul><li>MK-0457 is active in T315I phenotype patients </li></ul><ul><li>Need to avoid manufactured discontent </li></ul><ul><li>Need to focus on cure </li></ul>
  57. 58. Questions on Patients and/or Studies with/of Hematologic Malignancies or Refractory Solid Tumors? <ul><li>[email_address] </li></ul><ul><li>832-606-0285 </li></ul>

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