S Stintzing1, L Miller-Phillips2, D P Modest3, L Fischer von Weikersthal4, T Decker5, A Kiani6, U Vehling-Kaiser7, S-E Al-Batran8, T Heintges9, C Kahl10, G Seipelt11, F Kullmann12, M Stauch13, W Scheithauer14, S Held15, M Moehler16, A Jagenburg17, T Kirchner18, A Jung19, V Heinemann20. 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 eitherbevacizumab 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.
RCT Entities:
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.
Authors: Federico Innocenti; Fang-Shu Ou; Xueping Qu; Tyler J Zemla; Donna Niedzwiecki; Rachel Tam; Shilpi Mahajan; Richard M Goldberg; Monica M Bertagnolli; Charles D Blanke; Hanna Sanoff; James Atkins; Blasé Polite; Alan P Venook; Heinz-Josef Lenz; Omar Kabbarah Journal: J Clin Oncol Date: 2019-03-13 Impact factor: 44.544
Authors: Gregor A Stavrou; Marcello Donati; Mohammad H Fard-Aghaie; Martin Zeile; Tessa M Huber; Axel Stang; Karl J Oldhafer Journal: Visc Med Date: 2017-11-30