Fabio PuglisiDipartimento di Oncologia

Azienda Ospedaliero Universitaria di Udine

Antiangiogenic Treatment

Mediterranean School of Oncology

Inhibiting angiogenesis

• Regression of existing microvasculature– Secondary tumor cell death

(response)

• “Normalization” of surviving mature vasculature– Synergistic effect with

chemotherapy

• Prevention of vessel re-growth/neo-vascularization– Improves time to progression

First-line trials

Study designE-2100 AVADO Ribbon-1

CapecitabineRibbon-1

A/T

Placebo Controlled

No Yes Yes Yes

ChemotherapyWeekly

paclitaxelQ3w

DocetaxelCapecitabine

Q3w doc/nabP

AC/FAC/EC/FEC

Dose of bevacizumab

10 mg/kg q2wk

7.5 or

15 mg/kg q3wk

15 mg/kg q3wk 15 mg/kg q3wk

Primary endpoint

PFS PFS (IRF) PFS (Inv) PFS (Inv)

IRF review Retrospective Yes Yes Yes

INDEPENDENT REVIEW OF E2100

Gray R, et al, J Clin Oncol 2009

First-line trials

Patient population

E-2100 AVADO Ribbon-1 Capecitabine

Ribbon-1

A/T

N 673 736 615 622

ER/PgR- 35% 22% 23% 24%

≥ 3 sites 45% 46% 44% 45%

Measurable disease

73% 83% 80% 84%

Adjuvant Chemotherapy (Taxane)

65% (16%) 66% (15%) 72% (40%) 45% (15%)

First-line trials

Efficacy

E-2100 AVADO Ribbon-1 Capecitabine

Ribbon-1

A/T

Control

Arm

Beva

Arm

Placebo

Arm

Beva

Arm

7.5/15 mg/kg

Placebo

Arm

Beva

Arm

Placebo

Arm

Beva

Arm

ORR 25% 49% 49% 55%/63% 24% 35% 38% 51%

PFS months

5.9 11.8 8.2 9/10.1 5.7 8.6 8.0 9.2

HR0.60

P<.0001

0.86 P=.12 (7.5 mg)

0.77 P=.006 (15 mg)

0.69

P=.0002

0.64

P<.0001

OS months

25.2 26.7 31.9 30.8/30.3 21.2 29 23.8 25.2

HR0.88

P=.16

1.05/1.03

P=.72/.85

0.85

P=.27

1.03

P=.83

Relative increase in RR 20-50%

Bevacizumab in MBC meta-analysis of RcTs

Lee J-B, et al. Invest New Drugs 2009

Response rate

Bevacizumab in MBC meta-analysis of RcTs

Lee J-B, et al. Invest New Drugs 2009

Progression free survival

Bevacizumab in MBC meta-analysis of RcTs

Lee J-B, et al. Invest New Drugs 2009

Overall survival

Safety of Bevacizumab in MBC meta-analysis of RcTs

Lee J-B, et al. Invest New Drugs 2009

RR (95% CI) P value

Hypertension 18.46 (1.18-289.38) 0.038

Proteinuria 11.03 (2.09-58.21) 0.005

Bleeding 1.75 (0.48-6.40) 0.395

Trombo-embolic event 1.07 (0.63-1.84) 0.797

RIBBON-2: Phase III Trial of Second-Line Bevacizumab + Chemotherapy in MBC

Patients with previously

treated MBC (HER2

negative or HER2 status unknown)

(N = 684)

Chemotherapy Regimens*Taxane or

Gemcitabine orCapecitabine or

Vinorelbine

Bevacizumab 15 mg/kg every 3 wks or 10 mg/kg every 2 wks† +

Chemotherapy(n = 459)

Placebo + Chemotherapy (n = 225)

Treat until

disease progression

Stratified by chemotherapy regimen, time between MBC diagnosis and

first PD, and hormone receptor status; randomized 2:1

*Dose and schedule of chemotherapy regimens (selected by investigator): Taxane: paclitaxel 90 mg/m2/wk for 3 of 4 wks; paclitaxel 175 mg/m2, nab-paclitaxel 260 mg/m2, or docetaxel 75-100 mg/m2 every 3 wks.Gemcitabine 1250 mg/m2 on Days 1 and 8 every 3 wks.Capecitabine 2000 mg/m2 on Days 1-14 every 3 wks.Vinorelbine 30 mg/m2/wk every 3 wks.†Dose of bevacizumab dependent on chemotherapy regimen used.

Brufsky A, et al. SABCS 2009.

RIBBON-2: PFS

Brufsky A, et al. SABCS 2009

1.0

0

Pro

po

rtio

n o

f P

rog

res

sio

n F

ree

Duration of PFS (Mos)

0.8

0.6

0.4

0.2

0

Primary Endpoint of PFS, ITT Population

Median PFS: 7.2 vs. 5.1 mosHR: 0.78 (P = .0072)

Chemo/placebo (n = 225)

Chemo/bevacizumab (n = 459)

2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34

Patients at Risk, nChemo/placeboChemo/bev

225 165 129 93 77 44 33 19 12 8 5 4 3 1 1 0 0 0459 381 334 254 190 130 87 47 27 18 9 5 2 1 1 0 0 0

Sorafenib 400 mg PO BID continuously +Capecitabine 1000 mg/m2 PO BID for 14 of 21 days

(n = 115)Patients with

locally advanced or metastaticbreast cancer

(N = 229)Placebo PO BID continuously +

Capecitabine 1000 mg/m2 PO BID for 14 of 21 days(n = 114)

Until disease

progression or

unacceptable toxicity

Stratified by visceral vs nonvisceral disease

SOLTI-0701: Phase IIb Study of Combination Sorafenib + Capecitabine

Baselga J, et al. SABCS 2009.

SOLTI-0701: PFS (ITT)

• Median PFS significantly longer with addition of sorafenib vs placebo:–6.4 vs 4.1 months–HR: 0.58 (95% CI: 0.41-0.81; P = 0.0006)

Baselga J, et al. SABCS 2009.

SOLTI-0701: safety

Baselga J, et al. SABCS 2009.

45

5 5 413

5 3 20

20

40

60

80

100

HFSR/HFS Diarrhea Dyspnea Neutropenia

Grade 3 AEsSorafenib + capecitabine (n = 112)

Placebo + capecitabine(n = 112)

Pat

ien

ts (

%)

The choice of the endpoint

Is overall survival still the

most appropriate endpoint in clinical trials of

metastatic breast cancer?

Probably no!

Survival post-progression

OS = PFS + SPPIf the progression eventis death, then SPP = 0

Broglio KR & Berry DA, JNCI 2009

Broglio, K. R. et al. J. Natl. Cancer Inst. 2009

Probability of statistically significant differences in overall survival (OS) as a function of median

survival postprogression (SPP)

First-line trials

Efficacy

E-2100 AVADO Ribbon-1 Capecitabine

Ribbon-1

A/TControl

Arm

Beva

Arm

Placebo

Arm

Beva

Arm

7.5/15 mg/kg

Placebo

Arm

Beva

Arm

Placebo

Arm

Beva

Arm

PFS months

5.9 11.8 8.2 9/10.1 5.7 8.6 8.0 9.2

HR0.60

P<.0001

0.86 P=.12 (7.5 mg)

0.77 P=.006 (15 mg)

0.69

P=.0002

0.64

P<.0001

OS months

25.2 26.7 31.9 30.8/30.3 21.2 29 23.8 25.2

HR0.88

P=.16

1.05/1.03

P=.72/.85

0.85

P=.27

1.03

P=.83

SPP

months19.3 14.9 23.7 21.8/20.2 15.5 20.4 15.8 16

CONCLUSIONS

• OS is a reasonable primary endpoint when median SPP is expected to be short but is too high a bar when median SPP is expected to be long (eg, longer than 12 months)

• As therapies for metastatic breast cancer improve, SPP would expect to increase, which may decrease the utility of OS as a clinical endpoint

Grazie per l’attenzione