Long-Term Clinical Outcomes and Correlative Efficacy Analyses in Patients (Pts) with Relapsed/Refractory Follicular Lymphoma (r/r FL) Treated with Tisagenlecleucel in the Elara Trial

Background: Tisagenlecleucel is the first CAR-T cell therapy approved in the United States and European Union for r/r FL in the third-line or later setting. In the primary analysis of the single-arm, open-label, Phase II ELARA trial, tisagenlecleucel demonstrated high response rates and an excellent safety profile in adult pts with high-risk r/r FL. Herein, we report >2-year follow-up data on the continued durability of response (DOR), longer-term safety, as well as biomarker and pharmacokinetic analyses from the ELARA trial.

Methods: Eligible pts had r/r FL (grades 1-3A) following ≥2 lines of therapy that included an anti-CD20 antibody and an alkylating agent or had relapsed after autologous stem cell transplant (SCT). Bridging chemotherapy was permitted. Following lymphodepleting (LD) chemotherapy, pts received single-dose tisagenlecleucel (0.6-6×10⁸ CAR+ viable T cells). Baseline clinical factors, tumor microenvironment (TME) assessment, blood soluble factors, and circulating blood cells were correlated with clinical response and progression-free survival (PFS). Cellular kinetics were determined by measurement of transgene levels by quantitative polymerase chain reaction.

Results: Among 94 pts evaluable for efficacy [median follow-up of 28.9 months (mo)], complete response rate was 68% (95% CI, 57.7-77.3) and overall response rate was 86.2% (95% CI, 77.5-92.4). Median PFS was not reached (NR); the estimated 24 mo-PFS post infusion was 57.4% (95% CI, 46.2, 67.0; Figure). The estimated 24 mo-DOR and OS post infusion were 64.6% (77.8% for pts with CR) and 87.7% (95% CI, 78.3, 93.2), respectively. No new safety signals were reported. Neurological events (NEs) were reported in 12 (12.3%) pts including 1 pt with probable progressive multifocal leukoencephalopathy who had prior grade 4 immune effector cell-associated neurotoxicity syndrome. Three new deaths (total 13 deaths) occurred during this longer-term follow-up period [progressive disease (PD), n=1; serious adverse events (SAEs), n=2, urothelial bladder carcinoma and post allogeneic SCT (alloSCT) complications]. No new deaths were treatment related. A total of 23 (24%) pts received at least one subsequent therapy post infusion. Of these, 4 pts received alloSCT, and one pt received only localized radiotherapy. Persistence of the CAR transgene was observed for up to 925 days (median, 210 days; range, 13 to 925 days). Eight pts had SARS-COV-2 infection at the time of data cut-off.

Among all parameters tested, elevated tumor burden [TB; total metabolic tumor volume (TMTV) ≥240 cm³] at baseline (pre-LD chemotherapy), progression of disease within 2 years of initial chemoimmunotherapy (POD24), and >4 nodal areas at inclusion were clinical factors that correlated significantly with lower efficacy. Furthermore, baseline serum IL-10 and TNF-α levels were highly correlated with TB (Spearman correlation = 0.80 and 0.86, respectively (both P<0.001), with higher levels significantly associated with non-response/relapse and shorter PFS. Additionally, baseline TME was characterized by fluorescence immunohistochemistry, and an increase in LAG3+ exhausted T cells (≥3% of total T cells) was the only factor that significantly associated with shorter PFS (median PFS, 5.9 mo vs NR, P=0.0017). Also, decreased CD8+ cytotoxic T cells and increased CD19+ B cells in peripheral blood at baseline were associated with poor outcome. POD24, >4 nodal areas at inclusion, baseline TB, and tumor infiltrated LAG3+CD3+ cells remained significant in multivariate Cox models for PFS analysis.

Cellular kinetics shows that the mean in vivo maximal expansion (C_max) in pts with no POD24 was higher compared with pts with POD24. Pts with high TB, based on TMTV at baseline, had a shorter DOR relative to pts with low TB.

Conclusions: Updated long-term data from the ELARA trial demonstrated robust durable responses >2 years post infusion, with a continued favorable safety profile. Correlative analyses suggest that high-risk disease characteristics (elevated TB at baseline, POD24, >4 nodal areas at inclusion), exhausted T cells in the TME, and increased IL-10 and TNF-α levels are associated with worse long-term outcomes following tisagenlecleucel in pts with r/r FL.

Dreyling:Astra Zeneca, Beigene, BMS/Celgene, Gilead/Kite, Janssen, Lilly/Loxo, Novartis, Roche: Consultancy; Amgen, Astra Zeneca, Gilead/Kite, Janssen, Lilly, Novartis, Roche: Honoraria; Abbvie, Bayer, BMS/Celgene, Gilead/Kite, Janssen, Roche: Research Funding. Dickinson:Roche, BMS, Novartis, Kite, Gilead, NKARTA, AdiCet Bio, Interius, Janssen, MSD, Amgen: Honoraria; Roche, BMS, Novartis, Kite, Gilead, NKARTA, AdiCet Bio, Interius, Janssen, MSD: Consultancy; Roche, Novartis, Kite, Gilead, MSD, Takeda, Celgene: Research Funding. Kolstad:Nordic Nanovector: Membership on an entity's Board of Directors or advisory committees, Research Funding. Chavez:Epyzime: Honoraria; ADC Therapeutics: Research Funding; Janssen: Research Funding; Merck: Research Funding; Astrazeneca: Research Funding; Kite, a Gilead Company: Consultancy, Membership on an entity's Board of Directors or advisory committees; BeiGene: Honoraria; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; TG Therapeutics: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Abbvie: Consultancy; AdiCet: Consultancy; GenMab: Consultancy. Bachy:Kite, Gilead, Novartis, Roche, Incyte, Miltenyi Biotech, Takeda, Sanofi: Honoraria; Roche, Gilead, ADC Therapeutics, Takeda, Novartis, Incyte: Membership on an entity's Board of Directors or advisory committees; Amgen, BMS: Research Funding; Hospices Civils de Lyon: Current Employment. Kato:Novartis: Consultancy, Honoraria; Daiichi Sankyo: Consultancy, Other: Grants or contracts from any entity ; Chugai: Consultancy, Honoraria, Other: Grants or contracts from any entity ; Meiji: Consultancy, Honoraria; Kyowa-Kirin: Honoraria, Other: Grants or contracts from any entity ; Takeda: Honoraria, Other: Grants or contracts from any entity ; AbbVie: Other: Grants or contracts from any entity ; Eisai: Other: Grants or contracts from any entity ; Janssen: Other: Grants or contracts from any entity ; Celgene: Other: Grants or contracts from any entity ; Ono: Other: Grants or contracts from any entity . Harigae:Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees; Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees; Symbio: Honoraria; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Chugai: Honoraria; Novartis: Honoraria. Kersten:Kite, a Gilead Company: Honoraria, Research Funding; BMS/Celgene: Honoraria, Research Funding; Adicet Bio: Honoraria; Takeda: Honoraria; Roche: Honoraria, Research Funding; Novartis: Honoraria; Miltenyi Biotech: Honoraria. Andreadis:Merck & Co., Inc.: Research Funding; Novartis: Research Funding; BMS: Honoraria; Kite: Honoraria. Riedell:Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Nektar Therapeutics: Membership on an entity's Board of Directors or advisory committees; Intellia Therapeutics: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; Karyopharm: Membership on an entity's Board of Directors or advisory committees; Sana Biotechnology: Consultancy; AbbVie: Membership on an entity's Board of Directors or advisory committees; BeiGene: Consultancy; Takeda: Membership on an entity's Board of Directors or advisory committees; Kite/Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; BMS: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; MorphoSys: Research Funding; Calibr: Research Funding; Tessa Therapeutics: Research Funding; Fate Therapeutics: Research Funding; Xencor: Research Funding. Ho:Regeneron: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; Gilead: Membership on an entity's Board of Directors or advisory committees; Antengene: Membership on an entity's Board of Directors or advisory committees. Perez-Simon:Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, and Expenses; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, and Expenses; GILEAD: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, and Expenses; JAZZ: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, and Expenses; ALEXION: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, and Expenses; ABBVIE: Research Funding; PFIZER: Research Funding. Chen:Mesolbast: Honoraria; Morphosys: Honoraria. Nastoupil:Genentech/Roche, MEI, Takeda: Other: DSMC; ADC Therapeutics, BMS, Caribou Biosciences, Epizyme, Genentech/Roche, Gilead/Kite, Genmab, Janssen, MEI, Morphosys, Novartis, Takeda: Honoraria; BMS, Caribou Biosciences, Epizyme, Genentech, Gilead/Kite, Genmab, Janssen, IGM Biosciences, Novartis, Takeda: Research Funding. von Tresckow:Pentixafarm: Consultancy; Novartis: Consultancy, Honoraria, Other: NA, Research Funding; IQVIA: Consultancy; MSD: Consultancy, Honoraria, Other: NA, Research Funding; Roche: Consultancy, Honoraria, Other: NA; Takeda: Consultancy, Honoraria, Other: NA, Research Funding; Pfizer: Consultancy; AstraZeneca: Honoraria, Other: NA; Amgen: Consultancy; Allogene: Consultancy; Abbvie: Other: NA; Miltenyi: Consultancy; BMS: Honoraria, Other: NA; Cerus: Consultancy; Gilead/Kite: Consultancy, Honoraria, Other: NA, Research Funding; Incyte: Consultancy, Honoraria. Ferreri:Amgen: Research Funding; Genmab: Research Funding; ADC Therapeutics: Research Funding; Gilead: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche: Membership on an entity's Board of Directors or advisory committees, Research Funding; PletixaPharm: Membership on an entity's Board of Directors or advisory committees; Incyte: Membership on an entity's Board of Directors or advisory committees; Adienne: Speakers Bureau; Pfizer: Research Funding; Ospedale San Raffaele srl: Patents & Royalties: NGR-hTNAF/RCHOP in relapsed/refractory PCNSL; SNGR-hTNF in brain tumours; Hutchison Medipharma: Research Funding; BMS: Research Funding; Pharmacyclics: Research Funding; Beigene: Research Funding. Teshima:NIPPON SHINYAKU: Research Funding; Bristol-Myers Squibb: Honoraria; Chugai: Research Funding; Astellas: Research Funding; TEIJIN PHARMA: Research Funding; Fuji Pharma: Research Funding; Sanofi: Research Funding; Pfizer: Honoraria; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; Merck Sharp & Dohme: Honoraria, Membership on an entity's Board of Directors or advisory committees; Luca Science Inc.: Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees, Other: Manuscript preparation, Research Funding; Janssen: Other: Manuscript preparation; Kyowa Kirin: Honoraria, Research Funding. Patten:ROCHE: Research Funding; GILEAD SCIENCES: Honoraria, Research Funding; ABBVIE: Honoraria; ASTRA ZENECA: Honoraria; JANSSEN: Honoraria; NOVARTIS: Honoraria; Beigene: Honoraria. McGuirk:Allovir: Consultancy, Honoraria, Research Funding, Speakers Bureau; BMS: Consultancy, Honoraria, Speakers Bureau; Novartis: Consultancy, Honoraria; Magenta Therapeutics: Consultancy, Honoraria, Research Funding; Juno Therapeutics: Consultancy, Honoraria, Research Funding; Kite, a Gilead Company: Consultancy, Honoraria, Research Funding, Speakers Bureau; Orca Bio: Research Funding; Nextar: Consultancy, Honoraria; Sana: Honoraria; CRISPR Therapeutics: Consultancy; In8bio, Inc.: Other: IIT Clinical Trial. Petzer:Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Kite-Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Speakers Bureau. Viardot:Kite Gilead: Consultancy, Honoraria, Other: Support for meeting attendance; Novartis: Consultancy, Honoraria, Other: Support for meeting attendance; BMS: Consultancy, Honoraria, Other: Support for meeting attendance; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Honoraria, Other: Support for meeting attendance; Janssen-Cilag: Honoraria, Other: Support for meeting attendance; Astra Zeneca: Honoraria, Other: Support for meeting attendance; Incyte: Consultancy, Other: Support for meeting attendance. Zinzani:Beigene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; ADC Therapeutics: Membership on an entity's Board of Directors or advisory committees; Servier: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Incyte: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; BMS: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen-Cilag: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Sandoz: Membership on an entity's Board of Directors or advisory committees; Eusapharma: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Gilead: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celltrion: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Secura Bio: Membership on an entity's Board of Directors or advisory committees; Kyowa Kirin: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Roche: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Takeda: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; TG Therapeutics: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; MSD: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; University of Bologna: Current Employment. Paule:Novartis: Current Employment. Awasthi:Novartis: Current Employment, Current equity holder in private company. Han:Novartis: Current Employment. Germano:Novartis: Current Employment. O'Donovan:Novartis: Current Employment. Ramos:Novartis: Current Employment, Divested equity in a private or publicly-traded company in the past 24 months. Masood:Novartis: Current Employment, Current holder of stock options in a privately-held company. Thieblemont:Celgene: Consultancy, Honoraria, Other: Travel Support; Takeda: Consultancy, Honoraria, Other: Travel Support; Incyte: Consultancy, Honoraria; Kite, a Gilead Company: Consultancy, Honoraria, Other: Travel Support; Novartis: Consultancy, Honoraria, Other: Travel Support, Research Funding; AbbVie: Consultancy, Honoraria; Roche: Consultancy, Honoraria, Other: Travel Support; Bristol Myers Squibb: Consultancy, Honoraria, Other: Travel Support. Fowler:Roche: Consultancy, Research Funding; Gilead: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; BostonGene Corporation: Current Employment, Other: Leadership. Schuster:AstraZeneca: Consultancy; BeiGene: Consultancy; Celgene: Consultancy, Honoraria, Research Funding; Genentech: Consultancy, Research Funding; Genmab: Consultancy; Fate Therapeutics: Consultancy; Roche: Consultancy, Research Funding; Incyte: Consultancy, Research Funding; Juno Therapeutics: Consultancy, Research Funding; Legend Biotech: Consultancy; Loxo Oncology: Consultancy; MorphoSys: Consultancy; Mustang Biotech: Consultancy; Nordic Nanovector: Consultancy; Novartis: Consultancy, Honoraria, Patents & Royalties: related to CD19 CAR T cells , Research Funding; Regeneron: Consultancy; AbbVie: Research Funding; Adaptive Biotechnologies: Research Funding; DTRM: Research Funding; Merck: Research Funding; Pharmacyclics: Research Funding; TG Therapeutics: Research Funding.