Abstract：
BACKGROUND: Approximately 20% of patients with DNA mismatch repair deficiency (dMMR) metastatic colorectal cancer do not respond to anti-programmed death-1 (PD-1) ligand therapy, and baseline biomarkers of response are lacking.
METHODS: We conducted a phase 2 study to evaluate the efficacy of cyclooxygenase (COX) inhibitors in combination with anti-PD-1 therapy in patients with dMMR metastatic colorectal cancer. The primary endpoint was objective response rate. The secondary endpoints included progression-free survival (PFS), overall survival (OS), disease control rate, duration of response, and safety.
RESULTS: A total of 30 patients were enrolled, and the objective response rate was 73.3%, meeting the predefined endpoint of 68%. The median PFS and median OS were not reached at a median follow-up period of 50.8 months. Disease control was achieved in 28 patients (93.3%). The median duration of response was not reached. The combination was well tolerated. Multiomics analysis revealed that the antigen processing and presentation pathway was positively associated with treatment response and PFS. Higher TAPBP expression was predictive of better PFS (log-rank p = 0.003), and this prognostic significance was confirmed in an immunotherapy validation cohort.
CONCLUSIONS: Thus, COX inhibitors combined with PD-1 blockade may be effective and safe treatment options for patients with dMMR metastatic colorectal cancer, and TAPBP may serve as a biomarker for immune checkpoint inhibitor therapy (this study was registered at ClinicalTrials.gov: NCT03638297).
BACKGROUND: Funded by the National Natural Science Foundation of China (81974369) and the program of Guangdong Provincial Clinical Research Center for Digestive Diseases (2020B1111170004).
METHODS: We conducted a phase 2 study to evaluate the efficacy of cyclooxygenase (COX) inhibitors in combination with anti-PD-1 therapy in patients with dMMR metastatic colorectal cancer. The primary endpoint was objective response rate. The secondary endpoints included progression-free survival (PFS), overall survival (OS), disease control rate, duration of response, and safety.
RESULTS: A total of 30 patients were enrolled, and the objective response rate was 73.3%, meeting the predefined endpoint of 68%. The median PFS and median OS were not reached at a median follow-up period of 50.8 months. Disease control was achieved in 28 patients (93.3%). The median duration of response was not reached. The combination was well tolerated. Multiomics analysis revealed that the antigen processing and presentation pathway was positively associated with treatment response and PFS. Higher TAPBP expression was predictive of better PFS (log-rank p = 0.003), and this prognostic significance was confirmed in an immunotherapy validation cohort.
CONCLUSIONS: Thus, COX inhibitors combined with PD-1 blockade may be effective and safe treatment options for patients with dMMR metastatic colorectal cancer, and TAPBP may serve as a biomarker for immune checkpoint inhibitor therapy (this study was registered at ClinicalTrials.gov: NCT03638297).
BACKGROUND: Funded by the National Natural Science Foundation of China (81974369) and the program of Guangdong Provincial Clinical Research Center for Digestive Diseases (2020B1111170004).
摘要：
背景：大约20％的DNA错配修复缺陷（dMMR）转移性结直肠癌患者对抗程序性死亡-1（PD-1）配体治疗无反应，缺乏反应的基线生物标志物。
方法：我们进行了一项2期研究，以评估环氧合酶（COX）抑制剂联合抗PD-1治疗对dMMR转移性结直肠癌患者的疗效。主要终点是客观缓解率。次要终点包括无进展生存期（PFS），总生存期（OS），疾病控制率,响应的持续时间，和安全。
结果：共纳入30例患者，客观反应率为73.3%，满足68%的预定义端点。在50.8个月的中位随访期未达到中位PFS和中位OS。28例患者（93.3%）实现疾病控制。未达到响应的中位持续时间。该组合耐受性良好。多组学分析显示，抗原加工和呈递途径与治疗反应和PFS呈正相关。较高的TAPBP表达预示着较好的PFS（log-rankp=0.003），这种预后意义在免疫治疗验证队列中得到证实.
结论：因此，COX抑制剂联合PD-1阻断可能是dMMR转移性结直肠癌患者安全有效的治疗选择。TAPBP可以作为免疫检查点抑制剂治疗的生物标志物(本研究在ClinicalTrials.gov:NCT03638297注册).
背景：由国家自然科学基金（81974369）和广东省消化疾病临床研究中心（2020B1111170004）资助。
方法：我们进行了一项2期研究，以评估环氧合酶（COX）抑制剂联合抗PD-1治疗对dMMR转移性结直肠癌患者的疗效。主要终点是客观缓解率。次要终点包括无进展生存期（PFS），总生存期（OS），疾病控制率,响应的持续时间，和安全。
结果：共纳入30例患者，客观反应率为73.3%，满足68%的预定义端点。在50.8个月的中位随访期未达到中位PFS和中位OS。28例患者（93.3%）实现疾病控制。未达到响应的中位持续时间。该组合耐受性良好。多组学分析显示，抗原加工和呈递途径与治疗反应和PFS呈正相关。较高的TAPBP表达预示着较好的PFS（log-rankp=0.003），这种预后意义在免疫治疗验证队列中得到证实.
结论：因此，COX抑制剂联合PD-1阻断可能是dMMR转移性结直肠癌患者安全有效的治疗选择。TAPBP可以作为免疫检查点抑制剂治疗的生物标志物(本研究在ClinicalTrials.gov:NCT03638297注册).
背景：由国家自然科学基金（81974369）和广东省消化疾病临床研究中心（2020B1111170004）资助。
