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

Radka Obermannová, E. Van Cutsem, T. Yoshino, G. Bodoky, J. Prausová, R. Garcia-Carbonero, T. Ciuleanu, P. Garcia Alfonso, D. Portnoy, A. Cohn, K. Yamazaki, P. Clingan, S. Lonardi, T. W. Kim, L. Yang, F. Nasroulah, J. Tabernero

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Abstract

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 firstline 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.

Original languageEnglish
Pages (from-to)2082-2089
Number of pages8
JournalAnnals of Oncology
Volume27
Issue number11
DOIs
Publication statusPublished - Jan 1 2016

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Keywords

  • CRC
  • Metastatic colorectal carcinoma
  • Phase III clinical trial
  • RAISE
  • Ramucirumab
  • VEGFR-2

ASJC Scopus subject areas

  • Hematology
  • Oncology

Cite this

Obermannová, R., Van Cutsem, E., Yoshino, T., Bodoky, G., Prausová, J., Garcia-Carbonero, R., Ciuleanu, T., Garcia Alfonso, P., Portnoy, D., Cohn, A., Yamazaki, K., Clingan, P., Lonardi, S., Kim, T. W., Yang, L., Nasroulah, F., & Tabernero, J. (2016). 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. Annals of Oncology, 27(11), 2082-2089. https://doi.org/10.1093/annonc/mdw402