[摘 要]：
BACKGROUND:Afamitresgene autoleucel (afami-cel) showed acceptable safety and promising efficacy in a phase 1 trial (NCT03132922). The aim of this study was to further evaluate the efficacy of afami-cel for the treatment of patients with HLA-A*02 and MAGE-A4-expressing advanced synovial sarcoma or myxoid round cell liposarcoma.METHODS:SPEARHEAD-1 was an open-label， non-randomised， phase 2 trial done across 23 sites in Canada， the USA， and Europe. The trial included three cohorts， of which the main investigational cohort (cohort 1)......更多
BACKGROUND:Afamitresgene autoleucel (afami-cel) showed acceptable safety and promising efficacy in a phase 1 trial (NCT03132922). The aim of this study was to further evaluate the efficacy of afami-cel for the treatment of patients with HLA-A*02 and MAGE-A4-expressing advanced synovial sarcoma or myxoid round cell liposarcoma.
METHODS:SPEARHEAD-1 was an open-label， non-randomised， phase 2 trial done across 23 sites in Canada， the USA， and Europe. The trial included three cohorts， of which the main investigational cohort (cohort 1) is reported here. Cohort 1 included patients with HLA-A*02， aged 16-75 years， with metastatic or unresectable synovial sarcoma or myxoid round cell liposarcoma (confirmed by cytogenetics) expressing MAGE-A4， and who had received at least one previous line of anthracycline-containing or ifosfamide-containing chemotherapy. Patients received a single intravenous dose of afami-cel (transduced dose range 1·0 × 109-10·0 × 109 T cells) after lymphodepletion. The primary endpoint was overall response rate in cohort 1， assessed by a masked independent review committee using Response Evaluation Criteria in Solid Tumours (version 1.1) in the modified intention-to-treat population (all patients who received afami-cel). Adverse events， including those of special interest (cytokine release syndrome， prolonged cytopenia， and neurotoxicity)， were monitored and are reported for the modified intention-to-treat population. This trial is registered at ClinicalTrials.gov， NCT04044768; recruitment is closed and follow-up is ongoing for cohorts 1 and 2， and recruitment is open for cohort 3.
FINDINGS:Between Dec 17， 2019， and July 27， 2021， 52 patients with cytogenetically confirmed synovial sarcoma (n=44) and myxoid round cell liposarcoma (n=8) were enrolled and received afami-cel in cohort 1. Patients were heavily pre-treated (median three [IQR two to four] previous lines of systemic therapy). Median follow-up time was 32·6 months (IQR 29·4-36·1). Overall response rate was 37% (19 of 52; 95% CI 24-51) overall， 39% (17 of 44; 24-55) for patients with synovial sarcoma， and 25% (two of eight; 3-65) for patients with myxoid round cell liposarcoma. Cytokine release syndrome occurred in 37 (71%) of 52 of patients (one grade 3 event). Cytopenias were the most common grade 3 or worse adverse events (lymphopenia in 50 [96%]， neutropenia 44 [85%]， leukopenia 42 [81%] of 52 patients). No treatment-related deaths occurred.
INTERPRETATION:Afami-cel treatment resulted in durable responses in heavily pre-treated 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 tumours and provides rationale to expand this approach to other solid malignancies.
FUNDING:Adaptimmune.
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