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