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[🔔综述] 错配修复缺陷肿瘤的非手术管理

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三叶草 发表于 4 天前 | 显示全部楼层 |阅读模式
SCI
15 May 2025

Nonoperative Management of Mismatch Repair–Deficient Tumors
(The New England Journal of Medicine, IF: 96.3)
  • A. Cercek, M.B. Foote, B. Rousseau, J.J. Smith, J. Shia, J. Sinopoli, J. Weiss, M. Lumish, L. Temple, M. Patel, C. Wilde, L.B. Saltz, G. Argiles, Z. Stadler, O. Artz, S. Maron, G. Ku, P. Gu, Y.Y. Janjigian, D. Molena, G. Iyer, J. Coleman, W. Abida, S. Cohen, K. Soares, M. Schattner, V.E. Strong, R. Yaeger, P. Paty, M. Shcherba, R. Sugarman, P.B. Romesser, A. Zervoudakis, A. Desai, N.H. Segal, I. El Dika, M. Widmar, I. Wei, E. Pappou, G. Fumo, S. Aparo, M. Gonen, M. Gollub, V.S. Jayaprakasham, T.-H. Kim, J. Garcia Aguilar, M. Weiser, and L.A. Diaz, Jr.
  • CORRESPONDENCE TO: diaz15@mskcc.org

BACKGROUND 背景

Among patients with mismatch repair–deficient (dMMR), locally advanced rectal cancer, neoadjuvant checkpoint blockade eliminated the need for surgery in a high proportion of patients. Whether this approach can be extended to all early-stage dMMR solid tumors, regardless of tumor site, is unknown.

在患有错配修复缺陷(dMMR)局部晚期直肠癌的患者中,新辅助检查点抑制治疗在很大比例的患者中消除了手术的需要。目前尚不清楚这种治疗方法是否可以推广到所有早期dMMR实体瘤患者,不论肿瘤部位如何


METHODS 方法

We conducted a phase 2 study in which patients with stage I, II, or III dMMR solid tumors that were amenable to curative-intent surgery were treated with neoadjuvant dostarlimab, a programmed cell death 1 (PD-1) blocking agent, for 6 months. The response to treatment was assessed in two cohorts: patients in cohort 1 had dMMR, locally advanced rectal cancer, and patients in cohort 2 had dMMR nonrectal solid tumors. Patients with a clinical complete response could elect to proceed with nonoperative management; those with residual disease were to undergo resection. In this analysis, the primary end point, assessed in cohort 1, was a sustained clinical complete response at 12 months. Recurrence-free survival and safety were evaluated.

我们开展了一项Ⅱ期临床研究,纳入了患有Ⅰ期、Ⅱ期或Ⅲ期dMMR实体瘤、且可接受根治性手术的患者。这些患者接受了为期6个月的程序性细胞死亡蛋白1(PD-1)抑制剂 dostarlimab 的新辅助治疗。在两个队列中评估治疗反应:队列1为局部晚期dMMR直肠癌患者,队列2为非直肠部位的dMMR实体瘤患者。在治疗后有临床完全缓解的患者,可选择非手术管理;对于残余病灶的患者,可计划进行切除手术。本次分析中,主要终点为队列1患者在治疗后12个月是否维持临床完全缓解;同时评估了无复发生存期和安全性。


RESULTS 结果

A total of 117 patients were included in the analysis. In cohort 1, all 49 patients who completed treatment had a clinical complete response and elected to proceed with nonoperative management. A total of 37 patients had a sustained clinical complete response at 12 months, a finding that met the criterion for efficacy. In cohort 2, a total of 35 of 54 patients who completed treatment had a clinical complete response, and 33 elected to proceed with nonoperative management. Among the 103 patients who completed treatment across both cohorts, 84 had a clinical complete response, and 82 did not undergo surgery. Among the 117 total patients, recurrence-free survival at 2 years was 92% (95% confidence interval, 86 to 99); the median follow-up for recurrence was 20.0 months (range, 0 to 60.8). The majority of patients (95%) had reversible, grade 1 or 2 adverse events (60%) or had no adverse events (35%). The option for curative resection was not compromised during or after treatment in any of the patients.

共有117名患者纳入分析。在队列1中,49名完成治疗的患者全部实现了临床完全缓解,并选择了非手术管理。在这些患者中,有37人在12个月时维持了临床完全缓解,达到了疗效评估标准。在队列2中,54名完成治疗的患者中有35名获得了临床完全缓解,其中33人选择了非手术管理。在两个队列共103名完成治疗的患者中,有84人获得了临床完全缓解,82人未接受手术治疗。在117名总患者中,2年无复发生存率为92%(95%置信区间:86–99);中位随访时间为20.0个月(范围:0–60.8个月)。大多数患者(95%)仅出现1级或2级的可逆性不良事件(60%),或未发生不良事件(35%)。在任何患者中,治疗期间或之后均未影响其接受根治性手术的可行性。


CONCLUSIONS 结论

Among patients with early-stage dMMR solid tumors that were amenable to curativeintent surgery, neoadjuvant PD-1 blockade led to organ preservation in a high proportion of patients.

对于那些患有早期、可接受根治性手术的dMMR实体瘤的患者,PD-1抑制剂的新辅助治疗在很大比例的患者中实现了器官保留。


AI解读

研究背景

错配修复缺陷(dMMR)的肿瘤对免疫检查点阻断(如PD-1抑制剂)高度敏感。尽管在转移性dMMR肿瘤中已证实其疗效,但能否通过新辅助免疫治疗避免早期dMMR实体瘤的手术尚不明确。本研究旨在探索PD-1抑制剂(dostarlimab)作为新辅助治疗,使患者免于手术的可能性。

研究方法

- 研究设计:单臂II期临床试验,分为两个队列:  

  - 队列1:49例局部晚期dMMR直肠癌患者。  

  - 队列2:67例其他非直肠dMMR实体瘤患者(如胃、结肠、泌尿生殖系统等)。  

- 治疗方案:患者接受6个月dostarlimab(每3周500 mg静脉注射)。  

- 评估标准:  

  - 主要终点:队列1的12个月持续临床完全缓解率(cCR)。  

  - 次要终点:无复发生存率(RFS)、安全性、ctDNA动态监测。  

- 非手术管理条件:影像学/内镜确认完全缓解的患者可选择不手术;未缓解者接受标准治疗或手术。

关键结果

1. 临床缓解率:  

  - 队列1(直肠癌):所有49例完成治疗的患者均达到cCR,其中37例(76%)维持12个月cCR。  

  - 队列2(非直肠肿瘤):35/54例(65%)达到cCR,33例选择非手术治疗。  

  - 总体:84/103例(82%)患者避免了手术。  

2. 复发与生存:  

  - 总人群2年RFS:92%(中位随访20个月)。  

  - 仅5例复发(4例淋巴结复发,1例原发部位复发),其中3例通过重启PD-1治疗再次缓解。  

3. 安全性:  

  - 95%患者仅出现1-2级可逆不良反应(如疲劳、皮疹),严重不良事件罕见。  

4. ctDNA监测:  

  - cCR患者ctDNA在治疗期间快速清除,未缓解者ctDNA持续阳性。  

  - ctDNA与活检结果高度一致(Kappa=0.76),可作为动态监测工具。

结论与意义

- 核心发现:新辅助PD-1阻断可使大部分早期dMMR实体瘤患者免于手术,器官功能得以保留,且未增加复发风险。  

- 临床意义:  

  - 为手术可能致残或影响生活质量的肿瘤(如直肠、膀胱癌)提供非手术选择。  

  - ctDNA动态监测为疗效评估提供了高灵敏度的新方法。  

- 局限性:  

  - 样本量较小,非直肠肿瘤随访时间较短(中位14.9个月)。  

  - 需更大规模随机试验验证长期生存获益(尤其是非直肠肿瘤)。  

未来方向

- 探索联合免疫治疗或延长疗程以提高非直肠肿瘤的cCR率。  

- 开展随机对照试验,比较PD-1阻断与标准手术的生存结局。  

- 优化ctDNA检测技术,推动其在临床实践中的标准化应用。  

研究价值:为早期dMMR实体瘤的治疗模式提供了变革性思路,可能改变传统手术主导的临床实践。


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