The results from the phase III FIRE-4 randomized clinical trial show that liquid biopsy accurately identified patients with RAS/BRAF V600E wild type–mutated metastatic colorectal cancer. The findings confirm the high clinical relevance of liquid biopsy performed at baseline before the start of therapy, according to the study authors. The study by Stintzing et al was published in the Journal of Clinical Oncology.

Current clinical practice guidelines from both ASCO and the European Society for Medical Oncology (ESMO) in the diagnosis, treatment, and follow-up for metastatic colorectal cancer (mCRC) call for treatment decisions in first-line therapy of the disease be informed by patient characteristics and the molecular makeup of the tumor. The guidelines recommend testing for DNA mismatch repair deficiency and BRAF V600E and RAS mutations before the start of targeted treatment in first-line therapy.

Study Methodology

The researchers randomly assigned 672 patients with first-line RAS-mutated wild type metastatic colorectal cancer to receive either fluorouracil, folinic acid, and irinotecan (FOLFIRI) plus cetuximab until disease progression or intolerable toxicity (standard arm) or FOLFIRI plus cetuximab followed by a switch maintenance treatment using fluorouracil plus bevacizumab (experimental arm). They then investigated the relevance of liquid biopsy RAS and BRAF testing compared with tissue-based analysis.

Liquid biopsies were taken at baseline and during treatment. They were analyzed for RAS and BRAF V600E mutations using in vitro diagnostics-certified ONCOBEAM RAS procedure and digital-droplet polymerase chain reaction technology.

Key Results

Of the 672 patients randomly assigned, 540 had sufficient baseline liquid biopsies, and a total of 357 patients provided follow-up liquid biopsies. The researchers found of those patients, 70 (13%) had tumors that were RAS-mutant, and 38 (7%) had tumors that were BRAF V600E–mutant. Patients with the RAS mutation had significantly shorter survival compared with patients with RAS wild-type (progression-free survival [PFS] = 9.0 months vs 11.5 months; P < .001; hazard ratio [HR] = 1.66; overall survival [OS] = 22.1 months vs 33.6 months; P < .001; HR = 1.85).

The patients with the RAS mutation had a numerically greater benefit from early switch maintenance compared with continuation of FOLFIRI/cetuximab (PFS = 10.1 months vs 6.4 months; HR = 0.82; OS = 24.9 months vs 16.3 months; HR = 0.57). The patients with a BRAF V600E mutation in liquid biopsy showed poor outcomes (PFS = 5.4 months; OS = 12.0 months). On the basis of serial liquid biopsy analyses, the researchers found the conversion rate from RAS wild-type to RAS-mutant at disease progression was significantly higher in the arm with continuous cetuximab administration than in the switch maintenance arm.

“Liquid biopsy allows the detection of RAS and BRAF mutations in patients deemed RAS wild-type on the basis of tissue analyses. These patients show outcome characteristics expected for RAS- and BRAF-mutant patients in tissue. The study thus confirms the high clinical relevance of liquid biopsy performed at baseline before the start of therapy,” concluded the study authors.

Clinical Relevance

In response to the study’s findings, Andrew H. Ko, MD, FASCO, Associate Editor of the Journal of Clinical Oncology, shared these comments in the study abstract: “Liquid biopsy plays an important and complementary role to tissue-based testing in patients with mCRC. Discordant findings at baseline, as well as change in RAS mutational status during treatment, may be useful to help guide selection of therapy.”

Sebastian Stintzing, MD, of the Charité Universitätsmedizin Berlin, is the corresponding author of this study in the Journal of Clinical Oncology.

Disclosure: For full disclosures of the study authors, visit ascopubs.org.