Biomarker analyses of second-line ramucirumab in patients with advanced gastric cancer from RAINBOW, a global, randomized, double-blind, phase 3 study

the RAINBOW Investigators

doi:10.1016/j.ejca.2019.10.026

Biomarker analyses of second-line ramucirumab in patients with advanced gastric cancer from RAINBOW, a global, randomized, double-blind, phase 3 study

the RAINBOW Investigators

Department of Biomedical Sciences

Research output: Contribution to journal › Article › peer-review

22 Citations (Scopus)

Abstract

Background: The RAINBOW trial showed that second-line ramucirumab with paclitaxel prolongs overall survival (OS) and progression-free survival (PFS) compared with placebo plus paclitaxel for treatment of advanced gastric/gastroesophageal junction cancer. Plasma samples were collected from patients during the trial and tested to identify predictive and prognostic biomarkers. Patients and methods: Circulating factors in plasma samples from mutually exclusive subsets of RAINBOW patients were assayed using: Intertek assays (24 markers, 380 samples, 57% of patients) and Lilly-developed assay (LDA) platform (5 markers, 257 samples, 39% of patients). Time-trend plots were generated for each marker from the Intertek assays. Baseline patient data were dichotomized into low- and high-marker subgroups. Markers were analyzed for predictive effects using interaction models and for prognostic effects using main-effects models. Results: The Intertek and LDA populations were representative of the full trial population. Plasma levels of VEGF-D and PlGF increased from baseline levels during treatment, then declined after treatment discontinued. Angiopoietin-2 exhibited a decrease during treatment, then increased after treatment discontinuation. No clear time trend was evident with the other markers. Analyses of baseline biomarker expression and its relationship with efficacy variables found no biomarker was predictive for efficacy outcomes, including VEGF-D. However, CRP, HGF, ICAM-3, IL-8, SAA, and VCAM-1 were identified as potential prognostic markers with low baseline levels corresponding to longer OS and PFS. Conclusions: Pharmacodynamic and prognostic relationships were found from the exploratory biomarker analyses in RAINBOW; however, no predictive markers for ramucirumab in gastric cancer were identified in this trial.

Original language	English
Pages (from-to)	150-157
Number of pages	8
Journal	European Journal of Cancer
Volume	127
DOIs	https://doi.org/10.1016/j.ejca.2019.10.026
Publication status	Published - 2020 Mar

Bibliographical note

Funding Information:
This work was supported by Eli Lilly and Company. D. Cunningham acknowledges support from NIHR Biomedical Research Centre at the Royal Marsden.EVC reports research grants paid to institution from Amgen, Bayer, Boehringer Ingelheim, Celgene, Ipsen, Lilly, Roche, Merck Sharp & Dohme, Merck KGaA, Novartis, Roche, Servier and consultancy for Astrazeneca, Bayer, Bristol-Myers Squibb, Celgene, Lilly, Merck Sharp & Dohme, Merck KGaA, Novartis, Roche, Servier, outside the submitted work. KM reports grants and personal fees from Eli Lilly, during the conduct of the study; grants from MSD, Daiichi Sankyo, Shionogi, Kyowa Hakko Kirin, Gilead Sciences, Sanofi, Pfizer, and Merck Serono; personal fees from Chugai, Taiho, Takeda, Bayer, and from Eli Lilly, outside the submitted work. DC reports grants from 4SC, AstraZeneca, Bayer, Celgene, Clovis, Eli Lilly, Janssen, Medimmune, Merck, Merrimack and Sanofi, outside the submitted work. SA-B reports an advisory role with Merck, Roche, Celgene, Lilly, Nordic Pharma, Bristol-Myers Squibb and MSD Sharp & Dohme; is a speaker for Roche, Celgene, Lilly, Nordic Pharma, AIO gGmbH, MCI, Promedicis, and Forum für Medizinische Fortbildung; is CEO/Founder of IKF Klinische Krebsforschung GmbH; and has received research grants from Sanofi, Merck, Roche, Celgene, Vifor, Medac, Hospira, Lilly, German Cancer Aid (Krebshilfe), German Research Foundation, and the Federal Ministry of Education of Research. ZAW reports personal fees from Lilly, Merck, personal fees from BMS, grants from Five Prime Therapeutics, outside the submitted work. AO reports grants and personal fees from BMS, and personal fees from Ono, Chugai, and Taiho, outside the submitted work. SRW, SM, DF, and RRH are Eli Lilly employees and own company stock. GB, AS, SC, JA, SCO report no conflicts of interest.

Funding Information:
This work was supported by Eli Lilly and Company . D. Cunningham acknowledges support from NIHR Biomedical Research Centre at the Royal Marsden .

Publisher Copyright:
© 2019 The Author(s)

Keywords

Biomarker
Gastric cancer
Gastroesophageal junction cancer
Predictive
Prognostic
Ramucirumab

ASJC Scopus subject areas

Oncology
Cancer Research

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1016/j.ejca.2019.10.026

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@article{f9bd9d717dc64e8aad98a59a34c30b51,

title = "Biomarker analyses of second-line ramucirumab in patients with advanced gastric cancer from RAINBOW, a global, randomized, double-blind, phase 3 study",

abstract = "Background: The RAINBOW trial showed that second-line ramucirumab with paclitaxel prolongs overall survival (OS) and progression-free survival (PFS) compared with placebo plus paclitaxel for treatment of advanced gastric/gastroesophageal junction cancer. Plasma samples were collected from patients during the trial and tested to identify predictive and prognostic biomarkers. Patients and methods: Circulating factors in plasma samples from mutually exclusive subsets of RAINBOW patients were assayed using: Intertek assays (24 markers, 380 samples, 57% of patients) and Lilly-developed assay (LDA) platform (5 markers, 257 samples, 39% of patients). Time-trend plots were generated for each marker from the Intertek assays. Baseline patient data were dichotomized into low- and high-marker subgroups. Markers were analyzed for predictive effects using interaction models and for prognostic effects using main-effects models. Results: The Intertek and LDA populations were representative of the full trial population. Plasma levels of VEGF-D and PlGF increased from baseline levels during treatment, then declined after treatment discontinued. Angiopoietin-2 exhibited a decrease during treatment, then increased after treatment discontinuation. No clear time trend was evident with the other markers. Analyses of baseline biomarker expression and its relationship with efficacy variables found no biomarker was predictive for efficacy outcomes, including VEGF-D. However, CRP, HGF, ICAM-3, IL-8, SAA, and VCAM-1 were identified as potential prognostic markers with low baseline levels corresponding to longer OS and PFS. Conclusions: Pharmacodynamic and prognostic relationships were found from the exploratory biomarker analyses in RAINBOW; however, no predictive markers for ramucirumab in gastric cancer were identified in this trial.",

keywords = "Biomarker, Gastric cancer, Gastroesophageal junction cancer, Predictive, Prognostic, Ramucirumab",

author = "{the RAINBOW Investigators} and {Van Cutsem}, E. and K. Muro and D. Cunningham and G. Bodoky and A. Sobrero and S. Cascinu and J. Ajani and Oh, {S. C.} and Al-Batran, {S. E.} and Wainberg, {Z. A.} and Wijayawardana, {S. R.} and S. Melemed and D. Ferry and Hozak, {R. R.} and A. Ohtsu",

note = "Funding Information: This work was supported by Eli Lilly and Company. D. Cunningham acknowledges support from NIHR Biomedical Research Centre at the Royal Marsden.EVC reports research grants paid to institution from Amgen, Bayer, Boehringer Ingelheim, Celgene, Ipsen, Lilly, Roche, Merck Sharp & Dohme, Merck KGaA, Novartis, Roche, Servier and consultancy for Astrazeneca, Bayer, Bristol-Myers Squibb, Celgene, Lilly, Merck Sharp & Dohme, Merck KGaA, Novartis, Roche, Servier, outside the submitted work. KM reports grants and personal fees from Eli Lilly, during the conduct of the study; grants from MSD, Daiichi Sankyo, Shionogi, Kyowa Hakko Kirin, Gilead Sciences, Sanofi, Pfizer, and Merck Serono; personal fees from Chugai, Taiho, Takeda, Bayer, and from Eli Lilly, outside the submitted work. DC reports grants from 4SC, AstraZeneca, Bayer, Celgene, Clovis, Eli Lilly, Janssen, Medimmune, Merck, Merrimack and Sanofi, outside the submitted work. SA-B reports an advisory role with Merck, Roche, Celgene, Lilly, Nordic Pharma, Bristol-Myers Squibb and MSD Sharp & Dohme; is a speaker for Roche, Celgene, Lilly, Nordic Pharma, AIO gGmbH, MCI, Promedicis, and Forum f{\"u}r Medizinische Fortbildung; is CEO/Founder of IKF Klinische Krebsforschung GmbH; and has received research grants from Sanofi, Merck, Roche, Celgene, Vifor, Medac, Hospira, Lilly, German Cancer Aid (Krebshilfe), German Research Foundation, and the Federal Ministry of Education of Research. ZAW reports personal fees from Lilly, Merck, personal fees from BMS, grants from Five Prime Therapeutics, outside the submitted work. AO reports grants and personal fees from BMS, and personal fees from Ono, Chugai, and Taiho, outside the submitted work. SRW, SM, DF, and RRH are Eli Lilly employees and own company stock. GB, AS, SC, JA, SCO report no conflicts of interest. Funding Information: This work was supported by Eli Lilly and Company . D. Cunningham acknowledges support from NIHR Biomedical Research Centre at the Royal Marsden . Publisher Copyright: {\textcopyright} 2019 The Author(s)",

year = "2020",

month = mar,

doi = "10.1016/j.ejca.2019.10.026",

language = "English",

volume = "127",

pages = "150--157",

journal = "European Journal of Cancer",

issn = "0959-8049",

publisher = "Elsevier Limited",

}

TY - JOUR

T1 - Biomarker analyses of second-line ramucirumab in patients with advanced gastric cancer from RAINBOW, a global, randomized, double-blind, phase 3 study

AU - the RAINBOW Investigators

AU - Van Cutsem, E.

AU - Muro, K.

AU - Cunningham, D.

AU - Bodoky, G.

AU - Sobrero, A.

AU - Cascinu, S.

AU - Ajani, J.

AU - Oh, S. C.

AU - Al-Batran, S. E.

AU - Wainberg, Z. A.

AU - Wijayawardana, S. R.

AU - Melemed, S.

AU - Ferry, D.

AU - Hozak, R. R.

AU - Ohtsu, A.

N1 - Funding Information: This work was supported by Eli Lilly and Company. D. Cunningham acknowledges support from NIHR Biomedical Research Centre at the Royal Marsden.EVC reports research grants paid to institution from Amgen, Bayer, Boehringer Ingelheim, Celgene, Ipsen, Lilly, Roche, Merck Sharp & Dohme, Merck KGaA, Novartis, Roche, Servier and consultancy for Astrazeneca, Bayer, Bristol-Myers Squibb, Celgene, Lilly, Merck Sharp & Dohme, Merck KGaA, Novartis, Roche, Servier, outside the submitted work. KM reports grants and personal fees from Eli Lilly, during the conduct of the study; grants from MSD, Daiichi Sankyo, Shionogi, Kyowa Hakko Kirin, Gilead Sciences, Sanofi, Pfizer, and Merck Serono; personal fees from Chugai, Taiho, Takeda, Bayer, and from Eli Lilly, outside the submitted work. DC reports grants from 4SC, AstraZeneca, Bayer, Celgene, Clovis, Eli Lilly, Janssen, Medimmune, Merck, Merrimack and Sanofi, outside the submitted work. SA-B reports an advisory role with Merck, Roche, Celgene, Lilly, Nordic Pharma, Bristol-Myers Squibb and MSD Sharp & Dohme; is a speaker for Roche, Celgene, Lilly, Nordic Pharma, AIO gGmbH, MCI, Promedicis, and Forum für Medizinische Fortbildung; is CEO/Founder of IKF Klinische Krebsforschung GmbH; and has received research grants from Sanofi, Merck, Roche, Celgene, Vifor, Medac, Hospira, Lilly, German Cancer Aid (Krebshilfe), German Research Foundation, and the Federal Ministry of Education of Research. ZAW reports personal fees from Lilly, Merck, personal fees from BMS, grants from Five Prime Therapeutics, outside the submitted work. AO reports grants and personal fees from BMS, and personal fees from Ono, Chugai, and Taiho, outside the submitted work. SRW, SM, DF, and RRH are Eli Lilly employees and own company stock. GB, AS, SC, JA, SCO report no conflicts of interest. Funding Information: This work was supported by Eli Lilly and Company . D. Cunningham acknowledges support from NIHR Biomedical Research Centre at the Royal Marsden . Publisher Copyright: © 2019 The Author(s)

PY - 2020/3

Y1 - 2020/3

N2 - Background: The RAINBOW trial showed that second-line ramucirumab with paclitaxel prolongs overall survival (OS) and progression-free survival (PFS) compared with placebo plus paclitaxel for treatment of advanced gastric/gastroesophageal junction cancer. Plasma samples were collected from patients during the trial and tested to identify predictive and prognostic biomarkers. Patients and methods: Circulating factors in plasma samples from mutually exclusive subsets of RAINBOW patients were assayed using: Intertek assays (24 markers, 380 samples, 57% of patients) and Lilly-developed assay (LDA) platform (5 markers, 257 samples, 39% of patients). Time-trend plots were generated for each marker from the Intertek assays. Baseline patient data were dichotomized into low- and high-marker subgroups. Markers were analyzed for predictive effects using interaction models and for prognostic effects using main-effects models. Results: The Intertek and LDA populations were representative of the full trial population. Plasma levels of VEGF-D and PlGF increased from baseline levels during treatment, then declined after treatment discontinued. Angiopoietin-2 exhibited a decrease during treatment, then increased after treatment discontinuation. No clear time trend was evident with the other markers. Analyses of baseline biomarker expression and its relationship with efficacy variables found no biomarker was predictive for efficacy outcomes, including VEGF-D. However, CRP, HGF, ICAM-3, IL-8, SAA, and VCAM-1 were identified as potential prognostic markers with low baseline levels corresponding to longer OS and PFS. Conclusions: Pharmacodynamic and prognostic relationships were found from the exploratory biomarker analyses in RAINBOW; however, no predictive markers for ramucirumab in gastric cancer were identified in this trial.

AB - Background: The RAINBOW trial showed that second-line ramucirumab with paclitaxel prolongs overall survival (OS) and progression-free survival (PFS) compared with placebo plus paclitaxel for treatment of advanced gastric/gastroesophageal junction cancer. Plasma samples were collected from patients during the trial and tested to identify predictive and prognostic biomarkers. Patients and methods: Circulating factors in plasma samples from mutually exclusive subsets of RAINBOW patients were assayed using: Intertek assays (24 markers, 380 samples, 57% of patients) and Lilly-developed assay (LDA) platform (5 markers, 257 samples, 39% of patients). Time-trend plots were generated for each marker from the Intertek assays. Baseline patient data were dichotomized into low- and high-marker subgroups. Markers were analyzed for predictive effects using interaction models and for prognostic effects using main-effects models. Results: The Intertek and LDA populations were representative of the full trial population. Plasma levels of VEGF-D and PlGF increased from baseline levels during treatment, then declined after treatment discontinued. Angiopoietin-2 exhibited a decrease during treatment, then increased after treatment discontinuation. No clear time trend was evident with the other markers. Analyses of baseline biomarker expression and its relationship with efficacy variables found no biomarker was predictive for efficacy outcomes, including VEGF-D. However, CRP, HGF, ICAM-3, IL-8, SAA, and VCAM-1 were identified as potential prognostic markers with low baseline levels corresponding to longer OS and PFS. Conclusions: Pharmacodynamic and prognostic relationships were found from the exploratory biomarker analyses in RAINBOW; however, no predictive markers for ramucirumab in gastric cancer were identified in this trial.

KW - Biomarker

KW - Gastric cancer

KW - Gastroesophageal junction cancer

KW - Predictive

KW - Prognostic

KW - Ramucirumab

UR - http://www.scopus.com/inward/record.url?scp=85078745947&partnerID=8YFLogxK

U2 - 10.1016/j.ejca.2019.10.026

DO - 10.1016/j.ejca.2019.10.026

M3 - Article

C2 - 32014812

AN - SCOPUS:85078745947

SN - 0959-8049

VL - 127

SP - 150

EP - 157

JO - European Journal of Cancer

JF - European Journal of Cancer

ER -

Biomarker analyses of second-line ramucirumab in patients with advanced gastric cancer from RAINBOW, a global, randomized, double-blind, phase 3 study

Abstract

Bibliographical note

Keywords

ASJC Scopus subject areas

UN SDGs

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