Baseline Liquid Biopsy in Relation to Tissue-Based Parameters in Metastatic Colorectal Cancer: Results From the Randomized FIRE-4 (AIO-KRK-0114) Study.

Abstract

The FIRE-4 study randomly assigned patients with first-line <i>RAS</i> wild-type (<i>RAS</i>wt) metastatic colorectal cancer to either flourouracil (FU), folinic acid, and irinotecan (FOLFIRI) plus cetuximab until progression or intolerable toxicity (standard arm) or to FOLFIRI plus cetuximab followed by a switch maintenance treatment using FU plus bevacizumab (experimental arm). Here, we investigate the relevance of liquid biopsy (LB) RAS and BRAF testing compared with tissue-based analyses. LBs were taken at baseline and during treatment and were analyzed for <i>RAS</i> and <i>BRAF</i>^V600E mutations using the in vitro diagnostics-certified ONCOBEAM RAS procedure (Sysmex Inostics) and digital-droplet polymerase chain reaction technology. Six hundred seventy-two <i>RAS</i>wt patients were randomly assigned. LBs of 540 patients were evaluable at baseline. Of those, 70 (13%) were <i>RAS</i> mutant (<i>RAS</i>mut) and 38 (7%) <i>BRAF</i>^V600E mutant. <i>RAS</i>mut patients had significantly shorter survival compared with <i>RAS</i>wt patients (progression-free survival [PFS], 9.0 months <i>v</i> 11.5 months; <i>P</i> < .001; hazard ratio [HR], 1.66; overall survival [OS], 22.1 months <i>v</i> 33.6 months; <i>P</i> < .001; HR, 1.85). <i>RAS</i>mut patients had a numerically greater benefit from early switch maintenance compared with continuation of FOLFIRI/cetuximab (PFS, 10.1 months <i>v</i> 6.4 months; HR, 0.82; OS, 24.9 months <i>v</i> 16.3 months; HR, 0.57). Patients with a <i>BRAF</i>^V600E mutation in LB showed poor outcome (PFS, 5.4 months; OS, 12.0 months). On the basis of serial LB analyses, the conversion rate from <i>RAS</i>wt to <i>RAS</i>mut at disease progression was significantly higher in the arm with continuous cetuximab administration than in the switch maintenance arm. LB allows the detection of <i>RAS</i> and <i>BRAF</i> mutations in patients deemed <i>RAS</i>wt on the basis of tissue analyses. These patients show outcome characteristics expected for <i>RAS</i>- and <i>BRAF</i>-mutant patients in tissue. The study thus confirms the high clinical relevance of LB performed at baseline before the start of therapy.