La malattia triplo negativa metastatica: quali trattamenti nella pratica clinica?

Transcription

1 2018 CARCINOMA MAMMARIO: I TRAGUARDI RAGGIUNTI E LE NUOVE SFIDE La malattia triplo negativa metastatica: quali trattamenti nella pratica clinica? Roma, 27 Ottobre 2018 Relatore: Francesca Poggio

2 Disclosure Information Relationship Relevant to this Session Poggio, Francesca: No relevant relationship to disclose.

3 Agenda Introduction Chemotherapy PARPi Immunotherapy Endocrine therapy Conclusions

4 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 Brewster AM et al, Lancet Oncol Brewster AM et al, Lancet Oncol

5 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 Carey LA et al, Clin Cancer Res 2007.

6 The Heterogeneity of TNBC 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

7 Agenda Introduction Chemotherapy PARPi Immunotherapy Endocrine therapy Conclusions

8 Cardoso F et al, Ann Oncol 2018

9 Performance of CT in HER2- Regimen Inv Ass PFS (m) ORR (%) (Measurable) Capecitabine Paclitaxel Tax/Anthra Cape + Beva Cape + Beva Cape + Beva (high risk) Cape + Beva (low risk) Paclitaxel + Beva Tax/Anthra + Beva Paclit + Beva (high risk) Paclit + Beva (low risk) Cape+ Vinor + Beva Robert, JCO 2011 Miles, EJC 2017 Robert, JCO 2011 Robert, JCO 2011 Welt, BCRT 2016 Brodowicz, BJC 2014 Brodowicz, BJC 2014 Miles, EJC 2017 Robert, JCO 2011 Brodowicz, BJC 2014 Brodowicz, BJC 2014 Welt, BCRT 2016 Ref

10 Beva-based CT When the response is an end point

11 MonoCT with Carboplatin TNT trial: study design 1:1 Tutt A, SABCS 2016.

12 MonoCT with Carboplatin TNT in unselected TNBC 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) Tutt A et al, Nature Medicine 2018

13 MonoCT with Carboplatin TNT in mbrca 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

14 Yardley D et al, Ann Oncol 2018 PolyCT with Carboplatin tnacity trial

15 Eribulin beyond first-line in TNBC Pooled analysis: Study 301 Eribulin TPC Study 305 Eribulin Capecitabine 1644 patients eribulin: 946 control: TNBC Pivot et al. Ann Oncol 2016

16 Antibody drug coniugate Sacituzumab Govitecan (IMMU-132) The phase III trial ASCENT is ongoing Bardia et al, J Clin Oncol 2017

17 Agenda Introduction Chemotherapy PARPi Immunotherapy Endocrine therapy Conclusions

18 BRCA and PARPi OlimpyAD trial 302 MBC BRCA+: 205 olaparib 97 standard CT (capecitabine, vinorelbine, eribuline) 2 previous CT lines About 75% with 2 mts sites Median PFS: 7 vs 4 months ORR 59.9 vs 28.8% Robson M et al, N Engl J Med 2017.

19 431 MBC BRCA+: 287 talazoparib 144 standard CT (cape, vino, eri) 3 previous CT lines About 70% with visceral mts BRCA and PARPi EMBRACA trial Median PFS: 8.6 vs 5.6 months ORR: 62.6 vs 27.2 % Litton J et al, N Engl J Med 2018.

20 BRCA and PARPi PFS results Poggio F et al, ESMO Open 2018.

21 Poggio F et al, ESMO Open BRCA and PARPi TNBC and platinum-naïve

22 Agenda Introduction Chemotherapy PARPi Immunotherapy Endocrine therapy Conclusions

23 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 % Ib ER+/HER2- PD-L1+ 1% TC Stroma % II TNBC 1 line, PD-L1+ >1 line 1 CPS % 4.7% Atezolizumab (anti-pd-l1) Ia TNBC 5% IC % Avelumab (anti-pd-l1) Ib All TNBC ER+/HER2-1% TC 5% TC 10%IC % 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.

24 Immunotherapy Combination with chemotherapy: results Drugs Phase Subtype Line of treatment N pts ORR Atezolizumab + nab-paclitaxel Ib mtnbc % 67% 25% 29% Pembrolizumab + Eribuline Ib/II mtnbc 1L 2-3L % 41.2% 27.3% Adams et al, ASCO 2016; Tolaney S et al, SABCS 2016

25 Schmid P, NEJM 2018 Immunotherapy IMpassion130: trial design

26 IMpassion130: PFS results ITT population PD-L1 positive Schmid P, NEJM 2018

27 IMpassion130: OS results ITT population PD-L1 positive Schmid P, NEJM 2018

28 Immunotherapy Ongoing phase III trials

29 Agenda Introduction Chemotherapy PARPi Immunotherapy Endocrine therapy Conclusions

30 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.

31 Endocrine therapy Ongoing studies

32 Agenda Introduction Chemotherapy PARPi Immunotherapy Endocrine therapy Conclusions

33 Conclusions Current standard treatment options for unselected TNBC remains chemotherapeutic approaches In mtnbc, a platinum regimen may be considered, especially in BRCA-associated Results of OLIMPYAD and EMBRACA lead to add single agent PARPi in the therapeutic repertoire of BRCA-associated breast cancers Combination of PD-L1 blockade and chemotherapy new standard for metastatic TNBC patients? Further research is needed to better select patients who are likely to benefit