Afamitresgene Autoleucel Granted Accelerated Approval as First Gene Therapy for Synovial Sarcoma
Expert Perspectives · Lyn Brook · 2024-08-05
The FDA has granted accelerated approval to afamitresgene autoleucel (Teclera®, Adaptimmune, LLC), a melanoma-associated antigen A4 (MAGE-A4)–directed genetically modified autologous T-cell immunotherapy, for adults 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 tumor expresses the MAGE-A4 antigen as determined by FDA-approved or -cleared companion diagnostic devices.
This is the first approval of a gene therapy to treat adult patients with metastatic synovial sarcoma.
Why it matters: “Synovial sarcoma is rare subtype of soft tissue sarcoma in desperate need of novel therapeutic approaches,” wrote Richard Riedel, MD, Oncology Data Advisor Editorial Board Member and Associate Professor in the Division of Medical Oncology at Duke University Medical Center regarding the SPEARHEAD-1 trial (NCT04044768), on which approval was based. “The accelerated approval of afamitresgene autoleucel represents a significant step forward for patients with advanced disease who otherwise have very limited systemic therapy options.”
What they studied: Efficacy was measured in the phase 2, single-arm, open-label trial which enrolled patients who were HLA-A*02:01-03 and 06 allele–positive with inoperable or metastatic synovial sarcoma who had received prior systemic therapy with either doxorubicin and/or ifosfamide and whose tumor expressed the MAGE-A4 tumor antigen. Patients received lymphodepleting chemotherapy with fludarabine and cyclophosphamide.
Of the 52 patients who were enrolled and underwent leukapheresis, eight did not receive afamitresgene autoleucel; three due to death, three due to loss of eligibility prior to lymphodepleting chemotherapy, one due to withdrawal, one due to investigator’s decision, and one who withdrew consent before treatment began. A total of 44 patients received a single infusion of afamitresgene autoleucel.
The primary efficacy end point measured was overall response rate according to RECIST v1.1, evaluated by independent review and supported by duration of response.
What they found: The overall response rate was 43.2%, with a median duration of response of six months and a median time to response of 4.9 weeks. Among those who were responsive to treatment, 45.6% had a duration of response greater than six months and 39.0% had a duration of response greater than 12 months.
Adverse events: The most common nonlaboratory adverse events experienced by ≥20% of patients receiving afamitresgene autoleucel were cytokine release syndrome, nausea, vomiting, fatigue, infections, pyrexia, constipation, dyspnea, abdominal pain, non-cardiac chest pain, decreased appetite, tachycardia, back pain, hypotension, diarrhea, and edema. The most common grade 3 or 4 laboratory abnormalities experienced by ≥20% of patients were lymphocyte count decreased, neutrophil count decreased, white cell blood count decreased, red blood cell decreased, and platelet count decreased.
The prescribing information includes a Boxed Warning for cytokine release syndrome (CRS), which was observed following administration of afamitresgene autoleucel in clinical trials. Patients should also be monitored for immune effector cell–associated neurotoxicity syndrome (ICANS) and should be advised not to drive or engage in hazardous occupations or activities for at least four weeks after receiving afamitresgene autoleucel.
Conclusion: “With an observed overall response rate greater than 40%, it is clear that cellular approaches targeting tumor-specific antigens, in this case MAGE-A4, have shown themselves to be a viable therapeutic option in this rare disease,” concluded Dr. Riedel. “The logistics associated with the preparation and administration of this autologous engineered T-cell receptor product will require a multidisciplinary team of individuals from apheresis, pharmacy, cell therapy, and medical oncology working together to optimize care for patients.”
Instructions: The recommended dosage of afamitresgene autoleucel is between 2.68×109 to 10×109 MAGE-A4 T-cell receptor–positive T cells, administered in one or more infusion bags. Do not use a leukodepleting filter or prophylactic systemic corticosteroids.