Yang Yingchi, Pang Kai, Lin Guole, Liu Xinzhi, Gao Jiale, Zhou Jiaolin, Xu Lai, Gao Zhidong, Wu Yingchao, Li Ang, Han Jiagang, Wu Guoju, Wang Xin, Li Fei, Ye Yingjiang, Zhang Jie, Chen Guangyong, Wang Hao, Kong Yuanyuan, Wu Aiwen, Xiao Yi, Yao Hongwei, Zhang Zhongtao
Department of General Surgery, Beijing Friendship Hospital, Capital Medical University, Beijing, China.
Department of General Surgery, Peking Union Medical College Hospital, Beijing, China.
Nat Med. 2025 Feb;31(2):449-456. doi: 10.1038/s41591-024-03360-5. Epub 2025 Jan 6.
Radiotherapy displays unique antitumor synergism with immune checkpoint inhibitors, which is indicated by high pathological complete response (pCR) rates from single-arm trials of locally advanced rectal cancer (LARC). Here we test the efficacy and safety of the radiation-immune checkpoint inhibitor combination in patients with LARC in a phase 2, randomized trial conducted in eight major colorectal cancer centers in Beijing. In total, 186 eligible all-comer (proficient mismatch repair and deficient mismatch repair) participants were enrolled. The patients were randomly assigned to receive neoadjuvant chemoradiation + concurrent/sequential PD-1 blockade (experiment groups A/B) or neoadjuvant chemoradiation alone (control group). Radical surgeries were scheduled after neoadjuvant treatments. The primary endpoint was the pCR rate. The pCR rates were 27.1%, 32.7% and 14.0% for experiment groups A and B and the control group, respectively. The difference in pCR rates between experiment group B and the control group reached statistical significance (risk ratio 2.332, 95% confidence interval 1.106-4.916; P = 0.019). No substantial differences between either one of the experiment groups and the control group were observed regarding adverse reaction, surgical complication and disease progression. Our results show that adding PD-1 blockade after neoadjuvant chemoradiation increases the pCR rate for patients with LARC and raises no substantial safety concerns. Phase 3 trials with larger sample sizes are warranted (ClinicalTrials.gov identifier NCT05245474 ).
放疗与免疫检查点抑制剂显示出独特的抗肿瘤协同作用，这在局部晚期直肠癌（LARC）单臂试验的高病理完全缓解（pCR）率中得到体现。在此，我们在北京八大结直肠癌中心进行的一项2期随机试验中，测试了放疗联合免疫检查点抑制剂对LARC患者的疗效和安全性。总共招募了186名符合条件的所有患者（错配修复熟练和错配修复缺陷）。患者被随机分配接受新辅助放化疗+同步/序贯PD-1阻断（试验组A/B）或单纯新辅助放化疗（对照组）。新辅助治疗后安排根治性手术。主要终点是pCR率。试验组A、B和对照组的pCR率分别为27.1%、32.7%和14.0%。试验组B与对照组的pCR率差异具有统计学意义（风险比2.332，95%置信区间1.106 - 4.916；P = 0.019）。在不良反应、手术并发症和疾病进展方面，未观察到试验组与对照组之间存在实质性差异。我们的结果表明，新辅助放化疗后添加PD-1阻断可提高LARC患者的pCR率，且不存在重大安全问题。有必要开展更大样本量的3期试验（ClinicalTrials.gov标识符NCT05245474）。
