(P 114) PRIMARY ANALYSIS OF EFFICACY AND SAFETY OF LETETRESGENE AUTOLEUCEL (LETE-CEL) AS FIRST-LINE TREATMENT FOR UNRESECTABLE OR METASTATIC SYNOVIAL SARCOMA (SS); SUBSTUDY 1 OF IGNYTE-ESO

Objective: Lete-cel is an autologous T-cell therapy targeting NY-ESO-1, which is expressed in SS and myxoid round cell liposarcoma (MRCLS). Lete-cel efficacy has been demonstrated in pilot studies for SS and MRCLS for patients (pts) with metastatic or unresectable disease. We explored the feasibility, efficacy, and safety of lete-cel for treatment-naïve pts in the first-line setting for metastatic or unresectable SS or MRCLS.

Methods: IGNYTE-ESO is a master protocol with two substudies (NCT03967223). Substudy 1 (SS1) is an open-label pilot study of lete-cel in treatment-naïve pts with metastatic or unresectable SS or MRCLS. The target enrollment was 10 pts. Key eligibility criteria were: age ≥10 years; HLA-A*02:01, A*02:05, or A*02:06; NY-ESO-1+ (≥30% of cells 2+/3+); optional bridging therapy consisting of 2 cycles of doxorubicin (dox) between apheresis and lymphodepletion (LD); and measurable disease. Pts received fludarabine (range: 60–120 mg/m^2) and cyclophosphamide (range: 1800–3600 mg/m^2) for LD, and a transduced T-cell dose between 1 to 15x10^9. LD dose reduction was allowed for age ≥60 years and renal impairment. Response was assessed at weeks 6, 12, 18, 24, then every 3 months (mo) until disease progression, death or withdrawal. The primary efficacy endpoint was investigator-assessed overall response rate (ORR) by RECIST v1.1. Secondary endpoints included disease control rate (DCR), time to response (TTR), duration of response (DOR), progression-free survival (PFS), and safety. To characterize the cellular pharmacokinetics of lete-cel we report the AUC from time 0 to day 28, and Cmax.

Results: Data cut: January 27, 2023. The primary analysis was conducted when all enrolled pts had received T-cell infusion and completed ≥2 post-baseline disease assessments or withdrawn. From January 2020 to May 2022, 52 pts screened for SS1, 7 pts enrolled, and 5 pts received LD and T-cell infusion (median T-cell dose 5.4x10^9). Due to slow accrual, study enrollment was terminated prior to reaching target enrollment. Two pts were not eligible for LD and T-cell infusion (developed a 2nd malignancy [1 pt] and received >2 cycles of dox for bridging therapy [1 pt]). All enrolled pts had SS. All 5 treated pts were metastatic at screening. One pt had a history of neoadj/adj chemo, and 1 pt received bridging chemo. Median time from date of locally advanced or metastatic disease to leukapheresis was 2.4 (range: 1.6–5.9) mo. Median time from leukapheresis to T-cell infusion was 2.3 (range: 2.1–11.3) mo. Median follow-up for PFS was 7.0 mo. The ORR was 80% (95% CI: 28.4–99.5%), with 1 CR and 3 PR. 1 pt had SD as best response, yielding a DCR of 80% (95% CI: 28.4–99.5%). Median TTR was 1.2 (range: 1.1–2.6) mo for the 4 pts with CR/PR. The median DOR and PFS were not mature, as the 4 responders were ongoing at the time of this analysis. The pt with SD as best response developed clinical disease progression, grade 5 hemoptysis from pulmonary metastases, and died from their disease. All pts had ≥1 treatment emergent adverse event (TEAE), 3 pts had ≥1 serious TEAE. The most common TEAEs were cytokine release syndrome (100%; grade 1 [3], grade 2 [1], grade 3 [1]), ALT increase (60%), fatigue (60%), and neutropenia (60%). 2 pts developed GvHD predominated by rash. Geometric means were 1,911,782.96 (%CV: 53.709) copies per µg gDNA times days for AUC(0–28d), and 119,701.64 (%CV: 68.267) copies per µg gDNA for Cmax. The 4 pts who responded to therapy continue to have detectable T-cell persistence during follow-up.

Conclusion: This study highlights the challenge to enroll advanced/metastatic treatment-naïve rare sarcoma pts in a cell therapy trial, with 7 pts enrolled over ~2.5 years. Encouraging efficacy was seen in a small population of treatment-naïve pts in the advanced/metastatic setting with 80% ORR, with all responses ongoing at the time of this analysis. The TEAEs for SS1 are consistent with the known safety profile of lete-cel. All responders have prolonged T cell persistence.