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

The oncologist

article

Johanna C. Bendell¹  Clara Montagut²  Cristina Santos Vivas³  Alberto Bessudo⁴  Patricia Plezia⁵  Veerle Moons⁶  Johannes Andel⁷  Jaafar Bennouna⁸  Andre van der Westhuizen⁹  Leslie Samuel^1,10  Simona Rossomanno^1,11  Tamara Sauri^1,12  Christophe Boetsch^1,11  Angelika Lahr^1,13  Izolda Franjkovic^1,13  Florian Heil^1,13  Katharina Lechner^1,13  Oliver Krieter^1,13  Herbert Hurwitz^1,14  Antonio Cubillo Gracián^1,15  Rafael Alvarez^1,15  Carlos López-López^1,16  Pilar García-Alfonso^1,17  Maen Hussein^1,18  Maria-Luisa Limon Miron^1,19  Andrés Cervantes^2,20 

[1] Sarah Cannon Research Institute and Tennessee Oncology;Hospital del Mar;Institut Català d'Oncologia and L'Institut d'Investigació Biomèdica de Bellvitge (IDIBELL), L'Hospitalet de Llobregat;California Cancer Associates for Research and Excellence;Arizona Clinical Research Center;Imelda General Hospital;County Hospital Steyr;Institut de Cancerologie de l'Ouest;Calvary Mater Hospital;Aberdeen Royal Infirmary, University of Aberdeen, United Kingdom;Roche Innovation Center Basel;Vall d‘Hebron University Hospital;Roche Innovation Center Munich;Duke University Medical Center;Hospital Madrid Norte Sanchinarro;Marqués de Valdecilla University Hospital;Hospital Universitario Gregorio Maranon;Florida Cancer Specialists;Hospital Universitario Virgen del Rocío;Department of Medical Oncology, Biomedical Research Institute, University of Valencia

关键词: First-line metastatic colorectal cancer;    Angiopoetin-2;    VEGF-A;    Vanucizumab;    Bevacizumab;   

DOI  :  10.1634/theoncologist.2019-0291

学科分类：地质学

来源: AlphaMed Press Incorporated

【 摘 要 】

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.

【 授权许可】

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