%0 Journal Article
%A Bendell, Johanna C.
%A Sauri, Tamara
%A Cubillo Gracian, Antonio
%A Alvarez, Rafael
%A Lopez-Lopez, Carlos
%A Garcia-Alfonso, Pilar
%A Hussein, Maen
%A Limon Miron, Maria-Luisa
%A Cervantes, Andres
%A Montagut, Clara
%A Santos Vivas, Cristina
%A Bessudo, Alberto
%A Plezia, Patricia
%A Moons, Veerle
%A Andel, Johannes
%A Bennouna, Jaafar
%A van der Westhuizen, Andre
%A Samuel, Leslie
%A Rossomanno, Simona
%A Boetsch, Christophe
%A Lahr, Angelika
%A Franjkovic, Izolda
%A Heil, Florian
%A Lechner, Katharina
%A Krieter, Oliver
%A Hurwitz, Herbert
%A McCAVE Study Grp
%T The McCAVE Trial: Vanucizumab plus mFOLFOX-6 Versus Bevacizumab plus mFOLFOX-6 in Patients with Previously Untreated Metastatic Colorectal Carcinoma (mCRC)
%D 2019
%@ 1083-7159
%U https://hdl.handle.net/10668/27428
%X 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-naive metastatic colorectal cancer. As a result, the further clinical development of the dual VEGF-A and Ang-2 inhibitor vanucizumab was discontinued.
%K First-line metastatic colorectal cancer
%K Angiopoetin-2
%K VEGF-A
%K Vanucizumab
%K Bevacizumab
%K Antitumor-activity
%K Clinical-outcomes
%K Phase-ii
%K Amg 386
%K Angiopoietin-2
%K Combination
%K Antibody
%K Hypertension
%K Oxaliplatin
%K Biomarker
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