title: A phase II study of the efficacy and safety of the combination therapy of the MEK inhibitor refametinib (BAY 86-9766) plus sorafenib for Asian patients with unresectable hepatocellular carcinoma.
abstract: OBJECTIVE
  There is an unmet need for treatment options in hepatocellular carcinoma (HCC). Sorafenib is currently the only approved systemic treatment for HCC. Refametinib, an oral, allosteric MEK inhibitor, has demonstrated antitumor activity in combination with sorafenib in vitro and in vivo. A phase II study evaluated efficacy and safety of refametinib plus sorafenib in Asian patients with HCC (NCT01204177).
  
  
  METHODS
  Eligible patients received twice-daily refametinib 50 mg plus twice-daily sorafenib 200 mg (morning)/400 mg (evening), with dose escalation to sorafenib 400 mg twice daily from cycle 2 if no grade ≥ 2 hand-foot skin reaction, fatigue, or gastrointestinal toxicity occurred. Primary efficacy endpoint: disease control rate. Secondary endpoints: time to progression, overall survival, pharmacokinetic assessment, biomarker analysis, safety, and tolerability.
  
  
  RESULTS
  Of 95 enrolled patients, 70 received study treatment. Most patients had liver cirrhosis (82.9%) and hepatitis B viral infection (75.7%). Disease control rate was 44.8% (primary efficacy analysis; n = 58). Median time to progression was 122 days, median overall survival was 290 days (n = 70). Best clinical responders had RAS mutations; majority of poor responders had wild-type RAS. Most frequent drug-related adverse events were diarrhea, rash, aspartate aminotransferase elevation, vomiting, and nausea. Dose modifications due to adverse events were necessary in almost all patients.
  
  
  CONCLUSIONS
  Refametinib plus sorafenib showed antitumor activity in patients with HCC and was tolerated at reduced doses by most patients. Frequent dose modifications due to grade 3 adverse events may have contributed to limited treatment effect. Patients with RAS mutations appear to benefit from refametinib/sorafenib combination.
authors.affiliation: Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center; Sungkyunkwan University School of Medicine, Seoul, Republic of Korea. hoylim@skku.edu.
authors.forename: Ho Yeong
authors.initials: HY
authors.lastname: Lim
authors.affiliation: Department of Internal Medicine, Pusan National University School of Medicine and Medical Research Institute, Busan, Republic of Korea.
authors.forename: Jeong
authors.initials: J
authors.lastname: Heo
authors.affiliation: Yonsei Cancer Center, Yonsei University Health System, Seoul, Republic of Korea.
authors.forename: Hye Jin
authors.initials: HJ
authors.lastname: Choi
authors.affiliation: Chi-Mei Medical Center, Tainan, Taiwan.
authors.forename: Cheng-Yao
authors.initials: CY
authors.lastname: Lin
authors.affiliation: Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, Seoul, Republic of Korea.
authors.forename: Jung-Hwan
authors.initials: JH
authors.lastname: Yoon
authors.affiliation: National Taiwan University Hospital, Taipei, Taiwan.
authors.forename: Chiun
authors.initials: C
authors.lastname: Hsu
authors.affiliation: Division of Hematology-Oncology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital of the Chang Gung Medical Foundation, Kaohsiung, Taiwan. Chang-Gung University, College of Medicine, Tao-Yuan, Taiwan.
authors.forename: Kun-Ming
authors.initials: KM
authors.lastname: Rau
authors.affiliation: Department of Surgery, University of Hong Kong, Hong Kong.
authors.forename: Ronnie T P
authors.initials: RT
authors.lastname: Poon
authors.affiliation: Department of Clinical Oncology, Chinese University of Hong Kong, Hong Kong.
authors.forename: Winnie
authors.initials: W
authors.lastname: Yeo
authors.affiliation: National Cancer Center, Goyang-si, Republic of Korea.
authors.forename: Joong-Won
authors.initials: JW
authors.lastname: Park
authors.affiliation: OncoCare Cancer Centre, Singapore, Singapore.
authors.forename: Miah Hiang
authors.initials: MH
authors.lastname: Tay
authors.affiliation: Cancer Science Institute of Singapore, Singapore.
authors.forename: Wen-Son
authors.initials: WS
authors.lastname: Hsieh
authors.affiliation: Bayer Pharma AG, Berlin, Germany.
authors.forename: Christian
authors.initials: C
authors.lastname: Kappeler
authors.affiliation: Bayer HealthCare Pharmaceuticals, Whippany, New Jersey.
authors.forename: Prabhu
authors.initials: P
authors.lastname: Rajagopalan
authors.affiliation: Bayer Pharma AG, Berlin, Germany.
authors.forename: Heiko
authors.initials: H
authors.lastname: Krissel
authors.affiliation: Bayer HealthCare Pharmaceuticals, Whippany, New Jersey.
authors.forename: Michael
authors.initials: M
authors.lastname: Jeffers
authors.affiliation: Internal Medicine, National Cheng Kung University Hospital, Tainan, Taiwan.
authors.forename: Chia-Jui
authors.initials: CJ
authors.lastname: Yen
authors.affiliation: Department of Internal Medicine, Liver Research Institute, Kyungpook National University School of Medicine, Daegu, Republic of Korea.
authors.forename: Won Young
authors.initials: WY
authors.lastname: Tak
mesh_terms: D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000627:therapeutic use*; D044466:Asian People; D015415:Biomarkers; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy* / Q000209:etiology / Q000401:mortality / Q000473:pathology*; D004159:Diphenylamine / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000493:pharmacokinetics; D005260:Female; D006801:Humans; D008113:Liver Neoplasms / Q000188:drug therapy* / Q000209:etiology / Q000401:mortality / Q000473:pathology*; D008297:Male; D008875:Middle Aged; D009362:Neoplasm Metastasis; D009367:Neoplasm Staging; D009536:Niacinamide / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000493:pharmacokinetics; D010671:Phenylurea Compounds / Q000008:administration & dosage / Q000493:pharmacokinetics; D000077157:Sorafenib; D013449:Sulfonamides / Q000008:administration & dosage / Q000493:pharmacokinetics; D016896:Treatment Outcome
chemical_list: D015415:Biomarkers; C544830:N-(3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-6-methoxyphenyl)-1-(2,3-dihydroxypropyl)cyclopropane-1-sulfonamide; D010671:Phenylurea Compounds; D013449:Sulfonamides; D009536:Niacinamide; D004159:Diphenylamine; D000077157:Sorafenib