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Stintzing, S.; Miller-Phillips, L.; Modest, D. P.; Fischer von Weikersthal, L.; Decker, T.; Kiani, A.; Vehling-Kaiser, U.; Al-Batran, S-E.; Heintges, T.; Kahl, C.; Seipelt, G.; Kullmann, F.; Stauch, M.; Scheithauer, W.; Held, S.; Moehler, M.; Jagenburg, A.; Kirchner, T.; Jung, A.; Heinemann, V. (2017): 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. In: European Journal of Cancer, Vol. 79: pp. 50-60
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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 antiepidermal 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 KaplaneMeier 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.