Higher-dose lymphodepleting regimens led to higher toxicity but high response rates.
Letetresgene autoleucel (lete-cel; GSK3377794) demonstrated anti-tumor activity with a tolerable safety profile in patients with advanced and metastatic myxoid/round cell liposarcoma (MRCLS), according to data from a phase 2, open-label study (NCT02992743).
Data from the study were presented at the 2022 American Society of Clinical Oncology (ASCO) meeting, held June 3-7, 2022, held both virtually and in Chicago, Illinois by Sandra P. D’Angelo, MD, oncologist, Memorial Sloan Kettering Cancer Center.
“MRCLS is an adipocytic malignancy accounting for about 10% of all soft tissue sarcoma. Most are characterized by a specific chromosomal translocation... A third of patients will develop metastatic disease and survival for these patients is quite poor. While responses to chemotherapy can be quite high, cures are seldom, therefore highlighting the need for alternative novel approaches,” D’Angelo said during her presentation.
Lete-cel is a novel T-cell receptor (TCR) therapy targeted toward NY-ESO-01, an antigen expressed in multiple solid tumor types, including 80-90% of MRCLS tumors. The therapy previously showed efficacy in advanced synovial sarcoma in a phase 1 pilot study (NCT01343043), yielding a 50% overall response rate (ORR), a median progression free survival (PFS) of 15.4 months (95%, 8.5-48.8), and a median overall survival (OS) of 24.3 months (95% CI, 8.5-48.8).
This study in MRCLS enrolled 23 patients between March 2017 and February 2020 with a median age of 47.0 years (range, 33-72). Twenty patients were dosed with lete-cel, 10 in each cohort treated with different doses of fludarabine and cyclophosphamide lymphodepletion (cohort 1, 30 mg/m2 fludarabine for 3 days + 600 mg/m2 cyclophosphamide for 3 days; cohort 2, 30 mg/m2 fludarabinefor 4 days + 900 mg/m2 cyclophosphamide for 3 days).
Eligible patients were at least 18 years of age with recurrent metastatic or unresectable MRCLS confirmed by histology and translocation and prior anthracycline treatment. Patients had 1 line of prior therapy (n = 8; 40%) 2 lines (n = 6; 30%) or 3 or more lines of prior therapy (n = 6; 30%).
Patients received 1x109 to 8 × 109 cells. The median transduced T cell dose was 4.6 x 109. Investigators followed up at weeks 4, 8, 12, 24, then every 3 months until disease progression, death, or withdrawal. Median follow-up was 5.6 months for cohort 1 and 12.9 months for cohort 2. The primary endpoint was ORR and secondary endpoints included safety, duration of response (DOR), PFS, and time to response (TTR), with OS as an exploratory endpoint.
Investigators found that cohort 1 had an ORR of 20%, with a partial response (PR) in 2 patients and stable disease (SD) in 8 patients. The median TTR was 1.9 months, median DOR was 5.3 months (95% CI, 1.9-8.7), and median PFS was 5.4 months (95% CI, 2.0-11.5). Cohort 2, treated with a higher-dose lymphodepletion regimen, had an ORR of 40%, with PRs in 4 patients and SD in 5 patients. The median TTR was 1.9 months, median DOR was 7.5 months (95% CI, 6.0-NE), and median PFS was 8.7 months (95% CI, 0.9-NE). OS is not yet evaluable.
All patients experienced at least 1 treatment-emergent adverse event (TEAE) and 55% of patients experienced serious TEAEs. All patients experienced at least 1 grade 4 hematopoietic cytopenia, including neutropenia, thrombocytopenia, aneia, leukopenia, and lymphopenia. All patients in cohort 2 experienced cytokine release syndrome, compared to 60% in cohort 1. There were no cases of graft-vs-host disease, immune effector cell–associated neurotoxicity syndrome, or Guillain-Barré Syndrome. One TE serious AE of cardiac arrest occurred.
"Lete-cel demonstrated a tolerable safety profile in both cohorts and toxicity was mostly consistent with lymphodepletion chemotherapy. There were no new safety signals identified. The efficacy and safety data from this trial has formed the basis for including MRCLS with the ongoing lete-cel pivotal program,” D’Angelo said.