Prognostic genomic signatures in patients with RAS and BRAF wild-type (wt) metastatic colorectal cancer (mCRC) from the phase III study of first-line FOLFIRI/cetuximab versus FOLFIRI/cetuximab followed by cetuximab (Cet) alone (ERMES study).
Authors: Nicola Normanno, Anna Maria Rachiglio, Riziero Esposito Abate, Armando Orlandi, Evaristo Maiello, Giuseppe Maglietta, Angela Damato, Monica Rosaria Maiello, Marianeve Carotenuto, Maria Alessandra Calegari, Lorenzo Antonuzzo, Roberto Bordonaro, Maria Giulia Zampino, Stefano Tamberi, Sara Lonardi, Antonio Avallone, Tiziana Pia Latiano, Emiliano Tamburini, Carlo Antonio Barone, Carmine Pinto
Journal: Journal of Clinical Oncology (2024)

3590 Background: The ERMES trial did not show non-inferiority of maintenance with Cet alone versus standard treatment. However, preliminary results suggested that a strategy of de-escalation treatment with only Cet might be effective in selected patients. Here we describe preliminary data from comprehensive genomic profiling (CGP) of CRC samples from the ERMES study. Methods: Patients with untreated RAS/BRAF wt mCRC were randomly assigned (1:1) to receive either FOLFIRI/Cet until PD/toxicity (arm A) or FOLFIRI/Cet for 8 cycles followed by Cet alone (arm B). DNA from tumor tissue samples was analyzed with the Oncomine Comprehensive Assay Plus covering hot spot mutations in over 500 genes. Variant calling was performed using the Ion Reporter v5.20 software. The prognostic value of genomic signatures was assessed in the intention-to-treat (ITT) patients’ population with available sequencing data. Results: CGP has been successfully completed so far for 139 patients of the ITT population (68 in arm A and 71 in arm B). This subgroup had a median progression free survival (mPFS) of 9.3 months. The comparison of the genomic profile of cases within the 25 th and the 75 th mPFS percentile (34 and 36 patients, respectively), identified two signatures that were defined: RES, 14 genes with genomic alterations unique to the 25 th percentile poor prognosis group; SENS, 34 genes altered only in the 75 th percentile good prognosis cohort. The RES signature was significantly associated with ERBB2, IL-4 and IL-13, MET activated PI3K/AKT, ESR, PI3K and FGFR4 signalling. When the RES signature was applied to the whole cohort, patients with at least one genomic alterations in any gene of the signature showed a mPFS of 2.4 months versus 15.2 months of the wt (Hazard Ratio, HR wt versus mutant 0.07). The SENS signature was associated with pathways related to gene transcription and expression, SMAD 2/3/4 transcription, DNA repair, chromatin modification and Activin signalling. The mPFS of SENS mutant and wt patients was 16.2 and 3.2 months, respectively (HR wt versus mutant 10.09). An exploratory analysis found no significant differences in mPFS for patients with good prognosis based on genomic signatures enrolled in the standard arm (A) versus the experimental arm (B). Conclusions: These preliminary data suggest that CGP of mCRC patients can identify prognostic genomic signatures, which might allow a better stratification of patients and the identification of subgroups that might benefit a treatment de-escalation strategy.