Department of Medical Oncology, Department of General Surgery, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou 510655, China; Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou 510655, China.
Department of Medical Oncology, Department of General Surgery, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou 510655, China; Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou 510655, China; Department of Radiology, State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou 510060, China.
Med. 2024 Aug 9;5(8):998-1015.e6. doi: 10.1016/j.medj.2024.05.002. Epub 2024 May 24.
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.
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.
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.
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).
Funded by the National Natural Science Foundation of China (81974369) and the program of Guangdong Provincial Clinical Research Center for Digestive Diseases (2020B1111170004).
约 20% 的错配修复缺陷（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，且缺乏反应的基线生物标志物。
我们进行了一项 2 期研究，以评估环氧化酶（COX）抑制剂联合抗 PD-1 治疗在 dMMR 转移性结直肠癌患者中的疗效。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、缓解持续时间和安全性。
共纳入 30 例患者，客观缓解率为 73.3%，达到了 68%的预设终点。中位随访 50.8 个月时，中位 PFS 和 OS 尚未达到。28 例（93.3%）患者疾病得到控制。中位缓解持续时间未达到。联合治疗耐受良好。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 表达与更好的 PFS 相关（对数秩检验 p = 0.003），这一预后意义在免疫治疗验证队列中得到了证实。
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有效且安全的治疗选择，TAPBP 可能作为免疫检查点抑制剂治疗的生物标志物（本研究在 ClinicalTrials.gov 注册：NCT03638297）。
国家自然科学基金（81974369）和广东省消化疾病临床研究中心项目（2020B1111170004）资助。
