新辅助化疗和放疗后手术切除直肠是局部晚期直肠癌的标准治疗方法。一部分直肠癌是由错配修复缺陷引起的。

符合条件的患者随机按1:1分配一线氯拉替尼(100 mg每日一次)或克唑替尼(250 mg每日两次);治疗组之间不允许交叉。肿瘤评估，包括CNS磁共振成像，在筛选时进行，然后每隔8周进行一次。对患者报告的结果进行定期评估。

在基线时有脑转移瘤和无脑转移瘤的患者中，通过盲法独立中心审查得出的PFS(12个月PFS率:78%对22%和78%对45%)与氯拉替尼相比有所改善。在基线时有脑转移(7% vs 72%)和无脑转移(1% vs 18%)的患者中，洛拉替尼与克唑替尼相比，CNS进展的12个月累积发生率较低。总的来说，35%的患者使用氯拉替尼后发生中枢神经系统不良事件，大多数为1级严重程度。CNS AEs的发生并没有导致患者报告的生活质量有临床意义的差异。在分析时，56%的中枢神经系统不良事件已经解决(33%未进行干预；洛拉替尼剂量调整后17%)，38%未解决；大多数不需要干预。洛拉替尼剂量调整对PFS无明显影响。

Abstract

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, 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.

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.).

原文链接

pubmed.ncbi.nlm.nih.gov/35660797/

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