Malattia triplo negativa

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Dr. Matteo Lambertini

U.O. Oncologia Medica 2

IRCCS AOU San Martino – IST, Genova

NOVITA’ SUL TRATTAMENTO DEL CARCINOMA MAMMARIO:

MALATTIA TRIPLO NEGATIVA

SUPERNOVAE IN ONCOLOGIA

Pisa, 14 novembre 2015

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• Introduction

• Neoadjuvant therapy

• Adjuvant therapy

• Therapy for metastatic disease

• Future perspectives

AGENDA

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• Introduction

• Neoadjuvant therapy

• Adjuvant therapy

• Therapy for metastatic disease

• Future perspectives

AGENDA

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Triple-Negative Breast Cancer (TNBC)

• TNBC lacks expression of ER (<1%), PgR (<1%) and HER2

• TNBC comprises approximately 15% of incident breast cancers

• Each year in the US alone out of 235,000 new cases 35,000 are TNBC

Vast majority are candidates for adjuvant or neoadjuvant therapy

Responsible for high degree of brest cancer mortality

Coates AS et al, Ann Oncol 2015; 26:1533-46. Brewster AM et al, Lancet Oncol 2014; 15:e625-34. www.seer.cancer.gov

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• TNBC is associated with African American ethnicity, younger age, frequently “interval tumors”, advanced stage at diagnosis and poorer outcome when compared with other BC subtypes.

• Possible etiologic heterogeneity: protective effect of breastfeeding.

• BRCA mutations in nearly 20% of TNBC patients (vs 5% in non- TNBC): 16% BRCA1 & 4% BRCA2.

• TNBC is characterised by high cell proliferation, poor cellular differentiation, many recurrent copy number imbalances, and mutations in the TP53.

Brewster AM et al, Lancet Oncol 2014; 15:e625-34. Islami F et al, Ann Oncol 2015 [Epub ahead of print]

Triple-Negative Breast Cancer (TNBC)

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Triple-Negative Breast Cancer (TNBC)

Oakman C et al, The Breast 2010; 19:312-21

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• Introduction

• Neoadjuvant therapy

• Adjuvant therapy

• Therapy for metastatic disease

• Future perspectives

AGENDA

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pCR and TNBC

Cortazar P et al, Lancet 2014; 384:164-72

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pCR and TNBC

Cortazar P et al, Lancet 2014; 384:164-72

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Slide 14

Breast-Conserving Surgery and TNBC

Golsham M et al, Ann Surg 2015; 262:434-9

BCS successful: 94% BCS successful: 91%

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Breast-Conserving Surgery and TNBC

Golsham M et al, Ann Surg 2015; 262:434-9

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Platinum Salts and NACT in TNBC

Von Minckwitz G et al, Lancet Oncol 2014; 15:747-56 Her2-pos: Trastuzumab 6(8) mg/kg q3w (for 1 year)

+ Lapatinib 750 mg/d 18 wks

TNBC: Bevacizumab 15 mg/kg q3w

Sur ger y

Non-pegylated liposomal doxorubicin

20 mg/m² q1w

Paclitaxel 80 mg/m² q1w Carboplatin AUC 1.5* q1w

*reduced from AUC 2 at amendment 1 after enrolment of 330 patients

R

N=595 centrally confirmed TNBC

or

HER2-positive breast cancer

PM

PMCb

GeparSixto (GBG 66) phase II study

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Platinum Salts and NACT in TNBC

Von Minckwitz G et al, Lancet Oncol 2014; 15:747-56

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Platinum Salts and NACT in TNBC

315 patients (53.6%)

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Platinum Salts and NACT in TNBC

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Platinum Salts and NACT in TNBC

Von Minckwitz G et al, ASCO Annual Meeting 2015

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Platinum Salts and NACT in TNBC

Sikov WM et al, J Clin Oncol 2015; 33:13-21

CALGB 40603 (Alliance) phase II study

Clinical Stage II-III

TNBC (n=443)

Primary endpoint: pathologic complete response (pCR) breast and breast + axilla

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Platinum Salts and NACT in TNBC

pCR breast=ypT0/is pCR breast/axilla=ypT0/is N0

Sikov WM et al, J Clin Oncol 2015; 33:13-21

CALGB 40603 (Alliance) phase II study

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Platinum Salts and NACT in TNBC

Von Minckwitz G et al, Lancet Oncol 2014; 15:747-56. Sikov WM et al, J Clin Oncol 2015; 33:13-21

Rates of pCR (ypT0 pN0)

with NACT with carboplatin in TNBC

Study No.

Patients

Standard CT

Standard CT +

carboplatin GeparSixto

wP+lipo doxo

315 37% 53%

CALGB 40603 wPddAC

443 41% 54%

15% absolute difference

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Nab-Paclitaxel and NACT in TNBC

Untch M et al, San Antonio Breast Cancer Symposium 2014

Out of 1204 patients enrolled, 275 (22.8%) had TNBC

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Nab-Paclitaxel and NACT in TNBC

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Nab-Paclitaxel and NACT in TNBC

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• Introduction

• Neoadjuvant therapy

• Adjuvant therapy

• Therapy for metastatic disease

• Future perspectives

AGENDA

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Benefit of Adjuvant CT in TNBC

Vaz-Luis I et al, J Clin Oncol 2014; 32:2142-50

Prospective cohort study NCCN database (4,113 patients):

T1a,b N0 tumors treated between 2000 and 2009

In TNBC (n=168 patients):

5-year DRFS pT1a: 93%

5-year DRFS pT1b: 90%

In TNBC (n=195 patients):

5-year DRFS pT1a: 100%

5-year DRFS pT1b: 96%

Distant Relapse-Free Survival

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Adjuvant CT in TNBC

Coates AS et al, Ann Oncol 2015; 26:1533-46

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Impact of Adjuvant CT in TNBC

Cossetti RJD et al, J Clin Oncol 2015; 33:65-73

British Columbia Cancer Agency stage I-III BC (7,178 patients):

a total of 1,132 (15.8%) patients with ER neg and HER2 neg BC

Cohort 1: 1986 - 1994 Cohort 2: 2004 - 2008

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Adjuvant Taxanes in TNBC

Sparano JA et al, N Engl J Med 2008; 358:1663-71. Sparano JA et al, J Clin Oncol 2015; 33:65-73

Invasive breast carcinoma (N= 4,950 pts)

- Radical surgery;

- N pos or high risk N neg;

- No distant metastasis.

1:1:1:1 AC x 4  P x 4 Q3 w

AC x 4  wD x 12

Primary endpoint: disease-free survival (DFS) AC x 4  wP x 12

AC x 4  D x 4 Q3 w

P vs D wT vs Q3T

E1199 Phase III Study

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Adjuvant Taxanes in TNBC

Sparano JA et al, N Engl J Med 2008; 358:1663-71. Sparano JA et al, J Clin Oncol 2015; 33:65-73

E1199 Phase III Study: 1,025 patients with TNBC

p=0.010

p=0.019

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Del Mastro L et al, Lancet 2015; 385:1863-72

Invasive breast carcinoma (N= 2,091 pts)

- Radical surgery;

- ≥ 1 pos nodes;

- No supraclavicolar nodes;

- No IBC, no stage IV.

1:1:1:1 EC x 4  T x 4 Q3 w

FEC x 4  T x 4 Q2 w

Primary endpoint: disease-free survival (DFS)

FEC x 4  T x 4 Q3 w

EC x 4  T x 4 Q2 w

EC vs FEC Q2 vs Q3

Adjuvant DD Chemotherapy in TNBC

GIM2 Phase III Study

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Adjuvant DD Chemotherapy in TNBC

GIM2 Phase III Study

EC vs FEC

Q2 vs Q3

DFS OS

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Adjuvant DD Chemotherapy in TNBC

GIM2 Phase III Study: 335 patients with HR negative BC

Disease-free survival:

Q2 (dose-dense) vs Q3 (standard duration)

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Budd GT et al, J Clin Oncol 2015; 33:58-64

Invasive breast carcinoma (N= 2,716 pts)

- Radical surgery;

- N pos or high risk N neg;

- No distant metastasis.

1:1:1:1

AC Q2 x 6  P Q2 x 6

wAC x 15  wP x 12

Primary endpoint: disease-free survival (DFS) wAC x 15  P Q2 x 6

AC Q2 x 6  wP x 12

DD AC vs wAC DD P vs wP

Adjuvant DD Chemotherapy in TNBC

SWOG S0221 Phase III Study

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Budd GT et al, J Clin Oncol 2015; 33:58-64

Adjuvant DD Chemotherapy in TNBC

SWOG S0221 Phase III Study: 680 patients with TNBC

Disease-free survival

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LINEE GUIDA AIOM 2015

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Adjuvant Ixabepilone in TNBC

Yardley DA et al, ASCO Annual Meeting 2015

609 patients

TITAN Phase III Study

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Adjuvant Ixabepilone in TNBC

Yardley DA et al, ASCO Annual Meeting 2015

Disease-Free Survival

Overall Survival

TITAN Phase III Study

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Cameron D et al, Lancet Oncol 2013; 14:933-42

Adjuvant Bevacizumab in TNBC

BEATRICE Phase III Study

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Cameron D et al, Lancet Oncol 2013; 14:933-42

Adjuvant Bevacizumab in TNBC

BEATRICE Phase III Study

Disease-Free Survival

Overall Survival

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Maintenance Adjuvant CT in TNBC

Colleoni M et al, ASCO Annual Meeting 2015

IBCSG 22-00 Phase III Study

C: 50 mg/day continuously M: 2.5 mg twice/day 1,2 week

75% TNBC

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Maintenance Adjuvant CT in TNBC

IBCSG 22-00 Phase III Study

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Maintenance Adjuvant CT in TNBC

IBCSG 22-00 Phase III Study

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• Introduction

• Neoadjuvant therapy

• Adjuvant therapy

• Therapy for metastatic disease

• Future perspectives

AGENDA

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Lines of Treatment in TNBC

Seah DSE et al, J Natl Compr Canc Netw 2014; 12:71-80

Dana-Farber Cancer Institute experience:

199 patients between 2004 and 2007, 44 with TNBC

Number of lines of chemotherapy Overall survival

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1 ^st Line Therapy: Platinum Salts

Hu XC et al, Lancet Oncol 2015; 16:436-46

Metastatic TNBC breast cancer (N=236pts)

- Chinese patients

- No prior therapy for advanced disease - ER and PR ≤ 10% and HER2 negative - Prior adjuvant taxanes allowed (> 6

months before study entry)

1:1

Cisplatin (75 mg/m

²

g1 q 21) + Gemcitabine (1250mg/m

²

g1,8 q 21)

Paclitaxel (175 mg/m

²

g1 q 21) + Gemcitabine (1250mg/m

²

g1,8 q 21)

Primary endpoints: progression-free survival (PFS)

1. To test non-inferiority of cisplatin plus gemcitabine compared with paclitaxel plus gemcitabine 2. If achieved, to test superiority of cisplatin plus gemcitabine compared with paclitaxel plus gemcitabine

CBCSG006 Trial

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1 ^st Line Therapy: Platinum Salts

Hu XC et al, Lancet Oncol 2015; 16:436-46

CBCSG006 Trial

Progression-Free Survival

Cisplatin: 7.73 months (95% CI, 6.16 – 9.30)

Paclitaxel: 6.47 months (95% CI, 5.76 – 7.18)

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1 ^st Line Therapy: Platinum Salts

Tutt A et al, San Antonio Breast Cancer Symposium 2014

TNT Trial: CRUK/07/012

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1 ^st Line Therapy: Platinum Salts

TNT Trial: CRUK/07/012

Progression-Free Survival Overall Survival

Objective Response Rate

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1 ^st Line Therapy: Platinum Salts

TNT Trial: CRUK/07/012

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1 ^st Line Therapy: Platinum Salts

TNT Trial: CRUK/07/012

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1 ^st and 2 ^nd Line Therapy: Platinum Salts

Isakoff SJ et al, J Clin Oncol 2015; 33:1902-9

TBCRC009 Trial

High Homologous Recombination and mutations:

BRCA mutant vs BRCA wild type

High Homologous Recombination and responses:

Responders vs Non responders

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2 ^nd Line Therapy: Eribulin

Kaufman PA et al, J Clin Oncol 2015; 33:594-602

Metastatic breast cancer (N= 1,102 pts)

- Prior anthracycline- and taxane-based therapy

- ≤ 3 lines of therapy (≤ 2 lines of therapy for advanced disease)

- No anti-HER2 agents if HER2 positive

1:1

Eribulin

1.4 mg/m

²

g1,8 q 21

Capecitabine

1,250 mg/m

²

BID g1-14 q 21

Primary endpoints: progression-free survival (PFS) and overall survival (OS)

NCT00337103 Phase III Study

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2 ^nd Line Therapy: Eribulin

Kaufman PA et al, J Clin Oncol 2015; 33:594-602

NCT00337103 Phase III Study

Overall Survival Progression-Free Survival

Overall Survival Subgroup Analysis

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• Introduction

• Neoadjuvant therapy

• Adjuvant therapy

• Therapy for metastatic disease

• Future perspectives

AGENDA

(57)

• The Heterogeneity of TNBC

• BRCA and PARP-I

• Endocrine therapy

• Immunotherapy

Future perspectives

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• The Heterogeneity of TNBC

• BRCA and PARP-I

• Endocrine therapy

• Immunotherapy

Future perspectives

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Subtype Gene expression profile Clinical

Basal-like 1 high Ki-67; DNA damage response BRCA-associated

Basal-like 2 GF pathways Higher pCR

Immunomodulatory Immune genes

Mesenchymal Cell motility Lower DDFS Mesenchymal stem-like Cell motility; claudin-low

Luminal androgen receptor Steroid pathways Apocrine features, higher LRF; PI3Kmut

The Heterogeneity of TNBC

Lehman BD et al, J Clin Invest 2011; 121:2750-67

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Subtype Gene Ontology IHC analysis Hysto type Possible sensitivity Basal-like 1 Cell cycle and cell

division

DNA damage response

High Ki67 -- Cisplatin

PARP-Inhibitors

Basal-like 2 Growth gactor signaling (EGFR, MET)

-- Medullary Anti-EGFR

Immuno- modulatory

Immune cell processes -- -- Immunotherapy?

Mesenchymal-like Cell motility and cell differentation (TGF-β, Src); GF patways

--

Metaplastic

PI3K-mTOR Inh (BEZ235)

Src-Inhibitors (Dasatinib) Mesenchymal

Stem-like

Angiogenesis

Low levels prolif genes Claudin-low

-- Anti-angio

Luminal AR Hormonally regulated pathways

AR + Molecular

Apocrine

AR antagonist

Courtesy of M. De Laurentiis

The Heterogeneity of TNBC

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• The Heterogeneity of TNBC

• BRCA and PARP-I

• Endocrine therapy

• Immunotherapy

Future perspectives

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BRCA and PARP-I

O’Shaughnessy J et al, N Engl J Med 2011; 364:205-14. O’Shaughnessy J et al, J Clin Oncol 2014; 32 …….

Overall Survival

Iniparib in Unselected TNBC

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BRCA and PARP-I

The Proof-of-Concept Trial:

Olaparib in BRCA1 and BRCA2 mutant BC (54% were TNBC)

Tutt A et al, Lancet 2010; 376: 235-44

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Livraghi L et al, BMC Med 2015; 13:188

Ongoing phase II and III studies

BRCA and PARP-I

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• The Heterogeneity of TNBC

• BRCA and PARP-I

• Endocrine therapy

• Immunotherapy

Future perspectives

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Endocrine Therapy

Gasparini P et al, PLOS One 2014; 9:e88525. Loibl S et al, Breast Cancer Res Treat 2011; 130:477-87. Proverbs-Singh T et al, Endocr Rel Cancer 2015; 22:R87-R106. Tung N et al, ASCO Annual Meeting 2015 (abstract 1005)

• Present in 10-30% (1-10% cut off)

• Better survival

• Expressed in older patients, lower grade tumors (G1-G2), higher PD-L1 expression

• Rare co-expression in patients with BRCA-mutation

Androgen Receptor in TNBC

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Endocrine Therapy

Gucalp A et al, Cancer Res 2013; 19:5505-12

TBCRC 011 phase II study

Bicalutamide 150 mg daily

IHC:

AR > 10%

12%

CBR = 19%

(95% CI, 7% - 39%)

PFS = 12 weeks

(95% CI, 11 - 22)

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Endocrine Therapy

Cortes J et al, ESMO-ECCO Annual Meeting 2015

MDV 3100-11 phase II study

Metastatic breast cancer (N= 118 pts)

- AR + (≥ 1% positive cells) advanced TNBC - Any number of prior therapies

- No brain metastasis

- Sufficient tissue available for biomarker discovery

Enzalutamide 160 mg/day

Stage 1

≥ 3 of 26 Evaluable have CBR16

“Go” to Stage 2

Stage 2

≥ 9 of 62 Evaluable have CBR16 Rejection of H₀

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0 80

40

20

PREDICT AR−

mOS 32.3 weeks (95% CI: 20.7, 48.3)

PREDICT AR+

mOS 75.6 weeks (95% CI: 51.6, 91.4)

0 8 16 24 33 41 49 61 64

Weeks

100

60

Overall Survival (%)

85

ITT Population

PREDICT AR+ mOS 18.0 months PREDICT AR – mOS 7.5 months

Endocrine Therapy

MDV 3100-11 phase II study

Cortes J et al, ESMO-ECCO Annual Meeting 2015

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Ongoing studies in breast cancer

Endocrine Therapy

Proverbs-Singh T et al, Endocr Rel Cancer 2015; 22:R87-R106

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• The Heterogeneity of TNBC

• BRCA and PARP-I

• Endocrine therapy

• Immunotherapy

Future perspectives

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Immunotherapy

Adams S et al, J Clin Oncol 2014; 32:2959-66. Dieci MV et al, Ann Oncol 2014; 25:611-8. Denkert C et al, J Clin Oncol 2015;

33:983-91. Dieci MV et al, Ann Oncol 2015; 26:1698-704. Salgado R et al, Ann Oncol 2015; 26:259-71. Sabatier R et al, Oncotarget 2015; 6:5449-64. Tung N et al, ASCO Annual Meeting 2015 (abstract 1005)

• Tumor Infiltrating Lymphocites (TIL):

 prognostic role in early stage TNBC and in patients with residual disease after neoadjuvant chemotherapy

 predictors of pCR after neaodjuvant chemotherapy (mainly in TNBC and HER2+)

• PD-L1 expression:

 Approximately 20-60% of TNBC

 Associated with: TIL, increased immune response genes and activation of immune pathways, AR+, no LVI

• Anti-PD-1 and anti-PD-L1 Abs break the immune tolerance at the tumor site leading to a lasting clinical benefit

The role of Immunity in TNBC

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Immunotherapy

Nanda R et al, San Antonio Breast Cancer Symposium 2014

• Recurrent or metastatic ER^– /PR^–/HER2^– breast cancer

• ECOG PS 0-1

• PD-L1⁺ tumor^a

• No systemic steroid therapy

• No autoimmune disease (active or history of)

• No active brain metastases

Pembro 10 mg/kg Q2W

Complete Response

Partial Response or Stable Disease

Confirmed

Progressive Disease^b

Discontinuation Permitted

Treat for 24 months or until progression or intolerable

toxicity

Discontinue

Phase Ib study of pembrolizumab (anti-PD-1) in TNBC

Patients Evaluable for Response^a

n = 27 Overall response rate 5 (18.5%) Best overall response

Complete response^b 1 (3.7%) Partial response^b 4 (14.8%) Stable disease 7 (25.9%) Progressive disease 12 (44.4%) No assessment^c 3 (11.1%)

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Immunotherapy

Phase Ia study of MPDL3280A (atezolimumab, anti-PD-L1)

Efficacy evaluable population with TNBC treated with MPDL3280A q 3 weeks:

n=21 patients

• PD-L1+ at IHC (2/3)

• ORR=19% (2 CR and 2 PR)

• Median duration of response not reached: 18-56 weeks

• PFS at 24 weeks: 27%

Emens AL et al, AACR Annual Meeting 2015

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Immunotherapy

Ongoing studies in breast cancer

TRIAL DRUG TARGET SETTING

PANACEA Pembrolizumab PD-1 Metastatic HER2+ BC

MK-3475 for Metastatic Inflammatory Breast Cancer (MIBC)

Pembrolizumab PD-1 Metastatic inflammatory BC

PLX3397 and Pembrolizumab in Advanced Melanoma and Other Solid Tumors

Pembrolizumab PD-1 Metastatic TNBC

MK-3475-012/KEYNOTE-012 in triple-negative breast cancer and head and neck cancer

Pembrolizumab PD-1 Metastatic TNBC

Safety study of nivolumab with Nab-Paclitaxel plus or minus Gemcitabine in Pancreatic Cancer, nab-

paclitaxel/carboplatin in stage IIIB/IV Non-Small Cell Lung Cancer or nab-paclitaxel in recurrent metastatic breast cancer

Nivolumab PD-1 Recurrent Metastatic BC

PDR001 in Patients With Advanced Malignancies PDR001 PD-1 Metastatic TNBC

RADVAX Pembrolizumab +

hypofractionated RT

PD-1 Metastatic BC

TONIC study (nivolumab after induction therapy for triple-negative breast cancer)

Nivolumab PD-1 Metastatic TNBC

JAVELIN Avelumab PD-L1 Metastatic BC

IMpassion130 (in combination with nab-paclitaxel) Atezolimumab PD-L1 Untreated metastatic TNBC

From: ClinicalTrials.gov. Courtesy of C. Solinas

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Conclusions

• TNBC is heterogeneous

• Chemotherapy is mainstay and (at the moment) in unselected TNBC is the same as for other subtype

 Neoadjuvant: platinum salts and nab-paclitaxel?

 Adjuvant: dose-dense chemotherapy

 Metastatic setting:

1

^st

line: taxanes (+/- bevacizumab) – platinum salts

2

^nd

line: eribulin – platinum salts

• BRCA associated TNBC may be different: PARP-I and platinum salts to be considered. In all settings?

• Personalized therapy approaches: near future?

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