Oncology Journal Club Addressing Imatinib-resistant CML

1
Oncology Journal ClubAddressing
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
Historical CML Survival Curve
3
(No Transcript)
4
Targets in CML Signaling Pathways
CEP701, MLN518 PKC412
5
Human tyrosine kinases
6
Human Kinase Dendrogram
Manning. Science 298 1912, 2002
7
ASH 2007, Abstract 25
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
Hochhaus A. et al
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
9
IRIS 6-Year Update Annual Event Rates
8
7.5
7
EventLoss of CHR,Loss of MCyR, AP/BC,Death
during treatment
6
4.8
5
Annual Rates
4
AP/BC
3.3
2.8
3
1.6
2
1.5
1.5
0.9
0.8
1
0.5
0.4
0
0
1st
2nd
3rd
4th
5th
6th
Year
Hochhaus A. et al, Blood. 110, 11. Abstract 25.
ASH 2007
10
Incidence of CML by Age
SEER 2001
11
Adherence to Imatinib May Decline Over Time

• In this US study, persistency was near 100 at
  month 4
• Persistency declined from 94 at month 5, to 23
  at month 14
• Imatinib plasma level testing may help identify
  patients who become less adherent

Time on therapy without significant gaps in
refills. Tsang J-P, Rudychev I, Pescatore SL.
Poster presented at ASCO 2006.
12
Genes Associated with CML Progression
Radich. PNAS 103 2794, 2006
13
Dasatinib in Blast Phase CML Overall Survival
1.0 0.8 0.6 0.4 0.2 0
N No. of deaths Median (mo)
CML-MB 109 49 11.8
CML-LB 48 27 5.3
Proportion alive
0 3 6 9 12 15 18 21
Months
Martinelli. ASH 2006. Abs 745
14
Clinical Resistance to Imatinib Mechanisms

• Primary resistance
• Insufficient inhibition of BCR-ABL
• Low plasma levels of imatinib
• Activity of drug pumps
• Secondary resistance
• Imatinib-resistant BCR-ABL kinase-domain
  mutations
• Overproduction of BCR-ABL
• BCR-ABL-independent mechanisms
• ? Activation of other kinases
• ? Other molecular events

Giles. Hematol Am Soc Hematol Educ
Program2005183-187 von Bubnoff.
Leukemia. 20317829.
15
Kinase Selectivity Profiles Of Nilotinib And
Dasatinib
Nilotinib 4 targets
Imatinib 4 targets
Dasatinib 15 targets
After Fabian et al. Nature Biotech. 200523329
16
Targets of Imatinib, Nilotinib, and Dasatinib Targets of Imatinib, Nilotinib, and Dasatinib Targets of Imatinib, Nilotinib, and Dasatinib Targets of Imatinib, Nilotinib, and Dasatinib Targets of Imatinib, Nilotinib, and Dasatinib
Imatinib Nilotinib Dasatinib Dasatinib 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
17
Dasatinib SRC/ABL Kinase Inhibitor
Shah. Science 305 399, 2004
18
Dasatinib 70 mg BID in CP-CML
Efficacy at 15.2 month Median Follow-up
Baccarani. Blood. 2006108 Abstr 164.
19
Progression-Free Survivalwith Dasatinib 70 mg
BID in CP CML
1.0 0.8 0.6 0.4 0.2 0
Proportion progression-free
N No. progressed
Intolerant 99 3
Resistant 287 37
Total 386 40
70 mg BID Progression defined as confirmed AP
/ BC, loss of CHR / MCyR, ? WBC count, or death
Baccarani. Blood 2006 108 Abstract 164.
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 (18171) 104 (11140) 101 (11171)
21
Dasatinib 70 mg BID in CP-CML Fluid
Retention/Cardiac AEs
Percentage Percentage
Any G3-4
Pleural effusion 27 6
Peripheral edema 18 0
Pericardial effusion 4 lt1
Pulmonary edema 1 lt1
Congestive heart failure 5 3
Other cardiac dysfunction 2 1
Baccarani. Blood 2006 108 abst 164
22
ASCO 2007, Abstract 7004
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
Shah NP. et al.
23
Dasatinib in CP-CML Study Design
International, 139-center, Randomized,
Open-label, Phase III
662 treated
670 randomized

• Accrual period July 2005March 2006 Total 662
  pts
• Minimum follow-up 6 months
• Median treatment duration, months (range) 8
  (lt115)

Shah et al .JCO 25 2007 Abstract 7004.
24
Dasatinib Phase III in CP-CML Failing Imatinib
(N 662)
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 lt0.001
Neutropenia 34 46 43 43 0.123
Thrombocytopenia 22 34 40 38 0.003
Pleural effusion 10 16 20 18 0.058
100 QD vs 70 BID
Shah, JCO. 200725 Abstract 7004
25
Dasatinib Phase III in CP-CML Failing
ImatinibProgression-free Survival
1.0 0.8 0.6 0.4 0.2 0
N No. progressed
100 mg QD 165 16
50 mg BID 167 22
140 mg QD 163 23
70 mg BID 167 30
Proportion progression free
0 2 4 6 8 10 12 14 16 18 20
Months
Kantarjiran. Blood. 2006108 Abstr 746
26
Dasatinib Pleural Effusions in CML

• 138 patients Phase I (50) Phase II (88)
• Pleural effusion 48 patients (35 grade 3/4 in
  23 17). 29 in CP, 50 in AP, 33 in BP
• MVA risk factors History of cardiac disease,
  hypertension, twice-daily schedule
• Exudative in 78 of assessable cases
• Increased RV systolic pressure documented
• Management included
• Drug interruption - 83
• Diuretics - 71
• Corticosteroids - 27
• Thoracentesis - 19

Quintás-Cardama. JCO 25 3908, 2007
27
ABL Binding Surfaces
Nilotinib
Imatinib
Weisberg. Ca Cell 7129, 2005 Manley. Biochem Bio
Acta 17543, 2005
28
Nilotinib / Imatinib Potency and Selectivity

Nilotinib (cell prolif. IC50) ABL (25 nM) gt PDGFR (53 nM) gt KIT (158 nM)
Imatinib (cell prolif IC50) PDGFR (39 nM) gt KIT (98 nM) gt ABL (649 nM)
Nilotinib has no significant effect on other
kinases evaluated, including Src, FLT3, VEGFR,
EGFR, InsR, RET, MET , IGFR at concentrations
lt3000 nM.
Mestan. Blood 104 546a Abs 1978, 2004 Weisberg.
Cancer Cell 7129, 2005
29
Nilotinib Pre-clinical Activity

• More potent, more selective, inhibitor of Bcr-Abl
  auto, substrate phosphorylation than imatinib
• Selectively induces apoptosis, inhibits
  proliferation of Bcr-Abl transfected and primary
  leukemia cells
• Increases survival in murine Bcr-Abl MPD models
  including imatinib-resistant models
• Inhibits PDGFRa,ß and KIT Imatinib
• STAT, CRKL inhibitor

Verstovsek et al. Cancer. 20051041230
Golemovic et al. Clin Ca Res. 2005114941
Griffin et al. Blood. 2004104160a Abs 551
Le Coutre et al. Blood.
2004104218a Abs 76Mahon et al. Blood.
2004104251b Abs 4670 Martinelli et al. Blood.
2004104255b Abs 4687
Weisberg et al. Br. J. Cancer 2006, 94, 1765
OHare et al. Cancer Res. 200565(11)4500-5
Manley et al. Biochim Biophys Acta. 2005
1754(1-2) Scuto et al. Blood. 2004104546a Abs
1977 Weisberg et al. Cancer Cell.
20057(2)129-41
30
Nilotinib Phase I Study CML Hematologic Responses
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
Kantarjian, Giles et al. N Engl J Med.
3542542, 2006 Indicates co-first author.
31
Nilotinib Phase I Study PK
Dose (mg)

• Median time to peak concentrations 3 hours post
  dose
• Mean apparent half-life 15 hours
• Steady state by day 8 in both QD and BID regimens
• All trough levels gt IC50 for cellular Bcr-Abl
  phosphorylation
• PK parameters dose proportional to 400 mg QD
• Exposure is greatest in the 600 mg BID group

Kantarjian, Giles et al. N Engl J Med.
3542542, 2006. Indicates co-first author.
32
Clinical Resistance to Imatinib Mechanisms

• Primary resistance
• Insufficient inhibition of BCR-ABL
• Low plasma levels of imatinib
• Activity of drug pumps
• Secondary resistance
• Imatinib-resistant BCR-ABL kinase-domain
  mutations
• Overproduction of BCR-ABL
• BCR-ABL-independent mechanisms
• ? Activation of other kinases
• ? Other molecular events

Giles. Hematol Am Soc Hematol Educ
Program2005183-187 von Bubnoff. Leukemia.
20317829.
33
BCR-ABL Mutations Associated With Imatinib
Resistance
34
Nilotinib Inhibits 32 of 33 Imatinib-resistant
BCR-ABL Mutant Phenotypes With IC50 lt 1 Um
35
Nilotinib Phase I StudyGrade 3/4 Possibly
Related Laboratory AEs
Kantarjian, Giles et al. N Engl J Med.
3542542, 2006 Indicates co-first author
36
ASH 2007, Abstract 471 and 735
Nilotinib Is Highly Active and Safe in Chronic
Phase Chronic Myelogenous Leukemia (CML-CP)
Patients with Imatinib-Resistance or Intolerance
Le Coutre P. et al. (471) Kantarjian HM. et al.
(735)
37
Nilotinib Phase II Baseline Demographics and
Disease Characteristics
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
Kantarjian HM et al. ASH abstract 735, Blood
2007 110 (11). Le Coutre P et al. ASH abstract
471, Blood 2007 110 (11).
38
Nilotinib Phase II Studies Dose Intensity
(mg/day)
le Coutre et al. ASH 2006 Abst 165 Kantarjian
et al. ASH 2006 Abst 2169
39
Nilotinib Phase II CML-CP Study Response Rates
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 (N178) 2.8 months
Median duration of MCyR has not been reached at the time of data cutoff Median duration of MCyR has not been reached at the time of data cutoff
40
Nilotinib Phase II CML-AP StudyResponse Rates
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)
41
Nilotinib Phase II Study CML-CP Overall
Survival Post Imatinib Failure


Kantarjian et al. ASH 2007 abstract 735

42
Phase II CML-AP StudyOverall Survival Post
Imatinib Failure
Le Coutre et al. ASH 2007 abstract 471
43
Phase II CML-CP StudyGrades 3/4 Biochemical
Laboratory Abnormalities
N 321 Grades 3/4 ()
AST 2
ALT 4
Bilirubin (total) 8
Bilirubin (direct) 5
Creatinine 1
Hypocalcemia 1
Hypomagnesemia lt1
Hypophosphatemia 14
Lipase elevation 15
Hyperglycemia 13


Kantarjian et al. ASH 2007
abstract 735
44
Phase II CML-CP Study Possibly Related
Non-hematologic AEs (frequency gt10)
N 321 All Grades () Grades 3/4 ()
Rash 30 2
Pruritus 25 lt1
Nausea 24 lt1
Fatigue 20 1
Headache 18 2
Vomiting 12 lt1
Constipation 12 0
Diarrhea 12 2
Kantarjian et al, ASH 2007 abstract 735
45
Cross-intolerance Between Imatinib and Nilotinib


Cortes et al. ASH abstract 29, Blood 2007110
(11)
46
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
47
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 Grade 3/4 Grade 3/4 Grade 3/4
Median Duration (days) 9 15 23
Median Onset (days) 61 55 42
48
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 Grade 3/4 Grade 3/4 Grade 3/4
Median Duration (days) 8 15 27
Median Onset (days) 14 21 21
49
Nilotinib CML CP After Dasatinib and Imatinib

1. Giles F et al. Presented at 43rd ASCO Annual
   Meeting June 1-5, 2007 Chicago, Ill. Abstract
   7038.
2. Giles F et al. Presented at 12th Congress of the
   EHA June 7-10, 2007 Vienna, Austria. Abstract
   554.

50
Cautions With Dasatinib / Nilotinib

• QTc prolongation Both Baseline EKG, Close K
  and Mg monitoring
• Past pancreatitis Nilotinib C/I
• Hypertension, COPD, CCF, Chest wall injury,
  Asthma, Pneumonia, GI bleeding, Auto-immune
  disorders, aspirin Dasatinib C/I

51

• Addressing Imatinib-resistant CML
• Future Directions

52
Young. Ca Res 661007, 2006
53
MK-0457 Phase I Patient with T315I CML BP
Giles. Blood. 109, 500 2007
54
Ph Chromosome And BCR-ABL Transcript Numbers As
Measures Of Residual Leukemia During Treatment
0
55
NilotinibNewly Diagnosed CML-CP
Jabbour E. ASCO 2006. Abstract 2172
56
Dasatinib in ECP CMLNon-Hematologic Adverse
Events
Percentage Percentage 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
Number of patients
57
ASCO 2007, Abstract 7023
Efficacy Of Dasatinib In Chronic Phase Chronic
Myelogenous Leukemia Patients After Imatinib
Failure According To Baseline BCR-ABL Mutations
Hochhaus A. et al.
58
Dasatinib Response Cellular IC50 Of
Post-imatinib Mutation (CP-CML)
Hochhaus et al. JCO 25 2007 Abstract 7023
59
ASCO 2007, Abstract 7024
Response Dynamics To Nilotinib Depend On The Type
Of Bcr-abl Mutations In Patients With Chronic
Myelogenous Leukemia (CML) After Imatinib Failure
Mueller MC. et al.
60
CML-CP Best Response Within 6 Months by Cellular
IC50 to Nilotinib
Baseline CellularMutation IC50 (nM)T315I
gt10,000 Y253H 700 E255K 548 F359C
161 F317L 91 D276G 77 M244V 67 E355G
47 H396R 41 M351T 38
IC50 gt10,000 nM 4 no response






















IC50 gt100 nM 2 PCyR2 CHR5 no response
IC50 lt100 nM 8 CCyR2 PCyR7 CHR1 no
response
Mueller et al.JCO 25 2007 Abstract 7024
61
CML Potential Antigen Targets

• Junction Peptides
• b3a2-p210Bcr/Abl
• b2a2-p210Bcr/Abl
• e1a2-p190Bcr/Abl
• Non-specific
• Hsp70

• Tissue-specific Antigens
• Proteinase 3
• Tryptase
• Cathepsin G
• Leukotriene-B4 omega hydroxylase
• C-pim, C-fes
• MRP14
• GM-CSF receptor ? chain

62
CML in 2008

• Imatinib (IM) optimal frontline therapy No role
  for frontline AlloSCT in adults
• Dasatinib / nilotinib are effective in IM-failure
  in equivalent patients with approved regimens
• Toxicities should dictate order of use of
  dasatinib and Nilotinib. Each will generate new
  patterns of resistance
• MK-0457 is active in T315I phenotype patients
• Need to avoid manufactured discontent
• Need to focus on cure

63
Questions on Patients and/or Studies with/of
Hematologic Malignancies or Refractory Solid
Tumors?

• frankgiles_at_aol.com
• 832-606-0285