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Two-Year Follow-up of Transcend NHL 001, a Multicenter Phase 1 Study of Lisocabtagene Maraleucel (liso-cel) in Relapsed or Refractory (R/R) Large B-Cell Lymphomas (LBCL)

2021; Elsevier BV; Volume: 138; Issue: Supplement 1 Linguagem: Inglês

10.1182/blood-2021-148948

1528-0020

Jeremy S. Abramson, M. Lia Palomba, Leo I. Gordon, Matthew A. Lunning, Michael Wang, Jon Arnason, Enkhtsetseg Purev, David G. Maloney, Charalambos Andreadis, Alison R. Sehgal, Scott R. Solomon, Nilanjan Ghosh, Ana Kostić, Yeonhee Kim, K. OGASAWARA, Christine Dehner, Tanya Siddiqi,

CAR-T cell therapy research

Abstract Background : LBCLs are prevalent and aggressive subtypes of NHL, with limited treatment options and historically poor outcomes in the third- or later-line setting. Liso-cel is an autologous, CD19-directed, defined composition, 4-1BB CAR T cell product administered at equal target doses of CD8 + and CD4 + CAR + T cells. TRANSCEND NHL 001 (NCT02631044) is a seamless design, pivotal, phase 1 study evaluating liso-cel in patients (pts) with R/R LBCLs (Abramson et al. Lancet 2020). We present 2-year follow-up data from the LBCL cohort. Methods: Pts ≥ 18 years of age with R/R DLBCL not otherwise specified (NOS, including de novo and transformed from any indolent lymphoma), high-grade B-cell lymphoma (HGBCL) with MYC and BCL2 and/or BCL6 rearrangements, primary mediastinal B-cell lymphoma (PMBCL), or follicular lymphoma grade 3B (FL3B) after ≥ 2 lines of therapy and with ECOG PS 0-2 were eligible. Pts with grade 3 or 4 cytopenias, mild to moderate organ dysfunction, and secondary CNS lymphoma were allowed. Bridging therapy was allowed at clinician discretion but reconfirmation of PET-positive disease was required before lymphodepletion with fludarabine and cyclophosphamide. Primary endpoints were treatment-emergent AEs (TEAE) and ORR. Key secondary endpoints were CR rate, duration of response (DOR), PFS, and OS. TEAEs, including investigator-identified neurological events (NE) related to liso-cel, were graded using NCI CTCAE v4.03; cytokine release syndrome (CRS) was graded per Lee 2014 criteria in the liso-cel-treated set (all pts who received ≥ 1 dose of liso-cel). ORR was assessed by an independent review committee (IRC) per Lugano 2014 criteria in the efficacy-evaluable set (all pts with confirmed PET-positive disease who received ≥ 1 dose of liso-cel). Pts were followed for 2 years after the last dose of liso-cel and were then asked to enroll in a separate long-term follow-up study for up to 15 years (NCT03435796). Results: A total of 345 pts underwent leukapheresis. In the liso-cel-treated set (N = 270), median age was 63 years (range, 18-86); 41% of pts were ≥ 65 years of age. Histologies included DLBCL NOS (de novo, 51%; transformed from indolent lymphoma, 29%), HGBCL (13%), PMBCL (6%), and FL3B (1%). Seven pts (3%) had secondary CNS lymphoma. Pts received a median of 3 prior lines of systemic therapy (range, 1-8) and 33% had prior autologous HSCT (prior allogeneic HSCT, 3%). Of all pts, 67% were chemotherapy refractory, 45% had never achieved CR, and 59% received bridging therapy. As of the Jan 4, 2021 data cut, study is ongoing; 268 pts had ≥ 24 months (mo) of follow-up, died, or withdrew from the study. Responses per IRC (ORR, 73%; CR rate, 53%) in the efficacy-evaluable set (N = 257) were durable with a median (95% CI) DOR of 23.1 mo (8.6-not reached), median PFS of 6.8 mo (3.3-12.7), and median OS of 27.3 mo (16.2-45.6) (Table). At 24 mo, the probabilities (95% CI) of continued response, PFS, and OS were 49.5% (41.4%-57.0%), 40.6% (34.0%-47.2%), and 50.5% (44.1%-56.5%), respectively. During the 90-day treatment-emergent (TE) reporting period, 79% of pts in the liso-cel-treated set (N = 270) had grade ≥ 3 TEAEs; 45% had serious TEAEs. CRS and NE of any grade occurred in 42% and 30% of pts, respectively (grade 3-4 CRS, 2%; grade 3-4 NE, 10%). Median (range) time to onset of CRS and NE was 5 (1-14) and 9 (1-66) days, respectively. Grade ≥ 3 infections and laboratory-based prolonged cytopenia at Day 29 occurred in 12% and 37% of pts, respectively. In the post-TE (Day 91 to end of study) reporting period, which included 17 pts who received liso-cel re-treatment, 23% of pts in the liso-cel-treated set (N = 249) had grade ≥ 3 AEs and 17% had serious AEs. The most common grade ≥ 3 AEs in the post-TE period were neutropenia (7%), anemia (6%), thrombocytopenia (4%), and febrile neutropenia (4%). Grade ≥ 3 infections occurred in 5% of pts. In the post-TE period, 100 pts (37% of all pts) died, mostly due to disease progression (86% of all post-TE deaths; 32% of all pts). CAR T cells were present in peripheral blood for up to 4 years. Conclusions: Liso-cel demonstrated durable remissions with estimated 2-year DOR and PFS rates of 49.5% and 40.6%, respectively, and a favorable safety profile in the extended follow-up analysis of this large CAR T cell study in R/R LBCLs. Most CAR T cell-associated AEs occurred within the initial 90-day TE reporting period. No new safety signals were observed during long-term follow-up. Figure 1 Figure 1. Disclosures Abramson: Genmab: Consultancy; Kite Pharma: Consultancy; C4 Therapeutics: Consultancy; Bristol-Myers Squibb Company: Consultancy, Research Funding; Kymera: Consultancy; Bluebird Bio: Consultancy; EMD Serono: Consultancy; Novartis: Consultancy; Morphosys: Consultancy; BeiGene: Consultancy; Allogene Therapeutics: Consultancy; Astra-Zeneca: Consultancy; Incyte Corporation: Consultancy; Seagen Inc.: Research Funding; AbbVie: Consultancy; Karyopharm: Consultancy; Genentech: Consultancy. Palomba: Rheos: Honoraria; Novartis: Consultancy; Lygenesis: Honoraria; Priothera: Honoraria; Juno: Patents & Royalties; Notch: Honoraria, Other: Stock; Pluto: Honoraria; Seres: Honoraria, Other: Stock, Patents & Royalties, Research Funding; Magenta: Honoraria; WindMIL: Honoraria; Kite: Consultancy; Ceramedix: Honoraria; Nektar: Honoraria; Wolters Kluwer: Patents & Royalties; PCYC: Consultancy; BeiGene: Consultancy. Gordon: Zylem Biosciences: Patents & Royalties: Patents, No royalties; Bristol Myers Squibb: Honoraria, Research Funding. Lunning: Myeloid Therapeutics: Consultancy; Spectrum: Consultancy; TG Therapeutics: Consultancy; AbbVie: Consultancy; Morphosys: Consultancy; Karyopharm: Consultancy; Beigene: Consultancy; Daiichi-Sankyo: Consultancy; Novartis: Consultancy; Kyowa Kirin: Consultancy; Legend: Consultancy; Janssen: Consultancy; ADC Therapeutics: Consultancy; Acrotech: Consultancy; Verastem: Consultancy; Celgene, a Bristol Myers Squibb Co.: Consultancy; AstraZeneca: Consultancy; Kite, a Gilead Company: Consultancy. Wang: Molecular Templates: Research Funding; BGICS: Honoraria; Miltenyi Biomedicine GmbH: Consultancy, Honoraria; Oncternal: Consultancy, Research Funding; Bayer Healthcare: Consultancy; Physicians Education Resources (PER): Honoraria; InnoCare: Consultancy, Research Funding; CAHON: Honoraria; OMI: Honoraria; Loxo Oncology: Consultancy, Research Funding; The First Afflicted Hospital of Zhejiang University: Honoraria; Lilly: Research Funding; Scripps: Honoraria; AstraZeneca: Consultancy, Honoraria, Research Funding; Clinical Care Options: Honoraria; Celgene: Research Funding; Imedex: Honoraria; Pharmacyclics: Consultancy, Research Funding; Chinese Medical Association: Honoraria; Mumbai Hematology Group: Honoraria; Dava Oncology: Honoraria; Moffit Cancer Center: Honoraria; Epizyme: Consultancy, Honoraria; DTRM Biopharma (Cayman) Limited: Consultancy; Genentech: Consultancy; CStone: Consultancy; Kite Pharma: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Research Funding; Anticancer Association: Honoraria; BeiGene: Consultancy, Honoraria, Research Funding; Hebei Cancer Prevention Federation: Honoraria; Newbridge Pharmaceuticals: Honoraria; Juno: Consultancy, Research Funding; BioInvent: Research Funding; VelosBio: Consultancy, Research Funding; Acerta Pharma: Consultancy, Honoraria, Research Funding. Arnason: Juno/BMS: Honoraria. Maloney: Janssen: Honoraria; MorphoSys: Honoraria; Novartis: Honoraria; Celgene: Honoraria, Other: Rights to royalties from Fred Hutchinson Cancer Research Center for patents licensed to Juno Therapeutics/Bristol Myers Squibb; BMS: Honoraria, Other: Rights to royalties from Fred Hutchinson Cancer Research Center for patents licensed to Juno Therapeutics/Bristol Myers Squibb; Amgen: Honoraria; Celgene: Other: Research funding was paid to my institution, Research Funding; Juno therapeutics: Other: Research funding was paid to my institution, Research Funding; Kite Pharma: Honoraria, Other: Research funding was paid to my institution, Research Funding; Navan Technologies: Honoraria, Other: Stock options; A2 Biotherapeutics: Honoraria, Other: Stock options; Umoja: Honoraria; Genentech: Honoraria; Legend Biotech: Honoraria; Juno Therapeutics: Honoraria, Other: Rights to royalties from Fred Hutchinson Cancer Research Center for patents licensed to Juno Therapeutics/Bristol Myers Squibb. Andreadis: Merck: Research Funding; BMS: Research Funding; CRISPR Therapeutics: Research Funding; GenMAB: Research Funding; Novartis: Research Funding; Roche: Current equity holder in publicly-traded company, Ended employment in the past 24 months; Epizyme: Honoraria; Incyte: Honoraria; TG Therapeutics: Honoraria; Kite: Honoraria; Karyopharm: Honoraria; Atara: Consultancy, Honoraria. Sehgal: Juno/Celgene: Research Funding; Kite/Gilead: Research Funding. Ghosh: Bristol Myers Squibb: Consultancy, Honoraria, Research Funding, Speakers Bureau; Genentech: Research Funding; Karyopharma: Consultancy, Honoraria; Pharmacyclics LLC, an AbbVie Company: Consultancy, Honoraria, Research Funding, Speakers Bureau; Genmab: Consultancy, Honoraria; Epizyme: Honoraria, Speakers Bureau; Seattle Genetics: Consultancy, Honoraria, Speakers Bureau; Janssen: Consultancy, Honoraria, Speakers Bureau; Incyte: Consultancy, Honoraria; TG Therapeutics: Consultancy, Honoraria, Research Funding; AstraZeneca: Consultancy, Honoraria, Speakers Bureau; ADC Therapeutics: Consultancy, Honoraria; Gilead: Consultancy, Honoraria, Research Funding, Speakers Bureau; Adaptive Biotech: Consultancy, Honoraria; AbbVie: Honoraria, Speakers Bureau. Kostic: Bristol Myers Squibb: Current Employment, Current equity holder in publicly-traded company. Kim: Bristol Myers Squibb: Current Employment, Current equity holder in publicly-traded company. Ogasawara: Bristol Myers Squibb: Current Employment, Current equity holder in publicly-traded company. Dehner: Bristol Myers Squibb: Current Employment, Current equity holder in publicly-traded company. Siddiqi: BMS: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Juno Therapeutics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees; Pharmacyclics LLC, an AbbVie Company: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; TG Therapeutics: Research Funding; Kite Pharma: Membership on an entity's Board of Directors or advisory committees, Research Funding; AstraZeneca: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; BeiGene: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Janssen: Speakers Bureau; Oncternal: Research Funding.