Outreach: Results from a Phase 2 Study of Lisocabtagene Maraleucel (liso-cel) Administered As Inpatient (Inpt) or Outpatient (Outpt) Treatment in the Nonuniversity Setting in Patients (Pts) with R/R Large B-Cell Lymphoma (LBCL)

Background: CAR T cell therapies are generally administered in an inpt setting owing to concerns of AE management. Infusion and monitoring of pts who receive CAR T cell therapy at nonuniversity medical centers (NMC) and in outpt settings have not been studied specifically. 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. In TRANSCEND NHL 001 (NCT02631044) in pts with third- or later-line LBCL, liso-cel treatment showed an ORR of 73% (CR rate, 53%), with grade ≥ 3 cytokine release syndrome (CRS) in 2%, and grade ≥ 3 neurological events (NE) in 10% of pts (Abramson et al. Lancet 2020). We report outcomes of liso-cel in pts with R/R LBCL across inpt and outpt settings at NMCs in the United States treated in the OUTREACH study (NCT03744676).

Methods: The study enrolled pts at NMCs, including those with university affiliations and centers naïve to CAR T cell therapy. Adults with R/R PET-positive LBCL after ≥ 2 lines of therapy and ECOG PS ≤ 1 were eligible. Pts with grade 3-4 cytopenias, mild to moderate organ function (LVEF ≥ 40%; serum CrCl > 30 mL/min), secondary CNS lymphoma, and prior autologous HSCT were eligible. After leukapheresis and lymphodepleting chemotherapy (LDC), pts received liso-cel at a target dose of 100 × 10 ⁶ CAR ⁺ T cells. Primary endpoint was incidence of grade ≥ 3 CRS, NEs, prolonged cytopenias (Day 29 grade ≥ 3 lab values), and infections. Secondary endpoints included safety, ORR, CR rate, duration of response (DOR), and liso-cel PK. B-cell depletion analyses were exploratory. AEs, including NEs, were graded using NCI CTCAE v4.03; CRS was graded per Lee criteria (2014). NEs were defined as investigator-identified neurological AEs related to liso-cel. All study sites had a multidisciplinary CAR T cell therapy team and standard operating procedures (SOP) for outpt monitoring of toxicity and admission for CRS/NE management.

Results: At data cutoff, 71 pts were treated with liso-cel at NMCs; 52 and 19 were monitored as outpts and inpts, respectively. Median age was 65 years (range, 28-83; ≥ 65 years, 51%; ≥ 75 years, 18%); 65% of pts had de novo DLBCL, 68% had screening ECOG PS of 1, 82% were chemotherapy refractory, 31% had ≥ 3 prior therapies, and 48% had markers of high tumor burden (pre-LDC LDH ≥ 500 U/L or SPD ≥ 50 cm ²). Demographics and baseline disease characteristics were generally similar in outpts and inpts, respectively, with differences of ≥ 20% noted in incidences of high-grade B-cell lymphoma (4% vs 42%) and DLBCL transformed from indolent lymphoma (29% vs 0%). Overall, any-grade CRS occurred in 39% of pts (no grade ≥ 3) and NEs in 32% (grade 3-4, 10%); 27% received tocilizumab and/or corticosteroids for CRS or NEs. Incidences of any-grade CRS and NEs were similar in outpts and inpts, while grade ≥ 3 NEs, infections, and prolonged cytopenias were numerically higher in outpts, but similar to pivotal trial observations (Table). The most common treatment-emergent AEs were neutropenia (68%), leukopenia (45%), CRS (39%), anemia (38%), thrombocytopenia (37%), and fatigue (35%). No grade 5 AEs were reported. Early (study Day ≤ 4) and overall hospitalization occurred in 33% and 69% of outpts, respectively; median time to hospitalization was 5.0 days (range 2-141) in outpts. The median (range) length of initial hospital stay after liso-cel administration was 6.0 days (1-28; n = 36) for outpts versus 10.0 days (0-31; n = 19) for inpts; 31% of outpts were not hospitalized. All pts were efficacy evaluable. The ORR was 77% and the CR rate was 51%. Median DOR was 14.8 months (95% CI, 3.9‒not reached [NR]) for outpts and was NR (95% CI, 2.0‒NR) for inpts at a median follow-up of 8.1 months and 11.3 months, respectively (Table). PK profiles were similar in outpts and inpts. Target depletion of CD19 ⁺ B cells in peripheral blood was also similar between oupts and inpts, and was maintained over the period of 1 year.

Conclusions: Pts with R/R LBCL were successfully treated with liso-cel in outpt and inpt settings at NMCs and monitored for CAR T cell therapy-related toxicities using SOPs and multidisciplinary teams. Liso-cel demonstrated durable clinical activity with a favorable safety profile in both outpts and inpts. Incidences of severe CRS and NEs were low, as was tocilizumab and/or corticosteroid use. These data support liso-cel administration at NMCs and in the outpt setting.

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