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)



Chronic Lymphocytic Leukemia (Abs 6508, 3065)



Front line CML-CP therapy trial updates
Second line TKI therapy
Myeloproliferative Neoplasms (Abs 6500, 6501,6514, 6515 )



BTK Inhibitor trial, CA-101 trial
Acute and Chronic Myeloid Leukemias (Abs 6509, 6510, 6511, 6518)


SGN35 trials
BTK Inhibitor trial, CA-101 (PI3-kinase inh) trial
Ruxolitinib Phase III trials
Ongoing Phase II JAK2 inhibitor trials
Multiple myeloma (Abs 8007, 8020 )


Phase III trials
Phase II trials
ABSTRACT 8031: Results of a Pivotal Phase 2 Study of
Brentuximab Vedotin (SGN-35) in Patients with Relapsed or
Refractory Hodgkin Lymphoma
R Chen, AK Gopal, SE Smith, SM Ansell, JD Rosenblatt, R Klasa,
JM Connors, A Engert, EK Larsen, DA Kennedy, EL Sievers, A Younes
ABSTRACT 8032: Durable Remissions with SGN-35
(Brentuximab Vedotin): Updated Results of a Phase II Study
in Patients with Relapsed or Refractory Systemic Anaplastic
Large Cell Lymphoma
B Pro , R Advani , P Brice , NL Bartlett, JD Rosenblatt, T Illidge, J Matous, R
Ramchandren, M Fanale, J M Connors, Y Yang, EL Sievers, DA Kennedy, A. R.
Shustov
Brentuximab Vedotin Mechanism of Action
Brentuximab vedotin (SGN-35) ADC
monomethyl auristatin E (MMAE), potent antitubulin agent
protease-cleavable linker
anti-CD30 monoclonal antibody
ADC binds to CD30
ADC-CD30 complex
traffics to lysosome
MMAE is released
MMAE disrupts
microtubule network
G2/M cell
cycle arrest
Apoptosis
Pivotal, Multicenter, Open-Label Study of Brentuximab
Vedotin in Relapsed/Refractory HL
Eligibility
Treatment (N=102)
• Relapsed or
refractory
CD30+ HL
• Brentuximab vedotin
1.8 mg/kg IV every
21 days
• Age ≥12 years
• Administered
outpatient over 30 min
• Measurable
disease ≥1.5 cm
• ECOG 01
• Prior ASCT
• Max 16 cycles for SD
or better
• Restage at Cycles
2, 4, 7, 10, 13, 16
Objectives: ORR (CR+PR), Survival (DOR, PFS, OS)
Follow-up
Every
12 weeks
Demographics and Baseline Characteristics
N=102
Age*
31 yr (1577)
Gender
48 M / 54 F
ECOG status
0
42 (41%)
1
60 (59%)
Refractory to frontline therapy
72 (71%)
Refractory to most recent treatment
43 (42%)
Prior chemotherapy regimens*
3.5 (113)
Prior radiation
67 (66%)
Prior ASCT
102 (100%)
Time from ASCT to first post transplant relapse*
6.7 mo (0131)
* Median (range)
Brentuximab Vedotin: Response Results
N=102
IRF
Investigator
Overall response rate (95% CI)
Complete remission
Partial remission
75% (65-83)
34%
40%
72% (62-80)
33%
38%
Stable disease
Progressive disease
22%
3%
27%
0%
Not evaluable
1%
1%
Tumor Size (% Change from Baseline)
Maximum Tumor Reduction per IRF
100
94% (96 of 102) of patients achieved tumor reduction
Individual Patients (n=98)*
* 4 patients were not included in the analysis
• 3 patients had no measurable lesions per IRF
• 1 patient had no postbaseline scans
% Patients Free of PD or Death
2º Endpoints: PFS and OS
Median (wks)
Overall survival
not reached
PFS per investigator 39.1
PFS per IRF
25.1
Time (Weeks)
Median (range) cycles of treatment = 9 (116)
Median DOR: 29 Wk (IRF); 47 Wk investigator
Treatment-Emergent Adverse Events of any Relationship
Occurring in ≥20% of Patients
Preferred Term
All Grades
Peripheral sensory neuropathy
47%
Fatigue
46%
Nausea
42%
Upper respiratory tract infection
37%
Diarrhea
36%
Pyrexia
29%
Neutropenia
22%
Vomiting
22%
Cough
21%
Patients with AEs leading to discontinuation = 20%
OTHER <20%: G3+4: Low Plats 8%, Anemia 6%, neuropathy
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
Eligibility
Treatment (N=58)*
• Relapsed or
refractory
systemic ALCL
• Brentuximab vedotin
1.8 mg/kg IV every
21 days
• Age ≥12 years
• Administered
outpatient over 30 min
• Measurable
disease ≥1.5 cm
FDG-avid
• ECOG 0 1
• Max 16 cycles for SD
or better
Follow-up
Every
12 weeks
• Restage† at Cycles
2, 4, 7, 10, 13, 16
* 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
SGN-35 in ALCL
Patient Characteristics
Male
Age
Alk negative
Median Prior therapies
Refractory to last treatment
Primary refractory
N = 58
57%
52 (14-76)
72%
2 (1-6)
50%
62%
SGN-35 in ALCL
■ RESULTS:
ORR
CR
DOR
86%
53%
NR (0.3-45.3 wks)
■ SAFETY:
PN
Nausea
Neutropenia
36% (> gr 3 10%)
24%
17%
Tumor Size (% Change from Baseline)
Maximum Tumor Reduction per IRF
97% of patients achieved tumor reduction
Individual Patients (n=57*)
* 57 of 58 patients with post-baseline CT assessments
% Patients Free of PD or Death
PFS by Disease Response, per IRF
CR
PR
SD
PD
HI*
Time (weeks)
* Histologically ineligible
(n=31)
(n=19)
(n=2)
(n=3)
(n=2)
Median PFS
not reached
19 weeks
12 weeks
5 weeks
not reached
Conclusions
SGN35 in 102 HD patients with post ASCT relapse


ORR = 75%; CR = 34%, median duration of response of 29 weeks

94% of patients achieved tumor reduction

Estimated 12-month overall survival = 88%

Manageable adverse events, PN largely reversible
SGN35 in R/R ALCL



ORR = 86%

CR = 53%

Adverse events manageable (PN, neutropenia, nausea, fatigue)
Further studies are ongoing
Non-Hodgkin’s Lymphoma/ B-cell Targets
B-Cell Signaling Kinases
CAL-101
PCI-32765
• 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
Nat Rev Imm 2:945
Abstract 6508: Activity and Tolerability
of the Btk Inhibitor PCI-32765 in
Patients with CLL/SLL: Interim
Results From a Phase IB/II Study
J Byrd, K Blum, J Burger, S Coutre, J
Sharman, R Furman, I Flinn, B Grant, D
Richards, W Zhao, N Heerema, A Johnson,
R Izumi, A Hamdy and S. O’Brien
Study Design

Single Agent BTK Inh: oral dosing

Cohort 1
Treatment Naïve (TN): >65 yo
 BTKI 420mg qd for 28-day cycle until disease progression


Cohort 2 (two doses)

Relapse Refractory (R/R): 2 prior treatments including 1
with Fludarabine



420mg qd for 28-day cycle until disease progression
840mg qd for 28-day cycle until disease progression
Objectives
ORR, DOR, PFS
 Safety, PK/PD

Subject Characteristics
TN 420mg/d,
N = 23
Age, y
Median
Range
Dx
CLL
SLL
Prior Tx:
Median
Range
Prior therapy
Nucleoside analog
Rituximab
Alkylator
Alemtumumab
Bendamustine
Ofatumumab
R/R 420mg/d,
N = 27
R/R 840mg/d,
N = 33
71
66 - 84
64
40 - 81
65
44 - 80
22 (96%)
1 (4%)
26 (96%)
32 (97%)
1 (3%)
0
3
2 - 10
5
2 - 12
N/A
27 (100%)
25 (93%)
24 (89%)
5 (19%)
8 (30%)
8 (30%)
33 (100%)
32 (97%)
27 (82%)
3 (9%)
13 (39%)
10 (30%)
Subject Characteristics (cont.)
TN 420mg/d,
N = 23
Prognostic Markers
IgVH unmutated
Del 17p
Del 11q
ß microglob
< 3mg/ml
> 3mg/ml
R/R
420mg/d, N = 27
R/R
840mg/d, N = 33
8/16 (50%)
2/17 (12%)
0/17
17/24 (71%)
9/24 (38%)
8/24 (33%)
18/24 (75%)
10/25 (40%)
12/25 (48%)
10/16 (62%)
6/16 (38%)
14/23 (61%)
9/23 (39%)
8/25 (32%)
17/25 (68%)
RESULTS: Responses
Treatment-Naïve
420 mg/d
Relapsed/refractory
420mg/d
Median f/u (months)
6.3 (1.4 -9.2)
7.8 (0.7 – 9.5)
Number of pts
23
27
CR
1 (5%)
1 (4%)
PR
13 (62%)
12 (44%)
ORR
67%
48%
Nodal
4 (19%)
11 (41%)
SD
2 (10%)
1 (4%)
PD
0
1 (4%)
NE
1 (5%)
1 (4%)
Best Response by Risk Features
Relapsed/refractory pts: 420 mg/d
Risk Features
N
WIG
Response
Nodal
Response
Overall
27
48%
41%
Del 17p
9
4/9 (44%)
3/9 (33%)
Del 11q
8
5/8 (63%)
3/8 (38%)
IgVH
unmutated
17
9/17 (53%)
5/17 (29%)
Common AEs (All Grades)
Treatment-Naive
420 mg/d (n=23)
Diarrhea
70%
48%
Nausea
33%
39%
Vomiting
22%
17%
Dyspepsia
Confusion
Relapsed/Refractory
420 mg/d (n=27)
19%
22%
33%
4%
Muscle spasms
17%
Fatigue
0%
37%
13%
17%
20%
33%
40%
Grade 1
4/13/2015 2:40:19 AM
11%
26%
Rash
URI
26%
80%
0%
Grade 2
Grade 3
60%
20%
40%
60%
80%
Grade 4
24
Conclusions
PCI-32765 is highly active in both treatmentnaïve and relapsed/refractory CLL/SLL patients
 Responses appear to be durable and
independent of high risk genomic features
 A high proportion (81%) of relapsed/refractory
pts are free- of –progression beyond 6 months
(420mg/d cohort)
 Toxicity of PCI-32765 is modest. The majority
of the AES are grade1 or 2

Abstract 3064: A Phase I Study of CAL-101, an isoformselective inhibitor of phosphatidylinositol 3-kinase P110d,
in Combination with anti-CD20 monoclonal antibody
therapy and/or Bendamustine in Patients with Previously
Treated B-cell Malignancies
W Flinn, M Schreeder, S Coutre, J Leonard, N Wagner-Johnston, S De
Vos, R Boccia, L Holes, S Peterman, L Miller, and A Yu
Background
1.
2.
CAL-101 is a selective inhibitor of p110d which may be
more active in hematopoietic malignancies
In a phase I trial, CAL-101 has shown promising activity in
indolent lymphoma (15/24, 62%), mantle cell lymphoma
(10/16, 62%) and CLL (ASH 2010 Abs 1777; ASCO 2011 Abs 3032)
Study Design

Two CAL-101 dose levels






CAL-101 100mg bid + Bendamustine 90mg/m2 d1,2
CAL-101 100mg bid + Rituximab 375mg/m2 d1
CAL-101 150mg bid + Bendamustine 90mg/m2 d1,2
CAL-101 150mg bid + Rituximab 375mg/m2 d1
Relapsed/refractory indolent NHL (iNHL) or
CLL
CAL-101 100mg
CAL-101 150mg
Accrual: Bendamustine
12
12
Rituximab
12
13
Patient Characteristics




Median age 64 years (range 41 – 87)
Males 65%
Refractory disease 43%
Median number of prior therapy: 3 (range 1 – 9)
28
RESULTS:

Efficacy
ORR
iNHL N = 22
CLL N = 13
Benda + CAL-101
10/12 (87%)
5/7 (78%)
Rituximab + CAL-101
9/10 (92%)
4/6 (62%)

Toxicity (Grade 3-4)
Neutropenia in Benda+CAL: 10/24
 Thrombocytopenia in Benda+CAL: 10/24
 Increased AST/ALT:

6/28 in iNHL
 1/21 in CLL

Conclusions
 CAL-101 shows acceptable toxicity
 Very Promising clinical activity in both
Rituximab and bendamustine cohorts
 Further studies on-going
ASCO 2011

Non-Hodgkin’s Lymphoma (Abs 8031, 8032, 6508, 3065)



Chronic Lymphocytic Leukemia (Abs 6508, 3065)



Front line TKI therapy
Second line TKI therapy
Myeloproliferative Neoplasms (Abs 6500, 6501,6514, 6515 )



BTK Inhibitor trial, CA-101 trial
Acute and Chronic Myeloid Leukemias (Abs 6511, 6518, )


SGN35 trials
BTK Inhibitor trial, CA-101 (PI3-kinase inh) trial
Ruxolitinib Phase III trials
Ongoing Phase II JAK2 inhibitor trials
Multiple myeloma (Abs 8007, 8020 )


Phase III trials
Phase II trials
“These two studies cap a remarkable decade of
progress in CML therapy and, for some, may raise
the question of whether we have reached the
limit of what we can hope to achieve. We know
that imatinib induces a long-lasting remission
but not a cure. Presumably, dasatinib and nilotinib
will perform similarly, but with deeper, longerlasting
remissions.”
Kantarjian et. al. ASCO a6510
Larson et. al. ASCO a6511
Study Design
Phase 3 open-label trial in
newly diagnosed chronic
phase CML
N = 502
139 sites
31 countries
Randomization is stratified based on Sokal risk
score and geographical regions.
R
A
N
D
O
M
I
Z
E
Bosutinib
500 mg/day
n = 250
5-year follow-up
Imatinib
400 mg/day
n = 252
5-year follow-up
1-year analysis

Key eligibility criteria: cytogenetic diagnosis of Philadelphia chromosome-positive chronic
phase chronic myeloid leukemia (CP CML) 6 mo prior, with no prior therapy other than
hydroxyurea or anagrelide

Primary endpoint: complete cytogenetic response (CCyR) at 12 months

Key secondary and exploratory endpoints:
 Major molecular response (MMR) at 12 months, duration of CCyR and MMR, time to
and incidence of transformation to accelerated or blast phase CML, event-free survival,
and overall survival
 Safety and tolerability
Gambacorti-Passerini et. al. ASCO a6509
Complete Cytogenetic Response Rates:
Intent-to-treat Population
●
The cumulative CCyR rate by 18 months was 79% for each treatment arm
●
Median time to first CCyR was faster for bosutinib (12.7 weeks) compared with
imatinib (24.6 weeks)
a
a
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.
aIndicates
Gambacorti-Passerini et. al. ASCO a6509
Major Molecular Response Rates:
Intent-to-treat Population
●
Cumulative MMR rates by 18 months were 55% for bosutinib and 45% for
imatinib, and cumulative CMR rates by 18 months were 18% and 10%, respectively
●
Median time to first MMR was faster with bosutinib (36.9 weeks) compared with
imatinib (72.3 weeks)
a
a
a
a
a
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.
aIndicates
Gambacorti-Passerini et. al. ASCO a6509
Transformation to AP/BP and Overall Deaths
a
AP, accelerated phase; BP blast phase.
aTreatment failure includes both disease progression and lack of efficacy (including transformation to AP/BP).
●
●
Transformation to AP/BP CML occurred in 4 (2%) patients in the bosutinib arm and 13
(5%) in the imatinib arm while on study treatment; no new transformation events have
occurred on bosutinib since the 12-month primary analysis, compared with 3 new events on
imatinib
Overall deaths occurred in 6 patients receiving bosutinib versus 13 receiving imatinib during
the study, the majority of which occurred after treatment discontinuation
 Deaths due to CML progression occurred in 5 patients receiving bosutinib and 9
receiving imatinib
Gambacorti-Passerini et. al. ASCO a6509
Treatment-emergent Adverse Events
Reported for 10% of Patients
Bosutinib
(n = 248)
Adverse event, %
Diarrhea
Vomiting
Nausea
Rash
Pyrexia
Upper abdominal pain
Abdominal pain
Headache
Upper respiratory tract infection
Fatigue
Arthralgia
Myalgia
Muscle cramps
Bone pain
Peripheral edema
Periorbital edema
Imatinib
(n = 251)
All grades
Grade 3/4
All grades
Grade 3/4
172 (69)
79 (32)
78 (31)
55 (22)
44 (18)
33 (13)
31 (13)
30 (12)
29 (12)
28 (11)
17 (7)
12 (5)
11 (4)
10 (4)
9 (4)
3 (1)
27 (11)
8 (3)
2 (1)
4 (2)
2 (1)
0
3 (1)
2 (1)
0
3 (1)
0
0
0
0
0
0
56 (22)
35 (14)
87 (35)
43 (17)
25 (10)
17 (7)
15 (6)
26 (10)
18 (7)
31 (12)
26 (10)
27 (11)
54 (22)
26 (10)
27 (11)
35 (14)
2 (1)
0
0
2 (1)
3 (1)
0
0
0
0
2 (1)
1 (1)
2 (1)
0
2 (1)
0
0
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 with
CML/AML: Preliminary findings from a Phase
I study in hematologic malignancies
M Talpaz, N Shah, M Deininger, M Mauro, I Flinn, S Lustgarten, W
Lindmark, J Gozgit, T Cclackson, C Turner, F Haluska, and J Cortez
Ponatinib(AP245534): Study Design



Oral multi-tyrosine kinase inhibitor; including
inhibition of bcr-abl and Flt3/ITD.
Goals: identify RP2D and estimate activity
Standard 3+3 Design


Oral daily dosing (cohorts 2, 4, 8, 15, 30 and 60 mg)
Demographics


Age
Disease




CML
PH (+) ALL
AML
# Prior Therapies
n=56
66 (26-85)
42 (31 CP, 6AP, 5 BP)
2
12 (Flt3/ITD 10/12)
3 (median)
Results: Ponatinib Responses

CML (R/R)






CHR
CCyR
MCyR
100%
57%
14%
CML AP/BC or ALL



85%
33%
48%
CML – T315I


CHR
CCyR
MCyR
MHR
CCyR
36%
9%
AML



ORR
CRi
PR
25%
16%
8%
Responses in Flt3 (+)
Only
Talpaz et al. Abstr 6518; ASCO 2011
Results: Safety

Related AE’s >10%:









Nausea/vomiting
Fatigue
Headache
Arthalgia/muscle spasma
Hot flashes
Rash
Elevated Lipase/Pancreatitis
G3/4 neutropenia
G3/4 thrombocytopenia
20%/15%
15%
13%
10%/10%
10%
10%
10% (4/12 at 60mg)
43%
40%
Results: Responses

Conclusions
RP2D= 45mg
 Well tolerated at RP2D
 CML: very promising

Active in T315 I mutation
 Active in AP/BC


AML: potentially promising
Active in treatment naïve Flt3(+)
 Combination with chemotherapy in Flt3 warranted

Talpaz et al. Abstr 6518; ASCO 2011
ASCO 2011

Non-Hodgkin’s Lymphoma (Abs 8031, 8032, 6508, 3065)



Chronic Lymphocytic Leukemia (Abs 6508, 3065)



Front line TKI therapy
Second line TKI therapy
Myeloproliferative Neoplasms (Abs 6500, 6501, 6514, 6515 )



BTK Inhibitor trial, CA-101 trial
Acute and Chronic Myeloid Leukemias (Abs 6509, 6510, 6511, 6518 )


SGN35 trials
BTK Inhibitor trial, CA-101 (PI3-kinase inh) trial
Ruxolitinib Phase III trials
Ongoing Phase II JAK2 inhibitor trials
Multiple myeloma (Abs 8007, 8020 )


Phase III trials
Phase II trials
Phase III Registration Trials
Verstovsek et. al. ASCO 2011 a6500
COMFORT I
Patients
with MF
(N = 309)
Randomized
1:1
INC424 (oral)
15 mg BID or
20 mg BID
Placebo (oral)
BID
COMFORT I Primary
Endpoint

USA, Canada, Australia
Harrison et. al. ASCO 2011 a6501
COMFORT II
Patients
with MF
(N = 219)
Randomized
2:1
INC424 (oral)
15 mg BID
or 20 mg BID
Best available therapy
Number of subjects achieving
≥ 35% reduction in spleen
volume from baseline to week
24*
COMFORT II Primary
Endpoint

Number of subjects achieving
≥ 35% reduction in spleen
volume from baseline to week
48*
EUROPE: Austria, Belgium, France, Germany, Italy,
Netherlands, Spain, Sweden, UK
* As measured by MRI (or CT scan in applicable subjects).
Both trials ongoing but
completed enrollment
Hematology Laboratory Values
(Worst Grade on Study)*
Ruxolitinib, n = 155
Placebo, n = 151
Grade 3
%
Grade 4
%
Grade 3
%
Grade 4
%
Hemoglobin
34.2
11.0
15.9
3.3
Platelets
9.0
3.9
1.3
0
Neutrophils
5.2
1.9
0.7
1.3
*Patients are included at their worst on study grade regardless of whether this represents a change from their
baseline.
• 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)
Verstovsek et. al. ASCO 2011 a6500
49
COMFORT-II Efficacy Results
Primary Endpoint
Key Secondary Endpoint
35
Ruxolitinib
95% CI: 21.3, 36.6
P < .0001
30
25
20
28.5%
15
BAT
95% CI: 0.0, 5.0
10
5
0
0
Ruxolitinib
% With ≥ 35% Spleen Volume Reduction
% With ≥ 35% Spleen Volume Reduction
40
BAT
Week 48
Harrison et. al. ASCO 2011 a6501
Ruxolitinib
95% CI: 24.4, 40.2
P < .0001
31.9%
BAT
95% CI: 0.0, 5.0
0
Ruxolitinib
Week 24
BAT
Change in EORTC QLQ-C30 Scores
From Baseline to Week 48
Harrison et. al. EHA 2011 (a1020) Oral Sunday
Ruxolitinib
BAT
5
6
4.8
3
0.4
0
-1.9
-5
Pain
-10
-15
9.5
Worsening
10
-6.3
-8.2
Dyspnea
-12.8
Fatigue
-12.3
Appetite
loss
Improvement
Mean change from baseline
15
Insomnia
• 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.
Harrison et. al. ASCO 2011 a6501
Comparing JAK2 Inhibitors
Efficacy
Spleen
MF
Symptoms
Anemia
JAK2
Ruxolitinib
NEJM 2010, EHAa505 & 1020
TG101348/ SAR302503
JCO 2011
SB1518
EHA a1022 & a907
CYT387
ASCO a6514
Phase I Testing
Targets
ASCO 2011

Non-Hodgkin’s Lymphoma (Abs 8031, 8032, 6508, 3065)



Chronic Lymphocytic Leukemia (Abs 6508, 3065)



Front line TKI therapy
Second line TKI therapy
Myeloproliferative Neoplasms (Abs 6500, 6501, 6514, 6515 )



BTK Inhibitor trial, CA-101 trial
Acute and Chronic Myeloid Leukemias (Abs 6509, 6510, 6511, 6518 )


SGN35 trials
BTK Inhibitor trial, CA-101 (PI3-kinase inh) trial
Ruxolitinib Phase III trials
Ongoing Phase II JAK2 inhibitor trials
Multiple myeloma (Abs 8007, 8020)


Phase III trials
Phase II trials
Lenalidomide Maintenance vs Placebo
CALGB 100104 Schema
Placebo
MM
< 70 years
> 2 cycles Rx
> SD
< 1 yr start of Rx
> 2 x 106 CD34/kg
1:1CR
MEL 200
ASCT
PR
SD
N = 418
Lenalidomide*
10 mg
*Increased to 15 mg daily after 3 months if no toxicity.
Median follow-up = 1 year
McCarthy PL, et al. Blood. 2010;116(21):37.
McCarthy PL, et al. J Clin Oncol. 2010;(15S). Abstract 8017.
Lenalidomide vs Placebo, TTP
Lenalidomide
Median TTP = 48 months
Probability of Progression
1.0
8.0

460 patients randomized

Median TTP

HR = 0.40

60% reduction in the risk of
disease progression
0.6
0.4
P< . 0001
0.2
Placebo
0.0 Median TTP = 21.8 months
0
500
1000
1500
Days post auto-SCT
TTP, time to progression; OS, overall survival.
McCarthy PL, et al. Blood. 2010;116(21):37.
McCarthy PL , et al. J Clin Oncol. 2010:(15S). Abstract 8017.
IMW Updated CALGB 100104
Placebo
n = 229
Lenalidomide
n = 231
HR [95%CI]
P
Median TTP
30.9 mo
48 mo
0.44 [0.32-0.60]
< 0.0001
Median EFS
30.9 mo
43.4 mo
0.51 [0.38-0.68]
< 0.0001
80%
90%
0.51 [0.26-1.014]
0.018
4
0
4
18
8
10
NR
NR
NR
NR
NR
NR
OS rate
2o malignancies
Hematological
Solid tumors
Median follow-up 28 months.
TTP, time to progression; EFS, event free survival; OS, overall survival; HR, hazard ratio; mo, months; NR, not
reported.
McCarthy P, et al. International Myeloma Workshop. 2011.
MP vs MPR vs MPR-R, Phase III
MPR-R
N = 152
MPR
N = 153
MP
N = 154
P
CR
16%
11%
4%
< 0.001
> VGPR
32%
33%
12%
< 0.001
31 mo
14 mo
13 mo
< 0.001
Median PFS
Progression-Free Survival
Median follow-up: 25 months
100
Patients (%)
75
MPR-R
MPR
50
MP
25
0
0
5
10
15
20
25
Time (months)
30
35
40
Palumbo A, et al. Blood. 2010;116(21):Abstact 622;J Clin Oncol Annual Meeting Abstracts. 2011;28(15S). Abstract 8007.
IMW Updated MM015
MPR-R
n = 150
MPR
n = 152
MP
n = 153
Total
12 (8.0%)
9 (5.9%)
4 (2.6%)
Hematologic
7 (4.7%)
5 (3.3%)
1 (0.7%)
Solid tumors
5 (3.3%)
4 (2.6%)
3 (2.0%)
MP, melphalan, prednisone; MPR, MP + lenalidomide; MPR-R, MPR with continued lenalidomide.
Palumbo A, et al. J Clin Oncol Annual Meeting Abstracts. 2011;28(15S). Abstract 8007
Palumbo A, et al. International Myeloma Workshop. 2011.
Rd → MPR vs Rd → MEL200 / ASCT
Untreated MM
< 65 yrs
Rd x 4 cycles
Rd
x4
MPR
1:1
No Maintenance
1:1
R1
R2
MEL 200
ASCT
Maintenance
R: lenalidomide; M: melphalan; P: prednisone; d: dexamethasone
Thromboprophylaxis was randomized between aspirin and low molecular weight heparin
MPR
n = 130
MEL200
n = 143
P
CR
20%
25%
0.49
> VGPR
60%
37%
0.24
24-month PFS
59%
73%
0.003
Response to Protocol
Median Follow-up = 20 months.
Palumbo A, et al. J Clin Oncol Annual Meeting Abstracts. 2011;28(15S). Abstract 8020.
Alternative Mode of Administration
IV Bortezomib
N = 73
SC Bortezomib
N = 145
P
ORR after 8 cycles
CR
> VGPR
52%
12%
25%
52%
10%
25%
NS
NS
NS
Median TTP
1-year OS
Any grade 3/4 AE
PN
Any grade
> grade 3
9.4 months
77%
70%
10.4 months
73%
57%
0.39
NR
NR
53%
16%
38%
6%
0.04
0.03
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.
Moreau P, et al. Blood. 2010;116(21). Abstract 312.
Newly Diagnosed: CRd Upfront, Phase I / II
Newly Diagnosed
MM
N = 32
1o Endpoint
MTD
o
2 Endpoint
DOR, TTP, OS, PFS, Safety
Carfilzomib
Lenalidomide
Low-dose dex
After 2 cycles
n = 25
After 4 cycles
n = 22
After 8 cycles
n = 12
Best response
N = 27
sCR / CR / nCR
> VGPR
24%
40%
36%
59%
67%
83%
55%
70%
> PR
96%
100%
100%
96%

Dose modifications required




3 (10%): carfilzomib
4 (13%): lenalidomide
2 (6%): dexamethasone
Most common grade 3/4 AE

Anemia, thrombocytopenia, hyperglycemia
Jakubowiak AJ, et al. Blood. 2010;116(21). Abstract.
Conclusions

Many Promising Drugs
New Monoclonal Ab’s
 New targeted therapeutics
 Many combination being tested


Can’t wait until ASH