The U.S. Food and Drug Administration (FDA) has granted accelerated approval to afamitresgene autoleucel (afami-cel), marketed as Tecelra, for the treatment of adult patients with unresectable or metastatic synovial sarcoma who have received prior chemotherapy, are HLA-A*02:01P, -A*02:02P, -A*02:03P, or -A*02:06P positive, and whose tumors express the MAGE-A4 antigen. This decision marks a significant advancement in the treatment of this rare and aggressive cancer. Tecelra is the first T-cell receptor (TCR) T-cell therapy approved for a solid tumor, offering a new therapeutic avenue for patients with limited options. The approval was announced August 2, 2024, providing a renewed sense of hope for this patient community.
Supporting Clinical Data
The FDA's approval was based on data from cohort 1 of the phase 2 SPEARHEAD-1 trial (NCT04044768), an open-label, nonrandomized study. The trial enrolled patients aged 16 to 75 years with metastatic or unresectable synovial sarcoma or myxoid round cell liposarcoma expressing MAGE-A4. Key inclusion criteria included HLA-A*02 positivity (excluding HLA-A*02:05), prior anthracycline- or ifosfamide-containing chemotherapy, measurable disease per RECIST 1.1, and adequate organ function.
Patients underwent lymphodepletion with fludarabine and cyclophosphamide before receiving afami-cel at a target dose of 1.0 × 10^9 to 10.0 × 10^9 T cells. The primary endpoint was overall response rate (ORR) per RECIST 1.1. Results showed an ORR of 43% (95% CI: 28%-59%) per independent review assessment, with a complete response rate of 4.5%. The median duration of response (DOR) was 6 months (95% CI, 4.6-not reached), and the 12-month DOR rate was 39%.
Additional data published in The Lancet showed that the median overall survival (OS) was not reached (95% CI, 15.4-not estimable) in patients with synovial sarcoma who experienced response. The estimated 12- and 24-month OS rates for responders in this population were 90% (95% CI, 65%-99%) and 70% (95% CI, 43%-87%), respectively.
Mechanism of Action and Biomarker Testing
Afami-cel is a personalized T-cell immunotherapy. It involves harvesting a patient's T cells, genetically engineering them to express a T-cell receptor that recognizes the MAGE-A4 protein found on synovial sarcoma cells, and then infusing the modified cells back into the patient. The therapy is specifically designed for patients whose tumors express MAGE-A4 and who have specific HLA-A*02 subtypes, as MAGE-A4 is presented to immune cells via HLA proteins.
Prior to treatment with Tecelra, patients must undergo biomarker testing for HLA type and MAGE-A4 tumor expression. Adaptimmune has partnered with Agilent Technologies for the MAGE-A4 IHC 1F9 pharmDx companion diagnostic and with Thermo Fisher Scientific to expand the labeling of the SeCore™ CDx HLA-A Locus Sequencing System.
Safety Profile and Warnings
All treated patients experienced treatment-emergent adverse events (AEs), with 92% related to afami-cel. Cytokine release syndrome (CRS) occurred in 71% of patients (2% grade 3, no grade 4). The median time to onset of CRS was 2 days (IQR, 2-3), and the median time to resolution was 3 days (IQR, 2-5). Immune effector cell-associated neurotoxicity syndrome (ICANS) was rare (2% Grade 1).
The prescribing information for afami-cel includes a boxed warning for cytokine release syndrome (CRS), a potentially serious or fatal reaction of the immune system.
Synovial Sarcoma: An Unmet Need
Synovial sarcoma is a rare soft tissue sarcoma, accounting for 5-10% of all soft tissue sarcomas. Approximately 1 to 2 people per million are diagnosed each year in the United States, with one-third of patients being under 30 years old. The five-year survival rate for metastatic disease is approximately 20%. Current treatments for advanced disease often lead to recurrence, highlighting the urgent need for new therapeutic options.
Expert Commentary
Sandra D’Angelo, MD, Sarcoma Medical Oncologist and Cell Therapist at Memorial Sloan Kettering Cancer Center and the SPEARHEAD Trial Principal Investigator, stated, “TECELRA (afami-cel), which uses each patient’s own immune cells to recognize and attack their cancer cells in a one-time infusion treatment, is significantly different than the current standards of care for advanced synovial sarcoma. This approval represents a much-needed new option for people diagnosed with this sarcoma and an important milestone for the use of cell therapies in solid tumor cancers.”
Adaptimmune's Commitment
Adaptimmune is committed to advancing its clinical pipeline and plans to progress lete-cel, another investigational treatment in its sarcoma franchise, with a rolling BLA submission to the FDA next year. The company has established AdaptimmuneAssist, an integrated support program, to aid patients, caregivers, and healthcare providers throughout the Tecelra treatment journey. Adaptimmune plans to have multiple authorized treatment centers operational within the first two years to ensure access to this novel therapy.
