Safety and Tolerability of Letetresgene Autoleucel (GSK3377794): Pilot Studies in Patients with Advanced Non-Small Cell Lung Cancer

• Published in: Clinical cancer research 2025-02, Vol.31 (3), p.529-542
• Main Authors: Altan, Mehmet, Lopes, Gilberto, Hiltermann, T Jeroen N, Govindan, Ramaswamy, Villaruz, Liza C, Calvo, Emiliano, Edelman, Martin J, Furqan, Muhammad, Neal, Joel, Felip, Enriqueta, Carlisle, Jennifer W, Heymach, John V, O'Cearbhaill, Róisín Eilish, Zauderer, Marjorie, Chisamore, Michael, Corigliano, Ellie, Eleftheriadou, Ioanna, Zajic, Stefan, Jenkins, Ben, Goodison, Sophia, Suchindran, Sunil, Ramos-Hernandez, Natalia, Tarek, Nidale, Schoenfeld, Adam J
• Format: Article
• Language: English
• Subjects: Adult; Aged; Aged, 80 and over; Antibodies, Monoclonal, Humanized - administration & dosage; Antibodies, Monoclonal, Humanized - adverse effects; Antibodies, Monoclonal, Humanized - therapeutic use; Antigens, Neoplasm - genetics; Antigens, Neoplasm - immunology; Biomarkers; Cancer Vaccines - administration & dosage; Cancer Vaccines - adverse effects; Cancer Vaccines - therapeutic use; Carcinoma, Non-Small-Cell Lung - drug therapy; Carcinoma, Non-Small-Cell Lung - genetics; Carcinoma, Non-Small-Cell Lung - pathology; Clinical Trial Results; Clinical Trials: Immunotherapy; Female; HLA-A2 Antigen - genetics; HLA-A2 Antigen - immunology; Humans; Immunotherapy, Adoptive - adverse effects; Immunotherapy, Adoptive - methods; Lung Cancer; Lung Neoplasms - drug therapy; Lung Neoplasms - genetics; Lung Neoplasms - immunology; Lung Neoplasms - pathology; Male; Membrane Proteins - genetics; Middle Aged; Neoplasm Staging; Pilot Projects; Treatment Outcome
• ISSN: 1078-0432; 1557-3265; 1557-3265
• DOI: 10.1158/1078-0432.CCR-24-1591

The study aims to evaluate the safety, tolerability, and antitumor response of letetresgene autoleucel (lete-cel), genetically modified autologous T cells expressing a T-cell receptor specific for New York esophageal squamous cell carcinoma 1 (NY-ESO-1)/LAGE-1a shared epitope, alone or in combination with pembrolizumab, in HLA-A*02-positive (HLA-A*02:01, HLA-A*02:05, and/or HLA-A*02:06) patients with NY-ESO-1- and/or LAGE-1a-positive non-small cell lung cancer. Study 208749 was a single-arm study of lete-cel alone. Study 208471 was a multiarm study of lete-cel alone or in combination with pembrolizumab in patients with advanced or recurrent non-small cell lung cancer. More than 2,500 patients were screened for target expression. In the multiarm study, 738 (45%) of 1,638 tested patients were HLA-A*02-positive. NY-ESO-1 and LAGE-1a testing was positive in 12% (62/525) and 4% (15/348) of tested patients, respectively. Forty-one patients positive for HLA-A*02 and antigen expression were screened in the single-arm study. Overall, 43 patients underwent leukapheresis and 18 received lete-cel across studies. Lete-cel demonstrated a manageable safety profile. No fatal treatment-related serious adverse events (AE) were reported in either study. Cytopenias and cytokine release syndrome were the most common treatment-emergent AEs. Combining pembrolizumab with lete-cel did not seem to increase toxicity over lete-cel alone. Limited antitumor activity was observed; one of 18 patients had a durable response persisting for 18 months. Pharmacokinetic data showed similar T-cell expansion in all patients. 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. Antitumor activity was observed in a limited number of patients.