letetresgene autoleucel (GSK3377794) / Adaptimmune - LARVOL DELTA

AGC, AdaptiMune and Lentiviral Vector Commercial Production Collaboration [Google translation] (HIT News) - "AGC Biologics announced a collaboration with Adaptimune to support commercial manufacturing of lentiviral vectors for the production of letetresgene autoleucel, a next-generation T cell receptor (TCR)-based cell therapy....Under the agreement, AGC Biologics will manufacture the lentiviral vectors required for lete-cel production and will support Adaptimmune’s Biologics License Application (BLA) through process characterization, stability studies, and vector supply."

Commercial • Liposarcoma • Synovial Sarcoma

Letetresgene Autoleucel in Advanced/Metastatic Myxoid/Round Cell Liposarcoma. (PubMed, J Clin Oncol) - P2 | "To our knowledge, this study is the first demonstrating the clinical promise of lete-cel in HLA-/NY-ESO-1-positive patients with advanced MRCLS."

Journal • Esophageal Cancer • Esophageal Squamous Cell Carcinoma • Hematological Disorders • Liposarcoma • Oncology • Sarcoma • Solid Tumor • Squamous Cell Carcinoma • CTAG1B • HLA-A

Letetresgene Autoleucel in Advanced/Metastatic Myxoid/Round Cell Liposarcoma (J Clin Oncol) - P2 | N=23 | NCT02992743 | Sponsor: GlaxoSmithKline | "Of 23 enrolled patients, 10 in cohort 1 and 10 in cohort 2 received lete-cel. Investigator-assessed ORR was 20% (95% CI, 2.5 to 55.6) and 40% (95% CI, 12.2 to 73.8), median duration of response was 5.3 months (95% CI, 1.9 to 8.7) and 7.5 months (95% CI, 6.0 to not estimable [NE]), and median progression-free survival was 5.4 months (95% CI, 2.0 to 11.5) and 8.7 months (95% CI, 0.9 to NE) in cohorts 1 and 2, respectively. AEs included cytokine release syndrome and cytopenias, consistent with T-cell therapy/LDR."

P2 data • Liposarcoma

Adaptimmune Announces U.S. FDA Breakthrough Therapy Designation Granted to Letetresgene Autoleucel (lete-cel) for Treatment of Myxoid/Round Cell Liposarcoma (MRCLS) (Adaptimmune Press Release) - "Adaptimmune Therapeutics plc...announced that letetresgene autoleucel (lete-cel), has been granted breakthrough therapy designation by the U.S. FDA for the treatment of patients with unresectable or metastatic myxoid/round cell liposarcoma (MRCLS) who have received prior anthracycline-based chemotherapy, are positive for HLA-A*02:01, HLA-A*02:05, or HLA-A*02:06, and whose tumor expresses the NY-ESO-1 antigen....Breakthrough therapy designation for lete-cel in MRCLS was based on the results in this indication from the Phase II IGNYTE-ESO trial."

Breakthrough therapy • Liposarcoma

Safety and Tolerability of Letetresgene Autoleucel (Lete-cel; GSK3377794): Pilot Studies in Patients With Advanced Non-Small Cell Lung Cancer. (PubMed, Clin Cancer Res) - "Extensive HLA-A*02 and antigen expression testing was performed to identify potential participants. Lete-cel was generally well tolerated and had no unexpected AEs. Anti-tumor activity was observed in a limited number of patients."

IO biomarker • Journal • Metastases • Esophageal Cancer • Esophageal Squamous Cell Carcinoma • Hematological Disorders • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • Squamous Cell Carcinoma • CTAG1B • CTAG2 • HLA-A

Study to Evaluate Safety and Antitumor Activity of Lete-Cel (GSK3377794) in HLA-A2+ Participants with NY-ESO-1 Positive Previously Treated Advanced (Metastatic or Unresectable) Synovial Sarcoma or Myxoid/Round Cell Liposarcoma (clinicaltrials.gov) - P2 | N=87 | Active, not recruiting | Sponsor: Adaptimmune

Metastases • New P2 trial • Liposarcoma • Oncology • Sarcoma • Solid Tumor • Synovial Sarcoma

PLANNED ANALYSIS OF THE PIVOTAL IGNYTE-ESO TRIAL OF LETE-CEL IN PATIENTS WITH SYNOVIAL SARCOMA OR MYXOID/ROUND CELL LIPOSARCOMA. (CTOS 2024) - No abstract available

Clinical • Liposarcoma • Oncology • Sarcoma • Solid Tumor • Synovial Sarcoma

Adaptimmune virtual KOL event November 18th (Adaptimmune Press Release) - "Adaptimmune will host a virtual event to discuss and review the IGNYTE-ESO dataset and the impact of engineered cell therapies on the treatment landscape in sarcoma."

P2 data • Synovial Sarcoma

Adaptimmune's Lete-cel Achieves Primary Endpoint in Pivotal Trial (Adaptimmune Press Release) - P2 | N=103 | IGNYTE-ESO (NCT03967223) | Sponsor: Adaptimmune | "In the analysis, 27/64 (42%) people with synovial sarcoma or MRCLS had RECISTv1.1 responses by independent review, with six complete responses and 21 partial responses. The response rate was 14/34 (41%) for people with synovial sarcoma and 13/30 (43%) for people with MRCLS. The median duration of response (DoR) was 12.2 months (95% CI 6.8, 19.5). In synovial sarcoma, the median duration of response was 18.3 months (95% CI 3.3, -)....Data to be presented at Connective Tissue Oncology Society 2024 Annual Meeting; Company plans to initiate a rolling BLA submission for lete-cel for the treatment of advanced or metastatic synovial sarcoma and MRCLS by end of 2025."

FDA filing • P2 data • Synovial Sarcoma

Adaptimmune to Participate in Scientific and Medical Conferences this November and December (Adaptimmune Press Release) - "Adaptimmune Therapeutics plc...announced presence and presentations at key scientific and medical conferences in November and December. [1] Society for Immunotherapy of Cancer (SITC) 39th annual meeting, November 6-10, Houston, TX; [2] Connective Tissue Oncology Society (CTOS) 2024 annual meeting, November 13-16, San Diego, CA; [3] American Society of Hematology (ASH) 66th Annual Meeting, December 7-10, San Diego, CA."

Clinical data • Liposarcoma • Synovial Sarcoma

Study to Evaluate Safety and Antitumor Activity of Lete-Cel (GSK3377794) in HLA-A2+ Participants With NY-ESO-1 Positive Previously Untreated Advanced (Metastatic or Unresectable) Synovial Sarcoma and Myxoid/Round Cell Liposarcoma (clinicaltrials.gov) - P2 | N=7 | Active, not recruiting | Sponsor: Adaptimmune | Trial completion date: Jul 2024 ➔ Jul 2025

Metastases • Trial completion date • Liposarcoma • Oncology • Sarcoma • Solid Tumor • Synovial Sarcoma • CTAG1B • HLA-A

Adaptimmune to Present Data from Planned Interim Analysis of Pivotal IGNYTE-ESO Trial with Lete-cel at ASCO; Data Continue to Support further Development of Sarcoma Franchise (Adaptimmune Press Release) - P2 | N=103 | IGNYTE-ESO (NCT03967223) | Sponsor: Adaptimmune | "'We look forward to sharing the full results of the IGNYTE-ESO trial in late 2024. We continue to work toward commercializing afami-cel later this year and lete-cel in 2026'....The overall response rate (ORR) of 40% was consistent across both SyS and MRCLS, and markedly greater than historical standard of care outcomes in these indications. The primary endpoint success criterion for efficacy was met by the interim analysis 40% ORR....The complete primary analyses from IGNYTE-ESO, including more mature duration of response, are currently in progress with a full dataset anticipated in late 2024....Given the success of the pivotal IGNYTE-ESO trial, Adaptimmune plans to initiate a rolling Biologics License Application (BLA) submission for lete-cel for the treatment of advanced or metastatic MRCLS and synovial sarcoma during 2025."

BLA • Launch • P2 data • Liposarcoma • Oncology • Sarcoma • Soft Tissue Sarcoma • Solid Tumor • Synovial Sarcoma

Lete-cel in patients with synovial sarcoma or myxoid/round cell liposarcoma: Planned interim analysis of the pivotal IGNYTE-ESO trial. (ASCO 2024) - P2 | "LD (fludarabine 120 mg/m 2 , cyclophosphamide 2700–3600 mg/m 2 , cumulative) was dose reduced for predefined risk factors. 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 • Anemia • Hematological Disorders • Leukopenia • Liposarcoma • Neutropenia • Oncology • Sarcoma • Solid Tumor • Synovial Sarcoma • Thrombocytopenia • CTAG1B

Adaptimmune Secures up to $125 Million Debt Financing with Hercules Capital (Adaptimmune Press Release) - "Adaptimmune Therapeutics plc...announced that it has entered into a $125 million five-year, term loan facility with Hercules Capital, Inc. (NYSE: HTGC) ('Hercules'). The transaction strengthens the Company's balance sheet as it executes on its sarcoma franchise with the commercial launch of afami-cel later this year and lete-cel planned for 2026. The Company will host a live webcast at 8:00 a.m. EDT (1:00 p.m. BST) today to report its Q1 financial and business updates."

Financing • Launch • Oncology

Adaptimmune Reports Q1 2024 Financial and Business Updates (Adaptimmune Press Release) - "Data from the planned interim analysis of the pivotal IGNYTE-ESO trial with lete-cel to be presented by Dr. Sandra P. D'Angelo, M.D., Sarcoma Medical Oncology, Memorial Sloan Kettering Cancer Center, in an oral presentation at ASCO...during the Developmental Therapeutics-Immunotherapy session in Hall D2 on June 3, 2024 at 11:30 a.m. CDT."

P2 data • Liposarcoma • Oncology • Sarcoma • Solid Tumor • Synovial Sarcoma

IGNYTE-ESO: 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 (clinicaltrials.gov) - P2 | N=103 | Active, not recruiting | Sponsor: Adaptimmune | Trial primary completion date: Nov 2022 ➔ Aug 2024

Combination therapy • Trial primary completion date • Oncology • Solid Tumor • CTAG1B • HLA-A

Pilot Immunotherapy Study With Letetresgene Autoleucel (Lete-cel, GSK3377794)T-cells in New York Esophageal Squamous Cell Carcinoma-1 (NY-ESO-1)/ LAGE-1a-positive Advanced Non-small Cell Lung Cancer (NSCLC) Either Alone or in Combination With Pembrolizumab (clinicaltrials.gov) - P1/2 | N=34 | Terminated | Sponsor: GlaxoSmithKline | Phase classification: P1b/2a ➔ P1/2

Combination therapy • Metastases • Phase classification • Esophageal Cancer • Esophageal Squamous Cell Carcinoma • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • Squamous Cell Carcinoma • CTAG1B • CTAG2 • HLA-A • PD-L1

Adaptimmune Receives Transfer of IND for Lete-cel Program (Adaptimmune Press Release) - "Company will lay out plans for its cell therapy sarcoma franchise including afami-cel and lete-cel in January 2024...Adaptimmune Therapeutics plc...announces the transfer of the IND for letetresgene autoluecel (lete-cel) from GSK to Adaptimmune for the pivotal IGNYTE-ESO (NCT03967223) clinical trial....As a result, the Company is evaluating the integration of lete-cel into its sarcoma franchise and is looking forward to sharing its development plans for lete-cel in the new year."

Licensing / partnership • Oncology • Sarcoma • Soft Tissue Sarcoma • Solid Tumor • Spindle Cell Sarcoma • Synovial Sarcoma

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 (CTOS 2023) - P2 | "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... 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."

Clinical • Metastases • Liposarcoma • Oncology • Sarcoma • Solid Tumor • Synovial Sarcoma • CTAG1B • HLA-A

Optimization of dose and regimen of letetresgene autoleucel for the treatment of synovial sarcoma: simulation of dose dependence and split dosing using quantitative systems pharmacology modeling (SITC 2023) - "Methods The developed QSP model consists of1 lymphodepletion including pharmacokinetics (PK) of fludarabine and cyclophosphamide, their effects on lymphocytes and IL-7 and IL-15 levels2; tumor growth and microenvironment in SS including biomarkers in blood; 3 PK and distribution of lete-cel after intravenous infusion4; killing of NY-ESO-1 positive cancer cells by lete-cel and activation of engineered T-cells followed by their expansion and cytokine secretion (IFNg, TNFa, IL-6). The optimal spilt-dose regimen among tested was 10% of the dose on day 1, 30% on day 2 and 60% on day 3. Split-dose cell therapy regimens may provide an improved safety profile while delivering comparable efficacy compared to single dose."

Oncology • Sarcoma • Solid Tumor • Synovial Sarcoma • CTAG1B • IFNG • IL15 • IL6 • IL7 • TNFA

Adaptimmune Reports Positive Data with Lete-cel[1] from an Interim Analysis of the Pivotal IGNYTE-ESO Trial for People with Synovial Sarcoma or MRCLS (Adaptimmune Press Release) - P2 | N=103 | IGNYTE-ESO (NCT03967223) | Sponsor: GlaxoSmithKline | "Adaptimmune Therapeutics plc...is reporting the outcome of a protocol-defined interim analysis of data from the pivotal IGNYTE-ESO trial with lete-cel for people with synovial sarcoma or myxoid/round cell liposarcoma (MRCLS) who received ≥ 2 prior lines of therapy....At the time of this analysis, 18/45 (40%) (99.6% CI: 20.3%, 62.3%) people with synovial sarcoma or MRCLS had RECISTv1.1 responses by independent review with two complete responses and 16 partial responses. The response rate was 9/23 (39%) for people with synovial sarcoma and 9/22 (41%) for people with MRCLS by independent review. Duration of Response (DoR) is still being followed in 9/18 (50%) of responders at the time of the data cut-off. The median duration of response was 10.6 months (95% CI: 3.3, NE)."

P2 data • Liposarcoma • Oncology • Sarcoma • Soft Tissue Sarcoma • Solid Tumor • Synovial Sarcoma

Adaptimmune Reports Positive Data with Lete-cel[1] from an Interim Analysis of the Pivotal IGNYTE-ESO Trial for People with Synovial Sarcoma or MRCLS (Adaptimmune Press Release) - P2 | N=103 | IGNYTE-ESO (NCT03967223) | Sponsor: GlaxoSmithKline | "Substudy 1 was designed to explore the feasibility, efficacy, and safety of lete-cel in the first-line setting for treatment-naïve patients with metastatic or unresectable synovial sarcoma or MRCLS. Of the five evaluable patients in the substudy, one exhibited a complete response, with an additional three partial responses, yielding an overall response rate of 80% (4/5) by investigator assessment. All five patients experienced cytokine release syndrome, all cases resolved; four were treated with tocilizumab. Overall, the substudy reveals encouraging efficacy in this small population of treatment-naïve patients in the advanced/metastatic setting with 80% ORR, with all responses ongoing at the time of this analysis."

P2 data • Liposarcoma • Oncology • Sarcoma • Soft Tissue Sarcoma • Solid Tumor • Synovial Sarcoma

Safety and Efficacy of NY-ESO-1 Antigen-specific T-cell Receptor Gene-Transduced T Lymphocytes in Patients with Synovial Sarcoma: A Phase I/II Clinical Trial (Clin Cancer Res) - "For the full analysis set (N=8; phase I, n=3; phase II, n=5), the ORR was 50.0% (95%CI: 15.7-84.3) with best overall partial response in 4 of 8 patients according to RECIST v1.1/irRECIST. All patients experienced adverse events and 7 of 8 patients (87.5%) had adverse drug reactions but no deaths were attributed to adverse events. Cytokine release syndrome occurred in 4 of 8 patients (50.0%) but all cases recovered with prespecified treatment. Immune effector cell-associated neurotoxicity syndrome, replication competent retrovirus, and lymphocyte clonality were absent."

Cytokine release syndrome • P1/2 data • Synovial Sarcoma

Study to Evaluate Safety and Antitumor Activity of Lete-Cel (GSK3377794) in HLA-A2+ Participants With NY-ESO-1 Positive Previously Untreated Advanced (Metastatic or Unresectable) Synovial Sarcoma and Myxoid/Round Cell Liposarcoma (clinicaltrials.gov) - P2 | N=7 | Active, not recruiting | Sponsor: GlaxoSmithKline

Metastases • New P2 trial • Liposarcoma • Oncology • Sarcoma • Solid Tumor • Synovial Sarcoma • CTAG1B • HLA-A

Adaptimmune Reports Second Quarter Financial Results and Business Update (Adaptimmune Press Release) - "Data from the completed pivotal clinical trial with lete-cel (IGNYTE-ESO) for the treatment of synovial sarcoma or myxoid/ round cell liposarcoma (MRCLS) is expected in late 2023. The transition of lete-cel to Adaptimmune from GSK is ongoing and terms were agreed during Q2 2023. The Company will determine next steps for lete-cel, including potential for a BLA, in early 2024....Initiated additional cohorts in the Phase 1 SURPASS trial in the earlier line treatment setting for head & neck and urothelial cancers in combination with checkpoint inhibitors. Data readouts anticipated in 2H 2024. An update on the Phase 1 SURPASS trial (ADP-A2M4CD8 alone or combined with nivolumab) will be featured as an oral presentation at the European Society of Medical Oncology (ESMO) 2023 Congress, Monday, October 23, 11:08-11:18 CET."

P1 data • P2 data • Genito-urinary Cancer • Head and Neck Cancer • Liposarcoma • Oncology • Sarcoma • Solid Tumor • Synovial Sarcoma • Urothelial Cancer