Cyramza® (ramucirumab): Biomarkörer i Gastrisk Cancer

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