Analysis of serum protein levels of angiogenic factors and their soluble receptors as markers of response to cediranib in the NCIC CTG BR.24 clinical trial

Abstract

Objectives: Prognostic and predictive ability of circulating vascular endothelial growth factor (VEGF), stromal derived factor (SDF)-1α and soluble VEGF receptors (sVEGFR) 2 and 3, were evaluated in non-small cell lung cancer (NSCLC) patients enrolled in NCIC Clinical Trials Group BR. 24 comparing chemotherapy with or without cediranib.

Materials and methods: Biomarker levels were assessed by ELISA in serum from 149/296 enrolled patients at baseline and 146/149 patients after one treatment cycle. Experimental cut-offs for baseline measures determined using a graphic method were:

Vegf-a: < or ≥1 ng/ml, SDF-1α: ≤ or >3.5 ng/ml, sVEGFR2: < or ≥11 ng/ml and sVEGFR3: < or ≥35.5 ng/ml. Changes in markers from baseline to on-treatment were predefined as increased ≥10%, stable within 10% or decreased ≥10%. Cox regression models were used to correlate biomarkers with patient characteristics and outcomes including progression-free survival (PFS) and overall survival (OS).

Results: No baseline biomarker was prognostic for OS, however, high baseline sVEGFR2 was prognostic for better PFS (p=0.0008) in the chemotherapy alone arm. Low baseline sVEGFR2 or sVEGFR3 were predictive of PFS benefit from cediranib (interaction p=0.06 and p=0.05, respectively). While on treatment, VEGF-A increases were associated with better PFS (p=0.02) and OS (p=0.01) for cediranib treated patients. Decreases in sVEGFR2 (p=0.01) or sVEGFR3 (p=0.02) were also predictive of better OS in cediranib treated patients.

Conclusions: Low baseline sVEGFR2 and sVEGFR3 were predictive for PFS benefit from cediranib, whereas increases in VEGF-A and decreases in sVEGFR2 or sVEGFR3 levels from baseline to on-treatment were predictive of an OS benefit from cediranib in chemotherapy treated NSCLC patients. Validation of these results is warranted.

Keywords: Biomarker; Cediranib; Non-small cell lung cancer; Predictive; Prognostic; Survival; VEGF; sVEGFR.