Gastroenterology, Oncology, Oncology / Haematology

Video Interview and Report: Analysis of KRAS/NRAS and BRAF mutations in FIRE-3 following the ECC2013/11/14

A randomised phase III study of FOLFIRI plus cetuximab or bevacizumab as first line treatment for wild-type KRAS (exon 2) metastatic colorectal cancer (mCRC) patients by Professor Volker Heinemann, University of Munich, Germany. 

A pre-planned secondary analysis of data from the German phase III clinical trial FIRE-3 shows that RAS wild-type patients treated with cetuximab plus FOLFIRI gained 7.5 months overall survival benefit compared with patients receiving bevacizumab plus FOLFIRI. The results of the analysis were presented as a late-breaking abstract by Professor Volker Heinemann from Munich, who is also the principal investigator on the FIRE-3 study.

Patients have been included in the FIRE-3 study since January 2007, at 150 centres in Germany and Austria, with the objective of comparing the efficacy of FOLFIRI plus cetuximab with FOLFIRI plus bevacizumab as first-line treatment in patients with mCRC. Initially patients were included independently of KRAS mutation status, but a protocol amendment effective from October 2008 limited inclusion to patients with KRAS wild-type tumours. The primary endpoint was the overall response rate (ORR) in accordance with the Response Evaluation Criteria In Solid Tumours (RECIST) guidelines version 1.0. Key secondary outcomes included progression-free survival (PFS), overall survival (OS), and resection rate. The initial results of the FIRE-3 study were presented at this year’s American Society of Clinical Oncology (ASCO) meeting and showed that whilst the cetuximab plus FOLFIRI and bevacizumab plus FOLFIRI treatment arms were comparable in terms of ORR (62% vs 57%; odds ratio [OR] 1.249) and median PFS (10.3 vs 10.4 months, hazard ratio (HR) 1.04; p=ns), OS was significantly better in the cetuximab arm with a survival benefit of 3.7 months (28.8 vs 25.0 months; HR 0.77; 95% CI 0.620-0.953; p=0.0164)) [1].

The FIRE-3 protocol included a pre-determined analysis to determine the impact of RAS mutation status on the clinical outcome. The primary efficacy analysis had included 592 patients with KRAS exon 2 wild-type status; these tumour samples were analysed using pyrosequencing to identify mutations in KRAS (exon 3 (codon 59/61), exon 4 (codon 117/146)), NRAS (exon 2 (codon 12/13), exon 3 (codon 59/61) and exon 4 (codon 117/146)) and BRAF (V600E). The resulting RAS evaluable population consisted of 407 samples in which the RAS mutation analyses had been successful in all locations, and was fully comparable with the KRAS wild-type exon 2 population in the FIRE-3 intention to treat (ITT) population, in terms of not only baseline and tumour-related characteristics but also the response parameters.

The results of the analysis showed that for RAS wild-type patients, ORR in the cetuximab plus FOLFIRI and bevacizumab plus FOLFIRI groups was similar to that observed in the KRAS exon 2 wild-type ITT population at 65.5% vs 59.86%; OR 1.28. In contrast, in patients with RAS mutations ORR was numerically lower in the cetuximab group (38.2% vs 58.1%; OR 0.45) although not significantly different. Similarly, PFS was largely comparable in the two groups in RAS wild-type patients (10.4 vs 10.2 months, HR 0.93; p=ns) but significantly lower in the cetuximab plus FOLFIRI group in patients with RAS mutations (6.1 vs 12.2 months, HR 2.22; p=0.004).[2].

The most important and dramatic difference between the two treatment groups was observed in overall survival: here, RAS wild-type patients showed a highly significant (both statistically and clinically) benefit of 7.5 months increased OS (33.1 vs 25.6 months; HR 0.70; 95% CI 0.53-0.92; p=0.011), whereas no such difference was observed in patients with RAS mutations (16.4 vs 20.6 months; HR 1.20; 95% CI 0.64-2.28; p=ns).

CLICK HERE for the survival curves for RAS wild-type patients.
Reproduced from presentation by V Heinemann at ECC 2013

In his conclusion of the results, Professor Heinemann reminded the audience that the FIRE-3 study is the first to compare cetuximab plus FOLFIRI and bevacizumab with FOLFIRI as first-line treatment options for mCRC, and stressed that the results of this per-protocol analysis strongly suggest that determining RAS mutation status upfront may significantly influence the outcome when initiating treatment in mCRC by identifying patients who are likely to derive clinical benefit from targeted therapy.


1.   Heinemann, V. and e. al, Randomized comparison of FOLFIRI plus cetuximab versus FOLFIRI plus bevacizumab as first-line treatment of KRAS wild-type metastatic colorectal cancer: German AIO study KRK-0306 (FIRE-3). J Clin Oncol, 2013. 31 suppl: p. LBA3506.

2.    Stinzing S et al., European Cancer Congress Late breaking abstract LBA17