III Sessione Carcinoma della mammella - Aiom III Sessione Carcinoma della mammella Novità nel ......

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

HR +

HER2 +

Triple Negative

10% to 15%2

25% to 30%1

60% to 70%3

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[1]

• Postmenopausal Patients: AIs due to improved efficacy vs tamoxifen[1]

• Fulvestrant has demonstrated similar efficacy vs tamoxifen[5]

• Preliminary evidence suggests that fulvestrant may demonstrate improved

efficacy vs anastrozole[6,7]

– TTP, fulvestrant vs anastrozole: 23.4 vs 13.1 mos[6]

AI Parameter AI vs Tamoxifen, Mos

Anastrozole[2] TTP 10.7 vs 6.4

Letrozole[3] TTP 9.4 vs 6.0

Exemestane[4] 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 Provenzano A, et al. Expert Rev. Anticancer Ther. 2012

Musgrove EA, et al. Nat Rev Cancer 2009

Augusto L, et al. ASCO 2016.

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 Median PFS, Mos Buparlisib +

Fulvestrant (n=576)

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


Resistance


Cyclin-dependent protein kinase

(CDK) 4/6 Inhibitors

Lange CA, et al. Endocr Relat Cancer 2011

Palbociclib

Abemaciclib

Ribociclib

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


postmenopausal Fulvestrant +/- Ribociclib


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


Resistance


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





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 [1]

Cameron D, 2011 [2,3]

CLEOPATRA [4,5]

TPC 25,1

T-DM1 30,9 EMILIA [6]

CAPE + LAP 15,8

T-DM1 22,7 TH3RESA [7,8]

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/m2 PO BID for 14d Q3W

(n = 228)

Trastuzumab† 6 mg/kg IV Q3W +

Capecitabine 1250 mg/m2 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

9.0 100

80

60

40

20

0

PF

S (

%)

Mos

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

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 80 10 20 30 40 50 60 70

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+, 1st 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





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





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 IHC1-6:

TNBC: 15% to 20%

AR expression in TNBC is associated with a more favorable

outcome5

Luminal AR:

• Older age

• Often G1-G2

• Rarely BRCA mutated

• Often PDL-1 positive

Agent MOA Pt Population Efficacy Drug-Related AEs

Enzalutamide[1] 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[2]

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[3] 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[4]

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, 1st 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

AI AI (Let) +

CDK4/6

AI (Exe) +

mTOR Chemo

Fulv +

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 AI (Let) +

CDK4/6

AI (Exe) +

mTOR Chemo

Fulv +

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





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

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.

Grazie!

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