Several biomarkers, including the T-cell inflamed 18-gene expression profile, were associated with improved pathologic complete response and event-free survival, both with and without Keytruda (pembrolizumab) therapy.
Results from an exploratory analysis of the KEYNOTE-522 study in high-risk, early triple-negative breast cancer were presented at 2024 San Antonio Breast Cancer Symposium.
Tumor mutational burden also correlated with improved event-free survival in the Keytruda plus chemotherapy arm, but not in the placebo plus chemotherapy arm. There were few patients with high tumor mutational burden in this patient population of those with triple-negative breast cancer.
Further, the Keytruda/chemotherapy regimen offered an efficacy advantage compared with chemotherapy alone, regardless of subgroups defined by several biomarkers such as tumor mutational burden, T-cell inflamed 18-gene expression profile and more.
About the KEYNOTE-522 Exploratory Analysis
The phase 3 KEYNOTE-522 study sought to evaluate the combination of neoadjuvant Keytruda with chemotherapy and adjuvant Keytruda in patients with newly diagnosed, previously untreated, high-risk, early-stage triple-negative breast cancer. Previously reported findings have shown that neoadjuvant Keytruda with chemotherapy followed by adjuvant Keytruda significantly improved pathologic complete response, event-free survival and overall survival versus neoadjuvant placebo plus chemotherapy with adjuvant placebo in patients with high-risk, early triple-negative breast cancer.
In this exploratory biomarker analysis, the end points included evaluating the association of tumor mutational burden, T-cell inflamed 18-gene expression profile and a set of non-T-cell inflamed 18-gene expression profile consensus signatures with pathologic complete response and event-free survival. Secondary end points included evaluating RNA sequence-based molecular subtypes, BRCA/HRD status, HER2 gene expression/signature, and PTEN loss signature associations with pathologic complete response and event-free survival.
Patients with newly diagnosed, previously untreated, high-risk, early triple-negative breast cancer and evaluable pretreatment tumor samples were enrolled in the study. A total of 1,172 patients were randomly assigned and treated, including 783 in the Keytruda plus chemotherapy arm and 389 in the placebo and chemotherapy arm. There were 946 patients who had whole-exome sequencing data, with 641 who received Keytruda/chemotherapy and 305 given placebo/chemotherapy, and 904 had RNAseq data, consisting of 618 and 286 across the study arms.
Tumor mutational burden was assessed through whole-exome sequencing, while T-cell–inflamed 18-gene expression profile and non–T-cell-inflamed 18-gene expression profile consensus signatures were evaluated using RNA sequencing.
Additional Findings
Among the non–T-cell-inflamed 18-gene expression profile consensus signatures, proliferation and glycolysis were positively associated with pathologic complete response in both arms but did not correlate with event-free survival.
For the secondary end points of the study, positive associations of PTEN loss signature and BRCA/HRD status with pathologic complete response were observed in both treatment arms. HER2 gene expression was linked with the T–cell-inflamed 18-gene expression profile; however, it did not show significant associations with pathologic complete response or event-free survival in the Keytruda/chemotherapy arm after adjustment for the T-cell–inflamed 18-gene expression profile.
Subgroup analyses of secondary biomarkers using prespecified cutoffs consistently confirmed the benefit of the Keytruda and chemotherapy combination over the chemotherapy and placebo combination.
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