PI3K INHIBITION Gianluca Gaidano, M.D., Ph.D Division of Hematology - - PowerPoint PPT Presentation

PI3K INHIBITION

Division of Hematology Department of Translational Medicine Amedeo Avogadro University of Eastern Piedmont Novara-Italy

Gianluca Gaidano, M.D., Ph.D

Disclosures

Roche (Advisory Board) Janssen (Advisory Board) Amgen (Advisory board, research support) Gilead (Speakers’ bureau) Novartis (Advisory Board) Morphosys (Advisory Board) Abbvie (Advisory Board) Karyopharm (Advisory Board)

Outline

• Rationale for the need to circumvent genotoxic refractoriness
• The B cell receptor in B cell malignancies
• Therapeutic targets of the B cell receptor cascade: PI3K

NF-kB

BIRC3 NFKBIE

NOTCH

NOTCH1 FBXW7 SPEN Apoptosis BCL2

TLR

MYD88

Molecularly deregulated cellular programs in indolent B-cell malignancies

mIR15/16 DNA damage response

P

TP53

P

TP53

P

Cell cycle TP53 ATM SF3B1 POT1 CDKN2A MYC

Puente, Nature 2015

Pathogenesis of CLL

Initiation Progression Chemorefractoriness Transformation Microenvironment Interactions Trasforming Lesion Secondary Lesion Predisposition Promotion/Accumulation

Polygenic IRF4 IRF8 MYC Other del13q +12 TP53 NOTCH1 SF3B1 BIRC3 ATM MYC CDKN2A Signaling pathways BCR NF-kB TLR CD38 VLA-4 integrins NOTCH CXCR4

Font size according to gene mutation prevalence Fabbri, J Exp Med 2011; Puente, Nature 2011; Rossi, Blood 2011; Quesada, Nat Genet 2011; Wang, N Engl J Med 2011; Rossi, Blood 2012, Puente, Nature 2015

CLL mutations disclosed by NGS studies

• One of the tumor with the lowest background mutation load (0.6 per Mb)
• No unifying gene mutations
• TP53, NOTCH1, SF3B1, ATM mutated in >5% CLL

TP53 abnormalities in CLL

5’ 3’ 1 DNA BINDING EX4 EX9 393 Missense Nonsense Frameshift

TP53

Frequency

0% 10% 20% 30% 40% 50% 60% 70% 80% 90% 100% MBL Early stage CLL CLL requiring treatment F-refactory CLL Richter syndrome TP53 M del17p13 TP53 M/del17p13 N=1/63 (1.5%) N=30/318 (9.4%) N=44/99 (44.4%) N=25/38 (65.7%) N=13/268 (4.8%) Dohner et al, New Engl J Med 2000 ; Rasi et al, Haematologica 2012; Zainuddin et al, Leuk Res 2011; Zenz et al J Clin Oncol 2010;Rossi et al Blood 2011

1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1

1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1

1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1

1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1

1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1

1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1

1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1

All normal IGHV U +12 17p- 11q- 13q- IGHV M

NOTCH1 SF3B1 TP53 17p 11q 12 13q IGHV-U

Chr17

DNA damage P p53 P p21 cyclin B p53 P cyclin B cdc2 p21 BAX Caspase 9 Apoptosis Cell cycle arrest

17p-censored 11q-censored +12q-censored 13q-single- censored No aberration- censored

Months Hallek et al, ASH 2009 0 6 12 18 24 30 36 42 48 1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0.0 0 6 12 18 24 30 36 42 48 54 PFS Months

FCR

17p- on FCR

TP53 abnormalities in CLL

Stilgenbaueret al, ASH 2012 FC and TP53WT FC and TP53mut FCR and TP53WT FCR and TP53mut

EHA-20: Ljungstrom S121; Tausch LB2070 (novel FCR prognosticators)

Allo-SCT in High-Risk CLL CLL3X: multicenter GCLLSG

24 48 72 96 50 100 unknown (18) 17p- (13) 11q- (26)

• ther (21)

13q- (12)

Months from SCT

Dreger P, et al., Blood 2010; Dreger P, et al. Blood 2013

Genomic aberrations

Event-free Survival

Clonal architecture of TP53 mutated CLL

Scenario 1 Scenario 2 Scenario 3

TP53 mutation representation 80% TP53 mutation representation 20% TP53 mutation representation 1%

Detectable by Sanger sequencing Barely detectable by Sanger sequencing Not detectable by Sanger sequencing

TP53 unmutated Solely subclonal TP53 M Clonal TP53 M

263 122 15 18 4 28 6 Events Total 5-year OS 95% CI 77 263 75.1% 69.5-80.7% 9 18 46.3% 22.0-70.6% 19 28 34.6% 15.8-53.4%

• .0042

.<.0001 .0042

• .6926

<.0001 .6926

• p from pairwise comparisons
• No. at risk

Small TP53 mutated subclones have the same unfavorable prognostic impact as clonal TP53 defects

Rossi, Blood 2014

• 20%

0% 20% 40% 60% 80% 100%

• 10 -5

5 10 15 20 25 30 35 40 45 del17p p.G244D

Allele frequency ID9245 0.9% 66.0% 58.0%

FCR CR Diagnosis months Relapse Refractoriness

TP53 M (p.G244D)

Small TP53 mutated subclones are selected by treatment because of their chemoresistance

Small TP53 mutated subclone admixed to TP53 wild type clones Removal of TP53 wild type clones and selection of the TP53 mutated subclone Expansion of the TP53 mutated clone

Diagnosis Chemotherapy Progression Chemotherapy Refractoriness

TP53 mutated CLL cell

TP53 unmutated Solely subclonal TP53 M Clonal TP53 M

Poor outcome

Rossi, Blood 2014

Outline

• Rationale for the need to circumvent genotoxic refractoriness
• The B cell receptor in B cell malignancies
• Therapeutic targets of the B cell receptor cascade: PI3K

VH genes=44-52 D genes=27 JH genes=6 Cm VH D JH Cm 6-26 aa CDR3 VL VH CL CH SHM

P P

LYN SYK LYN

P P

LYN SYK

P P

SYK

External antigens Cell autonomous BCR signal

P P P P

LYN SYK

Y Y Y Y P P P P

LYN SYK

Y Y Y Y

von Minden MD et al, Nature. 2012

BCR rearrangement is the first genetic hit in CLL

Interaction between the CDR3 region of one BCR with another BCR that functions as an autoantigen Autoantigens exposed on apoptotic cells Microbial antigens

Chu CC et al, Blood. 2008; Catera R et al, Mol Med. 2008; Steininger C et al, Blood. 2012

Chronic BCR signaling

Stromal cell Nurse like cell

SDF-1

(CXCL12)

Solid Tissue

Blood

Exit

Blood

BCR signaling TLR signaling

CD5

CLL

CXCR4 CD38 BCR

CLL

CXCR4 CD5 CD38 BCR

CLL

CXCR4 CD5 CD38 BCR

CLL

CXCR4 CD5 CD38 BCR

CLL

CXCR4 CD5 CD38 BCR CLL CXCR4 CD38 BCR CLL CXCR4 CD38 BCR

Release

Death Life

Proliferative compartment Resting, re-entry compartment

CD5

Bulk

CD5

Re-initiate or survive/rest

CLL cells interact with the microenvironment through the BCR to gain proliferative advantages

Antigens?

Structural evidences

• Frequent expression of stereotyped BCRs: recognition of common antigens

Functional evidences

• High levels of BCR target genes in CLL cells
• Expression of constitutively active BCR signaling molecules
• BCR activation supports CLL cell survival in vitro

Clinical evidences

• Strong association between clinical course and IGHV mutation status
• BCR reactivity in vitro correlates with clinical course
• Response to BCR inhibitors

Hamblin et al, Blood 1999 Damle et al, Blood 1999 Messmer et al, J Exp Med. 2004 Agathangelidis A et al, Blood. 2012 Herishanu Y et al. Blood 2011 Byrd et al, NEJM 2013

Evidence that the initial expansion

• f the CLL clones is BCR driven

Outline

• Rationale for the need to circumvent genotoxic refractoriness
• The B cell receptor in B cell malignancies
• Therapeutic targets of the B cell receptor cascade: PI3K

Therapeutic targeting of BCR signalling

BCR: B-cell receptor; CML: chronic myeloid leukaemia

Wiestner A. J Clin Oncol 2013;31:128–130.

Antigen BCR CD79 Extracellular Intracellular

P P P P P P P P P

BTK LYN LYN S Y K A B PI3Kδ AKT mTOR PLCγ2 PKCβ IKK

NF-ĸB

PIP2 PIP3

Ibrutinib Acalabrutinib Idelalisib

P

S Y K

The different PI3Ks

p110ɑ p110β

p110δ

p110γ p85ɑ,β p55ɑ,γ p50ɑ p101 PI3K-C2ɑ PI3K-C2β PI3K-C2γ hVps34p

? p150

I II III

PI

B Class

Regulation Tyr kinase / associations Gβγ

? ?

PI / PI4P / PI4,5P2

C

PIK

Ras-B

C2

PI / PI4P

Adaptor/Regulat

• ry

subunit Catalytic subunit

A

C

PIK

Ras-B

C2 C

PIK

Ras-B

C2

PX

C2 C

PIK

C2

Ras-B: Ras binding domain Adapted from Vanhaesebroeck B, et al. Nat Rev Mol Cell Biol 2012;13:195–203.

PI3Kδ activates many downstream signalling pathways and is involved in crosstalk between multiple receptors RTK

P P P P P P

PIP2

P P P

PIP3

Class IB p110γ

GTP

ɑ β/γ GPCR Class IA

SH2 SH2

p110 ɑ/β/δ p85ɑ/β

Ras

SH3

Stimulation-dependent activation of Class I PI3K

GPCR: G protein-coupled receptor: RTK: receptor tyrosine kinase Adapted from: Guillermet-Guibert J, et al. Proc Natl Acad Sci USA 2008; 105:8292–8297. Maier U, et al. J Biol Chem 1999; 274:29311–29317; Kubo H, et al. Biochem J 2005; 392:607–614.

PI3Kδ (p110δ) catalyses conversion of PIP2 to PIP3, which acts as a second messenger

PTEN: phosphatase and tensin homologue

• 1. Castillo JJ, et al. Onco Targets Ther 2014; 7:333‒342.
• 2. Somoza JR, et al. J Biol Chem 2015; 290:8439-8446.

PIP3 acts as a second messenger to activate pathways that regulate metabolism, proliferation and motility2

P p110 p85

PIP2 PIP3 PTEN Metabolism Migration Cell survival Cell and organ size Motility DNA damage Nutrient response Cell cycle

P P

PI3Kδ inhibition impacts multiple critical pathways in B-cell malignancies

Survival Survival Proliferation Chemokine secretion Motility Homing Retention Adhesion

BCAP: B-cell adaptor for PI3K; BCR: B-cell receptor; BTK: Bruton's tyrosine kinase; GEF: guanine nucleotide exchange factor; mTOR: mammalian target of rapamycin; PI3K: phosphatidylinositol-3- kinase; PKC: protein kinase C; SFK: Src family kinase; SYK: spleen tyrosine kinase Coutre S, et al. Leuk Lymphoma 2015; ePub ahead of print.

aCD19+ cells from patients with CLL

CLL: chronic lymphocytic leukaemia; FL: follicular lymphoma; PI3K: phosphatidylinositol-3-kinase; MZL: marginal zone lymphoma; WM: Waldenström macroglobulinaemia 1. Herman SE, et al. Blood 2010; 116:2078‒88.

• 2. Yahiaoui OI, et al. BMC Cancer 2014; 14:565.
• 3. Leseux L, et al. Blood 2006; 108:4156–4162.

PI3K is constitutively activated in B-cell malignancies

• PI3K pathway may be constitutively activated in

some patients with FL,2,3 WM and MZL

CLL cellsa have a significantly higher intrinsic PI3K activity than normal B cells (p=0.006)1

PI3K activity per µg of protein

1.75 1.00 0.75 0.50 0.25 1.25 1.50

CLL cells Normal B cells

Idelalisib: a potent and selective inhibitor of PI3Kδ

In vitro activitya (IC50)1 of Idelalisib and activity in cell-based assays (EC50)2 PI3K isoform IC50 (nM)1a IC50-based PI3Kδ fold selectivity1 EC50 (nM)2 EC50-based PI3Kδ fold selectivity2 19 1 8.9 1 8600 453 >10,000 1124 4000 210 1419 153 2100 110 2500 281

ɑ β γ δ

a In presence of 2xKm adenosine triphosphate

EC50: half maximal effective concentration; IC50: half maximal inhibitory concentration; PI3K: phosphatidylinositol-3-kinase

• 1. Somoza JR, et al. J Biol Chem 2015;290:8439-8446.
• 2. Zydelig CHMP assessment report (Jul 2014; available at

www.ema.europa.eu).

Propeller shape of Idelalisib contributes to its potency and selectivity for p110δ

Idelalisib is a first-in-class, oral, reversible inhibitor selective for PI3Kδ Idelalisib bound Idelalisib specifically binds to p110δ

To date, no mutations in the Idelalisib binding site have been reported

Idelalisib directly inhibits PI3Kδ activation via the BCR

Control BCR stimulation* Idelalisib Idelalisib + BCR stimulation*

P-Akt Akt ERK1/2 β-actin P-ERK1/2

Immunoblot using Ab or phospho-specific (P) Ab

Idelalisib inhibited BCR-induced AKT activation in CLL cells Idelalisib inhibited BCR-stimulated cell survival in IGHV mutated and unmutated CLL cells

CLL cell survival absolute numbers at 48 hours (%) Control BCR stimulation* Idelalisib (5μM) + BCR stimulation* 100 40 60 80 20

IGHV mutated IGHV unmutated

aStimulated with anti-IgM antibody

BCR: B-cell receptor; CLL: chronic lymphocytic leukaemia; PI3K: phosphatidylinositol-3-kinase Hoellenriegel J, et al. Blood 2011; 118:3603‒3612

Idelalisib abrogates survival signals from the tumour microenvironment

Idelalisib significantly inhibited survival of CLL cells co-cultured with NLCs * * * *

20 40 60 80 100 48 hours

CLL CLL + NLC CLL + NLC + Zydelig (0.5 µM) CLL + NLC + Zydelig (1 µM) CLL + NLC + Zydelig (5 µM) CLL + NLC + Zydelig (10 µM)

CLL cell survivala (%) +NLC

*p<0.05 Idelalisib + CLL + NCL vs CLL + NLC

a Viabilities of Idelalisib-treated

samples were normalised to values in CLL + NLC group NLC: nurse-like cells Hoellenriegel J, et al. Blood 2011; 118:3603‒3612.

Idelalisib inhibits CLL cell chemotaxis and migration

P-Akt Akt ERK1/2 β-actin P-ERK1/2

Control BCR stimulation* Idelalisib + BCR stimulation* CXCL12 Idelalisib Idelalisib + CXCL12 CXCL13 Idelalisib + CXCL13

Idelalisib decreased chemotaxis of CLL cells in response to CXCL12 and CXCL13

Control Idelalisib 2000 4000 6000 8000 10000 Control CXCL12 CXCL13

Chemotaxis (migrated cells)

No chemokine p<0.05 p<0.05

Idelalisib abrogated activation of CXCR4 and CXCR5 in CLL cells

*Stimulated with anti-IgM monoclonal antibody CXCL: C-X-C motif chemokine ligand; PI3K: phosphatidylinositol-3-kinase Hoellenriegel J, et al. Blood 2011; 118:3603‒12

2 4 6 8 1 0 1 2 1 4 1 6 1 8 2 0 2 2 2 4 2 6 2 0 4 0 6 0 8 0 1 0 0 T im e (m o n th s )

P ro g re s s io n -fre e S u rv iv a l (% )

2 4 6 8 1 0 1 2 1 4 1 6 1 8 2 0 2 2 2 4 2 6 2 0 4 0 6 0 8 0 1 0 0

T im e (m o n th s ) O ve ra ll S u rv iv a l (% )

Idelalisib + R (n=110) Placebo + R (n=110) Idelalisib + R (n=91) Placebo + R (n=93)

Sharman et al. Blood 2014 124:330 (ASH meeting abstracts).

Overall survival Progression-free survival

Salvage treatment: idelalisib ORR idelalisib+R: 77% ORR placebo+R: 15%

Highly unfavourable features: PFS <24 months after previous Tx Appropriate for non cytotoxic treatment

• ANC <1000
• Plt <50
• CrCl <60 ml/min
• CIRS >6

Updated results from Phase 3 idelalisib and ofatumumab: PFS

Robak et al., EHA 2016, #P213

Updated results from Phase 3 idelalisib and ofatumumab: OS

Robak et al., EHA 2016, #P213

Badoux Blood 2011; Fisher J Clin Oncol 2011; O’Brien, ASH 2014; Sharman ASH 2014; Byrd ASH 2015; Stilgenbauer, ASH 2015

Chemoimmunotherapy (CIT) vs novel agents in TP53 disrupted CLL

0% 20% 40% 60% 80% 100%

Response rate

0% 20% 40% 60% 80% 100%

CR PR PR-L

35% 7% 83% 78% 79%

12-months PFS

18% 22% 80% 79% 72%

Response rate PFS

CIT Novel agents CIT Novel agents

Relapsed/Refractory CLL

0.2 0.4 0.6 0.8 1.0 Proportion With PFS 6 12 18 24 30 36 42 Months del(17p) del(11q) No del(17p) or del(11q) + Censored

TP53 disruption is a prognostic biomarker in CLL treated with ibrutinib Ibrutnib in trials Venetoclax Idelalisib+R Ibrutinib in real-world practice

Byrd JC, Blood 2015; Thompson PA, Cancer 2015; Winqvist M, Haematologica 2016; Barrientos, ASCO,2015, 7011; Roberts, et al New Engl J Med 2016

Comprehensive approaches incorporating clinical, serum, genetic, and molecular markers into a single risk score: CLL-IPI

Kutsch N BJ, J Clin Oncol 2015;33(suppl). Abstract 7002; Wierda W, J Clin Oncol 2011;29:4088-4095; Pflug N, Blood 2014;124:49-62

Variable Adverse factor Coeff. HR TP53 (17p) deleted and/or mutated 1.442 4.2 Grading 4 Prognostic Score 0 – 10 IGHV status Unmutated 0.941 2.6 B2M, mg/L > 3.5 0.665 2.0 Clinical stage Binet B/C or Rai I-IV 0.499 1.6 Age > 65 years 0.555 1.7 2 1 2 1

Risk group Score Patients N (%) 5-year OS, % Very High 7 – 10 62 (5) 23.3 3.6 High 4 – 6 326 (27) 63.6 1.9 Intermediate 2 – 3 464 (39) 79.4 3.5 Low 0 – 1 340 (29) 93.2

Time (months) Overall survival

Low Intermediate High Very high

Time (months) Time to first treatment

Low Intermediate High Very high

CLL-IPI score and prognostic factor analysis in R/R CLL in patients treated with idelalisib

Soumerai et al. EHA 2016, #P214.

Lymph node

BCR

CLL

CLL

Blood

chemokines

Kinase Kinase

integrins

Kinase Inhibitor

De Rooij, Blood 2012; Ponader, Blood 2012; Herman, abstract #185 CLL CLL CLL CLL

Redistribution lymphocytosis

Ibrutinib:

• Bruising, bleeding
• Atrial fibrillation
• Hypertension
• Arthralgia
• Drug interactions

CYP3A4 inducers/inhibitors affect inrutinib levels

Toxicities of BCR inhibitors

Idelalisib:

• Transaminitis
• Diarrhea/colitis
• Pneumonitis
• Infections
• Drug interactions

Idelalisib inhibits CYP3A4

Mutations that are inert under chemotherapy may become dangerous under new agents and vice versa

FCR resitant subclone KI resistant subclone

FCR

BTK inhibitors

Switch to another BCRi

ORR = 67%

Mato et al, ASH 2015

Switch to venetoclax

Coutre et al, EHA 2016

Phase 2 study of venetoclax in R/R CLL to ibrutinib or idelalisib

Old and new agents for CLL treatment

Idelalisib Venetoclax

BCL2

BCR

PI3K BTK

Ibrutinib Acalabrutinib Fludarabine Cyclophosphamide Bendamustine Chlorambucil Obinutuzumab Rituximab Ofatumumab

Can treatment decision be informed by biomarkers?

Ibrutinib FCR/BR Clb+anti-CD20 Idelalisib+R Venetoclax Ibrutinib Chemoimmunotherapy

TP53 status IGHV status

Chemoimmunotherapy

TP53 status

Untreated Relapsed

Two patients had no post-baseline evaluation: a one patient was not evaluable and

b one patient had disease progression on the basis of lymph node biopsy, no baseline evaluation

SPD: sums of the products of the perpendicular dimensions Gopal AK, et al. ASH 2014 (Abstract 1708).

Idelalisib effectively reduced lymph node size in 89% of FL patients

56% of patients achieved lymph node response (long-term follow-up; June 2014 cut-off)

SPD of measured lymph nodes, best % change from baseline Individual FL patients (n=72) +50 –25 +25 –50 –75 –100

a b

Includes patients who achieved a complete response or partial response (or minor response for LPL/WM) according to independent review committee assessments Gopal AK, et al. ASH 2014 (Abstract 1708, poster presentation).

Disease progression delayed in a heavily pretreated iNHL population

PFS (%) Time from start of treatment (months)

Patients at risk, n 72 35 18 11 5 1 28 12 7 4 4 1 15 6 3 2 – – 10 7 5 5 3 2

Long-term follow-up Median PFS (all patients):11.0 months

100 50 75 25 6 12 24 30 18

MZL (n=15) LPL/WM (n=10) FL (n=72) SLL (n=28)

• 1. Gopal AK, et al. N Engl J Med 2014; 370:1008–1018.
• 2. Gopal AK, et al. ASH 2014 (Abstract 1708, poster presentation).

OS prolonged in a heavily pretreated iNHL population

100 50 75 25 3 15 21 18 24 6 9 12 OS (%) Time from start of treatment (months)

Updated median OS: 30.8 months2

Median OS: 20.3 months1

Mechanism of BCR inhibitors: main clinical implications

• BCR inhibitors “circumvent” the chemorefractoriness to genotoxic agents

(classical chemo)

• BCR inhibitors “circumvent” TP53 disruption
• The mechanism of BCR inhibitors is independent of acquisition of MRD

negativity

BCR

LYN

Fcγ-R

CD79A DAG

CARD11

CD79B BLNK Y Y Y Y

P P

ITAM

PKCβ SYK

BTK

PLCγ2 MALT1 BCL10

IP3

P

NF-κB

Target Genes IKBKB

IKKα IKKγ

P P CD22 P P SHP-1

TCF3 ID3

IgH IgL LYN PI3Kδ AKT

SHP-1

The BCR undergoes genetic mutations in B cell NHL