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U.S. Department of Health and Human Services

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FDA approves a labeling extension for bevacizumab (Avastin, Genentech) for second-line treatment of metastatic carcinoma of the colon or rectum

On June 20, 2006, the U.S. Food and Drug Administration granted approval for a labeling extension for bevacizumab (Avastin, Genentech), administered in combination with intravenous 5-fluorouracil-based chemotherapy, for the second-line treatment of metastatic carcinoma of the colon or rectum. This recommendation is based on the demonstration of a statistically significant improvement in overall survival (OS) in patients receiving Avastin plus FOLFOX4 (5-flourouracil, leucovorin, and oxaliplatin) when compared to those receiving FOLFOX4 alone.

The trial (E3200) supporting this approval was an open‑label, randomized, 3-arm, active-controlled, multi-center clinical trial evaluating AVASTIN alone (n=244), AVASTIN plus FOLFOX4 (n=293), and FOLFOX4 alone (n=292). Following a planned interim analysis, the AVASTIN monotherapy arm was closed to accrual based on evidence of decreased survival in patients treated with AVASTIN alone compared with FOLFOX4 alone. Patients entered on the trial had progressive or recurrent disease following prior 5-FU and irinotecan-based therapy. Patients (99%) received irinotecan with or without 5-FU as initial therapy for metastatic disease; those who received adjuvant irinotecan-based chemotherapy were required to have recurred within 6 months of completing therapy.

In both the combination and monotherapy arms, AVASTIN was administered at a dose of 10 mg/kg every 2 weeks. The FOLFOX4 regimen, administered every 2 weeks, consisted of oxaliplatin 85 mg/m2 and leucovorin 200 mg/m2 administered concurrently as an intravenous infusion, then 5‑FU 400 mg/m2 IV bolus followed by 5‑FU 600 mg/m2 continuous intravenous infusion on day 1. On day 2, patients received leucovorin 200 mg/m2 IV, then 5‑FU 400 mg/m2 IV bolus followed by 5‑FU 600 mg/m2 continuous intravenous infusion. When given in combination with FOLFOX4, AVASTIN was administered on day 1 prior to oxaliplatin and leucovorin.

Among the 829 randomized patients, the median age was 61 years and 49% had an ECOG performance status of 0. Twenty-six percent had received prior radiation therapy, 80% received prior adjuvant chemotherapy, and all received prior irinotecan therapy.

Overall survival, the trial’s primary endpoint, was significantly longer in patients receiving AVASTIN in combination with FOLFOX 4 as compared to those receiving FOLFOX4 alone (median OS 13.0 mos vs. 10.8 mos; hazard ratio 0.75, p=0.001 stratified log rank test). The survival benefit was also observed in subgroups defined by age (<65 vs. >65 yrs) and gender. Patients treated with the AVASTIN combination were reported by investigator assessment to have significantly longer progression-free survival and higher overall response rate.

The most serious, and sometimes fatal, AVASTIN toxicities are gastrointestinal perforation, wound healing complications, hemorrhage, arterial thromboembolic events, hypertensive crisis, nephrotic syndrome and congestive heart failure. The most common adverse events in patients receiving AVASTIN are asthenia, pain, abdominal pain, headache, hypertension, diarrhea, nausea, vomiting, anorexia, stomatitis, constipation, upper respiratory infection, epistaxis, dyspnea, exfoliative dermatitis, and proteinuria.

In Trial E3200, data were collected only for NCI-CTC grade 3-5 adverse events. Therefore, these data are likely to under-estimate the true adverse event rates. In addition, neither the time of onset nor the time to resolution of adverse events were collected. NCI-CTC grade 3-5 adverse events that were more common in patients receiving the AVASTIN compared to FOLFOX4 alone were fatigue (19% vs. 13%), diarrhea (18% vs. 13%), sensory neuropathy (17% vs. 9%), nausea (12% vs. 5%), vomiting (11% vs. 4%), dehydration (10% vs. 5%), hypertension (9% vs. 2%), abdominal pain (8% vs. 5%), hemorrhage (5% vs. 1%), other neurologic toxicities (5% vs. 3%), ileus (4% vs. 1%), and headache (3% vs. 0).

Fatal, treatment-related adverse events in patients receiving AVASTIN in this study included CNS hemorrhage, gastrointestinal hemorrhage, and gastrointestinal perforation with sepsis.

Full prescribing information including clinical trial information, safety, dosing, drug-drug interaction and contraindications is available in Drugs@FDA

 

 

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