Colorectal Cancer: Avastin Safety Profile

Metastatic colorectal cancer (MCRC)
Avastin, in combination with intravenous 5‑fluorouracil-based chemotherapy, is indicated for the first‑ or second‑line treatment of patients with metastatic colorectal cancer.

Avastin, in combination with fluoropyrimidine-irinotecan- or fluoropyrimidine-oxaliplatin-based chemotherapy, is indicated for the second-line treatment of patients with metastatic colorectal cancer who have progressed on a first-line Avastin-containing regimen.

Limitation of Use: Avastin is not indicated for adjuvant treatment of colon cancer.

Boxed WARNINGS

  • Gastrointestinal (GI) perforation
    • Discontinue for gastrointestinal perforation
  • Surgery and wound healing complications
    • Withhold Avastin for at least 28 days prior to elective surgery. Do not administer Avastin for at least 28 days after surgery and until the wound is fully healed
    • Discontinue in patients with wound healing complications requiring medical intervention
  • Hemorrhage
    • Severe or fatal hemorrhage have occurred
    • Do not administer Avastin to patients with serious hemorrhage or recent history of hemoptysis
    • Discontinue for Grade 3-4 hemorrhage

Consistent safety profile demonstrated in 3 large Phase III trials

Safety evaluated in 2919 patients receiving Avastin in clinical trials across indications[1]

First-line Study 2107: Avastin plus 5-fluorouracil (5-FU)/leucovorin (LV)/irinotecan (IFL)[1]

Grade 3–4 adverse events in MCRC patients (≥2% higher incidence in the Avastin arm)[1]

National Cancer Institute Common Terminology Criteria (NCI-CTC) grade 3–4 events  Patients (%)
Avastin + IFL (n=392) Placebo + IFL (n=396)
Asthenia 10 7
Abdominal pain 8 5
Pain 8 5
Hypertension 12 2
Deep vein thrombosis 9 5
Intra-abdominal thrombosis 3 1
Syncope 3 1
Diarrhea 34 25
Constipation 4 2
Leukopenia 37 31
Neutropenia* 21 14

*Central laboratories were collected on days 1 and 21 of each cycle. Neutrophil counts were available in 303 patients receiving placebo plus IFL and 276 patients receiving Avastin plus IFL.[1]

Boxed WARNINGS

  • Gastrointestinal (GI) perforation
    • Discontinue for gastrointestinal perforation
  • Surgery and wound healing complications
    • Withhold Avastin for at least 28 days prior to elective surgery. Do not administer Avastin for at least 28 days after surgery and until the wound is fully healed
    • Discontinue in patients with wound healing complications requiring medical intervention
  • Hemorrhage
    • Severe or fatal hemorrhage have occurred
    • Do not administer Avastin to patients with serious hemorrhage or recent history of hemoptysis
    • Discontinue for Grade 3-4 hemorrhage

Second-line Avastin-naive Study E3200: Avastin plus 5-FU/LV/oxaliplatin (FOLFOX4)[1]

Grade 3–5 adverse events (≥2% higher incidence in the Avastin arm)[1]†

NCI-CTC grade 3–5 (nonhematologic) and grade 4–5 (hematologic) events   Patients (%)
Avastin + FOLFOX4 (n=287) FOLFOX4 alone (n=285)
Fatigue 19 13
Diarrhea 18 13
Sensory neuropathy 17 9
Nausea 12 5
Vomiting 11 4
Dehydration 10 5
Hypertension 9 2
Abdominal pain 8 5
Hemorrhage 5 1
Neurological disorder 5 3
Ileus 4 1
Headache 3 0

These data are likely to underestimate the true adverse event rates due to the reporting mechanisms used in this study.[1]

The TML study: Avastin plus fluoropyrimidine-based chemotherapy[4

No new safety signals were observed in the TML study (ML18147) when Avastin was administered in second-line MCRC patients who progressed on an Avastin containing regimen in first-line MCRC. The safety data was consistent with the known safety profile established in first- and second-line MCRC.[4]

TML=Treatment through Multiple Lines (first and second line).
§Chemotherapy combinations included either an irinotecan- or oxaliplatin-containing regimen.[1]