FDA Grants Lete-cel BTD in Myxoid/Round Cell Liposarcoma

• The FDA has granted a breakthrough therapy designation (BTD) to letetresgene autoleucel (lete-cel) for the treatment of patients with unresectable or metastatic myxoid/round cell liposarcoma (MRCLS).
• Patients are required to have received prior anthracycline-based chemotherapy, be positive for HLA-A*02:01, HLA-A*02:05, or HLA-A*02:06, and have tumors that express the NY-ESO-1 antigen.
• Data from the phase 2 IGNYTE-ESO trial (NCT03967223) support this BTD.

The FDA has granted a BTD to letetresgene autoleucel (lete-cel) for the treatment of patients with unresectable or metastatic MRCLS who have received prior anthracycline-based chemotherapy, are positive for HLA-A02:01, HLA-A02:05, or HLA-A*02:06, and have tumors that express the NY-ESO-1 antigen, as supported by findings from the phase 2 IGNYTE-ESO trial.¹

Findings from the phase 2 trial were presented at the Connective Tissue Oncology Society (CTOS) 2024 annual meeting. In the phase 2 analysis, the objective response rate (ORR) by independent review was 42% (27/64), with 6 complete responses and 21 partial responses. The ORR was comparable across both histologies, with 41% in synovial sarcoma and 43% in MRCLS.^1,2

The median duration of response (DOR) was 12.2 months overall (95% CI, 6.8-19.5), with a longer median DOR observed in synovial sarcoma at 18.3 months. The median progression-free survival (PFS) was 5.3 months (95% CI, 4.0-8.0).

For safety, findings were consistent with the known profile of lete-cel, with the most common adverse events being cytopenias, cytokine release syndrome, and rash. Overall, toxicities were manageable.

"This designation by the FDA highlights the potential of lete-cel to address a critical need for new treatment options for patients with MRCLS. This is another important milestone in building out our sarcoma franchise, as we aim to bring lete-cel to market in 2026 for the treatment of synovial sarcoma and MRCLS. We look forward to initiating a rolling biologics license application for lete-cel later this year for the treatment of both sarcoma indications," said Adrian Rawcliffe, chief executive officer of Adaptimmune, in a press release.¹

Lete-cel is an investigational, engineered TCR T-cell therapy which targets NY-ESO-1. The agent is currently undergoing investigation in the pivotal, open-label, phase IGNYTE-ESO trial in patients with MRCLS who received prior treatment with anthracycline.³

Patients aged 10 years or older with a diagnosis of synovial sarcoma or MRCLS are eligible for enrollment in the study if they have a Lansky or Karnofsky performance score of 60 or an ECOG performance status of 0-1, depending on age. Patients are required to have adequate organ function and blood cell counts, within 7 days prior to leukapheresis, and measurable disease according to RECIST v1.1.

ORR serves as the primary end point in both substudy 1 and substudy 2 of the trial. Secondary end points include time to response, DOR, disease control rate, PFS, frequency of adverse events, pharmacokinetics, and number of patients with replication competent lentivirus and insertional oncogenesis. For substudy only, secondary end points also consist of OS, ORR, number of patients with positive anti-drug antibodies and titers of ADA against lete-cel autoleucel, and number of patients with clinically significant changes in hematology, clinical chemistry, and urinalysis parameters.

REFERENCES:

1. Adaptimmune announces U.S. FDA breakthrough therapy designation granted to letetresgene autoleucel (lete-cel) for treatment of myxoid/round cell liposarcoma (MRCLS). News release. Adaptimmune Therapeutics plc. January 13, 2025. Accessed January 13, 2025. https://tinyurl.com/nhkmapdv

2. Adaptimmune's lete-cel achieves primary endpoint in pivotal trial. News release. November 13, 2024. Accessed January 13, 2025. https://tinyurl.com/4u7k26ep

3. 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 13, 2025. https://clinicaltrials.gov/study/NCT03967223?tab=table