La malattia triplo negativa: quali trattamenti nella pratica clinica?

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Roma, 27 Ottobre 2018 Relatore: Francesca Poggio

La malattia triplo negativa metastatica:

quali trattamenti nella pratica clinica?

2018 CARCINOMA MAMMARIO: I TRAGUARDI RAGGIUNTI E LE NUOVE SFIDE

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Disclosure Information

Relationship Relevant to this Session

Poggio, Francesca:

No relevant relationship to disclose.

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• Introduction

• Chemotherapy

• PARPi

• Immunotherapy

• Endocrine therapy

• Conclusions

Agenda

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Triple-Negative Breast Cancer (TNBC)

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

• TNBC comprises approximately 15-20% of all breast cancers in the US

• BRCA mutations in nearly 20% of TNBC patients (vs 5%

in non-TNBC): 16% BRCA1 & 4% BRCA2

Coates AS et al, Ann Oncol 2015. Brewster AM et al, Lancet Oncol 2014. Brewster AM et al, Lancet Oncol 2014..

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Triple-Negative Breast Cancer (TNBC)

• Triple negative paradox aggressive clinical course, but high sensitivity to cytotoxic treatment

• Patients with metastatic TNBC experience poor

outcomes relative to patients with other breast cancer subtypes, with a median OS of ≈ 18 months or less

Gobbini EJC 2018. Carey LA et al, Clin Cancer Res 2007.

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Subtype Gene expression profile Possible sensitivity

Basal-like 1 high Ki-67; DNA damage response Platinum, PARPi

Basal-like 2 GF pathways AntiEGFR

Immuno-modulatory Immune genes Immunotherapy

Mesenchymal Cell motility PIK3i

Mesenchymal stem-like Cell motility; claudin-low Anti-angio Luminal androgen receptor Steroid pathways AR antagonist

The Heterogeneity of TNBC

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• Introduction

• Chemotherapy

• PARPi

• Immunotherapy

• Endocrine therapy

• Conclusions

Agenda

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Cardoso F et al, Ann Oncol 2018

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Regimen Inv Ass PFS (m) ORR (%) (Measurable)

Ref

Capecitabine 6.2 -

^Robert,JCO 2011

Paclitaxel 9.1 -

^Miles,EJC 2017

Tax/Anthra 8.2 -

Cape + Beva 9.2 -

Cape + Beva 8.8 -

^Welt,BCRT 2016

Cape + Beva (high risk) 8.3 30

Brodowicz,

BJC 2014

Cape + Beva (low risk) 11.5 28

Brodowicz,

BJC 2014

Paclitaxel + Beva 11.2 -

^Miles,EJC 2017

Tax/Anthra + Beva 10.3 -

Paclit + Beva (high risk) 11.1 46

Brodowicz,

BJC 2014

Paclit + Beva (low risk) 14.4 35

Brodowicz,

BJC 2014

Cape+ Vinor + Beva 9.6 -

^Welt,BCRT 2016

Performance of CT in HER2-

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Beva-based CT

When the response is an end point

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Tutt A, SABCS 2016.

MonoCT with Carboplatin

TNT trial: study design

1:1

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MonoCT with Carboplatin

TNT in unselected TNBC

Tutt A et al, Nature Medicine 2018

mPFS

Carboplatin vs. Docetaxel

3.1 vs 4.4 months (p=0.40)

ORR

Carboplatin vs. Docetaxel

31.4% vs 34.0%

(p=0.66)

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mPFS

Germline BRCA vs no germline

Carboplatin: 6.8 vs 2.9 months Docetaxel: 4.4 vs 4.6 months

(p=0.002)

ORR

Germline BRCA vs no germline

Carboplatin: 68.0% vs 28.1%

Docetaxel: 33.3% vs 34.5%

(p=0.01)

Tutt A et al, Nature Medicine 2018

MonoCT with Carboplatin

TNT in mBRCA

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PolyCT with Carboplatin

tnAcity trial

Yardley D et al, Ann Oncol 2018

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Eribulin beyond first-line in TNBC

• Pooled analysis:

• Study 301

• Eribulin

• TPC

• Study 305

• Eribulin

• Capecitabine

• 1644 patients

• eribulin: 946

• control: 698

• 352 TNBC

Pivot et al. Ann Oncol 2016

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Antibody drug coniugate

Sacituzumab Govitecan (IMMU-132)

The phase III trial ASCENT is ongoing…

Bardia et al, J Clin Oncol 2017

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• Introduction

• Chemotherapy

• PARPi

• Immunotherapy

• Endocrine therapy

• Conclusions

Agenda

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Median PFS: 7 vs 4 months ORR 59.9 vs 28.8%

Robson M et al, N Engl J Med 2017.

302 MBC BRCA+:

• 205 olaparib

• 97 standard CT (capecitabine, vinorelbine, eribuline)

≤ 2 previous CT lines

About 75% with ≥ 2 mts sites

BRCA and PARPi

OlimpyAD trial

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431 MBC BRCA+:

• 287 talazoparib

• 144 standard CT (cape, vino, eri)

≤ 3 previous CT lines

About 70% with visceral mts

Litton J et al, N Engl J Med 2018.

BRCA and PARPi

EMBRACA trial

Median PFS: 8.6 vs 5.6 months

ORR: 62.6 vs 27.2 %

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Poggio F et al, ESMO Open 2018.

BRCA and PARPi

PFS results

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Poggio F et al, ESMO Open 2018.

BRCA and PARPi

TNBC and platinum-naïve

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• Introduction

• Chemotherapy

• PARPi

• Immunotherapy

• Endocrine therapy

• Conclusions

Agenda

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Immunotherapy

PD-1 blockade: activity as single agent

Drug Phase Subtype PD-L1 N pts ORR

Pembrolizumab (anti-PD-1)

Ib TNBC

PD-L1+

≥ 1% TC Stroma+

32 18.5%

Ib ER+/HER2- PD-L1+

≥ 1% TC Stroma+

25 12%

II TNBC

1°line, PD-L1+

>1 line

≥1 CPS

52 170

23.1%

4.7%

Atezolizumab (anti-PD-L1)

Ia TNBC ≥5% IC 115 10%

Avelumab (anti-PD-L1)

Ib All

TNBC ER+/HER2-

≥1% TC

≥5% TC

≥10%IC

168 58 72

3.0%

5.2%

2.8%

Nanda R et al, J Clin Oncol 2016; Rugo H et al, SABCS 2015; Adams S et al, ASCO 2017; Schmid P et al, AACR 2017; Dirix YL et al, Breast Cancer Res and Treat 2017.

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Immunotherapy

Combination with chemotherapy: results

Drugs Phase Subtype Line of treatment

N pts ORR

Atezolizumab + nab-Paclitaxel

Ib mTNBC

1 2

≥3

24 9 8 7

42%

67%

25%

29%

Pembrolizumab + Eribuline

Ib/II mTNBC

1L 2-3L

39 17 22

33.3%

41.2%

27.3%

Adams et al, ASCO 2016; Tolaney S et al, SABCS 2016

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Immunotherapy

IMpassion130: trial design

Schmid P, NEJM 2018

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Schmid P, NEJM 2018

IMpassion130: PFS results

ITT population

PD-L1 positive

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Schmid P, NEJM 2018

IMpassion130: OS results

ITT population

PD-L1 positive

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Immunotherapy

Ongoing phase III trials

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• Introduction

• Chemotherapy

• PARPi

• Immunotherapy

• Endocrine therapy

• Conclusions

Agenda

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Endocrine therapy

Clinical evidence

Author N Drug CBR (%)

Gucalp 452 Bicalutamide 19

Traina 118 Enzalutamide 35

Bonnefoi 30 Abiraterone 20

Gucalp A, Clin Cancer Res 2013; Traina TA J Clin Oncol 2018; Bonnefoi H, Ann Oncol 2016.

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Endocrine therapy

Ongoing studies

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• Introduction

• Chemotherapy

• PARPi

• Immunotherapy

• Endocrine therapy

• Conclusions

Agenda

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