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

J. Tabernero, R. R. Hozak, T. Yoshino, A. L. Cohn, R. Obermannova, G. Bodoky, R. Garcia-Carbonero, T. E. Ciuleanu, D. C. Portnoy, J. Prausová, K. Muro, R. W. Siegel, R. J. Konrad, H. Ouyang, S. A. Melemed, D. Ferry, F. Nasroulah, E. Van Cutsem

Research output: Contribution to journalArticle

24 Citations (Scopus)

Abstract

Background: The phase III RAISE trial (NCT01183780) demonstrated that the vascular endothelial growth factor (VEGF) receptor (VEGFR)-2 binding monoclonal antibody ramucirumab plus 5-fluororuracil, leucovorin, and irinotecan (FOLFIRI) significantly improved overall survival (OS) and progression-free survival (PFS) compared with placebo + FOLFIRI as second-line metastatic colorectal cancer (mCRC) treatment. To identify patients who benefit the most fromVEGFR-2 blockade, the RAISE trial design included a prospective and comprehensive biomarker program that assessed the association of biomarkers with ramucirumab efficacy outcomes. Patients and methods: Plasma and tumor tissue collection was mandatory. Overall, 1072 patients were randomized 1: 1 to the addition of ramucirumab or placebo to FOLFIRI chemotherapy. Patients were then randomized 1: 2, for the biomarker program, to marker exploratory (ME) and marker confirmatory (MC) groups. Analyses were carried out using exploratory assays to assess the correlations of baseline marker levels [VEGF-C, VEGF-D, sVEGFR-1, sVEGFR-2, sVEGFR-3 (plasma), and VEGFR-2 (tumor tissue)] with clinical outcomes. Cox regression analyses were carried out for each candidate biomarker with stratification factor adjustment. Results: Biomarker results were available from>80% (n = 894) of patients. Analysis of the ME subset determined a VEGF-D level of 115 pg/ml was appropriate for high/low subgroup analyses. Evaluation of the combined ME + MC populations found that the median OS in the ramucirumab + FOLFIRI arm compared with placebo + FOLFIRI showed an improvement of 2.4 months in the high VEGF-D subgroup [13.9 months (95% CI 12.5-15.6) versus 11.5 months (95% CI 10.1-12.4), respectively], and a decrease of 0.5 month in the low VEGF-D subgroup [12.6 months (95% CI 10.7-14.0) versus 13.1 months (95% CI 11.8-17.0), respectively]. PFS results were consistent with OS. No trends were evident with the other antiangiogenic candidate biomarkers. Conclusions: The RAISE biomarker program identified VEGF-D as a potential predictive biomarker for ramucirumab efficacy in second-line mCRC. Development of an assay appropriate for testing in clinical practice is currently ongoing. Clinical trials registration: NCT01183780.

Original languageEnglish
Pages (from-to)602-609
Number of pages8
JournalAnnals of Oncology
Volume29
Issue number3
DOIs
Publication statusPublished - Mar 1 2018

Fingerprint

Vascular Endothelial Growth Factor D
Colorectal Neoplasms
Biomarkers
irinotecan
Placebos
Disease-Free Survival
Survival
Vascular Endothelial Growth Factor C
Vascular Endothelial Growth Factor Receptor-2
Leucovorin
ramucirumab
Neoplasms
Monoclonal Antibodies
Regression Analysis
Clinical Trials
Drug Therapy
Population

Keywords

  • Biomarkers
  • Colorectal cancer
  • Predictive
  • Ramucirumab
  • VEGF-D

ASJC Scopus subject areas

  • Hematology
  • Oncology

Cite this

Analysis of angiogenesis biomarkers for ramucirumab efficacy in patients with metastatic colorectal cancer from RAISE, a global, randomized, double-blind, phase III study. / Tabernero, J.; Hozak, R. R.; Yoshino, T.; Cohn, A. L.; Obermannova, R.; Bodoky, G.; Garcia-Carbonero, R.; Ciuleanu, T. E.; Portnoy, D. C.; Prausová, J.; Muro, K.; Siegel, R. W.; Konrad, R. J.; Ouyang, H.; Melemed, S. A.; Ferry, D.; Nasroulah, F.; Van Cutsem, E.

In: Annals of Oncology, Vol. 29, No. 3, 01.03.2018, p. 602-609.

Research output: Contribution to journalArticle

Tabernero, J, Hozak, RR, Yoshino, T, Cohn, AL, Obermannova, R, Bodoky, G, Garcia-Carbonero, R, Ciuleanu, TE, Portnoy, DC, Prausová, J, Muro, K, Siegel, RW, Konrad, RJ, Ouyang, H, Melemed, SA, Ferry, D, Nasroulah, F & Van Cutsem, E 2018, 'Analysis of angiogenesis biomarkers for ramucirumab efficacy in patients with metastatic colorectal cancer from RAISE, a global, randomized, double-blind, phase III study', Annals of Oncology, vol. 29, no. 3, pp. 602-609. https://doi.org/10.1093/annonc/mdx767
Tabernero, J. ; Hozak, R. R. ; Yoshino, T. ; Cohn, A. L. ; Obermannova, R. ; Bodoky, G. ; Garcia-Carbonero, R. ; Ciuleanu, T. E. ; Portnoy, D. C. ; Prausová, J. ; Muro, K. ; Siegel, R. W. ; Konrad, R. J. ; Ouyang, H. ; Melemed, S. A. ; Ferry, D. ; Nasroulah, F. ; Van Cutsem, E. / Analysis of angiogenesis biomarkers for ramucirumab efficacy in patients with metastatic colorectal cancer from RAISE, a global, randomized, double-blind, phase III study. In: Annals of Oncology. 2018 ; Vol. 29, No. 3. pp. 602-609.
@article{44e1026a03ab4bdcbacaee08c59a4f4b,
title = "Analysis of angiogenesis biomarkers for ramucirumab efficacy in patients with metastatic colorectal cancer from RAISE, a global, randomized, double-blind, phase III study",
abstract = "Background: The phase III RAISE trial (NCT01183780) demonstrated that the vascular endothelial growth factor (VEGF) receptor (VEGFR)-2 binding monoclonal antibody ramucirumab plus 5-fluororuracil, leucovorin, and irinotecan (FOLFIRI) significantly improved overall survival (OS) and progression-free survival (PFS) compared with placebo + FOLFIRI as second-line metastatic colorectal cancer (mCRC) treatment. To identify patients who benefit the most fromVEGFR-2 blockade, the RAISE trial design included a prospective and comprehensive biomarker program that assessed the association of biomarkers with ramucirumab efficacy outcomes. Patients and methods: Plasma and tumor tissue collection was mandatory. Overall, 1072 patients were randomized 1: 1 to the addition of ramucirumab or placebo to FOLFIRI chemotherapy. Patients were then randomized 1: 2, for the biomarker program, to marker exploratory (ME) and marker confirmatory (MC) groups. Analyses were carried out using exploratory assays to assess the correlations of baseline marker levels [VEGF-C, VEGF-D, sVEGFR-1, sVEGFR-2, sVEGFR-3 (plasma), and VEGFR-2 (tumor tissue)] with clinical outcomes. Cox regression analyses were carried out for each candidate biomarker with stratification factor adjustment. Results: Biomarker results were available from>80{\%} (n = 894) of patients. Analysis of the ME subset determined a VEGF-D level of 115 pg/ml was appropriate for high/low subgroup analyses. Evaluation of the combined ME + MC populations found that the median OS in the ramucirumab + FOLFIRI arm compared with placebo + FOLFIRI showed an improvement of 2.4 months in the high VEGF-D subgroup [13.9 months (95{\%} CI 12.5-15.6) versus 11.5 months (95{\%} CI 10.1-12.4), respectively], and a decrease of 0.5 month in the low VEGF-D subgroup [12.6 months (95{\%} CI 10.7-14.0) versus 13.1 months (95{\%} CI 11.8-17.0), respectively]. PFS results were consistent with OS. No trends were evident with the other antiangiogenic candidate biomarkers. Conclusions: The RAISE biomarker program identified VEGF-D as a potential predictive biomarker for ramucirumab efficacy in second-line mCRC. Development of an assay appropriate for testing in clinical practice is currently ongoing. Clinical trials registration: NCT01183780.",
keywords = "Biomarkers, Colorectal cancer, Predictive, Ramucirumab, VEGF-D",
author = "J. Tabernero and Hozak, {R. R.} and T. Yoshino and Cohn, {A. L.} and R. Obermannova and G. Bodoky and R. Garcia-Carbonero and Ciuleanu, {T. E.} and Portnoy, {D. C.} and J. Prausov{\'a} and K. Muro and Siegel, {R. W.} and Konrad, {R. J.} and H. Ouyang and Melemed, {S. A.} and D. Ferry and F. Nasroulah and {Van Cutsem}, E.",
year = "2018",
month = "3",
day = "1",
doi = "10.1093/annonc/mdx767",
language = "English",
volume = "29",
pages = "602--609",
journal = "Annals of Oncology",
issn = "0923-7534",
publisher = "Oxford University Press",
number = "3",

}

TY - JOUR

T1 - Analysis of angiogenesis biomarkers for ramucirumab efficacy in patients with metastatic colorectal cancer from RAISE, a global, randomized, double-blind, phase III study

AU - Tabernero, J.

AU - Hozak, R. R.

AU - Yoshino, T.

AU - Cohn, A. L.

AU - Obermannova, R.

AU - Bodoky, G.

AU - Garcia-Carbonero, R.

AU - Ciuleanu, T. E.

AU - Portnoy, D. C.

AU - Prausová, J.

AU - Muro, K.

AU - Siegel, R. W.

AU - Konrad, R. J.

AU - Ouyang, H.

AU - Melemed, S. A.

AU - Ferry, D.

AU - Nasroulah, F.

AU - Van Cutsem, E.

PY - 2018/3/1

Y1 - 2018/3/1

N2 - Background: The phase III RAISE trial (NCT01183780) demonstrated that the vascular endothelial growth factor (VEGF) receptor (VEGFR)-2 binding monoclonal antibody ramucirumab plus 5-fluororuracil, leucovorin, and irinotecan (FOLFIRI) significantly improved overall survival (OS) and progression-free survival (PFS) compared with placebo + FOLFIRI as second-line metastatic colorectal cancer (mCRC) treatment. To identify patients who benefit the most fromVEGFR-2 blockade, the RAISE trial design included a prospective and comprehensive biomarker program that assessed the association of biomarkers with ramucirumab efficacy outcomes. Patients and methods: Plasma and tumor tissue collection was mandatory. Overall, 1072 patients were randomized 1: 1 to the addition of ramucirumab or placebo to FOLFIRI chemotherapy. Patients were then randomized 1: 2, for the biomarker program, to marker exploratory (ME) and marker confirmatory (MC) groups. Analyses were carried out using exploratory assays to assess the correlations of baseline marker levels [VEGF-C, VEGF-D, sVEGFR-1, sVEGFR-2, sVEGFR-3 (plasma), and VEGFR-2 (tumor tissue)] with clinical outcomes. Cox regression analyses were carried out for each candidate biomarker with stratification factor adjustment. Results: Biomarker results were available from>80% (n = 894) of patients. Analysis of the ME subset determined a VEGF-D level of 115 pg/ml was appropriate for high/low subgroup analyses. Evaluation of the combined ME + MC populations found that the median OS in the ramucirumab + FOLFIRI arm compared with placebo + FOLFIRI showed an improvement of 2.4 months in the high VEGF-D subgroup [13.9 months (95% CI 12.5-15.6) versus 11.5 months (95% CI 10.1-12.4), respectively], and a decrease of 0.5 month in the low VEGF-D subgroup [12.6 months (95% CI 10.7-14.0) versus 13.1 months (95% CI 11.8-17.0), respectively]. PFS results were consistent with OS. No trends were evident with the other antiangiogenic candidate biomarkers. Conclusions: The RAISE biomarker program identified VEGF-D as a potential predictive biomarker for ramucirumab efficacy in second-line mCRC. Development of an assay appropriate for testing in clinical practice is currently ongoing. Clinical trials registration: NCT01183780.

AB - Background: The phase III RAISE trial (NCT01183780) demonstrated that the vascular endothelial growth factor (VEGF) receptor (VEGFR)-2 binding monoclonal antibody ramucirumab plus 5-fluororuracil, leucovorin, and irinotecan (FOLFIRI) significantly improved overall survival (OS) and progression-free survival (PFS) compared with placebo + FOLFIRI as second-line metastatic colorectal cancer (mCRC) treatment. To identify patients who benefit the most fromVEGFR-2 blockade, the RAISE trial design included a prospective and comprehensive biomarker program that assessed the association of biomarkers with ramucirumab efficacy outcomes. Patients and methods: Plasma and tumor tissue collection was mandatory. Overall, 1072 patients were randomized 1: 1 to the addition of ramucirumab or placebo to FOLFIRI chemotherapy. Patients were then randomized 1: 2, for the biomarker program, to marker exploratory (ME) and marker confirmatory (MC) groups. Analyses were carried out using exploratory assays to assess the correlations of baseline marker levels [VEGF-C, VEGF-D, sVEGFR-1, sVEGFR-2, sVEGFR-3 (plasma), and VEGFR-2 (tumor tissue)] with clinical outcomes. Cox regression analyses were carried out for each candidate biomarker with stratification factor adjustment. Results: Biomarker results were available from>80% (n = 894) of patients. Analysis of the ME subset determined a VEGF-D level of 115 pg/ml was appropriate for high/low subgroup analyses. Evaluation of the combined ME + MC populations found that the median OS in the ramucirumab + FOLFIRI arm compared with placebo + FOLFIRI showed an improvement of 2.4 months in the high VEGF-D subgroup [13.9 months (95% CI 12.5-15.6) versus 11.5 months (95% CI 10.1-12.4), respectively], and a decrease of 0.5 month in the low VEGF-D subgroup [12.6 months (95% CI 10.7-14.0) versus 13.1 months (95% CI 11.8-17.0), respectively]. PFS results were consistent with OS. No trends were evident with the other antiangiogenic candidate biomarkers. Conclusions: The RAISE biomarker program identified VEGF-D as a potential predictive biomarker for ramucirumab efficacy in second-line mCRC. Development of an assay appropriate for testing in clinical practice is currently ongoing. Clinical trials registration: NCT01183780.

KW - Biomarkers

KW - Colorectal cancer

KW - Predictive

KW - Ramucirumab

KW - VEGF-D

UR - http://www.scopus.com/inward/record.url?scp=85046092834&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85046092834&partnerID=8YFLogxK

U2 - 10.1093/annonc/mdx767

DO - 10.1093/annonc/mdx767

M3 - Article

C2 - 29228087

AN - SCOPUS:85046092834

VL - 29

SP - 602

EP - 609

JO - Annals of Oncology

JF - Annals of Oncology

SN - 0923-7534

IS - 3

ER -