Potential Predictive and Prognostic Biomarkers for Ziv-Aflibercept Treatment Identified

Interim results reported from a retrospective study of plasma samples from the VELOUR trial reveal multiple potential prognostic and predictive biomarkers to guide treatment of patients with metastatic colorectal cancer (mCRC) with the VEGF-inhibitor ziv-aflibercept (Zaltrap).

Presenter Tasha Sims, PhD, associate of clinical and translational sciences at Regeneron Pharmaceuticals Inc, Tarrytown, New York, said that while the ziv-aflibercept fusion protein is effective in binding and neutralizing ligands of VEGFR-1 and VEGFR-2 (eg, VEGF-A, PlGF, and VEGF B), biomarkers indicating either resistance or susceptibility to VEGF inhibition have not been validated.

Regeneron performed a retrospective analysis of circulating plasma proteins in 553 baseline plasma samples from the phase III VELOUR trial, measuring the levels of 98 different analytes using multiplex assays and ELISA. The biomarker study subpopulation was similar to the overall VELOUR population in terms of OS and demographics, including Eastern Cooperative Oncology Group (ECOG) status.

Biomarker values were divided around the median value (designated as either high or low) and analyzed with respect to impact on overall survival (OS). Several angiogenic and proinflammatory factors were identified as potentially predictive or prognostic biomarkers of OS, notably VEGF-A, VEGF-R2, VEGF-R3, neutropilin 1 (NRP-1), angiopoietin 2 (Ang-2), interleukin 8 (IL-8), C-reactive protein (CRP), macrophage migratory inhibitory factor (MIF), and surfactant protein D (SPD).

Patients in the high VEGF-A subgroup appeared to benefit the most from ziv-aflibercept treatment, which indicated that VEGF-A may be a predictive marker.

“Patients with plasma VEGF-A above the median value of 142 pg/mL who were treated with ziv-aflibercept did significantly better than the control group,” said Sims (HR = 0.644, 95% CI, 0.49-0.85;P= .001). Benefit may decline at the highest VEGF-A levels. “Above 335 pg/mL, representing the top 20% of patients, the ziv-aflibercept effect was not as pronounced.” Similar results were observed with VEGF R2 and VEGF-R3. Regeneron reported that above-median levels of plasma VEGF-R2 and VEGF-R3 may also be predictive for response to ziv-aflibercept, “although not statistically significant individually.”

Patients with plasma levels of factors neutropilin-1 (NRP-1) or angiopoietin-2 (Ang-2) below median values may do better on ziv-aflibercept. The prognostic effect of NRP-1 above median value of 160 ng/mL resulted in an HR = 2.104 in the ziv-aflibercept-treated group compared with an HR = 2.032 in untreated controls, while the prognostic effect of Ang-2 above median levels gave an HR = 1.83 in the ziv-aflibercept-treated group compared with an HR = 1.54 in controls.

In terms of inflammatory factors informative to ziv-aflibercept treatment, higher levels of interleukin-8 (IL-8) were said to be both prognostic and predictive under the treatment conditions in VELOUR. The prognostic effect of IL-8 above the median was HR = 2.319 with ziv-aflibercept treatment, compared with an HR = 4.48 in non-ziv-aflibercept controls. As a predictive biomarker, patients with plasma levels of IL-8 above the median value who were treated with ziv-aflibercept did better than the control group (HR = 0.632, 95% CI, 0.489-0.817;P= .0006).

VELOUR was a prospective, multicenter, multinational, randomized (1:1), double-blind, phase III study conducted in 1226 mCRC patients who failed on an oxaliplatin-based regimen with or without bevacizumab. Patients were randomized 1:1 (613 patients each) to ziv-aflibercept plus FOLFIRI or placebo plus FOLFIRI. The primary endpoint was overall survival (OS), with median OS of 12.1 months for ziv-aflibercept compared with 13.5 months for placebo (HR = 0.817, 95% CI, 0.714-0.935,P= .0032).¹

“Patient subsets with elevated expression of alternative angiogenic factors or increased proinflammatory markers may correlate with poor outcome overall, and in some cases are not improved by addition of ziv-aflibercept treatment,” Sims said. “These markers may be of interest as components of a signature. However, while we identified multiple potential prognostic and predictive biomarkers in VELOUR, these results are exploratory and require prospective studies for validation. Further investigation of this dataset continues, including analysis of on treatment plasma samples in a subset of patients.”

Reference

1. Van Cutsem E, Tabernero J, Lakomy R, et al. Addition of aflibercept to fluorouracil, leucovorin, and irinotecan improves survival in a phase III randomized trial in patients with metastatic colorectal cancer previously treated with an oxaliplatin-based regimen.J Clin Oncol. 2012;30(28):3499-3506.

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