The Role of Angiogenesis

Inhibition in Breast Cancer

Today: Lessons Learned

Hope S. Rugo, MD Professor of Medicine

Director, Breast Oncology and Clinical

Trials Education

UCSF Helen Diller Family Comprehensive Cancer Center

VEGF Binding Induces Multiple Downstream

Signaling Pathways

Selected Agents Targeting the

VEGF Pathway

Class Examples Targets Stage of Development Company

Agents targeting the VEGF ligand

Antibodies Bevacizumab

Ramucirumab

VEGF

VEGFR2

Phase III

Phase III

Genentech

ImClone

Soluble receptors

VEGF-TRAP (aflibercept)

VEGF and PlGF Phase III Regeneron/Sanofi Aventis

Agents targeting the VEGF Receptors

Small molecule inhibitors

Sunitinib

Axitinib

SU014813

Pazopanib

Sorafenib

VEGFR-2, PDGFR, c-Kit

VEGFR-2

VEGFR1,2; c-Kit

VEGFR1,2; (PDGFR, c-Kit)

Raf, VEGFR1,2; c-Kit

Phase III*

Phase II/III

Phase II

Phase II/III

Phase III**

Pfizer

Pfizer

Pfizer

GSK

Bayer/Onyx

Vatalanib

AEE788

VEGFR-1/2 PDGFR, c-Kit

VEGFR1,2; ErbB1,2

Phase II/III

Phase I/II

Novartis

Novartis

Vandetinib

Cediranib

Motesanib

ABT 869

Brivanib

TKI258

VEGFR-2/EGFR

VEGFR, c-Kit

VEGFR1,2; PDGFR, c-Kit

VEGFR1,2

VEGFR2, FGFR

VEGFR, FGFR, PDGFR

Phase II/III

Phase II/III

Phase II/III

Phase I/II

Phase II

Phase II

Astra Zeneca

Astra Zeneca

Amgen

Abbott

BMS

Novartis

Phase III Trial with Bevacizumab Therapy in

Metastatic Breast Cancer

Capecitabine

alone Capecitabine + bevacizumab

P Value

Overall response rate (%) 9.1 19.8 0.001

Progression-free survival (mo) 4.17 4.86 0.518

Overall survival (mo) 14.52 15.05 0.627

Capecitabine (n=230)

Capecitabine + bevacizumab

(15 mg/kg q3w) (n=232)

PD

PD

Miller et al. JCO 23:792-799, 2005.

R

A

N

D

O

M

I

Z

A

T

I

O

N

Previously treated

MBC

MBC not previously treated with

chemotherapy

(N = 722)

Stratification

- Disease-free interval

- Adjuvant therapy

- ER+, ER–, unknown

- Number of metastatic sites

Paclitaxel: 90 mg/m2 IV infusion over 1 hr weekly x 3 wk followed by 1 wk of rest

Bevacizumab: 10 mg/kg following paclitaxel Rx on wk 1 and 3 per cycle

R

Paclitaxel: 90 mg/m2 IV infusion over 1 hr weekly x 3 wk followed by 1 wk of rest

E2100:

Supported Accelerated Approval in 2008

Miller K, et al. NEJM, 2007.

0.8

0.6

0.4

0.2

0.0

1.0

36 30 24 12 6 0

Pro

po

rtio

n w

ith

ou

t even

t

HR = 0.483 (0.385, 0.607)

Log-rank test, p ≤ 0.0001

Paclitaxel (n = 354)

Paclitaxel + Bevacizumab (n = 368)

18

Time, mo

E2100 PFS by IRF (Kaplan-Meier)

Miller K, et al. NEJM 2007, JCO 2008

©2009 by American Society of Clinical Oncology

Patient Disposition, IRF Review of E2100

• 89.9% had at least one image

• 82% had both baseline/post baseline radiographic data

– 34 +255 censored (40% overall, 35% after day 1)

• 86.6% had PFS determined

• 472 (65%) had measurable disease at baseline

Gray R et al. JCO 2009;27:4966-4972.

3 Randomized Phase III Trials in Previously

Untreated MBC

Previously

untreated

MBC

Chemo +

No Bev

Chemo +

Bev

Optional

second-line

Chemo +

Bev

(AVADO and

RIBBON-1

only)*

E2100

Paclitaxel

AVADO

Docetaxel

RIBBON-1

Capecitabine,

Taxane, or

Anthracycline

Treat

until

PD

R

A

N

D

O

M

I

Z

E

*~ 50% of patients received bevacizumab at crossover

N=2,447 patients from 3 trials

Control (n=1,008); BV + chemo (n=1,439)

PFS primary endpoint HR for PFS relatively similar across trials

Bevacizumab And Chemotherapy in the

First-Line Setting: PFS

1.0

0.8

0.6

0.4

0.2

0

PFS

est

imat

e

0 6 12 18 24 30

Time (months)

9.2 8.0

AVADO

HR=0.67* (0.54–0.83) p=0.0002§

1.0

0.8

0.6

0.4

0.2

0

PFS

est

imat

e

0 6 12 18 24 30 36

Time (months)

8.1 10.0

Placebo + docetaxel (n=241) Bevacizumab 15mg/kg q3w + docetaxel (n=247)

Placebo + docetaxel (n=207) Bevacizumab + taxane/ anthracycline (n=415)

1.0

0.8

0.6

0.4

0.2

0 0 6 12 18 24 30

Time (months)

HR=0.64* (0.52–0.80) p<0.0001

HR=0.69* (0.56–0.84) p=0.0002

Placebo + capecitabine (n=206) Bevacizumab + capecitabine (n=409)

8.6 5.7

RIBBON-1‡: taxane/anthracycline cohort

HR=0.48* (0.39–0.61) p<0.0001

PFS

est

imat

e

1.0

0.8

0.6

0.4

0.2

0

PFS

est

imat

e

0 6 12 18 24 30 36

Time (months)

Paclitaxel (n=354) Bevacizumab + paclitaxel (n=368)

5.8 11.3

E2100 (IRF assessment)

RIBBON-1‡: capecitabine cohort

E21001 AVADO2

RIBBON-1§3

Capecitabine T/anthr

Pac

Bev

+ pac

Placebo

+ doc

Bev*

+ doc

Placebo

+ cap

Bev

+ cap

Placebo

+ T/a

Bev

+ T/a

Median OS,

months 24.8 26.5 31.9 30.2 21.2 29.0 23.8 25.2

HR

0.87

p=0.14

1.03

p=0.85

0.85

p=0.27

1.03

p=0.83

1-year OS

rate, %‡ 74 81 76 84 74 81 83 81

p=0.017 p=0.02 p=0.076 p=0.44

Secondary Endpoint: Overall Survival (OS)

*15mg/kg q3w; ‡Exploratory p values §

O’Shaughnessy et al. ASCO 2010. Abstract 1005.

Pooled Safety Analysis of Bevacizumab +

Chemotherapy vs Chemotherapy Alone

Select Grade ≥ 3 Adverse Event,* %

Chemotherapy +

Bevacizumab

(n = 1679)

Chemotherapy

Alone

(n = 982)

Neutropenia 10.0 7.1

Sensory neuropathy 9.5 8.5

Hypertension 9.0 1.2

Febrile neutropenia 6.5 3.5

Venous thromboembolic event 2.8 3.8

Proteinuria 2.3 0

Total deaths 51.3 55.8

MBC 47.4 51.5

Treatment-related 2.1 1.8

Other 1.5 1.4

*Occurring in ≥ 2% of pts in either arm

Caveats: Interpretation of OS: Chemotherapy,

Cross-Over and Subsequent Therapy • Is effect on absolute improvement in PFS drug or schedule

related? – Only ECOG 2100 used weekly paclitaxel

– AVADO discontinued chemo at a set time

• 51% of patients in the non-bev arm received bevacizumab post-progression compared to 40% who continued bev after first-line

• 42% vs 35% (non bev vs bev) received 3 or more subsequent lines of therapy following progression

• Was this trial powered to detect a survival benefit in an unselected first line population? (Broglio and Berry, JNCI, 2009)

• 11.11 FDA: “….women who take Avastin for metastatic breast cancer risk potentially life-threatening side effects without proof that the use of Avastin will provide a benefit, …., that would justify those risks. Nor is there evidence that use of Avastin will either help them live longer or improve their quality of life.”

Summary of Efficacy with Bevacizumab and

Paclitaxel in Breast Cancer:

PFS in First-Line Studies

Study Chemotherapy N PFS with bevacizumab

(mo)

E2100 Weekly paclitaxel 722 11.3

RIBBON I (2:1) Weekly paclitaxel/ anthracycline

622 9.2 (10.7 IRC)

Weekly taxane (exploratory)

307 9.2

CALGB 40502 Weekly paclitaxel

283 (paclitaxel arm only)

10.6

TURANDOT Weekly paclitaxel

564 11

Rugo et al, ASCO 2012, Zielinski et al, ESMO 2012, abstract 3170

All Patients GEPARquinto NSABP B-40

No Bev (969) Bev (956) No Bev (595) Bev (584)

pCR (inv) in breast (%) 20.6 24.6 28.2 34.5

0.04 P=0.02

pCR (inv) breast/node 18.3 21.7 23 27.6

0.07 P=.08

pCR (inv/noninv) breast/node

14.9 18.4

0.04 (HR1.29; 1.02-1.65)

TN Disease TN HR+

pCR (inv) in breast (%) 31 39.8 47 52 15.1 23.2

P=.022 P=.34 P=.007

pCR breast/node 32.7 40.1 41 44 11.1 16.8

Inv only in NSABP P=.059 P=.458 P=.03

pCR (inv/noninv) breast/node

27.9 39.3 Both trials: significant increase in pCR in tumors with high grade histology P=.003

von Minckwitz et al, NEJM 2012; Bear et al, NEJM 2012 Test for homogeneity NS

What Could Explain These Seemingly

Conflicting Results?

• Most straightforward

– Differences in study design

• German trial more locally advanced, non-responders withdrawn

• Different sequencing of drugs

– Local testing results are clearly variable, and may not be validated

with central testing

– Conclusions may therefore be biased in an

unknown direction

• Importance of central confirmation of IHC results

– Pathology reports reviewed centrally

• Subtype specificity

– Are we defining real biologic subtypes using IHC criteria?

• Host biology

– Conflicting results across disease types

• Clearly, we need a marker!

Subsets and Biomarkers:

Can clinical and biologic

markers predict response?

16

Hypoxic Signatures and Basal-like Tumors

VEGF 13-gene VEGF-signature

exp

ress

ion

Hypoxia related features are common in basal-like tumors; 13 gene hypoxia

signature correlates with poor outcome, includes VEGF and HIF-1a related genes.

Higher intratumoral VEGF levels in TNBC Linderholm et al. Ann Oncol 2009.

Hu et al., BMC Medicine 2009

No. at risk:

BEV + CT 112 65 26 8 4

Placebo + CT 47 11 4 2

TNBC population: PFS

PFS

BEV + CT

(n=112)

PLA + CT

(n=47)

Events, n (%) 94 (84) 42 (89)

Median, months 6.0 2.7

HRa (95% CI)

Log-rank test

0.494 (0.33–0.74)

p=0.0006

1.0

0.8

0.6

0.4

0.2

0

0 5 10 15 20 25

Time (months)

2.7 6.0

aStratified analysis (CT regimen, interval from

LR/MBC diagnosis to 1st progression)

Estimated

probability

BEATRICE: Phase III Trial of Adjuvant Bevacizumab

in Triple-Negative Breast Cancer

Cameron et al., SABCS 2012; abstract S6-5

• BEATRICE study design

Eligibility criteria: • Resected triple-negative (centrally confirmed) invasive early breast cancer

4-8 cycles of standard chemotherapy (investigator’s choice)

RANDOMI ZE

(N=2591)

4-8 cycles of standard chemotherapy (investigator’s choice) + bevacizumab 5 mg/kg/wk equivalent for 1 year duration

Chemotherapy options: •Taxane-based (≥4 cycles) •Anthracycline-based (≥4 cycles) •Anthracycline + taxane (3-4 cycles each)

Primary endpoint: DFS Secondary endpoints: OS, breast cancer-free interval, DFS, distant DFS, safety, biomarkers

BEATRICE: Phase III Trial of Adjuvant Bevacizumab

in Triple-Negative Breast Cancer

Cameron et al., SABCS 2012; abstract S6-5

• Efficacy results

– None of the subgroups examined (age, baseline ECOG performance status, region, race, menopausal status, tumor size, # of positive LNs, adjuvant chemotherapy, HR status, and surgery) showed a significant effect on invasive DFS

• Safety results

Outcome

Chemo alone (n=1290)

Chemo + bevacizumab (n=1301)

HR (95%CI)

P-value

3-yr invasive DFS 82.7% 83.7% 0.87 (0.72-1.07) .18

OS -- -- 0.84 (0.64-1.12) .23

Adverse events, % of patients

Chemo alone (n=1271)

Chemo + bevacizumab (n=1288)

Any AE Grade ≥3 AE Grade 5 AE

99% 57% 0.2%

99% 72% 0.3%

AE leading to chemo and/or bev discontinuation AE leading to bev discontinuation

2%

--

20%

18%

BEATRICE Trial: Biomarker Results

Baseline Plasma Concentration HR* P-Value

Median VEGF-A

High 0.81 .7415

Low 0.89

3rd Quartile VEGF-A

High 0.64 .3551

Low 0.92

Median VEGFR-2

High .61 .0291

Low 1.24

•Biomarker analysis performed to investigate potential predictive markers of benefit from adjuvant bevacizumab • Sub-study included 45% of total patient population • Evaluated correlation of biomarkers with invasive disease-free survival

* HR <1.0 indicates CT plus Bev better than CT alone

Carmeliet et al., SABCS 2012; abstract P3-06-34

Paclitaxel 90mg/m2 weekly

x 3 q4 weeks /

Placebo 10 mg/kg q2w

Paclitaxel 90 mg/m2 weekly x 3 q4 weeks /

Bevacizumab 10 mg/kg q2w

Confirmatory Study Schema: MERiDiAN

Co-Primary Endpoints: PFS (All Patients) , PFS (VEGF high subset)

Secondary Endpoints: OS; ORR; Symptoms/QoL; Safety

MBC, HER2-Negative Chemo-naïve

N=480

Stratification

• VEGF-A (low/high) • Adjuvant therapy (yes/no) • Hormonal status (ER +/-) R

A N

D O

M I Z

E D

LEA: Effect of Adding Bevacizumab to First-Line

Endocrine Therapy in Advanced Breast Cancer

• Design

– 380 patients, first line therapy, post-menopausal women

• Results:

– Baseline characteristics were well-balanced:

• Approximately 80% had metastatic disease

• Approximately 50% had received previous adjuvant hormonal therapy

• Approximately 90% of patients received letrozole; the remainder received fulvestrant

– Adverse events increased on the bevacizumab-containing arm included leukopenia and thrombocytopenia (P < .01); also fatigue, hypertension, hemorrhage, elevated liver enzymes, and proteinuria (P < .001).

Martin et al., SABCS 2012; abstract S1-7

Outcome

Endocrine therapy

Endocrine therapy + bevacizumab

HR (95% CI)

P-value

Median PFS 13.8 months 18.4 months 0.83 (0.65-1.06) .14

Median OS 42 months 41 months 1.18 (0.77-1.81) .47

Endocrine Therapy: Tamoxifen or Aromatase Inhibitor (letrozole) Double-blind, placebo-controlled Primary Endpoint: Progression-free Survival Circulating tumor and endothelial cells measured during treatment PI: Dickler

CALGB 40503: First-line Endocrine Rx +/- Bevacizumab

ER or PR+

MBC

1st line Rx

+/- Measurable

Post-Menopausal or

Ovarian suppression Endocrine therapy + Placebo

Endocrine therapy + Bevacizumab

(15mg/kg IV q3wks)

Endpoint

Capecitabine/

Sorafenib

(n = 115)

Capecitabine/

Placebo

(n = 114) HR P Value

Median PFS 6.4 months 4.1 months 0.576 .0006

First-line 7.5 months 4.1 months 0.498 .0022

Second-line 5.7 months 4.1 months 0.652 .0339

Overall Response Rate 38% 31% NR .1229

CR 2% <1% NR NR

PR 36.5% 30% NR NR

Baselga et al. J Clin Oncol: May, 2012.

Phase II Trial: Capecitabine/Sorafenib vs.

Capecitabine/Placebo as First- or Second-Line Therapy

for Locally Advanced or Metastatic BC: Results

• Efficacy was seen across all prespecified and exploratory subgroups, including those with prior

taxane and anthracycline exposure.

Safety:

– Sorafenib assoicated with • An increase in grade 3 HFSR with the sorafenib regimen (44% vs 13%)

• Increase in all grade rash, diarrhea, stomatitis, neutropenia, and hypertension

– Overall treatment discontinuation was less frequent with sorafenib (65% vs. 79%)

Phase III Resilience trial is in progress, using a reduced dose of sorafenib

Phase III trial of Docetaxel +/- Ramicirumab (IMC

1121B) as First-Line Therapy in HER2-Negative,

Unresectable LABC or MBC (closed to accrual)

Endpoints

• Primary: Progression-free survival

• Secondary: Time to treatment failure, overall survival

(n = 1113)

PI: John Mackey www.clinicaltrials.gov

VEGFR-2 directed recombinant human monoclonal antibody (IgG1)

Eligibility criteria:

• HER2– disease

• First-line treatment

• Locally recurrent or

metastatic breast

cancer

Docetaxel (75 mg/m2)

Placebo

q3w

Docetaxel (75 mg/m2)

Ramucirumab (10 mg/kg)

q3w

Angiopoietins (Ang)/Tie2 signaling pathway and its functions on vascular remodeling.

Cascone T , Heymach J V JCO 2012;30:441-444

©2012 by American Society of Clinical Oncology

2012 Ongoing Trials in NCI Database for

Breast Cancer (Selected)

• Therapeutic trials

– Bevacizumab (N=89)

– Sorafenib (n=10)

– Ramucirumab (n=3)

– Others (pazopanib, vascular disrupting

agents, angiopoeitin inhibitors)

• Bevacizumab – trials to look for

– Phase III adjuvant

• E5103: HER2 negative

• CALGB 40603: neoadjuvant TNBC

• BETH: HER2+

– Phase III metastatic

• CALGB 40503 (ER+)

• TANIA (Bev or not post progression)

• MERiDiAN

– Randomized phase II in TNBC

• Paclitaxel +/- MetMAB +/- bevacizumab

– GWAS and miRNA for biomarker evaluation

• Sorafenib

– Phase III - Resiliance

• Capecitabine +/-sorafenib

– Phase II

• With chemotherapy or hormone therapy

• Ramucirumab

– Phase III

• Paclitaxel +/- ramucirumab

– Randomized phase II

• Eribulin +/- ramucirumab

• Capecitabine +/- ramucirumab

• Vascular disrupting agents, angiopoeitin inhibitors

• Bevacizumab for lymphedema (phase I)

Paraphrasing William Osler:

• Antiangiogenic therapy still holds promise for the treatment of breast

cancer

We need to change our approach:

• Design better prospective trials we need a more accurate understanding

of biologic subtype and markers to predict response…..

– GEPARquinto and NSABP B-40: central IHC, subtyping and molecular

profiling

– Focus on biomarker development

– New targeted agents

• Countering resistance

– Immune modulation?

– Combination therapy?

The benefit of experience is not in treating

everyone, but in treating wisely.