title: Regorafenib plus best supportive care versus placebo plus best supportive care in Asian patients with previously treated metastatic colorectal cancer (CONCUR): a randomised, double-blind, placebo-controlled, phase 3 trial.
abstract: BACKGROUND
  In the international randomised phase 3 CORRECT trial (NCT01103323), regorafenib significantly improved overall survival versus placebo in patients with treatment-refractory metastatic colorectal cancer. Of the 760 patients in CORRECT, 111 were Asian (mostly Japanese). This phase 3 trial was done to assess regorafenib in a broader population of Asian patients with refractory metastatic colorectal cancer than was studied in CORRECT.
  
  
  METHODS
  In this randomised, double-blind, placebo-controlled, parallel-group, phase 3 trial done in 25 hospitals in mainland China, Hong Kong, South Korea, Taiwan, and Vietnam, we recruited Asian patients aged 18 years or older with progressive metastatic colorectal cancer who had received at least two previous treatment lines or were unable to tolerate standard treatments. Patients had to have an Eastern Cooperative Oncology Group performance status of 0 or 1, life expectancy of at least 3 months, and adequate bone marrow, liver, and renal function, without other uncontrolled medical disorders. We randomly allocated patients (2:1; with a computer-generated unicentric randomisation list [prepared by the study funder] and interactive voice response system; block size of six; stratified by metastatic site [single vs multiple organs] and time from diagnosis of metastatic disease [<18 months vs ≥18 months]) to receive oral regorafenib 160 mg once daily or placebo on days 1-21 of each 28 day cycle; patients in both groups were also to receive best supportive care. Participants, investigators, and the study funder were masked to treatment assignment. The primary endpoint was overall survival, and we analysed data on an intention-to-treat basis. This trial is registered with ClinicalTrials.gov, number NCT01584830.
  
  
  RESULTS
  Between April 29, 2012, and Feb 6, 2013, we screened 243 patients and randomly assigned 204 patients to receive either regorafenib (136 [67%]) or placebo (68 [33%]). After a median follow-up of 7·4 months (IQR 4·3-12·2), overall survival was significantly better with regorafenib than it was with placebo (hazard ratio 0·55, 95% CI 0·40-0·77, one-sided p=0·00016; median overall survival 8·8 months [95% CI 7·3-9·8] in the regorafenib group vs 6·3 months [4·8-7·6] in the placebo group). Drug-related adverse events occurred in 132 (97%) of 136 regorafenib recipients and 31 (46%) of 68 placebo recipients. The most frequent grade 3 or higher regorafenib-related adverse events were hand-foot skin reaction (22 [16%] of 136 patients in the regorafenib group vs none in the placebo group), hypertension (15 [11%] vs two [3%] of 68 patients in the placebo group), hyperbilirubinaemia (nine [7%] vs one [1%]), hypophosphataemia (nine [7%] vs none), alanine aminotransferase concentration increases (nine [7%] vs none), aspartate aminotransferase concentration increases (eight [6%] vs none), lipase concentration increases (six [4%] vs one [1%]), and maculopapular rash (six [4%] vs none). Drug-related serious adverse events occurred in 12 (9%) patients in the regorafenib group and three (4%) in the placebo group.
  
  
  CONCLUSIONS
  This phase 3 trial is the second to show an overall survival benefit with regorafenib compared with placebo in patients with treatment-refractory metastatic colorectal cancer, substantiating the role of regorafenib as an important treatment option for patients whose disease has progressed after standard treatments. In this trial, preceding standard treatments did not necessarily include targeted treatments. Adverse events were generally consistent with the known safety profile of regorafenib in this setting.
  
  
  BACKGROUND
  Bayer HealthCare Pharmaceuticals.
authors.affiliation: Department of Medical Oncology, Fudan University Shanghai Cancer Center, and Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China.
authors.forename: Jin
authors.initials: J
authors.lastname: Li
authors.affiliation: Department of Medical Oncology, Chinese People's Liberation Army Cancer Center of Nanjing Bayi Hospital, Nanjing, China.
authors.forename: Shukui
authors.initials: S
authors.lastname: Qin
authors.affiliation: Department of Medical Oncology, Sun Yat-Sen University Cancer Center, Collaborative Innovation Center for Cancer Medicine, Guangzhou, China.
authors.forename: Ruihua
authors.initials: R
authors.lastname: Xu
authors.affiliation: Department of Medicine, University of Hong Kong, Queen Mary Hospital, Hong Kong, China.
authors.forename: Thomas C C
authors.initials: TC
authors.lastname: Yau
authors.affiliation: Department of Clinical Oncology, Prince of Wales Hospital, Chinese University of Hong Kong, Hong Kong, China.
authors.forename: Brigette
authors.initials: B
authors.lastname: Ma
authors.affiliation: Medical Oncology, Sir Run Run Shaw Hospital Medical School, Zhejiang University, Hangzhou, China.
authors.forename: Hongming
authors.initials: H
authors.lastname: Pan
authors.affiliation: Beijing 307 People's Liberation Army Hospital Cancer Centre, Beijing, China.
authors.forename: Jianming
authors.initials: J
authors.lastname: Xu
authors.affiliation: Third Affiliated Hospital of Harbin Medical University, Harbin, China.
authors.forename: Yuxian
authors.initials: Y
authors.lastname: Bai
authors.affiliation: Department of Medical Oncology, Cancer Hospital, Chinese Academy of Medical Sciences, Beijing, China.
authors.forename: Yihebali
authors.initials: Y
authors.lastname: Chi
authors.affiliation: Comprehensive Cancer Center, Shanghai First People's Hospital, Shanghai Jiaotong University, Shanghai, China.
authors.forename: Liwei
authors.initials: L
authors.lastname: Wang
authors.affiliation: Department of Oncology, National Taiwan University Hospital, Taipei, Taiwan.
authors.forename: Kun-Huei
authors.initials: KH
authors.lastname: Yeh
authors.affiliation: Department of Medical Oncology, West China Hospital, Sichuan University, Chengdu, China.
authors.forename: Feng
authors.initials: F
authors.lastname: Bi
authors.affiliation: Jilin Provincial Tumor Hospital, Changchun, China.
authors.forename: Ying
authors.initials: Y
authors.lastname: Cheng
authors.affiliation: Department of Oncology, Cho Ray Hospital, Ho Chi Minh City, Vietnam.
authors.forename: Anh Tuan
authors.initials: AT
authors.lastname: Le
authors.affiliation: Department of Surgery, Taipei Veterans General Hospital, National Yang-Ming University, Taipei, Taiwan.
authors.forename: Jen-Kou
authors.initials: JK
authors.lastname: Lin
authors.affiliation: Department of Medical Oncology, Zhong Shan Hospital, Fudan University, Shanghai, China.
authors.forename: Tianshu
authors.initials: T
authors.lastname: Liu
authors.affiliation: Department of Medical Oncology, Guangdong General Hospital, Guangzhou, Guangdong, China.
authors.forename: Dong
authors.initials: D
authors.lastname: Ma
authors.affiliation: Bayer Pharma AG, Berlin, Germany.
authors.forename: Christian
authors.initials: C
authors.lastname: Kappeler
authors.affiliation: Bayer Pharma AG, Berlin, Germany.
authors.forename: Joachim
authors.initials: J
authors.lastname: Kalmus
authors.affiliation: Department of Oncology, Asan Medical Center, University of Ulsan College of Medicine, Songpa-gu, South Korea. Electronic address: twkimmd@amc.seoul.kr.
authors.forename: Tae Won
authors.initials: TW
authors.lastname: Kim
mesh_terms: D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage*; D044466:Asian People; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000453:epidemiology / Q000473:pathology; D018572:Disease-Free Survival; D004311:Double-Blind Method; D005260:Female; D006801:Humans; D053208:Kaplan-Meier Estimate; D008297:Male; D008875:Middle Aged; D009362:Neoplasm Metastasis; D010671:Phenylurea Compounds / Q000008:administration & dosage* / Q000009:adverse effects; D011725:Pyridines / Q000008:administration & dosage* / Q000009:adverse effects; D016896:Treatment Outcome
chemical_list: D010671:Phenylurea Compounds; D011725:Pyridines; C559147:regorafenib