Baseline liquid biopsy results in treatment efficacy of FOLFIRI/cetuximab in patients with tissue RAS-WT mCRC

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Published: 4 Jun 2023
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Prof Sebastian Stintzing - Universitätsmedizin Berlin, Berlin, Germany

Prof Sebastian Stintzing speaks to ecancer about the phase III FIRE-4 study.

The study investigated if an early switch from cetuximab to bevacizumab may prolong progression-free survival. Furthermore, serial baseline liquid biopsies were taken to analyse RAS and BRAF mutations.

This study found that liquid biopsy detected RAS mutation in 13% of patients deemed RASwt based on tissue analyses. These patients show outcome characteristics expected for RAS mutant patients (median PFS of 9.0 months and median OS of 22 months).

This proves the clinical relevance of liquid biopsy in the verification of RAS mutational status.


In the FIRE-4 study we were investigating two endpoints so we had two randomisations. The primary endpoint, which will be overall survival after randomisation 2, is basically analysing the question of whether cetuximab rechallenge in patients that have responded to cetuximab early on is meaningful or not. This is still ongoing and it’s still on follow-up so we do not have the data on this part of the study so far.

What we have talked about at this year’s ASCO was the influence of baseline liquid biopsy in a RAS wildtype metastatic colorectal cancer population treated with either FOLFIRI plus cetuximab as a standard arm until progression or intolerable toxicity. This was randomised against FOLFIRI/cetuximab as induction treatment for a total of 8-12 cycles and then we applied a switch maintenance containing 5FU, capecitabine and bevacizumab. 

Within the liquid biopsy programme we did a baseline liquid biopsy and also a follow-up liquid biopsy, especially at the end of the treatment or at the time of progression to get a better insight about the meaning of liquid biopsy in this setting. Quite unexpected, we found 13% of the liquid biopsies positive for a RAS mutation, so although it was a RAS wildtype population by tissue analysis, we found an addition of 13% of RAS mutant cases. Those cases actually had clinical outcomes according to a RAS mutant population. So at baseline we have a very strong prognostic and prospective value of the liquid biopsy.

Furthermore, as expected, we were able to detect around 7% of BRAF V600E mutant cases, again those cases had outcome parameters according to a BRAF V600E mutant patient population. The very short progression free survival and a very short overall survival, as I said, as expected for this kind of patient population.

How could this treatment impact the future treatment of metastatic colorectal cancer?

We have seen a lot of development when it comes to liquid biopsy during the last 5-10 years. So the sensitivity has become better, also there are more and more commercially available vendors where you could just order such kind of an analysis. The big question right now is what is covering the real tumour population better – liquid biopsy or tissue-based biopsy? As we were able to carve out another 13% of patients that do not benefit from anti-EGFR because of their RAS mutations that we were able to detect, it’s probably good to do both, if possible, to do a tissue test first and then, in addition, a liquid biopsy test. 

In my opinion, in the future, especially if tissue testing takes a lot of time, maybe we will be able to replace tissue-based RAS testing by liquid biopsy testing which is just more convenient and faster to get the results.