A randomized trial of bevacizumab, an antivascular endothelial growth factor antibody, for metastatic renal cancer

Presenters name
Institution

Renal-Cell Carcinoma
Kidney cancer: 3% of solid tumors in adults About half of the new cases are metastatic Renal-cell carcinoma (RCC): 80% of adult kidney cancers Current treatment for metastatic RCC: nephrectomy + IL-2 or INF treatment

1520% response rate, 68% cure rate

Clear-cell RCC (CCRCC): 7588% of RCCs Predisposition: von Hippel-Lindau (VHL) disease

modified from Murakata et al. Mod Pathol 2000

Rationale for targeting VEGF in clear-cell RCC

VHL

VHL

Hif1

Hif1

Hif1

Hif1

VEGF

VEGF

Journal of Clinical Oncology, Vol 19, No 3 (February 1), 2001: pp 843-850

Aims: Determine safety and pharmacokinetics of bevacizumab Inclusion Criteria: - 25 patients with refractory advanced solid tumors (sarcoma, renal, lung, etc.) - Eastern Cooperative Oncology Group (ECOG) performance status 1 - Normal hematologic function Dosages: 0.1, 0.3, 1, 3, and 10 mg/kg Safety: - well-tolerated - no CTC grade 3 or 4 treatment-related adverse events (AEs) - grade 1-2 asthenia, fever, headache most common AEs

Efficacy: - some patients had stable disease at day 70 assessment - stable disease in 5 out of 7 renal cell cancer patients
Pharmacokinetics: - linear kinetics between 0.3 mg/kg and 10 mg/kg - mean half life of 21 days

Phase II Randomized, Double-blind Bevacizumab Trial for Metastatic CCRCC

Primary end points: time to progression of disease response rate Secondary end point: survival (crossover allowed) Treatment: placebo or 3 mg/kg or 10mg/kg every 2 weeks Inclusion criteria: - CCRCC (histology) - measurable metastasis - documented progression - ECOG 2 Exclusion criteria: - history of CNS involvement - therapy or surgery (4 weeks) - history of intratumoral bleeding - serum creatinine > 2 mg/dL - serum bilirubin > 2 mg/dL - ischemic vascular disease

Adverse Events
No life-threatening, grade 4 AEs or death related to bevacizumab

Hypertension and asymptomatic proteinuria associated with bevacizumab Median onset of newly-diagnosed hypertension on bevacizumab = 131 days

High-dose bevacizumab prolongs the time to disease progression

High-dose Low-dose

Treatment Placebo Low-dose High-dose

Median time to progression (mo.) 2.5 3.0 4.8

P value (log rank test)

Treatment Placebo

Progression-free after 4 mo. (%) 20 39 64

Progression-free after 8 mo. (%) 5 14 30

0.041 < 0.001

Low-dose High-dose

Response rate to high-dose bevacizumab was 10%

Patient with partial response (PR)

Objective response: 4 patients (high-dose) Partial response: 1 patient

pretreatment

PR (2 years) Treatment High-dose Low-dose VEGF (5 weeks) 196 pg/mL 155 pg/mL VEGF (13 weeks) 246 pg/mL 170 pg/mL relapse (6 mo.)

PR (3 mo.)

Bevacizumab treatment provided no overall survival advantage

Possible reasons: - Crossover design - Rigorous indications for declaring progression and removing patients

Future directions
Bevacizumab in combination with IL-2 or INF therapy for metastatic RCC Other angiogenic targets in RC (FGF5)

Many thanks to
Acknowledged individuals and institutions