阿柏西普ZALTRAP(ziv-aflibercept)

ZALTRAP, in combination with 5-fluorouracil, leucovorin, irinotecan- (FOLFIRI), is indicated for patients with metastatic colorectal cancer (mCRC) resistant to or progressing on oxaliplatin-containing regimens.

Dosage and Administration

4 mg/kg, given as a 1-hour intravenous infusion every 2 weeks.

Do not administer by intravenous (IV) push or bolus.

Dosage Form and Strength

Single-Use Vial: 100 mg/4 mL (25 mg/mL), 200 mg/8 mL (25 mg/mL)

Contraindications

None

Warnings and Precautions

Adverse reactions, sometimes severe and life-threatening or fatal, have been seen in clinical trials with ZALTRAP, including:

(1) Fistula Formation: Discontinue ZALTRAP if fistula develops.

(2) Hypertension: Monitor blood pressure and treat hypertension. Temporarily withhold ZALTRAP if hypertension cannot be controlled. Discontinue ZALTRAP if hypertensive crisis occurs.
(3) Arterial thrombotic events (ATE) (e.g., transient ischemic attack, cerebrovascular accident, angina): Discontinue ZALTRAP if ATE occurs.

(4) Proteinuria: Monitor urine protein. Withhold ZALTRAP when proteinuria ≥ 2 g/24 hours. Discontinue ZALTRAP if nephrotic syndrome or thrombotic microangiopathy (TMA) occurs.

(5) Neutropenia and complications of neutropenia: Delay ZALTRAP/FOLFIRI administration until the neutrophil count is ≥ 1.5 x 109/L.

(6) Diarrhea and dehydration: The incidence of severe diarrhea and dehydration is increased. Monitor elderly patients more closely.

(7) Reversible posterior leukoencephalopathy syndrome (RPLS): Discontinue ZALTRAP.
Adverse Reactions
The most common adverse reactions (all grades, ≥20% incidence and at least greater than 2% for ZALTRAP/FOLFIRI regimen) were leukopenia, diarrhea, neutropenia, proteinuria, AST increased, stomatitis, fatigue, thrombocytopenia, ALT increased, hypertension, weight loss, anorexia, epistaxis, abdominal pain, dysphonia, serum creatinine increased, and headache.
FDA Approves Aflibercept for Colorectal Cancer
On August 3, 2012, the FDA approved Aflibercept (Zaltrap, Regeneron/Sanofi) for the treatment of metastatic colorectal cancer. The indication is for second-line treatment in combination with the traditional FOLFIRI regimen (irinotecan, leucovorin, 5-fluorouracil) in patients whose disease has progressed on an oxaliplatin-containing regimen. The same indication is awaiting approval in Europe and other countries.
The approval for this indication was based on results from the phase 3 VELOUR (Aflibercept vs Placebo in Patients with Metastatic Colorectal Cancer Who Have Failed Oxaliplatin) trial. In 1,226 patients, the addition of aflibercept to the FOLFIRI regimen significantly improved overall and progression-free survival.

Aflibercept is an angiogenesis inhibitor, a recombinant human fusion protein that binds tightly to circulating VEGF, preventing it from interacting with cell surface receptors. It binds to both the A and B forms of VEGF as well as placental growth factor, and has a broader mechanism of action than currently available antiangiogenic drugs such as bevacizumab.

Aflibercept is used in ophthalmology as Eylea (Regeneron and Bayer) and was approved by the FDA last year to treat neovascular (wet) age-related macular degeneration (AMD). Aflibercept is also being studied in prostate cancer, but Regeneron recently announced that there was no improvement in overall survival in the phase 3 VENICE study. In this study, aflibercept was added to docetaxel and prednisone as first-line treatment for patients with metastatic androgen-independent prostate cancer.
Improving survival in colorectal cancer
The results of the VELOUR clinical trial were first presented at the 2011 World Congress of Gastrointestinal Oncology. The addition of aflibercept doubled the response rate, from 10% to 20%. Progression-free survival improved by 2 to 3 months, and most importantly, overall survival increased from 12.0 months to 13.5 months. The FDA’s press release added details of the clinical trial: The median progression-free survival with the FOLFIRI regimen alone was 4.7 months, which increased to 6.9 months with the addition of aflibercept.
The FDA noted that the drug carries a black box warning because of the risk of serious or fatal bleeding, including gastrointestinal bleeding, and the risk of gastrointestinal perforation, in addition to the drug’s effects on wound healing.
The most common adverse reactions in patients receiving the aflibercept plus FOLFIRI regimen were neutropenia, diarrhea, oral ulcers, fatigue, hypertension, proteinuria, weight loss, decreased appetite, abdominal pain, and headache.