pi3k inhibitors in follicular lymphomapi3k inhibitors in follicular lymphoma anas younes, m.d....
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PI3KInhibitorsinFollicularLymphoma
Anas Younes, M.D.chief, Lymphoma ServiceMemorial Sloan Kettering Cancer Center
AKT
Receptortyrosine kinase
mTORC1
PIP2 PIP3
PI3-kinase
p85
p110
PTEN
S6K1 4EBP1Proteintranslation/synthesis
AKT
Receptortyrosine kinase
mTORC1
PIP2 PIP3
PI3-kinase
p85
p110
PTEN
S6K1 4EBP1Proteintranslation/synthesis
PI3K Pathway mutations do correlate with pathway activation in lymphoma
How to measure pathway activation?
Physiologic signaling Activated oncogenic signaling
RecurrentmTORC1-activatingRRAGCmutationsinfollicularlymphomaJessicaOkosun, RachelLWolfson, JunWang,Shamzah Araf,LucyWilkins, BrianMCastellano,LeireEscudero-Ibarz,Ahad Fahad AlSeraihi,JuliaRichter,StephanHBernhart,Alejo Efeyan,Sameena Iqbal,JanetMatthews,AndrewClear,JoséAfonso Guerra-Assunção, Csaba Bödör,HilmarQuentmeier,ChristopherMansbridge, PeterJohnson, AndrewDavies,JonathanCStrefford,GrahamPackham,SharonBarrans,AndrewJack,Ming-QingDu,MariaCalaminici, TAndrewLister,RebeccaAuer,SilviaMontoto,JohnGGribben, ReinerSiebert,ClaudeChelala, RobertoZoncu,DavidMSabatini&JudeFitzgibbon
NatureGenetics 48,183–188(2016)
Frequency 17%
Targeting PI3K/AKT/mTOR Pathway
mTORC1
AKT
S6K1 4EBP1
BADGSK3FOXOp53
SurvivalProlifera<onGrowthMetabolismApoptosisMo<lity
MK-2206XL-418VQD002
BEZ-235BGT226XL765
IdelalisibDuvelisibCopanlisibTGR-1202Buparlisib
EverolimusTemsirolimusRidaforolimus
PI 3-kinase Α, β, γ, δ
Single-agentActivityinRelapsedFollicular(andindolent)Lymphoma
UpdatedfromYounesA&BerryD.NatRevClinOncol 2012;9:643–653.
Respon
seRate
0%
25%
50%
75%
100%
Pathway Target DrugResponse Rate
DLBCL FL MCL SLL/CLL
T-Cell
HL
PI3K/AKT/mTOR
mTOR Everolimus 30% 50% 32% 18% 63% 42%
Temsirolimus 36% 56% 38% 10% - -
AKT MK2206 0% 25% 9% (50%) 0% 20%
PI3K-δ Idelalisib - 57% 40% 72% - 12%
TGR-1202 11% 42% 33% 63% - 13%
PI3K-γδ IPI-145 0% 67% 67% 54% 33% 33%
PI3K-αδ BAY80-6946 13% 40% 71% 67% 50% -
BKM120 12% 25% 23% - - -
B Cell Receptor (BCR)
Syk Fostamatinib 22% 10% 11% 55% 0% -
Btk Ibrutinib 26% 28% 75% 67% - -
Apoptosis Bcl-2 Venetoclax 15% 34% 75% 77%
Immune checkpoint
PD1 Nivolumab 36% 40% - - - 87%
Pambrolizumab - - - - - 66%
LeadingMolecularTargetsandDrugsinLymphoma
aCriterion for lymphadenopathy response [Cheson 2007]b 3 subjects no post baseline eva
□ 2 subjects NE ■ 1 subject PD luation:by Lymph Node biopsy
Phase 2 Idelalisib Monotherapy in Refractory iNHL Lymph Node Response
-100
-75
-25
0
-50a
+25
+50
IndividualPatients(N=125)
SPD
of M
easu
red
Lym
ph N
odes
,B
est %
Cha
nge
from
Bas
elin
e
•90% had improvement in lymphadenopathy•57% had ≥50% decrease from baseline
Gopal et al. NEJM 2014
Phase 2 Idelalisib Monotherapy in Refractory iNHL Duration Of Response and PFS
Analysis includes subjects who achieved a CR or PR (or MR for WM subjects) according to IRC assessments
Median DOR = 12.5 months
0
25
50
75
100
0 (71)
3(54)
6(34)
9(17)
12(9)
15(0)
18(0)
Time from Response, Months(N, Patients at Risk)
% C
ontin
ued
Res
pons
e
0
25
50
75
100
0(125)
3 (100)
6 (59)
9 (39)
12 (20)
15(13)
18(0)
Time from Start of Idelalisib, Months(N, Patients at Risk)
% P
rogr
essi
on-F
ree
Median PFS = 11 months
Gopal et al. NEJM 2014
PhaseIIStudyofBuparlisib (BKM120)inPatientswithRelapsed/RefractoryLymphoma
Younes.A,etal,ASH2015
PhaseIIStudyofBuparlisib (BKM120)inPatientswithRelapsed/RefractoryLymphoma
Younes.A,etal,ASH2015
PhaseIIStudyofBuparlisib (BKM120)inPatientswithRelapsed/RefractoryLymphoma
Younes.A,etal,ASH2015
Copanlisib (BAY80-6946)
Copanlisib (BAY80-6946)
MeasuringDrugEfficacyResponseRatevs PFS
DrugA:HDACi DrugB:rBV
-100
-75
-50
-25
0
25
50
1 3 5 7 9 11 13 15 17 19 21 23 25 27 29
-100
-75
-50
-25
0
25
50
75
1 3 5 7 9 11 13 15 17 19 21 23 25 27 29
BlockingResistanceMechanismsRationaleforcombiningPI3KiandBCL2i
mTORC1
AKT
S6K1 4EBP1
MK-2206XL-418VQD002
BEZ-235BGT226XL765
IdelalisibDuvelisibCopanlisibTGR-1202Buparlisib
EverolimusTemsirolimusRidaforolimus
PI 3-kinase Α, β, γ, δ
MCL1 BCL2 Venetoclax
BCL201/idelalisib comboinFLandMCL
CooperationBetweenPI3KandBCRSignalingPathway
PhaseI/IIOfIbrutinib +BKM120inrelapsedlymphoma
mTORC1
PI 3-kinase
AKT
IdelalisibIPI-145BKM-120BY80-6946
XL-147GDC-0941
GSK1059615
EverolimusTemsirolimusRidaforolimus
MK-2206XL-418VQD002
BEZ-235BGT226XL765
Myc Bcl2 ABT-199Myc Translation
EverolimusTemsirolimusSilvestrol
Myc TranscriptionHDACiBETi
CUDC-907Oral, dual inhibitor of HDAC and PI3K
HDACi PI3Ki
Enzyme HDAC PI3K
Isotype 1 2 3 6 10 α δ β γ
IC50 (nM) 1.7 5 1.8 27 2.8 19 39 54 311
SU-DHL 6
0.01 0.05 0.1 0.5 1+-
- - - - -
pS6 (S235/236)
p4EBP1 (Thr 37/46)
cMYC
Beta Actin
DMSOCUDC-907
HBL-1
0.01 0.05 0.1 0.5 1+-
- - - - -24h
pPRAS40(T246)
NUDHL-1
0.01 0.05 0.1 0.5 1+ - - - - --
Beta Actin
Ac Histone H3
Beta Actin
PARPCleaved PARP
Caspase 3Cleaved Caspase 3
GCB ABC DH
HD
LM2
KM
H2
SUD
HL4
L-42
8B
JAB
HB
L1 DB
NU
DH
L1SU
DH
L-10
RA
MO
SR
AJI
R
i-1U
2932
CA
46
SUD
HL6
LY
-19
SUD
HL8
TMD
8LY
-10
U-2
973
0.001
0.01
0.1
1
10
Dru
g, u
M
IC 50 72h
-10 -9 -8 -7 -6 -5 -40
50
100
150
SUDHL4SUDHL6SUDHL-8OCY-LY-19DBU2932TMD8HBL1
NUDHL1SUDHL-10U2973HDLM-2KMH-2L428
Ri-1OCI-LY-10
T0 T24h T48h T72h0
100
200
300
400DMSOCUDC 0.01CUDC0.05CUDC 0.1CUDC 0.5CUDC 1CUDC 5CUDC 10
T0 T24h T48h T72h-100
0
100
200
300DMSOCUDC 0.01CUDC0.05CUDC 0.1CUDC 0.5CUDC 1CUDC 5CUDC 10T0 T24h T48h T72h
0
50
100
150
200
250DMSOCUDC 0.01CUDC0.05CUDC 0.1CUDC 0.5CUDC 1CUDC 5CUDC 10
T0 T24h T48h T72h-200
0
200
400
600DMSOCUDC 0.01CUDC0.05CUDC 0.1CUDC 0.5CUDC 1CUDC 5CUDC 10
T0 T24h T48h T72h0
200
400
600
800
1000DMSOCUDC 0.01CUDC0.05CUDC 0.1CUDC 0.5CUDC 1CUDC 5CUDC 10
T0 T24h T48h T72h0
100
200
300
400DMSOCUDC 0.01CUDC0.05CUDC 0.1CUDC 0.5CUDC 1CUDC 5CUDC 10
T0 T24h T48h T72h-100
0
100
200
300DMSOCUDC 0.01CUDC0.05CUDC 0.1CUDC 0.5CUDC 1CUDC 5CUDC 10
T0 T24h T48h T72h0
100
200
300
400
500
SUDHL- 4
DMSOCUDC 0.01CUDC0.05CUDC 0.1CUDC 0.5CUDC 1CUDC 5CUDC 10
HL
ABC
BL
DH
GCB
Wilde typeMutationTranslocationAmplification
MYCBCL2TP53
MTOREP300
CD79BMYD88
EZH2MLL2
CREBBP
CARD11A20
IC50 72HRS
SUDHL-4 SUDHL-8
HBL-1 U-2932 KMH-1 HDLM2
DMSO0.010.050.1
CUDC-907,µM
0.51510
SUDHL-6
TMD8
%Ce
ll V
iabi
lity
T0 T24h T48h T72h0
100
200
300
400DMSOCUDC 0.01CUDC0.05CUDC 0.1CUDC 0.5CUDC 1CUDC 5CUDC 10
T0 T24h T48h T72h0
100
200
300
400
500DMSOCUDC 0.01CUDC0.05CUDC 0.1CUDC 0.5CUDC 1CUDC 5CUDC 10
NUDHL-1 SUDHL-10
%Ce
ll V
iabi
lity
%Ce
ll V
iabi
lity
DOSE CURVE 72 HRS
100.01 0.1 10.001
Drug,µM
CUDC-907ActivityinLymphoma
PI
Annexin V-FITC
SUD
HL-6
HBL-1
KM
H-2
NU
DH
L-1
DMSOCUDC 907 0.1uM
+-
-+ +-
-+ -
+ -+
PARPCleaved PARP
SUDHL-6 HBL-1 NUDHL-1 KMH-2
-+ -
+
Beta-Actin
24h
Caspase 3
Cleaved Caspase3
0
20
40
60
80
100
% C
ells
Dea
th
KMH-2
ns
0
20
40
60
80
100
% C
ells
Dea
th
HBL-1
0
20
40
60
80
100
% C
ells
Dea
th
NUDHL-1
**
**
HBL-1
NUDHL-1
KMH-1
0
20
40
60
80
100
% C
ells
Dea
th
SUDHL-6
**
SUDHL-6DMSOCUDC-907(0.1 µM)
% a
popt
otic
cel
ls%
apo
ptot
ic c
ells
% a
popt
otic
cel
ls%
apo
ptot
ic c
ells
CUDC-907InducesApoptosisInLymphomaCellLines
ABC
GCB
DLBCL: Maximum Target Lesion Change per Investigator Assessment
Younes,Aetal,LancetOncology(InPress)
Conclusions• PI3KPathwayinhibitorshavesingleagentactivityinFL,CLL,
andMCL• Idelalisib isapprovedforreapsed CLLandFL• Toxicityprofilevariesbasedon
– PI3Kisoformselection– Durationofadministration– Combinations
• MutationinthePI3K/mTOR pathwayinFLmayexplainsensitivityinFL