LBA11 - Independent radiological evaluation of objective response, early tumor shrinkage, and depth of response in FIRE-3 (AIO KRK-0306) in the final RAS e...

Date 29 September 2014
Event ESMO 2014
Session Anti-EGFR or anti-VEGF in first-line RAS wild-type metastastic CRC patients: Can we define an "optimal" treatment strategy?
Topics Anti-Cancer Agents & Biologic Therapy
Colon Cancer
Rectal Cancer
Personalised Medicine
Presenter Sebastian Stintzing
Citation Annals of Oncology (2014) 25 (5): 1-41. 10.1093/annonc/mdu438
Authors S. Stintzing1, D.P. Modest1, L. Fischer von Weikersthal2, T. Decker3, A. Kiani4, U. Vehling-Kaiser5, S. Al-Batran6, T. Heintges7, C. Lerchenmueller8, C. Kahl9, G. Seipelt10, F. Kullmann11, W. Scheithauer12, S. Held13, C. Giessen1, M. Moehler14, A. Jagenburg15, A. Jung16, T. Kirchner17, V. Heinemann1
  • 1Hematology And Oncology, University of Munich, 81377 - Munich/DE
  • 2Medical Oncology, Gesundheitszentrum Klinikum Amberg, Amberg/DE
  • 3Private Practice, Onkologische Schwerpunktpraxis, DE-88214 - Ravensburg/DE
  • 4Department Of Medicine Iv, Klinikum Bayreuth, Bayreuth/DE
  • 5Medical, Schwerpunktpraxis für Hämatologie, Onkologie und Palliativmedizin Praxis Dr. Vehling - Kaiser, 84028 - Landshut/DE
  • 6Institut Für Klinisch-onkologische Forschung, Krankenhaus Nordwest, 60488 - Frankfurt/DE
  • 7Medical Department Ii, Lukaskrankenhaus Neuss, 41464 - Neuss/DE
  • 8Medical Oncology, Onkologische Schwerpunktpraxis, 48149 - Muenster/DE
  • 9Hematology/ Oncology, Klinikum Magdeburg, DE-39130 - Magdeburg/DE
  • 10Medical Oncology, Onkologische Schwerpunktpraxis Bad Soden, Bad Soden/DE
  • 11Department Of Medicine I, Kliniken Nordoberpfalz - Weiden, 92637 - Weiden/DE
  • 12Oncology, Medical University of Vienna, AT-1090 - Wien/AT
  • 13Statistics, ClinAssess GmbH, 51379 - Leverkusen/DE
  • 14I Medical Department, Uniklinik Mainz, DE-55131 - Mainz/DE
  • 15Radiology, radiology Consulting GmbH, 51381 - Leverkusen/DE
  • 16Institute Of Pathology, University of Munich, 80337 - Munich/DE
  • 17Institute Of Pathology, Univsersity of Munich, 81377 - Munich/DE



FIRE-3 compared 1st-line therapy with FOLFIRI plus either cetuximab or bevacizumab in 592 KRAS exon 2 wild-type mCRC patients. An independent radiological review was carried out to evaluate tumor response according to RECIST 1.1 and to define early tumor shrinkage (ETS) and depth of response (DpR).


Extended RAS analysis was carried out in KRAS and NRAS exon 2, 3 and 4 (codons 12, 13, 59, 61, 117 and 146) using pyro-sequencing technique. Radiological data were evaluated independently. ETS was defined as a reduction in tumor diameter of more than 20% at first-tumor assessment after baseline (week 6). DpR was defined as the maximal tumor shrinkage observed in a patient. Reviewers were blinded to patient data. Calculations were done for both, the ITT- and the extended RAS wild-type population.


Within the ITT population, 475 patients (80.2%) were successfully tested for all RAS locations. Primary outcome data for the RAS wt population (n = 400) (table).

FOLFIRI + Cetuximab (n= 199) FOLFIRI + Bevacizumab (n = 201) p HR
ORR (%) 65.8 58.2 0.92*
PFS (months) (95% CI) 10.3 (9.5 - 11.8) 10.2 (9.3 - 11.7) 0.77 0.97
OS (months) (95% CI) 33.1 (24.5 - 39.4) 25.0 (23.0 - 28.1) 0.0059 0.697

p = log-rank test; * = one-sided Fisher's exact test; HR = Hazard ratio 459 patients (77.5%) were evaluable according to RECIST. ORR significantly favored the FOLFIRI plus cetuximab arm (71.4% vs. 56.4%; two sided Fisher's exact test p = 0.015). The proportion of patients reaching ETS was significantly greater in the FOLFIRI plus cetuximab treated population (67.5% vs. 47.9% p = 0.0013), and was significantly associated with PFS in the cetuximab arm (logrank test p = 0.023) and OS (logrank test p = 0.0005 and p = 0.0043) in the respective treatment arms. Depth of response was significantly greater in FOLFIRI plus cetuximab treated patients (48.2% vs. 33.0%, Wilcoxon test p = 0.0005) and associated with post progression survival (Bravais Pearson test p < 0.0001). Updated results will be presented.


Based on an independent radiological review, FOLFIRI plus cetuximab induced a significantly higher ORR, a greater rate of ETS, and an increased DpR compared to FOLFIRI plus bevacizumab. These response-related outcomes may in part explain the significant OS advantage of FOLFIRI plus cetuximab observed in FIRE-3.


S. Stintzing: Honoraria: Amgen, Merck, Roche, Sanofi Travel expenses: Amgen, Merck, Roche, Sanofi; D.P. Modest: Honoraria and travel grants: Merck, Roche, Amgen; C. Giessen: Travel support: Roche; M. Moehler: Merck: Research grants and advisory board member Roche: congress speaker and advisory board member; V. Heinemann: Honoraria and travel expenses: Roche, Merck, Amgen, Sanofi, Bayer Research Fund: Merck, Roche. All other authors have declared no conflicts of interest.