Outcomes of Treatment with the Chimeric Antigen Receptor (CAR) T Cell Therapy Lisocabtagene Maraleucel (liso-cel) in the Nonuniversity Setting: Initial Results from the Outreach Study
Authors: Godwin John E. , Freytes Cesar O. , Maris Michael , Stevens Don A. , Hoda Daanish , Mattar Bassam , Varela Juan C. , Cherry Mohamad , Essell James , Courtright Jay , Fanning Suzanne R. , Yimer Habte A. , Trede Nikolaus S. , Youssef Marina , Lymp James , Bachier Carlos 
Published: November 2020

Background: Currently approved CAR T cell therapies are generally administered as inpatient treatment at university medical centers due to concerns about the frequency, onset, severity, and management of AEs, including cytokine release syndrome (CRS) and neurological events (NEs). Infusion and monitoring of patients who receive CAR T cell therapy at nonuniversity medical centers and in outpatient settings have not been specifically studied. Liso-cel is an investigational, CD19-directed, defined composition, 4-1BB CAR T cell product administered at equal target doses of CD8+ and CD4+ CAR+ T cells. The liso-cel clinical program allows outpatient treatment per investigator discretion, with standardized guidelines for safety monitoring and AE management. Here we present preliminary safety and efficacy outcomes of liso-cel in relapsed/refractory (R/R) aggressive large B-cell lymphoma (LBCL) across inpatient and outpatient settings at nonuniversity medical centers in the OUTREACH study (NCT03744676).
Methods: This open-label, multicenter, phase 2 study enrolled adult patients with R/R LBCL at nonuniversity medical centers, including those with university affiliations and centers naïve to CAR T cell therapy. Inclusion criteria included ECOG PS of 0-1, PET-positive disease, adequate organ function, and R/R disease after ≥2 lines of prior systemic therapy including chemoimmunotherapy. Prior autologous HSCT was permitted, but prior allogeneic HSCT was prohibited. After leukapheresis and 3 days of lymphodepleting chemotherapy, patients received liso-cel infusion at a dose of 100 × 106 CAR+ T cells. The primary endpoint was incidence of grade ≥3 CRS, NEs, prolonged cytopenias through day 29, and infections. Secondary endpoints included safety and overall response rate (ORR). All study sites had a multidisciplinary CAR T cell therapy team and standard operating procedures for toxicity monitoring/management of patients treated and/or monitored as outpatients. CRS was graded as per 2014 Lee criteria; NEs were defined as liso-cel-related investigator-assessed events and graded as per NCI CTCAE v4.03.
Results: At data cutoff, 34 patients were treated with liso-cel (inpatients, n = 12; outpatients, n = 22); 5 patients were treated at non-Foundation for the Accreditation of Cellular Therapy (FACT)-accredited sites. Demographics and baseline disease characteristics were similar between inpatients and outpatients (Table); overall, median age was 66 years (range, 34-83), 68% had diffuse LBCL not otherwise specified, and 88% were refractory to last therapy. CRS was reported in 4 inpatients (33%) and 9 outpatients (41%), with no grade ≥3 events. NEs were reported in 3 inpatients (25%) and 6 outpatients (27%), with 1 grade 3 event in the outpatient group. Median (range) time to onset of CRS and NEs, respectively, was 2.5 (1-3) and 10 (5-16) days for inpatients and 6 (2-9) and 8.5 (6-13) days for outpatients. Tocilizumab and/or corticosteroid use for CRS and/or NE management was generally low (inpatients, n = 2 [17%]; outpatients, n = 5 [23%]). Overall, the most common (≥45%) treatment-emergent AEs (TEAEs) were neutropenia (76%), leukopenia (50%), and anemia (47%). Prolonged cytopenias (grade ≥3 lab values at Day 29) were reported for 7 (21%) patients. No grade 5 TEAEs were reported. Early (≤ study Day 4) and overall hospitalization in outpatients was 18% and 50%, respectively; median time to hospitalization was 5 (2-9) days and median length of stay was 6 (1-18) days. Among efficacy-evaluable patients (n = 31), ORR was 75% for inpatients and 84% for outpatients; CR rate was 50% and 68%, respectively. Of the 5 patients treated at non-FACT-accredited sites (inpatients, n = 1; outpatients, n = 4), 2 had CRS and/or NEs, but none were grade ≥3 events; none of these patients received tocilizumab or corticosteroids. Of these 5 patients, 1 achieved CR and 1 achieved PR; 2 had stable disease and 1 had progressive disease.
Conclusions: Patients with R/R aggressive LBCL were successfully treated with liso-cel and monitored for CAR T cell therapy-related toxicities at nonuniversity medical centers in inpatient and outpatient settings using standard operating procedures and multidisciplinary teams. Incidences of severe CRS and NEs were low, as was tocilizumab and/or corticosteroid use. Liso-cel showed encouraging preliminary efficacy in both inpatients and outpatients. This trial is ongoing and actively recruiting.

Disclosures
Freytes: Sanofi: Speakers Bureau. Stevens:Amgen, MorphoSys: Consultancy. Varela:Neximmune: Consultancy, Current equity holder in private company. Cherry:Kite: Other: Ad Board; Bristol Myers Squibb: Membership on an entity's Board of Directors or advisory committees, Other: Ad Board; Epizyme: Other: Ad Board . Essell:Kite: Speakers Bureau; Bristol Myers Squibb: Speakers Bureau. Courtright:AbbVie: Other: Investigator in AbbVie-sponsored clinical trials.. Fanning:Takeda: Consultancy, Speakers Bureau; Abbvie: Consultancy; Sanofi Aventis: Speakers Bureau; TG Therapeautics: Consultancy; Bristol Myers Squibb: Consultancy, Speakers Bureau; Prisma Health: Current Employment. Yimer:Sanofi: Speakers Bureau; AstraZeneca: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company), Speakers Bureau; Janssen: Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company), Research Funding, Speakers Bureau; BeiGene: Other: TRAVEL, ACCOMODATIONS, EXPENSES (paid by any for-profit health care company), Research Funding, Speakers Bureau; Epizyme: Consultancy, Divested equity in a private or publicly-traded company in the past 24 months; Karyopharm: Consultancy, Divested equity in a private or publicly-traded company in the past 24 months, Membership on an entity's Board of Directors or advisory committees, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company), Speakers Bureau; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company), Speakers Bureau; Celgene, a Bristol-Myers Squibb Company: Consultancy, Membership on an entity's Board of Directors or advisory committees; Takeda: Speakers Bureau; TG Therapeutics: Consultancy; Texas Oncology: Current Employment. Trede:Juno Therapeutics, a Bristol-Myers Squibb Company: Current Employment; Bristol-Myers Squibb Company: Current equity holder in publicly-traded company. Youssef:Bristol-Myers Squibb Company: Current Employment, Current equity holder in publicly-traded company. Lymp:Juno Therapeutics, a Bristol-Myers Squibb Company: Current Employment; Bristol-Myers Squibb Company: Current equity holder in publicly-traded company. Bachier:Juno Therapeutics, a Bristol-Myers Squibb Company: Honoraria; CRISPR: Honoraria; AlloVir: Honoraria; Sanofi: Speakers Bureau.