Avastin Approved as First-Line Rx of Nonsquamous NSCLC

November 1, 2006

Avastin(bevacizumab, Genentech) has gainedFood and Drug Administration (FDA)approval in combination with carboplatinand paclitaxel for the first-line treatmentof unresectable, locally advanced, recurrent,or metastatic non-squamous-cell,non-small-cell lung cancer (NSCLC),which accounts for about three-quartersof newly diagnosed cases in the UnitedStates.

ROCKVILLE, Maryland--Avastin(bevacizumab, Genentech) has gainedFood and Drug Administration (FDA)approval in combination with carboplatinand paclitaxel for the first-line treatmentof unresectable, locally advanced, recurrent,or metastatic non-squamous-cell,non-small-cell lung cancer (NSCLC),which accounts for about three-quartersof newly diagnosed cases in the UnitedStates. The agency acted after reviewingfindings from a pivotal phase III studythat found the Avastin/chemotherapycombination increased overall survival by25%, compared with the two chemotherapeuticagents alone.

"Bevacizumab, in combination withchemotherapy, is the first therapy in 10years to improve on standard first-linetreatment for advanced lung cancer, andthe first FDA-approved therapy ever toextend survival for these patients beyondone year in a large, randomized clinicaltrial," said Alan Sandler, MD, directorof Medical Thoracic Oncology at Vanderbilt-Ingram Cancer Center. "With thissurvival benefit, bevacizumab representsan important therapy for many advancedlung cancer patients fighting this difficultdisease."

Dr. Sandler served as the lead investigatorfor the phase III trial, designatedE4599, which was led by the Eastern CooperativeOncology Group (ECOG).

Avastin is an antiangiogenic, recombinant,humanized monoclonal IgG1 antibodythat inhibits the biologic activityof human vascular endothelial growthfactor. As a result, tumors apparently cannotacquire the new blood vessels requiredfor them to grow. FDA initiallyapproved Avastin in combination withintravenous fluorouracil (5-FU) in February2004 for the first-line treatment ofmetastatic colorectal cancer. In June ofthis year, the drug received approval incombination with 5-FU as a second-linetreatment in the same disease.

Pivotal Study
Genentech supported its pivotalstudy--E4599, a randomized, activecontrolled,open-label, multicentertrial--with data from a smaller randomized,dose-ranging, active-controlled phase II study. E4599 researchers enrolled878 patients without prior chemotherapyand randomized them 1:1 toreceive six 21-day cycles of paclitaxel 200mg/m2 and carboplatin to AUC 6 (PC)on day 1 or PC plus 15 mg/kg of Avastinon day 1. When patients in the Avastintreatedarm completed or discontinuedchemotherapy, they continued to receiveAvastin alone until disease progressionor unacceptable toxicity. Duration of survivalserved as the primary outcome.

Median overall survival was a statisticallysignificant 12.3 months in theAvastin plus PC arm vs 10.3 months inthe PC-alone group (HR 0.80, P = .013).One-year survival was 51% in theAvastin-treated patients vs 44% in thePC-alone arm. Investigators reportedthat the Avastin-treated patients hadlonger progression-free survival, comparedwith PC alone, but their assessmentswere not independently verified. Exploratory analyses of subgroups foundAvastin had less overall survival impactin women, patients age 65 and older,and in those with 5% or greater weightloss at accrual.

The most common side effects associatedwith Avastin included weakness,abdominal pain, headache, diarrhea, andvomiting. The grade 3 to 5 adverse eventsobserved in E4599 were neutropenia,fatigue, hypertension, infection, andhemorrhage. Clinical experience withAvastin has revealed two different hemorrhagepatterns. One is minor, mostcommonly NCI-CTC grade 1 epistaxis.The second causes serious, sometimes fatalbleeding.

In E4599, pulmonary hemorrhage requiringmedical intervention occurred in10 of 427 patients (2.3%) in the Avastin/PC arm, compared with 2 of 441 (0.5%)in the PC-alone arm. Pulmonary bleedingcaused seven deaths in the Avastintreatedpatients vs one in those receivingPC alone. Typically, serious hemorrhagingoccurred as major or massive hemoptysiswithout a prior history of minorhemoptysis during Avastin therapy.

In the 98-patient phase II dosingstudy, 4 of 13 (31%) Avastin-treated patientswith squamous cell histology sufferedserious or fatal pulmonary hemorrhage.As a result, such patients wereexcluded from the E4599 study.

Among patients in the dosing studywith other than squamous cell histology,2 of 53 (4.0%) in the Avastin-treatedgroup experienced serious or fatal pulmonaryhemorrhage. None of the 32patients receiving chemotherapy alonehad a serious or fatal pulmonary hemorrhage.