Terapie antiangiogenetiche: revisione e gestione degli eventi avversi

Lucia Del MastroSS Sviluppo Terapie InnovativeModena- 18 Novembre 2011

IRCCS Azienda Ospedaliera Universitaria San Martino – IST Istituto Nazionale per la Ricerca sul Cancro

• Fatal adverse event– Death caused in all likelihhod by a drug -> major

cause of fatality in USA– 0.3% in prespective studies– 4.6% of all hospital fatality

• CAIRO study tested the optimal use of well-established cyctotoxic (capecitabine, irinoteca, oxaliplatin)

• 820 enrolled patients– 112 deaths (14%) occurring within 30 days of last

administration of study drug• 72 (9%) deaths caused by PD• 40 (5%) deaths without PD

Relationship between cause of death and study drugs changed in 65%of patients -> underestimation by local investigators of the relation between theadministration of study drugs and death

Beva vs contlAVF2119g: 0 eventsE2100: 0.5% vs 0.3%Avado: 0.8% vs 1.7%RIBBON1: 1.7% vs 2.7%

Overall: OR: 0.642 (95% CI 0.334-1.232; p=0.183

ATEs: Beva: 0.93%Cntl: 0.56

OR: 1.49 (0.69-3.19)P=0.3

VTEs: Beva: 2.6%Cntl: 2.6%

OR: 1.06 (0.70-1.61)P=0.78

Beva: 0.51%Cntl: 0.21%OR: 1.84P=0.327

Beva: 4.9%Cntl: 2.8%OR: 1.45 P=0.052

Beva: 9.7%Cntl: 0.64%OR: 12.76 (2.93-55.53)P=0.001

OR: 27.68P<0.0001

Beva: 1.31%Cntl: 0.28%OR: 4.07P=0.006

Beva: 1.73%Cntl: 0.78%OR: 2.25 (1.16-4.37)P=0.017

Beva: 1.6%Cntl: 0.4%RR 4.74 (1.66-11.18)P=0.001

Bevacizumab and osteonecrosis of the jaw

• Hypothesis: because healing after mucosal trauma requires re-vascularization, the combination of Beva and a biphosphonate could affect the incidence, the time to development of ONJ and/or the response to dental therapy.

Bevacizumab and osteonecrosis of the jaw

ONJ incidence

Biphosphonate alone 1-6%1

Bevacizumab alone 0.3-1% 2,3

Bevacizumab + biphosphonate 0.9-2.4% 2

1. Hoff AO, Ann NY Acad Sci 1218: 47-54; 20112. Guarneri V Breast Cancer Res Treat 122: 181-188; 20103. McArthur HL , ASCO 2008; abstr 9588

Bevacizumab and osteonecrosis of the jaw

Meta-analyses evaluating the safety of bevacizumab

Event Incidence RR

Hypertension grade 3-4 10-12% 12

Left ventricular dysfunction/CHF grade 3-4

1.6-1.8% 4.7

Hemorrhage grade 3-4 1.3% 4.07

Arterial/venous embolismGrade 3-4

4.2% 1.7 (ns)

Cortes, Ann Oncol 2011; Ranpura JAMA 2011; Choueiri JCO 2011