Terapie antiangiogenetiche: revisione e
gestione degli eventi avversi
Lucia Del Mastro
SS Sviluppo Terapie Innovative
Modena- 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 wellestablished 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 the
administration of study drugs and death
AVF2119g:
E2100:
Avado:
RIBBON1:
Beva vs contl
0 events
0.5% vs 0.3%
0.8% vs 1.7%
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: 1.84
P=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: 27.68
P<0.0001
Beva: 1.31%
Cntl: 0.28%
OR: 4.07
P=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.
2.
3.
Hoff AO, Ann NY Acad Sci 1218: 47-54; 2011
Guarneri V Breast Cancer Res Treat 122: 181-188; 2010
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 embolism
Grade 3-4
4.2%
1.7 (ns)
Cortes, Ann Oncol 2011; Ranpura JAMA 2011; Choueiri JCO 2011