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

Autor: Bendell, Johanna C., Sauri, Tamara, Gracián, Antonio Cubillo, Alvarez, Rafael, López López, Carlos, García Alfonso, Pilar, Hussein, Maen, Limon Miron, Maria Luisa, Cervantes, Andrés, Montagut Viladot, Clara, Santos, Cristina, Bessudo, Alberto, Plezia, Patricia, Moons, Veerle, Andel, Johannes, Bennouna, Jaafar, Westhuizen, Andre, Samuel, Leslie, Rossomanno, Simona, Boetsch, Christophe, Lahr, Angelika, Franjkovic, Izolda, Heil, Florian, Lechner, Katharina, Krieter, Oliver, Hurwitz, Herbert, McCAVE Study Group
Rok vydání: 2019
Předmět:
0301 basic medicine
Oncology
Cancer Research
medicine.medical_specialty
VEGF‐A
Vanucizumab
Bevacizumab
Angiopoetin-2
Organoplatinum Compounds
Colorectal cancer
Leucovorin
Phases of clinical research
First‐line metastatic colorectal cancer
Antibodies
Monoclonal
Humanized
VEGF-A
Disease-Free Survival
Metastasis
03 medical and health sciences
Folinic acid
0302 clinical medicine
Metàstasi
Càncer colorectal
Internal medicine
Gastrointestinal Cancer
Antineoplastic Combined Chemotherapy Protocols
medicine
Clinical endpoint
Humans
Neoplasm Metastasis
Angiopoetin‐2
business.industry
Hazard ratio
medicine.disease
Oxaliplatin
030104 developmental biology
Fluorouracil
030220 oncology & carcinogenesis
Camptothecin
business
Colorectal Neoplasms
First-line metastatic colorectal cancer
medicine.drug
Zdroj: Dipòsit Digital de la UB
Universidad de Barcelona
The Oncologist
ONCOLOGIST
r-INCLIVA. Repositorio Institucional de Producción Científica de INCLIVA
instname
ISSN: 1083-7159
Popis: 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.
This phase II trial evaluated the efficacy of vanucizumab plus mFOLFOX‐6 versus bevacizumab/mFOLFOX‐6 in the first‐line setting of metastatic colorectal cancer.
Databáze: OpenAIRE
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