Format

Send to

Choose Destination
Eur J Cancer. 2017 Jul;79:50-60. doi: 10.1016/j.ejca.2017.03.023. Epub 2017 Apr 29.

Impact 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.

Author information

1
Department of Hematology and Oncology, University of Munich, Marchioninistrasse 15, 81377, Munich, Germany. Electronic address: sebastian.stintzing@med.uni-muenchen.de.
2
Department of Hematology and Oncology, University of Munich, Marchioninistrasse 15, 81377, Munich, Germany.
3
Department of Hematology and Oncology, University of Munich, Marchioninistrasse 15, 81377, Munich, Germany. Electronic address: Dominik.modest@med.uni-muenchen.de.
4
MVZ Gesundheitszentrum St. Marien GmbH, Mariahilfbergweg 7, 92224, Amberg, Germany. Electronic address: weikersthal.ludwig@klinikum-amberg.de.
5
Studienzentrum Onkologie Ravensburg, Elisabethenstraße 19, 88212, Ravensburg, Germany. Electronic address: t.decker@lrz.tu-muenchen.de.
6
Klinikum Bayreuth GmbH, Preuschwitzer Straße 101, 95445, Bayreuth, Germany. Electronic address: alexander.kiani@klinikum-bayreuth.de.
7
Praxis Hämatologie/Onkologie/Palliativmedizin - Tagesklinik, Ländgasse 132-135, 84028, Landshut, Germany. Electronic address: info@vehling-kaiser.de.
8
Krankenhaus Nordwest, Medizinische Klinik II/Onkologie, Steinbacher Hohl 2-26, 60488, Frankfurt, Germany. Electronic address: albatran.salah@khnw.de.
9
Lukaskrankenhaus Neuss, Medizinische Klinik II, Preussenstr. 84, 41464, Neuss, Germany. Electronic address: heintges@lukasneuss.de.
10
Städtisches Klinikum Magdeburg, Hämatologie/Onkologie, Birkenallee 34, 39130, Magdeburg, Germany. Electronic address: christoph.kahl@klinikum-magdeburg.de.
11
Onkologische Schwerpunktpraxis und Tagesklinik, Kronbergerstraße 38, 65812, Bad Soden, Germany. Electronic address: onkologie-mtk@telemed.de.
12
Klinikum Weiden, Medizinische Klinik I, Söllnerstr. 16, 92637, Weiden, Germany. Electronic address: frank.kullmann@kliniken-nordoberpfalz.ag.
13
Praxis für Hämatologie und internistische Onkologie, Niederbronner Str. 2, 96317, Kronach, Germany. Electronic address: praxisdrstauch@t-online.de.
14
Univ.-Klinik für Innere Medizin I, Klin. Abteilung für Onkologie, Währinger Gürtel 18-20, 1090, Wien, Austria. Electronic address: werner.scheithauer@meduniwien.ac.at.
15
ClinAssess GmbH, Birkenbergstraße 82, 51379 Leverkusen, Germany. Electronic address: s.held@clinassess.de.
16
Johannes-Gutenberg Universität Mainz, 1. Medizinische Klinik und Poliklinik, 55101, Mainz, Germany. Electronic address: moehler@mail.uni-mainz.de.
17
Radiology Consulting GmbH, Burscheider Str. 398A, 51381, Leverkusen, Germany. Electronic address: info@radiology-consulting.com.
18
Institute of Pathology, University of Munich, Thalkirchner Str. 37, 82036, Munich, Germany. Electronic address: Thomas.kirchner@med.uni-muenchen.de.
19
Institute of Pathology, University of Munich, Thalkirchner Str. 37, 82036, Munich, Germany. Electronic address: Andreas.jung@med.uni-muenchen.de.
20
Department of Hematology and Oncology, University of Munich, Marchioninistrasse 15, 81377, Munich, Germany. Electronic address: Volker.heinemann@med.uni-muenchen.de.

Abstract

BACKGROUND:

RAS and BRAF mutations have been identified as negative prognostic factors in metastatic colorectal cancer. Efficacy of 5-fluorouracil, leucovorin, irinotecan (FOLFIRI) plus bevacizumab in patients with RAS-mutant tumours needs to be further evaluated. Whether to treat patients with BRAF-mutant tumours with either bevacizumab or anti-epidermal growth factor receptor (EGFR) antibodies remains unclear.

METHODS:

Patients treated within the FIRE-3 trial were retrospectively tested for BRAF and RAS mutations using formalin fixated paraffin embedded (FFPE) tumour material applying pyrosequencing for KRAS and NRAS exon 2, 3 and 4 mutations as far as for BRAF mutations. Survival analysis was done using Kaplan-Meier estimation and differences were expressed using the log-rank test. Overall response rate (ORR) was compared using Fisher's exact test. Data from a central independent radiological response evaluation were used to calculate early tumour shrinkage (ETS) and depth of response (DpR).

RESULTS:

Overall, 188 patients with RAS-mutant tumours and 48 with BRAF-mutant tumours were identified. In BRAF-mutant patients, ORR was numerically higher in the cetuximab versus the bevacizumab arm (52% versus 40%), while comparable results were achieved for progression-free survival (PFS; hazard ratio [HR] = 0.84, p = 0.56) and overall survival (OS; HR 0.79, p = 0.45). RAS mutation was associated with a trend towards lower ORR (37% versus 50.5%, p = 0.11) and shorter PFS (7.4 versus 9.7 months; HR 1.25; p = 0.14) in patients receiving FOLFIRI plus cetuximab versus bevacizumab, but OS was comparable (19.1 versus 20.1 months; HR 1.05; p = 0.73), respectively. ETS identified subgroups sensitive to cetuximab-based treatment in both BRAF- (9/17) and RAS-mutant (18/48) patients and was associated with significantly longer OS. DpR was comparable between both treatment arms in RAS- and BRAF-mutant patients, respectively.

CONCLUSIONS:

In BRAF- and RAS-mutant patients, cetuximab- and bevacizumab-based treatment had comparable survival times. ETS represents an early parameter associated with the benefit from anti-EGFR, while this was not the case with vascular endothelial growth factor A blockade.

KEYWORDS:

BRAF; Bevacizumab; Cetuximab; Colorectal cancer; RAS

PMID:
28463756
DOI:
10.1016/j.ejca.2017.03.023
[Indexed for MEDLINE]

Supplemental Content

Full text links

Icon for Elsevier Science
Loading ...
Support Center