Efficacy in MCRC

Data from a retrospective analysis of Study 2107 suggest that patients derived clinical benefit from Avastin plus IFL regardless of k-ras, b-raf, p53 status, and P53 expression

Avastin survival based on biomarker status1*†

Avastin survival based on biomarker status

  • *Forest plots illustrating HRs for risk of death according to biomarker status and treatment subgroup. Relative size of circles indicates number of patients. Horizontal lines indicate 95% confidence intervals (CIs). Dashed vertical line indicates the HR of all subjects (0.57).
  • †Median survival times in each biomarker subgroup were estimated from Kaplan-Meier curves, and HRs and 95% CIs were estimated using Cox regression analysis. HRs represent median survivals of those with no mutation relative to those with a mutation in each treatment arm.

Biomarker subtypes and Avastin plus IFL

  • In all 4 biomarker subgroups (k-ras, b-raf, p53 status, and P53 expression), estimated HRs for death were <1 for patients treated with Avastin plus IFL compared with those for patients treated with placebo plus IFL1
  • Similar results were found for PFS and ORR when assessed by biomarker status1,2

“…[A]ll subgroups benefited from the addition of bevacizumab to IFL, regardless of the status of markers of Ras/Raf/Mek/Erk pathway activity or of p53. Although patients without mutations in the k-ras and b-raf genes demonstrated statistically significant better overall survival than those with a mutation in one or both genes, this difference was observed irrespective of the treatment received.”

– Ince et al. J Natl Cancer Inst. 2005;97:981-988.

Important safety information—Study 2107

  • The most common grade 3–4 events in Study 2107, which occurred at a ≥2% higher incidence in the Avastin plus IFL vs IFL groups, were asthenia (10% vs 7%), abdominal pain (8% vs 5%), pain (8% vs 5%), hypertension (12% vs 2%), deep vein thrombosis (9% vs 5%), intra-abdominal thrombosis (3% vs 1%), syncope (3% vs 1%), diarrhea (34% vs 25%), constipation (4% vs 2%), leukopenia (37% vs 31%), and neutropenia (21% vs 14%)

Indication

Avastin is indicated for the first- or second-line treatment of patients with metastatic carcinoma of the colon or rectum in combination with intravenous 5-fluorouracil–based chemotherapy.

Boxed WARNINGS and additional important safety information

  • Gastrointestinal (GI) perforation: Serious and sometimes fatal GI perforation occurs at a higher incidence in Avastin-treated patients compared to controls. The incidences of GI perforation ranged from 0.3% to 2.4% across clinical studies. Discontinue Avastin in patients with GI perforation

  • Surgery and wound healing complications: The incidence of wound healing and surgical complications, including serious and fatal complications, is increased in Avastin-treated patients. Do not initiate Avastin for at least 28 days after surgery and until the surgical wound is fully healed. The appropriate interval between termination of Avastin and subsequent elective surgery required to reduce the risks of impaired wound healing/wound dehiscence has not been determined. Discontinue Avastin at least 28 days prior to elective surgery and in patients with wound dehiscence requiring medical intervention

  • Hemorrhage: Severe or fatal hemorrhage, including hemoptysis, GI bleeding, hematemesis, central nervous system hemorrhage, epistaxis, and vaginal bleeding, occurred up to 5-fold more frequently in patients receiving Avastin. Across indications, the incidence of grade ≥3 hemorrhagic events among patients receiving Avastin ranged from 1.2% to 4.6%. Do not administer Avastin to patients with serious hemorrhage or recent hemoptysis (≥1/2 tsp of red blood). Discontinue Avastin in patients with serious hemorrhage (ie, requiring medical intervention)

  • Additional serious and sometimes fatal adverse events for which the incidence was increased in the Avastin-treated arm vs control included non-GI fistula formation (≤0.3%), arterial thromboembolic events (grade ≥3, 2.4%), and proteinuria including nephrotic syndrome (<1%). Additional serious adverse events for which the incidence was increased in the Avastin-treated arm vs control included hypertension (grade 3–4, 5%–18%) and reversible posterior leukoencephalopathy syndrome (RPLS) (<0.1%). Infusion reactions with the first dose of Avastin were uncommon (<3%), and severe reactions occurred in 0.2% of patients

  • The most common adverse reactions observed in Avastin patients at a rate >10% and at least twice the control arm rate were epistaxis, headache, hypertension, rhinitis, proteinuria, taste alteration, dry skin, rectal hemorrhage, lacrimation disorder, back pain, and exfoliative dermatitis. Across all studies, Avastin was discontinued in 8.4% to 21% of patients because of adverse reactions

  • In first-line MCRC, the most common grade 3–4 events in Study 2107, which occurred at a ≥2% higher incidence in the Avastin plus IFL vs IFL groups, were asthenia (10% vs 7%), abdominal pain (8% vs 5%), pain (8% vs 5%), hypertension (12% vs 2%), deep vein thrombosis (9% vs 5%), intra-abdominal thrombosis (3% vs 1%), syncope (3% vs 1%), diarrhea (34% vs 25%), constipation (4% vs 2%), leukopenia (37% vs 31%), and neutropenia (21% vs 14%)

  • In second-line MCRC, the most common grade 3–5 (nonhematologic) and 4–5 (hematologic) events in Study E3200, which occurred at a higher incidence (≥2%) in the Avastin plus FOLFOX4 vs FOLFOX4 groups, were diarrhea (18% vs 13%), nausea (12% vs 5%), vomiting (11% vs 4%), dehydration (10% vs 5%), ileus (4% vs 1%), neuropathy–sensory (17% vs 9%), neurologic–other (5% vs 3%), fatigue (19% vs 13%), abdominal pain (8% vs 5%), headache (3% vs 0%), hypertension (9% vs 2%), and hemorrhage (5% vs 1%)

Please see full Prescribing Information, including Boxed WARNINGS for additional safety information.

Next: First-line MCRC

References
  1. Ince WI, Jubb AM, Holden SN, et al. J Natl Cancer Inst. 2005;97:981-988.
  2. Hurwitz HI, Yi J, Ince W, et al. Oncologist. 2009;14:1-7.