Lete-Cel Receives FDA Breakthrough Therapy Designation for Advanced Myxoid/Round Cell Liposarcoma

The FDA has granted breakthrough therapy designation to letetresgene autoleucel (lete-cel) for the treatment of patients with unresectable or metastatic myxoid/round cell liposarcoma (MRCLS) who were previously treated with anthracycline-based chemotherapy, are positive for HLA-A*02:01, HLA-A*02:05, or HLA-A*02:06, and whose tumors have NY-ESO-1 antigen expressions.1

The breakthrough therapy designation was granted to lete-cel based on results from the phase 2 IGNYTE-ESO trial (NCT03967223). In an analysis from the nonrandomized, open-label trial, the overall response rate (ORR) was 42% in patients with synovial sarcoma or MRCLS (n = 64) per RECIST 1.1 criteria as assessed by independent review. Among responders (n = 27), 6 had complete responses and 21 had partial responses. The overall response rate (ORR) was 41% in those with synovial sarcoma and 43% in those with MRCLS. The median duration of response (DOR) was 12.2. months (95% CI, 3.3-19.5); the median DOR in patients with synovial sarcoma and MRCLS was 18.3 months (95% CI, 3.3-not evaluable [NE]) and 12.2 months (95% CI, 5.3-NE), respectively.

"This designation by the FDA highlights the potential of lete-cel to address a critical need for new treatment options for patients with MRCLS,” Adrian Rawcliffe, chief executive officer of Adaptimmune, stated in the news release. “We look forward to initiating a rolling biologics license application for lete-cel later [in 2025] for the treatment of both sarcoma indications."

Regarding safety, findings were consistent with the known safety profile of lete-cel. Treatment-emergent adverse effects (AEs) were experienced by all patients, which included cytopenias, cytokine release syndrome, and rash as the most common AEs. Toxicity was manageable and consistent with an acceptable benefit to risk profile.

Patients included in the trial were required to be over the age of 10 years, weigh at least 40 kg, were positive for HLA-A*02:01, HLA-A*02:05, or HLA-A*02:06 alleles, were positive for NY-ESO-1 expression verified by a designated central laboratory, had a diagnosis of synovial sarcoma or MRCLS, and had an ECOG performance status of 0 or 1.2

The trial included 2 arms: lete-cel in previously untreated metastatic or unresectable synovial sarcoma or MRCLS (substudy 1); or lete-cel in metastatic or unresectable synovial sarcoma or MRCLS after anthracycline-based chemotherapy (substudy 2). Eligible patients in substudies 1 and 2 were leukapheresed to manufacture engineered T cells, then subsequently receive lete-cel.

The primary end points of the study included ORR in substudy 1 until disease progression for up to 5 years per RECIST 1.1 criteria determined by local investigators; ORR in substudy 2 for up to 5 years per RECIST 1.1 criteria as assessed by central independent review. Secondary end points in both substudies included time to response, DOR, disease control rate, progression-free survival, and safety.

At the March 2, 2023, interim analysis for substudy 2, 98 patients were apheresed, 73 patients from the safety cohort received lete-cel, and 45 patients were evaluable for efficacy.3 The ORR was 40% (multiplicity-adjusted 99.6% CI, 20.3%-62.3%); 2 patients had complete responses and 16 had partial responses. Of note, the ORR was 39% and 41% of patients with synovial sarcoma and MRCLS, respectively. At the interim analysis, the substudy 2 portion met its primary end point.

References

1. Adaptaimmune announces U.S. FDA breakthrough therapy designation granted to letetresgene autoleucel (lete-cel) for treatment of myxoid/round cell liposarcoma (MRCLS). News release. Adaptimmune. January 13, 2025. Accessed January 14, 2025. https://www.adaptimmune.com/investors-and-media/news-center/press-releases/detail/281/adaptimmune-announces-u-s-fda-breakthrough-therapy
2. Master protocol to assess the safety and antitumor activity of genetically engineered T cells in NY-ESO-1 and/​or LAGE-1a positive solid tumors (IGNYTE-ESO). ClinicalTrials.gov. Updated October 15, 2024. Accessed January 14, 2025. https://clinicaltrials.gov/study/NCT03967223
3. D’Angelo S, Scott Furness AJ, Thistlethwaite F, et al. Lete-cel in patients with synovial sarcoma or myxoid/round cell liposarcoma: Planned interim analysis of the pivotal IGNYTE-ESO trial. J Clin Oncol. 2024;42(suppl 16):2500. doi:10.1200/JCO.2024.42.16_suppl.2500