RT Journal Article
T1 The McCAVE Trial: Vanucizumab plus mFOLFOX-6 Versus Bevacizumab plus mFOLFOX-6 in Patients with Previously Untreated Metastatic Colorectal Carcinoma (mCRC)
A1 Bendell, Johanna C.
A1 Sauri, Tamara
A1 Cubillo Gracian, Antonio
A1 Alvarez, Rafael
A1 Lopez-Lopez, Carlos
A1 Garcia-Alfonso, Pilar
A1 Hussein, Maen
A1 Limon Miron, Maria-Luisa
A1 Cervantes, Andres
A1 Montagut, Clara
A1 Santos Vivas, Cristina
A1 Bessudo, Alberto
A1 Plezia, Patricia
A1 Moons, Veerle
A1 Andel, Johannes
A1 Bennouna, Jaafar
A1 van der Westhuizen, Andre
A1 Samuel, Leslie
A1 Rossomanno, Simona
A1 Boetsch, Christophe
A1 Lahr, Angelika
A1 Franjkovic, Izolda
A1 Heil, Florian
A1 Lechner, Katharina
A1 Krieter, Oliver
A1 Hurwitz, Herbert
A1 McCAVE Study Grp, 
K1 First-line metastatic colorectal cancer
K1 Angiopoetin-2
K1 VEGF-A
K1 Vanucizumab
K1 Bevacizumab
K1 Antitumor-activity
K1 Clinical-outcomes
K1 Phase-ii
K1 Amg 386
K1 Angiopoietin-2
K1 Combination
K1 Antibody
K1 Hypertension
K1 Oxaliplatin
K1 Biomarker
AB 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.
PB Wiley
SN 1083-7159
YR 2019
FD 2019-09-30
LK https://hdl.handle.net/10668/27428
UL https://hdl.handle.net/10668/27428
LA en
DS RISalud
RD Apr 6, 2025