Morris Van K, Liu Suyu, Lin Kangyu, Zhu Haifeng, Prasad Seema, Mahvash Armeen, Bhosale Priya, Sun Baohua, Parra Edwin R, Wistuba Ignacio, Peddireddy Arjun, Yao James, Mendoza-Perez Julia, Knafl Mark, Woodman Scott E, Eng Cathy, Halperin Daniel
Department of Gastrointestinal Medical Oncology, The University of Texas - MD Anderson Cancer Center, Houston, Texas.
Department of Biostatistics, The University of Texas - MD Anderson Cancer Center, Houston, Texas.
Clin Cancer Res. 2025 May 1;31(9):1657-1666. doi: 10.1158/1078-0432.CCR-24-1512.
Anti-PD-L1 antibodies are associated with responses in <25% of patients with metastatic human papillomavirus-associated malignancies. VEGF signaling causes immune evasion and immune suppression within the tumor. We evaluated the anti-PD-L1 antibody atezolizumab and anti-VEGF antibody bevacizumab for patients with unresectable, advanced anal cancer.
For this phase II study, participants with previously treated, immunotherapy-naïve anal cancer received atezolizumab (1,200 mg) and bevacizumab (15 mg/kg) intravenously every 21 days. Responses were evaluated every 9 weeks (RECIST version 1.1). The primary endpoint was the best radiographic response. Median survival was estimated by Kaplan-Meier and compared for selected biomarkers (including paired pre- and on-treatment biopsies) using a log-rank test.
Among 20 participants, the overall response rate was 11% [95% confidence interval (CI): 1.2-32]. Median progression-free survival and overall survival were 4.1 months (95% CI, 2.6-not assessable) and 11.6 months (95% CI, 9.5-20), respectively. One grade 5 bevacizumab-related bowel perforation occurred. Analyses of 16 paired biopsies linked increases in IFN-γ (P = 0.03) and inflammatory response (P = 0.02) gene expression signatures with prolonged progression-free survival, as did increases in CD3+CD8+PD1+ (P = 0.02) cells and decreases in CD3+FoxP3+ cells (P = 0.04) from 10 paired biopsies with multiplex immunofluorescence. A subgroup of anal cancers characterized by the SBS31 "prior-platinum" signature demonstrated shorter median overall survival (HR, 6.3; 95% CI, 1.2-32; P = 0.01).
Atezolizumab and bevacizumab demonstrate activity similar to anti-PD-1 antibodies alone for unresectable anal cancer. Our translational data identify undescribed chromosomal and transcriptomic biomarkers associated with survival for metastatic anal cancer. These correlative findings warrant confirmation and further validation in larger, prospective immunotherapy trials for advanced anal cancer.
抗程序性死亡配体1（PD-L1）抗体仅使不到25%的转移性人乳头瘤病毒相关恶性肿瘤患者产生反应。血管内皮生长因子（VEGF）信号传导可导致肿瘤内的免疫逃逸和免疫抑制。我们评估了抗PD-L1抗体阿替利珠单抗和抗VEGF抗体贝伐单抗用于不可切除的晚期肛管癌患者的疗效。
在这项II期研究中，既往接受过治疗但未接受过免疫治疗的肛管癌参与者每21天静脉注射阿替利珠单抗（1200mg）和贝伐单抗（15mg/kg）。每9周评估一次反应（实体瘤疗效评价标准1.1版）。主要终点是最佳影像学反应。采用Kaplan-Meier法估计中位生存期，并使用对数秩检验比较选定生物标志物（包括配对的治疗前和治疗时活检组织）的生存期。
20名参与者中，总缓解率为11%[95%置信区间（CI）：1.2%-32%]。中位无进展生存期和总生存期分别为4.1个月（95%CI，2.6个月-不可评估）和11.6个月（95%CI，9.5个月-20个月）。发生了1例与贝伐单抗相关的5级肠穿孔。对16对活检组织的分析表明，IFN-γ（P=0.03）和炎症反应（P=0.02）基因表达特征的增加与无进展生存期延长相关，10对采用多重免疫荧光法检测的活检组织中CD3+CD8+PD1+细胞增加（P=0.02）和CD3+FoxP3+细胞减少（P=0.04）也与无进展生存期延长相关。以SBS31“铂类治疗前”特征为特点的肛管癌亚组的中位总生存期较短（风险比，6.3；95%CI，1.2-32；P=0.01）。
阿替利珠单抗和贝伐单抗对不可切除的肛管癌显示出与单独使用抗程序性死亡蛋白1（PD-1）抗体相似的活性。我们的转化医学数据确定了与转移性肛管癌生存相关的未描述的染色体和转录组生物标志物。这些相关性发现需要在更大规模的晚期肛管癌前瞻性免疫治疗试验中得到证实和进一步验证。
