Transcript Document

DEBATE: Do we have enough data to
eliminate chemotherapy from initial CLL
therapy? Can kinase inhibitors and
IMiDs replace chemotherapy?
Jennifer R Brown, MD PhD
Director, CLL Center
Dana-Farber Cancer Institute
October 25, 2013
Previously Untreated CLL
1960s
1970s
1980s
Purine nucleosides
Alkylating agents
- Fludarabine
- Chlorambucil
- Cyclophosphamide - Pentostatin
- Cladribine
5% CR
5% - 20% CR
Better PFS in
younger pts
1990s
2000s
Purine nucleosides
and alkylators
30% CR
Better PFS
Chemo-immunotherapy (CIT)
45% CR; better PFS & OS
Alemtuzumab monotherapy
24% CR
Bendamustine
30% CR
CLL8: Progression-Free Survival
Median PFS:
FCR: 51.8 mo
FC: 32.8 mo
(N=790
Hazard ratio 0.563,
p<0.001)
PFS rate 3 yrs
post
randomization:
FCR: 64.9%
FC: 44.7%
P<0.001
Incidence of Refractory Disease
• 20-35% to single agent fludarabine
• In GCLLSG CLL8:
PFS
% pts
OS
17p TP53
deln mutn
< 6 mos
(refractory)
11% (14.5 FC,
7.6 FCR)
21.9 mos
34%
44%
6 - <12
5.6%
21.2 mos
28%
24%
12 - < 24
14.3%
47.3 mos
11%
18%
30.9% of patients progressed within two years
CLL: Problems with Chemotherapy
• Continuous relapse at progressively shorter
intervals and progressive resistance to therapy
– Patients with 17p and/or complex cytogenetics respond
poorly from the start
• Elderly patients (most!) tolerate chemotherapy
poorly
– Myelosuppression, often persistent
• Risk of tMDS / AML
– Immunosuppression, often persistent
• Increased infection risks
• ? Increased risk of second malignancies
• Clonal evolution:
– ? Selection for pre-existing adverse clones vs induction of
new clones
What are the Alternatives?
• Mature data in previously untreated
patients:
(+/- rituximab)
– Lenalidomide
– Idelalisib (GS1101, CAL101)
– Ibrutinib
• Evolving data:
– Obinutuzumab
• Highly effective novel agents not yet tested
upfront: IPI-145, ABT199
What about Lenalidomide?
• Immunomodulatory agent
– Promotes CLL cell activation but is not
cytotoxic
– Promotes T cell function
• Effective in relapsed refractory CLL
with ORR 35-50%
– BUT can be difficult to tolerate, with tumor flare,
tumor lysis, myelosuppression
– Often better tolerated with antibody given first
• Mechanism of action still unclear
Lenalidomide for Upfront Therapy
in Elderly CLL Patients
88%
60%
Median F/U
24 mos
Blood 2011; 118:3489
Lenalidomide for Upfront Therapy
in Elderly CLL Patients
At 4 yr follow-up:
TTF NR
OS 82%
N=35 (58%) had
DOR >36 mos:
71% CRs
29% PRs
Blood 2013; 122:734
Immune Parameters Improved
on Lenalidomide
T cells
Immunoglobulins
Lenalidomide: Best Response (n=25)
CR
Median follow-up
Median follow-up
20.7 months - n (%) 53.2 months - n (%)
0
5 (20%)
PR
14 (56%)
13 (52%)
SD
10 (40%)
6 (24%)
PD
1 (4%)
1 (4%)
56%
72%
16.6 mos
40.4 mos
ORR
Median DOR
Median time to best response 18.1 months (1.8-63.4)
Chen C, et al: ASH 2012
PFS and OS Outcomes (n=25)
3 year PFS 64.6%
(95% CI: 47.5-87.8%)
3 year OS 85.3%
(95% CI: 71.1-100%)
 7 patients have progressed
 2 developed Richter’s transformation after discontinuation,
2 skin cancer, 1 recurrence of remote lung cancer
Summary: Status of Lenalidomide
• Mature data in previously untreated
elderly patients looks very promising
• BUT pivotal phase 3 study LEN vs
chlorambucil closed early due to
excess of deaths on LEN arm, plus
many patients dropped out early on
that arm
– Especially in patients >80
Targeting Kinases in the BCR
Pathway
Idelalisib (GS-1101; CAL-101)
Ibrutinib (PCI-32765)
Idelalisib: Highly Selective for PI3K Delta
PI3Kα
Alpha
PI3K
Beta
PI3Kδ
Delta
PI3Kγ
Gamma
Assay
System
PDGF induced
pAKT in
fibroblasts
LPA induced
pAKT in
fibroblasts
FceR1-induced
CD63 in basophils
fMLP-induced
CD63 in
basophils
EC50
>20,000
1,900
8
3,000
% +CD63 Cells
(normalized(control)
(nM)
Basophil Activation FceR1
100
75
EC50=65 nM
Whole Blood
50
PMBC (n=9)
25
Whole Blood
(n=20)
0
0.0001 0.001
0.01
0.1
1
CAL-101 (mM)
10
100
Less than 10-fold
shift in EC50 in
whole blood
Idelalisib + Rituximab in Frontline CLL
Phase 2 Single Arm, Open Label Study
Study Schema
Subject
Accrual
Oct 2010
Through
Apr 2012
Primary Study: 101-08
Idelalisib (150 mg BID) x 48 wks
Extension Study: 101-99
Therapy continues as long as
patient receives benefit
Rituximab
(375 mg/m2)
weekly x 8
Eligibility
• Age ≥65 years
• Treatment naive CLL requiring therapy (IWCLL
2008)
• No exclusions for cytopenias
Disease
Assessment
• Investigator determined
• Weeks 0, 8, 16, 24, 36, 48 and per SOC thereafter
Endpoints
• Primary: ORR
• Secondary: DOR, PFS, Safety
Idelalisib + Rituximab in Frontline CLL
Baseline Characteristics
Demographics and Baseline Characteristics
Age (yrs), median [range]
Rai Stage III-IV
β2 Microglobulin, mg/L, median [range]
Idelalisib + R
N = 64
(%)
71 [65-90]
27
42
4.0 (1.9-15.8)
Hematology Parameters
Hemoglobin < 11 g/dl
17
27
Platelets < 100 x103/µl
17
27
B-symptoms
26
41
Bulky adenopathy (≥ 5 cm)
7
11
IGHV unmutated (n = 60)
37
58
Either Del(17p) or TP53 mutation (n = 61)
9
14
Idelalisib + Rituximab in Frontline CLL
Idelalisib + R
Best Nodal
Response
+100
+100
+75
+75
+50
+50
% Change in SPD
% Change in SPD
Nodal Response
at 8 Weeks
+25
0
-25
+25
0
-25
-50
-50
-75
-75
-100
-100
Not evaluable N = 16
• Patients without adenopathy at baseline, N = 12
• Early withdrawal, N = 2
• No assessment, N = 2
Not evaluable N = 14
• Patients without adenopathy at baseline, N = 12
• Early withdrawal, N = 2
* Assessed by Physical Exam or CT
Idelalisib + Rituximab in Frontline CLL
Response Assessment
All Subjects
Del(17p) and/or
TP53 mutation
N = 64
(%)
N=9
(%)
Complete Response
12
(19)
3
(33)
Partial Response
50
(78)
6
(67)
Stable Disease
0
0
Progressive Disease
0
0
Not Evaluable
2
(3)
0
Overall Response
62
(97)
9
• Median Time to Response 1.9 months
• 24/26 patients with B symptoms resolved by week 16
No on-study progression
(100)
Idelalisib + Rituximab in Frontline CLL
Improvement in Cytopenias
200
150
11
100
10
P la te le t s N = 1 7
M e d , Q 1 ,Q 3
3
A N C x 1 0 /m l
H e m o g lo b in N = 1 7
9
4
3
3
2
2
1
1
0
0
0
2
4
6
8
10 12
16
20
24
32
T im e f r o m S t a r t o f Id e la lis ib , W e e k s
•
50
4
N e u t r o p h il N = 5
Hematologic response rate
– 17/17 with Anemia
– 16/17 with Thrombocytopenia
– 5/5 with Neutropenia
40
48
3
M e d , Q 1 ,Q 3
12
P la te le ts x 1 0 /m l
13
M e d Q 1 ,Q 3
H e m o g lo b in x g /d l
14
Idelalisib + Rituximab in Frontline CLL
All Cause AEs ≥25% in Primary and Extension Studies;
On-Study Lab Abnormalities
Adverse Event
n (%) with any Grade
n (%) with Grade ≥ 3
Diarrhea**
35 (55)
15 (23)
Pyrexia
27 (42)
2 (3)
Nausea
24 (38)
1 (2)
Rash
24 (38)
5 (8)
Chills
23 (36)
0
Cough
21 (33)
1 (2)
Fatigue
20 (31)
0
Pneumonia
17 (27)
11 (17)
**10 patients reported as Gr 3 colitis, including 6 lacking any AE report of Gr ≥ 3 diarrhea
Med time to Gr 3 diarrhea/colitis = 9 mos
Lab Abnormality*
Transaminase elevations
Neutropenia
Anemia
Thrombocytopenia
n (%) with Increase to Grade ≥ 3
15 (23)
18 (28)
2 (3)
1 (2)
Idelalisib + Rituximab in Frontline CLL
Progression-Free Survival
100
Probability of PFS
80
All Patients N=64
TP53 mutation/ Del (17p) N=9
60
PFS at 24 months: 93%
40
20
0
BL
5
10
15
20
25
30
Months
*ITT analysis of primary + extension study
Extension study assessments based on standard of care
Ibrutinib (PCI-32765): BTK Inhibitor
•
Forms a specific and
irreversible bond with
cysteine-481 in Btk
•
Potent Btk inhibition
O
NH 2
N
• IC50 = 0.5 nM
N
N
N
N
O
•
Orally available
•
Once daily dosing results in
24-hr sustained target
inhibition
PCYC-1102-CA: Phase Ib/II in CLL/SLL
(Treatment Naïve ≥ 65 yrs population)
Relapsed/Refractory
PCYC-1102-CA
117 patients
Dates enrolled
20th May 10
– 27th Jul 11
420 mg/d (n=27)
Treatment
Naïve
≥ 65 yrs
Median
follow-up
12.6months
420 mg/d (n=26)
Median follow-up 14.4 months
Relapsed/Refractory
840 mg/d (n=34)
Median follow-up 9.3 months
High-risk
Relapsed/Refractory
420 mg/d (n=25)
Median follow-up
2.8
Treatment
Naïve
≥ months
65 yrs
840 mg/d (n=5)*
Median follow-up 7.4 months
*The 840mg TN cohort was terminated after comparable activity and safety between doses was shown
in R/R patients. One patient in this cohort received only 420 mg daily.
24
Patient Characteristics
TN ≥65 yrs
(N=31)
Age, years
Median (Range)
≥ 70 years, (%)
71 (65 – 84)
74%
β2 Microglobulin > 3mg/L, %
26%
Rai Stage III/IV at Baseline
48%
Prognostic Markers, %
IgVH unmutated
del 17p13.1
del 11q22.3
55%
7%
3%
PCYC-1102-CA: Patient Disposition
(Treatment Naïve ≥ 65 yrs)
420 mg/d
(N=26)
Median time on treatment, months
Subjects Discontinued, # (%)
840 mg/d
(N=5)
21.3 (0.3, 26.6)
4 (15)
1 (20)
1 (4)a
0 (0)
2 (8)b,c
1 (20)e
Primary Reasons for Discontinuation, # (%)
Disease Progression
Adverse event
Unrelated: viral syndrome
Unrelated: Worsening GI hemorrhage
Possibly related: fatigue
Subject withdrew consent
“desired faster response”
Death on study, # (%)
1 (4)d
0
0
# days on ibrutinib: a) 280 days; b) 41 days; c) 115 days; d) 41 days; e) 9 days
Common AEs (>20%) Regardless of
Relationship
Diarrhea
Nausea
Fatigue
Dyspepsia
Rash
Contusion/Ecchymosis
Dizziness
Hypertension
Vomiting
0%
Grade 1
10%
20%
Grade 2
30%
40%
Grade 3
50%
60%
Grade 4
70%
Safety
Adverse Events ≥ Grade 3
Hematologic
Infectious
40%
30%
30%
20%
20%
10%
10%
0%
0%
any ≥ g3
infection
Anemia
40%
Thrombocytopenia
50%
Neutropenia
50%
Grade 3
Grade 4
Grade 5
Best Response
80%
71%
60%
3/31
4/31
13%
CR
PR
40%
18/31
PR w/
58%
lymphocytosis
SD
PD
20%
13% 10%
4/31
0%
3/31
0%
Treatment Naïve
(n=31)
2 not evaluable
PCYC 1102: Best Overall Response by
Risk Features
aOverall
response rate and 95% exact binomial CI
Immunoglobulin Levels Remain
Stable or Increased (IgA)
Durable Remissions with Ibrutinib
Monotherapy as Initial CLL Therapy
Summary
• Mature follow-up data with lenalidomide,
idelalisib-R, and ibrutinib demonstrate at
least comparable and possibly improved
PFS vs chemoimmunotherapy
• Oral agents are preferred by patients
and toxicities are manageable
• Can we improve further on these
outcomes?
GA101: Mechanisms of Action
Increased Direct Cell Death
Type II versus Type I antibody
Enhanced ADCC
Glycoengineering for
increased affinity to FcγRIIIa
Effector
cell
B cell
Lower CDC
GA101
Complement
CD20
FcγRIIIa
Type II versus Type I antibody
34
CLL11: Study Design
Stage I, n = 590
Previously
untreated CLL
with comorbidities
Total CIRS* score > 6
and/or creatinine
clearance < 70 ml/min
Age ≥ 18 years
N = 780 (planned)
•
•
•
•
R
A
N
D
O
M
I
Z
E
Additional 190 patients
to complete stage II
Chlorambucil x 6 cycles
1
:
2
:
2
GA101 + chlorambucil
x 6 cycles
Rituximab + chlorambucil
x 6 cycles
Stage Ia
G-Clb vs Clb
Stage Ib
R-Clb vs Clb
Stage II
G-Clb vs R-Clb
GA101: 1,000 mg days 1, 8, and 15 cycle 1; day 1 cycles 2–6, every 28 days
Rituximab: 375 mg/m2 day 1 cycle 1, 500 mg/m2 day 1 cycles 2–6, every 28 days
Clb: 0.5 mg/kg day 1 and day 15 cycle 1–6, every 28 days
Patients with progressive disease in the Clb arm were allowed to cross over to G-Clb
*Cumulative Illness Rating Scale
Summary
• Kinase inhibitors and IMiDs (+/- antiCD20 antibody) show durable remissions
in previously untreated patients
– Randomized comparisons to CIT ongoing
• ECOG FCR vs IR age < 70
• Alliance BR vs IR vs I age 65+
– Additional drugs (IPI-145, ABT199) are
poised to add to this landscape
• How do we best combine these agents,
i.e. how much does the antibody add?
– Is rapid remission induction important?
Open Questions
• How durable are the remissions in 17p
patients?
• How do we best sequence different novel
agents?
• Are more relapses occurring as Richter’s
transformation, even in previously untreated
patients?
• What are the long-term side effects of
continued therapy?
• Where do SCT or CAR T cell therapy fit?
Previously Untreated CLL
1960s 1970s
1980s
1990s
2000s
Purine nucleosides Purine nucleosides
Alkylating agents
- Fludarabine
and alkylators
- Chlorambucil
- Cyclophosphamide - Pentostatin
30% CR
- Cladribine
Better PFS
5% CR
5% - 20% CR
Better PFS in
younger pts
Chemo-immunotherapy (CIT)
45% CR; better PFS & OS
Alemtuzumab monotherapy
24% CR
Bendamustine
30% CR
2010s
Novel Targeted
Therapies
(BCR, BCL2,
IMiDs, ?)
+
Monoclonal
Antibodies
Acknowledgments
Richard Furman, Susan O’Brien, John Byrd, John Seymour, Valentin Goede
Brown Lab, DFCI
Bethany Tesar
Stacey Fernandes
Sasha Vartanov
Reina Improgo
Josephine Klitgaard
Wu Lab, DFCI
Catherine Wu
Dan-Avi Landau
Lili Wang
Youzhong Wan
Lymphoma Program, DFCI
Arnold S Freedman
David C Fisher
Center for Cancer
Ann S LaCasce
Genome Discovery,
Eric Jacobsen
DFCI
Philippe Armand
Megan Hanna
Matthew Davids
Laura Macconaill
DFCI Biostatistics
Donna Neuberg
Lillian Werner
Haesook Kim
Kristen Stevenson
Broad Institute
Eric Lander
Gaddy Getz
Carrie Sougnez
Nir Hacohen
Stacey Gabriel
Mike Lawrence
Petar Stojanov
Andrey Sivachenko
Kristian Cibulskis
David Deluca
Clinical Research
Karen Francoeur
Caitlin Tesmer-Brier
Karen Campbell
Shannon Milillo
Hazel Reynolds
Okonow-Lipton Fund
Melton Fund
Rosenbach Fund
NIH, NHGRI
CLL Research Consortium