title: Clinical and molecular assessment of regorafenib monotherapy.
abstract: Regorafenib has shown survival benefits in metastatic colorectal cancer patients who were exacerbated after all standard therapies. Some patients, however, exhibit severe adverse events (AEs) resulting in treatment discontinuation. Therefore, the selection of patients likely to benefit from regorafenib is crucial. Twenty patients were treated with regorafenib for metastatic colorectal cancer; 122 plasma samples were taken from 16 of these patients for monitoring of circulating tumor DNA (ctDNA) in the blood. The treatment response, AEs, overall survival (OS), progression-free survival (PFS) and tumor morphologic changes on CT images were evaluated. KRAS mutant ctDNA was determined using digital PCR. Median PFS and OS were 2.5 and 5.9 months, respectively. Treatment was discontinued because of disease progression (PD) in 10 patients, and AEs in another 10 patients. AEs included hyperbilirubinemia, severe fatigue and skin rash. Hyperbilirubinemia was seen in two patients with multiple bilateral liver metastases, and severe fatigue in another 2 patients with poor performance status (PS). These severe AEs resulted in treatment discontinuation. Ten patients had a median PFS of 2.1 months with AE related discontinuation; PD occurred at 3.5 months (p=0.00334). Four patients exhibited a morphologic response, achieving better PFS times of 3.5, 5.3, 5.6 and 14.2 months. Emergence of the KRAS mutation in ctDNA was observed during anti-EGFR antibody treatment in 3 patients among 11 with KRAS wild-type tumors; it was detectable in the blood prior to radiographic detection of PD. Moreover, the KRAS mutation declined in two patients during regorafenib monotherapy. These patients were re-challenged with anti-EGFR antibody. Patients with extensive multiple liver metastases or poor PS are unlikely to benefit from regorafenib. Patients with a morphologic response will probably benefit from regorafenib with adequate management of other AEs. KRAS monitoring in ctDNA could be useful regarding treatment response and in determining treatment strategy.
authors.affiliation: Department of Surgery, Saitama Medical Center, Jichi Medical University, Omiya-ku, Saitama 330-8503, Japan.
authors.forename: Nao
authors.initials: N
authors.lastname: Kakizawa
authors.affiliation: Department of Surgery, Saitama Medical Center, Jichi Medical University, Omiya-ku, Saitama 330-8503, Japan.
authors.forename: Koichi
authors.initials: K
authors.lastname: Suzuki
authors.affiliation: Department of Surgery, Saitama Medical Center, Jichi Medical University, Omiya-ku, Saitama 330-8503, Japan.
authors.forename: Taro
authors.initials: T
authors.lastname: Fukui
authors.affiliation: Department of Surgery, Saitama Medical Center, Jichi Medical University, Omiya-ku, Saitama 330-8503, Japan.
authors.forename: Yuji
authors.initials: Y
authors.lastname: Takayama
authors.affiliation: Department of Surgery, Saitama Medical Center, Jichi Medical University, Omiya-ku, Saitama 330-8503, Japan.
authors.forename: Kosuke
authors.initials: K
authors.lastname: Ichida
authors.affiliation: Department of Surgery, Saitama Medical Center, Jichi Medical University, Omiya-ku, Saitama 330-8503, Japan.
authors.forename: Yuta
authors.initials: Y
authors.lastname: Muto
authors.affiliation: Department of Surgery, Saitama Medical Center, Jichi Medical University, Omiya-ku, Saitama 330-8503, Japan.
authors.forename: Fumi
authors.initials: F
authors.lastname: Hasegawa
authors.affiliation: Department of Surgery, Saitama Medical Center, Jichi Medical University, Omiya-ku, Saitama 330-8503, Japan.
authors.forename: Fumiaki
authors.initials: F
authors.lastname: Watanabe
authors.affiliation: Department of Surgery, Saitama Medical Center, Jichi Medical University, Omiya-ku, Saitama 330-8503, Japan.
authors.forename: Rina
authors.initials: R
authors.lastname: Kikugawa
authors.affiliation: Department of Surgery, Saitama Medical Center, Jichi Medical University, Omiya-ku, Saitama 330-8503, Japan.
authors.forename: Shingo
authors.initials: S
authors.lastname: Tsujinaka
authors.affiliation: Department of Surgery, Saitama Medical Center, Jichi Medical University, Omiya-ku, Saitama 330-8503, Japan.
authors.forename: Kazushige
authors.initials: K
authors.lastname: Futsuhara
authors.affiliation: Department of Surgery, Saitama Medical Center, Jichi Medical University, Omiya-ku, Saitama 330-8503, Japan.
authors.forename: Yasuyuki
authors.initials: Y
authors.lastname: Miyakura
authors.affiliation: Department of Surgery, Saitama Medical Center, Jichi Medical University, Omiya-ku, Saitama 330-8503, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Noda
authors.affiliation: Department of Surgery, Saitama Medical Center, Jichi Medical University, Omiya-ku, Saitama 330-8503, Japan.
authors.forename: Toshiki
authors.initials: T
authors.lastname: Rikiyama
mesh_terms: D000368:Aged; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000009:adverse effects; D015179:Colorectal Neoplasms / Q000000981:diagnostic imaging / Q000188:drug therapy* / Q000235:genetics; D004273:DNA, Neoplasm / Q000097:blood*; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation; D009362:Neoplasm Metastasis; D010671:Phenylurea Compounds / Q000008:administration & dosage* / Q000009:adverse effects; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics; D011725:Pyridines / Q000008:administration & dosage* / Q000009:adverse effects; D016019:Survival Analysis; D014057:Tomography, X-Ray Computed; D016896:Treatment Outcome
chemical_list: D000970:Antineoplastic Agents; D004273:DNA, Neoplasm; C117307:KRAS protein, human; D010671:Phenylurea Compounds; D011725:Pyridines; C559147:regorafenib; D016283:Proto-Oncogene Proteins p21(ras)