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.

Figure 1

Kaplan–Meier plot of OS and PFS by high and low VEGFR2 groups in the placebo arm. Patients from the placebo arm with VEGFR2 IHC results from neoplastic vessels were dichotomised into the high and low subgroups, based on their individual VEGFR2 levels relative to the median level for the population (all patients across both arms with available results) (H-score median=35). Kaplan–Meier plots for (A) OS and (B) PFS are shown. Inset tables give median survival times (months) and 95% CIs. Abbreviations: CI, confidence interval; HR, hazard ratio; n, number of patients; VEGFR2, vascular endothelial growth factor receptor 2.

Figure 2

Kaplan–Meier plot of OS and PFS by treatment arm in the VEGFR2 high and low groups. Patients with VEGFR2 IHC results from neoplastic vessels were dichotomised into the high and low subgroups, based on their individual VEGFR2 levels relative to the median level for the population (H-score median=35). Kaplan–Meier plots for OS in patients in the (A) high VEGFR2 group (H-score ⩾35) and (B) low VEGFR2 group (H-score <35), and for PFS in the (C) high VEGFR2 group and (D) low VEGFR2 group are shown. Inset tables give median survival times (months) and 95% CIs. Abbreviations: CI, confidence interval; HR, hazard ratio; n, number of patients; PBO, placebo; RAM, ramucirumab; VEGFR2, vascular endothelial growth factor receptor 2.

Figure 3

OS plot and PFS survival plot by HER2 positivity and treatment arm. (A) OS times and (B) PFS times are shown for patients grouped by HER2 classification and treatment arm. Open circles indicate patients with censored OS/PFS times and solid dots indicate patients with uncensored times. Horizontal lines and inset table show Kaplan–Meier median survival times (months) and 95% CIs. Abbreviations: HER2, human epidermal growth factor receptor 2; n, number of patients; OS, overall survival; PBO, placebo; PFS, progression-free survival; RAM, ramucirumab.

Figure 4

Scatter plots of OS and PFS vs biomarkers VEGF-C, VEGF-D, VEGFR1, and VEGFR3. OS values were plotted for each patient by serum concentration of (A) VEGF-C, (C) VEGF-D, (E) VEGFR1, and (G) VEGFR3. PFS was similarly plotted for each patient by serum concentration of (B) VEGF-C, (D) VEGF-D, and (F) VEGFR1, and (H) VEGFR3. Data from patients treated with ramucirumab are shown with a red circle (n=18, except VEGFR1 where n=17); data from patients treated with placebo are indicated by a blue diamond (n=14). Censored observations are indicated with open symbols. The x-axis is discontinuous for plots A, B, E, and F.