109P - Prognostic genomic signatures in RAS/BRAF mutant (mut) metastatic colorectal cancer (mCRC) patients (pts) from the phase II study of NIVolumab (niv) plus FOLFOXIRI/Bevacizumab (bev) in first-line therapy of Advanced COloRectal cancer (NIVACOR- GOIRC-03-20

Background

In the NIVACOR trial, first-line niv with FOLFOXIRI/bev showed significant clinical activity in RAS/BRAF mut mCRC pts, with an objective response rate (ORR) of 76.7% and a median progression-free survival (mPFS) of 10.1 months. Here we describe preliminary data from comprehensive genomic profiling (CGP) of tumor samples from NIVACOR pts.

Methods

Pts with untreated RAS/BRAF mut mCRC received FOLFOXIRI/bev plus niv for 8 cycles followed by bev and niv as maintenance. DNA from tumor tissue was analyzed with the Oncomine Comprehensive Assay Plus, and RNA with the Ion AmpliSeq™ Transcriptome Human Gene Expression.

Results

DNA sequencing was successful for 49 microsatellite stable (MSS) and 6 microsatellite instable (MSI) tumors. The mPFS of this cohort was 10 months. Among the 49 MSS pts, 9 had a tumor mutation burden (TMB) >10.4 mutations/Mb and a mPFS of 18 months, while the 40 TMB-low pts showed a mPFS of 9 months (p= 0.06). By comparing the mutational profile of MSS cases within the 25^th and the 75^th PFS percentile, we identified two signatures: a resistance signature (RES) of 53 genes altered only in the 25^th percentile, poor prognosis subgroup, and associated with gene transcription and DNA repair pathways; a sensitivity signature (SENS) of 98 genes altered only in the good prognosis 75^th percentile and associated with different signal transduction pathways. When the RES signature was applied to the MSS subgroup, pts with at least one genomic alteration in any gene of the signature showed a mPFS of 8 months versus 20 months of the wild-type pts (wt; p<0.0001). The mPFS of SENS mutant and wt pts was 13 and 6.5 months, respectively (p= 0.0003). Finally, the differential RNA expression analysis between 25^th and the 75^th PFS percentile cohorts showed an upregulation of pathways involved in interferon gamma signalling and immune system activation in MSS cases with better prognosis.

Conclusions

These preliminary data suggest that CGP may identify prognostic genomic alterations in BRAF/RAS mut MSS mCRC pts receiving immune checkpoint inhibitors.

Legal entity responsible for the study

The authors.

Funding

Bristol Meyer Squibb Italy.

Disclosure

All authors have declared no conflicts of interest.