On August 2, the U.S. Food and Drug Administration (FDA) granted accelerated approval to afamitresgene autoleucel (Tecelra), 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.
SPEARHEAD-1
Efficacy was evaluated in cohort 1 of the SPEARHEAD-1 study (ClinicalTrials.gov identifier NCT04044768), a multicenter, single-arm, open-label clinical trial that enrolled HLA-A*02:01-03 and 06 allele–positive patients 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.
Fifty-two patients with synovial sarcoma were enrolled and underwent leukapheresis, eight of whom did not receive afamitresgene autoleucel due to death (n = 3), loss of eligibility prior to lymphodepleting chemotherapy (n = 3), withdrawal by patient (n = 1), and investigator decision (n = 1). Forty-five patients received lymphodepletion and 1 patient withdrew consent before treatment, for a total of 44 patients who received a single infusion of afamitresgene autoleucel.
The main efficacy outcome measure was overall response rate according to Response Evaluation Criteria in Solid Tumors version 1.1 evaluated by independent review, supported by duration of response. The overall response rate was 43.2% (95% confidence interval [CI] = 28.4%–59.0%). The median time to response was 4.9 weeks (95% CI = 4.4–8 weeks). The median duration of response was 6 months (95% CI = 4.6 months to not reached). Among patients who were responsive to treatment, 45.6% and 39.0% had a duration of response greater than or equal to 6 months and 12 months, respectively.
The prescribing information includes a Boxed Warning for serious or fatal cytokine-release syndrome, which may be severe or life-threatening.
The most common nonlaboratory adverse reactions (occurring in ≥ 20% of patients who received afamitresgene autoleucel) were cytokine-release syndrome, nausea, vomiting, fatigue, infections, pyrexia, constipation, dyspnea, abdominal pain, noncardiac chest pain, decreased appetite, tachycardia, back pain, hypotension, diarrhea, and edema. The most common grade 3 or 4 laboratory abnormalities (in ≥ 20% of patients) were decreased lymphocyte count, neutrophil count, white cell blood count, red blood cell count, and/or platelet count.
The recommended afamitresgene autoleucel dose 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.
This application is approved under the accelerated approval pathway. To verify the clinical benefit of afamitresgene autoleucel, the FDA and the sponsor agreed upon a postmarketing requirement for an ongoing study in 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.
This review used the Assessment Aid, a voluntary submission from the applicant to facilitate the FDA’s assessment.
This application was granted Regenerative Medicine Advanced Therapy, Priority Review, and Orphan Drug designation.
