Treatment paradigms in the management of mbc bgicc 2014

Treatment Paradigms in the Management of MBC

Mohamed Abdulla M.D.

Prof. of Clinical Oncology

Kasr El-Aini School of Medicine

Cairo University

BGICC – Roche SymposiumFairmont Hotel & Tower –HeliopolisThursday, 09/01/2014

Breast Cancer: Basic Facts:

• Most frequently encountered cancer among females.

• Most common cause of cancer related deaths among females.

• A national problem.

• Heterogeneous disease.

• HER2 +++ (20 – 25%) Poor prognosis.

• Anti-HER2 Targeted Therapies Changing the landscape of disease.

Breast Cancer:A Heterogeneous Disease:Intrinsic Subtype Clinico-Pathologic Definition

Luminal A ER &/or PR +veHER2 –ve

Ki-67 (<20%)

Luminal B (HER2 –ve)

ER &/or PR +veHER2 –ve

Ki-67 (>20%)

Luminal B (HER2 +ve)

ER &/or PR +veHER2 +ve

Ki-67 (Any)

Erb-B2 Overexpression

ER & PR –veHER2 +ve

Basal Like (Triple Negative)

ER & PR –veHER2 -ve

Surv

ival

Pro

bab

ility

Duration (months)

Sorlie et al PNAS 2001

Breast Cancer:Major Criteria of Metastatic Disease:

Major Criteria of Metastases Clinical Implications

Heterogeneity between primary

tumor and metastatic disease:

ER: 13%

PR: 28%

HER2: 5%

Ineffective therapy based on

primary tumor characteristics

Redundancy of mechanistic

pathways of growth

The need for combination therapy

Variable dormancy of malignant

cells

Delayed relapse

Contribution of cancer initiating

cells

Therapies targeting stem cells

Breast Cancer Metastases: Issues for the personalization of its prevention and treatment.Mariano N. et al. The American Journal of Pathology, Vol. 183, No. 4, October 2013.

Breast Cancer:HER2 Structure & Function:

PI3K MAPK Stat

Growth & Proliferation

AngiogenesisInvasion & Metastases

Breast Cancer:HER2 Directed Therapies Has Changed The Landscape of Disease:

Dawood S, et al. J Clin Oncol. 2010;28(1):92-98.

12 60483624

0.2

0.8

0.6

0.4

1.0Her2 +ve with Hereptin n=191

Her2 –ve n=1782

Her2 +ve no Herceptin n=191

Trastuzumab

Approval

(advanced

BC)

2004 2005 20061998 20032002 20082007

Her2+ Advanced Breast cancer:Major clinical advances:

20102009

Phase 2

Randomized

trial

TDM1

Phase 3

Pertuzumab

Lapatinib

Approval

(advanced

BC)

Initial

studies for:

TDM1,

Pertuzumab,

Afatinib,

Neratinib

TDM1

Approval

2L mBC

Pertuzumab

approved

(advanced

BC)

Everolimus

Approval

(advanced

BC)

White = clinical study results prior to 2013.Yellow = regulatory approvals prior to 2013.

2011 2012 2013

Adapted from Krop I. SABCS 2011, Abst ES1-3.

Breast Cancer:Trastuzumab: 1 Agent & 4 Targets:




1. Previously unexposed.

2. Previously exposed:a. > 6 months.

b. < 6 months.

3. 2nd line or later treatment.

Her2+ Advanced Breast cancer:Clinical Scenarios:

1. Unexposed Patients:

• 469 MBC• No ttt for

M-Stage.• HER2 +ve

Chemotherapy + Trastuzumab

Chemotherapy

(AC) + Trastuzumab

(Paclitaxel) + Trastuzumab

AC

PaclitaxelUse of Chemotherapy plus Monoclonal Antibody agents Against HER2 for MBC Overexpresses HER2. Slamon et al, N Engl J. 2001;344-783-921


Use of Chemotherapy plus Monoclonal Antibody agents Against HER2 for MBC Overexpresses HER2. Slamon et al, N Engl J. 2001;344-783-921


Use of Chemotherapy plus Monoclonal Antibody agents Against HER2 for MBC Overexpresses HER2. Slamon et al, N Engl J. 2001;344-783-921

1. Unexposed Patients:H0648g and M77001:Overall survival with trastuzumab first-line therapy

* IHC 2+ tumours not confirmed by in situ hybridisation; subgroup analysis p value not reported. † Statistically significant IHC 3+/FISH-positive.1. Smith IE. Anticancer Drugs 2001; 12(Suppl. 4):S3–S10; 2. Slamon DJ, et al. N Engl J Med 2001; 344:783–792;3. Marty M, et al. J Clin Oncol 2005; 23:4265–4274.

Su

rviv

al p

rob

ab

ilit

y

Time (months)

Trastuzumab + docetaxel (n = 92)

22.7 31.2

+37%

p = 0.0325†

Docetaxel (n = 94)

8.5 months

0

0.2

0.4

0.6

0.8

1.0

0 5 10 15 20 25 30 35 5040 45

M770013H0648g*1,2

(IHC 3+ paclitaxel subgroup)

Time (months)

1.0

Su

rviv

al p

rob

ab

ilit

y

0.6

0.8

0.4

0.2

0.018 25

Trastuzumab + paclitaxel (n = 68)

Paclitaxel (n = 77)

0 5 15 20 25 30 35 40 45

7 months

10

Herceptin vs Lapatinib in 1LmBC:COMPLETE STUDY (EGF 108919)

Primary end point:PFS

Secondary end points:OS & safety

Karen A. Gelmon ASCO 2012 LBA no. 671

• MBC Her 2+ve (IHC 3+ and/or FISH+)

• 1L MBC (no prior chemo)

(n=636)Taxane based Chemotherapy

+Lapatinib(n=318)

Taxane based chemotherapy+Herceptin

(n=318)

COMPLETE study (108919)Progression Free Survival


PFS: intent to ttt population PFS: centrally confirmed HER 2+

COMPLETE STUDY (EGF108919)Over all survival analysis


OS: intent to ttt population OS: centrally confirmed HER 2+

Unexposed Patients:MBC, HER2 +ve 1L Treatment:

NCCN. Clinical practice guidelines in oncology: breast cancer. v.2.2013.

Trastuzumab

Chemotherapy:• Taxanes.• Venoralbine• Capecitabine• Gemcitabine

+/- Platinum

Pertuzumab and Trastuzumab have complementary mechanisms of action

1. Eigenbrot et al Proc Natl Acad Sci. 2010. 107: 15039–15044.2. Cho et al. Nature 2003;421:756–760.

HER2

Pertuzumab1

Trastuzumab2HER3

ShcGRb2Sos

RAF

MEK

MAPKP

P

Akt

PI3KP P

PP PDK1

PP P

mTOR

Cyclin 01

GSK36

NF B

BAD

p27

CLEOPATRA: Study design:

Baselga J, et al. N Engl J Med 2012; 366:109–119.

Randomisation:Stratified by geographic region and prior treatment status ([neo]adjuvant chemotherapy received or not)

Dosing:–Pertuzumab/placebo: 840 mg loading dose, 420 mg maintenance q3w –Trastuzumab: 8 mg/kg loading dose, 6 mg/kg maintenance q3w–Docetaxel: 75 mg/m2, escalating to 100 mg/m2 if tolerated q3w

Patients withHER2-positive

mBCcentrally

confirmed(N = 808)

Placebo + trastuzumab (n = 406)

1:1

Docetaxel*≥6 cycles recommended

PD

Pertuzumab + trastuzumab(n = 402)

Docetaxel*≥6 cycles recommended

PD

*<6 cycles allowed for unacceptable toxicity or PD;

>6 cycles allowed at investigator discretionPD, progressive disease

R

Primary endpoint: Independently assessed PFS

D, docetaxel; PFS, progression-free survival; Pla, placebo; Ptz, pertuzumab; T, trastuzumab

0 5 10 15 20 25 30 35 40

0

10

20

30

40

50

60

70

80

90

100

Time (months)

Ptz + T + D: median 18.5 monthsPla + T + D: median 12.4 months

HR = 0.6295% CI 0.51‒0.75p<0.0001

∆ = 6.1 months

Pro

gres

sio

n-f

ree

surv

ival

(%

)

Baselga et al. N Engl J Med 2011

CLEOPATRA: Patients receiving the pertuzumab-based regimen had a 34% reduction in the risk of death

HR 0.66; 95% CI = 0.52–0.84p = 0.0008

Placebo + trastuzumab + docetaxel 154 events; median 37.6 months

Pertuzumab + trastuzumab + docetaxel 113 events; median not reached

Ove

rall

surv

ival

(%)

Time (months)

10

20

30

40

50

60

70

80

90

0

100

10 20 300 5 15 25 35 5540 45 50

Swain SM, et al. Lancet Oncol 2013; 14:461–471.

Not reached

37.6 months

Independently assessed PFS by prior Trastuzumab therapy in patients with (neo)adjuvant therapy

Placebo+ trastuzumab +

docetaxelMedian PFS, months

Pertuzumab+ trastuzumab +

docetaxelMedian PFS, months

Hazard ratio(CI)

Prior (neo)adjuvant trastuzumab treatment

(n = 88)10.4 16.9

0.62(0.35‒1.07)

No prior (neo)adjuvant trastuzumab treatment

(n = 288)12.6 21.6

0.60(0.43‒0.83)

Baselga et al. N Engl J Med 2011

Unexposed Patients:MBC, HER2 +ve, 1L Treatment:

• Trastuzumab + Pertuzumab + Chemotherapy.

• Trastuzumab + Chemotherapy.

Exposed Patients:MBC, HER2 +ve, 2L Treatment:

Trastuzumab + Chemotherapy

Dis

eas

e P

rogr

essi

on

Trastuzumab + Pertuzumab

Chemotherapy

Dis

eas

e P

rogr

essi

on

• Switch CTh.• Lapatinib.• Investigational.

Exposed Patients:MBC, HER2 +ve, 2L Treatment:

Ado-Trastuzumab Emtansine (T-DM1): Approved in 2013

Ado-Trastuzumab Emtansine: T-DM1:

Lewis Phillips GD, et al. Cancer Res.2008; 68:9280–9290.

Primary endpoints:

PFS by INV, safety

Key Secondary endpoints:

ORR, clinical benefit, OS, QOL, symptom control

TDM4450 Study DesignRandomized, phase II, international, open-label study

1:1 HER2-positive, recurrent locally advanced BC or MBC (n=137)

T-DM13.6 mg/kg Q3W until PD

Trastuzumab 8 mg/kg dose; 6 mg/kg Q3W

+ Docetaxel 75 or 100 mg/m2 Q3W

CrossoverT-DM1PD

Perez EA, et al. Abstr LBA3. ESMO 2010

Time (months)

BO21976 (TDM4450g): PFS by investigator Randomised patients

Hurvitz SA, et al.J Clin Oncol 2013; 31:1157–1163.

Pro

gre

ss

ion

-fre

e s

urv

iva

l (p

rop

ort

ion

)

Hazard ratio and log-rank p-value were from stratified analysis

Trastuzumab

+ docetaxel (n = 70)

T-DM1 (n = 67)

Median

PFS, moHazard

ratio 95% CI

Log-rank

P value

9.2

14.20.59 0.36– 0.97 0.035

CI, confidence interval; INV, investigator; PD, progressive disease; PFS, progression-free survival.

1.0

0.8

0.6

0.4

0.2

0.0

0 2 4 6 8 10 12 14 16 18 20

Due to

TDM-1

Cross

over

EMILIA Study Design:

Primary End Points: PFS by independent review, OS, and safety

Key Secondary End Points: PFS by investigator, ORR, duration of response, time to symptom progression

1:1

HER2+ (central) LABC or MBC (N=980)

• Prior taxane and trastuzumab

• Progression on metastatic tx or within 6 mos of adjuvant tx

T-DM1 3.6 mg/kg q3w IV

Capecitabine 1000 mg/m2 orally bid, days 1–14,

q3w+

Lapatinib 1250 mg/day orally qd

PD

PD

EMILIA: Progression-Free Survival by Independent Review

Median (mos) No. events

Cap + Lap 6.4 304

T-DM1 9.6 265

Stratified HR=0.650 (95% CI, 0.55, 0.77)

P<0.0001

0.0

0.2

0.4

0.6

0.8

1.0

0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30

Pro

po

rtio

n p

rogr

ess

ion

-fre

e

Time (mos)

Unstratified HR=0.66 (P<0.0001).

EMILIA: Overall Survival:Interim Analysis

Time (mos)

Pro

po

rtio

n s

urv

ivin

g

0.0

0.2

0.4

0.6

0.8

1.0

0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36

77.0% 65.4%

47.5%

84.7%

Median (mos) No. events

Cap + Lap 23.3 129

T-DM1 NR 94

Stratified HR=0.621 (95% CI, 0.48, 0.81)

P=0.0005Efficacy stopping boundary P=0.0003 or

HR=0.617

Unstratified HR=0.63 (P=0.0005). NR=not reached.

TH3RESA Study design:

HER2-positive (central)advanced BC(N=600)≥2 prior HER2-directedtherapies for advanced BCPrior treatment withtrastuzumab, lapatinib,and a taxane

T-DM13.6 mg/kg q3w IV(n=400)

Treatment ofphysician’s choice(TPC)a

(n=200)

PD

PDT-DM1c

(optionalcrossover)

1

2

Co-primary endpoints:PFS by investigator and OS

Key secondary endpoints:ORR by investigator and safety

A: TPC single-agent chemotherapy, hormonal therapy, or HER2-directed therapy, or a combination of a HER2-directed therapy with a chemotherapy, hormonal therapy, or other HER2-directed therapy.

Wildiers, et al. ESMO 2013

TPC* Treatment Category

TPC* treatment categoryTPC

(n=184a)

Combination with HER2-directed agent, % 83.2

Chemotherapyb + trastuzumab 68.5

Lapatinib + trastuzumab 10.3

Hormonal therapy + trastuzumab 1.6

Chemotherapyb + lapatinib 2.7

Single-agent chemotherapy b 16.8

T-containing80.4

a Includes patients who received study treatment.b The most common chemotherapy agents used were vinorelbine, gemcitabine, eribulin, paclitaxel, and docetaxel.* Treatment of physicians choice


PFS by Investigator Assessment

Median follow-up: TPC, 6.5 months; T-DM1, 7.2 months.

Unstratified HR=0.521 (P<0.0001).* TPC: Treatment of physicians choice


PFS for Patients Treated With Trastuzumab-Containing Regimens

Unstratified HR=0.54 (P<0.0001).* TPC: Treatment of physicians choice


First Interim OS Analysis

44 patients in the TPC arm received crossover T-DM1 treatment after documented progression.Unstratified HR=0.57 (P=0.004).* TPC: Treatment of physicians choice Wildiers, et al. ESMO 2013

ORR in Patients With Measurable DiseaseBy Investigator Assessment


* TPC: Treatment of physicians choice

Overview of AEsTPC

(n=184a)T-DM1

(n=403a)

All-grade AEs, % 88.6 93.5

Grade ≥3 AEs b % 43.5 32.3

AEs leading to treatment discontinuation,c % 10.9 6.7

AEs leading to dose reduction, % 19.6 9.4

LVEF <50% & ≥15%

decrease from baselined % 1.1 1.5

a One patient randomized to the TPC arm received 2 cycles of T-DM1 by mistake; this patient was included in the T-DM1 group for safety analyses. b Grade 5 AEs: TPC, 1.6% (n=3); T-DM1, 1.2% (n=5). Three were considered related to T-DM1: hepatic encephalopathy, subarachnoid hemorrhage, and pneumonitis. One was considered related to TPC: noncardiogenic pulmonary edema. c For any study drug. d No patient experienced an LVEF <40%. LVEF, left ventricular ejection fraction


Summary: HER2+ MBC

• 1st Line: Pertuzumab/trastuzumab/taxane

• 2nd/3rd line: T-DM1

• Other options after progression:– Trastuzumab/lapatinib– Lapatinib/capecitabine– Trastuzumab/other chemo– Trastuzumab or Lapatinib + AI– ??everolimus-based therapy

Health & Medicine

Treatment paradigms in the management of mbc bgicc 2014