An exploratory analysis of a pivotal trial has identified potential biomarkers linked to improved outcomes in patients with previously treated metastatic triple-negative breast cancer receiving pembrolizumab.
The phase 3 KEYNOTE-111 trial enrolled 622 participants with metastatic TNBC across 31 countries who were randomised to receive either pembrolizumab (n=312) or chemotherapy (n=310) as second- or third-line treatment.
Biomarker data were available for subsets of the treated population: tumour-infiltrating lymphocytes (TILs; n=551), T-cell–inflamed gene expression profile (TcellinfGEP; n=333), BRCA1/2 mutation and homologous recombination deficiency (BRCAm/HRD; n=218) and tumour mutational burden (TMB; n=255).
Pembrolizumab vs chemotherapy
The analysis, conducted by international teams of researchers, found that TIL levels ≥5% were significantly associated with improved objective response rate (ORR), progression-free survival (PFS) and overall survival (OS) in the pembrolizumab group, but not in the chemotherapy group.
Similarly, higher TcellinfGEP scores correlated with better outcomes in the pembrolizumab arm, with no corresponding benefit observed in chemotherapy-treated patients. Joint modelling suggested that TcellinfGEP may offer greater predictive value than TILs alone.
A trend toward a positive association was observed between TMB and clinical response in patients treated with pembrolizumab, but not in those receiving chemotherapy. While the association between TMB and ORR did not reach statistical significance, significant associations were seen for PFS and OS. Notably, although only 10.2% of participants had TMB ≥10 mutations per megabase, this group had longer OS.
In contrast, no associations were found between BRCAm/HRD status and clinical outcomes in either treatment arm.
The researchers noted that TcellinfGEP may reflect a pre-existing immune response and could help identify patients most likely to benefit from immunotherapy.
Limitations included the retrospective and exploratory nature of the analysis, small subgroup sizes and variability in tissue sample timing, they acknowledged.
The researchers concluded that TcellinfGEP score, TIL levels and TMB status may serve as predictive biomarkers of pembrolizumab response in patients with metastatic triple-negative breast cancer. They recommended further prospective validation of these biomarkers and exploration of their integration with PD-L1 testing to optimise patient selection for treatment in this challenging disease.
Reference
Cortes J et al. Association of potential biomarkers with clinical outcomes in metastatic triple-negative breast cancer treated with pembrolizumab or chemotherapy. npj Breast Cancer 2025;11:109.
