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Cyramza ® (ramucirumab)
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Biomarker Analyses in Gastric Cancer
Study Design
The REGARD trial was a phase 3, multicenter, randomized, double-blind, placebo-controlled trial in patients with metastatic or locally advanced gastric or GEJ adenocarcinoma treated previously with fluoropyrimidine- or platinum-based combination therapy with an ECOG PS of 0 or 1. Patients were randomly assigned in a 2:1 ratio (stratified by weight loss, region, and location of the primary tumor) to receive ramucirumab (8 mg/kg every 2 weeks) plus BSC (n=238) or placebo (every 2 weeks) plus BSC (n=117) until disease progression, unacceptable toxicity, withdrawal, or death.1
Biomarker Analysis
Based on the positive efficacy outcomes of single-agent therapy, the REGARD study provided a suitable clinical database to explore potential candidate biomarkers for correlation with OS and PFS including
tumor
HER2 and
VEGFR-2, and
serum
VEGF-C
VEGF-D
sVEGFR-1, and
sVEGFR-3.2
Exploratory candidate biomarker analysis of tumor biopsies and serum did not identify a significant predictive marker for ramucirumab efficacy.2
Study Design
The RAINBOW trial was a phase 3, multicenter, randomized, double-blind, placebo-controlled trial in patients with metastatic or locally advanced nonresectable gastric or GEJ adenocarcinoma following disease progression during or within 4 months after last dose of first-line platinum plus fluoropyrimidine combination chemotherapy with or without an anthracycline and an ECOG PS of 0 or 1. Patients were randomly assigned in a 1:1 ratio (stratified by region, measurable vs nonmeasurable disease, and TTP on first-line therapy) to receive ramucirumab (8 mg/kg days 1 and 15) plus paclitaxel (80 mg/m2 days 1, 8, and 15) (n=330) or placebo (days 1 and 15) plus paclitaxel (80 mg/m2 days 1, 8, and 15) (n=335) of a 28-day cycle until disease progression, unacceptable toxicity, withdrawal, or death.3
Study Design and Sample Collection
In order to assess the relationship between biomarkers and efficacy of ramucirumab, plasma samples were collected from patients at
baseline
prior to the 4th infusion
prior to the 7th infusion, and
at the 30-day follow-up visit.4
These plasma samples were assayed using
Intertek assays (evaluating 24 markers from 380 samples; 57% of patients in the study), and
LDA platform (evaluating 5 markers from 257 samples; 39% of patients in the study).4
Intertek assays were used to evaluate ANG-1, ANG-2, bFGF, soluble c-KIT, CRP, E-selectin, HGF, ICAM-1, ICAM-3, IL-4, IL-8, IL-12, sNRP-1, P-selectin, PDGF-A, P1GF, SAA, SDF-1a, thrombomodulin, VCAM-1, VEGF-C, VEGF-D, sVEGFR-1, and sVEGFR-2. Lilly-developed assays were used to evaluate VEGF-C, VEGF-D, sVEGFR-1, sVEGFR-2, and sVEGFR-3.4
Most biomarkers were assessed using time-trend plots and then
dichotomized at the median concentration
separated into high and low groups, and
analyzed to determine if there was
predictive (using interaction models), or
prognostic (using main-effects models) value for OS or PFS according to expression.4
Additional evaluation of the relationship between VEGF-D and OS and PFS was assessed using a STEPP analysis.4
Results
A strong pattern of expression over time was observed for 3 of the analyzed biomarkers. Compared with baseline, during treatment
VEGF-D increased by approximately 50% and then declined after treatment was discontinued
P1GF increased by approximately 900% and then declined after treatment was discontinued, and
angiopoietin-2 decreased and then increased after treatment was discontinued.4
None of the tested biomarkers, including VEGF-D, were found to be predictive of OS.4
Six biomarkers were found to be potentially prognostic with low baseline levels corresponding to longer PFS and OS (p<.05) including
CRP
HGF
ICAM-3
IL-8
SAA, and
VCAM-1.4
1. Fuchs CS, Tomasek J, Yong CJ, et al. Ramucirumab monotherapy for previously treated advanced gastric or gastro-oesophageal junction adenocarcinoma (REGARD): an international, randomised, multicentre, placebo-controlled, phase 3 trial. Lancet. 2014;383(9911):31-39. http://dx.doi.org/10.1016/S0140-6736(13)61719-5
2. Fuchs CS, Tabernero J, Tomášek J, et al. Biomarker analyses in REGARD gastric/GEJ carcinoma patients treated with VEGFR2-targeted antibody ramucirumab. Br J Cancer. 2016;115(8):974-982. https://doi.org/10.1038/bjc.2016.293.
3. Wilke H, Muro K, Van Cutsem E, et al. Ramucirumab plus paclitaxel versus placebo plus paclitaxel in patients with previously treated advanced gastric or gastro-oesophageal junction adenocarcinoma (RAINBOW): a double-blind, randomised phase 3 trial. Lancet Oncol. 2014;15(11):1224-1235. http://dx.doi.org/10.1016/S1470-2045(14)70420-6
4. Van Cutsem E, Muro K, Cunningham D, et al. Biomarker analysis of second-line ramucirumab in patients with advanced gastric cancer from RAINBOW, a global, randomized, double-blind, phase 3 study. Eur J Cancer. 2020;127:150-157. https://doi.org/10.1016/j.ejca.2019.10.026
Glossary
ANG-1 = angiopoietin 1
ANG-2 = angiopoietin 2
bFGF = basic fibroblast growth factor
BSC = best supportive care
c-KIT = tyrosine protein kinase kit
CRP = C-reactive protein
ECOG = Eastern Cooperative Oncology Group
GEJ = gastroesophageal junction
HER2 = human epidermal growth factor receptor 2
HGF = hepatocyte growth factor
HR = hazard ratio
ICAM-1 = intercellular adhesion molecule-1
ICAM-3 = intercellular adhesion molecule-3
IL-4 = interleukin 4
IL-8 = interleukin 8
IL-12 = interleukin 12
LDA = Lilly-developed assay
OS = overall survival
P1GF = placenta growth factor
PDGF = platelet-derived growth factor
PFS = progression-free survival
PS = performance status
SAA = serum amyloid A
SDF-1a = stromal derived growth factor-1a
sNRP-1 = soluble neuropilin
STEPP = subpopulation treatment effect pattern plot
sVEGFR-1 = soluble vascular endothelial growth factor receptor 1
sVEGFR-2 = soluble vascular endothelial growth factor receptor 2
sVEGFR-3 = soluble vascular endothelial growth factor receptor 3
TTP = time-to-progression
VCAM-1 = vascular cell adhesion molecule-1
VEGF-C = vascular endothelial growth factor-C
VEGF-D = vascular endothelial growth factor-D
VEGFR-2 = vascular endothelial growth factor receptor 2
Datum fӧr senaste ӧversyn 2020 M06 01