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Recent Update in Management of Breast Cancer:

Medical Oncology

Jin Hee Ahn, M.D., PhD.

23-April-2015

Department of Oncology, Asan Medical Center, UUCM, Seoul, Korea

2015 GBCC & 4th IBCS 1/37

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ER-positive breast cancer

Endocrine therapy…. and its potential new friends?

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Combining targeted and antiestrogen therapies in HR positive breast cancer

PI3K

AKT

PTEN

mTOR

RAS

RAF

MEK

MAPK

ER target gene transcription

P P

EGFR HER2

E

E

ER

E ER

E

ER

E

TKI

mTOR Inhibitors Everolimus Sirolimus Temsirolimus

Aromatase Inhibitor Nonsteroidal AIs

Anastrozole Letrozole

Steroidal AIs Exemestane

Selective Estrogen Receptor Modulators Tamoxifen Toremifene

ER Downregulator Fulvestrant

HDAC Inhibitor Entinostat

CDK 4/6 Inhibitor Palbociclib LEE011 LY2835219

Cell Cycle

Transcription Silencing

PI3K inhibitor BKM 120 GDC-0941 BYL 719

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BOLERO-2: Everolimus + Exemestaine increase the PFS & OS of ER+ HER2- MBC

Baselga J et al. NEJM 2012, 366: 520-529, Adv Ther 2013, 30: 870-84

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Phase II Randomized study: ER +, HER2 – MBC (1st line)

Primary endpoint: PFS

PALOMA-1 Trial

“Palbociclib”

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PALOMA1 trial: palbociclib + letrozole vs. letrozole median F/U: 29.6 mo

Finn RS et al. Lancet Oncol 2015; 16: 25

Median PFS: 10.2 vs. 20.2 months

(HR 0.488, 95% CI 0.319-0.748,P=0.0004)

Progression-Free Survival Overall Survival

Palbociclib + Letrozole

Letrozole

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Most common Treatment-Related AEs 10%

Palbociclib+ Letrozole (N=83) Letrozole (N=77)

Gr ½ (%) Gr 3 (%) Gr 4 (%) Gr ½ (%) Gr 3 (%) Gr 4 (%)

Neutropenia 19 48 6 1 1 0

Leukopenia 23 18 0 0 0 0

Anemia 23 4 1 0 0 0

Fatigue 22 2 0 14 0 0

Alopecia 22 0 0 3 0 0

Hot flush 18 0 0 10 0 0

Arthralgia 17 0 0 9 1 0

Thrombo-cytopenia

14 2 0 0 0 0

Nausea 14 1 0 1 0 0

Decreased appetite

8 1 0 0 0 0

Stomatitis 10 0 0 0 0 0

• Neutropenia was self-limited and not associated with infectious complications

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Timeline of approval of agents for HR-positive advanced breast cancer

Palbociclib (CDK 4/6 inhibitor)

(2015)

2015

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The PI3K/AKT/mTOR Pathway in Breast Cancer: Common Molecular Alterations

~40% of HR + breast cancer have PIK3CA mutations

Baselga J. Oncologist 2011; 16: Suppl 1: 12 Endocrine Rev. 2008; 29: 217-33.

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HER2-positive breast cancer

New standard treatment for HER+ MBC

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Molecular approaches to HER2 targeted therapy

Singh JC et al. BJC 2014, 111: 1888

1998

2005

2012 2013

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CLEOPATRA: Phase III trial of trastuzumab plus pertuzumab in the first-line setting

Baselga J et al. NEJM 2012; 366: 109

Study dosing q 3 week -Pertuzumab/placebo: 840 mg loading 420 mg maintenance -Trastuzumab: 8 mg/kg loading 6 mg/kg maintenance -Docetaxel: 75 mg/m2 100 mg/m2 escalation if tolerated

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CLEOPATRA: Phase III trial of trastuzumab plus pertuzumab in the first-line setting

Baselga J et al. NEJM 2012; 366: 109

PFS

Median follow-up period: 19.3 months

OS

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Swain et al, ESMO 2014, NEJM 2015; 372: 724-734

CLEOPATRA: Final OS Analysis (median f/u 50 months)

Median OS 56.5 vs. 40.8 months Difference: 15.7 months

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T-DM1 selectively delivers DM1 to HER2-positive tumor cells

LoRusso PM et al. Clin Cancer Res 2011

Antibody-drug conjugate: T-DM1

Highly potent DM1 is internalized within HER2+ cancer cells

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EMILIA study: Phase III trial of T-DM1 vs. Lapatinib+capecitabine after trastuzumab in HER2+ MBC

Sunil Verma et al. NEJM 2012; 367: 1783

• Primary end points: PFS by independent review, OS, and safety

• Secondary end points: PFS by investigator, ORR, duration of response,

time to symptom progression

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EMILIA study: Progression-Free Survival

Sunil Verma et al. NEJM 2012; 367: 1783

3.2 months

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EMILIA study: Overall survival

Sunil Verma et al. NEJM 2012; 367: 1783

OS = 5.8 months

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Cap + Lap

(n=488)

T-DM1

(n=490)

All-grade AE, n (%) 477 (97.7) 470 (95.9)

Grade ≥3 AE, n (%) 278 (57.0) 200 (40.8)

AEs leading to treatment discontinuation (for any

study drug), n (%)

52 (10.7)

29 (5.9)

AEs leading to death on treatment, n (%) 5 (1.0) 1 (0.2)

LVEF <50% and ≥15-point decrease from

baseline, %

7 (1.6)

8 (1.7)

EMILIA study: Adverse Events in the Safety Population

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TH3RESA Study Schema

• Co-primary end points: PFS by investigator and OS

• Secondary end points: ORR by investigator and safety

Krop IE et al, Lancet Oncol 2014, 15: 689-699

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TH3RESA Study: PFS

Krop IE et al, Lancet Oncol 2014, 15: 689-699

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TH3RESA Study: First Interim Analysis of OS

Krop IE et al, Lancet Oncol 2014, 15: 689-699

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Current ASCO guidelines

HER2 MBC

ER-/ER+ ER+

Taxane/trastuzumab/pertuzumab

Ado Trastuzumab Emtansine (T-DM1)

Lapatinib/Capecitabine Trastuzumab/Capecitabine Trastuzumab/Lapatinib Trastuzumab/Chemotherapy T-DM1 if not received earlier Pertuzumab if not received earlier

Letrozole +/- Lapatinib AI or tamoxifen +/- Trastuzumab

ER guidelines

* No OS advantage with hormone therapy plus anti-HERE2 therapy

Giordano et al. JCO 2014 (ASCO Guidelines)

(e.g. asymptomatic, low burden disease, patients at increased risk of toxicity from chemotherapy)

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Can resistance to anti-HER2 agents be overcome or modulated?

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Triple Negative Breast Cancer (TNBC)

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Molecular Heterogeneities of TNBC

Lehmann BD et al. J Clin Invest 2011, 121: 2750

SUBGROUPS

Basal-like 1

Basal-like 2

Immunomodulatory

Mesenchymal-like

Mesenchymal stem-like

Luminal AR

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Mayer et al. CCR 2014, 20: 782 BCRT 2011; 125: 627

Schematic illustration of overlap among TNBC, basal-like, and BRCA1-related tumors

(80%)

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How to Target Advanced TNBC ?

Impaired repair of DNA (Homologous Recombination Deficiency) * BRCA dysfunction

Methylation Somatic mutation Other epigenetic mechanisms

Blood vessel growth

Increased sensitivity to platinum chemotherapy ? PARP inhibitors?

Role of angiogenesis Inhibitors (Bevacizumab)?

High growth rate Increased sensitivity to chemotherapy ?

* DFCI 2014

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Platinum in unselected TNBC

Regimen N Overall RR PFS (mo) Dz-free-interval

(median)

Gemcitabine/

carboplatin1

1st line

2nd/3rd line

258

148

110

30% 4.1

4.6

2.9

15 months

15.9 months

13.8 months

Carboplatin or

cisplatin2

1st line / 2nd line

86 30%

32% / 20%

3.2 NA

1. ASCO 2011 (abstr) 2. ASCO 2011 (abstr)

ORR in BRCA ½ mutant 55% vs.

26% in BRCA ½ wild type

Highlights need for biomarkers of platinum response

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TNT: Carboplatin vs Docetaxel in Advanced TNBC or BRCA1/2+ BC

• Primary endpoint: ORR in ITT population

• Secondary endpoints: PFS, OS, ORR (crossover), toxicity

• Subgroup analyses: BRCA1/2 mutation, basal-like subgroups, HRD biomarkers

Tutt A, et al. SABCS 2014. Abstract S3-01.

Patients with ER-, PgR-/

unknown, and HER2- or

BRCA1/2+ metastatic or

recurrent LA BC

(N = 376)

Carboplatin AUC6 q3w

x 6 cycles (n = 188)

Docetaxel 100 mg/m2 q3w

x 6 cycles ( n = 188)

For both arms, crossover upon progression allowed

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TNT trial: Overall Response Rate

0

10

20

30

40

50

60

70

80

90

Resp

on

se a

t C

ycle

3 o

r 6 (

%)

All Pts (n = 376)

BRCA1/2 Mutation (n = 43)

No BRCA1/2 Mutation (n = 273)

31.4% 35.6%

P = .44

68.0%

33.3%

P = .03

28.1%

36.6%

P = .16

Carboplatin

Docetaxel

Crossover

Tutt A, et al. SABCS 2014. Abstract S3-01.

Survival, Mos Carboplatin Docetaxel

Median PFS 3.1 4.5

BRCA 1/2 mutated 6.8 4.8

BRCA 1/2 not mutated 3.1 4.6

Median OS 12.4 12.3

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A new modality for breast cancer? Immune checkpoint agents and immunomodulators

Pembrolizumab (Keytruda) [Anti PD-1 therapy]

• High affinity for the PD-1 receptor • Recently approved in the US for the pts with unresectable or metastatic melanoma

T-cell Targets for Immunotherapy

Mellman I et al. Nature 2011; 480

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Phase Ib KEYNOTE-012:

Pembrolizumab Holds Promise in TNBC, Early Studies Suggest

Pts with recurrent or metastatic ER/

PgR-/HER2-, PD-L1+ BC (N = 32)

Pembrolizumab

10 mg/kg q2w

Nanda R, et al. SABCS 2014. Abstract S1-09.

Individual Evaluable Pts

Confirmed CR (nodal disease)

Confirmed PR

SD

PD

100

80

60

40

20

0

-20

-40

-60

-80

-100 Ch

an

ge F

rom

Baselin

e i

n S

um

of

Lo

ng

est

Dia

mete

r o

f Targ

et

Lesio

n (

%)

Overall Response rate: 18.5% (5/27)

Stable disease: 25.9% (7/27)

Progressive disease: 44.4% (12/27)

3 responding pts on treatment for > 11 mos

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TNBC: Current and Future Potential Therapeutic Targets 36/37

Recent update of systemic therapy: SUMMARY

• ER + MBC

– mTOR inhibitor or CDK4/6 inhibitor with endocrine therapy to overcome endocrine

resistance

• HER2 + MBC

– Pertuzumab and T-DM1 lead to improved outcomes with favorable toxicity.

• TNBC

– Recent renewed interest in investigating the role of platinum in TNBC.

– BRCA 1/2 mutation status: important potential biomarker for platinum therapy.

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Thank you for your attention!

CDK 4 and 6 inhibitor

• Oral, highly selective inhibitor of CDK4/6 kinase

• Prevent cellular DNA synthesis by prohibiting progression

of the cell cycle from G1 to S phase

HER2 dimerization is essential for HER2 activity: Pertuzumab and trastuzumab bind to different regions

on HER2 and have synergistic activity

trastuzumab

Pertuzumab

More complete blockade of HER2 signal transduction

TIL (tumor infiltrating lymphocyte)

Higher levels in TNBC

Higher level of TIL = better survival in TNBC

Loi et al. JCO 2013

Lymphocyte-predominant BC

Pembrolizumab in Advanced TNBC : Toxicity

Nanda R, et al. SABCS 2014. Abstract S1-09.

Adverse Events in ≥ 5%, % N = 32

Any Grade Grade 3-5

Arthralgia 18.8 0

Fatigue 18.8 0

Myalgia 15.6 0

Nausea 15.6 0

ALT increased 6.3 0

AST increased 6.3 0

Diarrhea 6.3 0

Erythema 6.3 0

Headache 6.3 3.1 (1 patient)

Cross-talk between signal transduction and endocrine pathways

Endocrine Rev. 2008; 29: 217-33.

HER2 targeted therapy adds modestly to endocrine therapy

PFS Anastrozole + Trastuzumab > Anastrozole

Kaufman et al, JCO 2008

PFS Letrozole + Lapatinib > Letrozole

Johnston et al, JCO 2009

Addition of HER2-directed therapy improves PFS but not OS

Choice of Chemotherapy in TNBC

• HR deficiency characterizes breast cancers in BRCA 1/2 mutation carriers

– Due to loss of heterozygosity

at BRCA1 or BRCA2

• HR deficiency implicated in some sporadic TNBC

– Methylation

– Somatic mutation

– Other epigenetic mechanisms

Breast Cancer Genome Sequencing Results

Ellis MJ et al. Nature 2012; 486: 353

The genome wheels show point mutations, copy number changes, and chromosomal Translocations in aromatase inhibitor (AI) sensitive and AI-resistant breast cancers.

PI3K inhibitors in clinical development

SABCS 2014

Phase III trial: MARIANNE 1st line HER2+ MBC

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