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

T. Yoshino, D. C. Portnoy, R. Obermannová, G. Bodoky, J. Prausová, R. Garcia-Carbonero, T. Ciuleanu, P. García-Alfonso, A. L. Cohn, E. Van Cutsem, K. Yamazaki, S. Lonardi, K. Muro, T. W. Kim, K. Yamaguchi, A. Grothey, J. O'Connor, J. Taieb, S. R. Wijayawardana, R. R. HozakF. Nasroulah, J. Tabernero

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Abstract

Background:: Second-line treatment with ramucirumabþFOLFIRI improved overall survival (OS) versus placeboþFOLFIRI for patients with metastatic colorectal carcinoma (CRC) [hazard ratio (HR)¼0.84, 95% CI 0.73-0.98, P ¼ 0.022]. Post hoc analyses of RAISE patient data examined the association of RAS/RAF mutation status and the anatomical location of the primary CRC tumour (left versus right) with efficacy parameters. Patients and methods: Patient tumour tissue was classified as BRAF mutant, KRAS/NRAS (RAS) mutant, or RAS/BRAF wild-type. Left-CRC was defined as the splenic flexure, descending and sigmoid colon, and rectum; right-CRC included transverse, ascending colon, and cecum. Results: RAS/RAF mutation status was available for 85% of patients (912/1072) and primary tumour location was known for 94.4% of patients (1012/1072). A favourable and comparable ramucirumab treatment effect was observed for patients with RAS mutations (OS HR ¼ 0.86, 95% CI 0.71-1.04) and patients with RAS/BRAF wild-type tumours (OS HR ¼ 0.86, 95% CI 0.64-1.14). Among the 41 patients with BRAF-mutated tumours, the ramucirumab benefit was more notable (OS HR ¼ 0.54, 95% CI 0.25-1.13), although, as with the other genetic sub-group analyses, differences were not statistically significant. Progression-free survival (PFS) data followed the same trend. Treatment-by-mutation status interaction tests (OS P ¼ 0.523, PFS P ¼ 0.655) indicated that the ramucirumab benefit was not statistically different among the mutation sub-groups, although the small sample size of the BRAF group limited the analysis. Addition of ramucirumab to FOLFIRI improved left-CRC median OS by 2.5 month over placebo (HR ¼ 0.81, 95% CI 0.68-0.97); median OS for ramucirumab-treated patients with right-CRC was 1.1 month over placebo (HR ¼ 0.97, 95% CI 0.75-1.26). The treatment-by-sub-group interaction was not statistically significant for tumour sidedness (P ¼ 0.276). Conclusions: In the RAISE study, the addition of ramucirumab to FOLFIRI improved patient outcomes, regardless of RAS/RAF mutation status, and tumour sidedness. Ramucirumab treatment provided a numerically substantial benefit in BRAF-mutated tumours, although the P-values were not statistically significant.

Original languageEnglish
Pages (from-to)124-131
Number of pages8
JournalAnnals of Oncology
Volume30
Issue number1
DOIs
Publication statusPublished - Jan 1 2019

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Keywords

  • BRAF
  • Colorectal carcinoma
  • KRAS
  • Left
  • NRAS
  • Ramucirumab

ASJC Scopus subject areas

  • Hematology
  • Oncology

Cite this

Yoshino, T., Portnoy, D. C., Obermannová, R., Bodoky, G., Prausová, J., Garcia-Carbonero, R., Ciuleanu, T., García-Alfonso, P., Cohn, A. L., Van Cutsem, E., Yamazaki, K., Lonardi, S., Muro, K., Kim, T. W., Yamaguchi, K., Grothey, A., O'Connor, J., Taieb, J., Wijayawardana, S. R., ... Tabernero, J. (2019). 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. Annals of Oncology, 30(1), 124-131. https://doi.org/10.1093/annonc/mdy461