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

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.

Bispecific Antibodies and Antibody–Drug Conjugates for Cancer Therapy: Technological Considerations

“…The affinity of each Fab arm was essentially the same as that of the parental antibody, and the thermal stability was also similar to that of conventional IgG. The bsAb, vanucizumab, in combination with mFOLFOX-6 failed improve the progression-free survival of metastatic colorectal cancer (mCRC) patients relative to the bevacizumab-treated group [58]. A different Ang-2×VEGF CrossMab, faricimab, is being evaluated in a number of phase 3 clinical trials for the treatment of neovascular age-related macular degeneration (nAMD) (NCT03823287 and NCT03823300) and diabetic macular edema (NCT03622580 and NCT03622593).…”

Monoclonal antibodies and chimeric antigen receptor (CAR) T cells in the treatment of colorectal cancer

“…A phase I study using biweekly administration of vanucizumab in patients with solid tumors confirmed its safety and anti-angiogenesis activities [ 66 ]. Recently, the results of a phase II clinical trial, McCAVE trial, in patients with previously untreated metastatic CRC revealed that angiogenesis inhibition by vanucizumab does not provide additional benefits over bevacizumab for first‐line treatment of metastatic CRC [ 67 ].…”

Targeting cancer metastasis with antibody therapeutics

“…However, a Phase I clinical trial in patients with platinum‐resistant, recurrent ovarian cancer found that combination treatment with vanucizumab and atezolizumab did not promote antitumor activity better than atezolizumab monotherapy (Oaknin et al, 2017). Moreover, a Phase II clinical trial in patients with metastatic colorectal cancer found that combination treatment with vanucizumab and the chemotherapeutic regimen mFOLFOX‐6 led to reduced progression‐free survival compared to bevacizumab/mFOLFOLX‐6 combination therapy, and also resulted in a higher number of reported adverse effects (Bendell et al, 2020). These results have cast doubt on the clinical future of vanucizumab.…”