advances in the management of metastatic her 2 positive breast...

Advances in the Management of

Metastatic Her 2 Positive Breast Cancer

Sunil Verma MD, MSEd, FRCPC

Medical Oncologist

Research Lead, Division of Medical Oncology

Chair, Breast Medical Oncology

Sunnybrook Odette Cancer Centre

Associate Professor, University of Toronto

HER2 overexpression

associated with more

aggressive phenotype4

The Her 2 Journey

1. Ullrich A, et al. Nature 1984; 309:418−4253;

Anti-HER2 monoclonal

mouse antibody

humanised: trastuzumab6

HER2 gene is cloned2

HER2 protein found to be

overexpressed in breast tumours3

HER2/neu

gene identified1

Anti-HER2

monoclonal mouse

antibody

developed5

Trastuzumab

clinical trials begin

1993−1995

3. Sainsbury JR, et al. Lancet 1985; 1:364−366;

5. Huzdiak RM, et al. Mol Cell Biol 1989; 9:1165–1172;

4. Di Fiore PP, et al. Science 1987; 237:178–182

6. Carter P, et al. Proc Natl Acad Sci USA 1992; 89:4285–4289

2. Ishii S, et al. Proc Natl Acad Sci USA 1985; 82:4920–4924

Her 2 Story Poor Prognostic Marker

Outline

• First Line Treatment

• Second Line Treatment and Beyond

• Individualized Approach

• An Algorithm and Concluding Remarks

Outline

OS was a secondary endpoint in the study Chemotherapy = either doxorubicin or epirubicin + cyclophosphamide or paclitaxelOS, overall survival; RR, relative risk of death Adapted from Slamon DJ, et al. N Engl J Med 2001; 344:783–792.

Trastuzumab prolongs overall survival in

HER2-positive MBC

Chemotherapy (n = 234)

Chemotherapy + trastuzumab (n = 235)

Time (months after enrolment)

RR = 0.80 (95% CI = 0.64,1.00)

p = 0.046

Median OS:

20.3 months

Median OS:

25.1 months

5 15 25 35 450

First Line Treatment Approach (2001-

• A number of effective options with chemo and

anti-her2

– Taxanes and Herceptin

– Vinorelbine and Herceptin

– Capecitabine and Anti-Her2

– Doublet chemo with Her 2 generally not used

• Select group of patients may benefit from an

anti-Her2 and anti-estrogen approach

Recent Achievements in

Her 2 positive MBC

First Line

– MA.31

• Taxane + H vs. Taxane + L

– Bolero -1

• Paclitaxel + H vs. Paclitaxel + H +Everolimus

– CLEOPATRA

• Chemo + H vs. Chemo +H+P

Gelmon et. al ASCO 20129

Gelmon et. al ASCO 201210

This presentation is the intellectual property of the author/presenter. Contact them at shurvitz@mednet.ucla.edu for permission to reprint and/or distribute.

San Antonio Breast Cancer Symposium – December 9-13, 2014

BOLERO-1/TRIO 019: Study Design

Everolimus (10 mg PO daily) +

Paclitaxel2 + Trastuzumab3

Placebo +

Paclitaxel2 + Trastuzumab3

Stratification factors:• Prior neo/adjuvant TRAS

• Visceral metastases

• Primary: PFS (investigator-assessed)

• Overall population and

• HR subpopulation

N = 719

• Locally advanced or metastatic

HER2+ breast cancer

• No prior therapy for advanced or

metastatic disease (except

endocrine therapy)

• Prior (neo)adjuvant TRAS and/or

chemotherapy allowed1

• Measurable disease or presence of

bone lesions (lytic or mixed)

Randomized

Therapy until disease progression

or intolerable toxicity4

ABC, advanced breast cancer; CBR, clnical benefit rate; ORR, overall response rate; OS, overall survival; PFS, progression free survival.

• Secondary:

• OS, ORR, CBR, Time to response, Safety, Duration of

response

1Discontinued > 12 mo before randomization; 2Paclitaxel: 80 mg/m2 weekly; 3Trastuzumab: 4 mg/kg loading dose on day 1 at cycle 1 followed by 2 mg/kg weekly doses4Patients could discontinue any study treatment due to AEs; other study treatments continued until disease progression or intolerable toxicity

Endpoints

BOLERO-1/TRIO 019: PFS Full Population(Investigator-assessment)

480 416 365 324 289 260 217 178 151 130 122 107 94 80 72 63 58 48 42 35 26 21 17 13 10 5 3 3 0239 221 199 166 144 123 106 91 80 69 53 47 43 38 36 36 31 24 17 15 12 9 7 6 4 3 1 1 0

No. of patients still at risk

EverolimusPlacebo

Time (months)

0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36 38 40 42 44 46 48 50 52 54 56

Hazard Ratio = 0.89; 95% CI [0.73, 1.08]

Median PFS

Everolimus: 14.95 months; 95% CI [14.55, 17.91] (n/N = 271/480)

Placebo: 14.49 months; 95% CI [12.29, 17.08] (n/N = 154/239)

Log rank p value = 0.1166

- One-sided p-value is obtained from the log-rank test stratified by prior use of trastuzumab (Y/N) and Visceral metastasis (Y/N) from IWRS.

Censoring times

BOLERO-1/TRIO 019: Most Frequent Adverse Events (Safety set) [> 25% in everolimus arm]

AE/Grade

EVE + TRAS + PAC

(N = 472)

PBO + TRAS + PAC

(N = 238)

Any Grade 3 Grade 4 Any Grade 3 Grade 4

Non-hematologic

Stomatitis 67 13 0 32 1 0

Diarrhea 57 9 0 47 4 0

Alopecia 47 <1 0 53 0 0

Rash 40 1 0 21 <1 0

Cough 40 <1 0 33 1 0

Pyrexia 39 2 0 27 1 0

Fatigue 35 5 0 36 3 0

Epistaxis 33 0 0 18 0 0

Peripheral edema 33 1 0 24 <1 0

Nausea 33 1 0 35 1 0

Peripheral neuropathy 29 4 0 24 5 0

Headache 28 1 0 29 1 0

Vomiting 26 1 0 23 3 0

Pneumonitis* 16 4 1 4 <1 0

Hematologic

Neutropenia 38 21 4 25 11 4

Anemia 31 9 1 16 3 0

*AE of clinical importance

EVE, Everolimus; HR, hormone receptor; PAC, Paclitaxel; PBO, Placebo; TRAS, Trastuzumab.

CLEOPATRA study design

14HER2, human epidermal growth factor receptor 2; MBC, metastatic breast cancer; PD, progressive disease

Patients with

HER2-positive MBCcentrally confirmed

(N=808)

Placebo + trastuzumab

Randomization was stratified by geographic region and prior treatment status

(neo/adjuvant chemotherapy received or not)

Docetaxel≥6 cycles recommended

Pertuzumab + trastuzumab

Docetaxel≥6 cycles recommended

Swain et al. SABCS 2012 Poster P5-18-26 .

Updated Kaplan-Meier curves of

investigator-assessed PFS

15D, docetaxel; PFS, progression-free survival; Pla, placebo; Ptz, pertuzumab; T, trastuzumab

0 5 10 15 20 25 30 35 40

Time (months)

Ptz + T + D: median 18.7 monthsPla + T + D: median 12.4 months

HR=0.6995% CI 0.58−0.81

∆=6.3 months

n at risk

Ptz + T + D

Pla + T + D

primary

analysis

May 2011

Efficacy Analysis Milestones

May 2012

1st interim

analysis

2nd interim

analysis

HR 0.64 (p = 0.005)

Δ 6.1 months

HR 0.62 (p < 0.0001)

HR 0.66 (p = 0.0008)*

July 2012

Patients still on

placebo offered

crossover to

pertuzumab

Feb 2014

final analysis

Final OS AnalysisMedian follow-up 50 months (range 0–70 months)

ITT population. Stratified by geographic region and neo/adjuvant chemotherapy.

CI, confidence interval; Pla, placebo; Ptz, pertuzumab.17

0 10 20 30 40 50 7060

Time (months)

HR 0.68

95% CI = 0.56, 0.84

p = 0.0002

Ptz + T + D

Pla + T + D

128104226268318371

02391179230289350

n at risk

Ptz + T + D

Pla + T + D

months

monthsΔ 15.7

months

Cleopatra Overall Survival

Cross over patients (11%) excluded

Swain et. al NEJM 2015

Breast cancer therapies following

discontinuation of study treatment in patients

who had withdrawn from study treatment

Placebo+ trastuzumab + docetaxel

(n=338)

Pertuzumab+ trastuzumab + docetaxel

(n=298)

Any 260 (76.9) 225 (75.5)

In patients receiving subsequent breast cancer treatment

n=260 n=225

Any HER2-targeted treatment 178 (68.5) 160 (71.1)

Trastuzumab 104 (40.0) 106 (47.1)

Lapatinib 114 (43.8) 93 (41.3)

Trastuzumab emtansine 26 (10.0) 21 (9.3)

Capecitabine 140 (53.8) 113 (50.2)

Vinorelbine 70 (26.9) 51 (22.7)

Cyclophosphamide 43 (16.5) 30 (13.3)

Doxorubicin 46 (17.7) 29 (12.9)

Paclitaxel 32 (12.3) 21 (9.3)

Docetaxel 11 (4.2) 13 (5.8)

Adverse events (all grades) with ≥25%

incidence or ≥5% difference between arms

21Highlighted are adverse events with ≥5% higher incidence

n (%)Placebo + trastuzumab + docetaxel

(n=396)Pertuzumab + trastuzumab + docetaxel

(n=408)

Diarrhea 191 (48.2) 278 (68.1)

Alopecia 240 (60.6) 248 (60.8)

Neutropenia 197 (49.7) 216 (52.9)

Nausea 168 (42.4) 179 (43.9)

Fatigue 148 (37.4) 155 (38.0)

Rash 95 (24.0) 149 (36.5)

Decreased appetite 105 (26.5) 121 (29.7)

Mucosal inflammation 79 (19.9) 112 (27.5)

Asthenia 121 (30.6) 110 (27.0)

Vomiting 97 (24.5) 104 (25.5)

Peripheral edema 122 (30.8) 101 (24.8)

Pruritus 40 (10.1) 68 (16.7)

Constipation 101 (25.5) 63 (15.4)

Febrile neutropenia 30 (7.6) 56 (13.7)

Dry skin 23 (5.8) 44 (10.8)

Cardiac adverse events

* In patients with post-baseline assessment

LVEF, left ventricular ejection fraction; LVSD, left ventricular systolic dysfunction

n (%)Placebo

+ trastuzumab + docetaxelPertuzumab

+ trastuzumab + docetaxel

Data cutoff date May 2011(n=397)

May 2012(n=396)

May 2011(n=407)

May 2012(n=408)

LVSD (all grades) 33 (8.3) 34 (8.6) 18 (4.4) 22 (5.4)

Symptomatic LVSD 7 (1.8) 7 (1.8) 4 (1.0) 5 (1.2)

LVEF decline to <50% and by ≥10% points from baseline*

25/379 (6.6) 28/378 (7.4) 15/393 (3.8) 18/394 (4.6)

LVEF recovery to ≥50%* 18/25 (72.0) 25/28 (89.3) 13/15 (86.7) 16/18 (88.9)

KADCYLA is a HER2-targeted antibody and microtubule inhibitor conjugate

consisting of

• HERCEPTIN, a humanized anti-HER2 IgG1 monoclonal antibody

• DM1, a cytotoxic microtubule inhibitor derived from maytansine

− on average, KADCYLA has 3.5 DM1 molecules per antibody

• MCC, a stable thioether linker, covalently linking HERCEPTIN to DM1

T-DM1Mechanism of Action

Antibody

(HERCEPTIN)

Stable linker

Cytotoxic

agent (DM1)

Emtansine

DM: derivative of maytansine

MCC: 4-[N-maleimidomethyl] cyclohexane-1-

carboxylate

KADCYLA Product Monograph. Hoffmann-La Roche Limited. September 11, 2013.

Swanton C, Johnston SR, editors. Handbook of Metastatic Breast Cancer, 2nd ed. Informa Healthcare, New York, 2012.

In vitro studies in human breast cancer cells that overexpress HER2 have

shown that, like HERCEPTIN, KADCYLA

• Binds subdomain IV of the HER2 extracellular domain

• Inhibits HER2 signaling

• Mediates antibody-dependent cell-mediated cytotoxicity (ADCC)

• Inhibits shedding of the HER2 extracellular domain

T-DM1Retains Activity of Herceptinf

KADCYLA has the additional MOA of DM1. Upon binding to HER2, KADCYLA undergoes

• Receptor-mediated internalization

• Subsequent lysosomal degradation

• Intracellular release of DM1-containing cytotoxic catabolites

• DM1 binding to tubulin, disrupting microtubule networks in the cell, resulting in cell

cycle arrest and apoptotic cell death

T-DM1Intracellular Delivery of DM1

Lysosomal

degradation

release*

Internalization

Inhibition of

tubulin

polymerizatio

KADCYLA

*The primary DM1-containing cytotoxic catabolite released is lysine-MCC-DM1.

LoRousso PM, et al. Clin Cancer Res 2011.

PHASE II STUDY

T-DM1 vs. Docetaxel and Trastuzumab

1:1 HER2-positive,

recurrent locally

advanced breast

cancer or MBC

(N=137)

Trastuzumab 8 mg/kg loading dose; 6 mg/kg q3w IV

+ Docetaxel 75 or 100 mg/m2 q3w

(n=70)

Crossover to

(optional)PDa

T-DM13.6 mg/kg q3w IV

(n=67)

Hurvitz, et al., JCO, 2013

Objective Response by Investigator Patients With Measurable Disease at Baseline

Trastuzumab +

docetaxel

(n=69)a

(n=67)

Patients with an objective response,b n (%) 40 (58.0) 43 (64.2)

95% CI 45.5–69.2 51.8–74.8

Objective responses, n (%)

Complete response 3 (4.3) 7 (10.4)

Partial response 37 (53.6) 36 (53.7)

Stable disease 23 (33.3) 13 (19.4)

Progressive disease 4 (5.8) 8 (11.9)

Unable to evaluate or missing 2 (2.9) 3 (4.5)

Patients with clinical benefit,c n (%) 56 (81.2) 50 (74.6)

95% CI 70.7–89.1 63.2–84.2 aOne patient was not included in the efficacy analysis due to study site withdrawal.bDefined as complete or partial response based on RECIST 1.0 determined on 2 consecutive tumor assessments at least 4

weeks apart.cDefined as objective response any time during the study or maintained stable disease for at least 6 months

from randomization.

Hurvitz SA, et al. Abstract 5.001. ESMO 2011.

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Time (months)

Progression-Free Survival by InvestigatorRandomized Patients

ressio

0.00 2 4 6 8 10 12 14 16 18 20

Number of patients at risk

T+D 70 66 63 53 43 27 12 4 2 2 0

T-DM1 67 60 51 46 42 35 22 15 6 3 0

Hazard ratio and log-rank P value were from stratified analysis.

Trastuzumab

+ docetaxel (n=70)

T-DM1 (n=67)

Median

PFS, mos

Hazard ratio 95% CI

Log-rank Pvalue

14.20.59 0.36 –

0.97 0.035

Figure adapted from:http://clinicaltrials.gov/ct2/show/NCT01120184;

Roche. Data on file

MARIANNE: A clinical trial of pertuzumab and

T-DM1 in first-line metastatic breast cancer

HER2-positive,

progressive or

recurrent, locally

advanced or

untreated MBC

(N = 1092)

Pertuzumab + T-DM1

Trastuzumab + taxane (docetaxel or paclitaxel)

R Placebo + T-DM1

2010 2011–2012 2013

First patient in

July 2010

Last patient in

Q2 2012

T-DM1 ± pertuzumab: blinded, placebo-controlled

Trastuzumab + taxane: open-label

MARIANNEStatistical Analysis

Summary

First Line

• The standard of care should consist of

pertuzumab and trastuzumab along with

docetaxel (? other taxane alternative)

Future Questions

First Line• Can we combine Pertuzumab and Herceptin with other

partners

– Other taxanes (PERUSE)

– Other chemotherapies - Vino/Cape (VELVET/PHREXA)

– Other biologics – T-DM1 (MARIANNE negative)

• Developing effective drugs that can target brain

metastases

• Duration of targeted therapy for those responding

• Duration of chemotherapy when receiving dual targeted

therapy

• Combination of endocrine therapy with dual targeted

anti-Her 2 tx for ER+/Her 2 +ve pts32

Outline

Second Line

(2006-2010)

• There is continued benefit of trastuzumab

beyond progression

– Capecitabine and Trastuzumab

• There is benefit of Lapatinib in combination with

Capecitabine upon progression on Trastuzumab

Recent Achievements in

Her 2 positive MBC

Second Line and Beyond

– EGF 104900

• L+ H vs L alone

– EMILIA

• T-DM1 vs Cape + L

– Bolero-3

• Vinorelbine + H + Everolimus vs. Vinorelbine

Trastuzumab and LapatinibOverall Survival

EMILIA Study Design

HER2-positive LABC

or MBC (N=980)

• Prior taxane and

trastuzumab

• Progression on

metastatic treatment

or within 6 months of

adjuvant treatment

PDT-DM1

3.6 mg/kg q3w IV

Capecitabine

1000 mg/m2 PO bid, days 1–14, q3w

Lapatinib

1250 mg/day PO qd

Verma et al NEJM 2012

EMILIA: Progression Free Survival

EMILIA: Overall Survival

EMILIA

Adverse Events

T-DM1c

(optional

crossover)

TH3RESA Study Schema

• Stratification factors: World region, number of prior regimens for advanced BC,d

presence of visceral disease

• Co-primary endpoints: PFS by investigator and OS

• Key secondary endpoints: ORR by investigator and safety

PDT-DM1

3.6 mg/kg q3w IV(n=400)

Treatment of

physician’s choice

(TPC)b

(n=200)

HER2-positive (central)

advanced BCa

(N=600)

≥2 prior HER2-directed

therapies for advanced BC

Prior treatment with

trastuzumab, lapatinib,

and a taxane

a Advanced BC includes MBC and unresectable locally advanced/recurrent BC.b TPC could have been 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.c First patient in: Sep 2011. Study amended Sep 2012 (following EMILIA 2nd interim OS results) to allow patients in the TPC arm to receive

T-DM1 after documented PD.d Excluding single-agent hormonal therapy.

BC, breast cancer; IV, intravenous; ORR, objective response rate; PD, progressive disease; q3w, every 3 weeks.

Wildiers H, et al. ECC 2013; Abstract 15LBA.

PFS by Investigator Assessment

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

Unstratified HR=0.521 (P<0.0001).

198 120 62 28 13 6 1 0

404 334 241 114 66 27 12 0

No. at risk:Time (months)

1412108642

(n=198)

(n=404)

Median (months) 3.3 6.2

No. of events 129 219

Stratified HR=0.528 (95% CI, 0.422, 0.661)

P<0.0001

First Interim OS Analysis

No. at risk:

Time (months)

44 patients in the TPC arm received crossover T-DM1 treatment after documented progression.

Unstratified HR=0.57 (P=0.004).

1612108642

Observed 21% of targeted events

(n=198)

(n=404)

Median (months) 14.9 NE

No. of events 44 61

Stratified HR=0.552 (95% CI, 0.369, 0.826); P=0.0034

Efficacy stopping boundary HR<0.363 or P<0.0000013

O’Regan R, et al. ASCO 2013; Abstract 505. Not for distribution.

O Regan ASCO 201344

O Regan ASCO 201345

Summary

Second Line and Beyond• T-DM1 offers significant clinical benefit and superior

toxicity profile and is effective for second line Her 2 +

treatment

• Patients progressing on T-DM1 still may derive a benefit

from ongoing systemic tx with chemo with anti-Her 2

approaches

• The role of Lapatinib has evolved and now is generally

considered in third or later lines of treatment. One may

consider earlier use if:

– Progressive brain metastases despite radiation

– Lack of response to first/second line of herceptin based regimen

– ? Biomarkers – p95 still needs to be validated

Future Questions

• Is there a benefit of Pertuzumab or T-DM1 (along with

other partners) beyond progression?

• What is the effect on tumor biology once patients

progress on Pertuzumab/T-DM1?

– What are potential targeted agents that may help

overcome resistance?

• What will be the role of PI3K inhibitors in second line +

treatment?

• Who are the ideal patients for dual targeted treatment

alone?

• The Next Generation of anti-Her 2 Drugs….

PHEREXA: A clinical trial of pertuzumab

in second-line metastatic breast cancer

Last patient in Q3

HER2-positive MBC

(N = 450)

Arm A:

Pertuzumab + trastuzumab + capecitabine

Arm B:

Trastuzumab + capecitabine

Figure adapted from:Muñoz-Mateu M, et al. ASCO 2011 (Abstract TPS118: poster presentation);

Roche. Data on file.

MM-302 is a HER2-targeted antibody-drug conjugated liposomal formulation

Liposome

• Extended half-life

• Stably encapsulates doxorubicin

• Passive accumulation in tissues

possessing leaky vasculature

• Size precludes delivery to cardiac tissue

Membrane PEG

75-110 nm

Doxorubicin Crystals• Effective cytotoxic agent in Br Ca

• DNA intercalator, TOP2A inhibitor, free

radical generator

anti-HER2 scFv

• Targets liposome to HER2-overexpressing cells

• Promotes internalization

• Binds to different epitope than trastuzumab

• Does not inhibit HER2 signaling

• No uptake of F5 containing liposomes into

cardiomyocytes

T cell dependent bispecific antibody (TDB) platform

aTumor antigenFull length

Ridgeway...Carter. 1996 Prot. Engineering

Atwell...Carter. 1997 J. Mol Biol.

• Produced using modular “knobs into holes” technology

• Effector functions removed (E. coli production / N297A)

• Minimal immunogenic potential

• PK is similar to conventional IgG1

T366SL368AY407V T366W

Outline

Personalized Factors to Consider

• Hormone Receptor Status

• Prior Adjuvant Trastuzumab

• CNS Metastases

• Biomarkers

CLEOPATRA

PFS in predefined subgroups

ER, estrogen receptor; FISH, fluorescence in situ hybridization; IHC, immunohistochemistry; PFS, progression-free survival; PgR, progesterone receptor

808 0.69 0.58‒0.81

432 0.67 0.54‒0.85376 0.70 0.55‒0.90

306 0.70 0.53‒0.91135 0.60 0.40‒0.91114 0.54 0.34‒0.85253 0.81 0.60‒1.10

681 0.72 0.60‒0.87127 0.49 0.31‒0.76789 0.69 0.59‒0.8219 0.62 0.16‒2.40

480 0.65 0.52‒0.8030 0.50 0.16‒1.54261 0.81 0.60‒1.1037 0.47 0.20‒1.10

630 0.63 0.53‒0.76178 0.89 0.61‒1.31

388 0.76 0.60‒0.97408 0.62 0.49‒0.78

721 0.66 0.55‒0.79767 0.70 0.59‒0.83

n HR 95% CI

EuropeNorth AmericaSouth America

<65 years≥65 years<75 years≥75 years

WhiteBlackAsianOther

Visceral diseaseNon-visceral disease

PositiveNegative

IHC 3+FISH-positive

ER/PgR status

Disease type

Age group

Region

HER2 status

Prior (neo)adjuvant chemotherapy

Favorsplacebo

Favorspertuzumab

Hormone Receptor Status

Cleopatra PFS Subgroup Analysis

Cleopatra OS Subgroup Analysis

Cap + Lap T-DM1

Baseline characteristic

Totaln

Median (mos)

HR(95% CI)

T-DM1Better

Cap + LapBetter

All patients 991 25.1 30.9 0.70 (0.56, 0.87)

Age group

<65 years 853 24.6 30.9 0.66 (0.52, 0.83)

65–74 years 113 27.1 NR 0.74 (0.37, 1.47)

≥75 years 25 NR 11.1 3.45 (0.94, 12.65)

ER and PR status

ER+ and/or PR+ 545 25.3 31.9 0.62 (0.46, 0.85)

ER– and PR– 426 23.7 27.1 0.75 (0.54, 1.03)

Line of therapya

First-line 118 27.9 NR 0.61 (0.32, 1.16)

Second-line 361 NR 27.1 0.88 (0.61, 1.27)

Third- and later-line 512 23.3 33.9 0.62 (0.46, 0.84)

EMILIA

Overall Survival Subgroup Analyses

Hazard ratio 0.2 0.5 1 2 5aDefined as any systemic therapy including endocrine and chemotherapy.

NR, not reached.

From confirmatory OS analysis; data cut-off July 31, 2012.Verma et al. ESMO 2012; Oral Abstract #LBA12

BOLERO-3: PFS Subgroup Analyses by Local Assessment

Favors PBOFavors EVE

Subgroup N

All 569

Age < 65 years 472

≥ 65 97

Region Europe 223

North America 123

Asia 166

Latin America 36

Other 21

Prior lapatinib* Yes 161

No 408

Prior adj/neo trastuzumab** Yes 251

No 318

Baseline ECOG PS 0 3821 or 2 186

Hormonal status ER–/PgR– 250

ER+/PgR+ 317

Visceral involvement Yes 439

No 130

Hazard Ratio [95% CI]

0.78 [0.65-0.95]

0.77 [0.62-0.95]

0.93 [0.56-1.57]

0.72 [0.53-0.99]

0.86 [0.55-1.32]

0.83 [0.59-1.18]

0.61 [0.27-1.38]

1.28 [0.48-3.45]

0.79 [0.56-1.11]

0.78 [0.62-0.99]

0.65 [0.48-0.87]

0.92 [0.71-1.18]

0.79 [0.63-1.00]

0.75 [0.53-1.05]

0.65 [0.48-0.87]

0.93 [0.72-1.20]

0.89 [0.72-1.10]

0.48 [0.30-0.76]

Abbreviations: CI, confidence interval; ECOG PS, Eastern Cooperative Oncology Group

performance status.

BOLERO-1/TRIO 019: PFS HR– Subpopulation (Investigator Assessment)

• HR=0.66 [0.48, 0.9], p = 0.0043• Sensitivity analysis without censoring patients at the start of new antineoplastic therapy:

• Median PFS and 95% CIs– 20.27 mo (14.82, 24.08) for everolimus [n = 102]

– 12.88 mo (10.94, 16.56) for placebo [n = 68]

208 183 166 151 138 125 100 84 73 64 62 55 49 40 35 32 30 24 21 19 15 11 10 7 5 2 1 1 0103 96 83 68 58 49 43 34 32 28 24 21 20 19 19 19 17 13 7 6 5 4 2 1 1 0 0 0 0

No. of patients still at risk

EverolimusPlacebo

Hazard Ratio = 0.66; 95% CI [0.48, 0.91]

Median PFS

Everolimus: 20.27 months; 95% CI [14.95,24.08] (n/N = 97/208)

Placebo: 13.08 months; 95% CI [10.05,16.56] (n/N = 66/103)

Log rank p value = 0.0049

Time (months)

0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36 38 40 42 44 46 48 50 52 54 56

- One-sided p-value is obtained from the log-rank test stratified by prior use of trastuzumab (Y/N) and Visceral metastasis (Y/N) from IWRS.

Censoring times

CI, confidence interval; PFS, progression-free survival

CLEOPATRA: Independently assessed

PFS by prior trastuzumab therapy in

patients with (neo)adjuvant therapy

HTMedian PFS, months

PHTMedian PFS, months

Hazard ratio(CI)

Prior (neo)adjuvant trastuzumab treatment(n = 88)

10.4 16.90.62

(0.35, 1.07)

No prior (neo)adjuvant trastuzumab treatment(n = 288)

12.6 21.60.60

(0.43, 0.83)

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

Prior Trastuzumab

Cleopatra OS Subgroup Analysis

EMILIA: Progression-Free Survival Subgroup Analyses

ER and PR status9.0

0.72 (0.58, 0.91)

0.56 (0.44, 0.72)

ER+ and/or PR+

ER− and PR−

0.51 (0.30, 0.85)

0.69 (0.53, 0.91)

0.69 (0.55, 0.86)

Line of therapya

FirstSecond

Age9.8

0.62 (0.52, 0.74)

1.06 (0.68, 1.66)

<65 yrs≥65 yrs

Median,

(95% CI)

Median,

Baseline

characteristic

better

Cap + Lap

better

0.2 0.5 1 2 5

9.6 0.66 (0.56, 0.78)6.4991All pts

HRs were from unstratified analysis.aDefined as any systemic therapy, including endocrine or chemotherapy.

T-DM1Cap + Lap

Hazard ratio

Verma et al. N Eng J Med 2012 (incl. supplementary appendix)

Blackwell et al. ASCO 2012; Abst #LBA1

Data cut-off Jan 14, 2012

Prior Trastuzumab

Cap + Lap T-DM1

Baseline characteristic

Totaln

Median (mos)

HR(95% CI)

T-DM1Better

Cap + LapBetter

All patients 991 25.1 30.9 0.70 (0.56, 0.87)

Age group

<65 years 853 24.6 30.9 0.66 (0.52, 0.83)

65–74 years 113 27.1 NR 0.74 (0.37, 1.47)

≥75 years 25 NR 11.1 3.45 (0.94, 12.65)

ER and PR status

ER+ and/or PR+ 545 25.3 31.9 0.62 (0.46, 0.85)

ER– and PR– 426 23.7 27.1 0.75 (0.54, 1.03)

Line of therapya

First-line 118 27.9 NR 0.61 (0.32, 1.16)

Second-line 361 NR 27.1 0.88 (0.61, 1.27)

Third- and later-line 512 23.3 33.9 0.62 (0.46, 0.84)

EMILIA: Overall Survival Subgroup Analyses

Hazard ratio 0.2 0.5 1 2 5aDefined as any systemic therapy including endocrine and chemotherapy.

NR, not reached.

From confirmatory OS analysis; data cut-off July 31, 2012.Verma et al. ESMO 2012; Oral Abstract #LBA12

Prior Trastuzumab

EMILIA

CNS metastases at baseline and

Progression

CNS Metastases

EMILIA: Outcomes of patients with

CNS mets at Baseline

A. PFS Independent Assessment

B. PFS Investigator Assessment

D. Overall Survival

Krop et. al Annals of Oncology 2014

BIOMARKERS

68 | BGT226A2101 – CONFIDENTIAL

INFORMATION, NOT TO BE

DISTRIBUTED

Alterations in PI3K Pathway Signaling

Components Are Frequent in HER2+ Breast

Cancer

PI3K Pathway “activation status” Predicts

Response to Trastuzumab

Bernard R et al Cancer Cell. 2007 Oct;12(4):395-402

pCR and PIK3CA Status by Treatment Arm in NEO-ALTTO

• For each treatment arm, the pCR rate was lower in tumors with a PIK3CA mutation

• The difference was statistically significant in the combination arm

p=0.012

70124 112 119N=Baselga AACR 2013

PIK3CA Mutation Associated With Poorer Prognosis on Both Arms of Cleopatra Study

Baselga et al, SABCS 2012

Lap + Cap T-DM1

PIK3CA

mutation

status n

Median

(months) n

Median

(months)

Hazard

ratioa 95% CI

Mutated 39 4.3 40 10.9 0.45 0.25–0.82

Wild type 87 6.4 93 9.8 0.74 0.50–1.10

Lap + Cap (Mutated) 39 28 22 9 5 3 2 1 0 0 0 0 0 0 0

Lap + Cap (Wild type) 87 69 55 31 21 16 13 10 7 4 4 3 2 1 0

T-DM1 (Mutated) 40 31 26 18 15 12 8 6 6 5 2 2 1 0 0

T-DM1 (Wild type) 93 82 66 42 36 24 19 15 12 9 6 3 2 1 0

Lap + Cap (PIK3CA mutated)

Lap + Cap (PIK3CA wild type)

T-DM1 (PIK3CA mutated)

T-DM1 (PIK3CA wild type)

Time (months)

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

No. at risk:

aHazard ratios are based on unstratified analyses.

EMILIA Biomarker Analysis:

PFS by PIK3CA Mutation Status and Treatment Arm

Baselga et al, SABCS 2013

Lap + Cap T-DM1

PIK3CA

mutation

status n

Median

(months) n

Median

(months)

Hazard

ratioa 95% CI

Mutated 39 17.3 40 NE 0.26 0.12–0.57

Wild type 87 27.8 93 NE 0.68 0.40–1.15

aHazard ratios are based on unstratified analysesNE, not estimable.

39 34 32 31 28 27 22 17 14 10 8 6 4 3 2 0 0 0 0Lap + Cap (Mutated)

87 83 77 74 68 66 57 44 38 32 28 26 20 14 11 6 4 3 2Lap + Cap (Wild type)

40 40 40 40 38 37 36 34 27 25 21 14 12 7 4 4 3 2 2T-DM1 (Mutated)

93 91 89 86 82 78 69 52 44 37 30 27 21 17 12 7 5 3 2T-DM1 (Wild type)

Time (months)

Lap + Cap (PIK3CA mutated)Lap + Cap (PIK3CA wild type)T-DM1 (PIK3CA mutated)T-DM1 (PIK3CA wild type)

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

No. at risk:

EMILIA Biomarker Analysis:

OS by PIK3CA Mutation Status and Treatment Arm

Outline

HISTORY – 30 YEARS IN THE MAKING

Milestones in the Management of HER2-positive MBCOverall Survival

Verma et. al The Oncologist 2013Abbreviations: Ana, anastrozole; Cape, capecitabine; CT, chemotherapy; Doc, docetaxel; Lap, lapatinib; Let, letrozole; OS, overall survival; Pac, paclitaxel; Pert, pertuzumab; T-DM1, trastuzumab emtansine; Tras, trastuzumab.

First Line

Second

Line +

An Algorithm to Manage Her 2 positive MBC

Verma et. al The Oncologist 2013

An Algorithm to Manage Her 2 positive MBC

Is there still activity of Trastuzumab/Lapatini

b post T-DM1?

Can we consider

Pertuzumabfor DFI 6m-

1year?

Can we consider another taxane with

P + H?

Verma et. al The Oncologist 2013

Beyond Breast Cancer

Development of Targeted Therapy

2000 2020201520102005

Conclusion

Raising the Bar

• The outcome of patients with Her 2 positive

breast cancer has significantly improved in the

past two decades

• Novel targeted drugs are improving survival and

reducing toxicity for patients with advanced

breast cancer

• The future looks quite bright as we can now

envision a total targeted approach for some of

these patients…..and an overall survival in

excess of five years for some of our patients!

advances in the management of metastatic her 2 positive breast...

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