Sustained Disease Control for Adult Patients with Relapsed or Refractory Diffuse Large B-Cell Lymphoma: An Updated Analysis of Juliet, a Global Pivotal Phase 2 Trial of Tisagenlecleucel
Authors: Schuster Stephen J. , Bishop Michael R. , Tam Constantine , Borchmann Peter , Jaeger Ulrich , Waller Edmund K. , Holte Harald , McGuirk Joseph P. , Jaglowski Samantha , Tobinai Kensei , Andreadis Charalambos , Fleury Isabelle , Mielke Stephan , Teshima Takanori , Westin Jason R. , Bachanova Veronika , Foley Stephen Ronan , Ho P Joy , Magenau John M. , Wagner-Johnston Nina D. , Kato Koji , Kersten Marie Jose , Van Besien Koen , Chu Jufen , Jary Aline , Anak Özlem , Salles Gilles , Maziarz Richard Thomas T. 
Published: October 2019

Abstract

BACKGROUND
JULIET (NCT02445248) is a single-arm, open-label, multicenter, global, pivotal phase 2 trial of tisagenlecleucel, a chimeric antigen receptor (CAR)-T cell therapy targeting CD19, that has shown a high rate of durable complete responses (CR) and a manageable safety profile in adult patients with clinically active relapsed/refractory (r/r) diffuse large B-cell lymphoma (DLBCL). The primary objective was met at the interim analysis, with an overall response rate (ORR) of 59% (CR, 43%; partial response [PR], 16%). Here, we present an updated analysis of the JULIET trial, with a median of 19 months of follow-up, an additional 5 months since the previous report (Schuster et al. EHA 2018), demonstrating sustained activity in this patient population.
METHODS
Eligible patients were ≥18 years with r/r DLBCL, had received ≥2 lines of therapy, including rituximab and an anthracycline, and were ineligible for or had failed autologous stem cell transplant (ASCT). Tisagenlecleucel was centrally manufactured at 2 facilities (Morris Plains, NJ, USA [main cohort] and Leipzig, Germany [cohort A]) using cryopreserved apheresis material and provided to patients at 27 treatment sites across 10 countries on 4 continents using a global supply chain. The primary endpoint was ORR (CR + PR) per independent review committee. Efficacy results are reported for patients in the main cohort with ≥3 months of follow-up or earlier discontinuation; safety is reported for all infused patients.
RESULTS
At data cutoff (May 21, 2018), 167 patients were enrolled and 115 were infused (99 in the main cohort and 16 in cohort A) with a single dose of tisagenlecleucel (median, 3.0×108 [range, 0.1-6.0×108] CAR-positive viable T cells). 90% of infused patients received bridging therapy and 93% received lymphodepleting chemotherapy. Median time from infusion to data cutoff was 19.3 months. Median age was 56 years (range, 22-76 years); 23% were aged ≥65 years. At study entry, 77% of infused patients had stage III/IV disease and 17% had double/triple hit disease. 55% and 43% had germinal center and activated B-cell molecular subtypes, respectively. 51% of patients had received ≥3 prior lines of antineoplastic therapy (range, 1-6); 49% had undergone a prior ASCT.
All 99 patients in the main cohort had ≥3 months of follow-up or discontinued earlier and were evaluable for efficacy. ORR was 54% (95% CI, 43%-64%), with 40% CR and 13% PR. ORR was consistent across prognostic subgroups (including prior ASCT and double/triple-hit lymphoma).
Median duration of response (DOR) was not reached; the probability of being relapse free was 66% (95% CI, 51%-78%) at 6 months and 64% (95% CI, 48%-76%) at 12 and 18 months. DOR was similar by age group (≥ vs < 65 years) and by relapsed or refractory status (Figure). No relapses were observed beyond 11 months after infusion. Median OS for all infused patients was 11.1 months (95% CI, 6.6 months-NE) and not reached (95% CI, 21 months-NE) for patients in CR. OS probability was 48% (95% CI, 38%-57%) at 12 months and 43% (95%CI, 33%-53%) at 18 months (max follow-up, 29 months). No patients proceeded to allogeneic SCT or ASCT while in remission.
Grade 3 or 4 adverse events (AEs) of special interest within 8 weeks of infusion included cytopenias lasting >28 days (34%), cytokine release syndrome (CRS; 23%, by the Penn scale), infections (19%), febrile neutropenia (15%), neurological events (11%; 1 case of grade 2 cerebral edema), and tumor lysis syndrome (2%). 16% of patients received tocilizumab for CRS management. 3 patients died within 30 days of infusion (all due to disease progression). No treatment-related mortality was reported. Since the previous report, no new deaths occurred due to causes other than disease progression.
CONCLUSION
Results from this longer-term follow-up show that tisagenlecleucel produced high response rates and durable responses in a cohort of heavily pretreated adult patients with r/r DLBCL. Efficacy was consistent in all predefined subgroups, including elderly patients, patients with r/r disease, and other clinical or biological subgroups expected to have a worse prognosis with available treatments, as demonstrated by similar and sustained DOR and OS following tisagenlecleucel treatment.
Figure. Figure.

Disclosures
Schuster: Genentech: Honoraria, Research Funding; Merck: Consultancy, Honoraria, Research Funding; Gilead: Membership on an entity's Board of Directors or advisory committees; Nordic Nanovector: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis Pharmaceuticals Corporation: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Dava Oncology: Consultancy, Honoraria. Bishop:Juneau Therapeutics: Speakers Bureau; Celgene: Honoraria, Speakers Bureau; Seattle Genetics: Consultancy, Membership on an entity's Board of Directors or advisory committees; United Healthcare: Employment; Novartis Pharmaceuticals Corporation: Speakers Bureau. Tam:AbbVie: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Beigene: Honoraria. Borchmann:Novartis: Consultancy, Honoraria. Jaeger:Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda-Millenium: Membership on an entity's Board of Directors or advisory committees; Infinity: Membership on an entity's Board of Directors or advisory committees; Mundipharma: Membership on an entity's Board of Directors or advisory committees; Takeda-Millenium: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees; MSD: Research Funding; Gilead: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bioverativ: Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; GSK: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie: Consultancy, Honoraria; AOP Orphan: Membership on an entity's Board of Directors or advisory committees. Waller:Pharmacyclics: Other: Travel Expenses, EHA, Research Funding; Celldex: Research Funding; Kalytera: Consultancy; Novartis Pharmaceuticals Corporation: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Cambium Medical Technologies: Consultancy, Equity Ownership. Holte:Novartis Pharmaceuticals Corporation: Membership on an entity's Board of Directors or advisory committees; Roche, Norway: Research Funding. McGuirk:Novartis Pharmaceuticals Corporation: Honoraria, Other: speaker, Research Funding; Kite Pharma: Honoraria, Other: travel accommodations, expenses, speaker ; Fresenius Biotech: Research Funding; Pluristem Ltd: Research Funding; Gamida Cell: Research Funding; Bellicum Pharmaceuticals: Research Funding; Astellas Pharma: Research Funding. Jaglowski:Kite Pharma: Consultancy, Research Funding; Novartis Pharmaceuticals Corporation: Consultancy, Research Funding; Juno: Consultancy. Tobinai:Abbvie: Research Funding; SERVIER: Research Funding; Takeda: Honoraria, Research Funding; Mundipharma: Honoraria, Research Funding; Eisai: Honoraria, Research Funding; GlaxoSmithKline: Research Funding; Janssen: Honoraria, Research Funding; Ono Pharmaceutical: Honoraria, Research Funding; Kyowa Hakko Kirin: Honoraria, Research Funding; Chugai Pharma: Honoraria, Research Funding; HUYA Bioscience International: Consultancy, Honoraria; Zenyaku Kogyo: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Research Funding. Andreadis:Cellerant Therapeutics: Research Funding; Novartis Pharmaceuticals Corporation: Honoraria, Research Funding; Incyte Pharmaceuticals: Research Funding; Pharmacyclics: Research Funding; Amgen: Research Funding; Genentech Inc.: Honoraria, Research Funding; Seattle Genetics: Honoraria; Gilead Sciences: Honoraria; Astellas: Honoraria. Fleury:F. Hoffmann-La Roche Ltd: Consultancy; Lundbeck: Consultancy; Gilead: Consultancy; Seattle Genetics: Consultancy; Janssen: Consultancy; Merck: Consultancy; Novartis Pharmaceuticals Corporation: Consultancy; Celgene: Consultancy. Mielke:Celgene: Speakers Bureau; KIADIS Pharma: Speakers Bureau; Miltenyi Biotec: Speakers Bureau; DGHO: Speakers Bureau; EHA: Speakers Bureau. Westin:Apotex: Membership on an entity's Board of Directors or advisory committees; Kite Pharma: Membership on an entity's Board of Directors or advisory committees; Celgen: Membership on an entity's Board of Directors or advisory committees; Novartis Pharmaceuticals Corporation: Membership on an entity's Board of Directors or advisory committees. Bachanova:Kite Pharma: Membership on an entity's Board of Directors or advisory committees; Gamida Cell: Research Funding; GT Biopharma: Research Funding. Foley:Celgene: Honoraria, Speakers Bureau; Novartis Pharmaceuticals Corporation: Consultancy, Honoraria, Other: Travel expenses ; Amgen: Honoraria; Janssen: Speakers Bureau; Jazz Pharma: Other: Travel expenses . Ho:Amgen: Honoraria; Janssen: Honoraria; Novartis: Honoraria; Takeda: Honoraria, Other: travel to meeting; Celgene: Other: travel to meeting. Wagner-Johnston:JUNO: Honoraria, Membership on an entity's Board of Directors or advisory committees; Merck: Research Funding; ADC Therapeutics: Honoraria, Membership on an entity's Board of Directors or advisory committees; ASTEX: Research Funding; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Research Funding; Celgene: Research Funding. Kersten:Millennium/Takeda: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Roche: Honoraria, Research Funding; Kite/Gilead: Honoraria; Novartis Pharmaceuticals Corporation: Honoraria. Chu:Novartis Pharmaceuticals Corporation: Employment. Jary:Novartis Pharma AG: Employment. Anak:Novartis Pharma AG: Employment. Salles:Celgene: Honoraria, Other: Advisory Board, Research Funding; F. Hoffmann-La Roche Ltd: Consultancy, Honoraria, Research Funding; Pfizer: Honoraria; Takeda: Honoraria; Amgen: Honoraria; Servier: Honoraria, Other: Advisory Board; Merck: Honoraria; Janssen: Honoraria, Other: Advisory Board; Gilead: Honoraria, Other: Advisory Board; Novartis: Consultancy, Honoraria; Acerta: Honoraria; Morphosys: Honoraria; Servier: Honoraria; BMS: Honoraria, Other: Advisory Board; Epizyme: Honoraria; Abbvie: Honoraria. Maziarz:Novartis Pharmaceuticals Corporation: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Incyte: Consultancy, Honoraria; Juno Therapeutics: Consultancy, Honoraria; Kite Therapeutics: Honoraria; Athersys, Inc.: Patents & Royalties.