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Targeting NY-ESO-1 and MAGE-A4 with novel adoptive cellular therapies led to responses in at least a third of patients with recurrent or metastatic synovial sarcoma, findings from two phase I studies showed.

Among 45 patients treated with letetresgene autoleucel, 33% responded to the NY-ESO-1-targeting agent, including one complete response, while another 55.5% achieved stable disease, reported Sandra D'Angelo, MD, of Memorial Sloan Kettering Cancer Center in New York City.

And in 16 patients treated with T cells targeting MAGE-A4, 44% responded and 50% achieved stable disease, according to Brian Van Tine, MD, PhD, of Washington University in St. Louis.

Results of the trials were presented at the virtual Connective Tissue Oncology Society annual meeting.

The two studies used engineered T-cell receptors specific for tumor antigens NY-ESO-1 and MAGE-A4, both of which are expressed in 70-80% of synovial sarcomas, noted session discussant Breelyn Wilky, MD, of the University of Colorado Anschutz Medical Campus in Aurora.

Patients in the studies also had to have tumors that express human leukocyte antigen (HLA)-A*02. The engineered T-cell receptors can only bind with this HLA subtype, which is expressed in about 30-40% of synovial sarcoma patients and mostly those of Caucasian race.

Wilky called engineered T cells "incredibly exciting" therapies, for the right patients with synovial sarcomas. But she tempered this enthusiasm by cautioning that identifying eligible patients is a challenge.

"In addition to selecting patients who are fit enough to tolerate therapy -- despite heavy pretreatment with chemotherapy, particularly ifosfamide -- the requirements for HLA-A*02 allele status and high target expression limits the applicability of the therapy, particularly in regions of the country or the world which have higher numbers of patients with non-Caucasian ethnic backgrounds," she said.

Ideally the ability to test synovial sarcomas for expression of these antigens would occur upfront at diagnosis, she said.

NY-ESO-1 Targeting

The phase I trial of letetresgene autoleucel, or lete-cel, enrolled patients with unresectable or metastatic synovial sarcoma into four cohorts based on NY-ESO-1 tumor expression and tested a high-dose lymphodepletion regimen using cyclophosphamide (1,800 mg/m²) plus fludarabine (30 mg/m²), cyclophosphamide alone, or the combination with a lower dose of cyclophosphamide (600 mg/m²).

Patients had a median age of 32 years (range 11-73), most were white (87%), and all had received prior systemic therapy. Three of the four cohorts included patients with high NY-ESO-1 expression (immunohistochemistry [IHC] score of 2+ or 3+ in at least 50% of tumor cells), and one cohort included patients with lower expression.

The highest response (50%) and longest overall survival (24 months) was observed in the cohort that enrolled patients with high tumor expression of NY-ESO-1 and who were treated with the more intensive lymphodepletion regimen, D'Angelo noted.

Across cohorts, responses ranged from 20-50%, with median durations of response lasting 9 to 32 weeks. Median progression-free survival (PFS) across groups ranged from 9 to 22 weeks, and overall survival ranged from 10 to 24 months. Responders tended to have higher persistence of T cells compared with non-responders.

Grade ≥3 adverse events (AEs) were reported in 98% of patients. Cytokine release syndrome (CRS) of any grade occurred in 44% (grade 3/4 in 9%). Additionally, two patients experienced serious cases of grade 3 Guillain-Barré syndrome.

"Final results from the study show that lete-cel infusion following lymphodepletion chemotherapy has persistent clinically meaningful activity with a manageable safety profile in patients with previously treated advanced synovial sarcoma," said D'Angelo. "A single lete-cel infusion resulted in deep responses that were durable in a subset of patients and showed encouraging overall survival in responding patients."

Despite the small number of patients, the response rates compare favorably to approved agents in this setting, she said.

MAGE-A4 Targeting

The study from Van Tine and colleagues tested ADP-A2M4 SPEAR T cells to target MAGE-A4 in 16 patients with advanced synovial sarcoma. Lymphodepletion consisted of cyclophosphamide (600 mg/m²) plus fludarabine (30 mg/m²).

Patients had a median age of 49 years, most were white (87.5%), and half had at least two lines of prior therapy, including ifosfamide in all patients, an anthracycline in 81%, and pazopanib (Votrient) in 44%.

Median duration of response was 28 weeks and median PFS was 20.4 weeks. Median overall survival was not reached; 67% of patients were alive at data cutoff.

Grade ≥3 AEs occurred in all patients, including lymphopenia in all patients, CRS in 88%, leukopenia in 81%, neutropenia in 81%, thrombocytopenia in 44%, anemia in 44%, and hypophosphatemia in 44%.

Additionally, serious AEs occurred in 56% of patients, which included CRS in 44%, and cases of pyrexia, pancytopenia, arrhythmia, sepsis, and a fatal case of aplastic anemia.