Department of Colorectal Surgery, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, China.
Department of General Surgery, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, China.
Cancer Med. 2024 Jun;13(12):e7224. doi: 10.1002/cam4.7224.
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.
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.
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). 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).
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.
DNA 错配修复 proficient/microsatellite stable（pMMR/MSS）结直肠癌（CRC）占所有 CRC 病例的 85%，对免疫检查点抑制剂（即抗 PD-1 抗体）反应不佳。局部晚期癌症的 pMMR/MSS CRC 患者需要有效的联合治疗。
在这项初步研究中，我们对 cT4NxM0 结肠或高位直肠癌症患者进行了六次术前每 2 周一次的抗 PD-1 抗体信迪利单抗（固定剂量 200mg）、奥沙利铂和 5-FU/CF（mFOLFOX6）联合五次贝伐珠单抗（为避免手术延迟，减少剂量）治疗。新辅助治疗的最后一剂后大约 2 周进行根治性手术。主要终点是病理完全缓解（pCR）。我们还评估了主要病理缓解（MPR，≤10%残留存活肿瘤）、影像学和病理学消退、安全性、肿瘤突变负担（TMB）和肿瘤微环境（TME）特征。
截至截止日期（2023 年 9 月），22 名 cT4NxM0 pMMR/MSS 结肠或高位直肠癌症患者入组，中位随访时间为 24.7 个月（IQR：21.1-26.1）。所有患者均接受了无治疗相关手术延迟的 R0 手术切除。22 例切除肿瘤中有 12 例（54.5%）发生 pCR，18 例（81.8%）发生 MPR。截至截止日期，所有患者均存活，21/22 例无复发。22 例患者中有 2 例（9.1%）发生 3 级或以上治疗相关不良事件。在 pCR 肿瘤中，有两例发现存在 POLE 突变。病理消退程度明显大于影像学消退程度（p=1.35×10）。与非 pCR 肿瘤相比，预处理活检组织中肿瘤和基质中的 CD3+/CD4+细胞数量明显较低（p=0.038 和 p=0.015）。
新辅助信迪利单抗联合贝伐珠单抗和 mFOLFOX6 治疗副作用少，不延迟手术，分别导致 54.5%和 81.8%的病例 pCR 和非 pCR。肿瘤和基质中 CD3/CD4 表达的下调与 pCR 相关。然而，PD-1 阻断增强靶向化疗的分子机制仍需进一步研究。
