错配修复缺陷（dMMR）发生在多种癌症中，这些肿瘤是抗程序性细胞死亡1疗法的有吸引力的候选者，例如最近批准的免疫检查点抑制剂dostarlimab。 GARNET 试验是一项 1 期、开放标签、单组、多中心研究，于 2017 年 5 月 8 日开始招募。参与者患有晚期或复发性 dMMR 和微卫星不稳定性高 (MSI-H) 或聚合酶epsilon (POLE) 改变的实体瘤。本次中期分析的数据截取自 2021 年 11 月 1 日起，中位随访时间为 27.7 个月。患者每 3 周静脉注射 500 mg 多斯塔利单抗，共 4 剂，然后每 6 周接受 1000 mg，直至疾病进展、停药或主要目的是使用实体瘤反应评估标准 1.1 版，通过盲法独立中央审查来评估 dMMR 实体瘤患者的客观反应率和反应持续时间。疗效人群包括 327 名患者（中位[范围]年龄， 63 [24-85] 岁；235 [71.9%] 女性；7 [2.1%] 亚洲人，6 [1.8%] 黑人和 206 [63.0%] 白人患者），其中 141 名患者 (43.1%) 患有 dMMR 子宫内膜癌其中，105 名患者 (32.1%) 患有 dMMR 结直肠癌，81 名患者 (24.8%) 患有其他 dMMR 肿瘤类型。所有患者均至少接受过 1 种既往治疗。 dMMR 实体瘤每次盲法独立中央审查评估的客观缓解率为 44.0%（95% CI，38.6% 至 49.6%）。未达到中位缓解持续时间（范围≥1.18至≥47.21个月）； 72.2% 的响应者（144 人中的 104 人）的响应持续了 12 个月或更长时间。中位无进展生存期为 6.9 个月（95% CI，4.2 至 13.6 个月）； 24 个月无进展生存概率为 40.6%（95% CI，35.0% 至 46.1%）。未达到中位总生存期（95% CI，31.6 个月未达到）。最常见的免疫相关不良事件是甲状腺功能减退症 (25 [6.9%])、丙氨酸转氨酶升高 (21 [5.8%]) 和关节痛 (17 [4.7%])。没有发现新的安全问题。在这项非随机对照试验中，dostarlimab 是一种耐受性良好的治疗选择，对多种 dMMR 实体瘤患者具有快速、强大和持久的抗肿瘤活性。这些研究结果表明，dostarlimab 为需求未得到满足的人群提供了有意义的长期益处。ClinicalTrials.gov 标识符：NCT02715284。

Mismatch repair deficiency (dMMR) occurs in various cancers, and these tumors are attractive candidates for anti-programmed cell death 1 therapies, such as dostarlimab, a recently approved immune checkpoint inhibitor.To assess the antitumor activity and safety of dostarlimab in patients with advanced or recurrent dMMR solid tumors.The GARNET trial was a phase 1, open-label, single-group, multicenter study that began enrolling May 8, 2017. Participants had advanced or recurrent dMMR and microsatellite instability-high (MSI-H) or polymerase epsilon (POLE)-altered solid tumors. The data cut for this interim analysis was from November 1, 2021, with median follow-up of 27.7 months.Patients received 500 mg of dostarlimab intravenously every 3 weeks for 4 doses, then 1000 mg every 6 weeks until disease progression, discontinuation, or withdrawal.The primary objective was to evaluate objective response rate and duration of response in patients with dMMR solid tumors by blinded independent central review using Response Evaluation Criteria in Solid Tumors, version 1.1.The efficacy population included 327 patients (median [range] age, 63 [24-85] years; 235 [71.9%] female; 7 [2.1%] Asian, 6 [1.8%] Black, and 206 [63.0%] White patients), with 141 patients (43.1%) with dMMR endometrial cancer, 105 patients (32.1%) with dMMR colorectal cancer, and 81 patients (24.8%) with other dMMR tumor types. All patients had at least 1 previous line of therapy. Objective response rate assessed per blinded independent central review for dMMR solid tumors was 44.0% (95% CI, 38.6% to 49.6%). Median duration of response was not reached (range, ≥1.18 to ≥47.21 months); 72.2% of responders (104 of 144) had a response lasting 12 or more months. Median progression-free survival was 6.9 months (95% CI, 4.2 to 13.6 months); probability of progression-free survival at 24 months was 40.6% (95% CI, 35.0% to 46.1%). Median overall survival was not reached (95% CI, 31.6 months to not reached). The most frequent immune-related adverse events were hypothyroidism (25 [6.9%]), alanine aminotransferase increase (21 [5.8%]), and arthralgia (17 [4.7%]). No new safety concerns were identified.In this nonrandomized controlled trial, dostarlimab was a well-tolerated treatment option with rapid, robust, and durable antitumor activity in patients with diverse dMMR solid tumors. These findings suggest that dostarlimab provides meaningful long-term benefit in a population with high unmet need.ClinicalTrials.gov Identifier: NCT02715284.