Johanna C Bendell1, Tamara Sauri2, Antonio Cubillo Gracián3, Rafael Alvarez3, Carlos López-López4, Pilar García-Alfonso5, Maen Hussein6, Maria-Luisa Limon Miron7, Andrés Cervantes8, Clara Montagut9, Cristina Santos Vivas10, Alberto Bessudo11, Patricia Plezia12, Veerle Moons13, Johannes Andel14, Jaafar Bennouna15, Andre van der Westhuizen16, Leslie Samuel17, Simona Rossomanno18, Christophe Boetsch18, Angelika Lahr19, Izolda Franjkovic19, Florian Heil19, Katharina Lechner19, Oliver Krieter19, Herbert Hurwitz20. 1. Sarah Cannon Research Institute and Tennessee Oncology, Nashville, Tennessee, USA jbendell@tnonc.com. 2. Vall d'Hebron University Hospital, Barcelona, Spain. 3. Centro Integral Oncológico Clara Campal, Hospital Madrid Norte Sanchinarro, Madrid, Spain. 4. Marqués de Valdecilla University Hospital, Santander, Spain. 5. Hospital Universitario Gregorio Maranon, Madrid, Spain. 6. Florida Cancer Specialists, Leesburg, Florida, USA. 7. Hospital Universitario Virgen del Rocío, Sevilla, Spain. 8. Department of Medical Oncology, Biomedical Research Institute, INCLIVA, University of Valencia, Valencia, Spain. 9. Hospital del Mar, Barcelona, Spain. 10. Institut Català d'Oncologia and L'Institut d'Investigació Biomèdica de Bellvitge (IDIBELL), L'Hospitalet de Llobregat, Spain. 11. California Cancer Associates for Research and Excellence, San Diego, California, USA. 12. Arizona Clinical Research Center, Tucson, Arizona, USA. 13. Imelda General Hospital, Bonheiden, Belgium. 14. County Hospital Steyr, Steyr, Austria. 15. Institut de Cancerologie de l'Ouest, Saint Herblain, France. 16. Calvary Mater Hospital, Newcastle, Australia. 17. Aberdeen Royal Infirmary, University of Aberdeen, Aberdeen, United Kingdom. 18. Roche Innovation Center Basel, Basel, Switzerland. 19. Roche Innovation Center Munich, Penzberg, Germany. 20. Duke University Medical Center, Durham, North Carolina, USA.
Abstract
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.
RCT Entities:
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.
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