An exploratory biomarker analysis from the phase 3 KEYNOTE-522 trial suggests that tumor mutational burden (TMB) and T-cell-inflamed gene expression profile (TcellinfGEP) may be linked to treatment response in early-stage triple-negative breast cancer (TNBC). The analysis was presented at the 2024 San Antonio Breast Cancer Symposium (Abstract LBA1-07).
The study focused on the relationship of TMB and TcellinfGEP to outcomes in patients receiving neoadjuvant pembrolizumab (Keytruda) plus chemotherapy. “This prespecified exploratory analysis of KEYNOTE-522 found that several biomarkers, including T-cell–inflamed GEP, were possibly prognostic for pathologic complete response (pCR) and/or event-free survival (EFS), but were not predictive of benefit from pembrolizumab,” said lead author Joyce O’Shaughnessy, MD, of Texas Oncology in Houston, at the meeting.
The KEYNOTE-522 trial previously demonstrated that neoadjuvant pembrolizumab plus chemotherapy, followed by adjuvant pembrolizumab, significantly improved EFS and overall survival (OS) compared with chemotherapy alone in patients with high-risk early-stage TNBC. This latest analysis evaluated the association of TMB, TcellinfGEP, and a range of non-TcellinfGEP signatures with pCR and EFS.
Of the 1,172 patients in the KEYNOTE-522 trial, 946 had whole-exome sequencing (WES) data available and 904 had RNA sequencing (RNAseq) data. The analysis showed that TcellinfGEP was strongly linked to improved pCR and EFS in both the pembrolizumab-chemotherapy and placebo-chemotherapy groups (P≤.001). TMB also showed a clear association with better pCR and EFS in the pembrolizumab group (P≤.001); however, this relationship was not observed in the placebo group (pCR, P=.011; EFS, P=0.422).
“Patients whose cancers had high TMB for the prespecified cut-off had a markedly higher EFS rate with pembrolizumab,” Dr. O’Shaughnessy said.
Subgroup analyses using prespecified cutoffs for TcellinfGEP and TMB showed that EFS curves consistently favored pembrolizumab-chemotherapy over chemotherapy alone, regardless of subgroup. The study’s authors noted that these findings highlight pembrolizumab’s efficacy across a range of biomarker-defined subgroups.
Among the non-TcellinfGEP signatures, proliferation and glycolysis were positively associated with pCR, but did not predict EFS. Secondary analyses showed that BRCA/homologous recombination deficiency status and PTEN loss signature were positively associated with pCR in both the pembrolizumab and placebo groups. HER2 gene expression was negatively correlated with TcellinfGEP (correlation coefficient = −0.32), but HER2 levels and molecular subtypes did not show significant associations with pCR or EFS in the pembrolizumab group after adjusting for TcellinfGEP.
Dr. O’Shaughnessy said that TcellinfGEP was prognostic for better pCR and EFS, regardless of pembrolizumab use. However, TMB’s association with improved EFS was observed only in the pembrolizumab group. These results may inform the design of future studies aimed at optimizing immunotherapy-based treatment strategies for TNBC, she said.
The data suggest a potential role for biomarkers such as TcellinfGEP and TMBin preselecting patients who may benefit most from immune checkpoint inhibitors, said Azka Ali, MD, medical oncologist at the Cleveland Clinic Taussig Cancer Institute in Ohio. Dr. Ali, who was not a part of the study, told Oncology News Central that patients who have more tumor instability, which is a hallmark of high-risk TMB, tend to have better pCR and EFS outcomes.
Although these findings are unlikely to change clinical practice right away, they represent an essential step toward precision oncology for these patients, Dr. Ali said. This effort is part of a broader push to understand who may or may not respond and to adjust treatment strategies accordingly.
“It’s almost like an ongoing query to try to better understand biomarkers,” Dr. Ali said. “What we need to do more of – and I think we’re doing a better job now with designing our trials – is to collect the biomarker-level data, because we know some patients have inherent resistance to our therapies.”
The KEYNOTE-522 trial was sponsored by Merck Sharp & Dohme LLC.
Dr. O’Shaughnessy reported various industry relationships, including research funding from Merck and Rahway.
Dr. Ali reported no relevant disclosures.