Purpose We evaluated the combination of talimogene laherparepvec plus ipilimumab versus ipilimumab alone in patients with advanced melanoma in a phase II study. To our knowledge, this was the first randomized trial to evaluate addition of an oncolytic virus to a checkpoint inhibitor. Methods Patients with unresectable stages IIIB to IV melanoma, with no more than one prior therapy if BRAF wild-type, no more than two prior therapies if BRAF mutant, measurable/injectable disease, and without symptomatic autoimmunity or clinically significant immunosuppression were randomly assigned 1:1 to receive talimogene laherparepvec plus ipilimumab or ipilimumab alone. Talimogene laherparepvec treatment began in week 1 (first dose, ≤ 4 mL × 106 plaque-forming units/mL; after 3 weeks, ≤ 4 mL × 108 plaque-forming units/mL every 2 weeks). Ipilimumab (3 mg/kg every 3 weeks; up to four doses) began week 1 in the ipilimumab alone arm and week 6 in the combination arm. The primary end point was objective response rate evaluated by investigators per immune-related response criteria. Results One hundred ninety-eight patients were randomly assigned to talimogene laherparepvec plus ipilimumab (n = 98), or ipilimumab alone (n = 100). Thirty-eight patients (39%) in the combination arm and 18 patients (18%) in the ipilimumab arm had an objective response (odds ratio, 2.9; 95% CI, 1.5 to 5.5; P = .002). Responses were not limited to injected lesions; visceral lesion decreases were observed in 52% of patients in the combination arm and 23% of patients in the ipilimumab arm. Frequently occurring adverse events (AEs) included fatigue (combination, 59%; ipilimumab alone, 42%), chills (combination, 53%; ipilimumab alone, 3%), and diarrhea (combination, 42%; ipilimumab alone, 35%). Incidence of grade ≥ 3 AEs was 45% and 35%, respectively. Three patients in the combination arm had fatal AEs; none were treatment related. Conclusion The study met its primary end point; the objective response rate was significantly higher with talimogene laherparepvec plus ipilimumab versus ipilimumab alone. These data indicate that the combination has greater antitumor activity without additional safety concerns versus ipilimumab.

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评估 Talimogene Laherparepvec 联合 Ipilimumab 与单独使用 Ipilimumab 治疗晚期、不可切除黑色素瘤患者的疗效和安全性的随机、开放标签 II 期研究

目的 我们在一项 II 期研究中评估了 talimogene laherparepvec 加伊匹单抗与单独伊匹单抗治疗晚期黑色素瘤患者的组合。据我们所知，这是第一次评估在检查点抑制剂中添加溶瘤病毒的随机试验。方法 不可切除的 IIIB 至 IV 期黑色素瘤患者，如果 BRAF 野生型，既往治疗不超过一种，如果 BRAF 突变，可测量/可注射疾病，并且没有症状性自身免疫病或临床上显着的免疫抑制，患者被随机分配 1 :1 接受talimogene laherparepvec 加ipilimumab 或单独ipilimumab。Talimogene laherparepvec 治疗在第 1 周开始（首剂，≤ 4 mL × 106 斑块形成​​单位/mL；3 周后，每 2 周≤ 4 mL × 108 斑块形成​​单位/mL）。Ipilimumab（每 3 周 3 mg/kg；最多四剂）在 ipilimumab 单药组第 1 周开始，在联合组第 6 周开始。主要终点是研究人员根据免疫相关反应标准评估的客观反应率。结果 198 名患者被随机分配到 talimogene laherparepvec 加易普利姆玛（n = 98）或单独易普利姆玛（n = 100）。联合组 38 名患者 (39%) 和易普利姆玛组 18 名患者 (18%) 有客观反应（优势比，2.9；95% CI，1.5 至 5.5；P = .002）。反应不仅限于注射病变；在联合组 52% 的患者和 ipilimumab 组 23% 的患者中观察到内脏病变减少。经常发生的不良事件 (AE) 包括疲劳（联合用药，59%；单独使用易普利姆玛，42%）、寒战（联合用药，53%；单独使用易普利姆玛，3%）和腹泻（联合使用，42%；单独使用易普利姆玛，35%）。≥ 3 级 AE 的发生率分别为 45% 和 35%。联合组中的三名患者有致命的 AE；没有一个是治疗相关的。结论 该研究达到了主要终点；与单独使用 ipilimumab 相比，talimogene laherparepvec 加 ipilimumab 的客观缓解率显着更高。这些数据表明，与 ipilimumab 相比，该组合具有更高的抗肿瘤活性，而没有额外的安全问题。与单独使用 ipilimumab 相比，talimogene laherparepvec 加 ipilimumab 的客观缓解率显着更高。这些数据表明，与 ipilimumab 相比，该组合具有更高的抗肿瘤活性，而没有额外的安全问题。与单独使用 ipilimumab 相比，talimogene laherparepvec 加 ipilimumab 的客观缓解率显着更高。这些数据表明，与 ipilimumab 相比，该组合具有更高的抗肿瘤活性，而没有额外的安全问题。