VEGFR2 blockade in patients with solid tumors: Mechanism of hypertension and effects on vascular function

Abstract

3037 Background: Hypertension is the most common side effect in trials with inhibitors of vascular endothelial growth factor (VEGF) signaling, although the underlying pathophysiology is unclear. As the use of anti-VEGF therapy is increasing, hypertension and related serious adverse events are likely to become more important. Methods: To better understand this pathophysiology,blood pressure and vascular function parameters were assessed in this substudy of a phase I trial in patients with advanced solid tumours treated with BAY 57–9352, an oral VEGF receptor 2 (VEGFR2) inhibitor. Blood pressure, flow-mediated dilatation (FMD), nitroglycerin-mediated dilatation (NMD) and pulse-wave velocity (PWV) were measured at baseline and after 5 weeks of daily treatment in 10 patients. Patients were spread out over different cohorts, taking different dosages of study drug. Results: Mean systolic blood pressure increased from 129.0 mm Hg to 139.4 mm Hg after 5 weeks of treatment (difference 10.4 mm Hg; 95% confidence interval (CI) 5.0–15.7 mm Hg; p=0.002). Mean diastolic blood pressure increased from 80.9 to 87.4 mm Hg (difference 6.5 mm Hg; 95% CI 1.7–11.3; p=0.013). Endothelium-dependent vasodilatation (FMD) decreased from 5.6% to 3.0% (95% CI 1.1–3.9%; p=0.003). NMD, indicating endothelium-independent vasodilatation, also decreased from 12.9% to 7.7% (95% CI 2.7–7.6%; p=0.001). Arterial stiffness (PWV), increased from 9.4 m/s to 10.3 m/s (p=0.07). Conclusions: Inhibition of VEGFR2 significantly increases systolic and diastolic blood pressure. As VEGF enhances endothelial nitric oxide (NO) synthetase activity, the clear decrease in FMD could be explained by reduced bioavailability of NO. The decrease in NMD may be a direct effect of VEGFR2 inhibition on vascular smooth muscle cells. However, a more likely hypothesis for these profound vascular effects is a reduced number of microvessels (i.e. rarefaction). As the microcirculation is largely responsible for peripheral resistance, the rarefaction associated with VEGFR2 inhibition is likely to increase peripheral resistance and lead to hypertension. [Table: see text]

Urinary biomarkers of kidney injury in patients treated with anti-VEGF drugs

“…Афлиберцепт и рамуцирумаб подавляют неоангиогенез за счет связывания рецепторов VEGFR1 и VEGFR2 [19]. Нефротоксичность антиангиогенных препаратов проявляется АГ, протеинурией и снижением СКФ, которые обусловлены системной эндотелиальной дисфункцией, тромботической микроангиопатией (ТМА) и подоцитопатией [21][22][23][24].…”

“…через 8 нед лечения отмечено нами почти у 1/2 пациентов, что несколько выше, чем по данными литературы. Например, наиболее часто (42,4%) АГ вызывает афлиберцепт, другие препараты показывают меньшую частоту развития АГ: при лечении рамуцирумабом -21%, бевацизумабом -23,6% [21][22][23].…”

Anti-VEGF Cancer Therapy in Nephrology Practice

“…Hence, blockage of VEGF would lead to vasoconstriction [ 29 – 31 ]. Vascular rarefaction has also been hypothesized as a mechanism of hypertension induced by anti-VEGF therapy [ 32 ]. Hypertension may also reflect a renal parenchymal disorder (i.e., acute renal injury, glomerulopathy, and thrombotic microangiopathy) ( Figure 1 ).…”

Sorafenib Dose Escalation Is Not Uniformly Associated With Blood Pressure Elevations in Normotensive Patients With Advanced Malignancies

“…Hypertension is a common, mechanism-based effect of VEGF-signaling-pathway (VSP) inhibitors. Prior investigations suggested that blood pressure (BP) might be a valid, quantitative biomarker of VSP inhibitor pharmacodynamic effects ( 1 – 7 ). Several more recent studies have found that patients who develop hypertension with VSP inhibitor treatment have better progression-free and overall survival than those who do not ( 8 – 10 ).…”