title: 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.
abstract: BACKGROUND
  FIRE-3 compared first-line 5-fluorouracil, leucovorin, and irinotecan (FOLFIRI) plus cetuximab with FOLFIRI plus bevacizumab in patients with KRAS exon 2 wild-type metastatic colorectal cancer. The same study also reported an exploratory analysis of a subgroup of patients with tumours that were wild-type at other RAS genes (KRAS and NRAS exons 2-4). We report here efficacy results for the FIRE-3 final RAS (KRAS/NRAS, exons 2-4) wild-type subgroup. Moreover, new metrics of tumour dynamics were explored during a centralised radiological review to investigate how FOLFIRI plus cetuximab conferred overall survival benefit in the absence of differences in investigator-assessed objective responses and progression-free survival.
  
  
  METHODS
  FIRE-3 was a randomised phase 3 trial comparing FOLFIRI plus cetuximab with FOLFIRI plus bevacizumab in the first-line treatment of patients with KRAS exon 2 wild-type metastatic colorectal cancer. The primary endpoint of the FIRE-3 study was the proportion of patients achieving an objective response according to Response Evaluation Criteria In Solid Tumors (RECIST) 1.0 in the intention-to-treat population. A centralised radiological review of CT scans was done in a post-hoc analysis to assess objective response according to RECIST 1.1, early tumour shrinkage, depth of response, duration of response, and time to response in the final RAS wild-type subgroup. Comparisons between treatment groups with respect to objective response rate and early tumour shrinkage were made using Fisher's exact test (two-sided), while differences in depth of response were investigated with a two-sided Wilcoxon test. This trial is registered at ClinicalTrials.gov, number NCT00433927.
  
  
  RESULTS
  In the final RAS wild-type population (n=400), median overall survival was better in the FOLFIRI plus cetuximab group than the FOLFIRI plus bevacizumab group (33·1 months [95% CI 24·5-39·4] vs 25·0 months [23·0-28·1]; hazard ratio 0·70 [0·54-0·90]; p=0·0059), although investigator-assessed objective response and progression-free survival were comparable between treatment groups. Centralised radiological review of CT-assessable patients (n=330) showed that the proportion of patients achieving an objective response (113 of 157, 72·0% [95% CI 64·3-78·8] vs 97 of 173, 56·1% [48·3-63·6]; p=0·0029), frequency of early tumour shrinkage (107 of 157, 68·2% [60·3-75·4] vs 85 of 173, 49·1% [41·5-56·8]; p=0·0005), and median depth of response (-48·9% [-54·3 to -42·0] vs -32·3% [-38·2 to -29·2]; p<0·0001) were significantly better in extended RAS wild-type patients receiving FOLFIRI plus cetuximab versus those receiving FOLFIRI plus bevacizumab. No differences in duration of response and time to response were observed between treatment groups.
  
  
  CONCLUSIONS
  This analysis provides a new framework that connects alternative metrics of response to overall survival. Superior response-related outcome parameters, such as early tumour shrinkage and depth of response, obtained by centralised radiological review correlated with the overall survival benefit conferred by FOLFIRI plus cetuximab compared with FOLFIRI plus bevacizumab in the extended RAS wild-type subgroup.
  
  
  BACKGROUND
  Merck KGaA and Pfizer.
authors: Department of Hematology and Oncology, University of Munich, Munich, Germany; DKTK, German Cancer Consortium, German Cancer Research Centre (DKFZ), Heidelberg, Germany. Electronic address: sebastian.stintzing@med.uni-muenchen.de.
authors: Sebastian
authors: S
authors: Stintzing
authors: Department of Hematology and Oncology, University of Munich, Munich, Germany; DKTK, German Cancer Consortium, German Cancer Research Centre (DKFZ), Heidelberg, Germany.
authors: Dominik P
authors: DP
authors: Modest
authors: Department of Hematology and Oncology, University of Munich, Munich, Germany.
authors: Lisa
authors: L
authors: Rossius
authors: Klinik und Poliklinik für Innere Medizin A, Universitätsmedizin Greifswald, Greifswald, Germany.
authors: Markus M
authors: MM
authors: Lerch
authors: MVZ Gesundheitszentrum St. Marien GmbH, Amberg, Germany.
authors: Ludwig Fischer
authors: LF
authors: von Weikersthal
authors: Studienzentrum Onkologie Ravensburg, Ravensburg, Germany.
authors: Thomas
authors: T
authors: Decker
authors: Klinikum Bayreuth GmbH, Bayreuth, Germany.
authors: Alexander
authors: A
authors: Kiani
authors: Praxis Hämatologie/Onkologie/Palliativmedizin-Tagesklinik, Landshut, Germany.
authors: Ursula
authors: U
authors: Vehling-Kaiser
authors: Krankenhaus Nordwest, Medizinische Klinik II/Onkologie, Frankfurt, Germany.
authors: Salah-Eddin
authors: SE
authors: Al-Batran
authors: Lukaskrankenhaus Neuss, Neuss, Germany.
authors: Tobias
authors: T
authors: Heintges
authors: Gemeinschaftspraxis f. Hämatologie u. Onkologie, Münster, Germany.
authors: Christian
authors: C
authors: Lerchenmüller
authors: Städtisches Klinikum Magdeburg, Hämatologie/Onkologie, Magdeburg, Germany.
authors: Christoph
authors: C
authors: Kahl
authors: Onkologische Schwerpunktpraxis und Tagesklinik, Bad Soden, Germany.
authors: Gernot
authors: G
authors: Seipelt
authors: Klinikum Weiden, Medizinische Klinik I, Weiden, Germany.
authors: Frank
authors: F
authors: Kullmann
authors: Praxis für Hämatologie und internistische Onkologie, Kronach, Germany.
authors: Martina
authors: M
authors: Stauch
authors: Univ.-Klinik für Innere Medizin I, Klin. Abteilung für Onkologie, Wien, Austria.
authors: Werner
authors: W
authors: Scheithauer
authors: ClinAssess GmbH, Leverkusen, Germany.
authors: Swantje
authors: S
authors: Held
authors: Department of Hematology and Oncology, University of Munich, Munich, Germany.
authors: Clemens
authors: C
authors: Giessen-Jung
authors: Universität Mainz, 1. Medizinische Klinik und Poliklinik, Mainz, Germany.
authors: Markus
authors: M
authors: Moehler
authors: Radiology Consulting GmbH, Leverkusen, Germany.
authors: Andreas
authors: A
authors: Jagenburg
authors: Institute of Pathology, University of Munich, Munich, Germany; DKTK, German Cancer Consortium, German Cancer Research Centre (DKFZ), Heidelberg, Germany.
authors: Thomas
authors: T
authors: Kirchner
authors: Institute of Pathology, University of Munich, Munich, Germany; DKTK, German Cancer Consortium, German Cancer Research Centre (DKFZ), Heidelberg, Germany.
authors: Andreas
authors: A
authors: Jung
authors: Department of Hematology and Oncology, University of Munich, Munich, Germany; DKTK, German Cancer Consortium, German Cancer Research Centre (DKFZ), Heidelberg, Germany.
authors: Volker
authors: V
authors: Heinemann
mesh_terms: D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage / Q000627:therapeutic use*; D000068258:Bevacizumab / Q000008:administration & dosage; D002166:Camptothecin / Q000008:administration & dosage / Q000031:analogs & derivatives; D000068818:Cetuximab / Q000008:administration & dosage; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology; D005260:Female; D005472:Fluorouracil / Q000008:administration & dosage; D011905:Genes, ras; D006801:Humans; D002955:Leucovorin / Q000008:administration & dosage; D008297:Male; D008875:Middle Aged; D009362:Neoplasm Metastasis; D066066:Response Evaluation Criteria in Solid Tumors; D014057:Tomography, X-Ray Computed
chemical_list: D000068258:Bevacizumab; D000068818:Cetuximab; D002955:Leucovorin; D005472:Fluorouracil; D002166:Camptothecin