Desarrollo clínico del Bevacizumab en el tratamiento del cáncer renal metastásico Dr Miguel A....

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


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


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



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


24

HR=0.55, p<0.0001Median progression-free survival:

PFS: Motzer subgroup – intermediate


Placebo + IFN 180 67 28 60


0

4.5 10.2

AVOREN

PFS: Motzer subgroup – poorP

rob

abili

ty o

f b

ein

g

pro

gre

ssio

n-f

ree


Placebo + IFN 25 2 1 10


0


24

1.0

0.9

0.8

0.7

0.6

0.5

0.4

0.3

0.2

0.1

0



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


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


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


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*


AVOREN

Pro

ba

bili

ty o

f su

rviv

al


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)



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





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


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


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

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