Clinical Advances in Lymphoma

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1 Conflicts of Interest Clinical Advances in Lymphoma Alex F. Herrera, MD Assistant t Professor Department of Hematology and HCT City of Hope BMS research funding (institutional), consultancy Genentech research funding (in), consultancy Merck research funding (in), consultancy Seattle Genetics - research funding (in) Pharmacyclics - research funding (in), consultancy Immune Design - research funding (in) AstraZeneca research funding Presentation Outline Targeted therapies BTK inhibitors Novel classes of anti-lymphoma agents Targeted therapies Checkpoint inhibitors and immunomodulators CAR T-cells Antibodies and antibody-drug conjugates Hodgkin lymphoma Aggressive NHL Indolent NHL and MCL B-cell Herrera AF and Jacobsen EJ CCR

2 Targeted therapies venetoclax (BCL2 inhibition) Targeted therapies PI3K inhibitors Idealisib, TGR- 1202, copanlisib B-cell Konopleva M, et al. Cancer Discovery 2016 Herrera AF and Jacobsen EJ CCR 2014 Targeted therapies Other Checkpoint inhibition: PD-1 Pathway EZH2 inhibitors Proteasome inhibitors HDAC inhibitors JAK inhibitors Pardoll DM. Nature Reviews Cancer 12, (April 2012) Effects of PD-L1 binding: Inhibits T-cell activation Inhibits cytokine production Decreased cytolytic activity of CD4+ and CD8+ cells 2

3 PD-1 Pathway in Cancer PD-1 inhibitors: nivolumab, pembrolizumab Herrera AF, et al ASH 2016, ICML 2017 Pardoll DM. Nature Reviews Cancer 12, (April 2012) Chimeric antigen receptor (CAR) modified T-cells CAR T-cell Workflow Maus, M et al Blood 2014 Novartis Pharmaceuticals, via OncLive.com 3

4 Antibody drug conjugates (e.g. brentuximab vedotin) Novel monoclonal antibodies (e.g. obinutuzumab Brentuximab vedotin antibody-drug conjugate (ADC) Monomethyl auristatin E (MMAE), microtubule-disrupting agent Protease-cleavable linker Anti-CD30 monoclonal antibody ADC binds to CD30 ADC-CD30 complex is internalized and traffics to lysosome CD-30 MMAE is released MMAE disrupts microtubule network G2/M cell cycle arrest Apoptosis Courtesy of AS LaCasce Advances in Hodgkin Lymphoma (HL) 3 FDA-approved drugs in last 5 years ADC: Brentuximab vedotin (BV) PD-1 inhibitors (nivolumab, pembrolizumab) AutoSCT for Relapsed/Refractory HL Only about half of HL patients remain free from treatment failure after ASCT Schmitz et al. Lancet

5 Survival after AutoSCT Failure in HL Patients with post-asct relapse traditionally have had poor outcomes Brentuximab vedotin in Rel/Ref HL ORR 72% CR 33% 38% of CR pts with durable (5yr) remission i Moskowitz AJ et al. BJH 2009 Younes et al. JCO 2012 AETHERA: BV consolidation prolongs post-asct PFS for rel/ref HL PD-1 pathway in Hodgkin Lymphoma Binding of PD-1 by its ligands PD-L1 or PD-L2 leads to downregulation of T-cell function HL harbors near-universal amplification at 9p24.1, leading to overexpression of PD-L1 and PD-L2 HL may be uniquely vulnerable to PD-1 blockade Roemer et al. J Clin Oncol Moskowitz et al. Lancet Oncol

6 Nivolumab in Hodgkin Lymphoma Pembrolizumab in rel/ref HL Chen R et al JCO 2017 Nivolumab in rel/ref HL CHECKMATE 205 9p24.1 Alterations, PD-L1 Expression and Response to Nivolumab 100 Genetic Analysis of 9p24.1 IHC/FISH Analysis of PD-L1 Bes st reduction from base eline in target lesion (%) Asterisks ( * ) represent responders ** ***************** *** **************** ***************** Patients 95% of evaluable patients showed a reduction in tumor burden Timmerman et al. ASH 2016 High degree of genetic alterations leading to increased PD-L1 expression correlated with high ORR (overall response rate) to nivolumab therapy Association between best overall response, gene dosage and level of PD-L1 expression; nonetheless, most patients (83%) with polysomy achieved PR Younes A, et al. Lancet Oncol. 2016;17(9):

7 BV as 2 nd line therapy BV plus Nivolumab as 2 nd line therapy 85% objective response rate with 63% complete responses CR 27% (45%) Moskowitz AJ Lancet Oncol 2015 SPD change from baseline Max SUV change from baseline N = 59 n(%) Complete response (CR) 37 (63) Deauville 2 29 (49) Deauville 3 7 (12) Deauville 5 a 1 (2) Partial response (PR) 13 (22) Deauville 4 7 (12) Deauville 5 6 (10) No metabolic response (SD) 5 (8) Deauville 5 5 (8) Progressive disease (PD) 3 (5) Deauville 5 2 (3) Missing 1 (2) Clinical Progression (CP) 1 (2) a. 1 pt had uptake in lymph node, but no evidence of disease was found on biopsy SPD, sum of the product of the diameters; SUV, standard uptake value Herrera AF et al. ICML 2016 Advances: Hodgkin Lymphoma Advances: Aggressive B-NHL Upfront therapy: BV+AVD (5% PFS) Salvage regimens BV-based therapy (trials) PD-1 inhibitors (trials) Transplantation (consolidation) BV (FDA approved) PD-1 inhibitors (trials) Multiply relapsed/refractory BV (FDA approved) PD-1 inhibitors (FDA approved) Unmet need: No FDA-approved agents since rituximab! Significant focus on improving on R- CHOP 7

8 Upfront Dose Intensity for Aggressive NHL? R-CHOP vs R-EPOCH Multicenter Phase 3 R-CHOP (14 vs. 21) Multicenter Phase 2 DA-EPOCH-R 5-yr PFS 65% 5-yr TTP 81% Fisher RI et al. N Engl J Med 1993;328: Coiffier B et al NEJM 2002 Cunningham et al. Lancet. 2013;381: Wilson et al. Haematologica. 2012;97: CALGB Event Free Survival CALGB Overall Survival ty Probability event free R-CHOP DA-EPOCH-R Median follow-up 5.0 y HR=1.14 ( ) p = Survival Probabilit R-CHOP DA-EPOCH-R Median follow-up 5.0 y HR=1.18 ( ) p = Years from Study Entry Arm N Events 3 Y (95% CI) 5 Y (95% CI) R-CHOP ( ) 0.69 ( ) DA-EPOCH-R ( ) 0.66 ( ) Years from Study Entry Arm N Events 3 Y (95% CI) 5 Y (95% CI) R-CHOP ( ) 0.80 ( ) DA-EPOCH-R ( ) 0.76 ( ) 8

9 R-CHOP vs obinutuzumab plus CHOP Improve on R-CHOP? HDAC inhibitors = no Bortezomib = no Next up: Lenalidomide (immunomodulator) Polatuzumab vedotin (anti-cd79b ADC) Venetoclax (BCL2 inhibitor) SGN-CD19A (anti-cd19 ADC) Vitolo U et al JCO 2017 Double-hit lymphoma: the exception? Consolidative Autotransplant Petrich AM et al Blood 2014 Landsburg DJ et al JCO

10 Novel Agents in DLBCL Lenalidomide maintenance after R- CHOP in elderly DLBCL pts Ibrutinib Venetoclax Lenalidomide CAR T-cells Polatuzumab vedotin (anti-cd79b ADC) Thieblemont C et al JCO 2017 Ibrutinib in ABC-DLBCL Venetoclax in DLBCL Wilson WH et al Nature Medicine 2015 Davids M et al JCO

11 PD-1 Pathway in NHL PD-L1 expression in NHL occurs but is less common e.g. ~15% of DLBCL Higher in PMBCL, TCRHR PD-1/PD-L1 inhibitors in B-NHL Objective Response Rate, n (%) Complete Responses, n (%) Partial Responses, n (%) Stable Disease n (%) B Cell Lymphoma* (n=29) 8 (28) 2 (7) 6 (21) 14 (48) Follicular Lymphoma (n=10) 4 (40) 1 (10) 3 (30) 6 (60) Diffuse Large B Cell Lymphoma (n=11) 4 (36) 1 (9) 3 (27) 3 (27) T Cell Lymphoma (n=23) Mycosis Fungoides (n=13) Peripheral T Cell Lymphoma (n=5) 4 (17) 0 (0) 4 (17) 10 (43) 2 (15) 0 (0) 2 (15) 9 (69) 2 (40) 0 (0) 2 (40) 0 (0) Multiple Myeloma (n=27) 0 (0) 0 (0) 0 (0) 18 (67) Primary Mediastinal B Cell Lymphoma (n=2) 0 (0) 0 (0) 0 (0) 2 (100) Kiyashu et al Blood 2016 *includes other B cell lymphoma (n=8) includes other cutaneous T cell lymphoma (n=3) and other non cutaneous T cell lymphoma (n=2) Courtesy of Alexander Lesokhin. ASH 2014 Polatuzumab Vedotin in R/R DLBCL Polatuzumab vedotin plus obinutuzumab ge % chang Treatment Regimen Best Overall Response Pola mg/kg 51% 1 Pola mg/kg + rituximab 56% 2 R/R DLBCL from the ROMULUS trial: pola + rituximab Best SPD Change from Baseline Progression-Free Survival Pola 2.4 mg/kg + R Rituximab-refractoryOther refractory Not refractory 1. Palanca-Wessels MCA, et al. Lancet Oncol 2015; 16: ; 2. Morschhauser F, et al. Blood 2014; 124:4457 rate Survival 1. Median PFS = months (4.3, 12.8) Months FL (N=35) DLBCL (N=43) Objective response, n (%) 24 (69) 17 (40) Complete Response [90% CI] Partial Response [90% CI] 11 (31) [19 47] 13 (37) [24 52] 9 (21) [11 34] 8 (19) [10 31] Stable disease, n (%) 4 (11) 0 Progressive disease, n (%) 1 (3) 18 (42) Unable to evaluate, n (%) 6 (17) b 8 (19) c a Patients who received 1 dose of study treatment; assessment per Lugano Criteria (Cheson 2014) b No Pola dose due to IRR from G, taken off-study (n=2); no PET assessment (n=2); taken off-study due to neutropenia before assessment (n=1); fatal pneumonia before assessment (n=1) c Died before assessment (n=1); PD not by PET (n=4); not assessed due to hospitalization / taken off study (n=2); W/D consent / not dosed (n=1) Data Cut-Off: 26 JUL 2016 Download this presentation: 11

12 Pola + R/G-bendamustine Investigator-Assessed Response by PET/CT a FL DLBCL Pola + BR (n=6) Pola + BG (n=26) Pola + BR (n=6) Pola + BG (n=27) Best Objective Response ORR, n (%) CR PR SD PD UE 6 (100) 4 (67) 2 (33) (89) 17 (65) 6 (23) 0 1 (4) 2 (8) 3 (50) 2 (33) 1 (17) 0 2(33) 1 (17) 16 (60) 11 (41) 5 (19) 2 (7) 6 (22) 3 (11) Objective Response at End of Treatment ORR, n (%) CR 5 (83) 4 (67) 21 (81) 17 (65) 3 (50) 2 (33) 10 (37) 9 (33) PR 1 (17) 4 (15) 1 (17) 1 (4) Median duration of response, 16.1 mo (range) b ( ) Median PFS, mo 18.4 (range) b ( ) NR ( ) NR ( ) NR ( ) NR ( ) NR ( ) 5.4 ( ) a Modified Lugano 2014 response criteria: for CR, repeat bone marrow biopsy required to confirm clearance of bone marrow if involved at screening. b Kaplan-Meier method; range data are at clinical data cut-off. CT, computed tomography; ORR, objective response rate; PD, progressive disease; PET, positron emission tomography; PFS, progression-free survival; PR, partial response; SD, stable disease; UE, unable to evaluate. CAR T-cells in Aggressive B-NHL: KiTE (ZUMA-1) Phase 2 Phase 1 Cohort 1 Refractory DLBCL Refractory (n = 72) DLBCL/PMBCL/TFL (cohort of n = 6) Cohort 2 Refractory PMBCL/TFL (n = 20) Eligibility criteria Aggressive NHL: DLBCL, PMBCL, TFL Chemotherapy-refractory disease: no response to last chemotherapy or relapse 12 months post-asct Prior anti-cd20 mab and anthracycline ECOG PS 0-1 Primary end point Phase 2: Objective response rate (ORR) tested in the first 92 patients dosed a Key secondary end points DOR, OS, safety, levels of CAR T and cytokines a Type 1 error was controlled at the 1-sided level and split between the testing of cohort 1 and cohorts 1 and 2 combined with the exact binomial test comparing observed ORR to a hypothesized rate of 20%. ORR was also assessed in all patients dosed (mitt) and in all patients enrolled (ITT). ASCT, autologous stem cell transplant; axi-cel, axicabtagene ciloleucel; CAR, chimeric antigen receptor; DLBCL, diffuse large B cell lymphoma; DOR, duration of response; ECOG PS, Eastern Cooperative Oncology Group performance score; mab, monoclonal antibody; NHL, non-hodgkin lymphoma; OS, overall survival; PMBCL; primary mediastinal B-cell lymphoma; TFL, transformed follicular lymphoma. 46 Patient Consort Diagram Patient Characteristics Patients not treated: SAE (n = 5) No measurable disease (n = 2) Product unavailable (n = 1) SAE (n = 2) Enrolled (n = 111) Conditioning Cy 500 mg/m 2 + Flu 30 mg/m 2 3 d Axi-cel CAR+ cells/kg (N = 101) No bridging therapy allowed N = 92: primary analysis N = 101: modified intent-to-treat (mitt) Data cutoff: January 27, 2016 Median follow-up: 8.7 months 22 sites enrolled; 99% manufacturing success rate 91% of enrolled patients received axi-cel 17-day average turnaround time from apheresis to delivery to clinical site Characteristic DLBCL (n = 77) PMBCL/TFL (n = 24) All Patients (N = 101) Median (range) age, y 58 (25 76) 57 (23 76) 58 (23 76) 65 y, n (%) 17 (22) 7 (29) 24 (24) Men, n (%) 50 (65) 18 (75) 68 (67) ECOG PS 1, n (%) 49 (64) 10 (42) 59 (58) Disease stage III/IV, n (%) 67 (87) 19 (79) 86 (85) IPI score 3-4, n (%) 37 (48) 11 (46) 47 (47) 3 prior therapies, n (%) 49 (64) 21 (88) 70 (69) History of primary refractory disease, n (%) 23 (30) 3 (13) 26 (26) History of refractory to 2 consecutive lines, n (%) 39 (51) 15 (63) 54 (54) Response to last chemotherapy regimen, n (%) 10 (13) 4 (17) 14 (14) Stable disease Progressive disease 51 DLBCL (66) PMBCL/TFL Refractory Subgroup Before Enrollment 15 (63) All 66 Patients (65) (n = 77) (n = 24) (N = 101) Refractory to second- or later-line therapy, n (%) 59 (77) 19 (79) 78 (77) Relapse post-asct, n (%) 16 (21) 5 (21) 21 (21) axi-cel, axicabtagene ciloleucel; CAR, chimeric antigen receptor; Cy, cyclophosphamide; Flu, fludarabine; SAE, serious adverse event. 47 ASCT, autologous stem cell transplant, DLBCL, diffuse large B cell lymphoma; ECOG PS, Eastern Cooperative Oncology Group performance status; IPI, International Prognostic Index; PMBCL; primary mediastinal B cell lymphoma; TFL, transformed follicular lymphoma

13 Responses to CD19-specific CAR T-cells (KiTE) Responses Were Consistent Across Key Covariates Best Response ORR (%) ZUMA-1 Phase 2 DLBCL TFL/PMBCL Combined CR (%) ORR (%) CR (%) ORR (%) CR (%) mitt b n = 77 n = 24 n = a Inferential testing when 92 axi-cel dosed patients had 6 months of follow-up. ORR 82%, P< b mitt (modified intention-to-treat) set of all patients dosed with axi-cel. CR, complete response; DLBCL, diffuse large B cell lymphoma; ORR; objective response rate; PMBCL; primary mediastinal B-cell lymphoma; TFL, transformed follicular lymphoma. 49 a LCI and UCI are calculated using the Clopper-Pearson Method. ASCT, autologous stem cell transplant; IPI, International Prognostic Index; LCI, lower 95% confidence interval; ORR, objective response rate; UCI, upper 95% confidence interval. 50 Response Rates Were Consistent Between ABC and GCB DLBCL Subgroups Responses Were Durable: 44% Ongoing At 8.7 Months of Follow Up Baseline Characterstic, n (%) All Patients (N = 101) Evaluable for DLBCL cell of origin a 69/101 (68) ABC 17/69 (25) GCB 49/69 (71) Unclassified 3/69 (4) Response, n (%) ABC (N = 17) GCB (N = 49) ORR 13 (76) 43 (88) ZUMA-1 Phase 2 (mitt population a ) DLBCL (n = 77) ORR CR (%) (%) TFL/PMBCL (n = 24) ORR (%) CR (%) Combined (N = 101) ORR (%) CR (%) Month Ongoing b CR 10 (59) 28 (57) Ongoing 6 (35) 23 (47) a Molecular subgroup analysis was available for 69 patients, 3 of whom were unclassified. ABC, activated B cell; CR, complete response; DLBCL, diffuse large B cell lymphoma; GCB, germinal center B cell; ORR, objective response rate. a mitt set of all patients dosed with axi-cel. b Ongoing with a median follow-up of 8.7 months. axi-cel, axicabtagene ciloleucel; CR, complete response; DLBCL, diffuse large B cell lymphoma; mitt, modified intention-to-treat ; ORR; objective response rate; PMBCL; primary mediastinal B cell lymphoma; TFL, transformed follicular lymphoma

14 Duration of Responses At a Median Follow-Up of 8.7 Months Median OS Not Reached At a Median Follow-Up of 8.7 Months ORR 8.2 (3.3-NR) CR NR (8.2-NR) PR 1.9 ( ) Median OS (95% CI), mo ZUMA-1 NR (10.5-NR) 6-month OS rate: 80% CR, complete response; NR, not reached; ORR, objective response rate; PR, partial response. NR, not reached; OS, overall survival. 54 Summary of CAR T-cell related AEs Summary: Advances in Aggressive B-NHL AE, n (%) Interim Analysis (N = 62) Primary Analysis (N = 101) Grade 3 AE 59 (95) 95 (95) Grade 3 CRS 11 (18) 13 (13) Grade 3 NE 21 (34) 28 (28) Grade 5 AE 3 (3) a 3 (3) a CRS and NE were generally reversible All CRS events resolved except 1 case of HLH and 1 case of cardiac arrest All NE resolved except 1 grade 1 memory impairment 43% received tocilizumab, 27% received steroids No new axi-cel related grade 5 AEs a As previously reported, grade 5 AEs occurred in 3 patients. Axi-cel related, 2 (2%; HLH and cardiac arrest); axi-cel unrelated, 1 (1%; pulmonary embolism). AE, adverse event; axi cel, axicabtagene ciloleucel; CRS, cytokine release syndrome; HLH, hemophagocytic lymphohistiocytosis; NE, neurologic event. 55 Still can t beat R-CHOP! Intensive induction for DHL Targeted therapy has a role, but limited to small subgroups CAR T-cells are toxic, but effective Antibody drug conjugates have a future u 14

15 Advances: Mantle cell lymphoma Upfront therapy Elderly/transplant ineligible Chemo plus bortezomib (FDA approved) Lenalidomide plus rituximab Fit/Young no clarity on best regimen Transplantation maintenance rituximab Relapsed/Refractory disease Ibrutinib (FDA approved) Venetoclax CAR T-cells VR-CAP vs R-CHOP for new MCL 59% improvement in PFS, median OS was 56.3% vs. not reached in favor of VR-CAP CR 42% vs. 53%, not stat. significant Lenalidomide plus rituximab induces deep responses and well-tolerated MCL Younger: High dose Ara-C increases response rate with deeper remissions Control arm Cytarabine arm ORR to induction 90% 94% CR 39% 55% ORR after ASCT MRD-ve PB after induction MRD-ve after ASCT 97% 98% 47% 79% 68% 85% Hermine et al, lancet 2016; 388 : Ruan J et al NEJM

16 Do you need CHOP? R-bendamustine plus high dose Ara-C induction Ibrutinib is effective in Rel/Ref MCL R+Bendamsutine X 3 CR/PR/SD Rituximab + HiDAC X 3 Disease Assessment BEAM based ASCT PFS at a median fu of 13 months MRD- achieved in 77% after RB and 93% after RB-RC induction Armand et al: BJH 2016 (173) The median PFS is 13 months, DOR 17.5 months. 2-year PFS was 31%, and 2-year OS was 47%. Wang et al, NEJM 2013 Wang et al. Blood 2016 Post Ibrutinib Failure Venetoclax in MCL/FL Median OS 2.9 months Median OS 5.8 months Tx MCL Duration of response FL Martin P et al. Blood 2016 Davids M et al JCO

17 Rituximab maintenance after ASCT improves PFS Rituximab maintenance after ASCT improves OS mfu: 50.2m ( ) mfu: 50.2m ( ) PFS Obs (95%CI) vs Rituximab (95%CI) 24m: 79.8 % ( ) 93.3 % ( ) 36m: 72.8 % ( ) 89.1 % ( ) 48m: 64.6 % ( ) 82.2 % ( ) OS Obs (95%CI) vs Rituximab (95%CI) 24m: 93.3 % ( ) 93.3 % ( ) 36m: 85.4 % ( ) 93.3 % ( ) 48m: 81.4 % ( ) 88.7 % ( ) PFS (months) from randomization OS (months) from randomization Summary: Advances in MCL Transplant ineligible Lenalidomide a legitimate chemo-free option Bortezomib vs just R-benda Transplant eligible Use rituximab maintenance! Relapsed/Refractory Ibrutinib and venetoclax induce responses in the majority of patients Advances in Indolent NHL Follicular lymphoma Novel antibodies (obinutuzumab) Novel antibodies (obinutuzumab) Novel PI3K inhibitors (copanlisib) Other targeted agents Checkpoint inhibition Marginal zone lymphoma Ibrutinib 17

18 Obinutuzumab prolongs PFS in upfront FL treatment N = 1202 FL pts G-chemo (benda, CVP, CHOP) vs R- chemo Increased cytopenias, infections with G Overall rate high in study (benda?) Lenalidomide in untreated FL N=65, multicenter US 12 cycles of lenalidomide Rituximab followed by extended therapy FLIPI 0-2 (low-risk population) ORR 95%, 72% CR 2y/3y/4y PFS = 86%/81%/73% OS = 100% Marcus et al ASH 2016 Martin P et al ICML 2017 Copanlisib: a new PI3K inhibitor in indolent B-NHL Other Targeted Agents in FL FL (n=104) ORR 59% CR 14% MZL (n=23) ORR 70% CR 8% DOR ~2yrs Few immunerelated AEs Dreyling M ICML 2017 Tazemetostat (EZH2 inhibition) ORR 92% in EZH2 mutated pts (n=19) ORR 26% in EZH2 WT (n=54) Venetoclax (BCL2 inhibition) ORR 38%, 14% CR Ibrutinib (BTK inhibition) ORR 21%, 11% CR, disease control 34% Median DOR 19.4 months 18

19 PD-L1 inhibition in FL DRAFT Response adapted R-bendamustine for MALT lymphomas Patients (%) Investigator-Assessed End of Induction PET/CT Response 4% 56% ORR (CMR + PMR) at End of Induction response assessment 6 patients achieved CMR at End of Induction, with all patients achieving response (CMR/PMR) by the Mid Induction response assessment N = 60, Spain Restaging after 3 cycles CR total 4 cycles PR total 6 cycles (only 25% of pts) mpfs was 311 days 6-month PFS: 82% 12-month PFS: 45% 2-year EFS 93% 4-year EFS 88% n = 23 Salar et al Lancet Haematology Palomba et al. Atezolizumab + Obinutuzumab in NHL, ICML Ibrutinib is effective in MZL Summary: Advances in indolent B-NHL FL Upfront: New antibodies and chemotherapy-free options emerging chemotherapy free options emerging FL R/R: role for novel agents, but no major successes MZL bendamustine confirmed as highly active Ibrutinib effective and is FDA-approved Noy A et al Blood

20 Conclusions Thank you! Checkpoint inhibitors a key therapy in Hodgkin lymphoma CAR T-cells may provide durable remissions in a subset of aggressive B- NHL pts Novel agents effective in treating indolent B-NHL and MCL Still tremendous unmet need for effective therapies in refractory lymphoma patients 20