Treatment of Metastatic

TRIPLE NEGATIVE BREASTCANCERSRebecca Dent, MD FRCP (Canada)Senior Consultant, Medical Oncology

Overview of TNBC

Still best way to define in clinical practice!?

Treatment options and survival vary greatly by breast cancer subtype

Metastatic breast cancer survival: SEER data1,2

TNBC15%

HER2+20%

ER/PR+65%

Chemotherapy+/-BevacizumabPARPi (BRCA)

TrastuzumabT-DM1PertuzumabLapatinibNeratinibChemotherapy

TamoxifenAromatase inhibitorsFulvestrantCDK4/6 inhibitorsmTOR inhibitors

100

80

60

40

20

00 10 20 30 40 50

Surv

ival

(%

)

Survival (months)

Log-rank p

4

How Can TNBC be Stratified?

Perou C, SABCS 2016

5

Clinically Targetable Pathways in TNBCN

um

be

r o

f s

am

ple

s w

ith

ab

err

ati

on

s

PI3K/mTOR DNA Repair Ras/MAPK Cell Cycle GFRs0

10

20

30

40TSC1

PIK3CA

PTEN

PIK3R1

RICTORRAPTORAKT1AKT2

AKT3

BRCA1

BRCA2ATM

RB1

AURKA

CDNK2A

CCNE1

CCND3

CCND2

CCND1

CDK6CDK4

NF1CRAFBRAF

KRASEGFR

MET

IGF1RKITFGFR1

FGFR2

FGFR4

PI3K/mTOR/AKT inhibitors

Targeted RTK inhibitors

DNA-repair targeting

agents

Cell cycle/mitotic spindle inhibitors

RAF/MEK inhibitors

~90% of all patients had an aberration in at

least one of these pathways

IMMUNOTHERAPY

Balko JM et al. Cancer Discovery 2014.

6

Epidemiology

Foulkes WD et al. NEJM 2010.

7

HR of Progression & Death: TNBC vs non-TNBC

Dent R, CCR 2007 Liedtke C, JCO 2008

Median Time to Distant RecurrenceTNBC = 2.6 yrsOther = 5 yrsp < 0.0001

0.35

0.30

0.25

0.15

0.10

0.05

0

HR

0.20

0 1 2 3 4 5 6 7 8 9 10

Yrs After First Surgery

Other (290 of 1421)Triple negative (61 of 180)

8

Chemosensitivity of TNBC:Post-NACT pCR & Survival

Liedtke C, JCO 2008

CTneoBC, Lancet 2014

1.0

0.9

0.8

0.7

0.6

0.5

0.41

Yrs After Surgery2 3 4 5 6 7

Pro

bab

ility

of

Bei

ng

Aliv

e

pCR/non-TNBCpCR/TNBCRD/non-TNBCRD/TNBC

98%94%

88%

68%

P = .24

P = .0001

von Minckwitz G, JCO 2012

9Kassam F …Dent et al BCRT 2009

10

What are the treatment options for metastatic TNBC in 1st line and beyond?

• Taxane (+/- Bevacizumab)• Nab-paclitaxel• Platinum single agent• Platinum combination (e.g. Gemcitabine/platinum)• Eribulin• Capecitabine (+/- Ixabepilone)• Vinorelbine (+/- Capecitabine)• Anthracycline (including liposomal)• Low dose Cyclophosphamide/MTX or CMF• Oral etoposide• Clinical trials

If given in the adjuvant setting, a taxane can be re-

used as 1st line therapy, particularly if there has

been at least one year of disease-free survival

(LoE: 1 A) (92%).

HER-2 NEGATIVE MBC

?

(01)

(00)

(43)

(44)

2.2%

0.0%

97.7%

Total # of votes:

1. YES:

2. NO:

3. ABSTAIN:

TRIPLE NEGATIVE ABC

New statement

For non-BRCA-associated triple negative ABC, there are no data supporting different or specific CT recommendations. Therefore, all CT recommendations for HER-2 negative disease also apply for triple negative ABC.(LoE: 1 A)

13

Study 301: Eribulin vs Capecitabine in Previously Treated LABC or MBC

Eribulin Mesylate 1.4 mg/m2

D1,8 q21d(n = 554)

Capecitabine 1250 mg/m2 BDD1-14 q21d

(n = 548)

≤3 prior chemo(≤2 for advanced disease)

prior anthracycline & taxaneN = 1102

Stratified by geographical region, HER2 status

Kaufman PA et al, JCO 2015.

14

Study 301: Eribulin vs Capecitabine

Twelves C et al, Breast Cancer (Auckl) 2016.

Overall 0.879 (0.770, 1.003) 15.9 14.5

HER2 status

Positive 0.965 (0.688, 1.355) 14.3 17.1

Negative 0.838 (0.715, 0.983) 15.9 13.5

ER status

Positive 0.897 (0.737, 1.093) 18.2 16.8

Negative 0.779 (0.635, 0.955) 14.4 10.5

Triple negative

Yes 0.702 (0.545, 0.906) 14.4 9.4

No 0.927 (0.795, 1.081) 17.5 16.6

Subgroup HR (95% CI) Eribulin CapecitabineMedian (months)

ITT population

0.2 0.5 1.0 2 5

n=755

n=449

n=284

Favours Eribulin Favours Capecitabine

15

TNT: Carboplatin vs Docetaxel in Advanced TNBC or BRCA1/2+ Breast Cancer

Tutt A et al. SABCS 2014.

16

TNT: ORR of Carboplatin vs Docetaxel in Advanced TNBC or BRCA1/2+ Breast Cancer

Tutt A et al. SABCS 2014.

0

10

20

30

40

50

60

70

80

90

Res

po

nse

at

Cyc

le 3

or

6 (

%)

All Pts(n = 376)

C→D D→CCrossover*

(All pts; n = 182)

BRCA1/2 Mutation(n = 43)

No BRCA1/2Mutation(n = 273)

31.4%35.6%

22.8%25.6%

P = .44

P = .73

68.0%

33.3%

P = .03

28.1%

36.6%P = .16

CarboplatinDocetaxelCrossover

*Excludes those with no first progression or not starting crossover treatment.

17

TNT: Platinum Sensitivity Was Not Associated with Higher HRD Scores in mTNBC

Tutt A et al. SABCS 2014.

19/65(29.2%)

17/49(34.7%)

0 20 40 60 80 100

Carboplatin

Docetaxel

Percentage with OR at #3 or #6 (95% CI)

13/34(38.2%)

20/47(42.6%)

0 20 40 60 80 100

Carboplatin

Docetaxel

Percentage with OR at #3 or #6 (95% CI)

17

Absolute difference (C-D)-4.4% (95% CI -26.0 to 17.2)

Exact P = 0.82

High HRD score(n = 81)

Low HRD score(n = 114)

Absolute difference (C-D)-5.4% (95% CI -22.7 to 11.9)

Exact P = 0.55

Interaction: randomised treatment & dichotomised HRD score: P = 0.91

?

(02)

(02)

(39)

(43)

4.6%

4.6%

90.6%

Total # of votes:

1. YES:

2. NO:

3. ABSTAIN:

TRIPLE NEGATIVE ABC

New statement

In triple-negative ABC patients (regardless of BRCA status), previously treated with anthracyclines with or without taxanes in the (neo)adjuvant setting, carboplatin demonstrated comparable efficacy and a more favorable toxicity profile, compared to docetaxel, and is therefore an important treatment option.

(LoE: 1 A)

?

(04)

(02)

(38)

(44)

9.0%

4.5%

86.3%

Total # of votes:

1. YES:

2. NO:

3. ABSTAIN:

In patients with BRCA-associated triple negative or endocrine-resistant MBC previously treated with an anthracycline with or without a taxane (in the adjuvant and/or metastatic setting), a platinum regimen is the preferred option, if not previously administered and no suitable clinical trial is available.

(LoE: 1 A)

All other treatment recommendations are similar to sporadic MBC.

BRCA-associated MBC

Modified statement

20

Olaparib: Phase II Study in gBRCA mut Breast Cancer

Tutt A et al. Lancet 2010.

• Proof-of-concept phase II trial

• Olaparib 400 mg BD group:

– N = 27

– 67% BRCA1

– 50% TNBC

– Median 3 prior lines

Olaparib versus physicians’ choice: the phase III OLYMPIAD study

Robson et al, New Engl J Med 2017

Olaparib

300 mg bd

Chemotherapy

TPC

163 (79.5) 71 (73.2)

7.0 4.2HR 0.58

95% CI 0.43 to 0.80; P=0.0009

Primary end point: centrally-evaluated PFS

22

Clinical Practice?

• Not clear how it compares to platinum or if

efficacy similar in platinum resistant patients

• Not recommended in unselected TNBC

23

TNBC ER positive

Mutation rate higher in TNBC compared to other subtypes

Luminal ALuminal BHER2BasalNormal

SynonymousNonsynonymous

10864

02

No

. mu

tati

on

s/M

b

Somatic mutations in breast cancer subtypes

Are All Cancers Equally Suitable for Immunotherapy?

Banerji S, et al. Nature. 2012;486(7403):405-409.

24

Immune Checkpoint Inhibitors in mTNBC

Nanda et al, JCO 2016; Schmid et al, AACR 2017; Dirix et al, SABCS 2015

Pembrolizumab(n = 32)

Atezolizumab (n = 71)

Avelumab(n=58 /9)

Target PD-1 PD-L1 PD-L1

Tumour PD-L1 ≥1% (58%+) ≥5% All / ≥1%

ORR 18.5% 13% 8.6% / 44.4%

SD 25.9% 18% 22.4%

• Durable responses in heavily pre-treated pts

25

Pembrolizumab Antitumor Activity in Previously Treated and Previously Untreated mTNBC

Cohort A (N = 170): Previously Treated,

Regardless of PD-L1 Expression

Cohort B (N = 52)1: Previously Untreated,

PD-L1 Positive

0

4

8

12

16

20

24

28

32

36

40

OR

R, %

0

4

8

12

16

20

24

28

32

36

40

OR

R, %

23.1%

Complete response

Partial response

Total PD-L1Positive

PD-L1Negative

Total(All PD-L1 Positive)

Stable disease≥24 wk

4.7%

9.5%7.6%

26

Combination Immune-and Chemotherapy in

TNBCNab-Paclitaxel + anti-PD-L1 (atezolizumab)

Adams S, SABCS 2015; Tolaney, S SABCS 2016, ESMO 2017

2nd/≥3rd line Patients

1st line Patients

All1st line

(n=17)

2nd/3rd L

(n=18)

ORR 34.4% 41.2% 27.3%

CBR 40.6% 47.1% 36.4%

Eribulin + anti-PD-1 (pembrolizumab)

Independent

of PD-L1

status

27

Basal immune activated

Basal immune suppressed

Mesenchymal

Luminal AR

TNBC: Gene expression subtypes (Baylor)

Heterogeneity of TNBC and Immunotherapy Strategies

Basal-like

Luminal

Inflamed

Uninflamed

Single agent immune therapy (eg, PD-1; PD-L1)

Combination immune therapy (eg, PD-1/PD-L1;

CTLA4)

Modify antigens?

Adapted from: Burstein MD, et al. Clin Cancer Res. 2015;21(7):1688-1698.

28

Clinical Practice

• No evidence of immune check point inhibitors

outside of clinical trials (many ongoing!!!)

Randomised, non-comparator, international, AZ Investigator Initiated TrialAnd Duke-Singapore/Duke-USA Collaborative Grant for Translational Studies

DORA Study Design: A Randomized Phase 2 Maintenance study of PARP Inhibition alone vs PARP Inhibition + Anti-PD-L1 therapy

Olaparib 300mg bid daily

1° Endpoint = PFS

Olaparib 300mg bid daily

Eligibility:

• Mets TNBC

• Response after 4 cycles of platinum chemo as 1st or 2nd line therapy

R

A

N

D

O

M

I

Z

E

D

Durvalumab 1500mg q 4 weeklyCT q8 weeks

R Dent, T Tan and K Blackwell

30

Targeting the Androgen Receptor (AR) in TNBC

Bicalutamide Enzalutamide

RR (%) 0 7.7

CBR (%) 19 34.6

Enzalutamide

MDV3100-11. Cortes J et al, IMPAKT 2015.TBCRC011. Gulpa A et al, CCR 2013.

AR-Driven Biology in TNBC using Gene Expression Profiling Assay

Parker et al, ASCO 2015

31

Is AR PREDICT picking out good prognosis

TNBC?Progression-Free Survival

ITT Population 100

80

60

40

20

0

Pro

gre

ssio

n-F

ree

Su

rviv

al

(%)

0 8 16 24 3341 49 6164 80 85Weeks

Subpopulation 0–1 Prior Regimens100

80

60

40

20

0

Pro

gre

ssio

n-F

ree

Su

rviv

al (%

)

0 8 16 24 33 41 49 6164 80 85Weeks

ITT Population100

80

60

40

20

0

Ove

rall

Su

rviv

al (%

)

Weeks0 8 16 24 33 41 49 6164 10285

Subpopulation 0–1 Prior Regimens100

80

60

40

20

0

Ove

rall

Su

rviv

al (%

)

Weeks0 8 16 24 33 41 49 6164 10285

Dx+ (n = 26)mPFS 32.3 weeks(95% CI: 14.7, 60.3)

Dx− (n = 36)mPFS 8.3 weeks(95% CI: 7.1, 16.1)

Dx+ (n = 56) mPFS 16.1 weeks(95% CI: 10.4, 27.4)

Dx− (n = 62)mPFS 8.1 weeks(95% CI: 7.4, 12.6)

Dx+ (n = 56)

mOS 21.3 months(95% CI: 12.9, 21.3)

Dx+ (n = 28) mOS NYR(95% CI: 14.0, NYR)

Dx− (n = 62)

mOS 7.5 months(95% CI: 4.8, 11.2)

Dx− (n = 37)

mOS 10.1 months(95% CI: 6.6, NYR)

Overall Survival

Dx+ Dx–

32

Clinical Practice?

33

LOTUS: AKT Inhibition in mTNBC

Stratified by

• (Neo)adjuvant chemo (yes vs no)

• Chemo-free interval (≤12 vs >12 mo vs no prior)

• Tumour PTEN status (H-score 0 vs 1-150 vs >150, by Targos IHC)

• LABC/MBC• No prior systemic therapy for

ABC/MBC• Archival or newly obtained tumor

tissue for central PTEN assessment• Chemo-free interval ≥6 mo

N = 124

R1:1

Paclitaxel 80 mg/m2 D1, 8, & 15 + Ipatasertib 400 mg OD D1-21 q28d

Paclitaxel 80 mg/m2 D1, 8, & 15 + placebo D1-21 q28d

Treatment until PD, intolerable toxicity, or withdrawal of consent

Dent R ASCO 2017; Kim SB et al, Lancet Oncol 2017

34

LOTUS: AKT Inhibition in MBC

Dent R ASCO 2017; Kim SB et al, Lancet Oncol 2017

35

LOTUS: AKT Inhibition in MBC

PFS

(%

)

PIK3CA/AKT1/PTEN Altered* Ipat + Pac(n = 26)

Pbo + Pac(n = 16)

PFS events, n (%) 12 (46) 13 (81)

mPFS, mos (IQR) 9.0 (3.7-NE) 4.9 (1.9-6.3)

Unstratified HR (90% CI) 0.44 (0.22-0.87)

100

80

60

40

20

0

Ipatasertib + Paclitaxel (n = 26)Placebo + Paclitaxel (n = 16)

0 2 4 6 8 10 12 14 16 18Mos

Dent R ASCO 2017; Kim SB et al, Lancet Oncol 2017

36

Cell Surface Markers: Targets for Antibody-Drug Conjugates

37

Glembatumab (gpNMB) vedotin (CDX-011):

Antibody Drug Conjugates

ParameterHigh gpNMB

Expression

Triple Negative &

High gpNMB

Expression

CDX-011

n=25

IC

n=8

CDX-011

n=12

IC

N=4

Response 32% 13% 33% 0%

Disease Control Rate 64% 38% 75% 25%

Median PFS (months) 2.7 1.5 3.0 1.5

p=0.14 p=0.008

Median OS (months) 10.0 5.7 10.0 5.5

p=0.18 p=0.003

CR011 Ab MMAE

GPNMB

Cell membrane

CDX-011 binds to GPNMB

on cancer cells

vc Linker

CDX-011 is internalized

and the linker is cleaved

by endosomal enzymes

Cleavage

Free MMAE inhibits

tubulin polymerization,

leading to cell death

Tubulin inhibition

Binding

Rose AA, et al. CCR 2010

38

METRIC: Ongoing Phase III Trial

Pts with mTNBCoverexpressing gpNMB

(≥ 25% tumour cells by IHC)N = 300 Capecitabine

1250 mg/m2 BDD1-14 q21d

Glembatumumab vedotin1.88 mg/kg IV

D1 q21d

Treat until unacceptable toxicity or PD

Tumour assessments (6w intervals x 6 mo; 9w intervals thereafter) until documented PD

Survival follow-up (12w intervals)

RA

ND

OM

ISE

2:1

• Study at approx 100-150 sites in US, Canada and Australia

• Primary endpoint: PFS

39

Sacituzumab Govitecan (IMMU-132)

• Humanised IgG Antibody against Trop-2

• Conjugated with a pH-sensitive linker to SN-38

• Heavily pretreated TNBC

• Median number of prior therapies = 4 (1-11)

40

Sacituzumab Govitecan: FDA Breakthrough Designation

Bardia A et al. JCO 2017.

ORR 30%

41

Case AH

• 38F previously well, nulliparous, no family

history

• Sep 2011

– 3.5cm, Grade 3, 2 LN +, TNBC

– BRCA negative

– Treated with AC-weekly paclitaxel completed Jan

2012

42

AH cont…

• 2 years after completion of adjuvant

chemotherapy, presents with…

– Cough, SOBOE, nausea and headaches

– CT CAP – multiple pulmonary nodules consistent with

metastases, left supraclavicular LN and mediastinal

LN

– CT brain – multiple CNS metastases

• Biopsy of supraclavicular LN = TNBC

• Treated with Whole brain radiation treatment

43

CNS & Lung metastases

44

Question 1:

What systemic therapy would you offer this patient? (note: recent CNS mets post WBRT, ineligible for trial – received adjuvant AC-T 2 years ago)

1. Taxane single agent

2. Eribulin

3. Capecitabine +/- Navelbine

4. Platinum alone

5. Platinum combo (ie. Carbo/Gem)

6. Other

45

AH cont…

Patient treated with 3 cycles of carbo/gem with

resolution of cough and SOB and first restaging

scan shows response

46

After 3 cycles Carbo/Gem

47

After 6 cycles, significant

myelosuppression, pt requesting

break…

• Chemo break

• Continue carbo/gem until max response or

toxicity

• Continue carboplatin only

• Switch to maintenance oral cyclo/MTX

• Switch to maintenance oral capecitabine

• Switch to other chemo

• Palliative care

Usually each regimen (except anthracyclines) should be given until

progression of disease or unacceptable toxicity. What is considered

unacceptable should be defined together with the patient.

(LoE: 1 B) (72%)

49

AH cont…

• Unfortunately after 6 cycles, by the time patient

had restaging scans - new onset cough and

mild hemoptysis (i.e. patient didn’t get

opportunity to make decision)

50

AH cont…

• What will you offer her?

1. Eribulin

2. Capecitabine +/- Vinorelbine

3. Taxane

4. Liposomal doxorubicin

5. CMF (oral or IV)

6. Palliative Care

7. Other

51

AH cont…

• After cycle 1 clinical improvement with resolution

of hemoptysis and cough

• After cycle 3, new onset fever, worsening cough

and hemoptysis

52

AH cont…

• Patient worked up for pembrolizumab trial,

biopsy sent for central review, ER 30% +, thus

ineligible for trial

• And Asx Progression of

Brain Metastases

53

AH cont…

• Asymptomatic brain metastases – minimal

burden of disease, opted not to treat

• What would you offer her now?

54

In Practice: Management of Metastatic TNBC

• No standard chemotherapy• mOS remains 12mo – get pall care early!• PARP inhibitors show very promising results await

approval for germline BRCA• Immunotherapy

– Await results of ongoing trials– Single agent vs combination therapy– Need for predictive signature

• PIK3CA/mTOR/AKT pathway is intriguing• Await Phase III data on ADCs• Refer tor trials early!!

55