Hypertension 11% 1.5% 41% 19%
Respiratory, thoracic and mediastinal disorders
Epistaxis 7% 0 28% 0.2%
Dysphonia 3% 0 25% 0.5%
Dyspnea 9% 0.8% 12% 0.8%
Oropharyngeal Pain 3% 0 8% 0.2%
Rhinorrhea 2% 0 6% 0
Gastrointestinal disorders
Diarrhea 57% 8% 69% 19%
Stomatitis 33% 5% 50% 13%
Abdominal Pain 24% 2% 27% 4%
Abdominal Pain Upper 8% 1% 11% 1%
Hemorrhoids 2% 0 6% 0
Rectal Hemorrhage 2% 0.5% 5% 0.7%
Proctalgia 2% 0.3% 5% 0.3%
Skin and subcutaneous tissue disorders
Palmar-Plantar Erythrodysesthesia Syndrome 4% 0.5% 11% 3%
Skin Hyperpigmentation 3% 0 8% 0
Renal and urinary disorders
Proteinuria* 41% 1% 62% 8%
Serum creatinine increased 19% 0.5% 23% 0
General disorders and administration site conditions
Fatigue 39% 8% 48% 13%
Asthenia 13% 3% 18% 5%
Investigations
AST increased 54% 2% 62% 3%
ALT increased 39% 2% 50% 3%
Weight decreased 14% 0.8% 32% 3%
Infections occurred at a higher frequency in patients receiving Zaltrap/FOLFIRI (46%, all grades; 12%, Grade 3–4) than in patients receiving placebo/FOLFIRI (33%, all grades; 7%, Grade 3–4), including urinary tract infection, nasopharyngitis, upper respiratory tract infection, pneumonia, catheter site infection, and tooth infection.
In patients with mCRC, severe hypersensitivity reactions have been reported with Zaltrap/FOLFIRI (0.3%) and placebo/FOLFIRI (0.5%).
In patients with mCRC, venous thromboembolic events (VTE), consisting primarily of deep venous thrombosis and pulmonary embolism, occurred in 9% of patients treated with Zaltrap/FOLFIRI and 7% of patients treated with placebo/FOLFIRI. Grade 3–4 VTE occurred in 8% of patients treated with Zaltrap/FOLFIRI and in 6% of patients treated with placebo/FOLFIRI. Pulmonary embolism occurred in 5% of patients treated with Zaltrap/FOLFIRI and 3.4% of patients treated with placebo/FOLFIRI.
Immunogenicity
As with all therapeutic proteins, there is a potential for immunogenicity. In patients with various cancers across 15 studies, 1.4% (41/2862) of patients tested positive for anti-product antibody (APA) at baseline. The incidence of APA development was 3.1% (53/1687) in patients receiving intravenous ziv-aflibercept and 1.7% (19/1134) in patients receiving placebo. Among patients who tested positive for APA and had sufficient samples for further testing, neutralizing antibodies were detected in 17 of 48 ziv-aflibercept-treated patients and in 2 of 40 patients receiving placebo.
The mean free ziv-aflibercept trough concentrations were lower in patients with positive neutralizing antibodies than in the overall population. The impact of neutralizing antibodies on efficacy and safety could not be assessed based on limited available data.
Immunogenicity data are highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of antibody positivity in an assay may be influenced by several factors, including sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of th
