Loi Sherene, Salgado Roberto, Schmid Peter, Cortes Javier, Cescon David W, Winer Eric P, Toppmeyer Deborah L, Rugo Hope S, De Laurentiis Michelino, Nanda Rita, Iwata Hiroji, Awada Ahmad, Tan Antoinette R, Sun Yuan, Karantza Vassiliki, Wang Anran, Huang Lingkang, Saadatpour Assieh, Cristescu Razvan, Yearley Jennifer, Lunceford Jared, Jelinic Petar, Adams Sylvia
Peter MacCallum Cancer Centre, Melbourne, VIC, Australia.
University of Melbourne, Parkville, Australia.
JCO Precis Oncol. 2023 Apr;7:e2200317. doi: 10.1200/PO.22.00317.
In the two-cohort phase II KEYNOTE-086 study (ClinicalTrials.gov identifier: NCT02447003), first-line and second-line or later pembrolizumab monotherapy demonstrated antitumor activity in metastatic triple-negative breast cancer (mTNBC; N = 254). This exploratory analysis evaluates the association between prespecified molecular biomarkers and clinical outcomes.
Cohort A enrolled patients with disease progression after one or more systemic therapies for metastatic disease irrespective of PD-L1 status; Cohort B enrolled patients with previously untreated PD-L1-positive (combined positive score [CPS] ≥ 1) metastatic disease. The association between the following biomarkers as continuous variables and clinical outcomes (objective response rate [ORR], progression-free survival [PFS], and overall survival [OS]) was evaluated: PD-L1 CPS (immunohistochemistry), cluster of differentiation 8 (CD8; immunohistochemistry), stromal tumor-infiltrating lymphocyte (sTIL; hematoxylin and eosin staining), tumor mutational burden (TMB; whole-exome sequencing [WES]), homologous recombination deficiency-loss of heterozygosity, mutational signature 3 (WES), mutational signature 2 (apolipoprotein B mRNA editing catalytic polypeptide-like; WES), T-cell-inflamed gene expression profile (TcellGEP; RNA sequencing), and 10 non-TcellGEP signatures (RNA sequencing); Wald test values were calculated, and significance was prespecified at α = 0.05.
In the combined cohorts (A and B), PD-L1 ( = .040), CD8 ( < .001), sTILs ( = .012), TMB ( = .007), and TcellGEP ( = .011) were significantly associated with ORR; CD8 ( < .001), TMB ( = .034), Signature 3 ( = .009), and TcellGEP ( = .002) with PFS; and CD8 ( < .001), sTILs ( = .004), TMB ( = .025), and TcellGEP ( = .001) with OS. None of the non-TcellGEP signatures were associated with outcomes of pembrolizumab after adjusting for the TcellGEP.
In this exploratory biomarker analysis from KEYNOTE-086, baseline tumor PD-L1, CD8, sTILs, TMB, and TcellGEP were associated with improved clinical outcomes of pembrolizumab and may help identify patients with mTNBC who are most likely to respond to pembrolizumab monotherapy.
在两项队列的II期KEYNOTE-086研究（ClinicalTrials.gov标识符：NCT02447003）中，一线及二线或后续帕博利珠单抗单药治疗在转移性三阴性乳腺癌（mTNBC；N = 254）中显示出抗肿瘤活性。这项探索性分析评估了预先设定的分子生物标志物与临床结局之间的关联。
队列A纳入了在接受一种或多种转移性疾病全身治疗后出现疾病进展的患者，无论其PD-L1状态如何；队列B纳入了先前未接受过治疗的PD-L1阳性（联合阳性评分[CPS]≥1）转移性疾病患者。评估了以下作为连续变量的生物标志物与临床结局（客观缓解率[ORR]、无进展生存期[PFS]和总生存期[OS]）之间的关联：PD-L1 CPS（免疫组织化学）、分化簇8（CD8；免疫组织化学）、基质肿瘤浸润淋巴细胞（sTIL；苏木精和伊红染色）、肿瘤突变负荷（TMB；全外显子测序[WES]）、同源重组缺陷-杂合性缺失、突变特征3（WES）、突变特征2（载脂蛋白B mRNA编辑催化多肽样；WES）、T细胞炎症基因表达谱（TcellGEP；RNA测序）以及10种非TcellGEP特征（RNA测序）；计算了Wald检验值，显著性预先设定为α = 0.05。
在联合队列（A和B）中，PD-L1（P = 0.040）、CD8（P < 0.001）、sTILs（P = 0.012）、TMB（P = 0.007）和TcellGEP（P = 0.011）与ORR显著相关；CD8（P < 0.001）、TMB（P = 0.034）、特征3（P = 0.009）和TcellGEP（P = 0.002）与PFS相关；CD8（P < 0.001）、sTILs（P = 0.004）、TMB（P = 0.025）和TcellGEP（P = 0.001）与OS相关。在对TcellGEP进行校正后，没有一种非TcellGEP特征与帕博利珠单抗的结局相关。
在这项来自KEYNOTE-086的探索性生物标志物分析中，基线肿瘤PD-L1、CD8、sTILs、TMB和TcellGEP与帕博利珠单抗改善的临床结局相关，可能有助于识别最有可能对帕博利珠单抗单药治疗产生反应的mTNBC患者。
