Sandra P. D’Angelo1, Jonathan Noujaim2, Fiona Thistlethwaite3, Albiruni R. Abdul Razak4, Silvia Stacchiotti5, Warren Chow6, John B.A.G. Haanen7, Anna Chalmers8, Steven I. Robinson9, Brian A. Van Tine10, Kristen N. Ganjoo11, Melissa L. Johnson12, 13 13 13 13 13 14 15 IGNYTE-ESO: a master protocol to assess safety and activity of letetresgene autoleucel (lete-cel; GSK3377794) Victoria L. Chiou , Thomas Faitg , Mary Woessner , Laura Pearce , Aiman Shalabi , Jean-Yves Blay , George D. Demetri 1Memorial Sloan Kettering Cancer Center, New York, NY, USA; 2Institut D’Hématologie-Oncologie, Hôpital Maisonneuve-Rosemont, Montreal, QC, Canada; 3The Christie NHS Foundation Trust and University of Manchester, Manchester, United Kingdom; 4Princess Margaret Cancer Centre and in HLA-A*02+ patients with synovial sarcoma or myxoid/round cell liposarcoma (Substudies 1 and 2) Mount Sinai Hospital, Toronto, ON, Canada; 5Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy; 6City of Hope Comprehensive Cancer Center, Duarte, CA, United States; 7Antoni van Leeuwenhoek Ziekenhuis, Amsterdam, Netherlands; 8Huntsman Cancer Institute, University of Utah, Salt Lake City, UT, USA; 9Mayo Clinic, Rochester, MN, USA; 10Washington University in St. Louis, St. Louis, MO, USA; 11Stanford University Medical Center, Stanford, CA, USA; 12Sarah Cannon Research Institute, Nashville, TN, USA; 13GlaxoSmithKline, Philadelphia, PA, USA; Poster No. TPS11582 14Centre Léon Bérard, Lyon, France; 15Dana-Farber Cancer Institute and Ludwig Center at Harvard, Boston, MA, USA Background Study design Study phases Unmet need IGNYTE-ESO (NCT03967223) is a master protocol that enables evaluation of multiple cell therapies Figure 3 displays the patient journey for both substudies, which includes leukapheresis for lete-cel manufacture, lymphodepletion chemotherapy, lete-cel infusion, and follow-up. in multiple tumor types and treatment stages across separate substudies. There is an unmet need for effective therapies in many metastatic or advanced stage solid tumor • Lymphodepletion prior to lete-cel infusion may enhance immune reconstitution via facilitation of T-cell expansion and trafficking; it may also enhance the activity of the adoptively transferred cells by decreasing types, including soft tissue sarcomas (STS) for which novel immunotherapies present a promising The first 2 substudies are single-arm, open-label, multicenter trials investigating lete-cel in activity of regulatory T cells.10–12 therapeutic option. biomarker-selected advanced metastatic or unresectable SS/MRCLS (Figure 2). • Synovial sarcoma (SS) and myxoid/round cell liposarcoma (MRCLS), both of which harbor • Substudy 1: Previously untreated patients Figure 3. Patient journey chromosomal translocations, each represent approximately 5%–10% of STS.1-3 • Substudy 2: Patients with disease progression following prior treatment with anthracycline- – Objective response rates to standard therapies among patients with metastatic, recurrent, based chemotherapy Eligibility Leukapheresis Lymphodepletion Long-term Follow-up and/or unresectable SS and MRCLS are poor, particularly after failure of first-line PART 1 PART 2 PART 3 PART 4 The protocol may be amended in the future to add additional substudies for different patient screening & Manufacture Treatment & Follow-up (Study 208750) systemic chemotherapy.3,4 populations or tumor types. o For second-line treatment, a recent multicenter study identified a <15% response rate among 249 patients with advanced SS.3 Manufacturing of NY-ESO-1 Figure 2. Study Design T cells lete-cel o Although response rates in individual studies can be high,5 data among a larger cohort Master protocol design (IGNYTE-ESO) (n=101) indicated <20% response rates to first- and second-line treatments in patients with advanced MRCLS.3 Substudy 1 (n=10) Target Expression Leukapheresis Treatment Lymphodepletion Lete-cel Eligibility Screening Eligibility Flu x 4 days Long-term Follow-up Advanced Previously HLA-A*02 Lete-cel Screening Infusion Letetresgene autoleucel (lete-cel; GSK3377794) Leukapheresis Confirmed Cy x 2 days Follow-up metastatic or untreated participants HLA-A*02+ New-York esophageal squamous cell carcinoma 1 (NY-ESO-1) is an immunogenic cancer unresectable with NY-ESO-1 and NY-ESO-1 28 days prior to apheresis Days −17 to −8 Days −7 to −4 Day 1 Up to 15 years after lete-cel infusion testis antigen present in several types of tumors, including 70%‒80% of SS and 80%‒90% of SS or MRCLS positive tumors Fludarabine Response evaluation 2, 6 30 mg/m2/day x 4 days RECIST 1.1 MRCLS tumors. Long (Day −7 to −4) Primary endpoints: • Letetresgene autoleucel (lete-cel; GSK3377794) is an autologous T-cell therapy using genetically Substudy 2 (n=45*) Cyclophosphamide ORR 1800 mg/m2/day x 2 days Secondary endpoints: - 7 follow term modified T-cell receptors to target cancer cells expressing NY-ESO-1 (Figure 1). Advanced Disease HLA-A*02 Lete-cel (Day −5 to −4) TTR, DOR, DCR, PFS, OS, safety specific T cells T specific – metastatic or progression participants • Unlike CAR-T cells that recognize cell surface proteins, T-cell receptors can recognize antigenic 1 - unresectable post chemotherapy with NY-ESO-1 epitopes of intracellular proteins that are processed and presented on the surface of the cancer SS or MRCLS positive tumors 8 cell in the context of human leukocyte antigen (HLA). ESO Cy, cyclophosphamide; DCR, disease control rate; DoR, duration of response; flu, fludarabine; HLA, human leukocyte antigen; lete-cel, letetresgene autoleucel; NY-ESO-1, New-York esophageal squamous cell carcinoma 1; PFS, progression-free survival; - - up and safety and up ORR, objective response rate; OS, overall survival; RECIST, TTR, time to response. Potential additional substudy Figure 1. Lete-cel mechanism of action Other NY-ESO-1–specific T cells or tumor types other cell-based therapies, Study objectives and endpoints Summary alone or combined with other agents Table 2 describes the endpoints for each substudy. There is an unmet need for safe and effective novel therapies in patients with solid tumors such as SS and MRCLS, with promising results observed using autologous TCR Potential additional substudy T-cell immunotherapy. TCR engineered NY TCRengineered Table 2. Study objectives and endpoints Other NY-ESO-1–specific T cells, or • A previous Phase I study has shown that lete-cel infusion has persistent clinically tumor types other cell-based therapies, Substudy 1 Substudy 2 alone or combined with other meaningful activity with a manageable safety profile in patients with previously treated agents ORR per RECIST v1.1 assessed by advanced SS.7 Overall response rate (ORR) per central independent review *Intended sample size for treatment with commercial vector supply and manufacturing process. − Additionally, recent interim analysis results from a pilot study of lete-cel in HLA, human leukocyte antigen; lete-cel, letetresgene autoleucel; MRCLS, myxoid/round cell liposarcoma; NY-ESO-1, Primary RECIST v1.1 assessed by ● ORR will be compared with the New York esophageal squamous cell carcinoma-1; SS, synovial sarcoma; TCR, T-cell receptor. endpoint investigators; no formal hypotheses historical control assuming at least advanced MRCLS identified durable partial responses (ORR, 40%) and prolonged were evaluated statistically 90% power with 0.025 one-sided stable disease along with a manageable safety profile in this population (please type I error see poster 11521).9 Study population Efficacy Safety Pharmacokinetic Lete-cel is currently being investigated in multiple tumor types as a single agent ● Time to response ● Adverse event ● Maximum transgene (including in SS and MRCLS) or in combination with pembrolizumab (including in non- Key inclusion criteria Key exclusion criteria ● Duration of response frequency/severity expansion (Cmax) small cell lung cancer). Secondary ● Disease control rate ● Serious adverse ● Time to Cmax ● ≥10 years of age ● Central nervous system metastases endpoints events Substudies 1 and 2 of the IGNYTE-ESO master protocol study will examine the efficacy, ● Progression-free ● Area under the time ● Advanced metastatic or unresectable ● Clinically significant other systemic illness besides ● Adverse events of curve from zero to time safety, and pharmacokinetics of lete-cel in previously untreated (Substudy 1) patients or HLA-A*02 denotes subtypes HLA-A*02:01, HLA-A*02:05, and HLA-A*02:06. SS or MRCLS SS or MRCLS survival special interest (AUC0–t) patients who have progressed following treatment with anthracycline-based chemotherapy HLA, human leukocyte antigen; lete-cel, letetresgene autoleucel; NY-ESO-1, New York esophageal squamous cell ● Overall survival* carcinoma-1; TCR, T-cell receptor. ● Measurable disease ● Prior gene therapy with any NY-ESO-1–specific (Substudy 2) with biomarker-selected advanced metastatic or unresectable SS or MRCLS. ● Positive for HLA-A*02:01, A*02:05 and/or A*02:06 T cells, vaccine, or targeting antibody; or with the integrating vector *Secondary endpoint for Substudy 2 only; exploratory endpoint for Substudy 1. This innovative study design allows additional patient populations, tumor types, and • A Phase I clinical study (NCT01343043) identified response rates to lete-cel of 20–50% and a ● Tumor expression of NY-ESO-1 RECIST, Response Evaluation Criteria in Solid Tumors. ● Prior autoimmune disease or allogeneic other cell-based therapies with different combination strategies to be assessed in manageable safety profile among patients with advanced/metastatic