生物标志物与帕博利珠单抗单药治疗转移性三阴性乳腺癌患者临床结局之间的关联：KEYNOTE-086 探索性分析

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 (Tcell inf GEP; RNA sequencing), and 10 non-Tcell inf GEP signatures (RNA sequencing); Wald test P values were calculated, and significance was prespecified at α = 0.05.

In the combined cohorts (A and B), PD-L1 ( P = .040), CD8 ( P < .001), sTILs ( P = .012), TMB ( P = .007), and Tcell inf GEP ( P = .011) were significantly associated with ORR; CD8 ( P < .001), TMB ( P = .034), Signature 3 ( P = .009), and Tcell inf GEP ( P = .002) with PFS; and CD8 ( P < .001), sTILs ( P = .004), TMB ( P = .025), and Tcell inf GEP ( P = .001) with OS. None of the non-Tcell inf GEP signatures were associated with outcomes of pembrolizumab after adjusting for the Tcell inf GEP.

In this exploratory biomarker analysis from KEYNOTE-086, baseline tumor PD-L1, CD8, sTILs, TMB, and Tcell inf GEP were associated with improved clinical outcomes of pembrolizumab and may help identify patients with mTNBC who are most likely to respond to pembrolizumab monotherapy.