Letetresgene autoleucel safe, active in advanced synovial sarcoma
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Letetresgene autoleucel demonstrated clinical activity among patients with advanced synovial sarcoma, according to final phase 1 study results presented at the virtual Society for Immunotherapy of Cancer Annual Meeting.
The investigational T-cell receptor therapy induced more frequent and durable responses among patients whose tumors had high expression of the NY-ESO-1 antigen. It also had a manageable safety profile, according to the investigators.
Letetresgene autoleucel (Adaptimmune/GlaxoSmithKline), also known as lete-cel, comprises autologous CD4-positive and CD8-postive T cells that are genetically altered to express a T-cell receptor that recognizes NY-ESO-1 bound to HLA-A*02 on the surface of cancer cells.
“Patients with metastatic synovial sarcoma have limited therapeutic options,” Sandra P. D'Angelo, MD, medical oncologist at Memorial Sloan Kettering Cancer Center, told Healio.
“NY-ESO-1 is highly expressed in most tumors, and prior experience with T-cell therapy targeting this protein [has shown] promise.”
The investigators conducted a phase 1 clinical trial to determine the safety and efficacy of lete-cel in combination with lymphodepletion among patients with relapsed or refractory synovial sarcoma.
The trial enrolled 50 participants (median age, 32 years; range, 11-73; 53% men), 45 of whom received an infusion of lete-cel. Most patients (93%) were HLA-A*02:01-positive, and 71% had high expression of NY-ESO-1. All patients experienced disease progression after at least one previous line of systemic therapy.
The original trial was expanded from a single-cohort, nonrandomized pilot study to include four cohorts depending on NY-ESO-1 expression and lymphodepletion regimen:
- Cohort 1 (n = 12) included patients with high NY-ESO-1 expression who received high doses of fludarabine and cyclophosphamide for lymphodepletion.
- Cohort 2 (n = 13) included patients with low NY-ESO-1 expression who received high doses of fludarabine and cyclophosphamide for lymphodepletion.
- Cohort 3 (n = 5) included patients with high NY-ESO-1 expression who received a high dose of cyclophosphamide for lymphodepletion.
- Cohort 4 (n = 15) included patients with high NY-ESO-1 expression who received low doses of fludarabine and cyclophosphamide for lymphodepletion.
Overall response rate by investigator assessment per RECIST version 1.1 served as the study’s primary efficacy outcome. Additional efficacy measures include duration of response, PFS and OS, with safety evaluated throughout the study.
The investigators noted that the study was neither designed nor powered for statistical comparisons among the four cohorts.
The efficacy analysis showed ORRs of 50% (95% CI, 0.21-0.79) in cohort 1, 31% (95% CI, 0.09-0.61) in cohort 2, 20% (95% CI, 0.01-0.72) in cohort 3 and 27% (95% CI, 0.08-0.55) in cohort 4. Fourteen patients across all cohorts achieved partial response to therapy, and one patient in cohort 1 achieved complete response.
Median duration of response was longest in cohort 3 (32.1 weeks), followed by cohort 1 (31 weeks), cohort 4 (16.4 weeks) and cohort 2 (8.6 weeks) — the only cohort of patients with low NY-ESO-1 expression.
Median PFS was 22.4 weeks for cohort 4, 15.4 weeks for cohort 1, 13.1 weeks for cohort 2 and 8.6 weeks for cohort 3.
Cohort 1 had the longest median OS, at 24.3 months, followed by 19.9 months for cohort 3 and 9.9 months for cohort 2. OS data for cohort 4 had not yet matured at the time of analysis.
“These responses are clinically meaningful and similar to approved therapies in this setting,” D’Angelo told Healio.
All but one patient experienced a grade 3 or greater treatment-related adverse event. Most adverse events were hematologic in nature. Rates of serious grade 3 or greater adverse events ranged from 27% for cohort 4 to 60% for cohort 3.
One patient in cohort 2 died of cytopenia approximately 3 months after lete-cel infusion due to bone marrow failure likely related to lymphodepletion.
Twenty patients (44%) experienced cytokine release syndrome (CRS), including three patients with grade 3 CRS and one with grade 4 CRS. Median time to CRS onset was 5 days, with 90% of patients experiencing onset within 14 days.
Four patients received tocilizumab (Actemra, Genentech) to resolve CRS symptoms.
Two patients in cohort 2 developed Guillain-Barré syndrome, symptoms of which resolved after treatment with IV immunoglobulin.
There were no reports of immune effector cell-associated neurotoxicity syndrome among participants in the study.
“This therapy was found to be safe and efficacious with durable responses and survival for a subset of patients,” D’Angelo said.
Researchers continue to study lete-cel in the IGNYTE-ESO master protocol trial (NCT03967223), she added.
The phase 2 trial is designed to evaluate the efficacy and safety of lete-cel among patients with advanced synovial sarcoma before expanding to patients with other treatment-refractory solid tumors. The study will follow patients for up to 15 years after their initial lete-cel infusion.
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D’Angelo S, et al. Abstract 298. Presented at: Society for Immunotherapy of Cancer Annual Meeting (virtual); Nov. 9-14, 2020.
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