Original ResearchImpact of BRAF and RAS mutations on first-line efficacy of FOLFIRI plus cetuximab versus FOLFIRI plus bevacizumab: analysis of the FIRE-3 (AIO KRK-0306) study
Introduction
In metastatic colorectal cancer (mCRC), median overall survival (OS) of 30 months has been reached in clinical trials investigating the RAS wild-type population [1], [2], [3]. While meaningful progress has been achieved for this population, outcome of patients with RAS- or BRAF-mutant tumours remains poor. With the introduction of monoclonal antibodies (mAbs) such as bevacizumab targeting the vascular endothelial growth factor A (VEGF-A) and cetuximab or panitumumab targeting the epithelial growth factor receptor (EGFR), the question arose which targeted agent should be used in first-line treatment of mCRC. Two phase III studies addressed the question whether VEGF-A or EGFR blockade should be applied in the first-line treatment of mCRC of KRAS exon 2 wild-type tumours [1], [3]. Retrospective analyses for both the FIRE-3 and the CALGB 80405 trial analysed the extended RAS wild-type population, excluding mutations in KRAS and NRAS exon 2, 3 and 4, as the licensed patient population for anti-EGFR mAbs.
About 50% of mCRC patients present with RAS wild-type tumours and can be treated with either anti-EGFR or anti-VEGF agents. However, there is increasing evidence that the sequence of targeted therapy is clinically important, and first-line use of an anti-EGFR agent followed by an anti-VEGF–based treatment may provide optimal survival outcome [4], [5].
Exclusion of patients with RAS-mutant tumours from treatment with cetuximab or panitumumab was based on the consistent lack of efficacy observed for anti-EGFR agents in several studies [1], [6]. Optimal treatment of patients suffering from RAS- or BRAF-mutant tumours has not been defined so far. For the RAS-mutant population, data on a pooled analysis of 166 KRAS mutant patients of seven bevacizumab-containing trials are available [7]. Within this pooled analysis, the addition of bevacizumab to chemotherapy prolonged progression-free survival (PFS) significantly, but OS was not affected [7]. Data coming from single trials are limited [8] leading to an uncertainty if bevacizumab should be a default first-line therapy in RAS-mutant mCRC.
Analysis of BRAF mutations in mCRC patients has been suggested by the National Comprehensive Cancer Network (NCCN) guidelines for several years [9] and has recently also been recommended by the European Society of Medical Oncology (ESMO) consensus guideline [10]. BRAF mutation occurs at a rate of 8–10% in mCRC patients and is notably associated with a poor prognosis. Until now, optimal therapy has remained a matter of controversial debate.
Treatment with a BRAF inhibitor alone has no efficacy in mCRC [11] due to a feedback activation of the EGFR signalling [12]. The combination of BRAF inhibition plus MEK inhibition has shown positive results [13], and triple combinations of EGFR antibodies, BRAF inhibition and MEK pathway inhibition have been tested in early phase I/II studies with encouraging results [14], [15]. But currently those drug combinations are not approved and accordingly not available for most patients.
Due to the rather small subgroups of patients with BRAF-mutant tumours, the respective evaluations of phase III studies are, at the most, explorative and do not allow firm conclusions [16], [17] and two meta-analyses have not been able to provide more clarity to the issue [18], [19]. Therefore, it remains unclear whether cetuximab should be recommended as an active agent in BRAF-mutant patients.
Data are similarly limited for the use of bevacizumab in patients with BRAF-mutant tumours. However, the combined use of 5-FU, Oxaliplatin, Irinotecan (FOLFOXIRI) plus bevacizumab has recently been introduced as a so-called ‘standard of care’ for treatment of BRAF-mutant mCRC. This recommendation is based on an exploratory subgroup analysis of 28 BRAF-mutant patients in the TRIBE study [20] where FOLFOXIRI plus bevacizumab appeared to be more effective than 5-fluorouracil, leucovorin, irinotecan (FOLFIRI) plus bevacizumab. Due to the trial design, it can be concluded that intensification of treatment from FOLFIRI to FOLFOXIRI was effective, while the proper effect of bevacizumab could not be defined [20], [21].
The current analyses of the FIRE-3 (AIO KRK-0306) trial aim to evaluate the efficacy of FOLFIRI plus cetuximab or bevacizumab in the RAS- and BRAF-mutant subgroups.
Section snippets
Patients
Within FIRE-3 (AIO KRK-0306; NCT00433927) histologically confirmed KRAS exon 2 wild-type mCRC patients were treated with the FOLFIRI regimen as published elsewhere [1]. Patients were centrally randomized to either FOLFIRI bevacizumab or FOLFIRI cetuximab. The primary end-point, which was overall response rate (ORR), showed comparable results in both arms. PFS was also comparable between both arms, but OS showed a statistically significant prolongation for patients treated with FOLFIRI plus
Results
The consort diagram (Fig. 1) gives an overview of the subpopulations analysed in the current study. In short, 336 patients had been randomised prior to 2008 without knowledge of the RAS status. Of those, 113 were identified to suffer from KRAS exon 2 mutant tumours and were excluded from the intent-to-treat (ITT). Of the 592 patients of the ITT population (KRAS exon 2 wild type), 488 tumour samples were available and 475 revealed a result for RAS and BRAF analyses (Fig. 1). Within those, an
Discussion
The current data provide a final analysis of the RAS- and BRAF-mutant subpopulations of the FIRE-3 study. For now, there is strong evidence that anti-EGFR agents are not active in patients with RAS-mutant tumours. A detrimental effect of anti-EGFR agents has, however, only been observed when oxaliplatin-containing chemotherapies were used [6], [23]. Optimal treatment of BRAF-mutant mCRC still remains an open question [16], [18]. This study is the first to define the role of anti-EGFR substances
Conclusion
In conclusion, RAS and even more BRAF mutations are associated with a worse prognosis than expected for the RAS/BRAF wild-type population. In this retrospective analysis of the FIRE-3 study, comparable survival times (PFS and OS) were observed in RAS- and BRAF-mutant patients irrespective of the treatment with FOLFIRI plus cetuximab or FOLFIRI plus bevacizumab. This clearly demonstrates that optimal first-line treatment of these prognostic unfavourable subgroups has still to be defined. The
Conflict of interest statement
Author disclosures: Sebastian Stintzing received honoraria for talks, advisory boards and travel expenses from Roche, Merck KgaA, Amgen, Bayer, Lilly, Sanofi and Sirtex. Dominik Modest received honoraria for talks, advisory boards and travel expenses from Roche, Merck KgaA, Amgen, Bayer, Lilly, Sanofi, Sirtex and Servier. Andreas Jagenburg received honoraria for talks, advisory boards and travel expenses from B. Braun. Alexander Kiani received honoraria for talks, advisory boards and travel
References (34)
- et al.
ESMO consensus guidelines for the management of patients with metastatic colorectal cancer
Ann Oncol
(2016) - et al.
FOLFIRI plus cetuximab versus FOLFIRI plus bevacizumab as first-line treatment for patients with metastatic colorectal cancer-subgroup analysis of patients with KRAS: mutated tumours in the randomised German AIO study KRK-0306
Ann Oncol
(2012) - et al.
Predictive role of BRAF mutations in patients with advanced colorectal cancer receiving cetuximab and panitumumab: a meta-analysis
Eur J Cancer
(2015) - et al.
FOLFOX4 plus cetuximab treatment and RAS mutations in colorectal cancer
Eur J Cancer
(2015) - et al.
Addition of cetuximab to chemotherapy as first-line treatment for KRAS wild-type metastatic colorectal cancer: pooled analysis of the CRYSTAL and OPUS randomised clinical trials
Eur J Cancer
(2012) - et al.
Bevacizumab plus chemotherapy continued beyond first progression in patients with metastatic colorectal cancer previously treated with bevacizumab plus chemotherapy: ML18147 study KRAS subgroup findings
Ann Oncol
(2013) - et al.
Maintenance strategies after first-line oxaliplatin plus fluoropyrimidine plus bevacizumab for patients with metastatic colorectal cancer (AIO 0207): a randomised, non-inferiority, open-label, phase 3 trial
Lancet Oncol
(2015) - et al.
FOLFIRI plus cetuximab versus FOLFIRI plus bevacizumab for metastatic colorectal cancer (FIRE-3): a post-hoc analysis of tumour dynamics in the final RAS wild-type subgroup of this randomised open-label phase 3 trial
Lancet Oncol
(2016) - et al.
Initial therapy with FOLFOXIRI and bevacizumab for metastatic colorectal cancer
N Engl J Med
(2014) - et al.
CALGB/SWOG 80405: phase III trial of irinotecan/5-FU/leucovorin (FOLFIRI) or oxaliplatin/5-FU/leucovorin (mFOLFOX6) with bevacizumab (BV) or cetuximab (CET) for patients (pts) with KRAS wild-type (wt) untreated metastatic adenocarcinoma of the colon or rectum (MCRC)
J Clin Oncol
(2014)
Innovative strategies designed to improve adult pneumococcal immunizations in safety net patient-centered medical homes
Popul Health Manag
Impact of subsequent therapies on outcome of the FIRE-3/AIO KRK0306 trial: first-line therapy with FOLFIRI plus cetuximab or bevacizumab in patients with KRAS wild-type tumors in metastatic colorectal cancer
J Clin Oncol
Panitumumab-FOLFOX4 treatment and RAS mutations in colorectal cancer
N Engl J Med
Efficacy and safety of bevacizumab in metastatic colorectal cancer: pooled analysis from seven randomized controlled trials
Oncologist
The clinical benefit of bevacizumab in metastatic colorectal cancer is independent of K-ras mutation status: analysis of a phase III study of bevacizumab with chemotherapy in previously untreated metastatic colorectal cancer
Oncologist
NCCN guidelines colon cancer version 1.2017
Phase II pilot study of vemurafenib in patients with metastatic BRAF-mutated colorectal cancer
J Clin Oncol
Cited by (107)
European expert panel consensus on the clinical management of BRAF<sup>V600E</sup>-mutant metastatic colorectal cancer
2023, Cancer Treatment ReviewsBRAF<sup>V600E</sup> in colorectal cancer reduces sensitivity to oxidative stress and promotes site-specific metastasis by stimulating glutathione synthesis
2022, Cell ReportsCitation Excerpt :These results demonstrate that lowering the reductive capacity of BRAFV600E PDOs by simultaneous targeting of the GSH and the TXN systems is an efficient strategy to sensitize them to vemurafenib treatment. BRAFV600E is associated with distant metastasis formation.34,35,36,37 In this study, we identified the GSH-synthesizing enzyme GCLC as an essential mediator of distant metastasis formation to the liver and lungs in a PDO model of BRAFV600E metastatic CRC.