PD-1 阻断在错配修复缺陷、局部晚期直肠癌中的应用。
PD-1 Blockade in Mismatch Repair-Deficient, Locally Advanced Rectal Cancer.
机构信息
From the Division of Solid Tumor Oncology (A.C., M.L., J. Sinopoli, J.W., M.L.-E., I.H.E.D., N.S., M.S., R.S., Z.S., R.Y., B.R., G.A., M.P., A.D., L.B.S., L.A.D.) and the Departments of Pathology (J. Shia), Surgery (J.J.S., M.W., E.P.P., P.P., J.G.-A., M.R.W.), Radiation Oncology (C.C., P.B.R.), Epidemiology and Biostatistics (M. Gonen), and Radiology (M. Gollub), Memorial Sloan Kettering Cancer Center, New York; and the Department of Pathology, Yale University School of Medicine, New Haven, CT (K.I., J.Z., N.G., K.A.S.).
出版信息
N Engl J Med. 2022 Jun 23;386(25):2363-2376. doi: 10.1056/NEJMoa2201445. Epub 2022 Jun 5.
BACKGROUND
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.
METHODS
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.
RESULTS
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, F-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.
CONCLUSIONS
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; ClinicalTrials.gov number, NCT04165772.).
背景
新辅助化疗和放疗后行直肠切除术是局部晚期直肠癌的标准治疗方法。一小部分直肠癌是由错配修复缺陷引起的。由于错配修复缺陷的结直肠癌在转移性疾病中对程序性死亡 1（PD-1）阻断有反应，因此假设检查点阻断在错配修复缺陷的局部晚期直肠癌患者中可能有效。
方法
我们启动了一项前瞻性 2 期研究，在局部 II 期或 III 期直肠腺癌中，每 3 周给予单药 dostarlimab（一种抗 PD-1 单克隆抗体），连续 6 个月，然后进行标准的放化疗和手术。在 dostarlimab 治疗完成后出现临床完全缓解的患者将无需进行放化疗和手术。主要终点是 dostarlimab 治疗完成后 12 个月持续临床完全缓解或 dostarlimab 治疗完成后无论是否联合放化疗的病理完全缓解以及新辅助 dostarlimab 治疗联合或不联合放化疗的总体反应。
结果
共有 12 例患者完成了 dostarlimab 治疗并接受了至少 6 个月的随访。所有 12 例患者（100%；95%置信区间，74%至 100%）均出现临床完全缓解，磁共振成像、F-氟脱氧葡萄糖正电子发射断层扫描、内镜评估、数字直肠检查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）没有报告进展或复发病例。没有报告 3 级或更高级别的不良事件。
结论
错配修复缺陷的局部晚期直肠癌对单药 PD-1 阻断高度敏感。需要更长时间的随访来评估反应持续时间。（由 Simon 和 Eve Colin 基金会等资助；ClinicalTrials.gov 编号，NCT04165772。）
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