title: Randomized study of FOLFIRI plus either panitumumab or bevacizumab for wild-type KRAS colorectal cancer-WJOG 6210G.
abstract: This randomized phase II trial compared panitumumab plus fluorouracil, leucovorin, and irinotecan (FOLFIRI) with bevacizumab plus FOLFIRI as second-line chemotherapy for wild-type (WT) KRAS exon 2 metastatic colorectal cancer (mCRC) and to explore the values of oncogenes in circulating tumor DNA (ctDNA) and serum proteins as predictive biomarkers. Patients with WT KRAS exon 2 mCRC refractory to first-line chemotherapy containing oxaliplatin and bevacizumab were randomly assigned to panitumumab plus FOLFIRI or bevacizumab plus FOLFIRI. Of 121 randomly assigned patients, 117 were eligible. Median overall survival (OS) for panitumumab plus FOLFIRI and bevacizumab plus FOLFIRI were 16.2 and 13.4 months [hazard ratio (HR), 1.16; 95% CI, 0.76-1.77], respectively. Progression-free survival (PFS) was also similar (HR, 1.14; 95% CI, 0.78-1.66). KRAS, NRAS, and BRAF status using ctDNA was successfully examined in 109 patients, and mutations were identified in 19 patients (17.4%). Panitumumab plus FOLFIRI showed favorable survival compared with bevacizumab plus FOLFIRI in WT patients and unfavorable survival in those with mutations (P for interaction = 0.026 in OS and 0.054 in PFS). OS with bevacizumab plus FOLFIRI was better than panitumumab plus FOLFIRI in patients with high serum vascular endothelial growth factor-A (VEGF-A) levels and worse in those with low levels (P for interaction = 0.016). Second-line FOLFIRI plus panitumumab and FOLFIRI plus bevacizumab showed a similar efficacy in patients with WT KRAS exon 2 mCRC. RAS and BRAF mutation in ctDNA could be a negative predictive marker for panitumumab.
authors.affiliation: Department of Gastroenterology and Gastrointestinal Oncology, National Cancer Center Hospital East, Kashiwa, Japan.
authors.forename: Kohei
authors.initials: K
authors.lastname: Shitara
authors.affiliation: Department of Medical Oncology, Kinki University Faculty of Medicine, Osaka, Japan.|Department of Medical Oncology, Izumi Municipal Hospital, Osaka, Japan.
authors.forename: Kimio
authors.initials: K
authors.lastname: Yonesaka
authors.affiliation: Division of Gastroenterology, Chiba Cancer Center, Chiba, Japan.
authors.forename: Tadamichi
authors.initials: T
authors.lastname: Denda
authors.affiliation: Division of Gastrointestinal Oncology, Shizuoka Cancer Center, Shizuoka, Japan.
authors.forename: Kentaro
authors.initials: K
authors.lastname: Yamazaki
authors.affiliation: Division of Gastroenterology, University of Tsukuba, Tsukuba, Japan.
authors.forename: Toshikazu
authors.initials: T
authors.lastname: Moriwaki
authors.affiliation: Department of Gastroenterological Oncology, Hyogo Cancer Center, Akashi, Japan.
authors.forename: Masahiro
authors.initials: M
authors.lastname: Tsuda
authors.affiliation: Department of Medical Oncology, Toranomon Hospital, Tokyo, Japan.
authors.forename: Toshimi
authors.initials: T
authors.lastname: Takano
authors.affiliation: Department of Medical Oncology, Keiyukai Sapporo Hospital, Sapporo, Japan.
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Okuda
authors.affiliation: Department of Gastrointestinal Medical Oncology, National Hospital Organization Shikoku Cancer Center, Matsuyama, Japan.
authors.forename: Tomohiro
authors.initials: T
authors.lastname: Nishina
authors.affiliation: Department of Genome Biology, Kindai University Faculty of Medicine, Osaka, Japan.
authors.forename: Kazuko
authors.initials: K
authors.lastname: Sakai
authors.affiliation: Department of Genome Biology, Kindai University Faculty of Medicine, Osaka, Japan.
authors.forename: Kazuto
authors.initials: K
authors.lastname: Nishio
authors.affiliation: Medical Information Center, Kyushu University Hospital, Fukuoka, Japan.
authors.forename: Shoji
authors.initials: S
authors.lastname: Tokunaga
authors.affiliation: Department of Biostatistics, Yokohama City University, Yokohama, Japan.
authors.forename: Takeharu
authors.initials: T
authors.lastname: Yamanaka
authors.affiliation: Division of Gastrointestinal Medical Oncology, National Cancer Center Hospital, Tokyo, Japan.
authors.forename: Narikazu
authors.initials: N
authors.lastname: Boku
authors.affiliation: Division of Gastroenterology, University of Tsukuba, Tsukuba, Japan.
authors.forename: Ichinosuke
authors.initials: I
authors.lastname: Hyodo
authors.affiliation: Department of Clinical Oncology, Aichi Cancer Center Hospital, Nagoya, Japan.
authors.forename: Kei
authors.initials: K
authors.lastname: Muro
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000483:Alleles; D000911:Antibodies, Monoclonal / Q000008:administration & dosage; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000627:therapeutic use*; D000068258:Bevacizumab / Q000008:administration & dosage; D014408:Biomarkers, Tumor; D002166:Camptothecin / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000627:therapeutic use; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000235:genetics*; D005260:Female; D005472:Fluorouracil / Q000009:adverse effects / Q000627:therapeutic use; D006801:Humans; D053208:Kaplan-Meier Estimate; D002955:Leucovorin / Q000009:adverse effects / Q000627:therapeutic use; D008297:Male; D008875:Middle Aged; D009154:Mutation; D009362:Neoplasm Metastasis; D000077544:Panitumumab; D048493:Proto-Oncogene Proteins B-raf; D019233:Retreatment; D016896:Treatment Outcome; D018631:ras Proteins / Q000235:genetics*
chemical_list: D000911:Antibodies, Monoclonal; D014408:Biomarkers, Tumor; D000068258:Bevacizumab; D000077544:Panitumumab; D048493:Proto-Oncogene Proteins B-raf; D018631:ras Proteins; D002955:Leucovorin; D005472:Fluorouracil; D002166:Camptothecin
keywords: Bevacizumab; RAS mutation; colorectal cancer; liquid biopsy; panitumumab