Malattia triplo negativa

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TERAPIA DELLA MALATTIA METASTATICA

MALATTIA TRIPLO NEGATIVA

Gaia Griguolo - Maria Vittoria Dieci

DiSCOG - Università di Padova

Oncologia Medica 2 - Istituto Oncologico Veneto IRCCS

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n

^Brain ^Liver ^Lung ^Bone ^Distant

Nodal

Pleural/

peritoneal

Other

Luminal A

⁴⁵⁸ ^7.6 ^28.6 ^23.8 ^66.6 ^15.9 ^28.2 ^13.5

Luminal B

³⁷⁸ ^10.8 ^32.4 ^30.4 ^71.4 ^23.3 ^35.2 ^19.3

Luminal/HER2

¹¹⁷ ^15.4 ^4.4 ^36.8 ⁶⁵ ^22.2 ^34.2 ^13.7

HER2 enriched

¹³⁶ ^28.7 ^45.6 ^47.1 ^59.6 ²⁵ ^31.6 ^16.9

Basal Like

¹⁵⁹ ^25.2 ^21.4 ^42.8 ³⁹ ^39.6 ^29.6 ^23.9

TN non basal

¹⁰⁹ ²² ^32.1 ^35.8 ^43.1 ^35.8 ^28.4 ^25.7

p

<0.001 <0.001 <0.001 <0.001 <0.001 <0.001 0.32 0.006

Kennecke H, JCO 2010 Gong Y, Sci Rep 2017

Behaviour of MBC according to molecular subtype

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Seah DSE, J Natl Compr Canc Netw 2014

Lines of chemotherapy and duration according to BC subtype

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Current standard for metastatic TNBC

• Chemotherapy has been the standard for decades

• Most pts received A-T as adjuvant/neoadjuvant treatment

• Frequent visceral metastases, poor survival from the onset of MBC

• High attrition rate: a long-term treatment sequence is not possible

• Clinical trials

• Best option first

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Controversies and updates in metastatic TNBC

•TNBC definition and biopsy of relapse

•Platinum and PARPi

•Immunotherapy

•New drugs/combinations

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Controversy: TNBC definition

3055 stage II-III HER2-negative patients treated with NACT followed by surgery

Villegas SL, SABCS 2018 Fujii T, Ann Oncol 2017

>4000 patients from Gepar5-6-7 trials N=184 TNBC patients (ER & PgR <10%) treated with NACT at IOV Padova

• n=157 ER<1% and n=27 ER>1&<10%

ER<1%

ER>1%&<10%

Giorgi CA, accepted as poster, AIOM 2019

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Receptor conversion from primary to metastasis:

metanalysis

Receptor conversion Rate

ER+→ER- 22.5%

ER-→ER+ 21.5%

PgR+→PgR- 49.4%

PgR-→PgR+ 15.9%

HER2+→HER2- 21.3%

HER2-→HER2+ 9.5%

Schrijver ,JNCI 208

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Tumor phenotype discordance and prognosis

Dieci MV, Ann Oncol 2013

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Controversies and updates in metastatic TNBC

•TNBC definition and biopsy of relapse

•Platinum and PARPi

•Immunotherapy

•New drugs/combinations

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10

ORR %

Study Drug Setting All/ Unselected BRCA wt BRCA mut

TBCR009

¹

Cisplatin or Carboplatin 1-2 line 26% 20% 54.5%

BALI

²

Cisplatin 1-2 line 10% -- --

Byrski

³

Cisplatin 1-2 line -- -- 80%

1. Isakoff SJ, J Clin Oncol 2015; 2. Baselga J et al, J Clin Oncol 2013; 3. Byrski T et al, Breast Cancer Res 2012

Platinum for gBRCAmut metastatic TNBC

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TNT phase III trial for TN metastatic BC

Tutt A et al, Nat Med 2018

N=376

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Tutt A et al, Nat Med 2018

TNT phase III trial for TN metastatic BC

66% of pts: previously unexposed to taxane

Median PFS BRCA1/2 mut Carbo: 6.8 months

Doc: 4.4 months

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tnAcity Phase II

nab-P/C nab-P/G G/C

Median PFS, months 8.3 5.5 6.0

HR (95% CI) P value

– –

0.59 (0.38 - 0.92) 0.02^a

0.58 (0.37 - 0.90) 0.02^a

12-month PFS rate, % 30 13 11

aCompared with nab-P/C.

Yardley D et al, Ann Oncol 2018

nab-P/C nab-P/G G/C

Median OS, months 16.8 12.1 12.6

HR (95% CI) P value

– –

0.73 (0.47 - 1.13) 0.16^a

0.80 (0.52 - 1.22) 0.29^a

a Compared with nab-P/C.

N=191; 70-75% DFI >12 months, 64% prev exposed to taxane

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Controversies and updates in metastatic TNBC

•TNBC definition and biopsy of relapse

•Platinum and PARPi

•Immunotherapy

•New drugs/combinations

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OlympiAD: PFS results

Robson M, NEJM 2017

Median 7.0 vs 4.8 months HR 0.58, 95% CI 0.43-0-80 P<0.001

50% TN; A/T PRETREATED; MOST pts RECEIVED CT FOR MBC; TN: NON-PLATINUM RESISTANT

Subgroup analyses: PFS by BICR

6/ 4/ 2017

Present ed by: Mark Robson, MD 16

PFS (%)

Months

12 8 4

0 16 20 24 28

Months

12 8 4

0 16 20 24 28

Progression/

deaths (%)

Olaparib TPC 50 (83.3) 21 (80.8)

HR 0.67 95% CI 0.41 to 1.14

Progression/

deaths (%)

Olaparib TPC 113

(77.9) 50 (70.4) HR 0.60 95% CI 0.43 to 0.84

PFS (%)

100

80 60 40

20 0

100

80 60 40

20 0

Prior platinum No prior platinum

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OlympiAD: OS results

Robson M, Ann Oncol 2019

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EMBRACA trial: Talazoparib vs TPC in MBC with gBRCAmut

Litton J, NEJM 2018

Median PFS 8.6 vs 5.6 months HR 0.54, 95%CI 0.41-0.71

P<0.001

Median OS 22.3 vs 19.5 months HR 0.76, 95%CI 0.55-1.06

P=0.11

ORR 62.6% (T) vs 27.2% (CT)

Median duration of repsonse: 5.4 (T) and 3.1 (CT) months

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Controversies and updates in metastatic TNBC

•TNBC definition and biopsy of relapse

•Platinum and PARPi

•Immunotherapy

•New drugs/combinations

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Adams S, ASCO 2017; Emens L, JAMA Oncol 2018; Dirix L, BCRT 2018

Immune checkpoint inh as monotherapy in mTNBC:

key results from phase I/II studies

• Modest overall response rates, higher in 1st line (up to 24%)

• Responses in both PD-L1+ and PD-L1- patients

• Durable responses were observed

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Schmid P, ESMO 2018, NEJM 2018

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Primary analysis: PFS

Schmid P, NEJM 2018

PFS ITT

Events/pts mPFS, months (95%CI) 1yr PFS% (95%CI) Atezo+Nab 358/451 7.2 (5.6-7.5) 23.7 (19.6-27.9) Plac+Nab 378/451 5.5 (5.3-5.6) 17.7 (14.0-21.4)

HR 0.80 (95%CI 0.69-0.92) P=0.0025

PD-L1+ mPFS, months (95%CI) 1yr PFS% (95%CI) Atezo+Nab 7.5 (6.7-9.2) 29.1 (22.2-36.1) Plac+Nab 5.0 (3.8-5.6) 16.4 (10.8-22.0)

PFS by PD-L1

41% PD-L1+

SP142, 1% of positively stained IC over the total tumor area

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IMpassion130: OS

2° interim (59% deaths in ITT population)

ITT By PD-L1

Schmid P, ASCO 2019

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• First phase III study reporting benefit from immunotherapy for mTNBC

• Safety manageable

• Benefit in PD-L1+; increase in OS > PFS

• Accelerated FDA-approval in US on march 8, 2019

• Open question:

• Duration and timing of immunotherapy

• Backbone CT

• Biomarkers?

IMpassion130: comments

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Atezo + nab-paclitaxel Carbo + taxane (nab) Taxane+/- Bev

BRCAwt: DFI>12months

1 ^st line treatment of metastatic TNBC, BRCAwt

Carbo +/- Gem

Capecitabine +/- VNB Carbo + taxane (nab)

Taxane +/- Bev

PD-L1+ PD-L1-

BRCAwt: DFI<12months

In yellow: not yet approved/off-label

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Atezo + nab-paclitaxel PARPi

Carbo-based

BRCAmut: DFI>12months

1 ^st line treatment of metastatic TNBC, BRCAmut

PD-L1+ PD-L1-

BRCAmut: DFI<12months

In yellow: not yet approved/off-label

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Atezo + nab-paclitaxel PARPi

Carbo-based

BRCAmut: DFI>12months

1 ^st line Treatment of metastatic TNBC, BRCA mut

BRCAmut: DFI<12months

PD-L1+ PD-L1-

In the absence of direct comparison evidence sequence choice based on: OS data in OlympiAD 1st line subgroup, safety, HRQoL, preference.

However: platinum performance is worse in >=2nd line; the increase use of platinum for early disease will further challenge the algorithm

PARPi

Carboplatin-based

PARPi

Carboplatin-based

In yellow: not yet approved/off-label

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