1645P - STAT3, ACTA2, and SPARC stromal markers predict response to Gemcitabine/Cisplatin/Nab-paclitaxel (GCN) in patients with advanced pancreatic adenocarcinoma (apdac)

Background

GN is front-line therapy for aPDAC. Addition of Cisplatin showed high overall response rate, progression free survival (PFS), and median overall survival (mOS) in aPDAC patients in a phase II study. However, biomarkers predicting response or resistance to GCN are lacking. We hypothesize that addition of cisplatin alters the aPDAC tumor microenvironment.

Methods

Analysis of 1379 aPDAC patients using Next-Gen sequencing (NGS) of the DNA (NextSeq, 592 genes or NovaSeq, WES) and RNA (NovaSeq, WTS) (Caris Life Sciences, Phoenix, AZ) was done to determine biomarkers of response to GCN versus GN (DNA damage repair mutations/DDRMs and stromal gene markers). Real-world mOS was extracted from insurance claims data and calculated using Kaplan-Meier estimates for molecularly defined cohorts from first treatment of GN or GCN to last contact. Time on treatment (ToT) was obtained similarly as the time of first treatment of GN or GCN to last treatment.

Results

1204 aPDAC patients received GN therapy among which 47% were female. 175 aPDAC patients received GCN regimen (47.5% were female). GCN was associated with higher mOS (534 vs 275 days(d), HR:0.61, p<0.001) and longer ToT (238 vs 105 d, HR:0.43, p<0.001) compared to GN. No difference in mOS and ToT was seen with either regimen in patients harboring somatic DDRMs (BRCA, CHEK, FANC, MSH, MLH and others). High STAT3 (957 vs 421 d, HR:0.44, p=0.017), ACTA2 (957 vs 421 d, HR:0.45, p=0.019) and SPARC (1029 vs 421 d, HR:0.49, p=0.038) gene expressions were associated with improvement in mOS on GCN whereas STAT2 had no association. Several stromal genes including TGFB1, TGFB2, HAS-2 and IL-6 correlated with worse mOS following GN therapy. High MMP-2 expression was associated with better mOS (p=0.007) and longer ToT (p=0.006) in patients who received GN.

Conclusions

GCN demonstrated higher mOS and ToT compared to GN. There was no difference in outcome among patients with somatic DDRMs. High expression of STAT3, ACTA2, and SPARC was associated with significant mOS benefit in patients who received GCN. In patients who received GN, MMP-2 was associated with better outcome. Analysis of stromal markers STAT3, ACTA2, and SPARC in a prospective trial is ongoing.

Clinical trial identification

Editorial acknowledgement

Legal entity responsible for the study

The authors.

Funding

Has not received any funding.

Disclosure

T. Bekaii-Saab: Financial Interests, Institutional, Advisory Board: Bayer, Pfizer, Incyte, Ipsen, Seattle Genetics, Genentech, Merck KGA, Merus, Eisai, Servier; Financial Interests, Institutional, Other, DSMB: Merck; Financial Interests, Personal, Advisory Board: AbbVie, Boehringer Ingelheim, Janssen, AstraZeneca, Daiichi Sankyo, Natera, Celularity, Exact Science, Sobi, BeiGene, Xilis, Foundation Medicine, Stemline, Blueprint, Celularity, Caladrius, GSK, Deciphera, Zai Labs, Illumina, Sanofi; Financial Interests, Personal, Other, DSMB: AstraZeneca, Exelixis, The Valley Hospital, FibroGen; Financial Interests, Personal, Other, DSMC: PanCAN; Financial Interests, Personal, Royalties, WO/2018/183488: Human PD1 Peptide vaccines and uses thereof – Licensed to Imugene: Imugene; Financial Interests, Personal, Royalties, WO/2019/055687: Methods and compositions for the treatment of cancer Cachexia – Licensed to Recursion: Recursion; Financial Interests, Institutional, Research Grant: Agios, Arys, Bayer, Amgen, Ipsen, Clovis, Pfizer, Celgene, Novartis, Arcus, Atreca, BMS, Mirati, Merus, Abgenomics; Financial Interests, Institutional, Coordinating PI: Boston Biomedical, Incyte; Financial Interests, Institutional, Steering Committee Member: Seattle Genetics; Non-Financial Interests, Advisory Role: Imugene, Sun Biopharma. All other authors have declared no conflicts of interest.