Treatment Landscape in R/R DLBCL Novel Targets and Strategies. Wyndham H. Wilson, M.D., Ph.D. Senior Investigator

Transcription

1 Treatment Landscape in R/R DLBCL Novel Targets and Strategies Wyndham H. Wilson, M.D., Ph.D. Senior Investigator

2 Gene-expression profiling of DLBCL subtypes Roschewski, M. et al. (2013) Nat. Rev. Clin. Oncol.

3 Key signaling pathways in GCB DLBCL Targeting PI3K Roschewski, M. et al. (2013) Nat. Rev. Clin. Oncol.

4 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)

5 Copanlisip: PI3 Kinase pan-class I inhibitor 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 Lenz et al, ASCO Proceedings, 2017 Better response rate in ABC Interaction of PI3K with BCR signaling likely important

6 Key signaling pathways in GCB DLBCL Targeting mtor and AKT Nelfinovir Everolimus Roschewski, M. et al. (2013) Nat. Rev. Clin. Oncol.

7 Everolimus in R/R Aggressive Lymphoma Disease type N ORR (95 CI) CR PR Total (20 41) 3 20 DLBCL (17 45) 0 14 MCL (13 57) 2 4 FL-III 8 38 (9 76) 1 2 Other ! Witzig et al. Leukemia (2011) 25,

8 GCB ABC 56% BCL-2 Translocations in GCB DLBCL Malignant transformation BCL2 translocation mir amplification Apoptosis mtor activation BCL2 amplification NF-kappa B Malignant transformation Apoptosis PTEN deletion ING1 deletion MDM2 gain or amplification P53 mutation MYC translocation Genomic instability Interleukin-6 and interleukin-10 19q gain or amplification Trisomy 3 INK4A-ARF deletion STAT3 IRF4 SPIB FOXP1 Senescence Essential regulatory network Genomic instability AID MYC amplification Aberrant switch translocations Germinal center B-cell Plasmablast Plasma cell

9 GCB ABC BCL-2 Amplification In ABC DLBCL Malignant transformation Malignant transformation BCL2 translocation mir amplification Apoptosis mtor activation BCL2 amplification NF-kappa B Apoptosis PTEN deletion ING1 deletion MDM2 gain or amplification P53 mutation MYC translocation Genomic instability Interleukin-6 and interleukin-10 19q gain or amplification Trisomy 3 INK4A-ARF deletion STAT3 IRF4 SPIB FOXP1 Senescence Essential regulatory network Genomic instability AID MYC amplification Aberrant switch translocations Germinal center B-cell Plasmablast Plasma cell

10 BCL-2-Rearrangement versus Expression

11 GCB MYC translocation in GCB ABC Malignant transformation Malignant transformation BCL2 translocation mir amplification Apoptosis mtor activation BCL2 amplification NF-kappa B Apoptosis 10% PTEN deletion ING1 deletion MDM2 gain or amplification P53 mutation MYC translocation Genomic instability Interleukin-6 and interleukin-10 19q gain or amplification Trisomy 3 INK4A-ARF deletion STAT3 IRF4 SPIB FOXP1 Senescence Essential regulatory network Genomic instability AID MYC amplification Aberrant switch translocations Germinal center B-cell Plasmablast Plasma cell

12 GCB ABC MYC amplification In ABC Malignant transformation Malignant transformation BCL2 translocation mir amplification Apoptosis mtor activation BCL2 amplification NF-kappa B Apoptosis PTEN deletion ING1 deletion MDM2 gain or amplification P53 mutation MYC translocation Genomic instability Interleukin-6 and interleukin-10 19q gain or amplification Trisomy 3 INK4A-ARF deletion STAT3 IRF4 SPIB FOXP1 Senescence Essential regulatory network Genomic instability AID MYC amplification Aberrant switch translocations Germinal center B-cell Plasmablast Plasma cell

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14 Key signaling pathways in GCB DLBCL Targeting BCL-2 Venetoclax (ABT-199) Roschewski, M. et al. (2013) Nat. Rev. Clin. Oncol.

15 Davids et al JCO 2016 Phase 1 Study of Venetoclax (ABT-199 / GDC-0199) in Patients with Relapsed/Refractory Non-Hodgkin Lymphoma

16 Davids et al JCO 2016 Phase 1 Study of Venetoclax (ABT-199 / GDC-0199) in Patients with Relapsed/Refractory Non-Hodgkin Lymphoma

17 Phase 1 Study of Venetoclax (ABT-199 / GDC-0199) in Patients with Relapsed/Refractory Non-Hodgkin Lymphoma Unimpressive response rate in DLBCL DE does not appear to increase ORR Davids et al JCO 2016

18 Venetoclax in DLBCL How do you select patients? Role of combination treatment? ABT-199, Ibrutinib and Lenalidomide: drug vs drug interactions Synergy (deltabliss SumNeg) Thomas et al NCI data

19 NF-kB Target Genes Are Highly Expressed in Targeting NFKB in ABC DLBCL Activated B Cell-like Diffuse Large B Cell Lymphoma NF-kB target gene Lymphoma biopsy samples Staudt et al NCI data

20 BCR and MYD88 Pathways IRAK4(inhibitors( Ibru%nib( Ruxoli%nib( SB15108( Idelalisib( Ibru%nib( Enzastaurin( Sotrastaurin( MALT(inhibitors( Everolimus( Temsirolimus( Bortezomib( Lenalidomide( IRF4(

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22 Figure 1 Ibrutinib in ABC DLBCL a Evaluable tumor (% change from baseline in SPD) ABC GCB b % Response (CR + PR) (14/38) CR PR (0/4) ABC * (1/20) PR GCB c 1.0 Median PFS (months) d 1.0 Median OS (months) Probability of survival ABC GCB Probability of survival ABC GCB ** *** Progression-free survival (months) Overall survival (months) At risk: ABC: At risk: ABC: GCB: GCB: Wilson et al Nat Med 2015

23 Ibrutinib in ABC DLBCL Hyperaddiction % response (CR + PR) % response (CR + PR) 50 (10/25) (4/12) 40 (1/3) 30 (4/5) (0/7) 0 0 Mutant WT CD79B: Mutant Mutant WT MYD88 TIR MYD88: WT Mutant Mutant domain All other: 12/35 10/32 14/30 P value: vs. other Live cells (% DMSO) * % response (CR + PR) (0/3) 0 Mutant (8/24) WT CARD11 coiled-coil domain % response (CR + PR) (0/5) 0 Inactive (8/21) WT TNFAIP3 Ibrutinib (nm) Cell line: HBL1 DLBCL subtype: ABC MYD88 mutation: L265P BCR mutation: CD79B TMD8 ABC L265P CD79B Ly10 ABC L265P CD79A Hyperaddiction HLY1 ABC S219C WT SUDHL2 ABC S222R WT BJAB GCB WT WT Ly1 GCB WT WT Ly8 GCB WT WT Wilson et al Nat Med 2015

24 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)

25 Primary CNS Lymphoma Mutations in MYD88 and CD79 Mutation Summary Any: 76% CD79B: 53% MYD88: 56% Both: 37% Suggest hyper addiction to BCR signaling

26 Primary CNS Lymphoma 282 Untreated Patients MSKCC Abrey et al. JCO 2006, 24:5711

27 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

28 DA-TEDDi-R Development TMD8 Cell Line Ibrutinib-Cytotoxic Drug Killing B 0 DNA damage Anti-folate C 7 DNA damage Anti-folate -1 6 DBSumNeg value (Ibrutinib synergy) DBSumPos value (Ibrutinib antagonism) Doxorubicin Etoposide Cytarabine Methotrexate Raltitrexed Pralatrexate DNA damage Anti-folate 1 0 Doxorubicin Etoposide Cytarabine Methotrexate Raltitrexed Pralatrexate DNA damage Anti-folate

29 Dose Adjusted-TEDDI-R No MTX Temozolomide"100"mg/m 2 /day"po"days"2"to"5" Etoposide"50"mg/m 2 /day"iv"days"2"to"5"" Doxil"50"mg/m 2 "IV"day"2""" Dexamethasone"10"mg/m 2 "BID"PO"days"1"to"5" Ibru6nib"(560%TBD"mg)"PO"days"%14"to"5"" Rituximab"375"mg/m 2 "IV"on"days"1"and"2"" Filgras6m"300"μg"SQ"on"days"6+"un6l"ANC>5,000"(past"nadir)"""" """Cytarabine"70"mg""IT"or"ICV"on"days"1"and"5"of"cycles"2"to"6" Ibrutinib window """"""Filgras6m"300"μg"SQ"on"days"6+" un6l"anc>5,000"(past"nadir)" D%14" d%1" d"1" d"2" d"3" d"4" d"5" d"6" d"7" d"8" d"9" d"10" Repeat"cycle"q21"days"x"6" Dose%Adjustment:"Etoposide"and"Temozolomide""increase"20%"if"ANC"nadir">"500""

30 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

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

32 Ibrutinib Response in 14-day Window A. 250 Ibrutinib monotherapy (n=18) Disease reduction from baseline * Relapsed/ refractory Previously untreated -100 *

33 TEDDi-R Response D. Prior treatment status Refractory Untreated Refractory Untreated Refractory Relapsed Untreated Relapsed Refractory Untreated Untreated Refractory Refractory Refractory Refractory Refractory Refractory Refractory Months on study Pt. # CR 12 PR 13 SD PD 16 Death NE

34 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: %)

35 Kiyasu et al. Blood 2015; 126:2193 PD-L-1 Expression in 262 DLBCL Samples

36 PD-L-1 Expression Associated with Lower Survival Kiyasu et al. Blood 2015; 126:2193

37 PD-1 Blockade with Nivolumab in R/R PCNSL PCNSL Patients: N= 5 Refractory N=1; Relapsed N=4 CR N=4; PR N=1 PFS 13+; 14; 14+; 17; 17+ Nayak et al. Blood 2017; 129:3071

38 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