Abstract：
BACKGROUND: S-588410, a cancer peptide vaccine (CPV), comprises five HLA-A*24:02-restricted peptides from five cancer-testis antigens. In a phase 2 study, S-588410 was well-tolerated and exhibited antitumor efficacy in patients with urothelial cancer. Therefore, we aimed to evaluate the efficacy, immune response, and safety of S-588410 in patients with completely resected esophageal squamous cell carcinoma (ESCC).
METHODS: This phase 3 study involved patients with HLA-A*24:02-positive and lymph node metastasis-positive ESCC who received neoadjuvant therapy followed by curative resection. After randomization, patients were administered S-588410 and placebo (both emulsified with Montanide™ ISA 51VG) subcutaneously. The primary endpoint was relapse-free survival (RFS). The secondary endpoints were overall survival (OS), cytotoxic T-lymphocyte (CTL) induction, and safety. Statistical significance was tested using the one-sided weighted log-rank test with the Fleming-Harrington class of weights.
RESULTS: A total of 276 patients were randomized (N = 138/group). The median RFS was 84.3 and 84.1 weeks in the S-588410 and placebo groups, respectively (P = 0.8156), whereas the median OS was 236.3 weeks and not reached, respectively (P = 0.6533). CTL induction was observed in 132/134 (98.5%) patients who received S-588410 within 12 weeks. Injection site reactions (137/140 patients [97.9%]) were the most frequent treatment-emergent adverse events in the S-588410 group. Prolonged survival was observed in S-588410-treated patients with upper thoracic ESCC, grade 3 injection-site reactions, or high CTL intensity.
CONCLUSIONS: S-588410 induced immune response and had acceptable safety but failed to reach the primary endpoint. A high CTL induction rate and intensity may be critical for prolonging survival during future CPV development.
METHODS: This phase 3 study involved patients with HLA-A*24:02-positive and lymph node metastasis-positive ESCC who received neoadjuvant therapy followed by curative resection. After randomization, patients were administered S-588410 and placebo (both emulsified with Montanide™ ISA 51VG) subcutaneously. The primary endpoint was relapse-free survival (RFS). The secondary endpoints were overall survival (OS), cytotoxic T-lymphocyte (CTL) induction, and safety. Statistical significance was tested using the one-sided weighted log-rank test with the Fleming-Harrington class of weights.
RESULTS: A total of 276 patients were randomized (N = 138/group). The median RFS was 84.3 and 84.1 weeks in the S-588410 and placebo groups, respectively (P = 0.8156), whereas the median OS was 236.3 weeks and not reached, respectively (P = 0.6533). CTL induction was observed in 132/134 (98.5%) patients who received S-588410 within 12 weeks. Injection site reactions (137/140 patients [97.9%]) were the most frequent treatment-emergent adverse events in the S-588410 group. Prolonged survival was observed in S-588410-treated patients with upper thoracic ESCC, grade 3 injection-site reactions, or high CTL intensity.
CONCLUSIONS: S-588410 induced immune response and had acceptable safety but failed to reach the primary endpoint. A high CTL induction rate and intensity may be critical for prolonging survival during future CPV development.
摘要：
背景：S-588410，一种癌症肽疫苗（CPV），包含来自五种癌-睾丸抗原的五种HLA-A*24:02限制性肽。在第二阶段的研究中，S-588410在尿路上皮癌患者中耐受性良好，并具有抗肿瘤功效。因此,我们的目的是评估疗效，免疫反应，S-588410在完全切除的食管鳞状细胞癌（ESCC）患者中的安全性。
方法：这项3期研究涉及HLA-A*24:02阳性和淋巴结转移阳性的ESCC患者，他们接受新辅助治疗，然后进行根治性切除。随机化后,患者接受S-588410和安慰剂(均用Montanide™ISA51VG乳化)皮下给药.主要终点是无复发生存期（RFS）。次要终点是总生存期（OS），细胞毒性T淋巴细胞（CTL）诱导，和安全。使用单侧加权对数秩检验和Fleming-Harrington类权重检验统计显著性。
结果：共276例患者被随机分组（N=138/组）。S-588410和安慰剂组的中位RFS分别为84.3和84.1周，分别为(P=0.8156)，而中位OS为236.3周，未达到，分别为(P=0.6533)。在12周内接受S-588410的132/134（98.5％）患者中观察到CTL诱导。注射部位反应(137/140患者[97.9%])是S-588410组中最常见的治疗引起的不良事件。在S-588410治疗的上胸段ESCC患者中观察到了延长的生存期，3级注射部位反应，或高CTL强度。
结论：S-588410可诱导免疫反应，具有可接受的安全性，但未能达到主要终点。高CTL诱导速率和强度对于在未来的CPV发展中延长存活可能是关键的。
方法：这项3期研究涉及HLA-A*24:02阳性和淋巴结转移阳性的ESCC患者，他们接受新辅助治疗，然后进行根治性切除。随机化后,患者接受S-588410和安慰剂(均用Montanide™ISA51VG乳化)皮下给药.主要终点是无复发生存期（RFS）。次要终点是总生存期（OS），细胞毒性T淋巴细胞（CTL）诱导，和安全。使用单侧加权对数秩检验和Fleming-Harrington类权重检验统计显著性。
结果：共276例患者被随机分组（N=138/组）。S-588410和安慰剂组的中位RFS分别为84.3和84.1周，分别为(P=0.8156)，而中位OS为236.3周，未达到，分别为(P=0.6533)。在12周内接受S-588410的132/134（98.5％）患者中观察到CTL诱导。注射部位反应(137/140患者[97.9%])是S-588410组中最常见的治疗引起的不良事件。在S-588410治疗的上胸段ESCC患者中观察到了延长的生存期，3级注射部位反应，或高CTL强度。
结论：S-588410可诱导免疫反应，具有可接受的安全性，但未能达到主要终点。高CTL诱导速率和强度对于在未来的CPV发展中延长存活可能是关键的。
