Desarrollo cl

1
Desarrollo clínico del Bevacizumab en el
tratamiento del cáncer renal metastásicoDr
Miguel A. ClimentInstituto Valenciano de
Oncología
2
Perspectiva histórica del desarrollo clínico
1. Yang, et al. NEJM 2003 2. Bukowski, et al. J
Clin Oncol 2007 3. Hainsworth et al. ASCO 2005
(Abstract 4542)4. Escudier, et al. Lancet 2007
5. Rini, B. ASCO GU 2008 (Abstract 350)
3
Evolving treatment landscape in RCC
Perspectiva histórica del desarrollo clínico

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

4
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
5
Estudios fase II randomizado bevacizumab frente a
placebo en segunda línea (AVF0890g)
100 80 60 40 20 0

• Second line (trial AVF0890g)1

Patients progression free ()
4.8
3.0
2.5
0 6 12 18 24 30 36
Time (months)
HR p
Bevacizumab 10 mg/kg frente placebo 2,55 plt0,001
Bevacizumab 3 mg/kg frente placebo 1,26 p0,053
1.
6
Estudio fase II comparativo bevacizumaberlotinib
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 supervive
ncia global
7
Avastin is active as a single agent in mRCC
Estudio fase II comparativo bevacizumaberlotinib
frente a bevacizumab.
PFS ORR
Bevacuzumab placebo 9,9 m 13 Bevacizumab
erlotinib 8,5 m 14
Time (months)
100 80 60 40 20 0
First line (trial RACE)2
Avastin Tarceva Avastin placebo
Patientsprogression free ()
HR0.86 (95 CI 0.501.49) p0.58
8.5
9.9
0 3 6 9 12 15
Time (months)
1. Yang, et al. NEJM 2003 2. Bukowski, et al.
JCO 2007
8
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
AVOREN

• B. Escudier, P. Koralewski, A. Pluzanska, A.
  Ravaud,S. Bracarda, C. Szczylik, C. Chevreau, M.
  Filipek, B. Melichar, N. Moore

9
AVOREN
Avastin IFN-a2a (n327)
Patients with advanced RCC (n649) Stratification
Country MSKCC risk group
PD
11
IFN-a2a placebo (n322)
PD

• 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

Escudier, et al. Lancet 2007
10
Objectives
AVOREN

• Primary objective
• To evaluate the efficacy of the combination of
  bevacizumab plus IFN-a2a as compared with IFN-a2a
  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-a2a compared with IFN-a2a alone
• Safety profile of bevacizumab plus IFN-a2a versus
  IFN-a2a alone
• Pharmacokinetics and pharmacodynamics of
  bevacizumab

11
Statistical design
AVOREN

• Sample size calculation
• 80 power to detect an improvement in overall
  survival from13 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

12
Key eligibility criteria
AVOREN

• Inclusion criteria
• Confirmed metastatic RCC with gt50 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
13
Patient characteristics
AVOREN
Variable IFN placebo (n322) Avastin IFN (n327)
Female () 27 32
Male () 73 68
Median age, years (range) 60 (1881) 61 (3082)
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
Escudier, et al. Lancet 2007
14
Tumor response (Investigator assessed)
AVOREN
Response IFN placebo(n289) Bevacizumab IFN(n306)
Overall response rate () Complete response Partial response 13 2 11 31 1 30
Median duration of response (months) Median duration of stable disease (months) 11 7 13 10
plt0.0001
Patients with measurable disease only
15
Independent review of PFS and ORR
Investigator1 Investigator1 IRC2 IRC2
IFN Bevacizumab (n327) IFN placebo(n322) IFN Bevacizumab (n288) IFN placebo(n281)
ORR () 31 13 31 12
p value lt0.0001 lt0.0001 lt0.0001 lt0.0001
Median PFS (months) 10.2 5.4 10.4 5.5
HR (95 CI) 0.63 (0.520.75) 0.63 (0.520.75) 0.57 (0.450.72) 0.57 (0.450.72)
p value lt0.0001 lt0.0001 lt0.0001 lt0.0001
1. Escudier, et al. Lancet 2007 2. Roche, data
on file
16
Tumor response
AVOREN
IFN placebo(n289)
Bevacizumab IFN(n306)
Percentage change of sum longest diameter of
target lesions
100 80 60 40 20 0 20 40 60 80 100
100 80 60 40 20 0 20 40 60 80 100
39
70
30
30
Patients with measurable disease only
investigator assessed
17
Progression free survival
AVOREN
Avastin IFN IFN placebo
1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0
HR0.63 plt0.0001
Probability of beingprogression free
5.4
10.2
0 6 12 18 24
Time (months)
No. of patients at risk Avastin
IFN 327 196 107 18 0 IFN placebo 322 137
59 15 0
Escudier, et al. Lancet 2007
18
PFS Motzer subgroup favorable
AVOREN
1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0
HR0.60, p0.004 Median progression-free
survival
Bevacizumab IFN 12.9 months Placebo IFN
7.6 months
Probability of being progression-free
7.6
12.9
0 6 12 18 24
Number ofpatients at risk Placebo
IFN 93 57 25 7 0 Bevacizumab IFN 87 65 39 8 0
Time (months)
19
PFS Motzer subgroup intermediate
AVOREN
1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0
HR0.55, plt0.0001 Median progression-free
survival
Bevacizumab IFN 10.2 months Placebo IFN
4.5 months
Probability of being progression-free
4.5
10.2
0 6 12 18 24
Number ofpatients at risk Placebo
IFN 180 67 28 6 0 Bevacizumab IFN 183 112 60 9 0
Time (months)
20
PFS Motzer subgroup poor
AVOREN
1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0
HR0.81, p0.457 Median progression-free
survival
Bevacizumab IFN 2.2 months Placebo IFN
2.1 months
Probability of being progression-free
0 6 12 18 24
Number ofpatients at risk Placebo
IFN 25 2 1 1 0 Bevacizumab IFN 29 7 1 0 0
Time (months)
21
Subgroup analysis for progression-free survival
in AVOREN
AVOREN
subgroups analyses
Baseline risk factor Total (n) HR
All patients 649 0.63
Sex Female Male 193456 0.600.64
Age (years) lt40 4064 ?65 26384239 0.650.540.77
Number of metastatic sites ?2 gt2 394252 0.670.54
Motzer score Favorable Intermediate Poor 180363 54 0.600.550.81
HR
0.2 0.5 1 2 5
22
subgroups analyses
AVOREN
Baseline risk factor Total (n) HR
HR
All patients 649 0.63
MSKCC score Favourable 180 0.60
Intermediate 363 0.55 Poor 54 0.81
Age (years) lt65 410 0.54 ?65 239 0.77
Creatinine clearance Low 191 0.65
High/normal 131 0.60
RCC histology Clear cell 564 0.64 Mixed
85 0.53
VEGF levels above median No 191 0.45
Yes 191 0.67
0.2 0.5 1 2 5
Escudier, et al. Lancet 2007
23
Interim analysis of overall survival
AVOREN
1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0
HR0.75 (95 CI 0.580.97), plt0.0267 Median
overall survival
Probability of survival
Bevacizumab IFN NR IFN placebo 19.8
months
19.8
0 6 12 18 24 30
Number ofpatients at risk IFN placebo
322 262 176 53 1 0 Bevacizumab
IFN 327 275 197 60 2 0
Time (months)
Stratified by Motzer score and region category
unstratified analysis HR0.79, p0.067
prespecified level of significance p0.0056 Not
reached
24
Final OS
AVOREN
1.0 0.8 0.6 0.4 0.2 0
Probability of survival
IFN Bevacizumab (n327) IFN placebo
(n322) HR0.86 (95 CI 0.721.04) p0.1291
(stratified)
21.3
23.3
0 6 12 18 24 30 36 42
Time (months)
Patients at risk (n) IFN Bevacizumab
327 278 237 194 157 124 84 27 IFN placebo
322 262 216 177 141 113 78 22
Stratified by Motzer score and region
25
Censoring crossover patients
AVOREN
1.0 0.8 0.6 0.4 0.2 0
Probability of survival
IFN Bevacizumab (n327) IFN placebo
(n322) HR0.84 (95 CI 0.701.02) p0.0766
23.3
20.8
0 6 12 18 24 30 36 42
Time (months)
Patients at risk (n) Bevacizumab
IFN 327 278 237 194 157 124 84 27 IFN placebo
322 262 216 173 131 101 69 19
Stratified by Motzer score and region
26
Summary of subsequent medical therapies
AVOREN
Treatment, n () IFN Bevacizumab (n327) IFN placebo (n322)
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 Protein TKI, pazopanib, erlotinib, blinded sorafenib, blinded sunitinib, angiogenesis inhibitors NOS, VEGF inhibitor NOS Temsirolimus, everolimus (RAD001) Antimetabolites, vinca alkaloids and antineoplastic agents Protein TKI, pazopanib, erlotinib, blinded sorafenib, blinded sunitinib, angiogenesis inhibitors NOS, VEGF inhibitor NOS Temsirolimus, everolimus (RAD001) Antimetabolites, vinca alkaloids and antineoplastic agents
27
Regional variation in subsequent treatment with
TKIs
AVOREN
IFN Bevacizumab IFN Bevacizumab IFN placebo IFN placebo
Therapy Western Europe(n180) Eastern Europe and other(n147) Western Europe(n177) Eastern Europe and other(n145)
TKIs, n ()
Sunitinib 52 (29) 31 (21) 64 (36) 28 (19)
Sorafenib 51 (28) 9 (6) 48 (27) 2 (1)
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Regional variation in OS
AVOREN
IFN Bevacizumab IFN Bevacizumab IFN placebo IFN placebo
Western Europe(n180) Eastern Europe and other(n147) Western Europe(n177) Eastern Europe and other(n145)
Events, n () 120 (67) 100 (68) 125 (71) 99 (68)
Median OS, months (95 CI) 24.5 (2129) 23.1 (1727) 23.7 (2128) 17.1 (1322)
HR (95 CI) 0.93 (0.711.21) 0.93 (0.711.21) 0.92 (0.711.20) 0.92 (0.711.20)
p value (log-rank) 0.5922 0.5922 0.5336 0.5336
Stratified by Motzer score and region
29
Subgroup analysis of OS
AVOREN
Baseline risk factor
Total (n)
HR
95 CI
HR
All patients
649
0.86
0.721.04
Sex Female Male
192 457
0.90 0.84
0.641.27 0.661.05
Age (years) lt65 65
410 239
0.78 0.99
0.610.99 0.731.35
Motzer score Favourable Intermediate Poor
180 366 55
0.86 0.83 0.86
0.571.30 0.651.06 0.471.59
Baseline VEGF gt median No Yes
192 192
0.74 0.88
0.501.10 0.621.24
Per cent body weight loss ?10 gt10
501 81
0.88 0.60
0.701.09 0.351.04
0.2 0.5 1 2 5
30
Subgroup analysis of OS (contd)
AVOREN
Baseline risk factor
Total (n)
HR
HR
95 CI
No. of metastatic sites 1 2 gt2
152 242 252
0.81 1.02 0.74
0.521.27 0.731.41 0.550.99
Lung metastases No Yes
173 473
1.10 0.77
0.731.66 0.610.96
Tumour in lung only No Yes
565 81
0.88 0.68
0.721.08 0.361.28
Bone metastases No Yes
0.701.09 0.581.32
521 125
0.87 0.88
Liver metastases No Yes
508 138
0.76 1.30
0.620.95 0.851.98
0.2 0.5 1 2 5
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Selected grade 3/4 adverse events
AVOREN
Number of patients () Number of patients () Number of patients ()
Adverse event IFN placebo (n304) IFN placebo (n304) Bevacizumab IFN (n337)
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) 1 (0.3) 4 (1.2)
Based on safety population
32
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
33
Tolerability improved by IFN dose reduction
AVOREN
25 20 15 10 5 0
Patients ()
Fatigue Pyrexia Anorexia Nausea Asthenia Flu-like
Vomiting Depression illness
Melichar, et al. Ann Oncol 2008, Abril
34
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
Median PFS
Probability of beingprogression free
Avastin reduced-dose IFN All Avastin IFN
patients
0 3 6 9 12 15 18 21 24
Time (months)
No. of patients at risk Avastin reduced-
dose IFN 131 118 96 88 55 28 12 4 0 All
Avastin IFN 327 259 196 170 107 54 18 6 0
Melichar, et al. Ann Oncol (In press)
35
PFS in patients treated with Bevacizumab
reduced-dose IFN
36
Estudio ProspectivoEvidence 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
• n150 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

37
Extensión del estudio BEVLiN
IFN 3MIU s.c. tiw
Avastin 10mg/kg i.v. every 2 weeks
PD
Avastin RAD001
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

38
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

39
Study Schema
CALGB 90206
RANDOMIZE
IFNA 9 MU TIW

• 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 lt 160/90 with meds
• No DVT within 1 year or arterial thrombotic event
  within 6 months
• Prior nephrectomy not required

STRATIFY
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
40
CALGB 90206
Baseline Demographics and Clinical Characteristics (n732) Baseline Demographics and Clinical Characteristics (n732) Baseline Demographics and Clinical Characteristics (n732)
Bevacizumab plus IFNA (n369) IFNA monotherapy (n363)
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)
41
Objective Response
CALGB 90206
Bev IFNA (n325) IFNA (n314)
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 lt 0.0001 p lt 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 p 0.362
Note patients with measurable disease only
42
(No Transcript)
43
MSKCC Prognostic groups
CALGB 90206
Median PFS (months) Median PFS (months)
Risk Group Bev IFNA (n369) IFNA(n363)
Favorable (0 risk factors) 26 11.1 5.7
(p 0.0012) (p 0.0012)
Intermediate (1-2 risk factors) 64 8.4 5.3
(p 0.0017) (p 0.0017)
Poor ( 3 risk factors) 10 3.3 2.6
(p 0.25) (p 0.25)
44
CALGB 90206
Kaplan-Meier Overall Survival by Treatment Arm
---- BEV/IFN Median OS 18.3 months
IFN Median OS 17.4 months
45
Overall Survival by MSKCC Risk Status
CALGB 90206
Median OS (months) Median OS (months)
Risk Group BEV/IFN (n369) IFN(n363)
Favorable (0 risk factors) 26 32.5 33.5
(p 0.524) (p 0.524)
Intermediate (1-2 risk factors) 64 17.7 16.1
(p 0.174) (p 0.174)
Poor ( 3 risk factors) 10 6.6 5.7
(p 0.25) (p 0.25)
Motzer R et al., JCO 20(1), 2002
46
Therapy Received in Patients who Discontinued
Protocol Therapy for Any Reason Other Than Death
CALGB 90206
Bevacizumab IFN (n351) IFN monotherapy (n350)
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
47
Selected grade 3 or 4 adverse events
CALGB 90206
Adverse event Bevacizumab IFNA (n366) IFNA (n349)
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 (lt1)
Hypertension 36 (11) 0 (0)
Hemorrhage 5 (2) 1 (lt1)
Venous thromboembolism 6 (2) 3 (1)
Gastrointestinal perforation 1 (lt1) 0 (0)
Arterial ischemia 5 (1) 0 (0)
48
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

49
SE PUEDE MEJORAR RESULTADOS EN CCR CON TERAPIA
COMBINATORIA ?

• Combinación aumenta supervivencia en Oncología
• mama, pulmón, colon, testículo, Ewings,
  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)

50
Combining therapy vertical combination
X
HIF
pVHL
mTOR
VEGFR
Adapted from Kaelin. Clin Cancer Res 2004
51
Combining therapy horizontal combination
X
HIF
pVHL
Avastin
VEGFR
PDGFR
EGFR
Sunitinib Sorafenib
Tarceva
Adapted from Kaelin. Clin Cancer Res 2004
52
Bevacizumab, Sorafenib, Temsirolimus trial
BeST trial
Avastin (n90)
PD
Avastin temsirolimus (n90)
Metastatic RCC (stratification by prior therapy
and MSKCC risk category)
PD
Avastin sorafenib (n90)
PD
Temsirolimus sorafenib (n90)
PD
Primary endpoints PFS Secondary endpoints
safety, RR, OS, SD at 6 months PI Keith
Flaherty, duration March 2008February 2012 US /
Canada Ongoing
53
INTORACTAvastin temsirolimus versus Avastin
IFN-a
Study 3311
Avastin temsirolimus (n411)
PD
Metastatic RCC patients (n822)
11
Avastin IFN-a2a (n411)
PD
Global study 25 countries, 200
sites Stratification factors nephrectomy and
Motzer score PI Bernard Escudier and Brian Rini,
duration March 2008February 2012 Ongoing ( n
26 so far)
54
(No Transcript)
55
TTP 5,3 meses OS 14,5 meses
56
RECORD 1Avastin everolimus versus Avastin
IFN-a
Avastin everolimus
PD
Metastatic RCC patients
11
PD
Avastin IFN-a2a
57
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
58
Conclusiones

• Los datos hasta la fecha y los perfiles de
  tolerabilidad favorecen a Avastin como compañero
  de combinación
• Los ensayos aleatorizados han sido iniciados para
  direccionar el potencial de Avastin
• Para maximizar los resultados del paciente,
  podría considerarse la secuencia completa de
  tratamiento antes de empezar la terapia de
  primera línea
• Avastin puede jugar un papel central en los
  avances futuros del tratamiento del RCC

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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 post-transcriptional processes that
  regulate VEGF synthesis
• Estudios preclínicos

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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

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Gracias por su atención
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Tolerability of single-agent Avastin in RCC
typical based on extensive experience
Adverse event Avastinfirst line1 Avastinsecond line2
Adverse event 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

NR not reported
1. Bukowski, et al. JCO 2007 2. Yang, et al.
NEJM 2003
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CALGB 90206