FDA Approval Summary: Afamitresgene Autoleucel for Adults with HLA-Restricted, MAGE-A4–Positive Unresectable or Metastatic Synovial Sarcoma after Prior Chemotherapy

On August 1, 2024, the FDA granted accelerated approval to afamitresgene autoleucel, a melanoma-associated antigen A4 (MAGE-A4)-directed genetically modified autologous T-cell immunotherapy, for the treatment of adults with unresectable or metastatic synovial sarcoma who have received prior chemotherapy, who are HLA-A*02:01P, -A*02:02P, -A*02:03P, or -A*02:06P positive, and whose tumors express MAGE-A4 as determined by FDA-approved or cleared companion diagnostic devices. Approval was based on results from the phase II, single-arm, open-label, multicenter Study ADP-0044-002. Patients received a single dose of afamitresgene autoleucel following lymphodepleting chemotherapy. Of the 44 efficacy-evaluable patients, the overall response rate was 43.2% (95% confidence interval, 28.4-59.0), with complete response in two patients (4.5%). The median duration of response was 6.0 months (95% confidence interval, 4.6-not reached) with a median follow-up of 21.9 months. Among the 44 patients, cytokine release syndrome occurred in 75% (grade ≥3, 2%), warranting a boxed warning. Grade ≥3 infections occurred in 14% of patients, and prolonged severe cytopenias also occurred. One patient developed grade 1 immune effector cell-associated neurotoxicity, and one patient developed Epstein-Barr virus-positive lymphoproliferative disease. Notably, during review of this application, the FDA identified issues with data quality and study conduct that prompted an independent re-review of imaging assessments. The results of the re-review were the basis for the FDA's determination of substantial evidence of effectiveness. This represents the first FDA approval of a T-cell receptor gene therapy. It is also the first FDA approval specifically for synovial sarcoma, representing a new treatment modality for this rare population that lacks effective therapies.