desarrollo clínico del bevacizumab en el tratamiento del cáncer renal metastásico dr miguel a....
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Desarrollo clínico del Bevacizumab en el tratamiento del cáncer renal
metastásico
Dr Miguel A. ClimentInstituto Valenciano de Oncología
Evolving treatment landscape in RCC
1. ESTUDIOS FASE II EN MONOTERAPIA Y COMBINACIÓN CON ERLOTINIB
2. ESTUDIOS FASE III EN COMBINACIÓN CON INTERFERON
3. NUEVAS PERSPECTIVAS DE COMBINACIONES CON BEVACIZUMAB
Perspectiva histórica del desarrollo clínico
Estudios fase II randomizado bevacizumab frente a placebo en segunda línea (AVF0890g)
Pacientes con cancer renal avanzado de células clarasEnfermedad medibleTratamiento previo con interleukina (o contraindicación para recibirla)
Randomización (116 pts):
placebo (40 pts)bevacizumab bajas dosis: 3 mg/kg/2sem (37 pts)bevacizumab altas dosis: 10 mg/kg/2sem (39 pts)
Objetivo principal:
tiempo a la progresióntasa de respuestassupervivencia global
Estudios fase II randomizado bevacizumab frente a placebo en segunda línea (AVF0890g)
Second line (trial AVF0890g)1
Pat
ien
ts
pro
gre
ssi
on
fre
e (%
)
Time (months)
100
80
60
40
20
00 6 12 18 24 30 36
4.83.02.5
Avastin 10mg/kg (PFS 4.8 months)
Avastin 3mg/kg (PFS 3.0 months)
Placebo (PFS 2.5 months)
1.
Bevacizumab 10 mg/kg frente placebo 2,55 p<0,001
Bevacizumab 3 mg/kg frente placebo 1,26 p=0,053
HR p
Estudio fase II comparativo bevacizumab+erlotinib frente a bevacizumab.
Pacientes con cáncer renal metastásico predominantemente de células clarasPrimera líneaNefrectomía previa
Randomización: 104 pts.
bevacizumab 10 mg/kg/2 sem + placebobevacizumab 10 mg/kg/2sem + erlotinib 150 mg/día
Objetivo principal:
supervivencia libre de progresióntasa de respuestassupervivencia global
Avastin is active as a single agent in mRCC
Time (months)100
80
60
40
20
00 3 6 9 12 15
Pat
ien
tsp
rog
res
sio
n f
ree
(%)
Time (months)
8.5 9.9
1. Yang, et al. NEJM 2003; 2. Bukowski, et al. JCO 2007
Avastin + Tarceva
Avastin + placebo
First line (trial RACE)2
HR=0.86 (95% CI: 0.50–1.49)p=0.58
Estudio fase II comparativo bevacizumab+erlotinib frente a bevacizumab.
Bevacuzumab + placebo 9,9 m 13%
Bevacizumab + erlotinib 8,5 m 14%
PFS ORR
AVOREN
A randomized, double-blind, placebo-controlled phase III study to evaluate the efficacy and safety
of bevacizumab in combination with interferon alfa-2a (Roferon) versus
interferon alfa-2a and placebo as first-line treatment administered to nephrectomized patients with
metastatic clear cell renal cell carcinoma
• B. Escudier, P. Koralewski, A. Pluzanska, A. Ravaud,S. Bracarda, C. Szczylik, C. Chevreau, M. Filipek,
B. Melichar, N. Moore
Avastin + IFN-2a (n=327)
IFN-2a + placebo (n=322)
PDPatients with advanced RCC
(n=649)
Stratification:Country
MSKCC risk group
1:1
PD
Escudier, et al. Lancet 2007
AVOREN
Bevacizumab/placebo 10mg/kg i.v. q2w until progression
IFN-2a 9MIU s.c. three times/week (maximum of 52 weeks) (dose reduction allowed)
Multinational ex-US study: 101 study sites in 18 countries
Stratification factors: country and Motzer score
Objectives
Primary objective To evaluate the efficacy of the combination of
bevacizumab plus IFN-α2a as compared with IFN-α2a alone based on overall survival
Secondary objectives Progression-free survival, time to disease progression,
time to treatment failure and objective response rates of bevacizumab plus IFN-α2a compared with IFN-α2a alone
Safety profile of bevacizumab plus IFN-α2a versus IFN-α2a alone
Pharmacokinetics and pharmacodynamics of bevacizumab
AVOREN
Statistical design
• Sample size calculation• 80% power to detect an improvement in overall survival from
13 to 17 months with a HR of 0.76 at a significance level of 0.05• required 445 events among 638 patients• interim analysis prespecified at 250 events
• A final progression-free survival analysis was specified in the Statistical Analysis Plan to occur at the time ofan interim overall survival analysis
• at least 90% power to detect an improvement in progression-free survival with a HR of 0.71 at a significance level of 0.05
• the study would be unblinded after the final progression-free survival analysis and continued on survival follow-up
AVOREN
Key eligibility criteria
RECIST = Response Evaluation Criteria in Solid Tumors; CNS = central nervous system
Inclusion criteria Confirmed metastatic RCC with >50% clear cell histology Nephrectomy Karnofsky performance status of ≥70% Measurable or non-measurable disease (according to RECIST)
Exclusion criteria Prior systemic treatment for metastatic RCC disease Evidence of current CNS metastases or spinal cord compression Evidence of bleeding diathesis or coagulopathy Full therapeutic doses of oral or parenteral anticoagulants
AVOREN
Patient characteristics
Variable IFN + placebo (n=322) Avastin + IFN (n=327)
Female (%) 27 32
Male (%) 73 68
Median age, years (range) 60 (18–81) 61 (30–82)
Karnofsky performance status (%) 100 90 80 70
393916 7
443218
6
Sites of metastases (%) Lung Lymph nodes Bone Liver
59362019
62341818
Motzer risk score (%) Favourable Intermediate Poor Not available
2956 8 7
275699
Escudier, et al. Lancet 2007
AVOREN
Independent review of PFS and ORR
Investigator1 IRC2
IFN + Bevacizumab
(n=327)
IFN +placebo(n=322)
IFN + Bevacizumab
(n=288)
IFN + placebo(n=281)
ORR (%) 31 13 31 12
p value <0.0001 <0.0001
Median PFS (months) 10.2 5.4 10.4 5.5
HR (95% CI) 0.63 (0.52–0.75) 0.57 (0.45–0.72)
p value <0.0001 <0.0001
1. Escudier, et al. Lancet 2007; 2. Roche, data on file
Tumor response* Bevacizumab + IFN
(n=306)IFN + placebo
(n=289)
100
80
60
40
20
0
–20
–40
–60
–80
–100
100
80
60
40
20
0
–20
–40
–60
–80
–100
–30–30
Per
cen
tag
e ch
an
ge
of
sum
lo
ng
est
dia
met
er o
f ta
rget
les
ion
s
*Patients with measurable disease only; investigator assessed
39% 70%
AVOREN
1.0
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0
No. of patients at risk
Avastin + IFN 327 196 107 18 0
IFN + placebo 322 137 59 15 0
Progression free survivalP
rob
abil
ity
of
bei
ng
pro
gre
ssio
n f
ree
Time (months)0 6 12 18 24
Avastin + IFN
IFN + placebo
5.4 10.2
Escudier, et al. Lancet 2007
HR=0.63; p<0.0001
AVOREN
HR=0.60, p=0.004Median progression-free survival:
Bevacizumab + IFN = 12.9 months
Placebo + IFN = 7.6 months
Pro
bab
ility
of
bei
ng
p
rog
ress
ion
-fre
e
Number ofpatients at risk
Placebo + IFN 93 57 25 70
Bevacizumab+ IFN 87 65 39 8
0
Time (months)0 6 12 18
24
1.0
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
07.6 12.9
PFS: Motzer subgroup – favorable
AVOREN
Bevacizumab + IFN = 10.2 months
Placebo + IFN = 4.5 months
Pro
bab
ility
of
bei
ng
p
rog
ress
ion
-fre
e1.0
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0
Time (months)0 6 12 18
24
HR=0.55, p<0.0001Median progression-free survival:
PFS: Motzer subgroup – intermediate
Number ofpatients at risk
Placebo + IFN 180 67 28 60
Bevacizumab+ IFN 183 112 60 9
0
4.5 10.2
AVOREN
PFS: Motzer subgroup – poorP
rob
abili
ty o
f b
ein
g
pro
gre
ssio
n-f
ree
Number ofpatients at risk
Placebo + IFN 25 2 1 10
Bevacizumab+ IFN 29 7 1 0
0
Time (months)0 6 12 18
24
1.0
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0
Bevacizumab + IFN = 2.2 months
Placebo + IFN = 2.1 months
HR=0.81, p=0.457Median progression-free survival:
AVOREN
Subgroup analysis for progression-free survival in AVOREN
Baseline risk factor Total (n) HR
All patients 649 0.63
Sex Female Male
193456
0.600.64
Age (years) <40 40–64 65
26384239
0.650.540.77
Number of metastatic sites 2 >2
394252
0.670.54
Motzer score Favorable Intermediate Poor
180363 54
0.600.550.81
0.2 0.5 1 2 5
HR
AVOREN
subgroups analyses
subgroups analyses
0.2 0.5 1 2 5
Baseline risk factor Total (n) HR HR
All patients 649 0.63
Age (years) <65 410 0.54 65 239 0.77
Creatinine clearance Low 191 0.65 High/normal 131 0.60
VEGF levels above median No 191 0.45 Yes 191 0.67
MSKCC score Favourable 180 0.60 Intermediate 363 0.55 Poor 54 0.81
RCC histology Clear cell 564 0.64 Mixed 85 0.53
Escudier, et al. Lancet 2007
AVOREN
Pro
babi
lity
of s
urvi
val
Final OS
Patients at risk (n)
IFN + Bevacizumab 327 278 237 194 157 124 84 27
IFN + placebo 322 262 216 177 141 113 78 22
21.3 23.3
0 6 12 18 24 30 36 42
Time (months)
1.0
0.8
0.6
0.4
0.2
0
IFN + Bevacizumab (n=327)
IFN + placebo (n=322)
HR=0.86 (95% CI: 0.72–1.04)
p=0.1291 (stratified*)
*Stratified by Motzer score and region
AVOREN
Pro
ba
bili
ty o
f s
urv
iva
l
Patients at risk (n)
IFN + B ev ac izum ab 327 278 237 194 157 124 84 27
IFN + p lacebo 322 262 216 177 141 113 78 22
21.3 23.3
0 6 12 18 24 30 36 42T im e (m onths)
1.0
0.8
0.6
0.4
0.2
0
IFN + Bevac izum ab (n= 327)
IFN + p lacebo (n= 322)
H R =0.86 (95% C I: 0.72–1.04)
p= 0.1291 (stratified*)
*S tratif ied by M otzer score and reg ion
Censoring crossover patients
Pro
bab
ilit
y o
f su
rviv
al
Patients at risk (n)
Bevacizumab + IFN 327 278 237 194 157 124 84 27IFN + placebo 322 262 216 173 131 101 69 19
0 6 12 18 24 30 36 42Time (months)
1.0
0.8
0.6
0.4
0.2
023.320.8
IFN + Bevacizumab (n=327)IFN + placebo (n=322)HR=0.84 (95% CI: 0.70–1.02)p=0.0766*
*Stratified by Motzer score and region
AVOREN
Pro
ba
bili
ty o
f su
rviv
al
Patients at risk (n)
Bevacizumab + IFN327 278 237 194 157 124 84 27
IFN + placebo 322 262 216 173 131 101 69 19
0 6 12 18 24 30 36 42Time (months)
1.0
0.8
0.6
0.4
0.2
023.320.8
IFN + Bevacizumab (n=327)IFN + placebo (n=322)HR =0.84 (95% C I: 0.70– 1.02)p=0.0766*
*S tra tif ied b y Motzer score and reg ion
Summary of subsequent medical therapies
Treatment, n (%)
IFN + Bevacizumab
(n=327)
IFN + placebo
(n=322)
Total patients with ≥1 treatment 180 (55) 202 (63)
VEGF inhibitors
Sunitinib 83 (25) 92 (29)
Sorafenib 60 (18) 50 (16)
Bevacizumab 10 (3) 12 (4)
Other* 7 (2) 6 (2)
mTOR inhibitors‡ 14 (4) 6 (2)
Cytokines 32 (10) 52 (16)
Chemotherapy§ 28 (9) 47 (15)*Protein TKI, pazopanib, erlotinib, blinded sorafenib, blinded sunitinib, angiogenesis inhibitors NOS, VEGF inhibitor NOS‡Temsirolimus, everolimus (RAD001)§Antimetabolites, vinca alkaloids and antineoplastic agents
AVOREN
Regional variation in subsequent treatment with TKIs
IFN + Bevacizumab IFN + placebo
Therapy
Western Europe(n=180)
Eastern Europe and other(n=147)
Western Europe(n=177)
Eastern Europe and other(n=145)
TKIs, n (%)
Sunitinib 52 (29) 31 (21) 64 (36) 28 (19)
Sorafenib 51 (28) 9 (6) 48 (27) 2 (1)
AVOREN
Regional variation in OS
IFN + Bevacizumab IFN + placebo
Western Europe(n=180)
Eastern Europe and other(n=147)
Western Europe(n=177)
Eastern Europe and other(n=145)
Events, n (%) 120 (67) 100 (68) 125 (71) 99 (68)
Median OS, months (95% CI) 24.5 (21–29) 23.1 (17–27) 23.7 (21–28) 17.1 (13–22)
HR (95% CI)* 0.93 (0.71–1.21) 0.92 (0.71–1.20)
p value (log-rank)*
0.5922 0.5336
*Stratified by Motzer score and region
AVOREN
Subgroup analysis of OS
0.2 0.5 1 2 5
Baseline risk factor Total (n) HR HR 95% CI
All patients 649 0.86 0.72–1.04
410
239
0.78
0.99
Age (years)
<65
≥650.61–0.99
0.73–1.35
Baseline VEGF > median
No
Yes192
192
0.74
0.88
0.50–1.10
0.62–1.24
192
457
0.90
0.84
Sex
Female
Male0.64–1.27
0.66–1.05
Motzer score
Favourable
Intermediate
Poor
180
366
55
0.86
0.83
0.86
0.57–1.30
0.65–1.06
0.47–1.59
Per cent body weight loss
10
>10
501
81
0.88
0.60
0.70–1.09
0.35–1.04
AVOREN
No. of metastatic sites
1
2
>2
152
242
252
0.81
1.02
0.74
0.52–1.27
0.73–1.41
0.55–0.99
Subgroup analysis of OS (cont’d)
Baseline risk factor Total (n) HR HR 95% CI
0.70–1.09
0.58–1.32
Bone metastases
No
Yes
521
125
0.87
0.88
565
81
0.88
0.68
Tumour in lung only
No
Yes0.72–1.08
0.36–1.28
0.2 0.5 1 2 5
Lung metastases
No
Yes
173
473
1.10
0.77
0.73–1.66
0.61–0.96
Liver metastases
No
Yes
508
138
0.76
1.30
0.62–0.95
0.85–1.98
AVOREN
Selected grade 3/4 adverse events*
Number of patients (%)
Adverse event
IFN + placebo
(n=304)
Bevacizumab + IFN
(n=337)
Any grade 3/4 adverse event 137 (45) 203 (60)
Fatigue/asthenia/malaise 46 (15) 76 (23)
Proteinuria 0 (0) 22 (6.5)
Hypertension 2 (0.7) 13 (3.9)
Hemorrhage 1 (0.3) 11 (3.3)
Venous thromboembolism 2 (0.7) 6 (1.8)
Gastrointestinal perforation 0 (0) 5 (1.5)
Arterial ischemia 1 (0.3) 4 (1.2)
*Based on safety population
AVOREN
Standard dose of IFN was 9MIU tiw s.c.
IFN was withheld if grade 3 adverse event attributable to IFN developed
IFN was restarted with one dose level reduction• to 6 or 3MIU upon resolution of toxicity to grade 1
• no re-escalation of IFN dose was allowed
No dose reduction of Avastin
Patients who received 1 dose reductions of IFN were included in the analysis
Escudier, et al. Lancet 2007
AVOREN
Tolerability improved by IFN dose reduction
6 weeks before IFN dose reduction
6 weeks after IFN dose reduction
Fatigue Pyrexia Anorexia Nausea Asthenia Flu-like Vomiting Depressionillness
25
20
15
10
5
0
Pat
ien
ts (
%)
Melichar, et al. Ann Oncol 2008, Abril
AVOREN
PFS in patients treated with Bevacizumab + reduced-dose IFN
1.0
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0
Time (months)0 3 6 9 12 15 18 21 24
No. of patients at risk
Avastin + reduced- dose IFN 131 118 96 88 55 28 12 40All Avastin + IFN 327 259 196 170 107 54 18 60
Median PFS
Avastin + reduced-dose IFN
All Avastin + IFN patients
Pro
bab
ilit
y o
f b
ein
gp
rog
ress
ion
fre
e
Melichar, et al. Ann Oncol (In press)
F in a l O S in red uced -d o se IF N p op u la tio n
26.023.3
Pro
ba
bili
ty o
f su
rviv
al
1.0
0.8
0.6
0.4
0.2
00 6 12 18 24 30 36 42
T ime (months)P atien ts at risk (n )
B evac izu m ab + red u ced -d o se IF N 131 116 102 85 72 57 38 16
B evac izu m ab + IF N 327 278 237 194 157 124 84 27
Bevacizumab + reduced-dose IF N (n=131)Bevacizumab + IF N (n=327)
PFS in patients treated with Bevacizumab + reduced-dose IFN
Estudio Prospectivo:“Evidence for Avastin + low-dose IFN (BEVLiN)
• Open-label, single-arm, phase II, multicentre study
• n=150 patients with clear cell metastatic RCC, good and intermediate risk
• Continue treatment until progression
• No dose modification permitted with IFN or Avastin (except for safety)
• Primary objective• PFS of Avastin + low-dose IFN
• Secondary objectives• further define the safety profile of Avastin + low-dose IFN• historical comparator AVOREN• assess second-line therapy• ancillary studies – QoL, biomarkers
• Ongoing
IFN 3MIU s.c. tiw
Avastin 10mg/kg i.v. every 2 weeks
Extensión del estudio BEVLiN
IFN 3MIU s.c. tiw
Avastin 10mg/kg i.v. every 2 weeks
Avastin + RAD001
PD
Sunitinib
• Objectives• primary: TTF• secondary: OS, safety, ORR, TTP
• Assumptions• Implement TML option for patients who progress• Potentially implement randomisation against sunitinib second
line – currently defining impact on patient numbers and budget
CALGB 90206: A Phase III Trial of Bevacizumab Plus Interferon-alpha versus Interferon-alpha Monotherapy in Metastatic
Renal Cell Carcinoma
Brian I. Rini 1, Susan Halabi 2,3, Jonathan E. Rosenberg 4, Walter M. Stadler 5, Daniel A.Vaena 6, San-San Ou 3, Laura Archer 3, James N. Atkins 7, Joel
Picus 8, Simon Tanguay 9, Janice Dutcher 10 and Eric J. Small 4
1. Cleveland Clinic Taussig Cancer Institute, Cleveland, OH2. Department of Biostatistics and Bioinformatics, Duke University Medical Center, Durham, NC3. CALGB Statistical Center, Durham, NC 4. University of California San Francisco, San Francisco, CA5. University of Chicago Medical Center, Chicago, IL6. University of Iowa, Iowa City, IA7. Southeast Cancer Control Consortium Inc.8. Washington University, St. Louis, MO9. McGill University, Montreal, Quebec and the National Cancer Institute Canada, Toronto, ON, Canada 10. New York Medical College, NY, NY and the Eastern Cooperative Oncology Group, Boston, MA
Study Schema
RANDOMIZE
IFNA 9 MU TIW
IFNA 9 MU TIW +
Bevacizumab 10 mg/kg IV
q d1 and d15
STRATIFY
• Patients stratified for nephrectomy status (yes/no) and MSKCC risk group (0 risk factors vs. 1-2 risk factors vs. 3 or more risk factors)*
Eligibility Criteria• Confirmed metastatic RCC with a
component of clear cell histology• Karnofsky PS ≥ 70%• Measurable or evaluable disease
(by RECIST)• No prior systemic treatment for
RCC• Adequate end-organ function• No CNS metastases• BP < 160/90 with meds• No DVT within 1 year or arterial
thrombotic event within 6 months• Prior nephrectomy not required
* Motzer R et al., JCO 20(1), 2002
CALGB 90206
Baseline Demographics and Clinical Characteristics (n=732)
Bevacizumab plus IFNA (n=369)
IFNA monotherapy (n=363)
Sex – no. (%)
Male
Female
269 (73%)
100 (27%)
239 (66%)
124 (34%)
Median Age, years
(inter-quartile range)
61
(56-70)
62
(55-70)
ECOG performance status – no. (%)
0
1
2
230 (62%)
132 (36%)
7 (2%)
227 (62%)
133 (37%)
3 (1%)
Previous nephrectomy – no. (%) 312 (85%) 308 (85%)
Previous radiation therapy – no. (%) 35 (9%) 38 (10%)
Common Sites of Metastases
Lung
Lymph node
Bone
Liver
252 (68%)
130 (35%)
104 (28%)
74 (20%)
254 (70%)
129 (36%)
109 (30%)
73 (20%)
Number of adverse risk factors
0 (favorable)
1-2 (intermediate)
≥ 3 (poor)
97 (26%)
234 (64%)
38 (10%)
95 (26%)
231 (64%)
37 (10%)
CALGB 90206
Objective Response
Note: patients with measurable disease only
Bev + IFNA (n=325) IFNA (n=314)
Overall Response rate 25.5% [95% CI = 20.9-30.6]
13.1%[95% CI = 9.5-17.3]
CR 3.4% 1.3%
PR 23.4% 12.7%
p < 0.0001
Duration of response 11.9 months [95% CI = 8.3 – 14.8]
9.7 months[95% CI = 7.6 – 19.8]
p = 0.362
CALGB 90206
MSKCC Prognostic groups
Median PFS (months)
Risk Group %Bev + IFNA
(n=369)IFNA
(n=363)
Favorable (0 risk factors) 26 11.1 5.7
(p = 0.0012)
Intermediate (1-2 risk factors) 64 8.4 5.3
(p = 0.0017)
Poor (≥ 3 risk factors) 10 3.3 2.6
(p = 0.25)
CALGB 90206
Time(months)
Ove
rall
Su
rviv
al (p
rob
ab
ility
) IFN BEV/IFNStratified log-rank p=0.069
Kaplan-Meier Overall Survival Curves by Treatment Arm
0 6 12 18 24 30 36 42 48 54 60
0.0
0.2
0.4
0.6
0.8
1.0
363 286 221 177 148 118 98 64 37 10 1369 314 242 190 160 139 116 94 42 17 2
IFNBEV/IFN
Number of Patients at Risk
---- BEV/IFN: Median OS 18.3 months
IFN: Median OS 17.4 months
Kaplan-Meier Overall Survival by Treatment ArmCALGB 90206
Overall Survival by MSKCC Risk Status*
Median OS (months)
Risk Group %BEV/IFN (n=369)
IFN(n=363)
Favorable (0 risk factors) 26 32.5 33.5
(p = 0.524)
Intermediate (1-2 risk factors) 64 17.7 16.1
(p = 0.174)
Poor (≥ 3 risk factors) 10 6.6 5.7
(p = 0.25)
* Motzer R et al., JCO 20(1), 2002
CALGB 90206
Therapy Received in Patients who Discontinued Protocol Therapy for Any Reason Other Than Death
Bevacizumab + IFN (n=351)
IFN monotherapy (n=350)
Percentage of patients receiving any second-line therapy
54% 62%
VEGF-targeted therapy 37% 46%
Bevacizumab 6% 14%
Chemotherapy 18% 14%
Investigational therapy 11% 18%
Cytokines 13% 14%
* Fifty-six percent of patients overall received at least one subsequent systemic therapy
CALGB 90206
Adverse event
Bevacizumab + IFNA
(n=366)
IFNA
(n=349)
Any grade 3/4 adverse event 289 (79%) 213 (61%)
Fatigue/asthenia/malaise 134 (37%) 104 (30%)
Anorexia 63 (17%) 28 (8%)
Proteinuria 56 (15%) 1 (<1%)
Hypertension 36 (11%) 0 (0)
Hemorrhage 5 (2%) 1 (<1%)
Venous thromboembolism 6 (2%) 3 (1%)
Gastrointestinal perforation 1 (<1%) 0 (0)
Arterial ischemia 5 (1%) 0 (0)
Selected grade 3 or 4 adverse events
CALGB 90206
Conclusions
Bevacizumab + IFN is an option in first-line treatment for patients with metastatic/advanced RCC
Bevacizumab + IFN significantly improves PFS as first-line therapy of patients with metastatic RCC
Although not statistically significant, a trend towards improved OS was
observed with bevacizumab + IFN combination. The results have been
confounded by• post-protocol bevacizumab• subsequent therapies
It seems that if IFN dose is reduced to manage side effects, clinical benefit is maintained
Bevacizumab plus IFN has a well-characterised tolerability profile
• Combinación aumenta supervivencia en Oncología:• mama, pulmón, colon, testículo, Ewing´s, osteosarcoma,
LNH, leucemias …
• ¿combinar o secuenciar?• En contra de combinar:
– Tratamientos paliativos– Más fármacos = más toxicidad (disminuir dosis)
• A favor de combinar:– Más fármacos, más actividad inicial– Estudios de “tracking” en USA sugieren que 1/3 pacientes que
progresan a una línea de tratamiento, no pueden seguir ttos.– Aparición de clones resistentes es función del tiempo (Goldie
Coldman)
¿ SE PUEDE MEJORAR RESULTADOS EN CCR CON TERAPIA COMBINATORIA ?
VEGFR
VEGF
pVHLX HIF mTORTemsirolimus
Everolimus
SunitinibSorafenibAxitinibPazopanib
Avastin
Adapted from Kaelin. Clin Cancer Res 2004
Combining therapy: vertical combination
Combining therapy: horizontal combination
VEGFR
VEGF
pVHL HIF
PDGFR
PDGF TGF-
EGFR
Avastin
SunitinibSorafenib
X
Tarceva
Adapted from Kaelin. Clin Cancer Res 2004
Bevacizumab, Sorafenib, Temsirolimus trial
Metastatic RCC (stratification by prior therapy and
MSKCC risk category)
Avastin(n=90)
PD
Avastin + temsirolimus(n=90) PD
Avastin + sorafenib(n=90)
PD
PDTemsirolimus + sorafenib
(n=90)Primary endpoints: PFS
Secondary endpoints: safety, RR, OS, SD at 6 months
PI: Keith Flaherty, duration March 2008–February 2012
US / Canada
Ongoing
BeST trial
Global study: ~25 countries, ~200 sites
Stratification factors: nephrectomy and Motzer score
PI: Bernard Escudier and Brian Rini, duration March 2008–February 2012
Ongoing ( n= 26 so far)
Avastin + temsirolimus (n=411)
Avastin + IFN-2a (n=411)
PD
Metastatic RCC patients (n=822)
1:1
INTORACTAvastin + temsirolimus versus Avastin + IFN-
PD
Study 3311
TTP= 5,3 mesesOS= 14,5 meses
Avastin +everolimus
Avastin + IFN-2a
PD
Metastatic RCC patients
1:1
RECORD 1:Avastin + everolimus versus Avastin + IFN-
PD
Sequential Two-agent Assessment in RCC Therapy
• Target enrolment: 240 patients
• Endpoints: PFS, OS, ORR, PD
Avastin
Avastin
Temsirolimus
Temsirolimus
Temsirolimus
Sunitinib
Avastin
Sunitinib
Sunitinib
START trial concept
Eligibility criteria• Clear cell mRCC• No CNS mets• Nephrectomy• No prior systemic
therapy
MD Anderson
• Aflibercept: • A protein comprised of segments of the extracellular domains
of human vascular endothelial growth factor receptors 1 (VEGFR1) and 2 (VEGFR2) fused to the constant region (Fc) of human IgG1 with potential antiangiogenic activity.
• Estudios fase III: próstata, pulmón, colorecto. Estudios fase II en otras patologías
• PTC 299: • Is a novel, orally administered, small molecule designed to
inhibit the production of VEGF by targeting the post-transcriptional processes that regulate VEGF synthesis
• Estudios preclínicos
Nuevas moléculas antiangiogénicas
Nuevas moléculas antiangiogénicas
• INGN 241: • Stimulates the immune system to attack cancer cells through IL-24
dependent mechanisms.• Efecto potenciador de bevacizumab en cáncer de pulmón
• IMC 1121B o ramucirumab:• Ac antiVEGFR-2• Estudios Fase II en cáncer de mama, ovario, próstata, colorecto y
pulmón
• CDP 791:• CDP-791 takes the novel approach of targeting and blocking
VEGFR-2 on blood vessel cells • Fase II en cáncer de pulmón
Gracias por su atención
Tolerability of single-agent Avastin in RCC typical based on extensive experience
Adverse event
Avastinfirst line1
Avastinsecond line2
Grade 3/4 (%) Grade 3/4 (%)
Proteinuria 6 8
Hypertension 26 21
Bleeding 4 0
Chest pain NR 5
GI perforation 0 NR
Neutropenia 0 NR
Diarrhoea 0 NR
Hand-foot syndrome 0 NR
Nausea + vomiting 0 NR
Stomatitis 0 NR
1. Bukowski, et al. JCO 2007; 2. Yang, et al. NEJM 2003
NR = not reported
CALGB 90206