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5/7/2018 Immune Based Treatment Options in Lymphoma: CAR-t cells Leo I. Gordon, MD, FACP Summary • We are entering a new era in treatment for lymphomas • CAR T-cell therapy may represent one of the more effective immunotherapeutic options • Challenges • Time to manufacture • Patient selection and toxicity management • integration with or replacement of existing modalities (chemotherapy, small molecule inhibitors, autologous vs allogeneic stem transplant) • cost • CAR T-cell therapy likely to alter how we treat DLBCL 1 5/7/2018 The Case for Cancer Cellular Therapy Presented By Carl June at 2016 ASCO Annual Meeting Graft vs. Leukemia/Lymphoma: The case for allogeneic transplant • Presence of GvHD reduces the likelihood of recurrence in leukemia patients who had an allogeneic transplant. • Provided rationale for “mini” transplants to take advantage of GvL effect without high dose chemotherapy 2 5/7/2018 CAR Design: Critical Elements CAR T cells are genetically altered to express CAR on the cell surface. T Cell Receptor Chimeric Antigen Receptor APC scFv: recognize tumor surface proteins pMHC CD28 L TCR T Cell CD28 Costimulatory Signal 2: CD28 or 4-1BB or OX40 Essential Signal 1: CD3z CD3z Activation Independent of MHC Limited to cell surface proteins CAR Construct: CD28 vs 4-1BB Kalawekar at el, 2016 CAR Construct: Antigen Selection • CD19 expression is generally restricted to B cells and B cell precursors1 • CD19 is expressed by most B-cell malignancies • • CD19 is not expressed on hematopoietic stem cells or other tissue CLL, B-ALL, DLBCL, FL, MCL Hematopoietic stem cell Pro-B Pre-B CD19 expression B cell lymphomas and leukemias preB-ALL Immature (IgM) Mature (IgM, IgD) Activated B cell Memory B cell (IgG, IgA) Plasma cell (IgG) Image adapted from Janeway CA, Travers P, Walport M, et al. Immunobiology. 5th ed. New York, NY: Garland Science; 2001:221-293; Scheuermann RH, et al. Leuk Lymphoma. 1995;18:385-397; and Feldman M, Marini JC. Cell cooperation in the antibody response. In: Roitt I, Brostoff J, Male D, eds. Immunology. 6th ed. Maryland Heights, Missouri: Mosby;2001:131-146. 3 5/7/2018 SCHOLAR-1 – Poor outcomes in R/R DLBCL Refractory DLBCL, n=636; ORR 26%, CR 7%; median OS 6.3 months Crump et al., Blood 2017 CAR T manufacturing and administration *large range on timing for processing Kochenderfer, J. N. & Rosenberg, S. A. (2013) Treating B-cell cancer with T cells expressing anti-CD19 chimeric antigen receptors. Nat. Rev. Clin. Oncol. doi:10.1038/nrclinonc.2013.46 4 5/7/2018 JULIET: Study Status (Data cut March 2017) Enrolled n = 147 Enrollment began July 2015 Discontinued before infusion Inability to manufacture Patient-status relateda Pending infusion n=5 Total = 43 n=9 n = 34 Infused n = 99 Evaluable for response n = 81 ASH 2017 a Death (n = 16); physician decision (n = 12); subject decision (n = 3); adverse event (n = 2); protocol deviation (n = 1). Schuster SJ, et al. Blood. 2017; 130(23):[abstract 577]. Approval date 12/2017 13 M-CTL-1176725 Duration of Response, 74% Relapse-free at 6 Months Probabilty of Relapse Free (%) 100 • Median DOR and OS not reached • Most patients achieving CR at month 3 have remained in CR • No patients proceeded to transplant while in response 80 60 40 20 0 0 1 Patients still at risk n = 43 36 2 3 4 5 6 7 8 9 10 11 12 2 1 0 Time From Onset of Response (months) 25 18 16 13 9 9 5 2 CR, complete response; DOR, duration of response; OS, overall response. Efficacy analysis set = All patients who received a tisagenlecleucel infusion at least 3 months prior to data-cut date. Schuster SJ, et al. Blood. 2017; 130(23):[abstract 577]. ASH 2017 Approval date 12/2017 14 M-CTL-1176725 JULIET: Adverse Events of Special Interest (N = 99) AESIa All grade, % Grade 3, % Grade 4, % 58 15 8 21 8 4 36 15 12 Infections 34 18 2 Febrile neutropenia 13 11 2 Cytokine release syndromeb Neurological events Prolonged cytopeniac • No deaths attributed to tisagenlecleucel, CRS or cerebral edema • 26 (26%) patients were infused as outpatients • 20/26 (77%) patients remained outpatient for ≥ 3 days after infusion a Occurring within 8 weeks of tisagenlecleucel infusion. b Cytokine release syndrome was graded using the Penn scale. c At day 28. AESI, adverse events of special interest. Schuster SJ, et al. Blood. 2017; 130(23):[abstract 577]. ASH 2017 Approval date 12/2017 15 M-CTL-1176725 5 5/7/2018 Progression-free Survival, Response Duration, and Overall Survival. Schuster SJ et al. N Engl J Med 2017. DOI: 10.1056/NEJMoa1708566 Presented by: Objective Response Rate among the 101 Treated Patients. Neelapu SS et al. N Engl J Med 2017. DOI: 10.1056/NEJMoa1707447 6 5/7/2018 Kaplan–Meier Estimates of the Duration of Response, Progression-free Survival, and Overall Survival. NeelapuSS et al. N Engl J Med 2017. DOI: 10.1056/NEJMoa1707447 Presented by: 7 5/7/2018 High CR Rates in Relapsed/Refractory Aggressive B-NHL Treated With the CAR TB-NHL Cell Product JCAR017 High Durable CRCD19-Directed Rates in R/R Aggressive Treated with (TRANSCEND NHL 001; maraleucel; NCT02631044) JCAR017 (lisocabtagene liso-cel) (TRANSCEND NHL 001): Defined Composition CD19-Directed CAR T Cell Product Allows for Dose Finding and Definition of Pivotal Cohort 1 M. Lia 2 Leo I. Gordon, 4 Jon Arnason,5 Michael 1 M. 2 Leo 3I.Matthew 3 Matthew 5 Michael Jeremy S.S. Abramson, Palomba, Lunning, Wang,6 Andres ForeroJeremy Abramson, Lia Palomba, Gordon, Lunning,4 Jon Arnason, Torres,7 David Maloney,8 Tina Albertson,9 Jacob Garcia,9 Daniel Li,9 Benhuai Xie,9 Tanya Siddiqi10 Wang,6 Andres Forero-Torres,7 Tina Albertson,8 Claire Sutherland,8 Benhuai Xie,8 Jacob Garcia,8 Tanya Siddiqi9 1 Massachusetts General Hospital Cancer Center, Boston, MA; 2Memorial Sloan Kettering Cancer Center, New York, NY; 3Northwestern University Robert H. Lurie Comprehensive Cancer Center, Chicago, IL; 4University of Nebraska Medical Center, Omaha, NE; 5Beth Israel Deaconess Medical Center, Boston, MA; 6University of 1Massachusetts General Hospital Cancer Center, Boston, MA; 2Memorial Sloan Kettering Cancer Center, New York, NY; 3Northwestern University Robert H. Lurie Comprehensive Cancer Center, Chicago, IL; Texas MD Anderson Cancer Center, Houston, TX; 7University of Alabama at Birmingham, Birmingham, AL; 8Fred Hutchinson Cancer Research Center, Seattle, WA; 4University of Nebraska Medical Center, Omaha, NE; 5Beth Israel Deaconess Medical Center, Boston, MA; 6University of Texas MD Anderson Cancer Center, Houston, TX; 7University of Alabama at Birmingham, 10 Therapeutics, Seattle, WA; Hope National Center, Duarte, Birmingham, AL; 8Juno Therapeutics, Seattle,City WA; 9of City of Hope NationalMedical Medical Center, Duarte, CA CA 9 Juno Multicenter, Seamless Design Pivotal Trial (TRANSCEND NHL 001; NCT02631044) Dose Findinga (DF) Cohorts Dose Expansiona (DE) Cohorts 5 × 107 cells (DL1), single dose (S)b DL1S 5 × 107 cells (DL1), double dose (D)c Pivotal DLBCL Cohort Dose Recommendation by Steering Committee DL2S DL2S 1 × 108 cells (DL2), single dose (S)b Data will be presented from DF and DE DLBCL cohorts Enrollment ongoing for pivotal patient population • 91 patients treated (FULL)d • 67 patients treated in identified pivotal patient population (CORE)e Disease-specific Dose Finding and Dose Expansion cohorts enrolled [DLBCL and MCL]. Administered on Day 1. Administered on Day 1 and Day 14. d DLBCL FULL cohort: DLBCL, NOS de novo and transformed from any indolent lymphoma, ECOG 0-2. e DLBCL CORE cohort: DLBCL, NOS de novo and transformed from FL, ECOG 0-1, high grade B-cell lymphoma. a b c 4 8 5/7/2018 TRANSCEND NHL 001 (NCT02631044) Enrollment & Apheresis PET-positive disease reconfirmed FOLLOW-UP Lymphodepletion JCAR017 (liso-cel) 2-7 days after FLU/CY FLU 30 mg/m2 and CY 300 mg/m2 x 3d Screen Initial: 12 months On-study: 24 months Long-term: up to 15 years after last JCAR017 treatment Liso-cel Manufacturinga ENROLLMENT COHORTS § § PATIENT ELIGIBILITY DLBCL after 2 lines of therapy: – DLBCL, NOS (de novo or transformed FL) – High grade B-cell lymphoma (double/triple hit) – DLBCL transformed from CLL or MZL – PMBCL – FL3B MCL after 1 line of therapy § § § § Pivotal population (CORE) All enrolled DLBCL population (FULL) Prior SCT allowedb Secondary CNS involvement allowed ECOG 0-2b No minimum absolute lymphocyte count requirement for apheresis FLU, fludarabine; CY, cyclophosphamide. a Therapy for disease control allowed. b ECOG 2 and prior allogeneic HSCT excluded from pivotal cohort. 5 CONSORT Diagram: DLBCL Cohort Leukapheresed (n = 140) Awaiting product (n=10) Withdrew before manufacturing (n = 2) Product unavailable (n = 2) § Product available for 98% (126/128) of patients apheresed in DLBCL cohort Product available (n = 18) • Awaiting treatment (n = 4) • Withdrew (n = 4) • PD or died (n = 10) § Six MCL subjects treated thus far with JCAR017 at DL1S JCAR017-Treated (n=108) • Received JCAR017, not yet evaluable (n = 6) • Received nonconforming JCAR017 (n = 11)a § Five patients treated in outpatient setting as of October 9 data snapshota Safety-Evaluable (n=91) DL1S (n = 45) a DL1D (n = 6) DL2S (n = 40) For further details, see Maloney et al (abstract 1552). Data as of October 9, 2017 6 TEAEs and Lab Abnormalities in DLBCL Cohort (FULL, N=91) TEAEs and Laboratory Abnormalities Occurring in ≥ 20% of Patientsa Any TEAEb,c Any related TEAEc Neutropeniad Thrombocytopeniad Anemiad Fatigue Cytokine release syndrome Nausea Diarrhea Constipation Decreased appetite Headache Dizziness Grade Hypotension 0 10 20 30 40 50 60 70 1 2 80 3 4 90 5 100 Percentage of Patients TEAE, treatment-emergent adverse event. a Data for 5 patients with MCL treated with conforming product at DL1 with at least 28 days of follow-up are not reported. b One grade 5 AE of septic shock, unrelated to JCAR017, occurred in the setting of disease progression. c One grade 5 AE of diffuse alveolar damage, investigator assessed as related to fludarabine, cyclophosphamide, and JCAR017, occurred on day 23 in a patient who refused mechanical ventilation for progressive respiratory failure while neutropenic on growth factors and broad-spectrum antibiotics and antifungals. d Laboratory abnormalities. Data as of October 9, 2017 8 9 5/7/2018 High Rates of Response in FULL DLBCL Population Homogeneous Patient Population Moving Forward in Pivotal Cohort By B-NHL Subtype FULL BOR, na tFL DLBCL, NOS tCLL/MZL FL3B/PMBCL 88 57 19 10 2 ORR, % (95% CI) 74 (63, 83) 74 (60, 85) 84 (60, 97) 50 (19, 81) 100 (16, 100) CR, % (95% CI) 52 (41, 63) 51 (37, 64) 63 (38, 84) 30 (7, 65) 100 (16, 100) ≥ 3-mo f/u, nb 72 46 15 9 3-mo ORR, % (95% CI) 53 (41, 65) 54 (39, 69) 67 (38, 88) 22 (3, 60) 50 (1, 99) 3-mo CR, % (95% CI) 44 (33, 57) 43 (29, 59) 60 (32, 84) 22 (3, 60) 50 (1, 99) 2 54 37 10 6 2 6-mo ORR, % (95% CI) 35 (23, 49) 35 (20, 53) 50 (19, 81) 0 (0, 46) 50 (1, 99) 6-mo CR, % (95% CI) 31 (20, 46) 32 (18, 50) 40 (12, 74) 0 (0, 46) 50 (1, 99) ≥ 6-mo f/u, nc BOR, best overall response; NOS, not otherwise specified. Homogeneous CORE patient population identified and will move forward in pivotal trial a b c Includes patients with event of PD, death, or 28-day restaging scans. Two patients did not have restaging scans available. The denominator is number of patients who received JCAR017 ≥ 3 months ago, prior to data snapshot date, with an efficacy assessment at month 3 or prior assessment of PD or death. The denominator is number of patients who received JCAR017 ≥ 6 months ago, prior to data snapshot date, with an efficacy assessment at month 6 or prior assessment of PD or death. Data as of October 9, 2017 10 Overall Survival (OS) Early OS Encouraging in High-Risk DLBCL Patient Population mOS (95% CI); 6 mo OS (95% CI) FULL 100 CORE 100 CR : NR (NR, NR); 94% (78, 98) 80 80 All : NR (NR, NR); 86% (73, 93) 60 60 All : NR (9.0, NR); 78% (66, 86) 40 PR : 9.0 mos (3.8, NR); 75% (40, 91) 20 0 Median F/U=6.2 months 3 6 12 53 35 12 6 37 25 8 4 20 16 2 2 13 12 0 1 15 18 4 4 0 0 0 PR : 9.0 mos (4.9, NR); 81% (44, 95) Nonresponders: 6.2 mos (0.6, NR); 66% (33, 86) 0 9 Overall Survival (months) 88 46 19 23 40 20 Nonresponders: 5.4 mos (1.5, NR); 46% (21, 68) 0 At Risk All CR PR Nonresponder % Survival % Survival CR : NR (13.7, NR); 92% (78, 98) Median F/U=6.2 months 0 3 At Risk All 65 CR 36 39 26 6 9 12 PR 16 11 8 2 0 Non- 13 responder 2 2 1 0 15 18 3 3 0 0 Overall Survival (months) 30 20 15 12 mOS, median OS; mos, months. 9 9 Data as of October 9, 2017 14 TRANSCEND NHL 001: Conclusions § JCAR017 (lisocabtagene maraleucel; liso-cel), a CD19-directed CAR T cell product with defined composition, shows potent and durable responses in poor-prognosis patients with R/R aggressive NHL § The pivotal cohort has begun enrollment in the CORE population based on encouraging durable response rate at dose level 2 – 74% ORR and 68% CR rate at 3 months and 50% CR at 6 months – Across dose levels, 80% of patients in CR at 3 months remain in response at month 6 and 92% of patients in CR at 6 months remain in response § Liso-cel toxicities have been manageable at all dose levels tested with a favorable safety profile that may enable outpatient administration – Low rates of severe CRS (1%) and NT (12%) – Evaluation of outpatient administration is ongoing in pivotal cohort (Maloney et al, abstract 1552) § Optimized, commercial-ready liso-cel defined cell product being utilized for pivotal cohort with expected apheresis to product release < 21 days 15 10 5/7/2018 CAR T Toxicities Challice L Bonifant, published online 20 April 2016. doi:10.1038/mto.2016.11 DLBCL AFTER CAR-T THERAPY BASELINE Day +30 11 5/7/2018 Summary • We are entering a new era in treatment for lymphomas • CAR T-cell therapy may represent one of the more effective immunotherapeutic options • Challenges • Time to manufacture • Patient selection and toxicity management • integration with or replacement of existing modalities (chemotherapy, small molecule inhibitors, autologous vs allogeneic stem transplant) • cost • CAR T-cell therapy likely to alter how we treat DLBCL 12 5/8/2018 Treatment of Newly Diagnosed DLBCL in 2018 John Pagel, M.D., Ph.D. Chief of Hematologic Malignancies Director of Hematopoietic Stem Cell Transplantation Program CENTER FOR BLOOD DISORDERS AND STEM CELL TRANSPLANTATION SWEDISH CANCER INSTITUTE COI • Consultant for Pharmacyclics and Gilead Sciences WHO Classification of Aggressive B- Cell Lymphoid Neoplasms 2008 v 2016 2008 2016 Diffuse large B-cell lymphoma (DLBCL), NOS − OPTIONAL Germinal Center/Activated B cell − T cell/histiocyte-rich large B-cell lymphoma − Primary DLBCL of the CNS − Primary cutaneous DLBCL, leg type − EBV positive DLBCL, NOS − EBV+ Mucocutaneous ulcer DLBCL associated with chronic inflammation Lymphomatoid granulomatosis Primary mediastinal (thymic) large B-cell lymphoma Intravascular large B-cell lymphoma ALK positive large B-cell lymphoma Plasmablastic lymphoma Primary effusion lymphoma Large B-cell lymphoma arising in HHV8-associated multicentric Castleman Dis Diffuse large B-cell lymphoma (DLBCL), NOS − REQUIRED Germinal Center DLBLC − REQUIRED ABC DLBCL − T cell/histiocyte-rich large B-cell lymphoma − Primary DLBCL of the CNS − Primary cutaneous DLBCL, leg type − EBV positive DLBCL, NOS − EBV+ Mucocutaneous ulcer DLBCL associated with chronic inflammation Lymphomatoid granulomatosis Primary mediastinal (thymic) large B-cell lymphoma Intravascular large B-cell lymphoma ALK positive large B-cell lymphoma Plasmablastic lymphoma Primary effusion lymphoma HHV8 positive DLBCL, NOS High grade B-cell lymphoma, NOS High grade B-cell lymphoma, with MYC and BCL2 and/or BCL6 rearrangements High grade B-cell lymphoma, NOS B-cell lymphoma, unclassifiable, with features intermediate between DLBCL and classical Hodgkin lymphoma Swerdlow et al. Blood (2016) http://dx.doi.org/10.1182/blood-2016-01-643569 *Excluding Precursor Neoplasms 1 5/8/2018 International Standard of Care: R-CHOP Rituximab 375 mg/m2 day 1 Cyclophosphamide 750 mg/m2 day 1 Doxorubicin 50 mg/m2 day 1 Vincristine 1.4 mg/m2 day 1 (2 mg max) Prednisone 40 mg/m2 (or 100 mg) daily x 5 Age > 60 Pegfilgrastim 6 mg subcut day 2 Original Gela LNH 98-5 confirmed in multiple studies Coiffier et al. ASCO 2007. Abstract 8009. GOYA R-CHOP v G-CHOP for DLBCL: Study design Previously untreated DLBCL Age ≥18 years IPI 2 or IPI 1 (not age) or IPI 0 with bulky disease 7.5cm ECOG PS ≤2 G-CHOP (N=706) G 1000mg C1 D1/8/15 and C2–8 D1 CHOP 6 or 8 cycles every 21 days Randomized 1:1 R-CHOP (N=712) R 375mg/m2 C1–8 D1 CHOP 6 or 8 cycles every 21 days Target enrolment: 1400 Primary endpoint • PFS (INV-assessed) • • • • • Secondary and other endpoints • PFS (IRC-assessed)§ • OS, EFS, DFS, DoR, TTNT • CR/ORR at EOI (+/− FDG-PET) • Safety Statistical assumption for primary endpoint: G-CHOP v R-CHOP HR = 0.75 Number of CHOP cycles pre-planned in advance for all pts at each site Stratification factors: number of CHOP cycles, IPI, geographic region §Confirmatory endpoint Exploratory endpoint: PFS by cell of origin Vitolo U, et al. ASH 2016 Abstract 470 GOYA: Investigator-assessed PFS and OS PFS 1.0 0.8 Probability Probability OS 1.0 0.8 0.6 0.4 0.2 0.6 0.4 0.2 R-CHOP (n=712) G-CHOP (n=706) R-CHOP (n=712) G-CHOP (n=706) 0 0 0 6 No. of patients at risk R-CHOP 712 616 G-CHOP 706 622 12 527 540 18 488 502 Pts with event, n (%) 1-yr PFS, % 24 30 36 Time (months) 42 413 425 96 102 227 240 142 158 48 41 39 54 6 2 60 0 6 No. of patients at risk R-CHOP 712 663 G-CHOP 706 659 12 18 24 30 36 Time (months) 42 48 54 617 616 586 582 540 552 138 138 71 67 9 8 R-CHOP, n=712 G-CHOP, n=706 215 (30.2) 201 (28.5) 79.8 81.6 1-yr OS, % Pts with event, n (%) 319 316 190 201 R-CHOP, n=712 G-CHOP, n=706 126 (17.7) 126 (17.8) 89.9 90.7 2-yr PFS, % 71.3 73.4 2-yr OS, % 83.7 83.9 3-yr PFS, % 66.9 69.6 3-yr OS, % 81.4 81.2 HR (95% CI), p-value* 0.92 (0.76, 1.11), p=0.3868 HR (95% CI), p-value* 1.00 (0.78, 1.28), p=0.9982 Vitolo U, et al. ASH 2016 Abstract 470 60 *Stratified analysis; stratification factors: IPI score, number of planned chemotherapy cycles. Median follow-up: 29 months 2 5/8/2018 Dose-Adjusted (DA)-EPOCH-R Drug Dose Rituximab 375 mg/m2 day 1 IVPB Doxorubicin 10 mg/m2/day x 4 by CI Vincristine 0.4 mg/m2/day x 4 by CI Etoposide 50 mg/m2/day x 4 by CI Cyclophosphamide 750 mg/m2 day 5 IVBP Prednisone 60 mg/m2 BID days 1-5 oral Filgrastim* Weight-adjusted dose starting day 5 until ANC > 5000/μL *Data from MSKCC showed identical rate of dose-adjustment with filgrastim or pegfilgrastim • • Dosed every 21 days if ANC > 1/μL and PLTS > 100KμL Dose-adjusted based on ANC nadir: – >500/μL, increase cytotoxic drugs by 20% – <500/μL for 1-3 days, no change – <500/μL for >3 days or FN, decrease cytotoxic drugs by 20% Wilson, J Clin Oncol 2008 26: 2717-2724; Lunning et al. SHO, abstract CALGB 59910: Multi-Center DA-EPOCH-R, Outcomes Wilson W H et al. Haematologica 2012;97:758-765 CALGB 50303: DA-EPOCH-R vs RCHOP21 DeNovo DLBCL No discordant disease CS IIX-IV • OBJECTIVES: R A N D O M I Z E DA-EPOCH-R R-CHOP n= 478 patients (239 per treatment arm) – Primary • EFS untreated de novo DLBCL treated with RCHOP vs DA-R-EPOCH • Determine molecular predictors of outcome (using molecular profiling) in patients treated with these regimens. – Secondary • Compare ORR and OS • Compare the toxicity of these regimens in these patients. • Correlate the clinical parameters (i.e., toxicity, response, survival outcomes, and laboratory results) with molecular profiling in patients treated with these regimens. • Determine the use of molecular profiling for pathological diagnosis • PET/CT parameters as potential biomarker, predictive value of interim PET, reproducibility and standardization of PET/CT Wilson et al. ASH 2016, Abstract 489 3 5/8/2018 CALGB 50303: Event-Free and Overall Survival PFS 0.8 0.6 0.2 0.4 Survival Probability 0.6 0.4 0.2 Probability event free 0.8 OS HR=1.14 (0.82-1.61) p = 0.4386 1 2 3 4 0 5 1 2 Years from Study Entry Arm HR=1.18 (0.79-1.77) p = 0.42 R-CHOP DA-EPOCH-R 0.0 0.0 R-CHOP DA-EPOCH-R 0 3 4 5 Years from Study Entry N Events 3 Y (95% CI) 5 Y (95% CI) R-CHOP 233 64 0.81 (0.75-0.85) 0.69 (0.62-0.75) DA-EPOCH-R 232 70 0.79 (0.73-0.84) 0.66 (0.59-0.72) Arm N Events 3 Y (95% CI) 5 Y (95% CI) R-CHOP 233 44 0.85 (0.80-0.89) 0.80 (0.74-0.85) DA-EPOCH-R 232 50 0.85 (0.79-0.89) 0.76 (0.70-0.71) Additional analyses pending including outcome by COO, DH and DE Wilson et al. ASH 2016, Abstract 489 CALG 50303: PET Sub-study n=171 PET neg = Deauville 1-3 EOT Post Cycle 6 Events= 23 Events= 19 p-value= 0.0339 4 PET-negative PET-positive N= 121 N= 29 Events= 25 Events= 10 p-value= 0.0567 0.0 2 0.6 0.2 N= 104 N= 55 0.0 PET-negative PET-positive 0 0.4 Probability event free 0.6 0.4 0.2 Probability event free 0.8 0.8 Interim Post Cycle 2 6 0 Years from Study Entry 2 Timing of PET 3 year EFS Interim 81% (-) vs 69% (+) 0.034 p End of treatment 80% (-) vs 72% (+) 0.057 4 6 Years from Study Entry Treatment arms combined for analysis Schoder, H, Menton, France 2016; Wilson et al. ASH 2016, Abstract 489 Methods for determination of COO • Gene Expression Profiling on fresh tissue – ‘The gold standard’ – Not practically applicable in clinical practice • Immunohistochemistry – Widely available – Reproducibility may be difficult – Many assays (Hans, Choi, Muris, Natkurman, Tally) – Lack of correlation with GEP in many studies • GEP of formalin-fixed paraffin-embedded (FFPE) tissue – Multiple platforms – Hybrid capture/fluorescent reporter emerging as a widely validated assay 4 5/8/2018 GOYA: COO is prognostic ABC Unclassified 1.0 0.8 0.8 0.6 0.4 0.2 Probability 1.0 0.8 Probability Probability GCB 1.0 0.6 0.4 0.2 R-CHOP (n=269) G-CHOP (n=271) 0 0 6 12 200 217 18 24 30 36 42 Time (months) 191 207 166 178 HR (95% CI)† 94 113 64 75 48 46 50 19 22 54 2 1 60 0.72 (0.50, 1.01) R-CHOP (n=75) G-CHOP (n=75) 0 0 6 No. of patients at risk R-CHOP 118 101 G-CHOP 125 106 71% vs 79%, R-CHOP vs G-CHOP 3-yr PFS 0.4 0.2 R-CHOP (n=118) G-CHOP (n=125) 0 No. of patients at risk R-CHOP 269 234 G-CHOP 271 246 0.6 12 84 90 18 24 30 36 42 Time (months) 77 84 HR (95% CI)† 65 79 36 42 21 31 15 17 48 5 8 54 1 1 0.86 (0.57, 1.29) 58% vs 61%, R-CHOP vs G-CHOP 3-yr PFS 60 6 12 18 No. of patients at risk R-CHOP 75 65 G-CHOP 75 63 0 54 57 52 51 HR (95% CI)† 3-yr PFS 24 30 36 42 Time (months) 43 43 36 28 25 17 15 10 48 54 6 3 1 60 1.02 (0.60, 1.75) 64% vs 62% R-CHOP vs G-CHOP *Exploratory analysis; COO classification available in 933 pts; missing COO classifications due to: restricted Chinese export license, n=252; CD20+ DLBCL not confirmed, n=102; missing/inadequate tissue, n=131; PFS HR=0.82 (0.64, 1.04) in pts with COO classification; PFS HR=1.18 (0.85, 1.64) in pts without COO classification †Unstratified analysis Vitolo U, et al. ASH 2016 Abstract 470 Double-Hit B-cell Lymphomas Translocation of BCL2 and/or BCL6 is seen in a subset of GC DLBCL; simultaneous translocation of MYC is seen in ~6% of cases of GC DLBCL. MYC Expression of MYC and BCL2 is a consequence of the biology of ABC DLBCL Reclassified in WHO as HGBCL with rearrangement of MYC and BCL2 and/or BCL6 BCL2 Mottock & Gascoyne, CCR 2014 MYC Translocation in DLBCL Associated with Poor Outcomes with CHOP-based Therapy MYC+ DLBCL “Double Hit” BCL2/MYC Translocated R-CHOP treated Savage KJ et al. Blood 2009; Johnson NA et al. Blood 2009 5 5/8/2018 DA-EPOCH-R for DLBCL with translocation of MYC and BCL2 and/or BCL6 Progression-Free Survival of DH Case (n=14)* 100 Characteristic 52 Median age 61 y (29-80) IPI Score 0-2 3-5 35% 65% Histology DLBCL BCL-U 86% 14% BCL2 translocated by FISH 14/31* *31 of 52 tested 90 * 80 Proportion Progression free Number 70 60 50 40 30 20 10 0 6 12 18 24 30 36 42 48 54 Months *Cases were censored if they were transplanted; number censored for transplant NOT REPORTED Dunleavy, ASH 2015 Impact of induction regimen and SCT on outcomes in DH lymphoma: a multicenter retrospective analysis Adam M. Petrich et al. Blood 2014;124:2354-2361 Lenalidomide for DLBCL: Impact of Cell of Origin CD10 BCL6 Lenalidomide cycles Median (Range) Response CR PR SD PD Unknown ORR (CR + PR) PFS, mo Median 95% CI All GCB 2 (1-35) 2 (1-21) Non-GCB 4 (1-35) 6 (15.0) 5 (12.5) 7 (17.5) 21 (52.5) 1 (2.5) 11 (27.5) 1 (4.3) 1 (4.3) 7 (30.4) 14 (60.9) 0 2 (8.7) 5 (29.4) 4 (23.5) 0 7 (41.2) 1 (5.9) 9 (52.9) 2.6 1.7 6.2 0.9-4.2 0.3-3.1 2.9-9.6 IRF4 Hernandez-Ilizaliturri et al, Cancer 2011 117:5058 6 5/8/2018 Mayo Series: Outcomes for RL-CHOP v R-CHOP Case Match Control by Cell of Origin Non-GC DLBCL GC DLBCL Nowakowski et al. ASH 2012, ASCO 2014 ROBUST (NCT02285062): Lenalidomide Plus R-CHOP Chemotherapy (R2-CHOP) Versus Placebo Plus RCHOP Chemotherapy in Subjects With Untreated ABC-DLBCL, Phase 3, double-blind, placebocontrolled Inclusion DLBCL, ABC-type, untreated COO by Lymph2Cx Measurable disease by CT/MRI ECOG 0-2 Age 18-80 IPI ≥2 Double-blind, placebo controlled Randomization 1:1 Placebo + R-CHOP × 4 Placebo + R-CHOP × 2 Lenalidomide + R-CHOP × 4 Lenalidomide + R-CHOP × 2 Lymphoma other than DLBCL HIV, HBV, HCV active infections LVEF <45% ⇑ Interim Evaluation NR off study Exclusion Study Start Date: January 2015 Estimated Study Completion Date: Estimated Primary Completion Date: ⇑ EOT Evaluation IWG 2007 with Deauville PET September 2022 June 2018 Peripheral neuropathy, grade ≥2 Other malignancies < 5 years disease free Clinical Endpoints Sample Size/Statistical Plan Evaluation Sample size: 560 Interim evaluation after cycle 4 90% to detect increase in PFS of 60% EOT (6 cycles) FDG-PET Primary: Progression-free survival Secondary: OS, CRR, Duration of CR, TTNT, ORR, QOL Conclusions • DLBCL should always be approached with curative intent – The majority of patients will be cured with R-CHOP – R-CHOP remains the standard of care for de novo DLBCL in most situations – DA-R-EPOCH is a reasonable alternative with OS ~80% at 5 years • No difference in EFS and OS – G-CHOP does not appear to be better than R-CHOP for newly diagnosed DLBCL • Not all DLBCL are created equally – GCB versus non-GCB • Data is limited for GCB versus non-GCB • MYC alteration and Double Hit DLBCL remain challenging • Many novel agents and approaches are in development and warrant further investigation 7 5/7/2018 Jasmine Zain, M.D. Director, T-Cell Lymphoma Program City of Hope National Medical Center NOVEL TREATMENTS OF DIFFUSE LARGE B-CELL LYMPHOMA Click to edit Master Presentation Date NO NEW FDA-APPROVED AGENTS SINCE RITUXIMAB! Fisher RI et al. N Engl J Med 1993;328:1002-1006. Coiffier B, et al. NEJM. 2002. POTENTIAL TARGETS FOR TREATING B-CELL MALIGNANCIES 1 5/7/2018 BROAD CATEGORIES FOR TARGETED AGENTS FOR DLBCL • Immune modifiers Lenalidomide • Molecualar targets- Ibrutinib, Venetoclax, Idelalisib • Antibodies and antibody drug conjugates – anti CD37 • Blinotumumab and other bispecific antibodies • Immune-check point inhibitors • Microenvoirnment targets- Anti CD47 • Epigenetic agents 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) LENALIDOMIDE Lenalidomide has an ORR of 19% and 28% in RR. Witzig, et al. Zinzani, et al. 2008. More effective in non-GCB subtype- ORR 53% vs 9%. Hernandez, et al. Cancer. 2011. Tested in combination with Rituximab, RICE and as maintenance post transplant. Feldman, et al. 2014. Lenalidomide maintenance vs placebo in elderly patients after RCHOP. PFS was not reached in the Len arm vs 58.9 months in the placebo arm. Diff was notable in the GCB subtype. Thieblemont, et al. Blood. 2017. 2 5/7/2018 TARGETED TERAPIES – PI3K INHIBITORS Idealisib, TGR1202, copanlisib B-cell Herrera AF and Jacobsen EJ. CCR. 2014. IBRUTINIB • Selective and irreversible inhibitor of BTK • Modest clinical activity in DLBCL as a single agent - 23% seen mostly in the ABC-subtype. • Phase 1b/2 study of Ibrutinib plus lenalidomide and Rituximab is underway. Preliminary results show a RR of 44%. • RCHOP vs RCHOP+ibrutinib for non-GCB subtype of DLBCL. • Most common side effects are rash and diarrhea. BCL-2 INHIBITION - VENETOCLAX SINGLE AGENT RESPOSNE RATE IN R/R DLBCL WAS 18% Konopleva M, et al. Cancer Discovery. 2016. 3 5/7/2018 POLATUZUMAB VEDOTIN- ADC TARGETS CD79B CONJUGATED TO MMAE POLATUZUMAB VEDOTIN IN R/R DLBCL Treatment Regimen Best Overall Response Pola 1.8–2.4 mg/kg 51%1 Pola 1.8–2.4 mg/kg + rituximab 56%2 R/R DLBCL from the ROMULUS trial: pola + rituximab: Best SPD Change from Baseline Progression-Free Survival Morschhauser F, et al. Blood 2014; 124:4457. Palanca-Wessels MCA, et al. Lancet Oncol 2015; 16: 704-15. POLATUZUMAB VEDOTIN PLUS OBINUTUZUMAB FL (N=35) Objective response, n (%) 24 (69) DLBCL (N=43) 17 (40) Complete Response 11 (31) 9 (21) [90% CI] [19–47] [11–34] Partial Response 13 (37) 8 (19) [90% CI] [24–52] [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 aPatients who received ≥1 dose of study treatment; assessment per Lugano Criteria (Cheson 2014) bNo 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: http://tago.ca/TPHI 4 5/7/2018 POLA + R/G-BENDAMUSTINE Investigator-Assessed Response by PET/CTa FL DLBCL Pola + BR (n=6) Pola + BG (n=26) Pola + BR (n=6) Pola + BG (n=27) 6 (100) 4 (67) 2 (33) 0 0 0 23 (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) Best Objective Response ORR, n (%) CR PR SD PD UE Objective Response at End of Treatment 5 (83) 4 (67) 1 (17) 21 (81) 17 (65) 4 (15) 3 (50) 2 (33) 1 (17) 10 (37) 9 (33) 1 (4) Median duration of response, mo (range)b ORR, n (%) CR PR 16.1 (3.8–16.3) NR (15.2–20.6) NR (0.03–14.5) NR (0.03–15.7) Median PFS, mo (range)b 18.4 (7.2–18.9) NR (1.4–17.1) NR (1.5–22.7) 5.4 (0.03–17.6) aModified Lugano 2014 response criteria: for CR, repeat bone marrow biopsy required to confirm clearance of bone marrow if involved at screening. bKaplan-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. EZH2 - INHIBITORS Enhancer of zeste homolog 2 (EZH2) results in methylation of the histone H3associated with gene repression EZH2 activating mutations and overexpression is seen in cancers, GCB type of DLBCL not ABC subtype EZH2 inhibitor Tazemostat is in clinical trials- first in class inhibitor of mutated and wild type EZH2. Initial trials showed promising activity in Bcell lymphomas. CHECKPOINT INHIBITION: PD-1 PATHWAY Pardoll DM. Nature Reviews Cancer. 12, 252-264 (April 2012). Effects of PD-L1 binding: Inhibits T-cell activation Inhibits cytokine production Decreased cytolytic activity of CD4+ and CD8+ cells 5 5/7/2018 CHECK POINT INHIBITORS IN DLBCL • CTLA-4 AND PD-1 are being targeted. • CT-011 (pidilizumab) in post ASCT- 16 mo PFS 72% including high risk patients. Armand, et al. 2013. • Nivolumab- ORR 36% Lesokin, et al. 2016. • Pembrolizumab- in trials – encouraging rates in PMBCL and CNS. • Combinations with other therapies especially CAR-T. Juarez-Salcedo, et al. 2017. BISPECIFIC ANTIBODIES Phase II study of single agent bispecific engager (BiTE®) antibody Blinatumomab– ORR was 43% including 19% CRs. Viardot, et al. 2016. Trials ongoing with lenalidmide and alternative strategies of administration (subcutaneous) using Blinatumomab, lenalidmide. Other targets – CD 20 bispecific engager antibodies- encouraging RR and do not require CD19. CONCLUSION • Many promising strategies to treat RR DLBCL • Combination therapies are likely to win • Attempts to improve upon RCHOP continue especially for double hit and ABC subtypes 6
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