Abstract
BACKGROUND: Biomarker-guided therapies are needed for patients with refractory metastatic colorectal cancer (mCRC). Liquid biopsy (LBx) circulating tumor DNA (ctDNA) comprehensive genomic profiling (CGP) could contribute to the clinical tailoring of molecular targeted therapies for these patients. PATIENTS AND METHODS: The CAVE-2 GOIM trial is a randomized phase II trial assessing the efficacy of adding avelumab to cetuximab compared with cetuximab monotherapy as anti-epidermal growth factor receptor (EGFR) rechallenge in refractory ctDNA RAS/BRAF(V600E) wild-type mCRC patients. Baseline plasma ctDNA CGP was carried out using the Foundation One Liquid CDx. RESULTS: LBx-based CGP was available for 324 patients out of 328 screened. A total of 1969 pathogenic variants (PVs) were detected. One hundred and thirty-five cases (41.7%) had single RAS/BRAF(V600) PVs, with 24 tumors (17.6%) having multiple RAS/BRAF(V600) PVs. Of 166 RAS/BRAF(V600) PVs, 95 (57.2%) consisted of subclonal alterations {median variant allele frequency [VAF] of 0.37% [interquartile range (IQR) 0.18%-1.0%] versus median VAF of 4.0% [IQR 0.65%-11.25%] in 71 cases of clonal PV; P < 0.0001}. Single RAS/BRAF(V600) alterations had higher clonality compared with co-occurring RAS/BRAF(V600) alterations [12.8% (IQR 1.93%-56.0%) versus 0.67% (IQR 0.37-3.35), P < 0.0001]. Among other genes potentially involved in anti-EGFR drug resistance, 174 non-RAS/BRAF(V600) PV were observed with 73 cases having both co-occurring RAS/BRAF(V600) and non-RAS/BRAF(V600) PV, while in 43 cases only non-RAS/BRAF(V600) PV were detected. Tumors harboring co-occurring non-RAS/BRAF(V600) PV had significantly lower clonality as compared with RAS/BRAF(V600) PV [1.52 (0.46-8.88) versus 17.0 (3.75-71.0), P < 0.0001]. Finally, a total of 332 genomic alterations with therapeutic relevance according to the European Society for Medical Oncology (ESMO) Scale for Clinical Actionability of Molecular Targets (ESCAT) were detected for 171 patients (52.7%). Of these, 120 tier I alterations were detected among 111 (34.3%) patients, which included high tumor mutational burden (≥10 mut/Mb, n = 101), BRAF(V600E) (n = 11), KRAS(G12C) (n = 7), and RET(fusion) (n = 1). CONCLUSIONS: LBx-based CGP might guide the appropriate use of anti-EGFR drug rechallenge or of other therapeutically actionable gene alterations in refractory mCRC.