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1194 Myc Expression and Tumor-Infiltrating T Cells Are Associated with Response in Patients (Pts) with Relapsed/Refractory Diffuse Large B-Cell Lymphoma (r/r DLBCL) Treated with Tisagenlecleucel in the Juliet Trial

Program: Oral and Poster Abstracts
Session: 626. Aggressive Lymphoma (Diffuse Large B-Cell and Other Aggressive B-Cell Non-Hodgkin Lymphomas)—Results from Prospective Clinical Trials: Poster I
Hematology Disease Topics & Pathways:
Biological, Adult, Diseases, Therapies, CAR-Ts, DLBCL, B-Cell Lymphoma, Biological Processes, Lymphoid Malignancies, Study Population, genomics, microenvironment
Saturday, December 5, 2020, 7:00 AM-3:30 PM

Ulrich Jaeger, MD1, Michael R. Bishop, MD2, Gilles Salles, MD, PhD3, Stephen J. Schuster, MD4,5, Richard T. Maziarz, MD6,7, Xia Han, MS8*, Alexander Savchenko, MD9*, Nathan Roscoe, Mbt10*, Elena Orlando, PhD11*, Dawson Knoblock, PhD8*, Ranjan Tiwari, MSc12*, Lida Bubuteishvili Pacaud, MD8* and Paolo Corradini13

1Clinical Division of Hematology and Hemostaseology, Department of Medicine I, Medical University of Vienna, Vienna, AA, Austria
2Department of Medicine, Section of Hematology/Oncology, University of Chicago, Chicago, IL
3Hematology Department, Hospices Civils de Lyon, Lyon-Sud Hospital, Pierre Bénite, France
4Division of Hematology-Oncology, Department of Medicine, University of Pennsylvania, Philadelphia, PA
5Lymphoma Program, Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA
6Knight Cancer Institute, Oregon Health and Science University, Portland, OR
7Department of Hematology, Oregon Health and Science University, Portland, OR
8Novartis Pharmaceuticals Corporation, East Hanover, NJ
9Oncology Precision Medicine, Novartis Pharmaceuticals Corporation, Cambridge, MA
10Navigate BioPharma, Carlsbad, CA
11Novartis Institutes for Biomedical Research, Cambridge, MA
12Novartis Healthcare Pvt. Ltd, Hyderabad, India
13Fondazione IRCCS Instituto Nazionale dei Tumori, University of Milan, Milan, Italy

Background: Tisagenlecleucel (tisa-cel; autologous anti-CD19 CAR-T cell therapy) has demonstrated durable responses and a manageable safety profile in adult pts with r/r DLBCL in the JULIET trial. Here we report updated efficacy results with a 40 month median follow-up and associations with baseline Myc overexpression in tumor and tumor microenvironment (TME) characteristics.

Methods: JULIET is a global, phase 2 trial of tisa-cel in adult pts with r/r DLBCL. The relationship between Myc overexpression (Myc+: >40% by immunohistochemistry [IHC]), TME characteristics (including CD3+ T-cell infiltration, myeloid-derived suppressor cells [MDSCs], and LAG3 expression by fluorescent IHC) with efficacy outcomes (Month 3 [M3] response, duration of response [DOR], progression-free survival [PFS], and overall survival [OS]), and genomic mutation profile with M3 response were assessed.

Results: As of February 20, 2020 (median follow-up of 40.3 mo), 115 pts received tisa-cel infusion. Among the 61 pts with a response, the relapse-free probability was 60.4% at 24 and 30 mo; median DOR was not reached (95% CI, 10-not estimable [NE]). Median OS among all 115 infused pts was 11.1 months (95% CI, 6.6-23.9). Survival probability at 12, 24, and 36 months was 48.2%, 40.4%, and 36.2%, respectively. Median OS of pts with CR (n=37) or PR (n=7) at M3 was not reached; 80% of CR pts had an OS benefit of 20 months or longer. No new safety signals were detected. Of the 23 pts with ongoing CR and B-cell count available, 11 had CD19+ B cells recovered back to normal after 1 year, with similar patterns observed for CD20+ and CD22+ B cells.

Of 111 pts whose baseline archival tumor biopsies were tested for baseline Myc expression, 73 were Myc+ and 38 were Myc−. Baseline Myc− status was associated with improved outcomes compared with Myc+ pts, including longer median DOR (not reached vs 19 months [95% CI, 3.4-NE]), PFS (6.2 months [95% CI, 2.9-NE] vs 2.5 months [95% CI, 1.7-3.0]; Fig.1A), and OS (21 months [95% CI, 10-NE] vs 7.8 months [95% CI, 4.6-18]). In the TME analysis of baseline biopsy, lack or low frequency of tumor-infiltrating CD3+ T cells (cutoff of ≤3%; n=16) was associated with shorter median PFS (2.2 months [95% CI, 0.92-2.8] vs 4.2 months [95% CI, 2.6-21]; Fig.1B) and OS (7 months [95% CI, 1.8-12] vs 21 months [95% CI, 6.7-NE]) compared with pts with >3% CD3+ T cells (n=64). Interrogation of checkpoint molecule expression on tumor-infiltrating CD3+ cells revealed that pts with the highest frequency of LAG3+CD3+ cells out of entire CD3+ T cell population (cutoff of >20%; n=12) at baseline had decreased median PFS (2.1 [95% CI, 0.82-3.1] vs 4.2 months [95% CI, 2.4-21]) and OS (4.3 [95% CI, 2.7-10] vs 21 months [95% CI, 10-NE]) compared with pts with ≤20% LAG3+CD3+ T cells (n=68). No differences in baseline clinical characteristics were observed in subgroups by Myc, CD3+, and LAG3+CD3+ expression. Additionally, in a small dataset, pts with the highest frequency of CD11b+HLA-DR− cells that represent MDSC phenotype at baseline were enriched with nonresponders.

In a survival tree analysis including infiltrating T cells, LAG3+ CD3+ cells, Myc, and LDH, pts with Myc− status and normal pre-infusion LDH levels (n=16) had longer PFS compared with normal LDH and Myc+, and pts with LDH 1- to 2-fold or >2-fold above the upper limit of normal, with the latter group having a poor PFS.

Whole exome sequencing of 46 baseline tumor samples was performed. No significant association with response was observed in mutations at the single-gene level. The correlation between molecular subtypes and M3 response was also investigated. Samples grouped into newly identified DLBCL subtypes (Chapuy et al. Nat Med. 2018; Schmitz et al. N Engl J Med. 2018; Wright et al. Cancer Cell. 2020) did not reveal an association with response, although the small sample size may limit interpretation.

Conclusions: Updated long-term data with 40 months median follow-up from the JULIET trial demonstrate sustained benefit in responding pts; in particular 80% of CR pts had a long-term OS (≥20 months). Taken together, the results suggest that Myc overexpression, or an unfavorable immunosuppressive TME with restricted T-cell response, may impact CAR-T cell efficacy in pts with DLBCL.

Disclosures: Jaeger: AbbVie: Honoraria; Novartis: Consultancy, Honoraria, Research Funding; Gilead: Honoraria, Research Funding; BMS/Celgene: Consultancy, Honoraria, Research Funding; Karyopharm: Honoraria; CDR Life AG: Consultancy, Research Funding; Miltenyi: Consultancy, Honoraria; F. Hoffmann-La Roche: Honoraria, Research Funding. Bishop: Incyte: Honoraria, Speakers Bureau; CRSPPR Therapeutics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Autolus: 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; Kite: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; BMS: Honoraria, Speakers Bureau. Salles: Autolus: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Other: Educational events; BMS: Honoraria; Merck: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Educational events; Novartis, Servier, AbbVie, Karyopharm, Kite, MorphoSys: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Educational events; Roche, Janssen, Gilead, Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Educational events; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Educational events; Epizyme: Consultancy, Honoraria. Schuster: Novartis, Genentech, Inc./ F. Hoffmann-La Roche: Research Funding; AlloGene, AstraZeneca, BeiGene, Genentech, Inc./ F. Hoffmann-La Roche, Juno/Celgene, Loxo Oncology, Nordic Nanovector, Novartis, Tessa Therapeutics: Consultancy, Honoraria. Maziarz: Novartis, Incyte, CRISPR Therapeutics, Artiva Biotherapeutics, and AlloVir: Consultancy; Novartis and Athersys: Other: DSMB participant; Novartis and Juno: Research Funding; Incyte, Kite, BMS/Celgene, PACT Pharma, Orca BioSystems, and Omeros: Honoraria; Athersys: Patents & Royalties. Han: Novartis Pharmaceuticals Corporation: Current Employment. Savchenko: Novartis Pharmaceuticals Corporation: Current Employment. Roscoe: Navigate BioPharma Services, Inc., a Novartis Subsidiary: Current Employment. Orlando: Novartis Institutes for BioMedical Research: Current Employment. Knoblock: Novartis Pharmaceuticals Corporation: Current Employment. Tiwari: Novartis: Current Employment. Bubuteishvili Pacaud: Novartis: Current Employment. Corradini: Daiichi Sankyo: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Other: Travel and accommodations paid by for; Gilead: Consultancy, Honoraria, Other: Travel and accommodations paid by for; Incyte: Consultancy; Janssen: Consultancy, Honoraria; Kite: Consultancy, Honoraria; KiowaKirin: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Other: Travel and accommodations paid by for; F. Hoffman-La Roche Ltd: Consultancy, Honoraria; Sanofi: Consultancy, Honoraria; Servier: Consultancy, Honoraria; Takeda: Consultancy, Honoraria, Other; BMS: Other; AbbVie: Consultancy, Honoraria, Other: Travel and accommodations paid by for; Amgen: Consultancy, Honoraria, Other: Travel and accommodations paid by for.

*signifies non-member of ASH