NOVITA SUL TRATTAMENTO DEL CARCINOMA MAMMARIO: MALATTIA TRIPLO NEGATIVA

SUPERNOVAE IN ONCOLOGIA NOVITA SUL TRATTAMENTO DEL CARCINOMA MAMMARIO: MALATTIA TRIPLO NEGATIVA Dr. Matteo Lambertini U.O. Oncologia Medica 2 IRCCS AOU San Martino IST, Genova Pisa, 14 novembre 2015

AGENDA Introduction Neoadjuvant therapy Adjuvant therapy Therapy for metastatic disease Future perspectives

Triple-Negative Breast Cancer (TNBC) TNBC lacks expression of ER (<1%), PgR (<1%) and HER2 TNBC comprises approximately 15% of incident breast cancers Each year in the US alone out of 235,000 new cases 35,000 are TNBC Vast majority are candidates for adjuvant or neoadjuvant therapy Responsible for high degree of brest cancer mortality Coates AS et al, Ann Oncol 2015; 26:1533-46. Brewster AM et al, Lancet Oncol 2014; 15:e625-34. www.seer.cancer.gov

Triple-Negative Breast Cancer (TNBC) TNBC is associated with African American ethnicity, younger age, frequently interval tumors, advanced stage at diagnosis and poorer outcome when compared with other BC subtypes. Possible etiologic heterogeneity: protective effect of breastfeeding. BRCA mutations in nearly 20% of TNBC patients (vs 5% in non- TNBC): 16% BRCA1 & 4% BRCA2. TNBC is characterised by high cell proliferation, poor cellular differentiation, many recurrent copy number imbalances, and mutations in the TP53. Brewster AM et al, Lancet Oncol 2014; 15:e625-34. Islami F et al, Ann Oncol 2015 [Epub ahead of print]

Triple-Negative Breast Cancer (TNBC) Oakman C et al, The Breast 2010; 19:312-21

AGENDA Introduction Neoadjuvant therapy Adjuvant therapy Therapy for metastatic disease Future perspectives

pcr and TNBC Cortazar P et al, Lancet 2014; 384:164-72

Breast-Conserving Surgery and TNBC Slide 14 BCS successful: 94% BCS successful: 91% Golsham M et al, Ann Surg 2015; 262:434-9

Breast-Conserving Surgery and TNBC Golsham M et al, Ann Surg 2015; 262:434-9

Surgery Platinum Salts and NACT in TNBC GeparSixto (GBG 66) phase II study N=595 centrally confirmed TNBC or R HER2-positive breast cancer PM PMCb Non-pegylated liposomal Paclitaxel 80 mg/m² q1w doxorubicin 20 mg/m² q1w Carboplatin AUC 1.5* q1w Her2-pos: Trastuzumab 6(8) mg/kg q3w (for 1 year) + Lapatinib 750 mg/d 18 wks TNBC: Bevacizumab 15 mg/kg q3w *reduced from AUC 2 at amendment 1 after enrolment of 330 patients Von Minckwitz G et al, Lancet Oncol 2014; 15:747-56

Platinum Salts and NACT in TNBC Von Minckwitz G et al, Lancet Oncol 2014; 15:747-56

Platinum Salts and NACT in TNBC 315 patients (53.6%) Von Minckwitz G et al, Lancet Oncol 2014; 15:747-56

Platinum Salts and NACT in TNBC Von Minckwitz G et al, Lancet Oncol 2014; 15:747-56

Platinum Salts and NACT in TNBC Von Minckwitz G et al, ASCO Annual Meeting 2015

Platinum Salts and NACT in TNBC CALGB 40603 (Alliance) phase II study Clinical Stage II-III TNBC (n=443) Primary endpoint: pathologic complete response (pcr) breast and breast + axilla Sikov WM et al, J Clin Oncol 2015; 33:13-21

Platinum Salts and NACT in TNBC CALGB 40603 (Alliance) phase II study pcr breast=ypt0/is pcr breast/axilla=ypt0/is N0 Sikov WM et al, J Clin Oncol 2015; 33:13-21

Platinum Salts and NACT in TNBC Rates of pcr (ypt0 pn0) with NACT with carboplatin in TNBC Study No. Patients Standard CT Standard CT + carboplatin GeparSixto wp+lipo doxo CALGB 40603 wp ddac 315 37% 53% 443 41% 54% 15% absolute difference Von Minckwitz G et al, Lancet Oncol 2014; 15:747-56. Sikov WM et al, J Clin Oncol 2015; 33:13-21

Nab-Paclitaxel and NACT in TNBC Out of 1204 patients enrolled, 275 (22.8%) had TNBC Untch M et al, San Antonio Breast Cancer Symposium 2014

Nab-Paclitaxel and NACT in TNBC Untch M et al, San Antonio Breast Cancer Symposium 2014

AGENDA Introduction Neoadjuvant therapy Adjuvant therapy Therapy for metastatic disease Future perspectives

Benefit of Adjuvant CT in TNBC Prospective cohort study NCCN database (4,113 patients): T1a,b N0 tumors treated between 2000 and 2009 Distant Relapse-Free Survival In TNBC (n=168 patients): 5-year DRFS pt1a: 93% 5-year DRFS pt1b: 90% In TNBC (n=195 patients): 5-year DRFS pt1a: 100% 5-year DRFS pt1b: 96% Vaz-Luis I et al, J Clin Oncol 2014; 32:2142-50

Adjuvant CT in TNBC Coates AS et al, Ann Oncol 2015; 26:1533-46

Impact of Adjuvant CT in TNBC British Columbia Cancer Agency stage I-III BC (7,178 patients): a total of 1,132 (15.8%) patients with ER neg and HER2 neg BC Cohort 1: 1986-1994 Cohort 2: 2004-2008 Cossetti RJD et al, J Clin Oncol 2015; 33:65-73

Adjuvant Taxanes in TNBC E1199 Phase III Study 1:1:1:1 AC x 4 P x 4 Q3 w Invasive breast carcinoma (N= 4,950 pts) - Radical surgery; - N pos or high risk N neg; - No distant metastasis. AC x 4 wp x 12 AC x 4 D x 4 Q3 w AC x 4 wd x 12 P vs D wt vs Q3T Primary endpoint: disease-free survival (DFS) Sparano JA et al, N Engl J Med 2008; 358:1663-71. Sparano JA et al, J Clin Oncol 2015; 33:65-73

Adjuvant Taxanes in TNBC E1199 Phase III Study: 1,025 patients with TNBC p=0.010 p=0.019 Sparano JA et al, N Engl J Med 2008; 358:1663-71. Sparano JA et al, J Clin Oncol 2015; 33:65-73

Adjuvant DD Chemotherapy in TNBC GIM2 Phase III Study Invasive breast carcinoma (N= 2,091 pts) - Radical surgery; - 1 pos nodes; - No supraclavicolar nodes; - No IBC, no stage IV. 1:1:1:1 EC x 4 T x 4 Q3 w FEC x 4 T x 4 Q3 w EC x 4 T x 4 Q2 w FEC x 4 T x 4 Q2 w EC vs FEC Q2 vs Q3 Primary endpoint: disease-free survival (DFS) Del Mastro L et al, Lancet 2015; 385:1863-72

Adjuvant DD Chemotherapy in TNBC GIM2 Phase III Study DFS OS EC vs FEC Q2 vs Q3 Del Mastro L et al, Lancet 2015; 385:1863-72

Adjuvant DD Chemotherapy in TNBC GIM2 Phase III Study: 335 patients with HR negative BC Disease-free survival: Q2 (dose-dense) vs Q3 (standard duration) Del Mastro L et al, Lancet 2015; 385:1863-72

Adjuvant DD Chemotherapy in TNBC SWOG S0221 Phase III Study 1:1:1:1 AC Q2 x 6 P Q2 x 6 Invasive breast carcinoma (N= 2,716 pts) - Radical surgery; - N pos or high risk N neg; - No distant metastasis. wac x 15 P Q2 x 6 AC Q2 x 6 wp x 12 wac x 15 wp x 12 DD AC vs wac DD P vs wp Primary endpoint: disease-free survival (DFS) Budd GT et al, J Clin Oncol 2015; 33:58-64

Adjuvant DD Chemotherapy in TNBC SWOG S0221 Phase III Study: 680 patients with TNBC Disease-free survival Budd GT et al, J Clin Oncol 2015; 33:58-64

LINEE GUIDA AIOM 2015

Adjuvant Ixabepilone in TNBC TITAN Phase III Study 609 patients Yardley DA et al, ASCO Annual Meeting 2015

Adjuvant Ixabepilone in TNBC TITAN Phase III Study Disease-Free Survival Overall Survival Yardley DA et al, ASCO Annual Meeting 2015

Adjuvant Bevacizumab in TNBC BEATRICE Phase III Study Cameron D et al, Lancet Oncol 2013; 14:933-42

Adjuvant Bevacizumab in TNBC BEATRICE Phase III Study Disease-Free Survival Overall Survival Cameron D et al, Lancet Oncol 2013; 14:933-42

Maintenance Adjuvant CT in TNBC IBCSG 22-00 Phase III Study C: 50 mg/day continuously M: 2.5 mg twice/day 1,2 week 75% TNBC Colleoni M et al, ASCO Annual Meeting 2015

Maintenance Adjuvant CT in TNBC IBCSG 22-00 Phase III Study Colleoni M et al, ASCO Annual Meeting 2015

AGENDA Introduction Neoadjuvant therapy Adjuvant therapy Therapy for metastatic disease Future perspectives

Lines of Treatment in TNBC Dana-Farber Cancer Institute experience: 199 patients between 2004 and 2007, 44 with TNBC Number of lines of chemotherapy Overall survival Seah DSE et al, J Natl Compr Canc Netw 2014; 12:71-80

1 st Line Therapy: Platinum Salts CBCSG006 Trial Metastatic TNBC breast cancer (N=236pts) - Chinese patients - No prior therapy for advanced disease - ER and PR 10% and HER2 negative - Prior adjuvant taxanes allowed (> 6 months before study entry) 1:1 Cisplatin (75 mg/m 2 g1 q 21) + Gemcitabine (1250mg/m 2 g1,8 q 21) Paclitaxel (175 mg/m 2 g1 q 21) + Gemcitabine (1250mg/m 2 g1,8 q 21) Primary endpoints: progression-free survival (PFS) 1. To test non-inferiority of cisplatin plus gemcitabine compared with paclitaxel plus gemcitabine 2. If achieved, to test superiority of cisplatin plus gemcitabine compared with paclitaxel plus gemcitabine Hu XC et al, Lancet Oncol 2015; 16:436-46

1 st Line Therapy: Platinum Salts CBCSG006 Trial Progression-Free Survival Cisplatin: 7.73 months (95% CI, 6.16 9.30) Paclitaxel: 6.47 months (95% CI, 5.76 7.18) Hu XC et al, Lancet Oncol 2015; 16:436-46

1 st Line Therapy: Platinum Salts TNT Trial: CRUK/07/012 Tutt A et al, San Antonio Breast Cancer Symposium 2014

1 st Line Therapy: Platinum Salts TNT Trial: CRUK/07/012 Objective Response Rate Progression-Free Survival Overall Survival Tutt A et al, San Antonio Breast Cancer Symposium 2014

1 st Line Therapy: Platinum Salts TNT Trial: CRUK/07/012 Tutt A et al, San Antonio Breast Cancer Symposium 2014

1 st and 2 nd Line Therapy: Platinum Salts TBCRC009 Trial High Homologous Recombination and mutations: BRCA mutant vs BRCA wild type High Homologous Recombination and responses: Responders vs Non responders Isakoff SJ et al, J Clin Oncol 2015; 33:1902-9

2 nd Line Therapy: Eribulin NCT00337103 Phase III Study Metastatic breast cancer (N= 1,102 pts) - Prior anthracycline- and taxane-based therapy - 3 lines of therapy ( 2 lines of therapy for advanced disease) - No anti-her2 agents if HER2 positive 1:1 Eribulin 1.4 mg/m 2 g1,8 q 21 Capecitabine 1,250 mg/m 2 BID g1-14 q 21 Primary endpoints: progression-free survival (PFS) and overall survival (OS) Kaufman PA et al, J Clin Oncol 2015; 33:594-602

2 nd Line Therapy: Eribulin NCT00337103 Phase III Study Overall Survival Progression-Free Survival Overall Survival Subgroup Analysis Kaufman PA et al, J Clin Oncol 2015; 33:594-602

AGENDA Introduction Neoadjuvant therapy Adjuvant therapy Therapy for metastatic disease Future perspectives

Future perspectives The Heterogeneity of TNBC BRCA and PARP-I Endocrine therapy Immunotherapy

The Heterogeneity of TNBC Subtype Gene expression profile Clinical Basal-like 1 high Ki-67; DNA damage response BRCA-associated Basal-like 2 GF pathways Higher pcr Immunomodulatory Immune genes Mesenchymal Cell motility Lower DDFS Mesenchymal stem-like Cell motility; claudin-low Luminal androgen receptor Steroid pathways Apocrine features, higher LRF; PI3Kmut Lehman BD et al, J Clin Invest 2011; 121:2750-67

The Heterogeneity of TNBC Subtype Gene Ontology IHC analysis Hysto type Possible sensitivity Basal-like 1 Basal-like 2 Immunomodulatory Cell cycle and cell division DNA damage response Growth gactor signaling (EGFR, MET) High Ki67 -- Cisplatin PARP-Inhibitors -- Medullary Anti-EGFR Immune cell processes -- -- Immunotherapy? Mesenchymal-like Cell motility and cell differentation (TGF-β, Src); GF patways Mesenchymal Stem-like Luminal AR Angiogenesis Low levels prolif genes Claudin-low Hormonally regulated pathways -- Metaplastic PI3K-mTOR Inh (BEZ235) Src-Inhibitors (Dasatinib) -- Anti-angio AR + Molecular Apocrine AR antagonist Courtesy of M. De Laurentiis

Future perspectives The Heterogeneity of TNBC BRCA and PARP-I Endocrine therapy Immunotherapy

BRCA and PARP-I Iniparib in Unselected TNBC Overall Survival Overall Survival O Shaughnessy J et al, N Engl J Med 2011; 364:205-14. O Shaughnessy J et al, J Clin Oncol 2014; 32.

BRCA and PARP-I The Proof-of-Concept Trial: Olaparib in BRCA1 and BRCA2 mutant BC (54% were TNBC) Tutt A et al, Lancet 2010; 376: 235-44

BRCA and PARP-I Ongoing phase II and III studies Livraghi L et al, BMC Med 2015; 13:188

Future perspectives The Heterogeneity of TNBC BRCA and PARP-I Endocrine therapy Immunotherapy

Endocrine Therapy Androgen Receptor in TNBC Present in 10-30% (1-10% cut off) Better survival Expressed in older patients, lower grade tumors (G1-G2), higher PD-L1 expression Rare co-expression in patients with BRCA-mutation Gasparini P et al, PLOS One 2014; 9:e88525. Loibl S et al, Breast Cancer Res Treat 2011; 130:477-87. Proverbs-Singh T et al, Endocr Rel Cancer 2015; 22:R87-R106. Tung N et al, ASCO Annual Meeting 2015 (abstract 1005)

Endocrine Therapy TBCRC 011 phase II study 12% IHC: AR > 10% CBR = 19% (95% CI, 7% - 39%) PFS = 12 weeks (95% CI, 11-22) Bicalutamide 150 mg daily Gucalp A et al, Cancer Res 2013; 19:5505-12

Metastatic breast cancer (N= 118 pts) - AR + ( 1% positive cells) advanced TNBC - Any number of prior therapies - No brain metastasis - Sufficient tissue available for biomarker discovery Endocrine Therapy MDV 3100-11 phase II study Enzalutamide 160 mg/day Stage 1 3 of 26 Evaluable have CBR16 Go to Stage 2 Stage 2 9 of 62 Evaluable have CBR16 Rejection of H 0 Cortes J et al, ESMO-ECCO Annual Meeting 2015

Overall Survival (%) Endocrine Therapy MDV 3100-11 phase II study ITT Population 100 80 60 PREDICT AR+ mos 75.6 weeks (95% CI: 51.6, 91.4) 40 20 PREDICT AR mos 32.3 weeks (95% CI: 20.7, 48.3) 0 0 8 16 24 33 41 49 61 64 85 Weeks PREDICT AR+ mos 18.0 months PREDICT AR mos 7.5 months Cortes J et al, ESMO-ECCO Annual Meeting 2015

Endocrine Therapy Ongoing studies in breast cancer Proverbs-Singh T et al, Endocr Rel Cancer 2015; 22:R87-R106

Future perspectives The Heterogeneity of TNBC BRCA and PARP-I Endocrine therapy Immunotherapy

Immunotherapy Tumor Infiltrating Lymphocites (TIL): prognostic role in early stage TNBC and in patients with residual disease after neoadjuvant chemotherapy predictors of pcr after neaodjuvant chemotherapy (mainly in TNBC and HER2+) PD-L1 expression: The role of Immunity in TNBC Approximately 20-60% of TNBC Associated with: TIL, increased immune response genes and activation of immune pathways, AR+, no LVI Anti-PD-1 and anti-pd-l1 Abs break the immune tolerance at the tumor site leading to a lasting clinical benefit Adams S et al, J Clin Oncol 2014; 32:2959-66. Dieci MV et al, Ann Oncol 2014; 25:611-8. Denkert C et al, J Clin Oncol 2015; 33:983-91. Dieci MV et al, Ann Oncol 2015; 26:1698-704. Salgado R et al, Ann Oncol 2015; 26:259-71. Sabatier R et al, Oncotarget 2015; 6:5449-64. Tung N et al, ASCO Annual Meeting 2015 (abstract 1005)

Immunotherapy Phase Ib study of pembrolizumab (anti-pd-1) in TNBC Recurrent or metastatic ER /PR /HER2 breast cancer ECOG PS 0-1 PD-L1 + tumor a No systemic steroid therapy No autoimmune disease (active or history of) No active brain metastases Pembro 10 mg/kg Q2W Complete Response Partial Response or Stable Disease Confirmed Progressive Disease b Discontinuation Permitted Treat for 24 months or until progression or intolerable toxicity Discontinue Patients Evaluable for Response a n = 27 Overall response rate 5 (18.5%) Best overall response Complete response b 1 (3.7%) Partial response b 4 (14.8%) Stable disease 7 (25.9%) Progressive disease 12 (44.4%) No assessment c 3 (11.1%) Nanda R et al, San Antonio Breast Cancer Symposium 2014

Immunotherapy Phase Ia study of MPDL3280A (atezolimumab, anti-pd-l1) Efficacy evaluable population with TNBC treated with MPDL3280A q 3 weeks: n=21 patients PD-L1+ at IHC (2/3) ORR=19% (2 CR and 2 PR) Median duration of response not reached: 18-56 weeks PFS at 24 weeks: 27% Emens AL et al, AACR Annual Meeting 2015

Immunotherapy Ongoing studies in breast cancer TRIAL DRUG TARGET SETTING PANACEA Pembrolizumab PD-1 Metastatic HER2+ BC MK-3475 for Metastatic Inflammatory Breast Cancer (MIBC) PLX3397 and Pembrolizumab in Advanced Melanoma and Other Solid Tumors MK-3475-012/KEYNOTE-012 in triple-negative breast cancer and head and neck cancer Safety study of nivolumab with Nab-Paclitaxel plus or minus Gemcitabine in Pancreatic Cancer, nabpaclitaxel/carboplatin in stage IIIB/IV Non-Small Cell Lung Cancer or nab-paclitaxel in recurrent metastatic breast cancer Pembrolizumab PD-1 Metastatic inflammatory BC Pembrolizumab PD-1 Metastatic TNBC Pembrolizumab PD-1 Metastatic TNBC Nivolumab PD-1 Recurrent Metastatic BC PDR001 in Patients With Advanced Malignancies PDR001 PD-1 Metastatic TNBC RADVAX Pembrolizumab + hypofractionated RT PD-1 Metastatic BC TONIC study (nivolumab after induction therapy for triple-negative breast cancer) Nivolumab PD-1 Metastatic TNBC JAVELIN Avelumab PD-L1 Metastatic BC IMpassion130 (in combination with nab-paclitaxel) Atezolimumab PD-L1 Untreated metastatic TNBC From: ClinicalTrials.gov. Courtesy of C. Solinas

Conclusions TNBC is heterogeneous Chemotherapy is mainstay and (at the moment) in unselected TNBC is the same as for other subtype Neoadjuvant: platinum salts and nab-paclitaxel? Adjuvant: dose-dense chemotherapy Metastatic setting: 1 st line: taxanes (+/- bevacizumab) platinum salts 2 nd line: eribulin platinum salts BRCA associated TNBC may be different: PARP-I and platinum salts to be considered. In all settings? Personalized therapy approaches: near future?

matteo.lambertini85@gmail.com