Primary efficacy and safety of letetresgene autoleucel (lete-cel; GSK3377794) pilot study in patients with advanced and metastatic myxoid/round cell liposarcoma (MRCLS).
Authors: D'Angelo Sandra P. , Druta Mihaela , Van Tine Brian Andrew , Liebner David A. , Schuetze Scott , Nathenson Michael , Holmes Andrew P. , D'Souza Jimson , Kapoor Gurpreet Singh , Zajic Stefan , Somaiah Neeta 
Published: June 2022

11500 Background: Lete-cel is an autologous T-cell therapy targeting NY-ESO-1 tumors using a genetically modified, high-affinity T-cell receptor. MRCLS is a sarcoma with poor response to current immunotherapy approaches and limited treatment options. The cancer testis antigen NY-ESO-1 is expressed in 80‒90% of MRCLS tumors, making this a promising target. This report summaries the primary efficacy and safety results of a pilot study of lete-cel in patients (pts) with advanced or metastatic MRCLS. Methods: This is an open label, study of lete-cel in pts with advanced or metastatic MRCLS following reduced-dose (Cohort 1 [C1]; 30 mg/m2 fludarabine [flu] x 3d + 600 mg/m2 cyclophosphamide [cy] x 3d) or standard dose (Cohort 2 [C2]; 30 mg/m2 flu x 4d + 900 mg/m2 cy x 3d) lymphodepletion (LD). Key eligibility criteria were: age ≥18 y; HLA-A*02:01; A*02:05, or A*02:06; advanced or metastatic NY-ESO-1+ MRCLS (≥30% of cells 2+/3+ by IHC); prior anthracycline treatment, and measurable disease. The transduced T cell dose range was 1– 8 × 109. Response was assessed at weeks 4, 8, 12, 24, then every 3 months (mo) until disease progression, death, or withdrawal. Investigator-assessed (IA) ORR by RECIST v1.1 was the primary efficacy endpoint. Secondary endpoints included safety, independently assessed ORR by RECIST v1.1, time to response (TTR), duration of response (DOR), progression-free survival (PFS). Overall survival (OS) was an exploratory endpoint. Results: 23 pts enrolled from March 2017 to February 2020. The median age was 47.0 yrs (range 33 to 72). 20 pts were dosed with T cells, 10 in each cohort with a median transduced T cell dose of 4.6 x 109. 8 of 20 pts (40%) had 1 line of prior therapy, 6 pts (30%) had 2 lines, and 6 pts (30%) had ≥3 lines. The median follow-up was 5.6 (C1) and 12.9 (C2) mo. In C1 the IA ORR was 20%, with best response (BR) of partial response (PR) in 2 pts and BR of stable disease (SD) in 8 pts. The median TTR was 1.9 mo, median DOR was 5.3 mo (95% CI: 1.9-8.7), and median PFS was 5.4 mo (95% CI: 2.0-11.5). In C2 the IA ORR was 40%, with BR of PR in 4 pts and BR of SD in 5 pts. The median TTR was 1.9 mo, median DOR was 7.5 mo (95% CI: 6.0-NE), and median PFS was 8.7mo (95% CI: 0.9-NE). OS is not yet mature. All pts experienced at least 1 treatment-emergent adverse event (TEAE). 55% of pts experienced serious TEAEs. 90% of pts had Gr ≥3 TE neutropenia, with 83% probability of resolution of initial Gr ≥3 occurrence by Day 30. Cytokine release syndrome occurred in 80% of pts, of which 25% were Gr 3, with 1st onset within 5d of infusion and median duration 7.5d. No Graft-vs-host disease, immune effector cell–associated neurotoxicity syndrome, Guillain-Barré Syndrome were reported. Conclusions: Treatment with a single dose of lete-cel showed anti-tumor activity, including response and long median PFS with an acceptable safety profile in pts with advanced and metastatic MRCLS. Clinical trial information: NCT02992743.