Lete-cel in patients with synovial sarcoma or myxoid/round cell liposarcoma: Planned interim analysis of the pivotal IGNYTE-ESO trial.

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 1^st 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 60^th 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.

Duke Scholars

Author Richard Francis Riedel Medicine, Medical Oncology