Cyramza ® (ramucirumab)

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Cyramza® (ramucirumab): Biomarkörer i Gastrisk Cancer

En prediktiv biomarkör för aktivitet har ännu inte identifierats för behandling med ramucirumab.

Biomarker Analyses in Gastric Cancer

REGARD Study

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

RAINBOW Study

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

Biomarker Analysis

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

  1. dichotomized at the median concentration

  2. separated into high and low groups, and

  3. 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

References

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

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