BACKGROUND: 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). PATIENTS AND METHODS: 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. RESULTS: 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. CONCLUSIONS: 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. TRIAL REGISTRATION: ClinicalTrials.gov, NCT01183780.

Department of Gastroenterology and Gastrointestinal Oncology National Cancer Center Hospital East Chiba Japan

Department of Gastrointestinal Oncology Shizouka Cancer Center Shizouka Japan

Department of Medical Oncology Istituto Oncologico Veneto IRCCS Padova Italy

Department of Oncology Asan Medical Center University of Ulsan College of Medicine Seoul South Korea

Department of Oncology Hospital General Universitario Gregorio Maraňón Madrid Spain

Department of Oncology Hospital Universitario Doce de Octubre Madrid Spain

Department of Oncology St László Hospital Budapest Hungary

Eli Lilly and Company Bridgewater USA

Eli Lilly and Company Buenos Aires Argentine Republic

Institutul Oncologic Ion Chiricuta and UMF Cluj Napoca Romania

Masaryk Memorial Cancer Institute Brno Czech Republic

Onocology Clinic Charles University Prague Czech Republic

Rocky Mountain Cancer Center Denver USA

Southern Medical Day Care Centre Wollongong NSW Australia

The West Clinic University of Tennessee Health Sciences Center Memphis

University Hospitals Leuven and KU Leuven Leuven Belgium

Vall d'Hebron University Hospital and Institute of Oncology Universitat Autònoma de Barcelona Barcelona Spain

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Biomarker analysis beyond angiogenesis: RAS/RAF mutation status, tumour sidedness, and second-line ramucirumab efficacy in patients with metastatic colorectal carcinoma from RAISE-a global phase III study

Analysis of angiogenesis biomarkers for ramucirumab efficacy in patients with metastatic colorectal cancer from RAISE, a global, randomized, double-blind, phase III study

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ClinicalTrials.gov
NCT01183780