FDA Grants Accelerated Approval to Afamitresgene Autoleucel for Unresectable or Metastatic Synovial Sarcoma

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 or ifosfamide and whose tumors express the MAGE-A4 tumor antigen. Patients received lymphodepleting chemotherapy with fludarabine and cyclophosphamide.

Fifty-two patients with synovial sarcoma were enrolled and underwent leukapheresis. Of those, 8 did not receive afamitresgene autoleucel because of 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% 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, which may be severe or life-threatening.

The most common nonlaboratory adverse reactions reported in at least 20% of the patients in the drug’s clinical trial 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 reported in at least 20% of patients in the clinical trial were decreased lymphocyte, neutrophil, white blood cell, red blood cell, and platelet counts.

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

The FDA approved the application under the accelerated approval pathway. To verify the clinical benefit of afamitresgene autoleucel, the FDA and the sponsor agreed on 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.

The applicant used the Assessment Aid to facilitate the FDA’s review. The FDA granted the application regenerative medicine advanced therapy, priority review, and orphan drug designation. FDA’s expedited programs are described in the Guidance for Industry: Expedited Programs for Serious Conditions—Drugs and Biologics.

Healthcare professionals should report all serious adverse events suspected to be associated with the use of any medicine and device to FDA’s MedWatch Reporting System or by calling 800-FDA-1088.

For assistance with single-patient applications for investigational oncology products regulated by the Center for Biologics Evaluation and Research, healthcare professionals may email OTPRPMS@fda.hhs.gov.