Two RNA Sequencing Inflammatory Scores as Predictors of Benefit From Pembrolizumab in Advanced Breast Cancer

The following article features coverage from the American Association for Cancer Research (AACR) 2019 meeting. Click here to read more of Cancer Therapy Advisor‘s conference coverage.

Prospective assessments of 2 RNA sequencing inflammatory signature scores, an 18-gene T-cell–inflamed gene expression profile (GEP), as well as a 37-gene tissue-resident memory (TRM) T-cell signature, both measured at baseline, as predictors of response to the programmed cell death 1 (PD-1) inhibitor, pembrolizumab, for patients with metastatic triple-negative breast cancer enrolled in the KEYNOTE-086 trial (ClinicalTrials.gov Identifier: NCT02447003) showed associations between both assays and clinical outcomes. The findings from this study were reported at the American Association for Cancer Research (AACR) Annual Meeting 2019.

The search for robust biomarkers of response to immune checkpoint blockade is ongoing, and both tumor expression of programmed cell death ligand 1 (PD-L1), as well as GEP, a more complex measure of a T-cell–inflamed phenotype,² have been shown to be predictive of response to PD-1/PD-L1 inhibitors in certain tumor types. The TRM represents another immune-related gene expression signature, and provides an assessment of a lineage of T cells that reside in specific tissues without recirculating.³

In this study, clinical outcomes of 154 of 254 patients with metastatic triple-negative breast cancer treated with single-agent pembrolizumab in 1 of 2 cohorts of the phase 2 KEYNOTE-086 trial (ie, either those with previously treated disease independent of PD-L1 status or patients with treatment-naive, PD-L1–positive disease) were adjusted for Eastern Cooperative Oncology Group (ECOG) performance status and compared with prospectively determined GEP and TRM signature scores. In addition, the 2 assays were assessed for correlation with each other.

Key results of this analysis showed that both the GEP and the TRM signature scores at baseline were statistically significantly associated with progression-free survival and overall survival (P <.001 for all assessments) in patients with metastatic triple-negative breast cancer receiving pembrolizumab. However, it was determined that these 2 assays were not independent predictors of clinical outcome, as GEP and TRM signature scores were highly correlated with each other.

“Results confirmed that there may be multiple ways to measure the inflammatory state of the TME, but understanding their relative clinical utility and potential use in conjunction with PD-L1 via immunohistochemistry will require larger, randomized studies,” the authors wrote in conclusion.

Disclosure: The presenters disclosed financial ties to various pharmaceutical companies. For a full list of disclosures, please see the original abstract.

Read more of Cancer Therapy Advisor‘s coverage of AACR 2019 meeting by visiting the conference page.

References

1. Loi S, Schmid P, Cortés J, et al. RNA molecular signatures as predictive biomarkers of response to monotherapy pembrolizumab in patients with metastatic triple-negative breast cancer: KEYNOTE-086. Presented at: American Association for Cancer Research (AACR) Annual Meeting 2019; March 29–April 3, 2019; Atlanta, GA. Abstract LBA225/4.
2. Ayers M, Lunceford J, Nebozhyn M, et al. IFN-γ-related mRNA profile predicts clinical response to PD-1 blockade. J Clin Invest. 2017;127(8):2930-2940.
3. Behr FM, Chuwonpad A, Stark R, van Gisbergen KPJM. Armed and ready: transcriptional regulation of tissue-resident memory CD8 T cells. Front Immunol. 2018;9:1770.