Treatment Landscape in R/R DLBCL Novel Targets and Strategies - - PowerPoint PPT Presentation

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Treatment Landscape in R/R DLBCL Novel Targets and Strategies - - PowerPoint PPT Presentation

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Treatment Landscape in R/R DLBCL Novel Targets and Strategies Wyndham H. Wilson, M.D., Ph.D. Senior Investigator Gene-expression profiling of DLBCL subtypes Roschewski, M. et al. (2013) Nat. Rev. Clin. Oncol. Key signaling pathways in GCB DLBCL

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Treatment Landscape in R/R DLBCL Novel Targets and Strategies

Wyndham H. Wilson, M.D., Ph.D. Senior Investigator

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Gene-expression profiling of DLBCL subtypes

Roschewski, M. et al. (2013) Nat. Rev. Clin. Oncol.

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Key signaling pathways in GCB DLBCL

Roschewski, M. et al. (2013) Nat. Rev. Clin. Oncol.

Targeting PI3K

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Genetic aberrations activating PI3K pathway in hematologic malignancies

  • Deletion PTEN 10q23 locus: 10% GCB
  • Inactivation PTEN: 55% GCB and 14% ABC DLBCL
  • Mutation distribution suggests relevant in GCB > ABC

(Testoni et al. Ann Oncol 2015)

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Copanlisip: PI3 Kinase pan-class I inhibitor

Lenz et al, ASCO Proceedings, 2017

  • 40 Relapsed/refractory DLBCL
  • ORR 25%; 50% CR
  • Subset by COO
  • GCB ORR 13.6%
  • ABC ORR 37.5%
  • ORR not associated with mutations
  • BCL2 (54%); TP53 (41%); BCL6 (30%); MYC (22%); CD79A/B (25%);

MYD88 (19%); TNFAIP3 (17%); CARD1 (13%)1

  • Better response rate in ABC
  • Interaction of PI3K with BCR signaling likely important
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Key signaling pathways in GCB DLBCL

Roschewski, M. et al. (2013) Nat. Rev. Clin. Oncol.

Everolimus Nelfinovir

Targeting mTOR and AKT

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Disease type N ORR (95 CI) CR PR Total 77 30 (20–41) 3 20 DLBCL 47 30 (17–45) 14 MCL 19 32 (13–57) 2 4 FL-III 8 38 (9–76) 1 2 Other 3

!

Everolimus in R/R Aggressive Lymphoma

Witzig et al. Leukemia (2011) 25, 341–347

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MYC MYC translocation translocation

GCB

BCL2 BCL2 translocation translocation BCL2 BCL2 amplifcation amplifcation NF-kappa B Interleukin-6 and interleukin-10 Aberrant switch translocations Essential regulatory network Genomic instability Senescence FOXP1 SPIB IRF4 STAT3 AID INK4A-ARF deletion Trisomy 3 19q gain or amplifcation miR-17-92 amplifcation PTEN deletion ING1 deletion MDM2 gain or amplifcation P53 mutation Genomic instability mTOR activation Apoptosis Apoptosis

Malignant transformation Malignant transformation ABC Plasma cell Plasmablast Germinal center B-cell

MYC amplifcation MYC amplifcation

BCL-2 Translocations in GCB DLBCL

56%

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MYC MYC translocation translocation

GCB

BCL2 BCL2 translocation translocation BCL2 BCL2 amplifcation amplifcation NF-kappa B Interleukin-6 and interleukin-10 Aberrant switch translocations Essential regulatory network Genomic instability Senescence FOXP1 SPIB IRF4 STAT3 AID INK4A-ARF deletion Trisomy 3 19q gain or amplifcation miR-17-92 amplifcation PTEN deletion ING1 deletion MDM2 gain or amplifcation P53 mutation Genomic instability mTOR activation Apoptosis Apoptosis

Malignant transformation Malignant transformation ABC Plasma cell Plasmablast Germinal center B-cell

MYC amplifcation MYC amplifcation

BCL-2 Amplification In ABC DLBCL

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BCL-2-Rearrangement versus Expression

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MYC MYC translocation translocation

GCB

BCL2 BCL2 translocation translocation BCL2 BCL2 amplifcation amplifcation NF-kappa B Interleukin-6 and interleukin-10 Aberrant switch translocations Essential regulatory network Genomic instability Senescence FOXP1 SPIB IRF4 STAT3 AID INK4A-ARF deletion Trisomy 3 19q gain or amplifcation miR-17-92 amplifcation PTEN deletion ING1 deletion MDM2 gain or amplifcation P53 mutation Genomic instability mTOR activation Apoptosis Apoptosis

Malignant transformation Malignant transformation ABC Plasma cell Plasmablast Germinal center B-cell

MYC amplifcation MYC amplifcation

MYC translocation in GCB

10%

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MYC MYC translocation translocation

GCB

BCL2 BCL2 translocation translocation BCL2 BCL2 amplifcation amplifcation NF-kappa B Interleukin-6 and interleukin-10 Aberrant switch translocations Essential regulatory network Genomic instability Senescence FOXP1 SPIB IRF4 STAT3 AID INK4A-ARF deletion Trisomy 3 19q gain or amplifcation miR-17-92 amplifcation PTEN deletion ING1 deletion MDM2 gain or amplifcation P53 mutation Genomic instability mTOR activation Apoptosis Apoptosis

Malignant transformation Malignant transformation ABC Plasma cell Plasmablast Germinal center B-cell

MYC amplifcation MYC amplifcation

MYC amplification In ABC

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Key signaling pathways in GCB DLBCL

Roschewski, M. et al. (2013) Nat. Rev. Clin. Oncol.

Venetoclax (ABT-199)

Targeting BCL-2

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Phase 1 Study of Venetoclax (ABT-199 / GDC-0199) in Patients with Relapsed/Refractory Non-Hodgkin Lymphoma

Davids et al JCO 2016

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Phase 1 Study of Venetoclax (ABT-199 / GDC-0199) in Patients with Relapsed/Refractory Non-Hodgkin Lymphoma

Davids et al JCO 2016

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Phase 1 Study of Venetoclax (ABT-199 / GDC-0199) in Patients with Relapsed/Refractory Non-Hodgkin Lymphoma

Davids et al JCO 2016

  • Unimpressive response rate in DLBCL
  • DE does not appear to increase ORR
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Venetoclax in DLBCL

Thomas et al NCI data

  • How do you select patients?
  • Role of combination treatment?

Synergy (deltaBliss SumNeg)

ABT-199, Ibrutinib and Lenalidomide: drug vs drug interactions

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Lymphoma biopsy samples

NF-kB target gene

NF-kB Target Genes Are Highly Expressed in Activated B Cell-like Diffuse Large B Cell Lymphoma

Targeting NFKB in ABC DLBCL

Staudt et al NCI data

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Ibru%nib( Ibru%nib( MALT(inhibitors( Idelalisib( IRAK4(inhibitors( Bortezomib( Lenalidomide( Ruxoli%nib( SB15108( Everolimus( Temsirolimus( IRF4( Enzastaurin( Sotrastaurin(

BCR and MYD88 Pathways

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Ibrutinib in ABC DLBCL

Overall survival (months) Probability of survival ABC GCB Median OS (months) 10.32 3.35

Figure 1

Probability of survival

38 24 17 12 4 1 1 20 10 5 4 3 3 1

(0/4)

*

% Response (CR + PR)

10 20 30 40 50 60 70 80 90 100

CR PR PR (1/20) (14/38)

At risk: ABC: GCB: ABC: GCB:

Evaluable tumor (% change from baseline in SPD)

At risk:

ABC GCB

a b c d

700 150 750 100 50 –50 –100

Progression-free survival (months)

0.2 0.4 0.6 0.8 1.0

ABC GCB Median PFS (months) 2.02 1.31

38 32 19 14 10 8 6 3 2 20 13 4 2 0.2 0.4 0.6 0.8 1.0 1 2 3 4 5 6 7 8 9 10 12 14 16 18 20 22 3 6 9 12 15 18 21

** ***

ABC GCB

Wilson et al Nat Med 2015

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Ibrutinib in ABC DLBCL

Wilson et al Nat Med 2015

WT Mutant WT CD79B: Mutant Mutant MYD88: WT Mutant Mutant All other: 12/35 10/32 14/30 P value:

  • vs. other

1.00 0.057 0.031 Mutant WT

% response (CR + PR)

WT Inactive

% response (CR + PR) % response (CR + PR) % response (CR + PR)

(10/25) (4/12) (1/3) (4/5) (0/7) (8/24) (0/3) 10 20 30 40 50 60 70 80 90 100 (8/21) (0/5) 10 20 30 40 50 60 70 80 90 100 10 20 30 40 50 60 70 80 90 100 10 20 30 40 50 60 70 80 90 100 100 80 60 40 20 1.5 3.0 6.25 12.5 25 50 Ibrutinib (nM) Cell line: MYD88 mutation: BCR mutation: DLBCL subtype: Ly10 L265P CD79A ABC HLY1 S219C WT ABC TMD8 L265P CD79B ABC HBL1 L265P CD79B ABC Ly1 WT WT GCB Ly8 WT WT GCB BJAB WT WT GCB SUDHL2 S222R WT ABC

Live cells (% DMSO)

MYD88 TIR domain CARD11 coiled-coil domain TNFAIP3

* Hyperaddiction Hyperaddiction

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Phoenix Trial

Targeting BTK in Untreated ABC DLBCL

Phase III double blind randomized study R-CHOP ± Ibrutinib International Registration trial 800 patients (Janssen sponsor) Study Completed Accrual 2015 Tumors analyzed for molecular subtype and NGS (Staudt et al)

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Primary CNS Lymphoma Mutations in MYD88 and CD79

Mutation Summary Any: 76% CD79B: 53% MYD88: 56% Both: 37% Suggest “hyper” addiction to BCR signaling

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Primary CNS Lymphoma

282 Untreated Patients MSKCC

Abrey et al. JCO 2006, 24:5711

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Phase I Study of Ibrutinib and TEDDi-R Objectives

Ibrutinib response rate Ibrutinib safe tolerated dose with DA-

TEDDI-R

DA-TEDDi-R response and duration Tumor mutations in CD79 and MYD88

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SLIDE 28

6 5 4 3 2 1 7

  • 1
  • 2
  • 3
  • 4
  • 5
  • 6
  • 7

Etoposide Doxorubicin Cytarabine Raltitrexed Methotrexate Pralatrexate DNA damage Anti-folate Etoposide Doxorubicin Cytarabine Raltitrexed Methotrexate Pralatrexate DBSumNeg value (Ibrutinib synergy) DBSumPos value (Ibrutinib antagonism) DNA damage Anti-folate

B C

Anti-folate DNA damage Anti-folate DNA damage

DA-TEDDi-R Development TMD8 Cell Line Ibrutinib-Cytotoxic Drug Killing

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Dose Adjusted-TEDDI-R

d"1" D%14" d"5" d"2" d"4" d"3" d%1" d"6" d"8" d"7" d"9" d"10"

""""""Filgras6m"300"μg"SQ"on"days"6+" un6l"ANC>5,000"(past"nadir)"

Dose%Adjustment:"Etoposide"and"Temozolomide""increase"20%"if"ANC"nadir">"500""

Temozolomide"100"mg/m2/day"PO"days"2"to"5" Etoposide"50"mg/m2/day"IV"days"2"to"5"" Doxil"50"mg/m2"IV"day"2""" Dexamethasone"10"mg/m2"BID"PO"days"1"to"5" Ibru6nib"(560%TBD"mg)"PO"days"%14"to"5"" Rituximab"375"mg/m2"IV"on"days"1"and"2"" Filgras6m"300"μg"SQ"on"days"6+"un6l"ANC>5,000"(past"nadir)""""

Repeat"cycle"q21"days"x"6"

"""Cytarabine"70"mg""IT"or"ICV"on"days"1"and"5"of"cycles"2"to"6"

No MTX

Ibrutinib window

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Patient Characteristics

Characteristics N= 18

Age (median) 66 years (49-87) Age > 60 years 67% Male gender 61% Untreated 28% (5/18) Refractory to standard treatment 77% (10/13) Relapsed 23% (3/13) Prior Rx (median) Prior Autologous Transplant 2 (1-6) 4 (31%) IELSG risk >=2 83%

Wilson et al. Cancer Cell 2017

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Pharmacokinetics of Ibrutinib 840 mg and PCI-45227 (active metabolite) CSF times above ibrutinib IC50: 24 hours AUC csf/plasma corrected for protein Binding: 29%

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Ibrutinib Response in 14-day Window

A.

250 100 50

  • 50
  • 100

Relapsed/ refractory Previously untreated

Disease reduction from baseline Ibrutinib monotherapy (n=18)

* *

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TEDDi-R Response

Months on study

3 6 9 12 15 18 21 24

D.

CR PR PD SD NE

Death

Refractory Untreated Relapsed

Prior treatment status

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18

  • Pt. #

27 Relapsed Refractory Refractory Refractory Refractory Refractory Refractory Refractory Refractory Refractory Untreated Untreated Untreated Untreated Refractory

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DA-TEDDi-R PFS R/R PCNSL

Median follow-up of 31.2 mos Median PFS not yet reached 2-year PFS: 54.5% (95% CI: 22.9-78.0%)

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PD-L-1 Expression in 262 DLBCL Samples

Kiyasu et al. Blood 2015; 126:2193

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Kiyasu et al. Blood 2015; 126:2193

PD-L-1 Expression Associated with Lower Survival

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PD-1 Blockade with Nivolumab in R/R PCNSL

Nayak et al. Blood 2017; 129:3071

  • PCNSL Patients: N= 5
  • Refractory N=1; Relapsed N=4
  • CR N=4; PR N=1
  • PFS 13+; 14; 14+; 17; 17+
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Novel Targets in R/R DLBCL

  • Targeting PI3K/AKT-mTOR in GCB and ABC
  • Targeting Bcl-2 in ABC and GCB
  • Single agent activity poor-Synergy with BTK targets
  • Role in double hit versus double expressor unknown
  • Ibrutinib targets BCR in ABC
  • High activity in PCNSL
  • PD-1 inhibition in PCNSL and extranodal ABC