Novità nel trattamento della malattia avanzata

III Sessione Carcinoma della

mammella

Novità nel

trattamento della malattia avanzata

G. Ricciardi

Università degli Studi di Messina

OUTLINE

 New insight in to HR-positive/HER2-negative MBC

 Emerging Therapeutic options in HER2-positive MBC

 Brain Metastases and HER2 disease

 Triple Negative Breast Cancer

 Other

OUTLINE

 New insight in to HR-positive/HER2-negative MBC

 Emerging Therapeutic options in HER2-positive MBC

 Brain Metastases and HER2 disease

 Triple Negative Breast Cancer

 Other

HR + HER2 +

Triple Negative 10% to 15%

25% to 30%

60% to 70%

1Slamon DJ, et al. New Eng J Med. 2001;

2Dawood S, et al. J Clin Oncol. 2009;

3 Bedard PL, et al. Breast Cancer Res Treat. 2008.

Current Clinical Subtypes in Breast Cancer

Barrios C, et al. Ann Oncol 2012

Therapeutic Options in Patients With Hormone

Receptor Positive Advanced Breast Cancer

Initial Treatment of Hormone Receptor–Positive Advanced Breast Cancer

• Premenopausal Patients: ovarian suppression or ablation plus endocrine therapy as recommended for postmenopausal women

• Postmenopausal Patients: AIs due to improved efficacy vs tamoxifen

• Fulvestrant has demonstrated similar efficacy vs tamoxifen

• Preliminary evidence suggests that fulvestrant may demonstrate improved efficacy vs anastrozole

– TTP, fulvestrant vs anastrozole: 23.4 vs 13.1 mos

AI Parameter AI vs Tamoxifen, Mos

Anastrozole

TTP 10.7 vs 6.4

Letrozole

TTP 9.4 vs 6.0

Exemestane

PFS 9.9 vs 5.8

1. Rugo HS, JCO 2016.

2. Bonneterre J, et al. Cancer. 2001.

3. Mouridsen H, et al. J Clin Oncol. 2003.

4. Paridaens RJ, et al. J Clin Oncol. 2008.

5. Howell A, et al. J Clin Oncol. 2004.

6. Robertson FJ, et al. Breast Cancer Res Treat. 2012.

7. Ellis MJ, et al. J Clin Oncol. 2015.

However, the present results suggest fulvestrant 500 mg extends OS versus anastrozole.

This finding now awaits prospective confirmation in the larger phase III FALCON (Fulvestrant and Anastrozole Compared in Hormonal Therapy Naïve Advanced Breast Cancer) trial

Ellis MJ, et al. JCO 2015

FALCON Trial: Press Release May 27, 2016

Astrazeneca’s Fulvestrant met primary endpoint extended

PFS in first- line treatment of advanced breast cancer

Endocrinotherapy: Guidelines

NCCN/ASCO

• Pts whose tumors express any level of ER and/or PgR. Treatment recommendations should be offered on the basis of type of adjuvant treatment, disease-free interval, and extent of disease at the time of

recurrence.

• Endocrine therapy should be recommended as initial treatment for patients with HR-positive MBC, except for patients with immediately life-threatening disease or for those experiencing rapid visceral recurrence during adjuvant endocrine therapy

• Sequential hormone therapy should be offered to patients with endocrine-responsive disease

• Treatment should be administered until there is unequivocal evidence of disease progression.

ESMO/ABC2

• the preferential use of endocrine therapy, even in the presence of visceral metastases,until clear evidence of endocrine resistance.

• Chemotherapy should be reserved for cases of rapidly progressive disease or proven endocrine resistance.

• Endocrine treatment after CT(maintenance ET)to maintain benefit is a reasonable option,althought his approach has not been assessed in randomized trials.

AIOM

• Tumori ormonosensibili HER2 negativi, in assenza di malattia aggressiva e crisi viscerale.

• Il trattamento ormonale dovrebbe essere proseguito (anche con linee di terapia successive) fino a quando è possibile considerare la malattia ormonosensibile.

• la scelta della terapia, sia per la prima linea che per quelle successive, si basa soprattutto sullo stato menopausale della paziente e sulle terapie precedentemente eseguite in fase adiuvante o metastatica.

Rugo HS, et al. JCO 2016 Cardoso F, et al. Ann Oncol 2014 Linee Guida AIOM 2015

“...Visceral crisis is defined as severe organ dysfunction as assessed by signs and symptoms, laboratory studies, and rapid progression of disease. Visceral

crisis is not the mere presence of visceral metastases, but implies important visceral compromise leading to a clinical indication for a more rapidly efficacious therapy, particularly since another treatment option at progression

will probably not be possible...”

ESO-ESMO 2nd international consensus guidelines for advanced breast cancer (ABC2)

About 50% of hormone receptor-positive breast cancers are de novo resistant to endocrine therapy. This intrinsic resistance occurs de novo at the initial exposure to endocrine therapy. However, 25% of ER+/PgR+

tumors, 66% of ER+/PgR- tumors and 55% of ER-/PgR+ tumors fail to respond to tamoxifen or develop early resistance to tamoxifen for reason that are unclear.

1.Gant M. Expert Rev. Anticancer Ther. 2012).

2.Moy B et al. Clin. Cancer Res. 2006

Almost all patients with advanced disease will develop acquired resistance to endocrine therapies. That acquired resistance manifests over time after an initial response to endocrine therapy.

The mechanisms of de novo and acquired resistance are likely similar, but are not completely understood .

The Problem in ER+HER2 neg Breast Cancer

Is Endocrine Therapy Resistance

 Low levels of ER and PgR

 ER mutations (ESR1)

 Truncated ER α, ERα 36

 Repression of ER regulated gene productus (i.e. PgR)

 Cytochrome P4502D6 (CYP2D6)

 VEGF overexpression

 HER2 alterations/mutations

 EGFR alterations

 IGF-1R alterations

 PI3K/Akt/mTOR alterations

 “omics” profile of endocrine-resistance

Markers of Endocrine-Resistance

Key Molecular Pathways of Endocrine Resistance

Adapted from Rugo HS, Educational ASCO 2016

Study Phase Treatment N Efficacy

NTC00107016 Neoadjuvant study (Baselga J, JCO 2009)

II Letrz + Plac Letrz+ Eve

132 138

Clinical response:

L+Pla 59.1%; L+ Eve 68.1% (p.0.06)

TAMRAD

AI resistant MBC (Bachelot, JCO 2012)

II Tam +Plac Tam+Eve

57 54

CBR:Tam + Plac: 42%; Tam + Eve 61%

PFS: Tam + Plac 4.5 mo; Tam + Eve 8.6* mo OS: Tam + Plac 16 mo; Tam + Eve 31 mo*

BOLERO2

Refractory to NSAI MBC

(Baselga, NEJM 2012, Yardley, Adv Ther 2013, Piccard, Ann Oncol 2014)

III Exe + Plac Exe + Eve

239 485

PFS: Exe + Plac: 4.1 mo; Exe + Eve: 11.0 mo*

OS: Eve+ Plac: 26.6 mo; Exe + Eve 31.0 mo

Randomized Trials of Everolimus in Patients with HR+/HER2- MBC

Everolimus significantly improves PFS in pts with ER+/HER2-MBC whose cancers are resistant to NSAI (FDA/EMA approval, NCCN/ASCO and AIOM guidelines .

* Statistically significant

Toxicities: stomatitis,

mucositis, pneumonia

Prevention of EVE/EXE stomatitis using a dexamethasone-based mouthwash:

the SWISH trial

Rugo HS, et al. ASCO 2016 INCIDENCE OF STOMATITIS

“…Prophylactic use of 0.5 mg/5 mL

dexamethasone oral solution markedly

decreases the incidence and severity of stomatitis in patients

receiving EVE/EXE for MBC and should be

considered a new standard of care in this

setting…”

…can you predict who benefit from mTOR

inhibitors in the clinic…

•The cfDNA analysis suggest that pts with harboring PI3KCA activating mutations derive a similar PFS benefit from everolimus compared to pts without PI3KCA mutations .

•This analysis support the previous observation that everolimus efficacy was indipendent of PI3KCA.

•Limitation of this analysis included the evaluation of only 3 PI3KCA and relatively small samples size for muation Site-specific subgroups.

Moynahan ME, et al. ASCO 2016

Lee JJ, et al. Cancer Biol Med. 2015

PI3K Inhibitors

BELLE-2: Study Design

• Primary endpoints: PFS in overall population, pts with known PI3K activation status (activated or not), and PI3K-activated only group

• Secondary endpoints: OS, ORR, CBR, safety, PK, QoL

• Exploratory endpoint: PFS by PIK3CA mutation status

Postmenopausal women with

HR+/HER2- inoperable locally advanced or metastatic BC, with progression on/after AI

therapy (N = 1147)

Buparlisib 100 mg/day + Fulvestrant 500 mg (n = 576)

Placebo + Fulvestrant 500 mg (n = 571)

Baselga J, et al. SABCS 2015. Abstract S6-01.

Stratified by PI3K pathway activation (yes vs

no vs unknown), visceral disease status

BELLE-2: Results

Median PFS, Mos

Buparlisib + Fulvestrant

(n=576)

Placebo + Fulvestrant

(n=571)

HR P Value

Overall population 6.9 (6.8-7.8) 5.0 (4.0-5.2) 0.78 <.001 PI3K-activated pts 6.8 (4.9-7.1) 4.0 (3.1-5.2) 0.76 .014^†

PFS in entire population:

- 1.9 mos benefit

PFS in PI3K activated

-No difference (4.0 vs 6.8 mos)

Evaluation of PI3KCA mutations in ctDNA

-587 pts analyzed (51%), 34% with PI3KCA mutations

-Toxicity significant

-G3/4 increased AST/ALT (>20%)

-G3/4 Hyperglicemia (15.4%), rash (8%), depression/ansiety (10%)

13% of pts discontinued treatment due to AEs

Future development of pan-PI3K do

not appear be feasible

Placebo + Fulvestrant

(n=571) HR P Value

ctDNA PI3KCA

mutant (n=200) 7.0 (5.0-10.0) 3.2 (2.0-5.1) 0.56 <.001

ctDNA PI3KCA non

mutant (n=387) 6.8 (4.7-8.5) 6.8 (4.7-8.6) 1.05 .642

ctDNA PI3KCA mutant median PFS 7.0 mos vs. 3.2 mos

(HR 0.56) Overall Population

median PFS: 6.9 mos vs. 5.0 mos (HR 0.78)

Baselga J, SABCS 2015

Key Molecular Pathways of Endocrine Resistance

Adapted from Rugo HS, Educational ASCO 2016

Cyclin-dependent protein kinase (CDK) 4/6 Inhibitors

Lange CA, et al. Endocr Relat Cancer 2011 Palbociclib

Abemaciclib Ribociclib

Slide 6

Finn R, at. 2016 ASCO Annual Meeting

PFS: Blinded Independent Central Review<br />Confirms PFS Advantage Observed Using Investigator Assessment

PALOMA-2: Efficacy

“…PALOMA-2 expands and confirms the significant clinical benefit and safety of P+L in ER+/HER2–

ABC pts who had not received prior systemic therapy for their advanced disease…”

Finn R, et al. 2016 ASCO Annual Meeting

Consistency of 1o and 2o Efficacy Endpoints Across PALOMA-1 and PALOMA-2 Studies

Finn R, et al. ASCO 2016

PALOMA-2: Safety

Overall incidence of SAEs was higher in pts receiving Palbociclib + Letrozole vs Placebo + letrozole (19.6%

vs 12.6%).9.7% of pts in the combination arm vs 5.9% in the placebo arm discontinued treatment due to AEs

Finn R, et al. 2016 ASCO Annual Meeting

PFS All population

Cristofanilli M, et al. Lancet 2016

“…Fulvestrant plus palbociclib was associated with significant and consistent improvement in progression-free survival compared with fulvestrant plus placebo , irrespective of hormone-receptor expression level, and PIK3CA mutational

status. The combination could be considered as a therapeutic option for patients with recurrent hormone-receptor- positive, HER2-negative metastatic breast cancer that has progressed on previous endocrine therapy…”

PFS in PIK3CA WT pts

PFS in PIK3CA mutated pts

Analysis of PALOMA 3 in pre-/peri-menopausal women

“…The combination of PAL+F with goserelin is an effective and well-tolerated trt for PreM women who developed endocrine resistant MBC. The data on PAL plus F/goserelin

support its use in HR+ MBC and expands the trt options for PreM women…”

ESR1 Mutation as an Acquired Mechanism of Endocrine Resistance

“The incidence of ESR1

mutations increases dramatically after treatment with long-term endocrine therapy for recurrent

or metastatic ER+ disease”

Prognostic & Predictive role of ESR1 mutation

Rugo HS, et al. Am Soc Clin Oncol Educ Book. 2016

Augusto L, et al. ASCO 2016

PFS by ESR1 mutation in SoFEA

PFS by ESR1 mutation in PALOMA-3

ESR1 positive

ESR1 positive

ESR1 negative

ESR1 negative

Fribbens C, et al. JCO 2016

MONARCH1: Results from phase II study of Abemaciclib, a CDK4/6 inhibitors, as monotherapy, in pts with HR+/HER2-

MBC, after chemotherapy for advanced disease

 Confirmed ORR: 19.7% (all PR);

CBR 42.4%; median OS 17.7 mos.

 Median PFS 6 months (95% CI 4.2, 7.5)

 Median time to response: 3.7 months

 Safety and toxicity profile was

consistent with previous experience

 Serious AEs: 24.2%

 AEs leading to treatment discontinuation:

7.6%

 Generally, diarrhea was experienced early on and resolved quickly

 Median time to onset: 7 days

 Median duration of grade 2= 7.5 days; grade 3= 4.5 days

 Diarrhea was manageable with common anti-diarrheal agents

Dickler M, et al. 2016 ASCO Annual Meeting

Other CDK4/6 Inhibitors in Phase 3 Trial in Advanced ER+/HER2- MBC

 Abemaciclib (LY2835219)

- MONARCH-2 (NCT 02107703)

postmenopausal Fulvestrant +/- Abemaciclib - MONARCH-3 (NCT 02246621)

postmenopausal NSAI +/- Abemaciclib

 Ribociclib (LEE 011)

- MONALEESA-2 (NCT 01958021)

postmenopausal Letrozolo +/- Ribociclib - MONALEESA-3 (NCT 02422615)

postmenopausal Fulvestrant +/- Ribociclib - MONALEESA-7 (NCT 02278129)

premenopausal Endocrine Therapy +/- Ribociclib

May 18, 2016: MONALEESA-2 Trial of LEE011 (Ribociclib) stopped due to

positive efficacy results in PFS at interim analysis in HR+/HER2-

advanced breast cancer

Key Molecular Pathways of Endocrine Resistance

Adapted from Rugo HS, Educational ASCO 2016

Immunotherapy for HR+ MBC: <br />Results of KEYNOTE 028

Hope Rugo ASCO 2016

Future Treatment in HR+ ABC: Reversing Resistance with Combination Therapy

Adapted fron Hope Rugo ASCO 2016

Immunotherapy?

OUTLINE

 New insight in to HR-positive/HER2-negative MBC

 Emerging Therapeutic options in HER2-positive MBC

 Brain Metastases and HER2 disease

 Triple Negative Breast Cancer

 Other

Overview of improvements in OS brought by anti HER2 agents

1 Slamon D, et al. NEJM 2001; ² Cameron D, et al. Oncologist 2010; ³ Geyer CE, et al. NEJM 2006; ⁴ Baselga J, et al. NEJM 2012; ⁵ Swain SM, et al.

NEJM 2015; ⁶ Verma S, et al. NEJM 2012; ⁷ Krop IE, et al. Lancet Oncol 2014; ⁸Wildiers H, et al. SABCS 2015.

CHT

0 10 20 30 40 50 60

20,3

CHT + H 25,1

CAPE 14,88 CAPE + LAP 17,25

D + H 40,8

D + H + P 56,5

Slamon D, 2001

Cameron D, 2011

CLEOPATRA

TPC 25,1

T-DM1 30,9

EMILIA

CAPE + LAP 15,8

T-DM1 22,7

TH3RESA

PHEREXA: Study Design

• Multicenter, randomized, open-label phase III trial

• Primary endpoint: PFS by independent review

• Secondary endpoints: OS, PFS by investigator, TTP, TTF, ORR, CBR, DoR, biomarkers, safety

Urruticoechea A, et al. ASCO 2016. Abstract 504.

Stratified by prior CNS disease, measurable/nonmeasurable disease,

response to first-line trastuzumab

Pts with HER2+

MBC who have received Tmab and a taxane and

progressed during/after Tmab-

based therapy (N = 452)

Pertuzumab* 420 mg IV Q3W + Trastuzumab

6 mg/kg IV Q3W +

Capecitabine 1000 mg/m

PO BID for 14d Q3W (n = 228)

Trastuzumab

6 mg/kg IV Q3W +

Capecitabine 1250 mg/m

PO BID for 14d Q3W (n = 224)

Treated until PD or unacceptable toxicity

*Loading dose: 840 mg IV. ^†Loading dose: 8 mg/kg IV.

PHEREXA: Survival

Urruticoechea A, et al. ASCO 2016. Abstract 504.

PFS (IRF) OS

Cape + Tmab + Pmab Cape + Tmab

Median PFS, Mos

11.1 100 9.0

80 60 40 20 0

PF S (%)

Mos

0 5 10 15 20 25 30 35 40 45 50 55 60 65

Arm A Arm B

224 228

142 165

74 99

38 58

26 39

21 23

11 9

5 5

3 4

2 3

1 2

0 1

0 0 0 0

Cape + Tmab + Pmab Cape + Tmab

Median OS, Mos 36.1 28.1 100

80 60 40 20 0

OS (%)

Mos

0 10 20 30 40 50 60 70 80

Arm A Arm B

224 228

190 205

130 162

51 66

19 31

6 12

0 1

0 0 0

0

HR: 0.82 (95% CI: 0.65-1.02) P = .07

HR: 0.68 (95%CI: 0.51-0.90)

• Addition of pertuzumab to trastuzumab + capecitabine in HER2+ MBC pts progressing during/after trastuzumab:

– Does not significantly improve PFS, as assessed by independent review facility

– Increases median OS by 8 mos; statistical significance could not be claimed due to hierarchical

test of OS after primary endpoint (PFS by IRF)

Management of HER2+ MBC

LG AIOM Mammella 2015

Neratinib: pan-HER inhibitor in HER2-positive MBC

STUDY Phase Drug(s) Population ORR PFS OS

Burstein, 2010 [1] II Neratinib

HER2+MBC with and without

prior trastuzumab

40%

22.3 weeks in prior T and 39.6 in non

prior T

N. R.

Martin M, 2013 [2] II

Neratinib vs.

Lap-Cape

HER2+ MBC, prior trastuzumab

29%

vs.

41%

4.5 mos vs.

6.8 mos

19.7 mos vs.

23.6 mos

Saura C, 2014 [3] I/II Neratinib + Cape

HER2+ MBC, prior trastuzumab and lapatinib

64% (no prior lapatinib) 57% (prior

lapatinib)

9.27 mos (no prior lapatinib) 8.26 mos (prior

lapatinib)

N.R.

TBCRC 022 [4] II Neratinib HER2+, BMs 8%* 1.9 mos N.R.

NEfERT-T [5] II

Neratinib-Tax vs.

H-Tax

HER2+, 1^st line

74.8%

vs.

77.6%

12.9 mos

vs. 12.9 mos N.R

1 Burstein HJ, JCO 2010; ²Martin M, et al. Eur J Cancer 2013; ³Saura C, et al. JCO 2014; ⁴Freedman RA, et al. JCO 2016; ⁵Awada A, et al. JAMA Oncol 2016

* Intracranial ORR

Heritage: A phase III safety and efficacy trial of the proposed trastuzumab biosimilar Myl-1401O versus Herceptin

Rugo HS, et al. ASCO 2016; Verma S. ASCO 2016

OUTLINE

 New insight in to HR-positive/HER2-negative MBC

 Emerging Therapeutic options in HER2-positive MBC

 Brain Metastases and HER2 disease

 Triple Negative Breast Cancer

 Other

HER2+ Brain Metastases

 A challenge born out of progress

 Significant advanced in HER2+

metastatic disease

 CNS tropism

 Excellent local therapy options:

stereotactic surgery

 Limited systemic options

 In the RegisHER study 37% of pts with HER2+ BC had brain mts detected over the study

 7% of diagnosis

 30% over course of their disease

 Worse outcome with presence of brain mts

 median survival 26.3 months with vs 44.6 months without

Sperduto PW, et al. J Neurooncol. 2013; Brufsky AM, et al. Clin Cancer Res 2011

Emerging therapeutic agents in HER2-positive BMs

Borges VF, et al. ASCO 2016

Phase 1b study of ONT-380, a CNS-penetrant TKI, in combination with T-DM1 in HER2+ MBC,

including pts with BMs

Phase I trial with the CNS penetrant TKI Tesevatinib in combination with Trastuzumab

in HER2+ MBC

Lin NU, et al. ASCO 2016

 Tesevatinib is a potent EGFR inhibitor and also inhibits HER2 and SRC while crossing the BBB in whole animal models and achieving CNS levels similar to plasma.

 This dose escalation study defined the MTD of

tesevatinib in HER2+ BC pts when combined with

trastuzumab 6 mg/kg IV every 3 weeks.

OUTLINE

 New insight in to HR-positive/HER2-negative MBC

 Emerging Therapeutic options in HER2-positive MBC

 Brain Metastases and HER2 disease

 Triple Negative Breast Cancer

 Other

Basal-like 1: cell cycle, DNA repair and

proliferation genes

Basal-like 2: Growth factor signaling (EGFR, MET, Wnt, IGF1R)

IM: immune cell

processes (medullary breast cancer)

M: Cell motility and differentiation, EMT processes

MSL: similar to M but

growth factor signaling, low levels of proliferation genes (metaplastic cancers)

LAR: Androgen receptor and downstream genes, luminal features

Lehmann et al JCI 2011

New classification of TNBC

Pathways, Targets and Emerging Targeted Agents in TNBC

Mayer IA, et al. Clin Cancer Res 2014: Lehmann BD JCI 2011

LAR SUBTYPE & AR IHC EXPRESSION IN TNBC: rationale for AR inhibition

[1] Agoff SN, et al. Am J Clin Pathol. 2003; [2] Choi JE, et al. Ann Surg Oncol. 2015; [3] Cochrane DR, et al. Breast Cancer Res.

2014; [4] Micello D, et al. Virchows Arch. 2010; [5] Ricciardi GRR, et al. PLoSONE 2015; [6] Lehmann BD, et al. J Clin Invest 2011

 AR is expressed in > 85% of all breast cancer subtypes

 Prevalence of AR by IHC

:

 TNBC: 15% to 20%

 AR expression in TNBC is associated with a more favorable outcome

Luminal AR:

• Older age

• Often G1-G2

• Rarely BRCA mutated

• Often PDL-1 positive

Agent MOA Pt Population Efficacy Drug-Related AEs Enzalutamide

Inhibits

androgen binding to AR,

AR nuclear translocation/

DNA binding

AR+ mTNBC  CBR16: 35%

(26/75)

 CBR24: 29%

(22/75)

 CR or PR: 3%

(6/75)

 mPFS: 14.7 wks

G1: fatigue, nausea, decreased appetite, constipation, diarrhea; G3:

fatigue (5%), constipation, back pain, and dyspnea

(1% each)

Abiraterone acetate + prednisone

Irreversible inhibitor of androgen-

producing enzymes

(CYP17)

AR+ mTNBC  CBR (6 mos): 20%

(1/34, CR; 5 with SD ≥ 6 mos, 1 pt PR at 12 mos)

 mPFS: 2.8 mos

G1: fatigue, nausea;

hypertension, hypokalemia;

G3: hypertension, adrenal insufficiency, hypokalemia

Bicalutamide

Androgen antagonist

AR+ ER/PgR- LA or MBC

 CBR (6 mos): 19%

(5/26, SD > 6 mos;

no CR or PR)

 mPFS: 12 wks

G1: limb edema, fatigue, hot flashes, transaminase

elevations; G3: 1 pt with liver enzyme abnormalities TAK-700

Androgen

synthesis inhibitor

AR+ mTNBC  Response Rate (Ongoing)

-

Phase II Trials of Androgen Receptor Inhibitors in mTNBC

1. Traina T, et al. ASCO 2015. Abstract 1003; 2. Bonnefoi H, et al. Ann Oncol. 2016;3. Gucalp A, et al. Clin

Cancer Res. 2013;19:5505-5512; 4..NCT01990209

Enzalutamide:additional results

AR-driver biology

1.Traina T, et al. ASCO 2015; 2. Cortes J, ESMO 2015

Immunotherapy and TNBC

Analysis of TGCA data showed higher

expression of PD-L1 mRNA in TNBC than non- TNBC (p< 0.001) (Mittendorf EA, et al. Cancer Immunol Res 2014)

Lehman B, et al. unpublished (from TCGA)

TNBC MUTATIONAL LOAD

García-Teijido P, et al. Clin Med Insights Oncol. 2016 Nivolumab

Pembrolizumab Avelumab Durvalumab

Ipilimumab Tremelimumab

Lehmann et al JCI 2011

“…The durability of response observed with pembrolizumab monotherapy in heavily pretreated mTNBC (median not reached;

range, 15.0 to . 47.3 weeks), including three responders who remain on study and have received treatment for > 1 year, is promising, given

that the duration of response to standard chemotherapy in this population is, at best, 4 to 12 weeks. This phase Ib study describes preliminary evidence of clinical activity and a potentially acceptable safety profile of pembrolizumab given every 2 weeks to patients with

heavily pretreated, advanced TNBC. ..”

PFS: 1.9 months 6-month PFS rate of 24.4%

OS: 11.2 months, 6-month and 12-month OS

rates: 66.7% and 43.1%

Nanda R, et al. JCO 2016

Atezolizumab + nab-paclitaxel in TNBC: a phase Ib trial

Adams S, et al. ASCO 2016

ANTI-PD1/PDL1 mAbs IN mTNBC:

WHERE ARE WE GOING

NAME PHASE POPULATION DRUG(S) PRIMARY

ENDPOINT(S) NCT02648477 II TNBC/HR+ MBC Pembrolizumab + Doxorubicin Hydrochloride or

Exemestane

Safety and ORR in unselected pts NCT02513472 I/II mTNBC, previous 0-2 lines Pembrolizumab + Eribulin mesilate Safety and ORR KEYNOTE-162 I/II mTNBC, 1-2 previous lines Pembrolizumab + Niraparib Estimate RP2D and

ORR KEYNOTE-086 II mTNBC, treatment-naïve

(PDL1+) and pretreated Pembrolizumab ORR

KEYNOTE-119 III mTNBC, 1-2 previous lines of therapy

Pembrolizumab vs. TPC (capecitabine, eribulin,

gemcitaine, vinorelbine) PFS, OS

NCT02755272 II mTNBC, 0-2 previous lines

of therapy Pembrolizumab + Carboplatin/Gemciitabine ORR, Safety IMpassion130 III mTNBC, 1^st line Atezolizumab + nab-paclitaxel vs. nab-paclitaxel PFS, OS NCT02708680 I/II advanced TNBC, <2 lines Atezolizumab + Entinostat RP2D, PFS

TONIC II mTNBC, 1-3 previous lines Nivolumab After Induction Treatment with radiation,

doxorubicin, cyclophosphamide or cisplatin PFS

NCT02628132 I/II mTNBC, PDL1+, >1 line Durvalumab + Paclitaxel Safety

NCT02536794 II mTNBC, >1 previous line Durvalumab + Tremelimumab ORR

NCT02484404 I/II mTNBC and ovarian cancer Durvalumab + Olaparib ± Cediranib Estimate RP2D, ORR

LG AIOM Mammella 2015

AI (Let) + AI CDK4/6

AI (Exe) +

mTOR Fulv + Chemo

CDK4/6 After surgery and

adjuvant treatment

1st progression

to MBC 2nd 3rd 4th

ER+

TNBC

PFS

PFS

Single agent ET

Chemo Chemo+ Immunotherapy

Delaying Chemotherapy: Future

Treatment Strategies for TNBC

Delaying Chemotherapy: Future Treatment Strategies for TNBC

AR inhibitor AR

combo? Chemo

AR+

TNBC

AI (Let) + AI CDK4/6

AI (Exe) +

mTOR Fulv + Chemo

CDK4/6

ER+

PFS

Single agent ET

5th

PFS

After surgery and adjuvant treatment

1st progression

to MBC 2nd 3rd 4th

TNBC

PFS

Chemo + Immunotherapy Chemo

OUTLINE

 New insight in to HR-positive/HER2-negative MBC

 Emerging Therapeutic options in HER2-positive MBC

 Brain Metastases and HER2 disease

 Triple Negative Breast Cancer

 Others

Overall survival of patients with HER2-negative metastatic breast cancer treated with a first-line paclitaxel with or without

bevacizumab in real-life setting: Results of a multicenter national observational study.

Delalonge S, et al. ASCO 2016

“...In this large-scale real-life setting database, patients with HER2-negative mBC who received P+B had a significantly

better OS and PFS than those receiving P alone...”

median OS was 27.7 vs.

19.8 mos (HR 0.67).

Despite robust methodology, real-world data

should be interpreted with

caution.

MF07-01: Study Design

• Multicenter phase III trial

• Primary endpoint: OS

• Secondary endpoints: morbidity and mortality, locoregional progression/relapse, QoL

Treatment-naive pts with de novo

stage IV breast cancer

amenable for complete resection (N = 274)

Local Resection of Breast ± Axilla

(n = 138)

Systemic Therapy (n = 136)

Local Therapy for Local Progression Systemic Therapy

•Chemotherapy given to all pts either immediately after randomization in ST arm or after surgical resection in the surgery arm.

•All women with HR+ BC received HT & c-ErbB2 positive pts received Trastuzumab

Soran A, et al. ASCO 2016

Slide 13

Surgery improved median survival by 9 mos

MF07-01:Results

Soran A, et al. ASCO 2016

MF07-01: OS by Pt Subgroups

Locoregional progression/relapse: surgery, 1% (n = 2); systemic therapy, 11% (n = 15); P = .001 5-Yr Survival, % Median OS, Mos

Subgroup Surgery ST P Surgery ST P

ER/PR+ (n = 218) 46.4 26.4 .011 49 42 .01

HER2/neu- (n = 189) 41.9 23.1 .012 46 34 .01

< 55 yrs of age (n = 159) 46.9 24.0 .01 56 42 .007 Bone only metastasis (n = 126) 45.1 31.1 .12 56 42 .09 Solitary bone metastasis (n =

53) 51.7 29.2 .038 45 35.5 .04

Multiple pulmonary/liver

metastases (n = 28) 31* 67* .05 17 48 .39

No locoregional

progression/relapse (n = 257) -- -- -- 46 33 .001

Soran A, et al. ASCO 2016. Abstract 1005.

*3-yr survival.

LG AIOM Mammella 2015

Grazie!