Mutations within the EGFR signaling pathway: Influence on efficacy in FIRE-3—A randomized phase III study of FOLFIRI plus cetuximab or bevacizumab as first-line treatment for wild-type (WT) KRAS (exon 2) metastatic colorectal cancer (mCRC) patients.

Cancers of the Colon and Rectum
Session Type and Session Title: 
General Poster Session C: Cancers of the Colon and Rectum
Oral Abstract Session: Cancers of the Colon and Rectum (eQ&A)
Abstract Number: 
J Clin Oncol 32, 2014 (suppl 3; abstr 445)
Sebastian Stintzing, Andreas Jung, Lisa Rossius, Dominik Paul Modest, Ludwig Fischer von Weikersthal, Thomas Decker, Alexander Kiani, Salah-Eddin Al-Batran, Ursula Vehling-Kaiser, Tobias Heintges, Markus Moehler, Werner Scheithauer, Thomas Kirchner, Volker Heinemann; Department of Hematology and Oncology, Klinikum Grosshadern and Comprehensive Cancer Center, LMU Munich, Munich, Germany; Pathologisches Institut der Ludwig-Maximilians-Universität München, München, Germany; Department of Hematology and Oncology, Comprehensive Cancer Center, Klinikum Großhadern, University of Munich, Munich, Germany; Department of Oncology, Gesundheitszentrum St. Marien GmbH, Amberg, Germany; Onkonet - Onkologie Ravensburg, Ravensburg, Germany; Klinik Herzoghöhe, Bayreuth, Germany; Institute of Clinical Cancer Research (IKF) at Krankenhaus Nordwest, UCT-University Cancer Center, Frankfurt am Main, Germany; Practice for Medical Oncology, Landshut, Germany; Städtisches Klinikum Neuss Lukaskrankenhaus GmbH, Medical Department II, Neuss, Germany; Department of Gastroenterology and Hepatology, University Medical Center of the Johannes Gutenberg University of Mainz, Mainz, Germany; Medical University of Vienna, Vienna, Austria; Department of Pathology, University of Munich, Munich, Germany

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Abstract Disclosures


Background: The FIRE-3 study (AIO KRK-0306) was designed as a randomized multicenter trial to compare the efficacy of FOLFIRI plus cetuximab (cet) to FOLFIRI plus bevacizumab (bev) as first-line treatment in KRAS WT mCRC patients. FOLFIRI plus cet as first-line treatment of KRAS WT mCRC patients resulted in comparable overall response rates (ORR) and progression free survival (PFS) when compared to FOLFIRI plus bev. Overall survival (OS) was significantly longer in the FOLFIRI plus cet arm. Methods: In a preplanned analysis, the effect of mutations within the EGFR dependent pathway were investigated. Next to mutations within KRAS (exon 2, 3, 4), NRAS (exon 2, 3, 4) and BRAF (V600E), mutations within PIK3CA (exon 9 and 20) and Akt were investigated and their impact on ORR, PFS and OS within the FIRE-3 population was evaluated. The analysis of all mutations was carried out employing pyrosequencing. Results: The ITT population consisted of 592 KRAS WT (exon 2) patients. The current analysis includes 488 cases (82.4%) with tumor tissue available. In 407 pts sequencing of all RAS mutations was possible. The ORR within the WT RAS patient group was higher in the FOLFIRI plus cet arm (65.5% vs 59.6%; Fisher´s p: 0.157). HRs (cet; bev) for pts with WT RASwere 0.93 (95% CI, 0.74-1.17; p = 0.54) for PFS and 0.70 (95% CI, 0.53-0.92; p = 0.01) for OS. PIK3CA mutation did not influence PFS nor OS when compared to the RAS wt population. Conclusions: ORR and OS were increased in patients with cet plus FOLFIRI as compared to bev plus FOLFIRI in patients without RAS mutations. Exclusion of patients with RAS mutations identifies a population which is more likely to benefit from cetuximab. Clinical trial information: NCT00433927.