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.
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 language | English |
|---|---|
| Pages (from-to) | e451-e459 |
| Number of pages | 9 |
| Journal | Oncologist |
| Volume | 25 |
| Issue number | 3 |
| Early online date | 30 Sept 2019 |
| DOIs | |
| Publication status | Published - Mar 2020 |
Bibliographical note
We thank the patients and their families for their participation in this study and the staff at the study sites. This study and editorial support for the preparation of this manuscript were funded by F. Hoffmann-La Roche Ltd. Support for third-party writing assistance for this article, furnished by Goran Westerburg, Ph.D., was provided by La Crocina Pharmaceutical Consultants Lp.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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