PD-1 Blockade in Mismatch Repair-Deficient, Locally Advanced Rectal Cancer.
PD-1 Blockade in Mismatch Repair-Deficient, Locally Advanced Rectal Cancer.
复制标题
DOI：
10.1056/nejmoa2201445
复制
发表时间：
2022-06-23
期刊：
影响因子：
--
通讯作者：
中科院分区：
文献类型：
--
作者：
新辅助化疗和放疗后手术切除直肠是局部进展期直肠癌的标准治疗方法。直肠癌的一个亚型是由错配修复不足引起的。由于错配修复缺陷的结直肠癌在转移疾病的背景下对程序性死亡1(PD-1)的阻断有反应，因此假设检查点阻断对于错配修复缺陷的局部进展期直肠癌患者可能是有效的。我们启动了一项前瞻性的2期研究，在这项研究中，一种抗PD-1的单抗多斯塔利马在错配修复缺陷II期或III期直肠腺癌患者中每隔3周给予一次，为期6个月。这种治疗之后是标准的放化疗和手术。在完成多司他利单抗治疗后临床完全缓解的患者将继续进行，而不进行放化疗和手术。主要终点是在多斯塔利姆单抗治疗完成12个月后持续的临床完全反应，或在多斯塔利姆单抗治疗完成后的病理完全反应，以及对新辅助多斯塔利姆单抗治疗加或不加放化疗的总体反应。共有12名患者完成了多斯塔利马的治疗，并进行了至少6个月的随访。所有12名患者(100%；95%可信区间，74~100)临床完全缓解，磁共振成像、18F-脱氧葡萄糖正电子发射断层扫描、内窥镜检查、直肠指检或活检均未发现肿瘤。在本报告时，没有患者接受放化疗或手术，在随访期间(6至25个月)也没有进展或复发的病例报告。没有3级或更高级别的不良事件的报告。错配修复缺陷的局部进展期直肠癌对单一药物PD-1阻断高度敏感。需要更长的随访时间来评估反应的持续时间。(由西蒙和伊芙·科林基金会等资助；临床试验编号，NCT04165772。)
Neoadjuvant chemotherapy and radiation followed by surgical resection of the rectum is a standard treatment for locally advanced rectal cancer. A subset of rectal cancer is caused by a deficiency in mismatch repair. Because mismatch repair–deficient colorectal cancer is responsive to programmed death 1 (PD-1) blockade in the context of metastatic disease, it was hypothesized that checkpoint blockade could be effective in patients with mismatch repair–deficient, locally advanced rectal cancer. We initiated a prospective phase 2 study in which single-agent dostarlimab, an anti–PD-1 monoclonal antibody, was administered every 3 weeks for 6 months in patients with mismatch repair–deficient stage II or III rectal adenocarcinoma. This treatment was to be followed by standard chemoradiotherapy and surgery. Patients who had a clinical complete response after completion of dostarlimab therapy would proceed without chemoradiotherapy and surgery. The primary end points are sustained clinical complete response 12 months after completion of dostarlimab therapy or pathological complete response after completion of dostarlimab therapy with or without chemoradiotherapy and overall response to neoadjuvant dostarlimab therapy with or without chemoradiotherapy. A total of 12 patients have completed treatment with dostarlimab and have undergone at least 6 months of follow-up. All 12 patients (100%; 95% confidence interval, 74 to 100) had a clinical complete response, with no evidence of tumor on magnetic resonance imaging, 18F-fluorodeoxyglucose–positron-emission tomography, endoscopic evaluation, digital rectal examination, or biopsy. At the time of this report, no patients had received chemoradiotherapy or undergone surgery, and no cases of progression or recurrence had been reported during follow-up (range, 6 to 25 months). No adverse events of grade 3 or higher have been reported. Mismatch repair–deficient, locally advanced rectal cancer was highly sensitive to single-agent PD-1 blockade. Longer follow-up is needed to assess the duration of response. (Funded by the Simon and Eve Colin Foundation and others; Clinical-Trials.gov number, NCT04165772.)