Fabio Puglisi Dipartimento 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 design E-2100AVADORibbon-1 Capecitabine Ribbon-1 A/T Placebo Controlled NoYes Chemotherapy Weekly paclitaxel Q3w Docetaxel Capecitabine Q3w doc/nabP AC/FAC/EC/FEC Dose of bevacizumab 10 mg/kg q2wk 7.5 or 15 mg/kg q3wk Primary endpoint PFSPFS (IRF)PFS (Inv) IRF review RetrospectiveYes

INDEPENDENT REVIEW OF E2100 Gray R, et al, J Clin Oncol 2009

First-line trials Patient population E-2100AVADORibbon-1 Capecitabine Ribbon-1 A/T N 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-2100AVADO 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% 55%/63%24%35%38%51% PFS months / HR 0.60 P< P=.12 (7.5 mg) 0.77 P=.006 (15 mg) 0.69 P= P<.0001 OS months / HR 0.88 P= /1.03 P=.72/ P= 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 ( )0.038 Proteinuria ( )0.005 Bleeding 1.75 ( )0.395 Trombo-embolic event 1.07 ( )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 or Capecitabine 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/m 2 /wk for 3 of 4 wks; paclitaxel 175 mg/m 2, nab-paclitaxel 260 mg/m 2, or docetaxel mg/m 2 every 3 wks. Gemcitabine 1250 mg/m 2 on Days 1 and 8 every 3 wks. Capecitabine 2000 mg/m 2 on Days 1-14 every 3 wks. Vinorelbine 30 mg/m 2 /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 Proportion of Progression Free Duration of PFS (Mos) Primary Endpoint of PFS, ITT Population Median PFS: 7.2 vs. 5.1 mos HR: 0.78 (P =.0072) Chemo/placebo (n = 225) Chemo/bevacizumab (n = 459) Patients at Risk, n Chemo/placebo Chemo/bev

Sorafenib 400 mg PO BID continuously + Capecitabine 1000 mg/m 2 PO BID for 14 of 21 days (n = 115) Patients with locally advanced or metastatic breast cancer (N = 229) Placebo PO BID continuously + Capecitabine 1000 mg/m 2 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: ; P = ) Baselga J, et al. SABCS 2009.

SOLTI-0701: safety Baselga J, et al. SABCS HFSR/HFSDiarrheaDyspneaNeutropenia Grade 3 AEs Sorafenib + capecitabine (n = 112) Placebo + capecitabine (n = 112) Patients (%)

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 + SPP If the progression event is death, then SPP = 0 Broglio KR & Berry DA, JNCI 2009

Broglio, K. R. et al. J. Natl. Cancer Inst Probability of statistically significant differences in overall survival (OS) as a function of median survival postprogression (SPP)

First-line trials Efficacy E-2100AVADO 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 PFS months / HR 0.60 P< P=.12 (7.5 mg) 0.77 P=.006 (15 mg) 0.69 P= P<.0001 OS months / HR 0.88 P= /1.03 P=.72/ P= P=.83 SPP months /

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

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