Oncologists Speak on Avastin

The evidence-based dose: Comments from leading oncologists

Ronald B. Natale, MD

"Given the results of this important study with a significant improvement in survival of patients with the 15 mg/kg dose, that dose remains the standard. To date, no other study has demonstrated either improved efficacy or decreased toxicity with a dose other than 15 mg/kg."

Ronald B. Natale, MD, is the Senior Research Advisor and National Director of the Lung Cancer Research Program for Aptium Oncology and an attending physician at the Cedars-Sinai Outpatient Cancer Center in Los Angeles, California. Dr Natale earned his medical degree from Wayne State University School of Medicine in Detroit, Michigan where he also did his medical residency. He completed a fellowship in hematology/oncology at the Memorial Sloan-Kettering Cancer Center in New York and a research fellowship at the National Cancer Institute. Prior to his current positions, he was a faculty member at the University of Michigan, where he also served as Associate Director of the Comprehensive Cancer Center, and at the University of Southern California, where he served as Associate Director of Medical Oncology.

Dr Natale is internationally renowned for his clinical research efforts in lung and genitourinary cancers. He has published over 250 articles and abstracts, co-authored several books, and presented results of his research at cancer research meetings all over the world. He has been cited as one of the best cancer doctors by Los Angeles Magazine, Good Housekeeping, and in each edition of Best Doctors in America since its inception.

Dr Ronald Natale BIO

Mark F. Kozloff, MD

"The E4599 Avastin dose was based on a Phase II ECOG study investigating paclitaxel/carboplatin plus or minus Avastin at doses of 7.5 or 15 mg/kg every 3 weeks. And within the Phase II study, the best results were clearly seen with 15 mg/kg every 3 weeks. Based on that Phase II study, the 15 mg/kg dose was recommended for the Phase III study, which demonstrated a significant survival advantage. So, that’s what I use in my practice."

Mark F. Kozloff, MD, is a Clinical Associate of Medicine in the Section of Hematology/Oncology at the University of Chicago in Chicago, Illinois, and Director of Oncology at the Ingalls Cancer Care Center at Ingalls Memorial Hospital in Harvey, Illinois. He also practices internal medicine in Orland Park and Tinley Park, Illinois, and in Munster, Indiana. Dr. Kozloff earned his medical degree from the University of Michigan in Ann Arbor. He served a residency in internal medicine at Michael Reese Hospital in Chicago and completed a fellowship in hematology at the University of Michigan. He is a member of the Eastern Cooperative Oncology Group, National Surgical Adjuvant Breast and Bowel Project, Southwest Oncology Group, American Society of Hematology, and American Society of Clinical Oncology. Dr. Kozloff is board certified in hematology and medical oncology.

Dr Mark Kozloff BIO

Edward S. Kim, MD

"The randomized Phase II trial that Dr David Johnson reported in the Journal of Clinical Oncology did test 2 different doses of Avastin—7.5 and 15 mg/kg every 3 weeks—in combination with paclitaxel/carboplatin….When the study data were reported, and all of the arms were compared, 15 mg every 3 weeks was clearly the better regimen."

Edward S. Kim, MD, is an Assistant Professor in the Department of Thoracic/Head and Neck Medical Oncology at the University of Texas MD Anderson Cancer Center in Houston, Texas, where he is also the Director of Educational Programs and Director of Residency Training in Oncology. He received his medical degree from Northwestern University in Chicago, Illinois. Dr Kim completed his residency in internal medicine at Baylor College of Medicine in Houston, and his medical oncology fellowship at the University of Texas MD Anderson Cancer Center. Dr Kim has served as principal investigator on numerous research projects and grant awards and has authored numerous publications on lung and other cancers.

Dr Ed Kim BIO

Oncologist comments were solicited in Genentech-sponsored interviews. Participating physicians received compensation for participating in the interviews. Opinions expressed herein reflect the professional views of the oncologists. Their opinions are provided for informational purposes only and should not substitute for your independent medical judgment or assessment of the risks and benefits of using Avastin to treat particular patients.

15 mg/kg IV q3w is the only dose of Avastin proven to increase OS in first-line advanced non-squamous NSCLC

15 mg/kg IV q3w was proven superior to 7.5 mg/kg IV q3w in a Phase II trial (Study AVF0757g)1
Time to Progression and Overall Survival
  • *Patients in the PC alone arm could cross over to an Avastin arm upon progression.
  • †P=0.023 vs control arm.
  • ‡P value was not significant vs control arm.
Important safety information—Study AVF0757g

The most common events of any severity (≥10% incidence) in the Avastin plus PC group in Study AVF0757g were nausea, leukopenia, neuropathy, peripheral neuritis, infection, paresthesia, vomiting, diarrhea, thrombocytopenia, and fever. In this trial, the incidence of serious or fatal pulmonary hemorrhage was 31% (4 of 13) in Avastin-treated patients with squamous cell histology and 4% (2 of 53) in Avastin-treated patients with histology other than squamous cell. As a result, patients with squamous cell histology were excluded from Study E4599.

Avastin dosing in first-line NSCLC3

Important treatment considerations—Women of childbearing potential

Avastin may impair fertility. Prior to initiation of therapy, advise patients of the potential risk of Avastin to the developing fetus. Counsel patients who become pregnant about the possible risks, including hazard to the fetus and/or loss of pregnancy, of both continued treatment and prolonged exposure following discontinuation, keeping in mind the approximate half-life of Avastin (20 days; range 11–50 days). Patients should also be counseled to continue adequate contraception for at least 6 months following the last dose of Avastin.

Indication

Avastin is indicated for the first-line treatment of unresectable, locally advanced, recurrent or metastatic non–squamous non–small cell lung cancer in combination with carboplatin and paclitaxel.

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

  • Grade 3–5 (nonhematologic) and grade 4–5 (hematologic) adverse events in Study E4599 occurring at a ≥2% higher incidence in Avastin-treated patients vs controls were neutropenia (27% vs 17%), fatigue (16% vs 13%), hypertension (8% vs 0.7%), infection without neutropenia (7% vs 3%), venous thrombus/embolism (5% vs 3%), febrile neutropenia (5% vs 2%), pneumonitis/pulmonary infiltrates (5% vs 3%), infection with grade 3 or 4 neutropenia (4% vs 2%), hyponatremia (4% vs 1%), headache (3% vs 1%), and proteinuria (3% vs 0%)

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

Next: Duration of Therapy

References
  1. Johnson DH, Fehrenbacher L, Novotny WF, et al. J Clin Oncol. 2004;22:2184-2191.
  2. Sandler A, Gray R, Perry MC, et al. N Engl J Med. 2006;355:2542-2550.
  3. Avastin Prescribing Information, Genentech, Inc. July 2009.