Transcript Bevacizumab combined with interferon-α: a new first

Desarrollo clínico del Bevacizumab
en el tratamiento del cáncer renal
metastásico
Dr Miguel A. Climent
Instituto Valenciano de Oncología
Perspectiva
histórica
del desarrollo
clínico
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
Estudios fase II randomizado bevacizumab frente a
placebo en segunda línea (AVF0890g)
Pacientes con cancer renal avanzado de células claras
Enfermedad medible
Tratamiento 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 progresión
tasa de respuestas
supervivencia global
Patients
progression free (%)
Estudios fase II randomizado bevacizumab frente a
placebo en segunda línea (AVF0890g)
100
80
Second line (trial AVF0890g)1
60
Avastin 10mg/kg (PFS 4.8 months)
Avastin 3mg/kg (PFS 3.0 months)
Placebo (PFS 2.5 months)
40
20
0
2.5
0
3.0 4.8
6
12
18
24
Time (months)
30
36
HR
1.
p
Bevacizumab 10 mg/kg frente placebo
2,55
p<0,001
Bevacizumab 3 mg/kg frente placebo
1,26
p=0,053
Estudio fase II comparativo bevacizumab+erlotinib frente
a bevacizumab.
Pacientes con cáncer renal metastásico predominantemente de células claras
Primera línea
Nefrectomía previa
Randomización: 104 pts.
bevacizumab 10 mg/kg/2 sem + placebo
bevacizumab 10 mg/kg/2sem + erlotinib 150 mg/día
Objetivo principal:
supervivencia libre de progresión
tasa de respuestas
supervivencia global
Estudio fase II comparativo bevacizumab+erlotinib
frente
bevacizumab.
Avastin is active
as a asingle
agent in mRCC
PFS
ORR
Bevacuzumab + placebo
9,9 m
13%
Bevacizumab + erlotinib
8,5 m
14%
Patients
progression free (%)
Time (months)
100
80
60
40
20
0
1.
First line (trial RACE)2
Avastin + Tarceva
Avastin + placebo
HR=0.86 (95% CI: 0.50–1.49)
p=0.58
8.5
0
3
9.9
6
9
12
Time (months)
Yang, et al. NEJM 2003; 2. Bukowski, et al. JCO 2007
15
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
AVOREN
Patients with
advanced RCC
(n=649)
Stratification:
Country
MSKCC risk group
Avastin +
IFN-a2a (n=327)
PD
IFN-a2a + placebo
(n=322)
PD
1:1
 Bevacizumab/placebo 10mg/kg i.v. q2w until progression
 IFN-a2a 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
Escudier, et al. Lancet 2007
AVOREN
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 of
an 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
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
RECIST = Response Evaluation Criteria in Solid Tumors; CNS = central nervous system
AVOREN
Patient characteristics
Variable
IFN + placebo (n=322)
Avastin + IFN (n=327)
Female (%)
27
32
Male (%)
73
68
60 (18–81)
61 (30–82)
Karnofsky performance status (%)
100
90
80
70
39
39
16
7
44
32
18
6
Sites of metastases (%)
Lung
Lymph nodes
Bone
Liver
59
36
20
19
62
34
18
18
Motzer risk score (%)
Favourable
Intermediate
Poor
Not available
29
56
8
7
27
56
9
9
Median age, years (range)
Escudier, et al. Lancet 2007
Independent review of PFS and ORR
Investigator1
ORR (%)
IFN +
Bevacizumab
(n=327)
IFN +
placebo
(n=322)
IFN +
Bevacizumab
(n=288)
IFN +
placebo
(n=281)
31
13
31
12
p value
Median PFS
(months)
HR (95% CI)
p value
IRC2
<0.0001
10.2
<0.0001
5.4
0.63 (0.52–0.75)
<0.0001
10.4
5.5
0.57 (0.45–0.72)
<0.0001
1. Escudier, et al. Lancet 2007; 2. Roche, data on file
AVOREN
Tumor response*
Percentage change of sum longest
diameter of target lesions
IFN + placebo
(n=289)
Bevacizumab + IFN
(n=306)
100
100
80
80
60
60
40
39%
40
20
20
0
0
–20
–30
–40
–20
–30
–40
–60
–60
–80
–80
–100
–100
*Patients with measurable disease only; investigator assessed
70%
AVOREN
Progression free survival
0.9
Avastin + IFN
IFN + placebo
0.8
HR=0.63; p<0.0001
Probability of being
progression free
1.0
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0
5.4
0
No. of patients at risk
Avastin + IFN
327
IFN + placebo
322
Escudier, et al. Lancet 2007
10.2
6
12
Time (months)
18
24
196
137
107
59
18
15
0
0
AVOREN
PFS: Motzer subgroup – favorable
1.0
HR=0.60, p=0.004
Median progression-free survival:
0.9
Probability of being
progression-free
0.8
Bevacizumab + IFN = 12.9 months
Placebo + IFN = 7.6 months
0.7
0.6
0.5
0.4
0.3
0.2
0.1
7.6
0
Number of
patients at risk
Placebo + IFN
Bevacizumab
+ IFN
0
6
12.9
12
Time (months)
18
24
93
57
25
7
0
87
65
39
8
0
AVOREN
PFS: Motzer subgroup – intermediate
1.0
HR=0.55, p<0.0001
Median progression-free survival:
0.9
Probability of being
progression-free
0.8
Bevacizumab + IFN = 10.2 months
Placebo + IFN = 4.5 months
0.7
0.6
0.5
0.4
0.3
0.2
0.1
4.5
0
Number of
patients at risk
Placebo + IFN
Bevacizumab
+ IFN
0
10.2
6
12
Time (months)
18
24
180
67
28
6
0
183
112
60
9
0
AVOREN
PFS: Motzer subgroup – poor
1.0
HR=0.81, p=0.457
Median progression-free survival:
0.9
Probability of being
progression-free
0.8
Bevacizumab + IFN = 2.2 months
Placebo + IFN = 2.1 months
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0
Number of
patients at risk
Placebo + IFN
Bevacizumab
+ IFN
0
6
12
Time (months)
18
24
25
2
1
1
0
29
7
1
0
0
Subgroup analysis forAVOREN
progression-free survival in AVOREN
subgroups analyses
Baseline risk factor
Total (n)
HR
All patients
649
0.63
Sex
Female
Male
193
456
0.60
0.64
Age (years)
<40
40–64
65
26
384
239
0.65
0.54
0.77
Number of metastatic sites
2
>2
394
252
0.67
0.54
Motzer score
Favorable
Intermediate
Poor
180
363
54
0.60
0.55
0.81
HR
0.2
0.5
1
2
5
AVOREN
subgroups analyses
Baseline risk factor
Total (n)
HR
All patients
649
0.63
MSKCC score
Favourable
Intermediate
Poor
180
363
54
0.60
0.55
0.81
Age (years)
<65
65
410
239
0.54
0.77
Creatinine clearance
Low
High/normal
191
131
0.65
0.60
RCC histology
Clear cell
Mixed
564
85
0.64
0.53
VEGF levels above median
No
Yes
191
191
0.45
0.67
HR
0.2
Escudier, et al. Lancet 2007
0.5
1
2
5
AVOREN
Final OS
Probability of survival
Probability of survival
1.0
IFN + Bevacizumab (n=327)
IFN + placebo (n=322)
HR=0.86
(95% CI: 0.72–1.04)
IFN + Bevacizumab (n=327)
p=0.1291
(stratified*)
IFN
+ placebo (n=322)
0.8
1.0
0.8
0.6
HR=0.86 (95% CI: 0.72–1.04)
p=0.1291 (stratified*)
0.6
0.4
0.4
0.2
0.2
00
00
21.3
21.3
66
12
12
278
237
194
262
216
Patients at risk (n)
IFN + Bevacizumab 327
IFN + placebo
Patients
at risk (n)
322
23.3
23.3
18
24
18
24
Time
Time(months)
(months)
30
30
3636
4242
157
124
84
27
177
141
113
78
22
124
IFN + Bevacizumab 327
278
237
194
157
IFN + placebo
262
216
177
141
322
84
27
*Stratified by Motzer score and region
113
78
22
*Stratified by Motzer score and region
AVOREN
Censoring crossover patients
Probability of survival
Probability of survival
1.0
IFN + Bevacizumab (n=327)
IFN + placebo (n=322)
HR=0.84 (95% CI: 0.70–1.02)
p=0.0766*
0.8
1.0
IFN + Bevacizumab (n=327)
IFN + placebo (n=322)
HR=0.84 (95% CI: 0.70–1.02)
p=0.0766*
0.8
0.6
0.6
0.4
0.4
0.2
0.2
00
00
20.8
20.8
66
12
12
Patients at risk (n)
Bevacizumab + IFN327
IFN + placebo
322
Patients at risk (n)
Bevacizumab + IFN327
IFN + placebo
322
278
262
278
262
23.3
23.3
18
24
18
24
Time (months)
(months)
Time
237
216
194
173
157
131
237
216
194
173
157
131
30
30
36
36
124
101
84
69
4242
27
19
124
84
27
101 by Motzer
69
19and region
*Stratified
score
*Stratified by Motzer score and region
AVOREN
Summary of subsequent medical therapies
IFN + Bevacizumab
IFN + placebo
Treatment, n (%)
(n=327)
(n=322)
Total patients with ≥1 treatment
180 (55)
202 (63)
Sunitinib
83 (25)
92 (29)
Sorafenib
60 (18)
50 (16)
Bevacizumab
10 (3)
12 (4)
7 (2)
6 (2)
mTOR inhibitors‡
14 (4)
6 (2)
Cytokines
32 (10)
52 (16)
Chemotherapy§
28 (9)
47 (15)
VEGF inhibitors
Other*
*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
Western
Europe
(n=180)
Eastern Europe
and other
(n=147)
Sunitinib
52 (29)
31 (21)
64 (36)
28 (19)
Sorafenib
51 (28)
9 (6)
48 (27)
2 (1)
Therapy
Eastern Europe
Western Europe
and other
(n=177)
(n=145)
TKIs, n (%)
AVOREN
Regional variation in OS
IFN + Bevacizumab
Events, n (%)
Median OS, months
(95% CI)
HR (95% CI)*
IFN + placebo
Western
Europe
(n=180)
Eastern Europe
and other
(n=147)
Western
Europe
(n=177)
Eastern Europe
and other
(n=145)
120 (67)
100 (68)
125 (71)
99 (68)
24.5 (21–29)
23.1 (17–27)
23.7 (21–28)
17.1 (13–22)
0.93 (0.71–1.21)
0.92 (0.71–1.20)
0.5922
0.5336
p value
(log-rank)*
*Stratified by Motzer score and region
AVOREN
Subgroup analysis of OS
Baseline risk factor
All patients
Sex
Female
Male
Age (years)
<65
≥65
Motzer score
Favourable
Intermediate
Poor
Baseline VEGF > median
No
Yes
Per cent body weight loss
10
>10
Total (n)
HR
HR
95% CI
649
0.86
192
457
0.90
0.84
410
239
0.78
0.99
0.61–0.99
0.73–1.35
180
366
55
0.86
0.83
0.86
0.57–1.30
0.65–1.06
0.47–1.59
192
192
0.74
0.88
0.50–1.10
0.62–1.24
501
81
0.88
0.60
0.70–1.09
0.35–1.04
0.72–1.04
0.64–1.27
0.66–1.05
0.2
0.5
1
2
5
AVOREN
Subgroup analysis of OS (cont’d)
Baseline risk factor
No. of metastatic sites
1
2
>2
Lung metastases
No
Yes
Tumour in lung only
No
Yes
Bone metastases
No
Yes
Liver metastases
No
Yes
Total (n)
HR
HR
95% CI
152
242
252
0.81
1.02
0.74
0.52–1.27
0.73–1.41
0.55–0.99
173
473
1.10
0.77
0.73–1.66
0.61–0.96
565
81
0.88
0.68
521
125
0.87
0.88
0.70–1.09
0.58–1.32
508
138
0.76
1.30
0.62–0.95
0.85–1.98
0.72–1.08
0.36–1.28
0.2
0.5
1
2
5
AVOREN
Selected grade 3/4 adverse events*
Number of patients (%)
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)
Adverse event
*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
25
6 weeks after IFN dose reduction
Patients (%)
20
15
10
5
0
Fatigue
Pyrexia
Melichar, et al. Ann Oncol 2008, Abril
Anorexia
Nausea
Asthenia
Flu-like
illness
Vomiting Depression
Probability of being
progression free
PFS in patients treated with Bevacizumab + reduceddose IFN
1.0
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0
Median PFS
Avastin + reduced-dose IFN
All Avastin + IFN patients
0
3
6
131
327
118
259
96
196
No. of patients at risk
Avastin + reduceddose IFN
All Avastin + IFN
Melichar, et al. Ann Oncol (In press)
9
12
15
Time (months)
88
170
55
107
28
54
18
21
24
12
18
4
6
0
0
PFS in patients treated with Bevacizumab + reduceddose IFN
Final OS in reduced-dose IFN population
Probability of survival
1.0
Bevacizumab + reduced-dose IFN (n=131)
Bevacizumab + IFN (n=327)
0.8
0.6
0.4
0.2
23.3
26.0
0
0
6
12
131
116
102
85
Bevacizumab + IFN 327
278
237
194
Patients at risk (n)
Bevacizumab +
reduced-dose IFN
18
24
Time (months)
30
36
42
72
57
38
16
157
124
84
27
Estudio Prospectivo:“Evidence for Avastin + low-dose IFN
(BEVLiN)
IFN 3MIU s.c. tiw
Avastin 10mg/kg i.v. every 2 weeks
•
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
Extensión del estudio BEVLiN
IFN 3MIU s.c. tiw
Avastin 10mg/kg i.v. every 2 weeks
PD
Sunitinib
Avastin + RAD001
• 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, OH
2. Department of Biostatistics and Bioinformatics, Duke University Medical Center, Durham, NC
3. CALGB Statistical Center, Durham, NC
4. University of California San Francisco, San Francisco, CA
5. University of Chicago Medical Center, Chicago, IL
6. University of Iowa, Iowa City, IA
7. Southeast Cancer Control Consortium Inc.
8. Washington University, St. Louis, MO
9. 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
CALGB 90206
Study Schema
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
S
T
R
A
T
I
F
Y
R
A
N
D
O
M
IZ
E
IFNA 9 MU TIW
IFNA 9 MU TIW
+
Bevacizumab
10 mg/kg IV
q d1 and d15
• 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)*
* 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)
269 (73%)
100 (27%)
239 (66%)
124 (34%)
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%)
Sex – no. (%)
Male
Female
Median Age, years
(inter-quartile range)
Previous radiation therapy – no. (%)
35 (9%)
308 (85%)
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
Overall Response rate
Bev + IFNA (n=325)
IFNA (n=314)
25.5%
13.1%
[95% CI = 20.9-30.6]
[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
9.7 months
[95% CI = 8.3 – 14.8]
[95% CI = 7.6 – 19.8]
p = 0.362
Note: patients with measurable disease only
CALGB 90206
MSKCC Prognostic groups
Median PFS (months)
Risk Group
%
Bev + IFNA
(n=369)
Favorable (0 risk factors)
26
11.1
IFNA
(n=363)
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
0.8
IFN
BEV/IFN
Stratified log-rank p=0.069
0.6
---- BEV/IFN: Median OS 18.3 months
0.2
0.4
IFN: Median OS 17.4 months
0.0
Overall Survival (probability)
1.0
Kaplan-Meier
Overall
Survival
by by
Treatment
Kaplan-Meier Overall
Survival
Curves
Treatment Arm
Arm
0
6
12
18
24
30
36
42
48
54
60
64
94
37
42
10
17
1
2
Time(months)
Number of Patients at Risk
IFN
363 286 221
BEV/IFN 369 314 242
177
190
148
160
118
139
98
116
CALGB 90206
Overall
Survival by MSKCC Risk Status*
Median OS (months)
Risk Group
%
BEV/IFN
(n=369)
Favorable (0 risk factors)
26
32.5
IFN
(n=363)
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%
6%
14%
Chemotherapy
18%
14%
Investigational therapy
11%
18%
Cytokines
13%
14%
Bevacizumab
* Fifty-six percent of patients overall received at least one subsequent systemic therapy
CALGB 90206
Selected grade 3 or 4 adverse events
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)
Adverse event
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
¿ SE PUEDE MEJORAR RESULTADOS EN CCR CON
TERAPIA COMBINATORIA ?
• 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)
Combining therapy: vertical combination
X
pVHL
Adapted from Kaelin. Clin Cancer Res 2004
HIF
mTOR
Temsirolimus
Everolimus
VEGF
Avastin
VEGFR
Sunitinib
Sorafenib
Axitinib
Pazopanib
Combining therapy: horizontal combination
X
pVHL
Avastin
HIF
VEGF
PDGF
TGF-a
VEGFR
PDGFR
EGFR
Sunitinib
Sorafenib
Adapted from Kaelin. Clin Cancer Res 2004
Tarceva
Bevacizumab, Sorafenib, Temsirolimus trial
BeST 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
Temsirolimus + sorafenib
(n=90)
PD
Primary endpoints: PFS
Secondary endpoints: safety, RR, OS, SD at 6 months
PI: Keith Flaherty, duration March 2008–February 2012
US / Canada
Ongoing
INTORACT
Avastin + temsirolimus versus Avastin + IFN-a
Study 3311
Metastatic RCC
patients (n=822)
Avastin + temsirolimus
(n=411)
PD
Avastin + IFN-a2a
(n=411)
PD
1:1
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)
TTP= 5,3 meses
OS= 14,5 meses
RECORD 1:
Avastin + everolimus versus Avastin + IFN-a
Avastin +everolimus
Metastatic RCC
patients
PD
1:1
Avastin + IFN-a2a
PD
Sequential Two-agent Assessment in RCC Therapy
START trial concept
Sunitinib
Avastin
Temsirolimus
Eligibility criteria
•
•
•
•
Clear cell mRCC
No CNS mets
Nephrectomy
No prior systemic
therapy
Avastin
Temsirolimus
Sunitinib
Avastin
Sunitinib
Temsirolimus
• Target enrolment: 240 patients
• Endpoints: PFS, OS, ORR, PD
MD Anderson
Nuevas moléculas antiangiogénicas
• 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 posttranscriptional processes that regulate VEGF synthesis
• Estudios preclínicos
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
Proteinuria
Hypertension
Bleeding
Chest pain
GI perforation
Neutropenia
Diarrhoea
Hand-foot syndrome
Nausea + vomiting
Stomatitis
NR = not reported
1. Bukowski, et al. JCO 2007; 2. Yang, et al. NEJM 2003
Avastin
first line1
Avastin
second line2
Grade 3/4 (%)
6
26
4
NR
0
0
0
0
0
0
Grade 3/4 (%)
8
21
0
5
NR
NR
NR
NR
NR
NR
CALGB 90206