Lete-cel in patients with synovial sarcoma or myxoid/round cell liposarcoma: Planned interim analysis of the pivotal IGNYTE-ESO trial.
Authors: D'Angelo Sandra P. , Furness Andrew James Scott , Thistlethwaite Fiona , Burgess Melissa Amber , Riedel Richard F. , Haanen John , Noujaim Jonathan , Chalmers Anna Weinberg , Pousa Antonio López , Chugh Rashmi , Davis Lara E. , Forcade Edouard , Agulnik Mark , Williams Dennis , Woessner Mary A. , Faitg Thomas , Ireland Beth , Nathenson Michael Jason , Norry Elliot , Abdul Razak Albiruni Ryan 
Published: June 2024

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Background: Letetresgene autoleucel (lete-cel) is an autologous engineered T cell receptor therapy targeting the NY-ESO-1 cancer testis antigen highly expressed in synovial sarcoma (SyS) and myxoid/round cell liposarcoma (MRCLS). Lete-cel pilots showed promising efficacy in patients (pts) with NY-ESO-1–expressing SyS or MRCLS. We report the planned interim analysis (IA) of IGNYTE-ESO substudy 2 (SS2). Methods: IGNYTE-ESO is an ongoing, international, open-label Phase 2 trial (NCT03967223). SS2 planned enrollment/apheresis of ~87 human leukocyte antigen (HLA)-A*02:01, *02:05, or *02:06-positive pts aged ≥10 years with NY-ESO-1–expressing (≥30% staining at 2+/3+ per IHC) metastatic or unresectable SyS or MRCLS, with a 0–1 ECOG PS. Pts must: have started/received anthracycline based chemotherapy before apheresis, have progression on their last prior line of therapy (bridging therapy excluded) and measurable disease per RECIST v1.1 before lymphodepletion (LD). LD (fludarabine 120 mg/m2, cyclophosphamide 2700–3600 mg/m2, cumulative) was dose reduced for predefined risk factors. Dose range: (1–15)×109 transduced cells. Primary endpoint: overall response rate (ORR) per RECIST v1.1 by central independent review. IA efficacy population: the 1st 45 evaluable pts who had ≥6 months follow-up. Safety population: pts who had received lete-cel at time of the IA. Pre-defined success criterion at IA: 14 responders of 45 evaluable pts with ≥6 months follow-up. Primary analysis occurs when the 60th dosed pt has 12 months follow-up. Results: As of the March 2, 2023 IA, 98 pts were apheresed, 73 pts received lete-cel (safety) and 45 pts were evaluable for efficacy. Median age was 46.0 years (range 18–68), 23 (51%) had SyS. Median transduced cell dose was 6.40×109 cells (range 2.1–11). ORR: 18 of 45 (40%, multiplicity-adjusted 99.6% CI: 20.3%, 62.3%) pts by independent review (2 CR, 16 PR); 9 of 23 (39%) for pts with SyS, 9 of 22 (41%) for pts with MRCLS. Median duration of response: 10.6 months (95% CI: 3.3, NE; data are immature with 12 of 18 pts censored). Adverse events (AEs) were consistent with those previously observed with lete-cel. Most common AEs (all grades) were cytokine release syndrome (CRS) in 65 (89%), neutropenia in 53 (73%), thrombocytopenia in 46 (63%), rash in 39 (53%), anemia in 38 (52%) and leukopenia in 36 (49%) pts. Grade ≥3 cytopenias occurred in 63 (86%) pts, including grade 5 neutropenia in 1 (1%) pt. 9 (12%) pts had grade 3 CRS and 17 (23%) pts had grade 3 rash (no grade 4 or 5 in either). Immune effector cell-associated neurotoxicity (ICANS) occurred in 3 (4%) pts; all grade 1. Conclusions: IGNYTE-ESO SS2 met the primary endpoint success criterion at this planned IA, with a 40% ORR consistent across SyS and MRCLS, and a known safety profile of hematologic toxicity and CRS. This supports the potential of lete-cel as a novel therapy for pts with advanced or metastatic SyS and MRCLS. Clinical trial information: NCT03967223 .