The McCAVE Trial: vanucizumab plus mFOLFOX-6 versus bevacizumab plus mFOLFOX-6 in patients with previously untreated metastatic colorectal carcinoma (mCRC)

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• dc.contributor.author Bendell, Johanna C.
• dc.contributor.author Montagut Viladot, Clara
• dc.contributor.author Hurwitz, Herbert
• dc.contributor.author McCAVE Study Group
• dc.date.accessioned 2020-05-13T07:12:20Z
• dc.date.available 2020-05-13T07:12:20Z
• dc.date.issued 2020
• dc.description.abstract 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.
• dc.format.mimetype application/pdf
• dc.identifier.citation Bendell JC, Sauri T, Gracián AC, Alvarez R, López-López C, García-Alfonso P, et al. The McCAVE Trial: vanucizumab plus mFOLFOX-6 versus bevacizumab plus mFOLFOX-6 in patients with previously untreated metastatic colorectal carcinoma (mCRC). Oncologist. 2020; 25(3):e451-e459. DOI: 10.1634/theoncologist.2019-0291
• dc.identifier.doi http://dx.doi.org/10.1634/theoncologist.2019-0291
• dc.identifier.issn 1083-7159
• dc.identifier.uri http://hdl.handle.net/10230/44511
• dc.language.iso eng
• dc.publisher Wiley
• dc.relation.ispartof Oncologist. 2020; 25(3):e451-e459
• dc.rights © 2019 The Authors. This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, https://creativecommons.org/licenses/by-nc-nd/4.0/ which permits useand distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adapta-tions are made.
• dc.rights.accessRights info:eu-repo/semantics/openAccess
• dc.rights.uri https://creativecommons.org/licenses/by-nc-nd/4.0/
• dc.subject.keyword Angiopoetin‐2
• dc.subject.keyword Bevacizumab
• dc.subject.keyword First‐line metastatic colorectal cancer
• dc.subject.keyword VEGF‐A
• dc.subject.keyword Vanucizumab
• dc.title The McCAVE Trial: vanucizumab plus mFOLFOX-6 versus bevacizumab plus mFOLFOX-6 in patients with previously untreated metastatic colorectal carcinoma (mCRC)
• dc.type info:eu-repo/semantics/article
• dc.type.version info:eu-repo/semantics/publishedVersion