帕博利珠单抗治疗复发性卵巢癌的临床结局的分子决定因素：KEYNOTE-100 的探索性分析。
Molecular determinants of clinical outcomes of pembrolizumab in recurrent ovarian cancer: Exploratory analysis of KEYNOTE-100.
机构信息
Department of Oncology, UCL Cancer Institute, University College London, London, United Kingdom.
The Ella Lemelbaum Institute for Immuno-Oncology, Sheba Medical Center, Tel HaShomer Hospital, Ramat Gan, Israel.
出版信息
Gynecol Oncol. 2023 Nov;178:119-129. doi: 10.1016/j.ygyno.2023.09.012. Epub 2023 Oct 18.
OBJECTIVE
This prespecified exploratory analysis evaluated the association of gene expression signatures, tumor mutational burden (TMB), and multiplex immunohistochemistry (mIHC) tumor microenvironment-associated cell phenotypes with clinical outcomes of pembrolizumab in advanced recurrent ovarian cancer (ROC) from the phase II KEYNOTE-100 study.
METHODS
Pembrolizumab-treated patients with evaluable RNA-sequencing (n = 317), whole exome sequencing (n = 293), or select mIHC (n = 125) data were evaluated. The association between outcomes (objective response rate [ORR], progression-free survival [PFS], and overall survival [OS]) and gene expression signatures (T-cell-inflamed gene expression profile [TcellGEP] and 10 non-TcellGEP signatures), TMB, and prespecified mIHC cell phenotype densities as continuous variables was evaluated using logistic (ORR) and Cox proportional hazards regression (PFS; OS). One-sided p-values were calculated at prespecified α = 0.05 for TcellGEP, TMB, and mIHC cell phenotypes and at α = 0.10 for non-TcellGEP signatures; all but TcellGEP and TMB were adjusted for multiplicity.
RESULTS
No evidence of associations between ORR and key axes of gene expression was observed. Negative associations were observed between outcomes and TcellGEP-adjusted glycolysis (PFS, adjusted-p = 0.019; OS, adjusted-p = 0.085) and hypoxia (PFS, adjusted-p = 0.064) signatures. TMB as a continuous variable was not associated with outcomes (p > 0.05). Positive associations were observed between densities of myeloid cell phenotypes CD11c and CD11c/MHCII/CD163/CD68 in the tumor compartment and ORR (adjusted-p = 0.025 and 0.013, respectively).
CONCLUSIONS
This exploratory analysis in advanced ROC did not find evidence for associations between gene expression signatures and outcomes of pembrolizumab. mIHC analysis suggests CD11c and CD11c/MHCII/CD163/CD68 phenotypes representing myeloid cell populations may be associated with improved outcomes with pembrolizumab in advanced ROC.
CLINICAL TRIAL REGISTRATION
ClinicalTrials.gov, NCT02674061.
目的
本探索性分析评估了基因表达谱、肿瘤突变负荷（TMB）和多重免疫组化（mIHC）肿瘤微环境相关细胞表型与 KEYNOTE-100 研究中晚期复发性卵巢癌（ROC）患者接受派姆单抗治疗的临床结局之间的关联。
方法
对接受评估的可评估 RNA 测序（n=317）、全外显子组测序（n=293）或选择性 mIHC（n=125）数据的派姆单抗治疗患者进行评估。使用逻辑回归（ORR）和 Cox 比例风险回归（PFS；OS）评估基因表达谱（T 细胞炎症基因表达谱[TcellGEP]和 10 个非 TcellGEP 谱）、TMB 和预先指定的 mIHC 细胞表型密度与结局（客观缓解率[ORR]、无进展生存期[PFS]和总生存期[OS]）之间的关联。TcellGEP、TMB 和 mIHC 细胞表型采用单侧 p 值，在预先指定的α=0.05 水平进行计算，而非 TcellGEP 谱则在α=0.10 水平进行计算；除 TcellGEP 和 TMB 外，所有结果均针对多重性进行了调整。
结果
未观察到 ORR 与基因表达关键轴之间存在关联的证据。在结局与 TcellGEP 调整后的糖酵解（PFS，调整后 p=0.019；OS，调整后 p=0.085）和缺氧（PFS，调整后 p=0.064）谱之间观察到负相关。TMB 作为连续变量与结局无关联（p＞0.05）。在肿瘤区中，髓细胞表型 CD11c 和 CD11c/MHCII/CD163/CD68 的密度与 ORR 呈正相关（调整后 p=0.025 和 0.013）。
结论
本项在晚期 ROC 中的探索性分析未发现基因表达谱与派姆单抗治疗结局之间存在关联的证据。mIHC 分析表明，代表髓细胞群体的 CD11c 和 CD11c/MHCII/CD163/CD68 表型可能与晚期 ROC 中派姆单抗治疗的改善结局相关。
临床试验注册
ClinicalTrials.gov，NCT02674061。
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