Abstract 2237P
Background
This trial explores the clinical efficacy and safety of AVE, CET and IRI for treatment refractory MSS mCRC. We aim at characterizing the immune response for biomarker discovery through associated translational research.
Methods
MSS, chemorefractory (anti-EGFR refractory if RAS wt) mCRC patients (pts) were enrolled (RAS wt: 28 pts, RAS mut: 27 pts) and treated with CET and IRI from week 1(W1) and AVE from W3. Clinical objectives (safety, tumor response, disease control rate (DCR), PFS and OS) were presented separately. Exploratory endpoints include predictive efficacy biomarkers (immunoscore (IS), immune tumor microenvironment, gene expression profile (GEP), ctDNA) and modification overtime. Multiplex immunofluorescence (MIF), RNAseq and ctDNA analyses were done (sequential metastasis biopsies and plasma samples at W0, W3, W11). CD3, CD8, CD45RO, PD1, PD-L1cells densities were quantified. RNA-seq data were used to perform several analyses (DESeq2, GSEA, deconvolution, gene ontology). OncoSELECT panel (58 genes) was used to follow ctDNA variation over time (mean variant allele frequency).
Results
Among 55 treated pts, 95 biopsies (W0: 39, W3: 29, W11: 27) were available for MIF (table: W0 results). On 23 pts (1st stage), upregulation of adaptive immune response signature was associated with tumor shrinkage, PFS>6 and OS>12 months (p. adj= 0.00). Few modifications of immune cells and GEP were observed overtime (W0, W3, W11). ctDNA decrease (>10%) was associated with tumor response (p=0.04) and PFS (6.6 vs 3.4 months, p=0.08). Table: 2237P
| Characteristics | IS (CD3/CD8) high | CD3/PD1 high | CD3/CD8/CD45RO/PD1 high |
| High/others:pts | 10/29 | 10/29 | 8/31 |
| RAS-wt/RAS-mut:OR, p-v | 1.39, p=0.73 | 0.82, p=0.99 | 0.83, p=0.99 |
| Tumor shrinkage: OR, p-v | 8.32, p=0.00 | 4.50, p=0.05 | 9.54, p=0.00 |
| DCR:OR, p-v | 8.02, p=0.05 | 3.16, p=0.26 | 5.55, p=0.12 |
| PFS:HR, p-v | 0.29, p=0.00 | 0.28, p=0.00 | 0.43, p=0.03 |
| OS:HR, p-v | 0.62, p=0.19 | 0.26, p=0.00 | 0.47, p=0.06 |
Conclusions
Independently of RAS mutation, existing adaptive immune response within metastases is associated with treatment benefit. ctDNA decrease is associated with tumor response.
Clinical trial identification
NCT03608046.
Editorial acknowledgement
Legal entity responsible for the study
Cliniques Universitaires Saint-Luc (Pr. MD. PhD. Marc van den Eynde).
Funding
Merck Serono.
Disclosure
All authors have declared no conflicts of interest.
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