Chemotherapy Options and Decision-Making for

Advanced Breast Cancer

Debu Tripathy, M.D.

Professor of Medicine

University of Southern California

31st Annual Miami Breast

Cancer Conference

March 6-9, 2014

Decision Points: Chemotherapy for Advanced Breast Cancer

• When to use chemotherapy for ER/PR+ or HER2+

disease

• Initial agents

• Combination vs. Single Agents

• Use of maintenance or holidays

• Options for refractory disease

• Triple negative subsets, basal/BRCA-related –

should they be treated differently?

Sequence of Therapy for Advanced Triple Negative or Hormonally

Refractory Breast Cancer

• Prior response/stability to

therapy

• Low disease burden, minimal

visceral involvement

• Low level of symptoms

• Monotherapy

• Significant visceral

involvement

• Significant symptoms

• Likely clinical sequelae

with small degree of

progression

• Combination therapy e.g.:

• Paclitaxel + gemcitabine

• Docetaxel + capecitabine

Maintenance

Therapy

“Induction”

• Drug Holiday

?Max Response

• e.g. Eribulin

Progression

Cell Cycle-Specific Activity of Cytotoxics

•Vinca Alkaloids Vinorelbine

Vinblastine

•Taxoids Paclitaxel

Docetaxel

Epothilones

•Antimetabolites 5-FU, fluoropyrimidines

Gemcitabine

Methotrexate

Cell Cycle Non-

Specific Agents

• Alkylating Agents

Platinum

Cyclophos-

phamide

Thiotepa

Nitrosoureas

• Antibiotics

Anthracyclines

o Doxorubicin

o Epirubicin

o Mitoxantrone

•Podopyllotoxins Etoposide

•Camptothecins Irinotecan

•Dynamic Microtubule Inhibitors Eribulin

Single vs Combination Chemotherapy: Recent Positive Trials in MBC - Overall Survival

O'Shaughnessy J et al JCO 2002

Albain K et al JCO 2009

Vahdat L et al. JCO 2007

11.5 14.5

Hazard ratio = 0.775

Log-rank

p=0.0126

Capecitabine/docetaxel

Docetaxel

15.8 18.5

0 10 20

Survival

Gemcitabine +

Paclitaxel (n=267)

Paclitaxel

(n=262)

12 mo 70.7% 60.9%

18 mo 50.7% 41.9%

Log rank P=0.018

HR 0.78 (0.63-0.96)

0 12 24

Months

Months

100%

100%

Combination vs. Single-Agent Therapy for MBC: Meta-Analysis of Randomized Trials

0 0.5 1.0 1.5 2.0

Combination better Single agent better

Efficacy: c2

17.5 (p=0.00002)

0.87 (0.78–0.97)

0.70 (0.59–0.84)

0.82 (0.75–0.90)

Hazard ratio of death

(combination:single agent)

Regimens

Single agent Combination

Subtotal (deaths/patients)

Subtotal (deaths/patients)

Total (deaths/patients)

AV A + DBD A + MMC VAC CF + P ± V A + ETO AV + MMC E + VDS FEC 75

CMF + VBL CMF CMFV + P CF + P ± V CF + P ± V

FEC 50

619/738

206/252

825/990

A A A A A A A E E

C PAM F CCNU I

E

649/747

225/249

874/996

Fossati R et al. J Clin Oncol 1998

Doxorubicin

+ Paclitaxel

36% 34% 47%

QOL

Median TTF

Response

Paclitaxel Doxorubicin

6 mos. 6 mos. 8 mos.

= = =

19 mos. 22 mos. 22 mos. Median Survival

Single vs. Combination vs. Sequential Chemotherapy

Crossover Responses: } A

T A

T = 22%

= 20%

NS

Sledge G et al. J Clin Oncol 2003

Study Treatment Schedules N

Med TTP

(mo)

p

Med OS

(mo)

p

Coates A et al

NEJM 1987

AC/CMF until PD

305

6

0.02

10.7

0.19 AC x 3 cycles 4 9.4

Harris AL et al

Lancet 1990

Mitoxantrone until PD 43

5.5 NS

11 NS

Mitoxantrone x 4 6.5 12

Muss H et al

NEJM 1991

FAC x 6 → CMF x 12

145

9.4

<0.001

21.1

0.67 FAC x 6 3.2 19.6

Ejlertsen B

Eur J Ca 1993

FEC + TAM x 18

254

14

< .003

23

0.03 FEC + TAM x 6 10 18

Gregory R et al

Eur J Ca 1997

VAC/VEC x 6 → MMM x 6

100

10

0.01

13.0

0.3 VAC/VEC/MMM x 6 7 10.5

Falkson G et al

JCO 1998

A x 6 → CMFPTH x 8

195

18.7

<0.0001

32.2

0.74 A x 6 7.8 28.7

Nooij M et al

Eur J Ca 2003

CMF until PD

196

5.2

0.01

14.0

0.77 CMF x 6 3.5 14.4

Trials Examining Continuous vs. Interrupted/Fixed Therapy

Study Treatment Schedules N

Med

TTP

(mo)

p

Med

OS

(mo)

p

Gennari A

et al

JCO 2006

E/A + P x 6-8 → P x 8

215

8.0*

0.817

26.0

0.547 E/A + P x 6-8 9.0* 29.0

Alba E

et al

BCRT 2010

A →T x 6 → PLD

155

13.2

8.4* 0.006*

0.002

24.8

0.44

A →T x 6 10.2

5.1* 22.0

Trials Examining Continuous vs. Interrupted/Fixed Therapy - Contemporary Regimens

* From time of randomization to maintenance arm

E = epirubicin; A = doxorubicin; P = paclitaxel; T = docetaxel; PLD

= pegylated liposomal doxorubicin

PLD Maintenance Treatment: Toxicity

PLD (n = 78) Observation (n = 77)

Toxicity Grade 1/2 Grade 3/4 Grade 1/2 Grade 3/4

Neutropenia 32% 12% 9% 0

Anemia 35% 0 12% 0

Nausea/Vomiting 21% 0 4% 0

Fatigue 32% 3% 8% 0

Alopecia 29% 0 4% 0

Mucositis 32% 5% 0 0

PPE 29% 4%* 0 0

PLD (n = 78) Observation (n = 77)

Decreased LVEF ≥10% 5 (6%) 1 (1%)

Congestive Heart Failure 0 0

* Grade 3 only Alba E, et al. Breast Cancer Res Treat 2010

Korean Cancer Study Group (KCSG-BR07-02) Phase III Maintenance Trial

• Metastatic/Recurrent Breast Cancer

• Stability or response after 6 cycles

• Paclitaxel 175 mg/m2 q 21 d

• Gemcitabine 1250 mg/m2 d 1, 8 q 21 d

Maintenance Therapy

With Same regimen

until PD or toxicity

Observation

Randomize

Stratification

• PR/CR vs. SD

• Visceral

• ER status

• Adjuvant taxane

Korean Cancer Study Group (KCSG-BR07-02) Phase III Maintenance Trial

Park JY, et al. J Clin Oncol 2013

Korean Cancer Study Group (KCSG-BR07-02) Phase III Maintenance Trial

Park JY, et al. J Clin Oncol 2013

KCSG-BR07-02: Grade 3/4 Toxicities

Park JY, et al. J Clin Oncol 2013

Meta-Analysis of Chemotherapy Duration Survival Impact

Gennari A, et al. J Clin Oncol 2011

≈1-2 months

Intermittent vs. Continuous Chemotherapy

Coates AS, et al. NEJM 1987

Intermittent vs. Continuous Chemotherapy Survival and Quality of Life

Coates AS, et al. NEJM 1987

QoL index

Uniscale Score

Physical Wellbeing

Pain

Mood

Appetite Nausea/

vomiting

What Constitutes “Best First Line” Single Agent Therapy?

• Numerous agents are active

• Effects on survival may be difficult to discern

because of heterogeneity of subsequent therapy

• Prior therapy with adjuvant anthracycline/taxane

or taxane-based therapy is common

• Initial therapy is typically taxane or capecitabine

• Taxanes are schedule dependent

• Optimal capecitabine dose undefined

• No established best initial therapy

Paclitaxel vs Docetaxel Every 3 weeks

Jones SE, et al. J Clin Oncol 2005

Randomized nab-Paclitaxel: CA012 Trial Progression-Free Survival

Albumin-bound paclitaxel 260

mg/m2

iv over 30 min q3w

No standard premedication

Paclitaxel 175 mg/m2

iv over 3 hrs q3w

Standard premedication with

dexamethasone and

antihistamines

Randomisation (1:1)

n = 460

Gradishar et al. J Clin Oncol 2005

Nab-Paclitaxel

Paclitaxel

p=0.006

Paclitaxel: Dose/Schedule Comparison

CALGB 9840

Seidman A, et al. J Clin Oncol 2008

Nab-Paclitaxel: Different Dose/Schedules vs. Docetaxel

Gradishar W et al. JCO 2009

100

mg/m2

q3w

n = 74

300

mg/m2

q3w

n = 76

100

mg/m2

qw 3/4

n = 76

150

mg/m2

qw 3/4

n = 74

Docetaxel Nab-Paclitaxel

Response Rates

Months From Study Entry

Pro

port

ion P

rog

ressio

n-F

ree

0 10 20 30

0.0

0.2

0.4

0.6

0.8

1

PacNabIxa

Comparison HR P-value 95% CI

nab vs. pac 1.19 0.12 0.96-1.49

ixa vs. pac 1.53 < 0.0001 1.24-1.90

CALGB 40502 Progression-Free Survival By Treatment Arm

paclitaxel nab-paclitaxel ixabepilone

Agent N Median PFS

paclitaxel 283 10.6

nab-Paclitaxel 271 9.2

ixabepilone 245 7.6

First Line Weekly Paclitaxel vs. Capecitabine w/ Bevacizumab

TURANDOT

Study

Lang I, et al. Lancet Oncol 2013

Overall survival (months)

0.0

0.2

0.4

0.6

0.8

1.0

0 28 26 24 22 20 18 16 14 12 10 8 6 4 2

Surv

ival pro

babili

ty

Overall Survival

Eribulin Median 13.12 months

TPC Median 10.65 months

HR* 0.81 (95% CI 0.66, 0.99) p-value†=0.041

2.47 months

TPC (n=254)

Eribulin (n=508) 53.9%

1 year survival

43.7%

ITT population; *HR Cox model including geographic region, HER2/neu status, and prior capecitabine therapy as strata †p value from stratified log-rank test (pre-defined primary analysis); HR, hazard ratio; CI, confidence intervals

Cortes et al 2010 Lancet 2011; 6736: 60070-6

Heterogeneity of Triple Negative Breast Cancer

Otto Metzger-Filho O et al., 2012

TNBC Responses to Platinum Agents

Baselga J et al. ESMO 2010; O’Shaughnessy J et al. SABCS 2007; Carey L, et al ASCO 2008; Isakoff J, et al. ASCO 2011; Byrski

T et al. JCO 2010; Gronwald, J, et al. ASCO 2009; Silver DP, et al. JCO 2010, Alba E, et al. ASCO 2011

Neo Adjuvant Population N pCR Rate Ref

CMF

BRCA 1

Mutation (retrospective)

14 7%

Byrski

AC 23 22%

FAC 28 21%

AT 25 8%

Cisplatin 12 83%

Cisplatin BRCA1 Mut 25 72% Gronwald

Cisplatin TNBC 28 21% Silver

EC D TNBC Basal

46 30% Alba

EC DP 47 30%

Stage IV Population ORR Ref

Control arm BALI-1 (CDDP) TNBC 10% Baselga

Control arm Phase III iniparib (Gem/carbo) TNBC 30% O’Shaughnessy

TBCRC 001 (Cetuximab/Carbo) TNBC 17% Carey

TBCRC 009 (Carboplatin or Cisplatin) TNBC 30% Isakoff

Eribulin vs. Capecitabine OS HR by Subsets

Kaufman P, et al. SABCS 2012, Abstr S6-6

Replication Lesions

• Base excision repair

PARP1

Mechanisms of DNA Repair

Single Strand Breaks

• Nucleotide excision repair

• Base excision repair

PARP1

Double Strand Breaks

• Non-homologous end-joining

• Homologous recombination

BRCA1/BRCA2

• Fanconi anemia pathway

• Endonuclease-mediated repair

DNA DAMAGE

Cell Death

Environmental factors

(UV, radiation, chemicals)

Normal physiology

(DNA replication, ROS)

MAJOR DNA REPAIR

PATHWAYS

Chemotherapy

(alkylating agents, antimetabolites)

Radiotherapy

Helleday et al. Nature Reviews. 2008

DNA Adducts/Base Damage

• Alkyltransferases

• Nucleotide excision repair

• Base excision repair

PARP1

Response to Olaparib in BRCA Mutation-Associated MBC

Tutt A et al. Lancet 2010

400 mg bid 100 mg bid

400 mg bid; N=27 100 mg bid; N=27

ORR 11 (41%) 6 (22%)

CR 1 (4%) 0 (0)

PR 10 (37%) 6 (22%)

PFS (mo) 5.7 (4.6 – 7.4) 3.8 (1.9-5.5)