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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. Purine nucleosides - PowerPoint PPT Presentation
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DEBATE: Do we have enough data to eliminate chemotherapy from initial CLL
therapy? Can kinase inhibitors and IMiDs replace chemotherapy?
Jennifer R Brown, MD PhDDirector, CLL Center
Dana-Farber Cancer InstituteOctober 25, 2013
1960s 1970s 1980s 1990s 2000s
Chemo-immunotherapy (CIT) 45% CR; better PFS & OSAlemtuzumab monotherapy 24% CRBendamustine 30% CR
Alkylating agents- Chlorambucil - Cyclophosphamide
5% CR
Purine nucleosides- Fludarabine- Pentostatin- Cladribine
5% - 20% CRBetter PFS in younger pts
Purine nucleosidesand alkylators
30% CRBetter PFS
Previously Untreated CLL
P<0.001
CLL8: Progression-Free Survival
Median PFS:FCR: 51.8 moFC: 32.8 mo(N=790Hazard ratio 0.563, p<0.001)
PFS rate 3 yrs post randomization:FCR: 64.9%FC: 44.7%
Incidence of Refractory Disease • 20-35% to single agent fludarabine• In GCLLSG CLL8:
PFS % pts OS 17p deln
TP53 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)
Median follow-up 20.7 months - n (%)
Median follow-up 53.2 months - n (%)
CR 0 5 (20%)
PR 14 (56%) 13 (52%)
SD 10 (40%) 6 (24%)
PD 1 (4%) 1 (4%)
ORR 56% 72%
Median DOR 16.6 mos 40.4 mos
Median time to best response 18.1 months (1.8-63.4)
Chen C, et al: ASH 2012
PFS and OS Outcomes (n=25)
7 patients have progressed 2 developed Richter’s transformation after discontinuation,
2 skin cancer, 1 recurrence of remote lung cancer
3 year PFS 64.6% (95% CI: 47.5-87.8%)
3 year OS 85.3% (95% CI: 71.1-100%)
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
PI3KαAlpha
PI3KBeta
PI3KδDelta
PI3KγGamma
Assay System
PDGF induced pAKT in
fibroblasts
LPA induced pAKT in
fibroblastsFceR1-induced
CD63 in basophils
fMLP-induced CD63 in
basophils
EC50 (nM) >20,000 1,900 8 3,000
0.0001 0.001 0.01 0.1 1 10 1000
25
50
75
100
Whole Blood (n=20)
PMBC (n=9)
CAL-101 (mM)
% +
CD
63
Ce
lls
(no
rma
lize
d(c
on
tro
l)
EC50=65 nMWhole Blood
Basophil Activation FceR1
Less than 10-fold shift in EC50 in whole blood
Idelalisib + Rituximab in Frontline CLL
Phase 2 Single Arm, Open Label Study
Study Schema
Primary Study: 101-08 Extension Study: 101-99
Rituximab(375 mg/m2)weekly x 8
Therapy continues as long aspatient receives benefit
Subject Accrual
Oct 2010
ThroughApr 2012
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 (150 mg BID) x 48 wks
Idelalisib + Rituximab in Frontline CLL
Demographics and Baseline CharacteristicsIdelalisib + R
N = 64 (%)
Age (yrs), median [range] 71 [65-90]
Rai Stage III-IV 27 42
β2 Microglobulin, mg/L, median [range] 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
Baseline Characteristics
Idelalisib + Rituximab in Frontline CLL
-100
-75
-50
-25
0
+25
+50
+75
+100
% C
han
ge
in S
PD
Nodal Response at 8 Weeks
Not evaluable N = 14• Patients without adenopathy at baseline, N =
12• Early withdrawal, N = 2
-100
-75
-50
-25
0
+25
+50
+75
+100
% C
han
ge
in S
PD
Not evaluable N = 16• Patients without adenopathy at baseline, N =
12• Early withdrawal, N = 2• No assessment, N = 2
Idelalisib + R Best Nodal Response
* 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 (100)
• Median Time to Response 1.9 months• 24/26 patients with B symptoms resolved by week 16
No on-study progression
Idelalisib + Rituximab in Frontline CLL
Improvement in Cytopenias
• Hematologic response rate– 17/17 with Anemia– 16/17 with Thrombocytopenia– 5/5 with Neutropenia
0 2 4 6 8 10 12 16 20 24 32 40 480
1
2
3
49
10
11
12
13
14
0
1
2
3
450
100
150
200
Platelets N=17
Neutrophil N=5Hemoglobin N=17
Time from Start of Idelalisib, Weeks
Hem
oglo
bin
x g/
dl M
ed, Q
1,Q
3P
late le ts x 1 0
3
/ lM
ed Q1,Q
3
AN
C x
10
3 / l
Med
, Q1,
Q3
Idelalisib + Rituximab in Frontline CLL
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* n (%) with Increase to Grade ≥ 3
Transaminase elevations 15 (23)Neutropenia 18 (28)Anemia 2 (3)Thrombocytopenia 1 (2)
All Cause AEs ≥25% in Primary and Extension Studies; On-Study Lab Abnormalities
Idelalisib + Rituximab in Frontline CLL
5 10 15 20 25 300
20
40
60
80
100
All Patients N=64
TP53 mutation/ Del (17p) N=9
BL
Months
Pro
bab
ility
of
PF
S
*ITT analysis of primary + extension studyExtension study assessments based on standard of care
Progression-Free Survival
PFS at 24 months: 93%
Ibrutinib (PCI-32765): BTK Inhibitor
• Forms a specific and irreversible bond with cysteine-481 in Btk
• Potent Btk inhibition • IC50 = 0.5 nM
• Orally available
• Once daily dosing results in 24-hr sustained target inhibition
N
N
NN
NH 2
O
N
O
PCYC-1102-CA: Phase Ib/II in CLL/SLL (Treatment Naïve ≥ 65 yrs population)
PCYC-1102-CA
117 patients
Dates enrolled20th May 10 – 27th Jul 11
Relapsed/Refractory420 mg/d (n=27)
Median follow-up 12.6monthsTreatment Naïve ≥ 65 yrs420 mg/d (n=26)
Median follow-up 14.4 months
Relapsed/Refractory840 mg/d (n=34)
Median follow-up 9.3 monthsHigh-risk
Relapsed/Refractory420 mg/d (n=25)
Median follow-up 2.8 monthsTreatment Naïve ≥ 65 yrs840 mg/d (n=5)*
Median follow-up 7.4 months
24
*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.
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)
840 mg/d(N=5)
Median time on treatment, months 21.3 (0.3, 26.6)
Subjects Discontinued, # (%) 4 (15) 1 (20)
Primary Reasons for Discontinuation, # (%)
Disease Progression
Adverse event Unrelated: viral syndrome Unrelated: Worsening GI hemorrhage Possibly related: fatigue
Subject withdrew consent “desired faster response”
1 (4)a
2 (8)b,c
1 (4)d
0 (0)
1 (20)e
Death on study, # (%) 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
Grade 1 Grade 2 Grade 3 Grade 4
Vomiting
Hypertension
Dizziness
Contusion/Ecchymosis
Rash
Dyspepsia
Fatigue
Nausea
Diarrhea
0% 10% 20% 30% 40% 50% 60% 70%
any
≥ g
3 in
fect
ion
0%10%20%30%40%50%
SafetyAdverse Events ≥ Grade 3
Ne
utr
op
en
ia
Th
rom
bo
cy
top
en
ia
An
em
ia
0%
10%
20%
30%
40%
50%
InfectiousHematologic
Grade 3 Grade 4 Grade 5
Best Response
0%
20%
40%
60%
80%
0%
Treatment Naïve(n=31)
2 not evaluable
CR
PR
SD
PD
71%
10%
13%
58%
3/31
18/31
3/314/31
PR w/ lymphocytosis
13%
4/31
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?
34
Lower CDCType II versus Type I antibody
Effectorcell
Increased Direct Cell DeathType II versus Type I antibody
Enhanced ADCCGlycoengineering for
increased affinity to FcγRIIIa
CD20 FcγRIIIa
ComplementGA101
B cell
GA101: Mechanisms of Action
• 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
RANDOMI
ZE 1:2:2
Rituximab + chlorambucil x 6 cycles
GA101 + chlorambucil x 6 cycles
Chlorambucil x 6 cyclesPreviously untreated CLL with comorbiditiesTotal CIRS* score > 6 and/or creatinine clearance < 70 ml/min
Age ≥ 18 years
N = 780 (planned)
Stage I, n = 590Additional 190 patients
to complete stage II
Stage IIG-Clb vs R-Clb
Stage IaG-Clb vs Clb
Stage IbR-Clb vs Clb
CLL11: Study Design
*Cumulative Illness Rating Scale
Summary • Kinase inhibitors and IMiDs (+/- anti-
CD20 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?
1960s 1970s 1980s 1990s 2000s
Chemo-immunotherapy (CIT) 45% CR; better PFS & OSAlemtuzumab monotherapy 24% CRBendamustine 30% CR
Alkylating agents- Chlorambucil - Cyclophosphamide
5% CR
Purine nucleosides- Fludarabine- Pentostatin- Cladribine
5% - 20% CRBetter PFS in younger pts
Purine nucleosidesand alkylators
30% CRBetter PFS
Previously Untreated CLL
2010s
Novel Targeted Therapies
(BCR, BCL2, IMiDs, ?)
+Monoclonal Antibodies
Acknowledgments
DFCI BiostatisticsDonna NeubergLillian WernerHaesook Kim Kristen Stevenson
Brown Lab, DFCIBethany TesarStacey FernandesSasha VartanovReina ImprogoJosephine Klitgaard
NIH, NHGRICLL Research Consortium
Okonow-Lipton FundMelton Fund Rosenbach Fund
Lymphoma Program, DFCIArnold S FreedmanDavid C FisherAnn S LaCasceEric Jacobsen Philippe ArmandMatthew Davids
Clinical ResearchKaren FrancoeurCaitlin Tesmer-BrierKaren CampbellShannon MililloHazel Reynolds
Center for CancerGenome Discovery, DFCIMegan HannaLaura Macconaill
Richard Furman, Susan O’Brien, John Byrd, John Seymour, Valentin Goede
Wu Lab, DFCICatherine WuDan-Avi LandauLili WangYouzhong Wan
Broad Institute Eric LanderGaddy GetzCarrie SougnezNir HacohenStacey GabrielMike LawrencePetar StojanovAndrey SivachenkoKristian CibulskisDavid Deluca