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

Johanna C. Bendell*, Tamara Sauri, Antonio Cubillo Gracian, Rafael Alvarez, Carols Lopez-Lopez, Pilar Garcia-Alfonso, Maen Hussein, Maria-Luisa Limon Miron, Andres Cervantes, Clara Montagut, Cristina Santos Vivas, Alberto Bessudo, Patrica Plezia, Veerle Moons, Johannes Andel, Jafaar Bennouna, Andre van der Westhuizen, Leslie Samuel, Simona Rossomanno, Christophe BoetschAngelika Lahr, Izolda Franjkovic, Florian Heil, Katharina Lechner, Oliver Krieter, Herbert Hurwitz

*Corresponding author for this work

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Abstract

Background. Bevacizumab, a VEGF-A inhibitor, in combina- tion with chemotherapy, has proven to increase progression- free survival (PFS) and overall survival in multiple lines of therapy of metastatic colorectal cancer (mCRC). The angio- genic 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 random- ized (vanucizumab, n = 94; bevacizumab, n = 95). The num- ber of PFS events was comparable (vanucizumab, n = 39; bevacizumab, n = 43). The hazard ratio was 1.00 (95% confi- dence 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 tar- get in first-line mCRC.
Original languageEnglish
Pages (from-to)e451-e459
Number of pages9
JournalOncologist
Volume25
Issue number3
Early online date30 Sep 2019
DOIs
Publication statusPublished - Mar 2020

Keywords

  • First-line metastatic colorectal cancer
  • Angiopoetin-2
  • VEGF-A
  • Vanucizumab
  • Bevacizumab
  • BIOMARKER
  • ANTIBODY
  • PHASE-II
  • OXALIPLATIN
  • ANGIOPOIETIN-2
  • ANTITUMOR-ACTIVITY
  • COMBINATION
  • HYPERTENSION
  • AMG 386
  • CLINICAL-OUTCOMES

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    Bendell, J. C., Sauri, T., Gracian, A. C., Alvarez, R., Lopez-Lopez, C., Garcia-Alfonso, P., Hussein, M., Limon Miron, M-L., Cervantes, A., Montagut, C., Santos Vivas, C., Bessudo, A., Plezia, P., Moons, V., Andel, J., Bennouna, J., van der Westhuizen, A., Samuel, L., Rossomanno, S., ... Hurwitz, H. (2020). The McCAVE Trial: Vanucizumab plus mFOLFOX-6 Versus Bevacizumab plus mFOLFOX-6 in Patients with Previously Untreated Metastatic Colorectal Carcinoma (mCRC). Oncologist, 25(3), e451-e459. https://doi.org/10.1634/theoncologist.2019-0291