In a phase II trial (SPEARHEAD-1) reported in The Lancet, D’Angelo et al found that the T-cell therapy afamitresgene autoleucel showed activity in patients with previously treated HLA-A*02 and MAGE-A4–expressing advanced synovial sarcoma or myxoid round cell liposarcoma.

As related by the investigators, “[Afamitresgene autoleucel] is an autologous T-cell receptor T-cell therapy engineered to express an affinity-enhanced T-cell receptor specifically targeting a MAGE-A4 antigen presented on cells by HLA-A*02…. Affinity-optimized engineered T-cell receptors have emerged as a promising tool for application of autologous T cells to treat solid tumors.”

Study Details

In the trial, 52 patients with synovial sarcoma (n = 44) and myxoid round cell liposarcoma (n = 8) were enrolled at sarcoma specialty sites in Canada, the United States, and Europe between December 2019 and July 2021. Eligible patients had HLA-A*02, were aged 16 to 75 years, had metastatic or unresectable synovial sarcoma or myxoid round cell liposarcoma expressing MAGE-A4, and had received at least one previous line of anthracycline-containing or ifosfamide-containing chemotherapy. Patients had received a median of three prior therapies. Patients received a single intravenous dose of afamitresgene autoleucel 1.0 × 10⁹ to 10.0 × 10⁹ T cells after lymphodepletion. The primary endpoint of the trial was overall response rate on masked independent review committee assessment.

Responses

Median follow-up was 32.6 months. Among all 52 patients, objective responses (all partial) were observed in 19 (37%, 95% confidence interval [CI] = 24%–51%); since the lower limit of the 95% confidence interval was greater than the prespecified null hypothesis rate of 18%, the trial met the predefined criterion for demonstration of efficacy.

Objective response was observed in 17 (39%, 95% CI = 24%–55%) of 44 patients with synovial sarcoma; median response duration was 11.6 months (95% CI = 4.4–18.0 months). Objective response was observed in two (25%, 95% CI =3%–65%) of eight patients with myxoid round cell liposarcoma; median response duration was 4.2 months (95% CI = 2.9–5.5 months).

Median progression-free survival was 3.7 months (95% CI = 2.8–5.6 months) among all patients, 3.8 months (95% CI = 2.8–6.4 months) among those with synovial sarcoma, and 2.4 months (95% CI = 0.9–7.4 months) among those with myxoid round cell liposarcoma. Postprogression, 45% of the patients with synovial sarcoma started additional systemic therapy. Median overall survival was 15.4 months (95% CI = 10.9–28.7 moths) in the total population, with a 12-momth rate of 60%. Among patients in the synovial sarcoma group with objective response, median overall survival was not reached (95% CI = 15.4 months to not reached), with rates at 12 and 24 months of 90% and 70%.

Adverse Events

The most common grade 3 or 4 adverse events related to afamitresgene autoleucel among all patients were cytopenias, including leukopenia (25%), decreased neutrophils (22%), and lymphopenia (18%). Cytokine-release syndrome occurred in 71% of patients (grade 3 in 1 patient). Immune effector cell–associated neurotoxicity syndrome occurred in one patient (grade 1). Serious adverse events occurred in 10% of patients. No treatment-related deaths were observed.

The investigators concluded, “Afamitresgene autoleucel treatment resulted in durable responses in heavily pretreated patients with HLA-A*02 and MAGE-A4–expressing synovial sarcoma. This study shows that T-cell receptor therapy can be used to effectively target solid tumors and provides rationale to expand this approach to other solid malignancies.”

Sandra P. D’Angelo, MD, of Memorial Sloan Kettering Cancer Center, is the corresponding author for The Lancet article.

Disclosure: The study was funded by Adaptimmune. For full disclosures of the study authors, visit thelancet.com.