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

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 Targeting PI3K Roschewski, M. et al. (2013) Nat. Rev. Clin. Oncol.

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)

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

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

Everolimus in R/R Aggressive Lymphoma Disease ORR (95 � CI) type N CR PR Total 77 30 � (20–41) 3 20 DLBCL 47 30 � (17–45) 0 14 MCL 19 32 � (13–57) 2 4 FL-III 8 38 � (9–76) 1 2 Other 3 0 0 0 ! Witzig et al. Leukemia (2011) 25, 341–347

GCB ABC BCL-2 Translocations in GCB DLBCL Malignant transformation Malignant transformation 56% BCL2 BCL2 ampli f cation ampli f cation BCL2 BCL2 translocation translocation Apoptosis Apoptosis miR-17-92 mTOR NF-kappa B ampli f cation activation Interleukin-6 and PTEN deletion STAT3 interleukin-10 ING1 deletion IRF4 Essential Genomic regulatory 19q gain or MDM2 gain or instability SPIB network ampli f cation ampli f cation Trisomy 3 FOXP1 P53 mutation INK4A-ARF deletion Senescence MYC MYC translocation translocation Genomic instability Aberrant switch AID translocations MYC ampli f cation MYC ampli f cation Germinal Plasmablast Plasma cell center B-cell

GCB ABC BCL-2 Amplification In ABC DLBCL Malignant transformation Malignant transformation BCL2 ampli f cation BCL2 ampli f cation BCL2 BCL2 translocation translocation Apoptosis Apoptosis miR-17-92 mTOR NF-kappa B ampli f cation activation Interleukin-6 and PTEN deletion STAT3 interleukin-10 ING1 deletion IRF4 Essential Genomic regulatory 19q gain or MDM2 gain or instability SPIB network ampli f cation ampli f cation Trisomy 3 FOXP1 P53 mutation INK4A-ARF deletion Senescence MYC translocation MYC translocation Genomic instability Aberrant switch AID translocations MYC ampli f cation MYC ampli f cation Germinal Plasmablast Plasma cell center B-cell

BCL-2-Rearrangement versus Expression

GCB ABC MYC translocation in GCB Malignant transformation Malignant transformation BCL2 BCL2 ampli f cation ampli f cation BCL2 BCL2 translocation translocation Apoptosis Apoptosis miR-17-92 mTOR NF-kappa B ampli f cation activation Interleukin-6 and PTEN deletion STAT3 interleukin-10 ING1 deletion IRF4 Essential Genomic regulatory 19q gain or MDM2 gain or instability SPIB network ampli f cation ampli f cation Trisomy 3 FOXP1 P53 mutation 10% INK4A-ARF deletion Senescence MYC translocation MYC translocation Genomic instability Aberrant switch AID translocations MYC ampli f cation MYC ampli f cation Germinal Plasmablast Plasma cell center B-cell

GCB ABC MYC amplification In ABC Malignant transformation Malignant transformation BCL2 ampli f cation BCL2 ampli f cation BCL2 BCL2 translocation translocation Apoptosis Apoptosis miR-17-92 mTOR NF-kappa B ampli f cation activation Interleukin-6 and PTEN deletion STAT3 interleukin-10 ING1 deletion IRF4 Essential Genomic regulatory 19q gain or MDM2 gain or instability SPIB network ampli f cation ampli f cation Trisomy 3 FOXP1 P53 mutation INK4A-ARF deletion Senescence MYC translocation MYC translocation Genomic instability Aberrant switch AID translocations MYC ampli f cation MYC ampli f cation Germinal Plasmablast Plasma cell center B-cell

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

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

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

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

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

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

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

Ibrutinib in ABC DLBCL Figure 1 a b 100 * 750 ABC 90 (% change from baseline in SPD) 700 GCB 80 150 % Response (CR + PR) 70 Evaluable tumor 100 60 50 50 (14/38) 40 0 30 CR 20 –50 10 PR (1/20) (0/4) PR 0 –100 ABC GCB c d 1.0 1.0 Median PFS Median OS (months) (months) ABC 2.02 ABC 10.32 0.8 0.8 ** *** Probability of survival Probability of survival GCB 1.31 GCB 3.35 0.6 0.6 0.4 0.4 0.2 0.2 0 0 0 1 2 3 4 5 6 7 8 9 10 12 14 16 18 20 22 0 3 6 9 12 15 18 21 Progression-free survival (months) Overall survival (months) ABC: 38 32 19 14 10 8 6 3 2 At risk: ABC: 38 24 17 12 4 1 1 At risk: GCB: 20 13 4 2 0 0 0 0 0 GCB: 20 10 5 4 3 3 1 Wilson et al Nat Med 2015

Ibrutinib in ABC DLBCL Hyperaddiction 100 100 * 100 100 90 90 90 90 % response (CR + PR) % response (CR + PR) % response (CR + PR) % response (CR + PR) (4/5) 80 80 80 80 70 70 70 70 60 60 60 60 50 50 50 50 (10/25) (8/21) 40 40 40 40 (4/12) (1/3) (8/24) 30 30 30 30 20 20 20 20 10 10 10 10 (0/7) (0/3) (0/5) 0 0 0 0 Mutant WT CD79B: Mutant Mutant WT Mutant WT Inactive WT MYD88: WT Mutant Mutant MYD88 TIR CARD11 TNFAIP3 domain coiled-coil All other: 12/35 10/32 14/30 domain P value: 1.00 0.057 0.031 vs. other 100 Ibrutinib (nM) 80 0 1.5 Live 60 3.0 cells 6.25 (% DMSO) 40 12.5 25 20 50 0 Cell line: HBL1 TMD8 Ly10 HLY1 SUDHL2 BJAB Ly1 Ly8 DLBCL subtype: ABC ABC ABC ABC ABC GCB GCB GCB MYD88 mutation: L265P L265P L265P S219C S222R WT WT WT BCR mutation: CD79B CD79B CD79A WT WT WT WT WT Wilson et al Nat Med 2015 Hyperaddiction

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)

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

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

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

B TMD8 Cell Line Ibrutinib-Cytotoxic Drug Killing DBSumNeg value Doxorubicin (Ibrutinib synergy) -6 -5 -4 -3 -2 -1 -7 0 Etoposide DNA damage Cytarabine Methotrexate DA-TEDDi-R Development Raltitrexed Anti-folate Pralatrexate DNA damage Anti-folate C DBSumPos value Doxorubicin (Ibrutinib antagonism) 0 1 2 3 4 5 6 7 Etoposide DNA damage Cytarabine Methotrexate Raltitrexed Anti-folate Pralatrexate DNA damage Anti-folate