asco review 2011 t martin, md asco, lugano, imf-paris highlights may - june, 2011

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




• 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




• 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 11:24 AM

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.


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.


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


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.


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



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)


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



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


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


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



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%

ConclusionsConclusions

Many Promising DrugsMany Promising Drugs New Monoclonal Ab’sNew Monoclonal Ab’s New targeted therapeuticsNew targeted therapeutics Many combination being testedMany combination being tested

Can’t wait until ASHCan’t wait until ASH

asco review 2011 t martin, md asco, lugano, imf-paris highlights may - june, 2011

Documents