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

Purpose: The FIRE-4 study randomly assigned patients with first-line wild-type (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.

Patients And Methods: LBs were taken at baseline and during treatment and were analyzed for and mutations using the in vitro diagnostics-certified ONCOBEAM RAS procedure (Sysmex Inostics) and digital-droplet polymerase chain reaction technology.

Results: Six hundred seventy-two wt patients were randomly assigned. LBs of 540 patients were evaluable at baseline. Of those, 70 (13%) were mutant (mut) and 38 (7%) mutant. mut patients had significantly shorter survival compared with wt patients (progression-free survival [PFS], 9.0 months 11.5 months; < .001; hazard ratio [HR], 1.66; overall survival [OS], 22.1 months 33.6 months; < .001; HR, 1.85). mut patients had a numerically greater benefit from early switch maintenance compared with continuation of FOLFIRI/cetuximab (PFS, 10.1 months 6.4 months; HR, 0.82; OS, 24.9 months 16.3 months; HR, 0.57). Patients with a 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 wt to mut at disease progression was significantly higher in the arm with continuous cetuximab administration than in the switch maintenance arm.

Conclusion: LB allows the detection of and mutations in patients deemed wt on the basis of tissue analyses. These patients show outcome characteristics expected for - and -mutant patients in tissue. The study thus confirms the high clinical relevance of LB performed at baseline before the start of therapy.