Malattia triplo negativa

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Terapia Neo-adiuvante:

malattia triplo negativa Valentina Guarneri

Università di Padova-IOV IRCCS

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Cortazar P, Lancet 2014

pCR rates as high as 30-40% with conventional A/T regimens

Chemosensitivity of TNBC: clinical paradox

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• Platinum salts

• PARPi

• Immune-checkpoints inhibitors

• Predictive markers

Neoadjuvant treatment for TNBC:

what’s new in 2017?

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Drug-Specific Chemotherapy for TNBC?

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0 10 20 30 40 50 60

TAC Gepar3¹

EC-D EC-D+Bev Gepar5³

PM PM+carbo (+ Bev) Gepar6⁴

P-AC P+carbo-AC (+/- Bev) CALGB40603⁵

P+carbo+bev Ca.Pa.Be⁶

nabP-EC Gepar7⁸ EC-P

(+/-gem) NeoTango²

nabP-carbo ADAPT⁷

1. Huober J, BCRT 2010; 2. Earl HM, Lancet Oncol 2014; 3. von Minckwitz, NEJM 2012; 4. von Minckwitz, Lancet Oncol 2014; 5. Sikov, J Clin Oncol 2015; 6. Guarneri V, Ann Surg Oncol 2015; 7. Gluz O, SABCS 2015; 8. Untch M, SABCS 2014

* Increased pCR rate gain in HRD deficient (HRD score high or tBRCAmutation)

pCR rates (breast/axilla) in TNBC

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Platinum-based PCT and pCR in TNBC: GEPAR6

Von Minckwitz G et al, Lancet Oncol 2014

P<0.005

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Untch M et al, ESMO 2017

GEPAR6: Survival analyses after 47.3 mos median

follow up

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Platinum-based PCT and pCR in TNBC:

CALGB 40603

Sikov W, J Clin Oncol 2014

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Sikov WM, SABCS 2015

Platinum-based PCT and DFS in TNBC:

CALGB 40603

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• Platinum salts

• PARPi

• Immune-checkpoints inhibitors

• Predictive markers

Neoadjuvant treatment for TNBC:

what’s new in 2017?

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BRIGHTNESS

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N=1,320

•

Study to start recruiting patients with TNBC; plan to add ER/PR+ patients once data available from PK/PD interactions (expected Mid 2014)

•

Primary endpoint: IDFS (invasive disease-free survival; STEEP approach)

•

HR=0.7 (CV=0.81), 90% power, 5% significance level, approx 330 events required

•

Assumes consistent treatment effect (HR=0.7) across patient groups

•

N=1320 (25% maturity), assuming 4 years recruitment, IDFS analysis estimated approx. 5.5–

6 years from FSI

Post-neoadjuvant gBRCA TNBC

Non pCR patients

Assumptions:

- Control arm 3-year EFS ~ 60%C

Post-adjuvant gBRCA TNBC Node positive or N0 with T>2 cm

Assumptions:

- Control arm 3-year EFS ~ 77%C

12 mos Olaparib 300mg bd

DDFS, OS 12 mos Placebo

IDFS 1:1 R

OlympiA

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• Platinum salts

• PARPi

• Immune-checkpoints inhibitors

• Predictive markers

Neoadjuvant treatment for TNBC:

what’s new in 2017?

(17)

I-SPY 2 TRIAL Schema: HER2- Signatures

Presented By Rita Nanda at 2017 ASCO Annual Meeting

I-SPY 2 TRIAL Schema: HER2- signatures

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Pembrolizumab graduated in all HER2- signatures:<br />Both HR+/HER2- and TN

Presented By Rita Nanda at 2017 ASCO Annual Meeting

Pembrolizumab graduated in all HER2- signatures

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HIGH RISK PRIMARY TNBC PTS WHO COMPLETED TREATMENT

WITH CURATIVE INTENT (SURGERY /CHEMOTHERAPY)

Stratum A: Adjuvant Stratum B: Post-neoadjuvant

R

Avelumab for 1 year Observation

Co-primary endpoints: 1. DFS in all-comers; 2. DFS in PD-L1+ patients Secondary endpoints: OS, Safety, Biomarkers

n=335 (for the 1

^st

co-primary endpoint)

Randomization 1:1 (after RT, if indicated) balanced for adjuvant and post-neoadjuvant patients.

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• Platinum salts

• PARPi

• Immune-checkpoints inhibitors

• Predictive markers

Neoadjuvant treatment for TNBC:

what’s new in 2017?

(21)

Basal-like 1 and Basal-like 2: Cell proliferation, DNA damage response

Immunomodulatory: Immune signalling Mesenchymal-like and Mesenchymal stem- like: EMT, motility and growth-factor pathways Luminal AR Androgen receptor signaling

Lehmann BD, et al. J Clin Invest 2011;121:2750–67.

Exploiting TNBC diversity to identify druggable pathways

Preclinical models for selection of targeted

therapy

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IM +/- across the 4 subtypes, implication for response?

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Denkert C, JCO 2010 A baseline immune

activation contributes to treatment response

TILs and neoadjuvant therapy

TILs on RD predicts for prognosis

Dieci MV, Ann Oncol 2014

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