The use of liquid biopsy comprehensive genomic profiling to identify the molecular landscape of patients with metastatic colorectal cancer who are candidates for anti-EGFR rechallange therapy: Findings from the CAVE-2 GOIM trial.

221 Background: In the era of precision medicine, biomarker guided therapies are necessary for patients with chemorefractory metastatic colorectal cancer (mCRC). Circulating tumor DNA (ctDNA) comprehensive genomic profiling (CGP) may contribute to the development of more effective treatments. Methods: CAVE-2 GOIM trial (ClinicalTrials.gov ID: NCT05291156) is the first randomized phase II study to assess the efficacy of avelumab plus cetuximab compared to cetuximab alone as rechallenge strategy in pre-treated plasma ctDNA RAS, BRAF WT mCRC patients. Before being enrolled in the trial, patients were selected by baseline plasma ctDNA analysis by Foundation One Liquid CDx (F1L CDx) 324 genes to identify ctDNA RAS/BRAF WT cases. Results: As of July 31th 2024, 229 (out of approximately 310) patients have been screened. A total of 1562 pathogenic variants (PV) were detected, with TP53 (86.0%), APC (84.2%), DNMT3A (30.5%) representing the most common altered genes. In these anti-EGFR pretreated patients different acquired mechanisms of resistance were observed. In particular, 72/229 (31.4%) patients had RAS or BRAF V600E PV (102 KRAS , 21 NRAS and 8 BRAF V600E mutations, respectively). Additionally, in these 72 patients, multiple RAS/BRAF V600E gene alterations (median of 1 PV, range 1-7) were observed in 41.6% cases. MAPK, RTK , and PI3K/AKT/mTOR PV were detected in 43.2%, 24.5% and 24.5% patients, respectively. Of note, the variant allele frequency of resistant PV was lower than other gene alterations, suggesting a high tumor heterogeneity as a consequence of the development and/or expansion of EGFR-inhibitor resistant cancer cell sub-clones. All patients were assessed for tumor mutational burden (TMB). Median TMB was 6 (IQR 4-10) mut/Mb, with 29.6% cases showing a TMB ≥10 mut/Mb. Finally, a total of 258 actionable genomic alterations were detected in 52,4% of patients according to the ESMO Scale for Clinical Actionability of Molecular Targets (ESCAT). Eighty-one tier I alterations were detected in 32.3% patients, which included TMB high (29,7%), BRAF V600E (3,5%), KRAS G12C (6,5%), and RET fusions (0,4%). Conclusions: These findings support liquid biopsy-based GCP for individualized therapeutic choices in chemorefractory mCRC. Up-dated final analyses of the entire screened patient population of the CAVE-2 GOIM trial will be presented. Clinical trial information: NCT05291156 .