title: Subgroup analysis in RAISE: a randomized, double-blind phase III study of irinotecan, folinic acid, and 5-fluorouracil (FOLFIRI) plus ramucirumab or placebo in patients with metastatic colorectal carcinoma progression.
abstract: The RAISE phase III clinical trial demonstrated that ramucirumab + FOLFIRI improved overall survival (OS) [hazard ratio (HR) = 0.844, P = 0.0219] and progression-free survival (PFS) (HR = 0.793, P < 0.0005) compared with placebo + FOLFIRI for second-line metastatic colorectal carcinoma (mCRC) patients previously treated with first-line bevacizumab, oxaliplatin, and a fluoropyrimidine. Since some patient or disease characteristics could be associated with differential efficacy or safety, prespecified subgroup analyses were undertaken. This report focuses on three of the most relevant ones: KRAS status (wild-type versus mutant), age (<65 versus ≥65 years), and time to progression (TTP) on first-line therapy (<6 versus ≥6 months).
  
  
  
  OS and PFS were evaluated by the Kaplan-Meier analysis, with HR determined by the Cox proportional hazards model. Treatment-by-subgroup interaction was tested to determine whether treatment effect was consistent between subgroup pairs.
  
  
  
  Patients with both wild-type and mutant KRAS benefited from ramucirumab + FOLFIRI treatment over placebo + FOLFIRI (interaction P = 0.526); although numerically, wild-type KRAS patients benefited more (wild-type KRAS: median OS = 14.4 versus 11.9 months, HR = 0.82, P = 0.049; mutant KRAS: median OS = 12.7 versus 11.3 months, HR = 0.89, P = 0.263). Patients with both longer and shorter first-line TTP benefited from ramucirumab (interaction P = 0.9434), although TTP <6 months was associated with poorer OS (TTP ≥6 months: median OS = 14.3 versus 12.5 months, HR = 0.86, P = 0.061; TTP <6 months: median OS = 10.4 versus 8.0 months, HR = 0.86, P = 0.276). The subgroups of patients ≥65 versus <65 years also derived a similar ramucirumab survival benefit (interaction P = 0.9521) (≥65 years: median OS = 13.8 versus 11.7 months, HR = 0.85, P = 0.156; <65 years: median OS = 13.1 versus 11.9 months, HR = 0.86, P = 0.098). The safety profile of ramucirumab + FOLFIRI was similar across subgroups.
  
  
  
  These analyses revealed similar efficacy and safety among patient subgroups with differing KRAS mutation status, longer or shorter first-line TTP, and age. Ramucirumab is a beneficial addition to second-line FOLFIRI treatment for a wide range of patients with mCRC.
  
  
  
  ClinicalTrials.gov, NCT01183780.
authors: Masaryk Memorial Cancer Institute, Brno, Czech Republic obermannova@mou.cz.
authors: R
authors: R
authors: Obermannová
authors: University Hospitals Leuven and KU Leuven, Leuven, Belgium.
authors: E
authors: E
authors: Van Cutsem
authors: Department of Gastroenterology and Gastrointestinal Oncology, National Cancer Center Hospital East, Chiba, Japan.
authors: T
authors: T
authors: Yoshino
authors: Department of Oncology, St László Hospital, Budapest, Hungary.
authors: G
authors: G
authors: Bodoky
authors: Onocology Clinic, Charles University, Prague, Czech Republic.
authors: J
authors: J
authors: Prausová
authors: Department of Oncology, Hospital Universitario Doce de Octubre, Madrid, Spain.
authors: R
authors: R
authors: Garcia-Carbonero
authors: Institutul Oncologic Ion Chiricuta and UMF, Cluj-Napoca, Romania.
authors: T
authors: T
authors: Ciuleanu
authors: Department of Oncology, Hospital General Universitario Gregorio Maraňón, Madrid, Spain.
authors: P
authors: P
authors: Garcia Alfonso
authors: The West Clinic-University of Tennessee Health Sciences Center, Memphis.
authors: D
authors: D
authors: Portnoy
authors: Rocky Mountain Cancer Center, Denver, USA.
authors: A
authors: A
authors: Cohn
authors: Department of Gastrointestinal Oncology, Shizouka Cancer Center, Shizouka, Japan.
authors: K
authors: K
authors: Yamazaki
authors: Southern Medical Day Care Centre, Wollongong, NSW, Australia.
authors: P
authors: P
authors: Clingan
authors: Department of Medical Oncology, Istituto Oncologico Veneto-IRCCS, Padova, Italy.
authors: S
authors: S
authors: Lonardi
authors: Department of Oncology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, South Korea.
authors: T W
authors: TW
authors: Kim
authors: Eli Lilly and Company, Bridgewater, USA.
authors: L
authors: L
authors: Yang
authors: Eli Lilly and Company, Buenos Aires, Argentine Republic.
authors: F
authors: F
authors: Nasroulah
authors: Vall d'Hebron University Hospital and Institute of Oncology (VHIO), Universitat Autònoma de Barcelona, Barcelona, Spain.
authors: J
authors: J
authors: Tabernero
mesh_terms: D000328:Adult; D000368:Aged; D000911:Antibodies, Monoclonal / Q000008:administration & dosage*; D061067:Antibodies, Monoclonal, Humanized; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage*; D002166:Camptothecin / Q000008:administration & dosage / Q000031:analogs & derivatives*; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D018572:Disease-Free Survival; D004311:Double-Blind Method; D005260:Female; D005472:Fluorouracil / Q000008:administration & dosage; D006801:Humans; D000077146:Irinotecan; D053208:Kaplan-Meier Estimate; D002955:Leucovorin / Q000008:administration & dosage; D008297:Male; D008875:Middle Aged; D009154:Mutation; D009362:Neoplasm Metastasis; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics*; D000096662:Ramucirumab
chemical_list: D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D002166:Camptothecin; D005472:Fluorouracil; D000077146:Irinotecan; D002955:Leucovorin; D016283:Proto-Oncogene Proteins p21(ras); D000096662:Ramucirumab; C117307:KRAS protein, human
keywords: CRC; RAISE; VEGFR-2; metastatic colorectal carcinoma; phase III clinical trial; ramucirumab