Novel anti-angiogenic therapeutic strategies in colorectal cancer

Tampellini, Marco; Sonetto, Cristina; Scagliotti, Giorgio Vittorio

doi:10.1517/13543784.2016.1161754

Cited by 67 publications

(47 citation statements)

References 114 publications

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“…Antiangiogenetic agents targeting the VEGF‐A–VEGFR pathway are currently the standard of care in patients with mCRC . Angiopoetin‐2 biology appears VEGF‐A dependent and downregulated in response to anti–VEGF‐A therapy ; indeed, in patients receiving bevacizumab‐containing treatment, low Ang‐2 baseline levels correlated with better PFS and OS .…”

Section: Discussionmentioning

confidence: 99%

The McCAVE Trial: Vanucizumab plus mFOLFOX-6 Versus Bevacizumab plus mFOLFOX-6 in Patients with Previously Untreated Metastatic Colorectal Carcinoma (mCRC)

et al. 2019

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Background Bevacizumab, a VEGF‐A inhibitor, in combination with chemotherapy, has proven to increase progression‐free survival (PFS) and overall survival in multiple lines of therapy of metastatic colorectal cancer (mCRC). The angiogenic factor angiopoetin‐2 (Ang‐2) is associated with poor prognosis in many cancers, including mCRC. Preclinical models demonstrate improved activity when inhibiting both VEGF‐A and Ang‐2, suggesting that the dual VEGF‐A and Ang‐2 blocker vanucizumab (RO5520985 or RG‐7221) may improve clinical outcomes. This phase II trial evaluated the efficacy of vanucizumab plus modified (m)FOLFOX‐6 (folinic acid (leucovorin), fluorouracil (5‐FU) and oxaliplatin) versus bevacizumab/mFOLFOX‐6 for first‐line mCRC. Patients and Methods All patients received mFOLFOX‐6 and were randomized 1:1 to also receive vanucizumab 2,000 mg or bevacizumab 5 mg/kg every other week. Oxaliplatin was given for eight cycles; other agents were continued until disease progression or unacceptable toxicity for a maximum of 24 months. The primary endpoint was investigator‐assessed PFS. Results One hundred eighty‐nine patients were randomized (vanucizumab, n = 94; bevacizumab, n = 95). The number of PFS events was comparable (vanucizumab, n = 39; bevacizumab, n = 43). The hazard ratio was 1.00 (95% confidence interval, 0.64–1.58; p = .98) in a stratified analysis based on number of metastatic sites and region. Objective response rate was 52.1% and 57.9% in the vanucizumab and bevacizumab arm, respectively. Baseline plasma Ang‐2 levels were prognostic in both arms but not predictive for treatment effects on PFS of vanucizumab. The incidence of adverse events of grade ≥3 was similar between treatment arms (83.9% vs. 82.1%); gastrointestinal perforations (10.8% vs. 8.4%) exceeded previously reported rates in this setting. Hypertension and peripheral edema were more frequent in the vanucizumab arm. Conclusion Vanucizumab/mFOLFOX‐6 did not improve PFS and was associated with increased rates of antiangiogenic toxicity compared with bevacizumab/mFOLFOX‐6. Our results suggest that Ang‐2 is not a relevant therapeutic target in first‐line mCRC. Implications for Practice This randomized phase II study demonstrates that additional angiopoietin‐2 (Ang‐2) inhibition does not result in superior benefit over anti–VEGF‐A blockade alone when each added to standard chemotherapy. Moreover, the performed pharmacokinetic and pharmacodynamic analysis revealed that vanucizumab was bioavailable and affected its intended target, thereby strongly suggesting that Ang‐2 is not a relevant therapeutic target in the clinical setting of treatment‐naïve metastatic colorectal cancer. As a result, the further clinical development of the dual VEGF‐A and Ang‐2 inhibitor vanucizumab was discontinued.

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Section: Discussionmentioning

confidence: 99%

The McCAVE Trial: Vanucizumab plus mFOLFOX-6 Versus Bevacizumab plus mFOLFOX-6 in Patients with Previously Untreated Metastatic Colorectal Carcinoma (mCRC)

et al. 2019

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“…In fact, VEGF-C neutralizing antibody (VGX-100) is under a Phase I clinical trial for adult patients with advanced or metastatic solid tumors (NCT01514123). 150 …”

Section: Lymphangiogenesismentioning

confidence: 99%

The Hepatic Lymphatic Vascular System: Structure, Function, Markers, and Lymphangiogenesis

Tanaka

Iwakiri

2016

Cellular and Molecular Gastroenterology and Hepatology

119

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The lymphatic vascular system has been minimally explored in the liver despite its essential functions including maintenance of tissue fluid homeostasis. The discovery of specific markers for lymphatic endothelial cells has advanced the study of lymphatics by methods including imaging, cell isolation, and transgenic animal models and has resulted in rapid progress in lymphatic vascular research during the last decade. These studies have yielded concrete evidence that lymphatic vessel dysfunction plays an important role in the pathogenesis of many diseases. This article reviews the current knowledge of the structure, function, and markers of the hepatic lymphatic vascular system as well as factors associated with hepatic lymphangiogenesis and compares liver lymphatics with those in other tissues.

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“…Clinical trials of agents that target molecules that facilitate lymphangiogenesis are in progress. For example, the above‐mentioned VEGF‐C neutralizing antibody is now in a phase I clinical trial for adult patients with advanced or metastatic solid tumors (NCT01514123) . Lymphangiogenesis is also related to liver fibrosis.…”

mentioning

confidence: 99%

The lymphatic system: A new frontier in hepatology

Iwakiri

2016

Hepatology

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Novel anti-angiogenic therapeutic strategies in colorectal cancer

Abstract: Introduction: Anti-angiogenetic agents are currently the standard of care in metastatic CRC

Cited by 67 publications

References 114 publications

The McCAVE Trial: Vanucizumab plus mFOLFOX-6 Versus Bevacizumab plus mFOLFOX-6 in Patients with Previously Untreated Metastatic Colorectal Carcinoma (mCRC)

The McCAVE Trial: Vanucizumab plus mFOLFOX-6 Versus Bevacizumab plus mFOLFOX-6 in Patients with Previously Untreated Metastatic Colorectal Carcinoma (mCRC)

The Hepatic Lymphatic Vascular System: Structure, Function, Markers, and Lymphangiogenesis

The lymphatic system: A new frontier in hepatology

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