An Updated Analysis of JULIET, a Global Pivotal Phase 2 Trial of Tisagenlecleucel in Adult Patients With Relapsed or Refractory Diffuse Large B-Cell Lymphoma Abstract S799 Borchmann P, Tam CS, Jäger U, McGuirk JP, Holte H, Waller EK, Jaglowski SM, Bishop MR, Andreadis C, Foley SR, Westin JR, Fleury I, Ho PJ, Mielke S, Salles G, Maziarz RT, Anak Ö, Pacaud LB, del Corral C, Awasthi R, Agoulnik S, Tai F, and Schuster SJ
R/R DLBCL Treatment Landscape First-line treatment with immuno-chemotherapy (ie, R-CHOP) is effective 1-3 3-year PFS ~ 75% and 3-year OS ~ 80% Standard of care for R/R DLBCL patients is high-dose chemotherapy followed by auto-sct; however, only a minority actually receive transplant 4 ~50% of patients with R/R disease are ineligible for transplant ~50% of eligible patients respond to salvage chemotherapy and go on to receive transplant Patients refractory to or relapsing after 2 nd -line treatment have a poor prognosis Very low response rates to conventional approaches (CR 8%; PR 18%) 5 Extremely poor OS (median 4.4 mo) 6 auto-sct, autologous stem cell transplant; CR, complete response; DLBCL, diffuse large B-cell lymphoma; OS, overall survival; PFS, progression-free survival; PR, partial response; R-CHOP, rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone; R/R, relapsed/refractory 1. Pfreundschuh M, et al. Lancet Oncol. 2008;9(2):105-116. 2. Pfreundschuh M, et al. Lancet Oncol. 2011;12(11):1013-1022. 3. Schmitz N, et al. Lancet Oncol. 2012;13(12): 1250-1259. 4. Friedberg JW. J Am Soc Hematol Educ Book. 2011;1:498-505. 5. Crump M, et al. Blood. 2017;130(16):1800-1808. 6. Van den Neste E, et al. BMT. 2016;51-57.
Chimeric Antigen Receptor T-Cell Therapy Tisagenlecleucel (CTL019) 1-3 First approved CAR T-cell therapy in the United States August 2017: For patients up to 25 years of age with B-cell precursor ALL refractory or in second or later relapse May 2018: For adult patients with R/R DLBCL after 2 or more lines of systemic therapy, based on the phase II JULIET study ALL, acute lymphoblastic leukemia 1. Milone MC, et al. Mol Ther. 2009;17(8):1453-1464. 2. Zhang H, et al. J Immunol. 2007;179(7):4910-4918. 3. Kalos M, et al. Sci Transl Med. 2011;3:95ra73.
JULIET: Only Global CAR T-Cell Trial in DLBCL 27 sites in 10 countries * * * Manufacturing sites
JULIET: Eligibility and Endpoints Updated results of the JULIET study are presented Median follow-up, 14 mo (max, 23 mo) Additional 8 mo of follow-up from the previous presentation (ASH 2017) 1 Key eligibility criteria 18 years of age Central confirmation of histology 2 prior lines of therapy for DLBCL PD after or ineligible for auto-sct No prior anti-cd19 therapy Endpoints Primary endpoint: best overall response rate (ORR: CR + PR) Lugano criteria used for response assessment by IRC 2 Secondary endpoints: DOR, OS, safety No active CNS involvement CNS, central nervous system; DOR, duration of response; IRC, Independent Review Committee; ORR, overall response rate; OS, overall survival; PD, progressive disease 1. Schuster SJ, et al. Blood. 2017;130: Abstract 577. 2. Cheson BD, et al. J Clin Oncol. 2014;32(27):3059-3068.
JULIET: Demographics and Baseline Disease Status Patients [N = 111] Age, median (range), years 56 (22-76) 65 years, % 23 ECOG performance status 0/1, % 55/45 Central histology review Diffuse large B-cell lymphoma, % 79 Transformed follicular lymphoma, % 19 Double/triple hits in CMYC/BCL2/BCL6 genes, % 17 Cell of origin b Germinal/nongerminal center B-cell type, % 57/41 Number of prior lines of antineoplastic therapy, % 2/3/4-6 44/31/21 IPI 2 at study entry, % 72 Refractory/relapsed to last therapy, % 55/45 Prior auto-sct, % 49 Bridging chemotherapy, n 102 Lymphodepleting chemotherapy, n 103 ECOG, Eastern Cooperative Oncology Group a CMYC + BCL2, n = 10; CMYC + BCL2 + BCL6, n = 5; CMYC + BCL6, n = 4 b Determined by the Choi algorithm
JULIET: Adverse Events of Special Interest Patients [N = 111] AESI a All Grades, % Grade 3, % Grade 4, % Cytokine release syndrome b 58 14 8 Prolonged cytopenia c 44 16 16 Infections 34 18 2 Febrile neutropenia 15 13 2 a Occurring within 8 weeks of tisagenlecleucel infusion. b Cytokine release syndrome was graded using the Penn scale. c At day 28. No deaths due to tisagenlecleucel, CRS, or cerebral edema The most common neurologic events were Confusional state (8% any grade; 2% grade 3) Encephalopathy (6% any grade; 1% grade 3 and 4% grade 4) AESI, adverse events of special interest; CRS, cytokine release syndrome
JULIET: Cytokine Release Syndrome Tocilizumab administered according to a protocol-specific treatment algorithm (CRS graded per the Penn scale 1 ) 3% of patients with grade 2 CRS 50% with grade 3 CRS 100% with grade 4 CRS Patients [N = 111] Time to onset, median (range), days a 3 (1-9) Duration, median (range), days a 7 (2-30) Hypotension that required intervention, % 26 High-dose vasopressors, % 6 Intubated, % 7 Anticytokine therapy, % 16 Tocilizumab, % 15 Corticosteroids, % 11 a Calculated based only on patients who had cytokine release syndrome (n = 64), excluding 1 patient who had onset on day 51. 1. Porter DL, et al. Sci Transl Med. 2015;7(303):303ra139.
JULIET: Predictors of Safety Effect of Pre-infusion Values Tumor volume ( vs < 100 ml) Ferritin ( vs < 1000 µg/l) CRP ( vs < 50 mg/l) LDH ( vs < 500 U/L) CAR-positive viable T-cell dose No significant relationship between dose and CRS when accounting for baseline tumor burden No relationship observed between dose and neurologic events No relationship between dose and efficacy Grade 1-4 CRS 2 4 6 8 10 12 Odds Ratio Grade 1-4 neurologic events CRP, C-reactive protein; CRS, cytokine release syndrome; LDH, lactate dehydrogenase
JULIET: ORR Consistent Across Subgroups Null hypothesis of ORR 20% ORR n/n (%) [95% CI] All patients 48/93 (52) [41-62] Age <65 years 35/71 (49) [37-61] 65 years 13/22 (59) [36-79] Sex Female 19/33 (58) [39-74.5] Male 29/60 (48) [35-62] Prior response status Refractory to last line 19/48 (40) [26-55] Relapsed to last line 29/45 (64) [49-78] IPI at enrollment <2 risk factors 14/25 (56) [35-76] 2 risk factors 34/68 (50) [38-62] Prior antineoplastic therapy 2 lines 26/49 (53) [38-67.5] >2 lines 22/44 (50) [35-65] Molecular subtype Activated B-cell 21/40 (52) [36-69] Germinal cell 24/50 (48) [34-63] Prior HSCT therapy No 26/52 (50) [36-64] Yes 22/41 (54) [37-69] Rearranged MYC/BCL2/BCL6 Double/Triple hits 8/16 (50) [25-75] Other 40/77 (52) [40-63.5] 0 10 20 30 40 50 60 70 80 90 100
JULIET: At 14 Months Median Follow-Up, Median DOR Not Reached ORR, 52% (95% CI, 41%-62%); 40% CR, 12% PR a Probability of Maintaining Response, % 1.0 0.8 0.6 0.4 0.2 0.0 No. at risk CR patients All patients Median (95% CI) All patients, NR (10.0-NE) a Best ORR within 3 months of infusion CR patients All patients 0 1 2 3 4 5 6 7 8 9 10 Time Since First Response, Months 11 12 13 14 15 16 17 37 36 35 32 31 30 26 26 26 23 21 15 9 8 8 8 7 4 48 37 32 27 27 22 10 9 8 Median DOR has not been reached 12-mo relapse-free survival rate 78.5% (95% CI, 60%-89%) among CR patients 65% (95% CI, 49%-78%) among all responders 54% (13/24) of patients converted from PR to CR, including 2 patients 9-12 mo after initial response Tisagenlecleucel transgene was detected in peripheral blood for up to 2 years in responding patients No patients proceeded to transplant while in response NE, not evaluable; NR, not reached
JULIET: Median Overall Survival Was Not Reached for CR Patients 1.0 Probability of Survival, % 0.8 0.6 0.4 0.2 CR patients All patients Median, mo (95% CI) CR patients, NE (17.9-NE) All patients, 11.7 (6.6-NE) 0.0 No. at risk CR patients All patients 0 2 4 6 8 10 12 14 16 18 20 22 Time Since Infusion, Months 40 40 40 40 39 39 38 38 37 36 30 29 23 16 16 12 9 9 7 3 2 1 1 111 94 71 60 50 40 28 19 11 8 2 1 Overall survival at 12 mo 49% among all infused patients 95% among CR patients
JULIET: Summary of Tisagenlecleucel in R/R Aggressive DLBCL In this update of the JULIET study, with a median follow-up of 14 months: AEs were effectively managed by appropriately trained study-site personnel No deaths were attributed to tisagenlecleucel, CRS, or cerebral edema Baseline tumor volume, LDH, ferritin, and CRP are associated with higher risk of any-grade CRS and neurotoxicity Tisagenlecleucel produced a high percentage of durable responses in patients with R/R DLBCL (ORR 52%; CR 40%) 49% overall survival rate at 12 mo (95% among CR patients) Median DOR was not reached 54% of patients with an initial PR converted to CR (up to 12 mo) 83% of patients in CR/PR at 3 mo remained progression free at 12 mo