386P - Exploratory biomarker analysis based on the PREDICT trial (AIO-PAK-0216) for response prediction to second-line nal-IRI/5-FU/FA chemotherapy (CTX) in metastatic PDAC patients (mPDAC Pts)

Background

The recent phase IIIb/IV PREDICT trial examined the predictive value of first-line CTX (Gem-nabPac) for second-line CTX (nal-IRI/5-FU/FA) in mPDAC Pts. The objective of this study was to determine molecular alterations in the tumor immune microenvironment (TiME) of treatment-naïve Pts associated with short (S) or long (L) time-to-treatment failure (TTF) of 2^nd line CTX and to identify corresponding liquid biomarker candidates predicting 2^nd line CTX success.

Methods

Pts were stratified into two groups based on S- or L-TTF (n = 10 Pts/group, 80/20% quantiles). Tissue specimens from surgical resection (CTX-naive) were enriched for tumor cell content via laser microdissection and subjected to RNA (NanoString™ PanCancer IO360) profiling. Selected omics results were confirmed via multiplexed immunohistochemistry (mIHC). PBMCs from 2^nd line treatment-naive Pts were screened by using flow cytometry.

Results

TTF group comparison revealed significantly increased inflammation (18-gene signature), immune cell activation (enriched TISIDB signatures: activated CD8⁺-T cells/CD4⁺-T cells/B cells), immune cell infiltration (CD8⁺-T cells, Neutrophils, Tregs), and immune exhaustion (upregulation of PDCD1, LAG3, CTLA4, TIGIT, IDO1, CD96) for L-TTF tumors. Additionally, the favorable Bailey immunogenic subtype was enriched for the L-TTF group. The most differentially regulated genes included CXCR3-binding chemokines: CXCL9, CXCL11, CXCL13. CXCR3 expression was also enhanced for L-TTF patients, and the increased infiltration of CXCR3⁺-CD8⁺ T cells was confirmed via mIHC. Analysis of PBMCs in 2^nd line treatment-naïve blood samples (n = 82) also revealed a significant increase (L-TTF group) in CXCR3⁺-CD8⁺ T cells, confirming this PBMC population as potential liquid biomarker for prediction of 2^nd line CTX response (mPDAC).

Conclusions

In this study, we have identified a favorable TiME for L-TTF (2^nd line CTX) mPDAC patients showing CD8⁺-T cell inflamed ("hot") tumor tissues prior to 2^nd line CTX. We further propose CXCR3⁺-CD8⁺ T cells as potential liquid biomarker for predicting 2^nd line nal-IRI/5-FU/FA success.

Clinical trial identification

NCT03468335.

Legal entity responsible for the study

Prof. Dr. T. Seufferlein.

Funding

AIO-Studien-GmbH, Servier Deutschland GmbH.

Disclosure

M.P. Lutz: Other, Advisory Role, Consulting, and advisory role for Servier: Servier Deutschland GmbH. All other authors have declared no conflicts of interest.