Biomarker analyses in REGARD gastric/GEJ carcinoma patients treated with VEGFR2-targeted antibody ramucirumab

Abstract

Background:Angiogenesis inhibition is an important strategy for cancer treatment. Ramucirumab, a human IgG1 monoclonal antibody that targets VEGF receptor 2 (VEGFR2), inhibits VEGF-A, -C, -D binding and endothelial cell proliferation. To attempt to identify prognostic and predictive biomarkers, retrospective analyses were used to assess tumour (HER2, VEGFR2) and serum (VEGF-C and -D, and soluble (s) VEGFR1 and 3) biomarkers in phase 3 REGARD patients with metastatic gastric/gastroesophageal junction carcinoma.Methods:A total of 152 out of 355 (43%) patients randomised to ramucirumab or placebo had ⩾1 evaluable biomarker result using VEGFR2 immunohistochemistry or HER2, immunohistochemistry or FISH, of blinded baseline tumour tissue samples. Serum samples (32 patients, 9%) were assayed for VEGF-C and -D, and sVEGFR1 and 3.Results:None of the biomarkers tested were associated with ramucirumab efficacy at a level of statistical significance. High VEGFR2 endothelial expression was associated with a non-significant prognostic trend toward shorter progression-free survival (high vs low HR=1.65, 95% CI=0.84,3.23). Treatment with ramucirumab was associated with a trend toward improved survival in both high (HR=0.69, 95% CI=0.38, 1.22) and low (HR=0.73, 95% CI=0.42, 1.26) VEGFR2 subgroups. The benefit associated with ramucirumab did not appear to differ by tumoural HER2 expression.Conclusions:REGARD exploratory analyses did not identify a strong potentially predictive biomarker of ramucirumab efficacy; however, statistical power was limited.

Heterogeneity in Gastric Cancer: From Pure Morphology to Molecular Classifications

“…Based on phase III clinical trials, trastuzumab (anti-HER2; human epidermal growth factor receptor 2) [4] and ramucirumab (anti-VEGFR2; vascular endothelial growth factor receptor 2) [5,6] monoclonal antibodies have recently been approved as clinically validated molecular targeted therapies in the treatment of advanced/metastatic GC. However, these therapies offer only a limited survival advantage of a few months (1.5-2.2 months) [4][5][6] and, to date, with the exception of HER2, there are no predictive biomarkers of tumour response to targeted therapies in GC [7]. Other biological agents (e.g., cetuximab and panitumumab, anti-EGFR monoclonal antibodies) have failed to demonstrate a survival benefit in GC [8,9].…”

Anti‐angiogenic therapies for gastric cancer

“…Two biomarker studies of ramucirumab were also conducted in the REGARD and RAINBOW trial cohorts . Although VEGF‐D and alpha‐fetoprotein (AFP) are potential biomarkers of ramucirumab for colorectal cancer and hepatocellular carcinoma, respectively, these studies did not reveal useful biomarkers in patients with gastric cancer.…”

Gastric cancer management: Kinases as a target therapy

“…Ramucirumab is a fully humanized monoclonal antibody that antagonizes vascular endothelial growth factor (VEGFR)‐2 and inhibits angiogenesis in tumour cells . The inclusion of ramucirumab was based on the positive results of the phase III REGARD and phase III RAINBOW trials, which demonstrated improved median PFS and overall survival (OS) benefits.…”