Dual VEGF/VEGFR inhibition in advanced solid malignancies

Mittal, Kriti; Koon, Henry; Elson, Paul; Triozzi, Pierre L.; Dowlati, Afshin; Chen, Helen; Borden, Ernest C.; Rini, Brian I.

doi:10.4161/cbt.29187

Cited by 21 publications

(13 citation statements)

References 56 publications

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“…Even small amounts of intravitreally injected VEGF-binding agents were found to alter systemic VEGF-A levels [ 24 – 26 ]. As a consequence, determination of systemic VEGF-A levels is part of the systemic safety analysis in various studies investigating VEGF-binding proteins [ 25 , 27 – 29 ]. However, due to the use of different protocols in quantifying systemic VEGF-A levels, comparison of the results remains difficult.…”

Section: Introductionmentioning

confidence: 99%

Pre-Analytical Parameters Affecting Vascular Endothelial Growth Factor Measurement in Plasma: Identifying Confounders

et al. 2016

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BackgroundVascular endothelial growth factor-A (VEGF-A) is intensively investigated in various medical fields. However, comparing VEGF-A measurements is difficult because sample acquisition and pre-analytic procedures differ between studies. We therefore investigated which variables act as confounders of VEGF-A measurements.MethodsFollowing a standardized protocol, blood was taken at three clinical sites from six healthy participants (one male and one female participant at each center) twice one week apart. The following pre-analytical parameters were varied in order to analyze their impact on VEGF-A measurements: analyzing center, anticoagulant (EDTA vs. PECT / CTAD), cannula (butterfly vs. neonatal), type of centrifuge (swing-out vs. fixed-angle), time before and after centrifugation, filling level (completely filled vs. half-filled tubes) and analyzing method (ELISA vs. multiplex bead array). Additionally, intrapersonal variations over time and sex differences were explored. Statistical analysis was performed using a linear regression model.ResultsThe following parameters were identified as statistically significant independent confounders of VEGF-A measurements: analyzing center, anticoagulant, centrifuge, analyzing method and sex of the proband. The following parameters were no significant confounders in our data set: intrapersonal variation over one week, cannula, time before and after centrifugation and filling level of collection tubes.ConclusionVEGF-A measurement results can be affected significantly by the identified pre-analytical parameters. We recommend the use of CTAD anticoagulant, a standardized type of centrifuge and one central laboratory using the same analyzing method for all samples.

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Section: Introductionmentioning

confidence: 99%

Pre-Analytical Parameters Affecting Vascular Endothelial Growth Factor Measurement in Plasma: Identifying Confounders

et al. 2016

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“…On the contrary, another registered TKI directed against VEGFR, sorafenib, combined with bevacizumab did not mention any occurrence of MAHA syndrome nor TMA [ 14 , 16 , 19 ]. Pazopanib combined with bevacizumab might damage the renal nephron, with a rapid onset of a microangiopathy closed to that reported in the combination of bevacizumab with sunitinib [ 28 ]. In addition, our series confirmed that this microangiopathic effect does not only occur in patients suffering from renal tumors.…”

Section: Discussionmentioning

confidence: 79%

“…The combination of the VEGF-directed monoclonal antibody bevacizumab with a tyrosine kinase inhibitor directed against VEGF receptors has already been investigated [ 28 ]. These combination regimens were difficult to manage since increased toxicities have been described, and some of them were even considered as not feasible despite promising efficacy.…”

Section: Discussionmentioning

confidence: 99%

“…Our results demonstrate that this vasculo-renal impairment can be induced in patients without any vascular or renal pre-existing risk. Thrombotic microangiopathy (TMA), as the initial phenomenon in the development of a MAHA syndrome, has been reported by several authors investigating the combination of sunitinib and bevacizumab [ 25 , 28 , 45 ]. On the contrary, another registered TKI directed against VEGFR, sorafenib, combined with bevacizumab did not mention any occurrence of MAHA syndrome nor TMA [ 14 , 16 , 19 ].…”

Section: Discussionmentioning

confidence: 99%

“…The concomitant blockade of VEGF ligand and receptors might contribute to improve the treatment efficacy. Some of these combinations have been attempted and reported promising results in terms of efficacy but their feasibility remains as a matter of debate [ 14 , 25 – 28 ].…”

Section: Introductionmentioning

confidence: 99%

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Phase I dose-escalation study of pazopanib combined with bevacizumab in patients with metastatic renal cell carcinoma or other advanced tumors

et al. 2017

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BackgroundVascular endothelial growth factor (VEGF) directed therapies are being used in a large number of advanced tumors. Metastatic renal cell carcinoma (mRCC) is highly dependent on the VEGF pathway; VEGF receptor (VEGFR) tyrosine kinase inhibitors (TKI) and humanized VEGF monoclonal antibody have been registered for clinical use in advanced renal cell carcinoma. The VEGFR TKI, pazopanib, with a rather manageable toxicity profile, was preferred to sunitinib by mRCC patients. We investigate the combination of pazopanib and bevacizumab to determine the maximum tolerated dose (MTD) in mRCC and other advanced solid tumors.MethodsIn this bicentric phase I trial with a 3 + 3 + 3 dose-escalation design, patients received oral pazopanib once daily plus intravenous infusion of bevacizumab every 2 weeks from D15, at one of the four dose levels (DL) planned according to the occurrence of dose limiting toxicities (DLT). 400 and 600 mg pazopanib were respectively combined with 7.5 mg/kg bevacizumab in DL1 and DL2, and 600 and 800 mg pazopanib with 10 mg/kg bevacizumab in DL3 and DL4. Tumor response was evaluated every 8 weeks. Blood samples were assayed to investigate pazopanib pharmacokinetics.ResultsTwenty five patients including seven mRCC were enrolled. Nine patients received the DL1, ten received the DL2. No DLT were observed at DL1, five DLT at DL2, and 3 DLT in the six additional patients who received the DL1. A grade 3 microangiopathic hemolytic anemia syndrome was observed in four (16%) patients. Five (22%) patients achieved a partial response. The mean (range) plasmatic concentrations of 400 and 600 pazopanib were respectively 283 (139–427) and 494 (227–761) μg.h/mL at Day 1, and 738 (487–989) and 1071 (678–1464) μg.h/mL at Day 15 i.e. higher than those previously reported with pazopanib, and were not directly influenced by bevacizumab infusion.ConclusionsThe combination of pazopanib and bevacizumab induces angiogenic toxicity in patients without any pre-existing renal or vascular damage. Even if a marginal efficacy was reported with five (22%) patients in partial response in different tumor types, the toxicity profile compromises the development of this combination.Trial registrationThe study was retrospectively registered on ClinicalTrials.gov (number NCT01202032) on 2010, Sept 14th.

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A new perspective on antiangiogenic antibody drug resistance: Biomarkers, mechanisms, and strategies in malignancies

Zhao,

Zeng,

Kang

et al. 2024

Drug Development Research

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Drug resistance of malignant tumor leads to disease progression be the bottleneck in clinical treatment. Antiangiogenic therapy, which aims to “starve” the tumor by inhibiting angiogenesis, is one of the key strategies in clinical oncology treatments. Recently, dozens of investigational antibody drugs and biosimilars targeting angiogenesis have obtained regulatory approval for the treatment of various malignancies. Moreover, a new generation of bispecific antibodies based on the principle of antiangiogenesis are being advanced for clinical trial to overcome antiangiogenic resistance in tumor treatment or enhance the efficacy of monotherapy. Tumors often develop resistance to antiangiogenesis therapy, presenting as refractory and sometimes even resistant to new therapies, for which there are currently no effective management strategies. Thus, a detailed understanding of the mechanisms mediating resistance to antiangiogenesis antibodies is crucial for improving drug effectiveness and achieving a durable response to antiangiogenic therapy. In this review, we provide a novel perspective on the tumor microenvironment, including antibody structure, tumor stroma, and changes within tumor cells, to analyze the multifactorial reasons underlying resistance to antiangiogenesis antibodies. The review also enumerates biomarkers that indicate resistance and potential strategies for monitoring resistance. Furthermore, based on recent clinical and preclinical studies, we summarize potential strategies and translational clinical trials aimed at overcoming resistance to antiangiogenesis antibodies. This review provides a valuable reference for researchers and clinical practitioners involved in the development of new drugs or therapeutic strategies to overcome antiangiogenesis antibodies resistance.

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Dual VEGF/VEGFR inhibition in advanced solid malignancies

Cited by 21 publications

References 56 publications

Pre-Analytical Parameters Affecting Vascular Endothelial Growth Factor Measurement in Plasma: Identifying Confounders

Pre-Analytical Parameters Affecting Vascular Endothelial Growth Factor Measurement in Plasma: Identifying Confounders

Phase I dose-escalation study of pazopanib combined with bevacizumab in patients with metastatic renal cell carcinoma or other advanced tumors

A new perspective on antiangiogenic antibody drug resistance: Biomarkers, mechanisms, and strategies in malignancies

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