On August 2, 2024, the Food and Drug Administration granted accelerated approval to afamitresgene autoleucel 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 tumour expresses the MAGE-A4 antigen as determined by FDA-approved or cleared companion diagnostic devices.

Full prescribing information for afamitresgene autoleucel will be posted at 2024 Biological License Application Approvals.

Efficacy was evaluated in SPEARHEAD-1, Cohort 1, 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 tumour expressed the MAGE-A4 tumour 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 one 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 (ORR) according to RECIST v1.1 evaluated by independent review, supported by duration of response (DOR). ORR was 43.2% (95% Confidence Interval [CI]: 28.4, 59.0). The median time to response was 4.9 weeks (95% CI: 4.4 weeks, 8 weeks). The median DOR was 6 months (95% CI: 4.6, not reached). Among patients who were responsive to the 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 (CRS), which may be severe or life-threatening.

The most common nonlaboratory adverse reactions (≥ 20%) were cytokine release syndrome, nausea, vomiting, fatigue, infections, pyrexia, constipation, dyspnea, abdominal pain, non-cardiac chest pain, decreased appetite, tachycardia, back pain, hypotension, diarrhoea, and oedema. The most common grade 3 or 4 laboratory abnormalities (≥ 20%) were lymphocyte count decreased, neutrophil count decreased, white cell blood count decreased, red blood cell decreased, and platelet count decreased.

The recommended afamitresgene autoleucel dose is between 2.68 x 109 to 10 x 109 MAGE-A4 T cell receptor (TCR) 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 tumour expresses the MAGE-A4 antigen.

This review used the Assessment Aid, a voluntary submission from the applicant to facilitate the FDA’s assessment.

Source: FDA