asco review 2011 t martin, md asco, lugano, imf-paris highlights may - june, 2011
DESCRIPTION
ASCO REVIEW 2011 T Martin, MD ASCO, Lugano, IMF-Paris Highlights May - June, 2011. ASCO in Review 2011. Non-Hodgkin’s Lymphoma ( Abs 8031, 8032, 3065) SGN35 trials BTK Inhibitor trial, CA-101 (PI3-kinase inh) trial Chronic Lymphocytic Leukemia ( Abs 6508, 3065 ) - PowerPoint PPT PresentationTRANSCRIPT
ASCO REVIEW 2011ASCO REVIEW 2011
T Martin, MDT Martin, MDASCO, Lugano, IMF-Paris ASCO, Lugano, IMF-Paris
Highlights Highlights May - June, 2011May - June, 2011
ASCO in Review 2011ASCO in Review 2011
Non-Hodgkin’s Lymphoma (Non-Hodgkin’s Lymphoma (AbsAbs 8031, 8032, 3065)8031, 8032, 3065) SGN35 trialsSGN35 trials BTK Inhibitor trial, CA-101 (PI3-kinase inh) trialBTK Inhibitor trial, CA-101 (PI3-kinase inh) trial
Chronic Lymphocytic Leukemia (Chronic Lymphocytic Leukemia (AbsAbs 6508, 30656508, 3065)) BTK Inhibitor trial, CA-101 trialBTK Inhibitor trial, CA-101 trial
Acute and Chronic Myeloid Leukemias (Acute and Chronic Myeloid Leukemias (AbsAbs 6509, 6510, 6509, 6510, 6511, 65186511, 6518)) Front line CML-CP therapy trial updatesFront line CML-CP therapy trial updates Second line TKI therapySecond line TKI therapy
Myeloproliferative Neoplasms (Myeloproliferative Neoplasms (AbsAbs 6500, 6501,6514, 6500, 6501,6514, 6515 6515 )) Ruxolitinib Phase III trialsRuxolitinib Phase III trials Ongoing Phase II JAK2 inhibitor trialsOngoing Phase II JAK2 inhibitor trials
Multiple myeloma (Multiple myeloma (AbsAbs 8007, 8020 8007, 8020 )) Phase III trialsPhase III trials Phase II trialsPhase II trials
ABSTRACT 8031: Results of a Pivotal Phase 2 ABSTRACT 8031: Results of a Pivotal Phase 2 Study of Brentuximab Vedotin (SGN-35) in Study of Brentuximab Vedotin (SGN-35) in
Patients with Relapsed or Refractory Hodgkin Patients with Relapsed or Refractory Hodgkin LymphomaLymphoma
R Chen, AK Gopal, SE Smith, SM Ansell, JD Rosenblatt, R R Chen, AK Gopal, SE Smith, SM Ansell, JD Rosenblatt, R
Klasa, Klasa, JM Connors, A Engert, EK Larsen, DA Kennedy, EL Sievers, A JM Connors, A Engert, EK Larsen, DA Kennedy, EL Sievers, A
YounesYounes
ABSTRACT 8032:ABSTRACT 8032: Durable Remissions with Durable Remissions with SGN-35 (Brentuximab Vedotin): Updated SGN-35 (Brentuximab Vedotin): Updated Results of a Phase II Study in Patients with Results of a Phase II Study in Patients with Relapsed or Refractory Systemic Anaplastic Relapsed or Refractory Systemic Anaplastic
Large Cell LymphomaLarge Cell Lymphoma
B Pro , R Advani , P Brice , NL Bartlett, JD Rosenblatt, T B Pro , R Advani , P Brice , NL Bartlett, JD Rosenblatt, T Illidge, J Matous, R Ramchandren, M Fanale, J M Connors, Y Illidge, J Matous, R Ramchandren, M Fanale, J M Connors, Y
Yang, EL Sievers, DA Kennedy, A. R. ShustovYang, EL Sievers, DA Kennedy, A. R. Shustov
Brentuximab Vedotin Mechanism Brentuximab Vedotin Mechanism of Actionof Action
Brentuximab vedotin (SGN-35) ADCmonomethyl auristatin E (MMAE), potent antitubulin agent
protease-cleavable linker
anti-CD30 monoclonal antibody
ADC binds to CD30
MMAE disruptsmicrotubule network
ADC-CD30 complex traffics to lysosome
MMAE is released
Apoptosis
G2/M cellcycle arrest
Pivotal, Multicenter, Open-Label Study of Pivotal, Multicenter, Open-Label Study of Brentuximab Vedotin in Relapsed/Refractory Brentuximab Vedotin in Relapsed/Refractory
HLHL
• Relapsed or refractory CD30+ HL
• Age ≥12 years
• Measurable disease ≥1.5 cm
• ECOG 01
• Prior ASCT
Follow-upTreatment (N=102)Eligibility
• Brentuximab vedotin 1.8 mg/kg IV every 21 days
• Administered outpatient over 30 min
• Max 16 cycles for SD or better
• Restage at Cycles 2, 4, 7, 10, 13, 16
Every 12 weeks
Objectives: ORR (CR+PR), Survival (DOR, PFS, OS)
Demographics and Baseline Demographics and Baseline CharacteristicsCharacteristics
N=102N=102Age* Age* 31 yr (1531 yr (1577)77)
GenderGender 48 M / 54 F48 M / 54 F
ECOG statusECOG status
00 42 (41%)42 (41%)
11 60 (59%)60 (59%)
Refractory to frontline therapyRefractory to frontline therapy 72 (71%)72 (71%)
Refractory to most recent treatmentRefractory to most recent treatment 43 (42%)43 (42%)
Prior chemotherapy regimens*Prior chemotherapy regimens* 3.5 (13.5 (113)13)
Prior radiationPrior radiation 67 (66%)67 (66%)
Prior ASCTPrior ASCT 102 (100%)102 (100%)
Time from ASCT to first post transplant Time from ASCT to first post transplant relapse*relapse*
6.7 mo 6.7 mo (0(0131)131)
* Median (range)* Median (range)
Brentuximab Vedotin: Brentuximab Vedotin: Response ResultsResponse Results
N=102N=102IRFIRF InvestigatorInvestigator
Overall response rate Overall response rate (95% CI)(95% CI)
75% (65-75% (65-83)83)
72% (62-72% (62-80)80)
Complete remission Complete remission 34%34% 33%33%
Partial remissionPartial remission 40%40% 38%38%
Stable diseaseStable disease 22%22% 27%27%
Progressive diseaseProgressive disease 3%3% 0%0%
Not evaluableNot evaluable 1%1% 1%1%
Maximum Tumor Reduction per Maximum Tumor Reduction per IRFIRF
* 4 patients were not included in the analysis• 3 patients had no measurable lesions per IRF • 1 patient had no postbaseline scans
Individual Patients (n=98)*
Tu
mo
r S
ize
(% C
hang
e fr
om
Bas
elin
e)
94% (96 of 102) of patients achieved tumor reduction
100
22º º Endpoints: PFS and OSEndpoints: PFS and OS
Time (Weeks)
% P
atie
nts
Fre
e of
PD
or
Dea
th
Median (range) cycles of treatment = 9 (1Median (range) cycles of treatment = 9 (116)16)
Median DOR: 29 Wk (IRF); 47 Wk investigatorMedian DOR: 29 Wk (IRF); 47 Wk investigator
Median Median (wks)(wks)
Overall survivalOverall survival not reachednot reachedPFS per PFS per investigatorinvestigator
39.139.1
PFS per IRFPFS per IRF 25.125.1
Treatment-Emergent Adverse Events of any Treatment-Emergent Adverse Events of any Relationship Occurring in ≥20% of PatientsRelationship Occurring in ≥20% of Patients
Preferred TermPreferred Term All GradesAll Grades
Peripheral sensory neuropathyPeripheral sensory neuropathy 47%47%
FatigueFatigue 46%46%
NauseaNausea 42%42%
Upper respiratory tract infectionUpper respiratory tract infection 37%37%
DiarrheaDiarrhea 36%36%
PyrexiaPyrexia 29%29%
NeutropeniaNeutropenia 22%22%
VomitingVomiting 22%22%
CoughCough 21%21%
Patients with AEs leading to discontinuation = 20%Patients with AEs leading to discontinuation = 20%
OTHER <20%: G3+4: Low Plats 8%, Anemia 6%, neuropathy OTHER <20%: G3+4: Low Plats 8%, Anemia 6%, neuropathy reversible (68%), onset at 27 wks, time to resolution 6.9 wks.reversible (68%), onset at 27 wks, time to resolution 6.9 wks.
Phase 2, Multicenter, Open-Label Study of Brentuximab Vedotin in Relapsed/Refractory sALCL
• Relapsed or refractory systemic ALCL
• Age ≥12 years
• Measurable disease ≥1.5 cm FDG-avid
• ECOG 0 1
Follow-upTreatment (N=58)*Eligibility
• Brentuximab vedotin 1.8 mg/kg IV every 21 days
• Administered outpatient over 30 min
• Max 16 cycles for SD or better
• Restage† at Cycles 2, 4, 7, 10, 13, 16
Every 12 weeks
• Relapsed or refractory systemic ALCL
• Age ≥12 years
• Measurable disease ≥1.5 cm FDG-avid
• ECOG 0 1
Follow-upTreatment (N=58)*Eligibility
• Brentuximab vedotin 1.8 mg/kg IV every 21 days
• Administered outpatient over 30 min
• Max 16 cycles for SD or better
• Restage† at Cycles 2, 4, 7, 10, 13, 16
Every 12 weeks
* Ongoing study† Revised Response Criteria for Malignant Lymphoma (Cheson, 2007)
1´ Endpoint: ORR 2 Endpoint: CR, DOR, PFS, OS Pro et al, Ab 8032; ASCO 2011
N N = 58= 58MaleMale 57%57%AgeAge 52 (14-76)52 (14-76)Alk negativeAlk negative 72%72%Median Prior therapiesMedian Prior therapies 2 2 (1-6)(1-6)Refractory to last treatmentRefractory to last treatment50%50%Primary refractoryPrimary refractory62%62%
N N = 58= 58MaleMale 57%57%AgeAge 52 (14-76)52 (14-76)Alk negativeAlk negative 72%72%Median Prior therapiesMedian Prior therapies 2 2 (1-6)(1-6)Refractory to last treatmentRefractory to last treatment50%50%Primary refractoryPrimary refractory62%62%
SGN-35 in ALCLPatient Characteristics
■■ RESULTS:RESULTS:
ORRORR 86%86%
CRCR 53%53%
DOR DOR NR (0.3-45.3 NR (0.3-45.3 wks)wks)
■ ■ SAFETY:SAFETY:
PNPN 36% (36% (>> gr 3 gr 3 10%)10%)
NauseaNausea 24%24%
Neutropenia Neutropenia 17% 17%
■■ RESULTS:RESULTS:
ORRORR 86%86%
CRCR 53%53%
DOR DOR NR (0.3-45.3 NR (0.3-45.3 wks)wks)
■ ■ SAFETY:SAFETY:
PNPN 36% (36% (>> gr 3 gr 3 10%)10%)
NauseaNausea 24%24%
Neutropenia Neutropenia 17% 17%
SGN-35 in ALCL
Maximum Tumor Reduction per IRF
97% of patients achieved tumor reduction
* 57 of 58 patients with post-baseline CT assessments
Individual Patients (n=57*)
Tum
or S
ize
(%
Cha
nge
fro
m B
ase
line
)
PFS by Disease Response, per IRF
Time (weeks)
% P
atie
nts
Fre
e of
PD
or
Dea
th
not reached(n=2)HI*5 weeks(n=3)PD12 weeks(n=2)SD19 weeks(n=19)PR
not reached(n=31)CRMedian PFS
not reached(n=2)HI*5 weeks(n=3)PD12 weeks(n=2)SD19 weeks(n=19)PR
not reached(n=31)CRMedian PFS
* Histologically ineligible
ConclusionsConclusions SGN35 in 102 HD patients with post ASCT SGN35 in 102 HD patients with post ASCT
relapserelapse ORR = 75%; CR = 34%, median duration of response of ORR = 75%; CR = 34%, median duration of response of
29 weeks29 weeks
94% of patients achieved tumor reduction94% of patients achieved tumor reduction
Estimated 12-month overall survival = 88%Estimated 12-month overall survival = 88%
Manageable adverse events, PN largely reversibleManageable adverse events, PN largely reversible
SGN35 in R/R ALCLSGN35 in R/R ALCL ORR = 86%ORR = 86%
CR = 53%CR = 53%
Adverse events manageable (PN, neutropenia, nausea, Adverse events manageable (PN, neutropenia, nausea, fatigue)fatigue)
Further studies are ongoingFurther studies are ongoing
Non-Hodgkin’s Lymphoma/ B-cell TargetsNon-Hodgkin’s Lymphoma/ B-cell TargetsB-Cell Signaling KinasesB-Cell Signaling Kinases
Nat Rev Imm 2:945
• B-cell antigen receptor (BCR) signaling is required for tumor expansion and proliferation
• Bruton’s Tyrosine Kinase (Btk) and PI3-Kinase are essential elements of the BCR signaling pathway
• Inhibitors of Btk and PI3-kinase block BCR signaling and induce apoptosis
CAL-101 PCI-32765PCI-32765
Abstract 6508: Activity and Abstract 6508: Activity and Tolerability of the Btk Tolerability of the Btk Inhibitor PCI-32765 in Inhibitor PCI-32765 in Patients with CLL/SLL: Patients with CLL/SLL: Interim Results From a Interim Results From a
Phase IB/II StudyPhase IB/II StudyJ Byrd, K Blum, J Burger, S J Byrd, K Blum, J Burger, S
Coutre, J Sharman, R Furman, I Coutre, J Sharman, R Furman, I Flinn, B Grant, D Richards, W Flinn, B Grant, D Richards, W
Zhao, N Heerema, A Johnson, R Zhao, N Heerema, A Johnson, R Izumi, A Hamdy and S. O’BrienIzumi, A Hamdy and S. O’Brien
Study DesignStudy Design Single Agent BTK Inh: oral dosingSingle Agent BTK Inh: oral dosing
Cohort 1Cohort 1 Treatment Naïve (TN): >65 yoTreatment Naïve (TN): >65 yo BTKI 420mg qd for 28-day cycle until disease BTKI 420mg qd for 28-day cycle until disease
progressionprogression Cohort 2 (two doses)Cohort 2 (two doses)
Relapse Refractory (R/R): 2 prior treatments Relapse Refractory (R/R): 2 prior treatments including 1 with Fludarabineincluding 1 with Fludarabine
420mg qd for 28-day cycle until disease progression420mg qd for 28-day cycle until disease progression 840mg qd for 28-day cycle until disease progression840mg qd for 28-day cycle until disease progression
ObjectivesObjectives ORR, DOR, PFSORR, DOR, PFS Safety, PK/PDSafety, PK/PD
Subject CharacteristicsSubject CharacteristicsTN TN 420mg/d, 420mg/d, N = 23N = 23
R/R 420mg/d, R/R 420mg/d, N = 27N = 27
R/R 840mg/d, R/R 840mg/d, N = 33N = 33
Age, yAge, y MedianMedian RangeRange
717166 - 8466 - 84
646440 - 8140 - 81
656544 - 8044 - 80
DxDx CLLCLL SLLSLL
22 (96%) 22 (96%) 1 (4%)1 (4%)
26 (96%)26 (96%) 32 (97%)32 (97%)1 (3%)1 (3%)
Prior Tx:Prior Tx: MedianMedian RangeRange
00 332 - 102 - 10
552 - 122 - 12
Prior therapyPrior therapy Nucleoside Nucleoside analoganalog RituximabRituximab AlkylatorAlkylator AlemtumumabAlemtumumab BendamustineBendamustine OfatumumabOfatumumab
N/AN/A 27 (100%)27 (100%)25 (93%)25 (93%)24 (89%)24 (89%) 5 (19%)5 (19%)8 (30%)8 (30%)8 (30%)8 (30%)
33 (100%)33 (100%)32 (97%)32 (97%)27 (82%)27 (82%) 3 (9%)3 (9%)
13 (39%)13 (39%)10 (30%)10 (30%)
Subject Characteristics (cont.)Subject Characteristics (cont.)
TN TN 420mg/d, 420mg/d, N = 23N = 23
R/RR/R420mg/d, N = 420mg/d, N = 2727
R/RR/R840mg/d, N 840mg/d, N = 33= 33
Prognostic Prognostic MarkersMarkers IgVH IgVH unmutatedunmutated Del 17pDel 17p Del 11qDel 11q ßß microglob microglob < 3mg/ml< 3mg/ml >> 3mg/ml 3mg/ml
8/16 (50%)8/16 (50%)2/17 (12%)2/17 (12%)
0/170/17
10/16 (62%)10/16 (62%)6/16 (38%)6/16 (38%)
17/24 (71%)17/24 (71%)9/24 (38%)9/24 (38%)8/24 (33%)8/24 (33%)
14/23 (61%)14/23 (61%)9/23 (39%)9/23 (39%)
18/24 (75%)18/24 (75%)10/25 (40%)10/25 (40%)12/25 (48%)12/25 (48%)
8/25 (32%)8/25 (32%)17/25 (68%)17/25 (68%)
RESULTS: ResponsesRESULTS: Responses
Treatment-NaïveTreatment-Naïve420 mg/d420 mg/d
Relapsed/Relapsed/refractoryrefractory420mg/d420mg/d
Median f/u Median f/u (months)(months)
6.3 (1.4 -9.2)6.3 (1.4 -9.2) 7.8 (0.7 – 9.5)7.8 (0.7 – 9.5)
Number of ptsNumber of pts 2323 2727
CR CR 1 (5%)1 (5%) 1 (4%)1 (4%)
PR PR 13 (62%)13 (62%) 12 (44%)12 (44%)
ORR ORR 67%67% 48%48%
NodalNodal 4 (19%)4 (19%) 11 (41%)11 (41%)
SDSD 2 (10%)2 (10%) 1 (4%)1 (4%)
PD PD 00 1 (4%)1 (4%)
NENE 1 (5%)1 (5%) 1 (4%)1 (4%)
Best Response by Risk Best Response by Risk FeaturesFeatures
Relapsed/refractory pts: 420 mg/dRelapsed/refractory pts: 420 mg/d
Risk Risk FeaturesFeatures
NN WIG WIG ResponseResponse
Nodal Nodal ResponseResponse
Overall Overall 2727 48%48% 41%41%
Del 17pDel 17p 9 9 4/9 (44%)4/9 (44%) 3/9 (33%)3/9 (33%)
Del 11qDel 11q 88 5/8 (63%)5/8 (63%) 3/8 (38%)3/8 (38%)
IgVH IgVH unmutatedunmutated
1717 9/17 (53%)9/17 (53%) 5/17 (29%)5/17 (29%)
Common AEs (All Grades)
24
Treatment-Naive420 mg/d (n=23)
Relapsed/Refractory420 mg/d (n=27)
Fatigue
Nausea
URI
Rash
Dyspepsia
Diarrhea
Vomiting
Confusion
Muscle spasms
48%
39%
17%
22%
26%
13%
17%
4%
17%
70%
33%
22%
19%
11%
33%
37%
33%
26%
04/19/23 10:50 PM
ConclusionsConclusions PCI-32765 is highly active in both treatment-PCI-32765 is highly active in both treatment-
naïve and relapsed/refractory CLL/SLL naïve and relapsed/refractory CLL/SLL patientspatients
Responses appear to be durable and Responses appear to be durable and independent of high risk genomic featuresindependent of high risk genomic features
A high proportion (81%) of A high proportion (81%) of relapsed/refractory pts are free- of –relapsed/refractory pts are free- of –progression beyond 6 months (420mg/d progression beyond 6 months (420mg/d cohort)cohort)
Toxicity of PCI-32765 is modest. The Toxicity of PCI-32765 is modest. The majority of the AES are grade1 or 2majority of the AES are grade1 or 2
Abstract 3064: A Phase I Study of CAL-101, Abstract 3064: A Phase I Study of CAL-101, an isoform-selective inhibitor of an isoform-selective inhibitor of
phosphatidylinositol 3-kinase P110phosphatidylinositol 3-kinase P110, in , in Combination with anti-CD20 monoclonal Combination with anti-CD20 monoclonal antibody therapy and/or Bendamustine in antibody therapy and/or Bendamustine in
Patients with Previously Treated B-cell Patients with Previously Treated B-cell MalignanciesMalignancies
W Flinn, M Schreeder, S Coutre, J Leonard, N W Flinn, M Schreeder, S Coutre, J Leonard, N Wagner-Johnston, S De Vos, R Boccia, L Holes, S Wagner-Johnston, S De Vos, R Boccia, L Holes, S
Peterman, L Miller, and A YuPeterman, L Miller, and A YuBackgroundBackground
1.1. CAL-101 is a selective inhibitor of CAL-101 is a selective inhibitor of p110p110which may be more active in which may be more active in
hematopoietic malignancieshematopoietic malignancies2.2. In a phase I trial, CAL-101 has shown In a phase I trial, CAL-101 has shown promising activity in indolent lymphoma promising activity in indolent lymphoma
(15/24, 62%), mantle cell lymphoma (10/16, (15/24, 62%), mantle cell lymphoma (10/16, 62%) and CLL (62%) and CLL (ASH 2010 Abs 1777; ASCO 2011 Abs ASH 2010 Abs 1777; ASCO 2011 Abs
30323032))
Study DesignStudy Design Two CAL-101 dose levelsTwo CAL-101 dose levels
CAL-101 CAL-101 100mg100mg bid + Bendamustine 90mg/m2 bid + Bendamustine 90mg/m2 d1,2d1,2
CAL-101 CAL-101 100mg100mg bid + Rituximab 375mg/m2 d1 bid + Rituximab 375mg/m2 d1 CAL-101 CAL-101 150mg150mg bid + Bendamustine 90mg/m2 bid + Bendamustine 90mg/m2
d1,2d1,2 CAL-101 CAL-101 150mg150mg bid + Rituximab 375mg/m2 d1 bid + Rituximab 375mg/m2 d1
Relapsed/refractory indolent NHL Relapsed/refractory indolent NHL (iNHL) or CLL(iNHL) or CLL
Accrual:Accrual:
CAL-101 CAL-101 100mg100mg
CAL-101 CAL-101 150mg150mg
BendamustineBendamustine 1212 1212
RituximabRituximab 1212 1313
Patient CharacteristicsPatient Characteristics
Median age 64 years (range 41 – 87)Median age 64 years (range 41 – 87) Males 65%Males 65% Refractory disease 43%Refractory disease 43% Median number of prior therapy: 3 Median number of prior therapy: 3
(range 1 – 9)(range 1 – 9)
28
RESULTS: RESULTS: EfficacyEfficacy
Toxicity (Grade 3-4)Toxicity (Grade 3-4) Neutropenia in Benda+CAL: 10/24Neutropenia in Benda+CAL: 10/24 Thrombocytopenia in Benda+CAL: 10/24Thrombocytopenia in Benda+CAL: 10/24 Increased AST/ALT: Increased AST/ALT:
6/28 in iNHL6/28 in iNHL 1/21 in CLL1/21 in CLL
ORRORR iNHL N = 22iNHL N = 22 CLL N = 13CLL N = 13
Benda + CAL-101Benda + CAL-101 10/12 (87%)10/12 (87%) 5/7 (78%)5/7 (78%)
Rituximab + CAL-Rituximab + CAL-101101
9/10 (92%)9/10 (92%) 4/6 (62%)4/6 (62%)
ConclusionsConclusions
CAL-101 shows acceptable CAL-101 shows acceptable toxicitytoxicity
Very Promising clinical activity Very Promising clinical activity in both Rituximab and in both Rituximab and bendamustine cohortsbendamustine cohorts
Further studies on-goingFurther studies on-going
ASCO 2011ASCO 2011
Non-Hodgkin’s Lymphoma (Abs Non-Hodgkin’s Lymphoma (Abs 8031, 8032, 6508, 3065)8031, 8032, 6508, 3065) SGN35 trialsSGN35 trials BTK Inhibitor trial, CA-101 (PI3-kinase inh) trialBTK Inhibitor trial, CA-101 (PI3-kinase inh) trial
Chronic Lymphocytic Leukemia (Abs Chronic Lymphocytic Leukemia (Abs 6508, 30656508, 3065)) BTK Inhibitor trial, CA-101 trialBTK Inhibitor trial, CA-101 trial
Acute and Chronic Myeloid Leukemias (Acute and Chronic Myeloid Leukemias (AbsAbs 6511, 6518, 6511, 6518, )) Front line TKI therapyFront line TKI therapy Second line TKI therapySecond line TKI therapy
Myeloproliferative Neoplasms (Abs Myeloproliferative Neoplasms (Abs 6500, 6501,6514, 6500, 6501,6514, 6515 6515 )) Ruxolitinib Phase III trialsRuxolitinib Phase III trials Ongoing Phase II JAK2 inhibitor trialsOngoing Phase II JAK2 inhibitor trials
Multiple myeloma (Abs Multiple myeloma (Abs 8007, 8020 8007, 8020 )) Phase III trialsPhase III trials Phase II trialsPhase II trials
““These two studies cap a remarkable decade ofThese two studies cap a remarkable decade of
progress in CML therapy and, for some, may raiseprogress in CML therapy and, for some, may raise
the question of whether we have reached thethe question of whether we have reached the
limit of what we can hope to achieve. We knowlimit of what we can hope to achieve. We know
that imatinib induces a long-lasting remissionthat imatinib induces a long-lasting remission
but not a cure. Presumably, dasatinib and nilotinibbut not a cure. Presumably, dasatinib and nilotinib
will perform similarly, but with deeper, longerlastingwill perform similarly, but with deeper, longerlasting
remissions.remissions.””Kantarjian et. al. ASCO a6510 Larson et. al. ASCO a6511
Study DesignStudy Design
Key eligibility criteria:Key eligibility criteria: cytogenetic diagnosis of Philadelphia chromosome- cytogenetic diagnosis of Philadelphia chromosome-positive chronic phase chronic myeloid leukemia (CP CML) positive chronic phase chronic myeloid leukemia (CP CML) 6 mo prior, 6 mo prior, with no prior therapy other than hydroxyurea or anagrelidewith no prior therapy other than hydroxyurea or anagrelide
Primary endpoint:Primary endpoint: complete cytogenetic response (CCyR) at 12 months complete cytogenetic response (CCyR) at 12 months
Key secondary and exploratory endpoints:Key secondary and exploratory endpoints: Major molecular response (MMR) at 12 months, duration of CCyR and Major molecular response (MMR) at 12 months, duration of CCyR and
MMR, time to and incidence of transformation to accelerated or blast MMR, time to and incidence of transformation to accelerated or blast phase CML, event-free survival, and overall survivalphase CML, event-free survival, and overall survival
Safety and tolerabilitySafety and tolerability
Phase 3 open-label trial in newly diagnosed chronic
phase CML
N = 502
139 sites
31 countries
Bosutinib 500 mg/day
n = 250
Imatinib 400 mg/day
n = 252
5-year follow-up
5-year follow-up
RANDOMIZE
1-year analysisRandomization is stratified based on Sokal risk score and geographical regions.
Gambacorti-Passerini et. al. ASCO a6509
Complete Cytogenetic Response Rates:Complete Cytogenetic Response Rates:Intent-to-treat PopulationIntent-to-treat Population
● The cumulative CCyR rate by 18 months was 79% for each The cumulative CCyR rate by 18 months was 79% for each treatment armtreatment arm
● Median time to first CCyR was faster for bosutinib (12.7 Median time to first CCyR was faster for bosutinib (12.7 weeks) compared with imatinib (24.6 weeks)weeks) compared with imatinib (24.6 weeks)
a a
aIndicates statistical significance with a P value 0.05. P values for all timepoints with the exception of Month 12 were exploratory and provided for descriptive purposes only.
Gambacorti-Passerini et. al. ASCO a6509
Major Molecular Response Rates:Major Molecular Response Rates:Intent-to-treat PopulationIntent-to-treat Population
● Cumulative MMR rates by 18 months were 55% for bosutinib Cumulative MMR rates by 18 months were 55% for bosutinib and 45% for imatinib, and cumulative CMR rates by 18 and 45% for imatinib, and cumulative CMR rates by 18 months were 18% and 10%, respectivelymonths were 18% and 10%, respectively
● Median time to first MMR was faster with bosutinib (36.9 Median time to first MMR was faster with bosutinib (36.9 weeks) compared with imatinib (72.3 weeks)weeks) compared with imatinib (72.3 weeks)
a a a a
a
aIndicates statistical significance with a P value 0.05. P values for all timepoints with the exception of Month 12 were exploratory and provided for descriptive purposes only.
Gambacorti-Passerini et. al. ASCO a6509
Transformation to AP/BP and Overall Transformation to AP/BP and Overall DeathsDeaths
● Transformation to AP/BP CML occurred in 4 (2%) patients in the Transformation to AP/BP CML occurred in 4 (2%) patients in the bosutinib arm and 13 (5%) in the imatinib arm while on study bosutinib arm and 13 (5%) in the imatinib arm while on study treatment; no new transformation events have occurred on bosutinib treatment; no new transformation events have occurred on bosutinib since the 12-month primary analysis, compared with 3 new events on since the 12-month primary analysis, compared with 3 new events on imatinibimatinib
● Overall deaths occurred in 6 patients receiving bosutinib versus 13 Overall deaths occurred in 6 patients receiving bosutinib versus 13 receiving imatinib during the study, the majority of which occurred receiving imatinib during the study, the majority of which occurred after treatment discontinuationafter treatment discontinuation Deaths due to CML progression occurred in 5 patients receiving Deaths due to CML progression occurred in 5 patients receiving
bosutinib and 9 receiving imatinibbosutinib and 9 receiving imatinib
AP, accelerated phase; BP blast phase.aTreatment failure includes both disease progression and lack of efficacy (including transformation to AP/BP).
a
Gambacorti-Passerini et. al. ASCO a6509
Treatment-emergent Adverse Events Treatment-emergent Adverse Events Reported for Reported for 10% of Patients10% of Patients
BosutinibBosutinib
(n = 248)(n = 248)ImatinibImatinib
(n = 251)(n = 251)
Adverse event, %Adverse event, % All gradesAll grades Grade 3/4Grade 3/4 All gradesAll grades Grade 3/4Grade 3/4
DiarrheaDiarrhea 172 (69)172 (69) 27 (11)27 (11) 56 (22)56 (22) 2 (1)2 (1)VomitingVomiting 79 (32)79 (32) 8 (3)8 (3) 35 (14)35 (14) 00NauseaNausea 78 (31)78 (31) 2 (1)2 (1) 87 (35)87 (35) 00RashRash 55 (22)55 (22) 4 (2)4 (2) 43 (17)43 (17) 2 (1)2 (1)PyrexiaPyrexia 44 (18)44 (18) 2 (1)2 (1) 25 (10)25 (10) 3 (1)3 (1)Upper abdominal painUpper abdominal pain 33 (13)33 (13) 00 17 (7)17 (7) 00Abdominal painAbdominal pain 31 (13)31 (13) 3 (1)3 (1) 15 (6)15 (6) 00HeadacheHeadache 30 (12)30 (12) 2 (1)2 (1) 26 (10)26 (10) 00Upper respiratory tract Upper respiratory tract
infectioninfection 29 (12)29 (12) 00 18 (7)18 (7) 00
FatigueFatigue 28 (11)28 (11) 3 (1)3 (1) 31 (12)31 (12) 2 (1)2 (1)ArthralgiaArthralgia 17 (7)17 (7) 00 26 (10)26 (10) 1 (1 (1)1)MyalgiaMyalgia 12 (5)12 (5) 00 27 (11)27 (11) 2 (1)2 (1)Muscle crampsMuscle cramps 11 (4)11 (4) 00 54 (22)54 (22) 00Bone painBone pain 10 (4)10 (4) 00 26 (10)26 (10) 2 (1)2 (1)Peripheral edemaPeripheral edema 9 (4)9 (4) 00 27 (11)27 (11) 00Periorbital edemaPeriorbital edema 3 (1)3 (1) 00 35 (14)35 (14) 00
Blue highlighting indicates adverse events more common with bosutinib than imatinib. Green highlighting indicates adverse events more common with imatinib than bosutinib.
Gambacorti-Passerini et. al. ASCO a6509
Abstract 6518: Ponatinib in patients Abstract 6518: Ponatinib in patients with CML/AML: Preliminary with CML/AML: Preliminary
findings from a Phase I study in findings from a Phase I study in hematologic malignancieshematologic malignancies
M Talpaz, N Shah, M Deininger, M Mauro, I Flinn, S M Talpaz, N Shah, M Deininger, M Mauro, I Flinn, S Lustgarten, W Lindmark, J Gozgit, T Cclackson, C Turner, Lustgarten, W Lindmark, J Gozgit, T Cclackson, C Turner,
F Haluska, and J CortezF Haluska, and J Cortez
Ponatinib(AP245534): Study Ponatinib(AP245534): Study DesignDesign
Oral multi-tyrosine kinase inhibitor; Oral multi-tyrosine kinase inhibitor; including inhibition of bcr-abl and Flt3/ITD.including inhibition of bcr-abl and Flt3/ITD.
Goals: identify RP2D and estimate activity Goals: identify RP2D and estimate activity Standard 3+3 Design Standard 3+3 Design
Oral daily dosing (cohorts 2, 4, 8, 15, 30 and 60 Oral daily dosing (cohorts 2, 4, 8, 15, 30 and 60 mg)mg)
Demographics n=56Demographics n=56 Age Age 66 (26-85)66 (26-85) DiseaseDisease
CMLCML 42 (31 CP, 6AP, 5 BP)42 (31 CP, 6AP, 5 BP) PH (+) ALLPH (+) ALL 2 2 AMLAML 12 (Flt3/ITD 10/12) 12 (Flt3/ITD 10/12)
# Prior Therapies# Prior Therapies 3 (median)3 (median)
Results: Ponatinib ResponsesResults: Ponatinib Responses CML (R/R)CML (R/R)
CHRCHR 85% 85% CCyRCCyR 33%33% MCyRMCyR 48%48%
CML – T315ICML – T315I CHRCHR 100%100% CCyRCCyR 57%57% MCyRMCyR 14%14%
CML AP/BC or ALLCML AP/BC or ALL MHRMHR 36%36% CCyRCCyR 9% 9%
AMLAML ORRORR 25% 25% CRiCRi 16% Responses in Flt3 16% Responses in Flt3
(+)(+) PRPR 8% Only 8% Only
Talpaz et al. Abstr 6518; ASCO 2011
Results: SafetyResults: Safety
Related AE’s >10%:Related AE’s >10%: Nausea/vomitingNausea/vomiting 20%/15% 20%/15% FatigueFatigue 15%15% HeadacheHeadache 13%13% ArthalgiaArthalgia /muscle spasma/muscle spasma 10%/10%10%/10% Hot flashesHot flashes 10%10% RashRash 10%10% Elevated Lipase/PancreatitisElevated Lipase/Pancreatitis 10% (4/12 at 60mg)10% (4/12 at 60mg) G3/4 neutropeniaG3/4 neutropenia 43%43% G3/4 thrombocytopeniaG3/4 thrombocytopenia 40%40%
Results: ResponsesResults: Responses
ConclusionsConclusions RP2D= 45mgRP2D= 45mg Well tolerated at RP2DWell tolerated at RP2D CML: very promisingCML: very promising
Active in T315 I mutation Active in T315 I mutation Active in AP/BCActive in AP/BC
AML: potentially promisingAML: potentially promising Active in treatment naïve Flt3(+)Active in treatment naïve Flt3(+) Combination with chemotherapy in Flt3 Combination with chemotherapy in Flt3
warrantedwarrantedTalpaz et al. Abstr 6518; ASCO 2011
ASCO 2011ASCO 2011
Non-Hodgkin’s Lymphoma (Abs Non-Hodgkin’s Lymphoma (Abs 8031, 8032, 6508, 3065)8031, 8032, 6508, 3065) SGN35 trialsSGN35 trials BTK Inhibitor trial, CA-101 (PI3-kinase inh) trialBTK Inhibitor trial, CA-101 (PI3-kinase inh) trial
Chronic Lymphocytic Leukemia (Abs Chronic Lymphocytic Leukemia (Abs 6508, 30656508, 3065)) BTK Inhibitor trial, CA-101 trialBTK Inhibitor trial, CA-101 trial
Acute and Chronic Myeloid Leukemias (Abs Acute and Chronic Myeloid Leukemias (Abs 6509, 65106509, 6510, , 6511, 6518 6511, 6518 )) Front line TKI therapyFront line TKI therapy Second line TKI therapySecond line TKI therapy
Myeloproliferative Neoplasms (Abs Myeloproliferative Neoplasms (Abs 6500, 6501, 6514, 6500, 6501, 6514, 6515 6515 )) Ruxolitinib Phase III trialsRuxolitinib Phase III trials Ongoing Phase II JAK2 inhibitor trialsOngoing Phase II JAK2 inhibitor trials
Multiple myeloma (Abs Multiple myeloma (Abs 8007, 8020 8007, 8020 )) Phase III trialsPhase III trials Phase II trialsPhase II trials
Phase III Registration Phase III Registration TrialsTrials
COMFORT I Primary COMFORT I Primary EndpointEndpoint
Number of subjects Number of subjects achieving ≥ 35% achieving ≥ 35% reduction in spleen volume reduction in spleen volume from baseline to week 24*from baseline to week 24*
COMFORT II Primary COMFORT II Primary
EndpointEndpoint Number of subjects Number of subjects
achieving ≥ 35% reduction achieving ≥ 35% reduction in spleen volume from in spleen volume from baseline to week 48*baseline to week 48*
* As measured by MRI (or CT scan in applicable subjects).
COMFORT I
EUROPE: Austria, Belgium, France, Germany, Italy, Netherlands, Spain, Sweden, UK
COMFORT II
USA, Canada, Australia
Randomized2:1
Patientswith MF(N = 309)
Patientswith MF(N = 309)
Randomized1:1
INC424 (oral) 15 mg BID or
20 mg BID
INC424 (oral) 15 mg BID or
20 mg BID
Placebo (oral) BID
Placebo (oral) BID
Patientswith MF(N = 219)
Patientswith MF(N = 219)
INC424 (oral) 15 mg BID
or 20 mg BID
INC424 (oral) 15 mg BID
or 20 mg BID
Best available therapyBest available therapy
Both trials ongoing but completed enrollment
Verstovsek et. al. ASCO 2011 a6500
Harrison et. al. ASCO 2011 a6501
• Grade 3 and grade 4 anemia and thrombocytopenia were more common in those with higher baseline grade
• Discontinuation of treatment because of anemia and thrombocytopenia was rare (1 patient in each treatment group for each event)
49
Hematology Laboratory Values(Worst Grade on Study)*
*Patients are included at their worst on study grade regardless of whether this represents a change from their baseline.
Verstovsek et. al. ASCO 2011 a6500
COMFORT-II COMFORT-II Efficacy ResultsEfficacy Results
Ruxolitinib BAT
Week 48
Ruxolitinib BAT
Week 24
Primary Endpoint Key Secondary Endpoint
28.5%28.5% 31.9%31.9%
Ruxolitinib95% CI: 21.3, 36.6
P < .0001
Ruxolitinib95% CI: 24.4, 40.2
P < .0001
% W
ith
≥ 3
5% S
ple
en V
olu
me
Re
du
ctio
n
% W
ith ≥
35%
Sp
leen
Vol
ume
Red
uctio
nBAT
95% CI: 0.0, 5.0BAT
95% CI: 0.0, 5.0
0 0
Harrison et. al. ASCO 2011 a6501
Change in EORTC QLQ-C30 Scores Change in EORTC QLQ-C30 Scores From Baseline to Week 48From Baseline to Week 48
• Patients in the ruxolitinib arm had more improvement in symptoms compared with patients in the BAT arm
• Improvements were seen by week 8 and continued through week 48 Scores selected represent symptoms relevant to MF patients.
Wo
rsen
ing
Imp
rove
me
nt
Pain
Appetite loss
Dyspnea
Fatigue Insomnia
Mea
n ch
ange
from
bas
elin
e
Ruxolitinib
BAT
Harrison et. al. EHA 2011 (a1020) Oral Sunday
Harrison et. al. ASCO 2011 a6501
Comparing JAK2 InhibitorsComparing JAK2 InhibitorsEfficacyEfficacy
SpleenSpleen MFSymptoms
MFSymptoms AnemiaAnemia JAK2JAK2 TargetsTargets
Phase I Testing
RuxolitinibNEJM 2010, EHAa505 & 1020
TG101348/ SAR302503JCO 2011
SB1518EHA a1022 & a907
CYT387ASCO a6514
ASCO 2011ASCO 2011
Non-Hodgkin’s Lymphoma (Abs Non-Hodgkin’s Lymphoma (Abs 8031, 8032, 6508, 3065)8031, 8032, 6508, 3065) SGN35 trialsSGN35 trials BTK Inhibitor trial, CA-101 (PI3-kinase inh) trialBTK Inhibitor trial, CA-101 (PI3-kinase inh) trial
Chronic Lymphocytic Leukemia (Abs Chronic Lymphocytic Leukemia (Abs 6508, 30656508, 3065)) BTK Inhibitor trial, CA-101 trialBTK Inhibitor trial, CA-101 trial
Acute and Chronic Myeloid Leukemias (Abs Acute and Chronic Myeloid Leukemias (Abs 6509, 65106509, 6510, , 6511, 6518 6511, 6518 )) Front line TKI therapyFront line TKI therapy Second line TKI therapySecond line TKI therapy
Myeloproliferative Neoplasms (Abs Myeloproliferative Neoplasms (Abs 6500, 6501, 6514, 6500, 6501, 6514, 6515 6515 )) Ruxolitinib Phase III trialsRuxolitinib Phase III trials Ongoing Phase II JAK2 inhibitor trialsOngoing Phase II JAK2 inhibitor trials
Multiple myeloma (Abs Multiple myeloma (Abs 8007, 80208007, 8020)) Phase III trialsPhase III trials Phase II trialsPhase II trials
Lenalidomide Maintenance vs Lenalidomide Maintenance vs PlaceboPlacebo
1:1
Placebo
Lenalidomide*10 mg
MEL 200ASCT
MM < 70 years > 2 cycles Rx> SD< 1 yr start of Rx> 2 x 106 CD34/kg
CRPRSD
N = 418
*Increased to 15 mg daily after 3 months if no toxicity.
McCarthy PL, et al. J Clin Oncol. 2010;(15S). Abstract 8017. Median follow-up = 1 year
CALGB 100104 Schema
McCarthy PL, et al. Blood. 2010;116(21):37.
Lenalidomide vs Placebo, TTPLenalidomide vs Placebo, TTP 460 patients 460 patients
randomizedrandomized
Median TTPMedian TTP HR = 0.40 HR = 0.40
60% reduction in the 60% reduction in the risk of disease risk of disease progressionprogression
McCarthy PL, et al. Blood. 2010;116(21):37. McCarthy PL , et al. J Clin Oncol. 2010:(15S). Abstract 8017.
TTP, time to progression; OS, overall survival.
1.0
8.0
0.6
0.4
0.0
0 500 1000 1500
Pro
bab
ility
of
Pro
gre
ssio
n
Days post auto-SCT
P< . 0001
LenalidomideMedian TTP = 48 months
PlaceboMedian TTP = 21.8 months
0.2
IMW Updated CALGB 100104IMW Updated CALGB 100104PlaceboPlacebon = 229n = 229
LenalidomiLenalidomidede
n = 231n = 231
HR [95%CI]HR [95%CI] PP
Median TTPMedian TTP 30.9 mo30.9 mo 48 mo48 mo 0.44 [0.32-0.60]0.44 [0.32-0.60] < < 0.00010.0001
Median EFSMedian EFS 30.9 mo30.9 mo 43.4 mo43.4 mo 0.51 [0.38-0.68]0.51 [0.38-0.68] < < 0.00010.0001
OS rateOS rate 80%80% 90%90% 0.51 [0.26-1.014]0.51 [0.26-1.014] 0.0180.01822oo malignancies malignancies HematologicalHematological Solid tumorsSolid tumors
440044
1818881010
NRNRNRNRNRNR
NRNRNRNRNRNR
TTP, time to progression; EFS, event free survival; OS, overall survival; HR, hazard ratio; mo, months; NR, not reported.
Median follow-up 28 months.
McCarthy P, et al. International Myeloma Workshop. 2011.
MP vs MPR vs MPR-R, Phase MP vs MPR vs MPR-R, Phase IIIIII
Median follow-up: 25 months
MPR-R MPR-R N = 152N = 152
MPRMPR N = 153 N = 153
MP MP N = 154N = 154
PP
CRCR 16%16% 11%11% 4%4% < 0.001< 0.001
>> VGPR VGPR 32%32% 33%33% 12%12% < 0.001< 0.001
Median PFSMedian PFS 31 mo31 mo 14 mo14 mo 13 mo13 mo < 0.001< 0.001
100
75
50
25
00 5 10 15 20 25 30
Time (months)
Patients
(%)
35 40
MPR-R
MPR
MP
Palumbo A, et al. Blood. 2010;116(21):Abstact 622;J Clin Oncol Annual Meeting Abstracts. 2011;28(15S). Abstract 8007.
Progression-Free Survival
IMW Updated MM015IMW Updated MM015
MPR-RMPR-Rn = 150n = 150
MPRMPRn = 152n = 152
MPMPn = 153n = 153
TotalTotal 12 (8.0%)12 (8.0%) 9 (5.9%)9 (5.9%) 4 (2.6%)4 (2.6%)
HematologicHematologic 7 (4.7%)7 (4.7%) 5 (3.3%)5 (3.3%) 1 (0.7%)1 (0.7%)
Solid tumorsSolid tumors 5 (3.3%)5 (3.3%) 4 (2.6%)4 (2.6%) 3 (2.0%)3 (2.0%)
MP, melphalan, prednisone; MPR, MP + lenalidomide; MPR-R, MPR with continued lenalidomide.
Palumbo A, et al. International Myeloma Workshop. 2011.
Palumbo A, et al. J Clin Oncol Annual Meeting Abstracts. 2011;28(15S). Abstract 8007
Rd → MPR vs Rd → MEL200 / Rd → MPR vs Rd → MEL200 / ASCTASCT
R: lenalidomide; M: melphalan; P: prednisone; d: dexamethasoneThromboprophylaxis was randomized between aspirin and low molecular weight heparin
Palumbo A, et al. J Clin Oncol Annual Meeting Abstracts. 2011;28(15S). Abstract 8020.
Response to ProtocolResponse to Protocol MPRMPRn = 130n = 130
MEL200MEL200n = 143n = 143
PP
CRCR 20%20% 25%25% 0.490.49
>> VGPR VGPR 60%60% 37%37% 0.240.24
24-month PFS24-month PFS 59%59% 73%73% 0.0030.003
1:1MPR
MEL 200 ASCT
Untreated MM < 65 yrs
Rd x 4 cycles
1:1No Maintenance
Maintenance
R1 R2
Rdx 4
Median Follow-up = 20 months.
Alternative Mode of Alternative Mode of AdministrationAdministration
Moreau P, et al. Blood. 2010;116(21). Abstract 312.
IV IV BortezomibBortezomib
N = 73N = 73
SC BortezomibSC BortezomibN = 145N = 145
PP
ORR after 8 cyclesORR after 8 cycles CRCR >> VGPR VGPR
52%52%12%12%25%25%
52%52%10%10%25%25%
NSNSNSNSNSNS
Median TTPMedian TTP 9.4 months9.4 months 10.4 months10.4 months 0.390.391-year OS1-year OS 77%77% 73%73% NRNRAny grade 3/4 AEAny grade 3/4 AE 70%70% 57%57% NRNRPN PN Any gradeAny grade >> grade 3 grade 3
53%53%16%16%
38%38%6%6%
0.040.040.030.03
IV: intravenous; SC: subcutaneous; CR: complete response; VGPR: very good partial response; TTP: time to progression; OS: overall survival; AE: adverse event; PN: peripheral neuropathy.
Newly Diagnosed: CRd Upfront, Newly Diagnosed: CRd Upfront, Phase I / IIPhase I / II
Dose modifications requiredDose modifications required 3 (10%): carfilzomib3 (10%): carfilzomib 4 (13%): lenalidomide4 (13%): lenalidomide 2 (6%): dexamethasone2 (6%): dexamethasone
Most common grade 3/4 AEMost common grade 3/4 AE Anemia, thrombocytopenia, hyperglycemiaAnemia, thrombocytopenia, hyperglycemia
CarfilzomibLenalidomideLow-dose dex
Newly Diagnosed MM
N = 32
1o EndpointMTD
2o EndpointDOR, TTP, OS, PFS, Safety
Jakubowiak AJ, et al. Blood. 2010;116(21). Abstract.
After 2 After 2 cyclescyclesn = 25n = 25
After 4 After 4 cycles cycles n = 22n = 22
After 8 After 8 cycles cycles n = 12n = 12
Best Best responseresponseN = 27N = 27
sCR / CR / sCR / CR / nCR nCR
24%24% 36%36% 67%67% 55%55%
>> VGPR VGPR 40%40% 59%59% 83%83% 70%70%>> PR PR 96%96% 100%100% 100%100% 96%96%