terapia neo-adiuvante: malattia triplo negativa valentina...
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Terapia Neo-adiuvante:
malattia triplo negativa
Valentina Guarneri Università di Padova-IOV IRCCS
Cortazar P, Lancet 2014
pCR rates as high as 30-40% with conventional A/T regimens
Chemosensitivity of TNBC: clinical paradox
• Platinum salts
• PARPi
• Immune-checkpoints inhibitors
• Predictive markers
Neoadjuvant treatment for TNBC: what’s new in 2017?
Drug-Specific Chemotherapy for TNBC?
0
10
20
30
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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
Platinum-based PCT and pCR in TNBC: GEPAR6
Von Minckwitz G et al, Lancet Oncol 2014
P<0.005
Untch M et al, ESMO 2017
GEPAR6: Survival analyses after 47.3 mos median
follow up
Platinum-based PCT and pCR in TNBC:
CALGB 40603
Sikov W, J Clin Oncol 2014
Sikov WM, SABCS 2015
Platinum-based PCT and DFS in TNBC:
CALGB 40603
• Platinum salts
• PARPi
• Immune-checkpoints inhibitors
• Predictive markers
Neoadjuvant treatment for TNBC: what’s new in 2017?
BRIGHTNESS
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
• Platinum salts
• PARPi
• Immune-checkpoints inhibitors
• Predictive markers
Neoadjuvant treatment for TNBC: what’s new in 2017?
I-SPY 2 TRIAL Schema: HER2- Signatures
Presented By Rita Nanda at 2017 ASCO Annual Meeting
I-SPY 2 TRIAL Schema: HER2- signatures
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
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 1st co-primary endpoint)
Randomization 1:1 (after RT, if indicated) balanced for adjuvant and post-neoadjuvant patients.
• Platinum salts
• PARPi
• Immune-checkpoints inhibitors
• Predictive markers
Neoadjuvant treatment for TNBC: what’s new in 2017?
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
IM +/- across the 4 subtypes, implication for response?
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
- Sequential Anthracycline/Taxane first choice
- Majority of TNBC need alkylating agents
- Platinum salts benefit seems not restricted to BRCA-mut, but other
HRD tests not validated
- PARP inhibitors hold great promises for BRCA-mut patients - Immunotherapy on the horizon: predictive biomarkers? - Biological subtypes have high variable response to standard
neoadjuvant chemotherapy, including platinum regimens - These research assays are not validated for clinical decision
making - RD in TNBC is likely enriched for mesenchymal and LAR
phenothypes: implication for post-neoadjuvant studies?
Conclusions