Clinical Application of Evolving Treatment Paradigms in Advanced Breast Cancer

Clifford A. Hudis, MD

Chief, Breast Cancer Medicine Service

Memorial Sloan Kettering Cancer Center

Professor of Medicine

Weill Cornell Medical College

New York, NY

Expert Review of Breast Cancer Treatment

• 47 year-old woman, BRCA1 (+) with h/o stage IIa breast cancer (3-years ago) at age 44

─ ER weakly positive

─ PR negative

─ HER2 negative

─ Treatment: dose-dense AC→T and on tamoxifen for 2+ years

• Presents now with RUQ pain, 4kg weight loss, and fatigue

─ LFTs normal

─ CT with multiple hepatic metastases confirmed by biopsy c/w original tumor

Case 1

Case 1

Which treatment option would you recommend: Hormone therapy

Chemotherapy

Bevacizumab

Case 1

Which treatment option would you recommend: Hormone therapy

Chemotherapy

Bevacizumab

Recommended Approach: Clinical considerations for selection of appropriate treatment

will be discussed

Management of Metastatic Breast CancerDiagnosis of Metastatic Breast Cancer

No Response

Determination of sites and extent of disease. Assessment of HER2, hormonal receptor status, disease-free interval, age, and menopausal status

No life-threatening diseaseHormone-responsive

Hormone-unresponsive, orLife-threatening disease

1st-line hormonal therapy 1st-line chemotherapy

ResponseNo

Response

2nd-line hormonal therapy

2nd-line chemotherapy

Progression

Progression

Progression

Progression

3rd-line hormonal therapy

Response

No Response

3rd-line chemotherapy

Supportive care

Many Chemotherapy Options

• Spindle toxins

– paclitaxel (Pac)

– docetaxel (Doc)

– vinorelbine (Vin)

– nab-Pac* (ABI-007)

– Ixabepilone (Ixa)

• Nucleoside analogues

– gemcitabine (Gem)

– capecitabine (Cap)

– 5-fluorouracil (5-FU_

• Topoisomerase inhibitors

– CPT-11 (Topo)

– doxorubicin (Dox)

• Platinums

• Antifolates

– methotrexate (MTX)

– pemetrexed (PTX)

• Unique delivery

– liposomal doxorubicin (LD)

• Targeted therapy

– HER2: trastuzumab (Trastuzumab) and lapatinib (Lap)

– VEGF: BVM and small-molecule TKIs (investigational)

– farnesyltransferase inhibitors

– EGFR inhibitors (investigational)

*Albumin-bound paclitaxel.CPT = camptothecin; VEGF = vascular endothelial growth factor; BVM = bevacizumab; mAb = monoclonal antibody; TKI = tyrosine kinase inhibitor; EGFR = epidermal growth factor receptor.

Approval is Different from Common Usage

Taxanes (after A) Taxanes (after A) Cap (after A+T)

Cap (after A + T) Cap (after A + T) Ixa (after A+T+Cap)

Ixa (after A + T +Cap) Cap (after A + T)

CombinationCap+taxane

(after A)Gem + taxane

(after A)Cap + Ixa

(after A + T)

Metastatic1

3rd Line2nd Line1st Line

Adjuvant

Anthracyclines (A)

Taxanes (T)

1. Adapted from National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology: Breast Cancer V.2.2007. http://www.nccn.org. Accessed April 30, 2007;

2. Bernard-Marty C et al. Oncologist. 2004;9(6):617-632;

3. Longley DB, Johnson PG. J Pathol. 2005;205(2):275-292.

• Despite treatment, most advanced tumors become resistant and progress2

• Chemoresistance is the major cause of treatment failure3

Rationale for Combination Therapy

in the Treatment of MBC

Principles of Treatment With Multiple AgentsPrinciples of Treatment With Multiple Agents

• MBC-inherent drug resistance = barrier to response (cure)

– There are many subpopulations of cancer cells with different types of resistance

– Combination CT should reduce the different sensitive subpopulations of cancer cells, leading to an improved disease response

• Improved disease response will translate into an improvement in outcome

– Meta-analysis (2005): standard CT vs intensified CT (10 trials, 2126 patients)

– Intensified CT associated with OR=0.60 for response

– Tumor response was predictive of survival (P<0.001)

• Median OS: CR=29 mon; PR=21 mon; NR=15 mon

OR = odds ratio; OS = overall survival; CR = complete response; PR = partial response; NR = no response.

Bruzzi P et al. J Clin Oncol. 2005;23(22):5117-5125.

Single-agent vs Combination Front-line CT in MBC

• Response rate favors combination

• TTP favors combination

• Survival ?

• Toxicity favors single agent

• Quality of life ?

TTP = time to progression.

Very few combination trials using investigational drugs truly tested the hypothesis of combination vs sequential single-agent therapy

Single-agent vs Combination Trials

Clinical Trial*Median TTP

(mon)

Overall Survival (mon)

Grade IV Neutropenia

(%)

Albain et al (N=529)

PacPac + Gem

2.9

5.2

15.8

18.5

7

17

O’Shaughnessy et al (N=511)Docetaxel (Doc) Doc + Cap

4.26.1

11.514.5

1112

Albain KS et al. J Clin Oncol. 2004;22(14) Abstract 810. O'Shaughnessy J et al. J Clin Oncol. 2002;20(12):2812-2823.

E1193 Phase III Trial Dox vs Pac vs Dox + Pac Combination in MBC

Outcome Dox Pac Dox + Pac P Value

Response rate (%) 36 34 470.007*

0.004†

Median survival (mon) 18.9 22.2 22.0 NS

TTP (mo) 6.0 6.3 8.20.0022*0.0567†

Gr III/IV leukopenia (%) 47 60 55 —

Gr III/IV infection (%) 4.1 8.3 12.7 —

Gr III/IV neurologic complications (%)

1.6 3.7 10.7 —

*Sledge GW et al. J Clin Oncol. 2003;21(4):588-592.

Results: Efficacy and Tolerability

*Dox vs Dox + Pac; †Pac vs Dox + Pac.

CALGB 9840: Design

Seidman AD et al. J Clin Oncol. 2004;22(14 suppl): Abstract 512.

Pac q wk + Trastuzumab

Pac q 3 wks + Trastuzumab

Pac q wk

Pac q 3 wks

2000–2003 (N=406)(HER2 status known)

1998–2000 (N=171)(HER2 status unknown)

Pac 80 mg/m2 q wk –or– 175 mg/m2 q 3 wks

Tras 4-mg/kg load, then 2 mg/kg/wk

CALGB 9840Results (All Patients)

Seidman AD et al. J Clin Oncol. 2004;22(14 suppl): Abstract 512.

28

40

0

10

20

30

40

50

Pac Weekly(N=344)

Pac q 3 Wks(N=373)

Res

pons

e R

ate

(%)

Tumor Response

HR=1.61; P=0.017

Time to Progression

5

9

0

2

4

6

8

10

Tim

e (

mon

)

Pac Weekly(N=344)

Pac q 3 Wks(N=373)

Adjusted HR=1.45; P=0.0008

Events/patients: 221/350 324/385

• Pac once weekly is superior to Pac q 3 wks for the treatment of MBC (with respect to response rate and TTP)

• Pac once weekly is associated with slightly less frequent myelosuppression but more frequent neurotoxicity than Pac q 3 wks

• Trastuzumab does not improve outcome when added to Pac in HER2-neutral MBC

CALGB 9840Conclusions

Seidman AD et al. J Clin Oncol. 2004;22(14 suppl): Abstract 512.

TAX-31: Docetaxel vs Paclitaxel s/p anthracycline / 0-1 prior chemo for MBC

Docetaxel 100q3w

(N=225)

Paclitaxel 175q3w

(N=224)

ORR (ITT)

TTP

OS

32%

5.7*

15.4*

25%

3.6

12.7

Severe AE (>5%)

Neutropenia*

Feb Neutropenia*

Infection

Anemia*

Neurosensory

Neuromotor

Asthenia*

Peripheral oedema*

Stomatitis

Diarrhea*

(3 deaths)

93%

15%

10%

10%

7%

5%

21%

7%

11%

5%

(0 deaths)

55%

2%

2%

7%

4%

2%

5%

1%

0%

1%

*P ≤ 0.05

Jones et al. JCO 2005.

New Formulations

Nab-Pac Transport & Tumor TargetingTapping Into Biology of Albumin and Rapid Cell Growth

Tumor cell

Lumen of tumor

microvessel

Caveolae (vesicles)

Leaky junctionTumor interstitium

Albumin-receptor (gp60, albondin)

SPARC

Tumor cell

SPARC

(A) Albumin,the body’s natural

transporter of water-insoluble

nutrients

(B) Receptor-mediated transcytosis of albumin complexes

(gp60/caveolin-1 pathway)

(C) High tumor uptake (SPARC binding of albumin complexes)

SPARC = secreted protein and rich in cysteine.

Phase III TrialAlbumin-Bound (Nab) Pac vs Pac in MBC

Albumin-Bound (Nab) Pac

(N=229)

Pac

(N=225)

P Value

ORR (%) 33 19 0.001

TTP (wk) 23.0 16.9 0.006

Gr IV neutropenia (%) 9 22 <0.001

Gr III sensory neuropathy (%) 10* 2 <0.001

Albumin-bound Pac: 260 mg/m2 q3w; Pac: 175 mg/m2 q3w

Gradishar WJ et al. J Clin Oncol. 2005;23(31):7794-7803.

*Median time to improvement: 22 days.

Phase II Study of Weekly or q3wk Nab-Pac Phase II Study of Weekly or q3wk Nab-Pac vs q3wk Doc as First-line Therapy in MBCvs q3wk Doc as First-line Therapy in MBC

Eligibility criteria:

• Stage IV adenocarcinoma

• No prior CT for metastatic disease

Gradishar W et al. SABCS 2006. Abstract 46.

RANDOMIZE

RANDOMIZE

Arm A: nab-Pac 300 mg/m2 q3wk

Arm B: nab-Pac 100 mg/m2

weekly, 3 out of 4

Arm C: nab-Pac 150 mg/m2

weekly, 3 out of 4

Arm D: Doc 100 mg/m2 q3wk

Primary endpoint Antitumor response (q 8 wks) and toxicity

Comparisonsnab-Pac vs Doc (A, B, C vs D) weekly vs q3wk nab-Pac (B, C vs A) low- vs high-dose weekly nab-Pac (B vs C)

Where Exactly Are We?

Hudis JCO 2005.

Novel Microtubule Inhibitors

Need for change in Novel microtubule inhibitors

Toxicity profile Albumin-bound Pac (nab-Pac)

Therapeutic Efficacy Halicrobdrin analogue (E7389)

– Improve effect at target site Epothilones (Ixa, patupilone)

– Overcome resistance Polyglutamic acid conjugated Pac (CT 2103)

– Cross blood-brain barrier Vinflunine (novel vinca alkaloid)

Lee JJ, Swain SM. Semin Oncol. 2005;23(2 suppl 7):S22-26. Cortes J, Baselga J. Oncologist. 2007;12(3):271-280.

Agent (Manufacturer)

Epothilone AnalogPhase in

DevelopmentClinical Toxicities

EPO-906/patupiloneEpothilone B

(natural product)III Diarrhea

ZK-EPOEpothilone B

(fully synthetic)II Neuropathy, nausea, ataxia

KOS-1584Epothilone D

(desoxyepothilone B)II Myelosuppression, neuropathy

BMS-310705Epothilone B

(semi-synthetic)I / II

Hypersensitivity reactions, pancytopenia, neuropathy,

arthralgia/myalgia

Epothilones in Clinical Developmentfor Breast Cancer

Goodin S et al. J Clin Oncol. 2004;22(10):2015-2025.

Kolman A. Curr Opin Investig Drugs. 2005;6(6):616-622.

Schmid P et al. J Clin Oncol. 2005;23(16 suppl): Abstract 2051.

Ixabepilone (Ixa) First in the New Class of Epothilones

S

N

HN

O OOH

O

OH

IxabepiloneSemi-synthetic analog

of epothilone B

• Naturally occurring epothilone Bchemically modified to improvemetabolic activity, proteinbinding, and antitumor activity1

• Tubulin-binding mode distinctfrom other microtubule-stabilizing agents1

• Active against multiple tumor xeno grafts, including drug-resistant types that overexpressP-gP, MRP-1, and III tubulinisoforms1

• Active in taxane-resistant disease2,3

1. Ixempra (ixabepilone) [prescribing information]. Princeton, NJ: Bristol-Myers Squibb Company; 2007. 2. Perez E et al. J Clin Oncol. 2007;25(23):3407-3414.

3. Thomas E et al. J Clin Oncol. 2007;25(23):3399 3406.

Ixa: Mechanism of Action

Ixa

ß-tubulin

Ixa

MRP-1

P-gP

Tubulin

ßIII-tubulin

Extracellular

Intracellular

• Poor substrate for efflux pumps, eg, P-gP and MRP-11

– P-gP and MRP-1 are involved in drug resistance2

• Binds multiple ß-tubulin isoforms, including ßIII-tubulin to inhibit microtubule dynamics1

– Overexpression of ßIII is associated with in vivo and clinical resistance to taxanes3,4

1. Ixempra (ixabepilone) [prescribing information]. Princeton, NJ: Bristol-Myers Squibb Company; 2007. 2. Lee JJ, Swain SM. Semin Oncol. 2005;32(6 suppl 7):S22-S26.

3. Kamath K et al. J Biol Chem. 2005;280(13):12902-12907.4. Mozzetti S et al. Clin Cancer Res. 2005;11:298-305.

Phase II Trial Ixa in Anthracycline-, Taxane-, and Capecitabine-Resistant MBC

Efficacy

Perez E et al. J Clin Oncol. 2007;25(23):3407-3414.

Efficacy (N=113 Evaluable Patients)

ORR 11.5%

SD 50.0%

Median PFS 3.1 mo

Grade III/IV Toxicities %

Neutropenia 54

Peripheral neuropathy 14

Fatigue 10

Myalgia 7

Stomatitis 7

Single-agent Ixa 40 mg/m2 IV over 3 hrs q3w until disease progression

Ixa Study 046Design

MBC

Demonstratedresistance toanthracyclineand taxane

N=752

Combination therapy:

Ixa 40 mg/m2 IV over 3 h q 21 days +Cap 2000 mg/m2/d PO Days 1–14

Monotherapy:

Cap 2500 mg/m2/d PO Days 1–14

Primary Endpoint

PFS (IRR)

Strict resistance criteria prospectively defined as• Disease progression = 3 mon of the last anthracycline dose in the metastatic

setting –OR– recurrence = 6 mon in the adjuvant or neoadjuvant setting

–AND–

• Disease progression = 4 mon of the last taxane dose in the metastatic setting –OR– recurrence = 12 mon in the adjuvant or neoadjuvant setting

Imprexa (ixabepilone) [prescribing information]. Princeton, NJ: Bristol-Myers Squibb Company; 2007.

Thomas ES et al. J Clin Oncol. 2007; 25(33):5210-5217.

Ixa in Combination With Cap in Patients Resistant to an Anthracycline and a Taxane

*Pts who received a minimum cumulative dose of 240 mg/m2 of Dox or 360 mg/m2 of epirubicin were also eligible.

RR = independent radiologic review.

Ixabepilone Study 046Significant Improvement in Median PFS*

*Based on IRR of ITT population; †Stratified by visceral metastasis in liver/lung, prior CT in metastatic setting, and anthracycline resistance..

Months

1.0

0.9

0.8

0.7

0.6

0.5

0.4

0.3

0.2

0.1

0.0

0 4 8 12 16 20 24 28 32 36 40

Ixa + Cap

Cap

P=0.0003†

Pro

port

ion

not P

rogr

esse

d

Median PFS

5.8 mosvs

4.2 mos(95% CI, 3.8–4.5)

HR = 0.75(95% CI, 0.64–0.88)

Thomas ES et al. J Clin Oncol. 2007; Early online release; 0: JCO.2007.12.6557v1.

Grade 3/4 Non-hematologic ToxicitiesP

erip

hera

l

neur

opat

hy

23

0

Mya

lgia

8

0.3

Han

d-fo

ot

synd

rom

e

18 17

Dia

rrhe

a

69

Muc

ositi

s

3 2

Vom

iting

4 2

Fatig

ue

9

3

Nau

sea

3 2

Art

hral

gia

30

0

% o

f P

atie

nts

Ixabepilone + Capecitabine (N=369)

Capecitabine (N=368)

20

40

60

80

What About Anti-angiogenics?

E2100 Study Design

Miller KD et a. SABCS 2005. Abstract 3.

RANDOMIZE

Pac28-day cycle

Pac 90 mg/m2

D1, 8, and 15BVM 10 mg/kg

D1 and 15

Stratify:• DFI ≤24 mon

vs >24 mon• <3 vs ≥3

metastatic sites• Adjuvant CT:

yes vs no• ER(+) vs ER(–)

vs ER unknown

Pac + Bev

DFI = disease-free interval.

First-line Therapy of Metastatic Breast Cancer with Bevacizumab Added to Paclitaxel Improved PFS

0.0

0.2

0.4

0.6

0.8

1.0

Months

PFS

Pro

babili

ty

0 6 12 18 24 30

HR = 0.51 (0.43-0.62)

Log Rank Test P < 0.0001

Pac. + Bev. 11.4 mos

Paclitaxel 6.11 mos

484 events reportedMiller K, NEJM 2007.

*Docetaxel was administered for a maximum of 9 cycles, but earlier discontinuation was permitted

AVADODouble-blind, Placebo-controlled Trial

• Primary endpoint: Progression-free survival

• Secondary endpoints: Overall response rate, duration of response, time to treatment failure, overall survival, safety, quality

of life

Docetaxel* 100mg/m2 + placebo q3w

Docetaxel* + bevacizumab 7.5mg/kg q3w

Docetaxel* + bevacizumab 15mg/kg q3w

All patientsgiven optionto receive

bevacizumabwith

2nd linechemotherapy

1st line locally recurrent or mBC (N=705)

Stratification factors:• region• prior taxoid/time to

relapse since adjuvant chemo

• measurable disease• hormone receptor

status

Treat withplacebo/

bevacizumabto disease

progression

Progression-free Survival (ITT population)

Months

PF

S e

stim

ate

*Data censored for non-protocol therapy prior to PD†mg/kg q3w

HR + 95% CI (unstratified)

Bev 7.5† +docetaxel (n=248)

1.0

0.8

0.6

0.4

0.2

0.0 0 6 12 18Months

PF

S e

stim

ate

1.0

0.8

0.6

0.4

0.2

0.0 0 6 12 18

HR + 95% CI (stratified*) 0.69 (0.54–0.89)P = 0.0035

0.79 (0.63–0.98)P = 0.0318

Placebo +docetaxel (n=241)

Median 8.78.0

HR + 95% CI (stratified*) 0.61 (0.48–0.78)P < 0.0001

Median 8.88.0

0.72 (0.57–0.90)P = 0.0036

HR + 95% CI (unstratified)

Bev 15† +docetaxel (n=247)

Placebo +docetaxel (n=241)

Sorafenib Targets Both Tumor-cell Proliferation and Angiogenesis

Wilhelm SM, et al. Cancer Res 2004;64:7099–109.

PDGF = platelet-derived growth factor

EGF = epidermal growth factorVEGF = vascular endothelial growth factor

TGF-a = transforming growth factor-alpha

Mcl-1 = myeloid cell leukemia-1

RAS

Endothelial cell or pericyte

Proliferation

Angiogenesis:

PDGF-VEGF

VEGFR-2PDGFR-

Paracrine stimulation

DifferentiationMitochondria

Apoptosis

Tumour cell

PDGF

VEGF

EGF/TGF-

Proliferation

Survival

Mitochondria

EGF/IGF

HIF-2

Nucleus

Autocrine loop

Apoptosis

ERK

RAS

MEK

RAF

Nucleus

ERK

MEK

RAF

Sorafenib

MigrationTubule formation

Mcl-1

Sorafenib in Breast CancerSix Randomized, Double-blind, Placebo-controlled Phase 2b Trials

1. Letrozole, anastrozole, or exemestane2. Paclitaxel/bevacizumab +/- sorafenib3. Bevacizumab-progressors

PaclitaxelDr. GRADISHAR(Northwestern,

ACORN)Started Jun 07

Capecitabine*Dr. BASELGA

(SOLTI)Started Aug 07

AromataseInhibitors*1

Dr. PEREZ(MCCRC)Planned

Docetaxel orLetrozole

Dr. GIANNI(Michelangelo)

Planned

Gemcitabine*3

Drs. HUDIS & SCHWARTZBERG

(MSKCC/ACORN)

Started Jun 07

Triplet2

Dr. SLEDGE(HOG)

Planned

TRIALS INVESTIGATING THE EFFECTS

OF SORAFENIB IN BREAST

CANCER

*includes 2nd line patients

Conclusions

• Newly approved and other novel agents for the treatment of patients with MBC continue to improve outcomes

– The addition of biologics may make a substantial impact

• There is a clear and immediate need for larger, better designed clinical trials to assess the role of these new agents

– As monotherapy

– As combination therapy

– As additions to therapies employing a growing number of biologics