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Abstract：
BACKGROUND: Patients with DNA mismatch repair-proficient/microsatellite stable (pMMR/MSS) colorectal cancer (CRC), which accounts for 85% of all CRC cases, display a poor respond to immune checkpoint inhibitors (i.e., anti-PD-1 antibodies). pMMR/MSS CRC patients with locally advanced cancers need effective combined therapies.
METHODS: In this pilot study, we administered six preoperative doses of each 2-week cycle of the anti-PD-1 antibody sintilimab (at a fixed dose of 200 mg), oxaliplatin, and 5-FU/CF (mFOLFOX6) combined with five doses of bevacizumab (the number of doses was reduced to prevent surgical delays) to patients with cT4NxM0 colon or upper rectal cancers. And radical surgery was performed approximately 2 weeks after the last dose of neoadjuvant therapy. The primary endpoint was a pathologic complete response (pCR). We also evaluated major pathologic response (MPR, ≤10% residual viable tumor), radiological and pathological regression, safety, and tumor mutation burden (TMB), and tumor microenvironment (TME) characteristics.
RESULTS: By the cutoff date (September 2023), 22 patients with cT4NxM0 pMMR/MSS colon or upper rectal cancers were enrolled and the median follow-up was 24.7 months (IQR: 21.1-26.1). All patients underwent R0 surgical resection without treatment-related surgical delays. pCR occurred in 12 of 22 resected tumors (54.5%) and MPR occurred in 18 of 22 (81.8%) patients. At the cutoff date, all patients were alive, and 21/22 were recurrence-free. Treatment-related adverse events of grade 3 or higher occurred in of 2/22 (9.1%) patients. Among the pCR tumors, two were found to harbor POLE mutations. The degree of pathological regression was significantly greater than that of radiological regression (p = 1.35 × 10-8). The number of CD3+/CD4+ cells in the tumor and stroma in pretreated biopsied tissues was markedly lower in pCR tumors than in non-pCR tumors (p = 0.038 and p = 0.015, respectively).
CONCLUSIONS: Neoadjuvant sintilimab combined with bevacizumab and mFOLFOX6 was associated with few side effects, did not delay surgery, and led to pCR and non-pCR in 54.5% and 81.8% of the cases, respectively. Downregulation of CD3/CD4 expression in the tumor and stroma is related to pCR. However, the molecular mechanisms underlying PD-1 blockade-enhanced targeted chemotherapy require further investigation.
METHODS: In this pilot study, we administered six preoperative doses of each 2-week cycle of the anti-PD-1 antibody sintilimab (at a fixed dose of 200 mg), oxaliplatin, and 5-FU/CF (mFOLFOX6) combined with five doses of bevacizumab (the number of doses was reduced to prevent surgical delays) to patients with cT4NxM0 colon or upper rectal cancers. And radical surgery was performed approximately 2 weeks after the last dose of neoadjuvant therapy. The primary endpoint was a pathologic complete response (pCR). We also evaluated major pathologic response (MPR, ≤10% residual viable tumor), radiological and pathological regression, safety, and tumor mutation burden (TMB), and tumor microenvironment (TME) characteristics.
RESULTS: By the cutoff date (September 2023), 22 patients with cT4NxM0 pMMR/MSS colon or upper rectal cancers were enrolled and the median follow-up was 24.7 months (IQR: 21.1-26.1). All patients underwent R0 surgical resection without treatment-related surgical delays. pCR occurred in 12 of 22 resected tumors (54.5%) and MPR occurred in 18 of 22 (81.8%) patients. At the cutoff date, all patients were alive, and 21/22 were recurrence-free. Treatment-related adverse events of grade 3 or higher occurred in of 2/22 (9.1%) patients. Among the pCR tumors, two were found to harbor POLE mutations. The degree of pathological regression was significantly greater than that of radiological regression (p = 1.35 × 10-8). The number of CD3+/CD4+ cells in the tumor and stroma in pretreated biopsied tissues was markedly lower in pCR tumors than in non-pCR tumors (p = 0.038 and p = 0.015, respectively).
CONCLUSIONS: Neoadjuvant sintilimab combined with bevacizumab and mFOLFOX6 was associated with few side effects, did not delay surgery, and led to pCR and non-pCR in 54.5% and 81.8% of the cases, respectively. Downregulation of CD3/CD4 expression in the tumor and stroma is related to pCR. However, the molecular mechanisms underlying PD-1 blockade-enhanced targeted chemotherapy require further investigation.
摘要：
背景：DNA错配修复-精通/微卫星稳定（pMMR/MSS）结直肠癌（CRC）患者，占所有CRC病例的85%，对免疫检查点抑制剂的反应较差(即，抗PD-1抗体）。患有局部晚期癌症的pMMR/MSSCRC患者需要有效的联合治疗。
方法：在这项试点研究中，我们给予6个术前剂量的抗PD-1抗体sintilimab的每2周周期（以200毫克的固定剂量），奥沙利铂,5-FU/CF（mFOLFOX6）联合5剂贝伐单抗（减少剂量以防止手术延迟）治疗cT4NxM0结肠癌或上段直肠癌患者。在最后一次新辅助治疗后约2周进行根治性手术。主要终点是病理性完全缓解（pCR）。我们还评估了主要病理反应(MPR，≤10%残留活肿瘤)，放射学和病理学回归，安全,和肿瘤突变负荷（TMB），和肿瘤微环境（TME）特征。
结果：截止日期（2023年9月），纳入22例cT4NxM0pMMR/MSS结肠癌或上直肠癌患者，中位随访时间为24.7个月（IQR：21.1-26.1）。所有患者均接受R0手术切除，无治疗相关手术延迟。22例切除肿瘤中有12例发生pCR（54.5％），22例患者中有18例发生MPR（81.8％）。在截止日期，所有的病人都活着,21/22无复发。2/22（9.1％）患者发生3级或更高的治疗相关不良事件。在pCR肿瘤中，两个被发现携带POLE突变。病理消退程度明显大于放射学消退程度(p=1.35×10-8)。pCR肿瘤和预处理活检组织中肿瘤和基质中CD3/CD4细胞的数量明显低于非pCR肿瘤（分别为p=0.038和p=0.015）。
结论：新辅助药sintilimab联合贝伐单抗和mFOLFOX6几乎没有副作用，没有延误手术,并导致54.5%和81.8%的病例出现pCR和非pCR，分别。肿瘤和间质中CD3/CD4表达下调与pCR有关。然而,PD-1阻断增强靶向化疗的分子机制需要进一步研究.
方法：在这项试点研究中，我们给予6个术前剂量的抗PD-1抗体sintilimab的每2周周期（以200毫克的固定剂量），奥沙利铂,5-FU/CF（mFOLFOX6）联合5剂贝伐单抗（减少剂量以防止手术延迟）治疗cT4NxM0结肠癌或上段直肠癌患者。在最后一次新辅助治疗后约2周进行根治性手术。主要终点是病理性完全缓解（pCR）。我们还评估了主要病理反应(MPR，≤10%残留活肿瘤)，放射学和病理学回归，安全,和肿瘤突变负荷（TMB），和肿瘤微环境（TME）特征。
结果：截止日期（2023年9月），纳入22例cT4NxM0pMMR/MSS结肠癌或上直肠癌患者，中位随访时间为24.7个月（IQR：21.1-26.1）。所有患者均接受R0手术切除，无治疗相关手术延迟。22例切除肿瘤中有12例发生pCR（54.5％），22例患者中有18例发生MPR（81.8％）。在截止日期，所有的病人都活着,21/22无复发。2/22（9.1％）患者发生3级或更高的治疗相关不良事件。在pCR肿瘤中，两个被发现携带POLE突变。病理消退程度明显大于放射学消退程度(p=1.35×10-8)。pCR肿瘤和预处理活检组织中肿瘤和基质中CD3/CD4细胞的数量明显低于非pCR肿瘤（分别为p=0.038和p=0.015）。
结论：新辅助药sintilimab联合贝伐单抗和mFOLFOX6几乎没有副作用，没有延误手术,并导致54.5%和81.8%的病例出现pCR和非pCR，分别。肿瘤和间质中CD3/CD4表达下调与pCR有关。然而,PD-1阻断增强靶向化疗的分子机制需要进一步研究.
