Systemic treatment for - PowerPoint Presentation

Slide1

Systemic treatment for breast cancer brain metastases: New options and future directions

Chris TwelvesProfessor of Clinical Cancer Pharmacology and OncologyLeeds Institute of Cancer and PathologyUniversity of Leeds andSt James’s Institute of Oncology, Leeds

Slide2

Systemic treatment for BC BM: New options and future directionsThe challenge of BC BMEtirinotecan pegolThe BEACON study Patients with BC BMSupporting evidenceConclusions

Slide3

Systemic treatment for BC BM: New options and future directionsThe challenge of BC BMEtirinotecan pegolThe BEACON study Patients with BC BMSupporting evidenceConclusions

Slide4

Challenge of Metastatic Breast Cancer With Brain MetastasesBreast cancer is the 2nd most common solid tumor for brain metastasesUp to 50% of HER2+ subtypeFrom 25-46% of TNBC subtypeRising incidence, most likely due toLonger natural history of MBC (especially HER2 +ve)Better imaging and lower threshold for imaging/screening

Median survival after diagnosing brain metastases ~ 6 monthsNancy Lin Breast cancer brain metastases: new directions in systemic therapyecancer medicalscience 2013-see references 4,6-8 for incidence and 14-19 for survivalBrufsky et al Clin Cancer Res 2011, 17, 4834-43Pivot et al SABCS 2011

Slide5

Witzel, 6th Annual Brain Metastases Research and Emerging Therapy Conference

Breast cancer brain metastases after 2000and received surgical resection of the brain metastasesand/or radiotherapy of the brain metastasesand/or systemic therapy for metastatic breast cancer. KPS > 70%

Characteristics

Number

Median (

range) or

percentage

Median

age

at

diagnosis

of

BM (

range)153556.0 years (22 – 90 yrs) Primary tumor subtypeHER2-positive 61246.6 % Triple-negative28421.6% Luminal 41831.8%

GBG 79:

Brain Metastases in Breast Cancer Network Germany (BMBC)

Slide6

Witzel, 6th Annual Brain Metastases Research and Emerging Therapy Conference

Breast cancer brain metastases after 2000and received surgical resection of the brain metastasesand/or radiotherapy of the brain metastasesand/or systemic therapy for metastatic breast cancer. KPS > 70%GBG 79: Brain Metastases in Breast Cancer Network Germany (BMBC)Survival and subtypesMedian OS 7 months

HER2 +ve: 11.2 monthsLuminal 5.6 months,

TNBC 4.4 months

Slide7

Graded prognostic index modified for breast cancer and incorporating BC subtypePrognosis of patients with MBC and brain metastases

Subbiah et al, J Clin Oncol 2015, 33, 2239 - 2245

Slide8

Loco-regional management of MBC brain metastases: Whole brain RT (WBRT)

Standard treatment for poor prognosis patients with multiple lesions, poor PS, uncontrolled systemic diseaseCan improve symptomsSignificant toxicityMagnitude of benefit uncertain

Slide9

Loco-regional management of MBC brain metastases: Surgery (+/- RT)

Kocher et al J Clin Oncol 2011, 29, 134-41

Surgery preferred treatment for better prognosis patients with a limited number of accessible lesions

WBRT/Stereotactic RT reduces brain relapse BUT does not improve OS vs surgery alone

Slide10

Loco-regional management of MBC brain metastases: Stereotactic RT

Fontanella et al Cancer Treatment Reviews 2016, 46, 80-88

Delivers high dose radiotherapy to <5 brain metastases of <3 cm diameter that are not operableAppears at least as effective as WBRT but with fewer neurocognitive side effects

Slide11

Loco-regional management of MBC brain metastases

Fontanella et al Cancer Treatment Reviews 2016, 46, 80-88

Slide12

Systemic management of MBC brain metastases

Brain metastases can respond but appear less sensitive than other disease sitesNo cytotoxic of targeted therapies specifically approved for patients with MBC and brain metastasesGenerally recommend to continue current systemic therapy (especially anti-HER2) if other sites controlledUsually trastuzumab

Slide13

T-DM1 in patients with HER2 +ve MBC and brain metastases

Slide14

Krop IE, et al. Ann Oncol 2015;26(1):113-9.

T-DM1 in patients with HER2 +ve MBC and brain metastases

A retrospective, exploratory analysis in the EMILIA trial of patients with CNS

metastases

T-DM1

Lapatinib + Capecitabine

Slide15

CLEOPATRA: HER2 +ve MBC brain metastases

Docetaxel, trastuzumab +/- pertuzumab

Brain metastases developed in 13.7 vs 12.6% of patients +/- pertuzumab, but seen later in the

pertuzumab arm (15.0 vs 11.9 months)These patients had better outcomes

in the

pertuzumab

arm

Slide16

Systemic treatment for BC BM: New options and future directionsThe challenge of BC BMEtirinotecan pegolThe BEACON study Patients with BC BMSupporting evidenceConclusions

Slide17

Etirinotecan pegol:

The First Long-Acting Topoisomerase I-InhibitorSingh Y, et al. Noninvasive Detection of Passively Targeted Poly(ethylene glycol) Nanocarriers in Tumors. Mol. Pharmaceutics 2012, 9, 144−155Maeda H, et al. The EPR effect for macromolecular drug delivery to solid tumors: Improvement of tumor uptake, lowering of systemic toxicity, and distinct tumor imaging in vivo. Adv Dr Deliv Rev 65 (2013) 71–79

17

Slide18

Comparative Pharmacokinetics of SN38: Irinotecan vs Etirinotecan Pegol

Plasma Active

Metabolite SN38

Concentration

(ng/mL)

Dose Schedule (weeks)

1 week

100

10

1

0.1

0

3

6

9

12

= Irinotecan

1

=

Etirinotecan

pegol

2

Etirinotecan

pegol

design results in low initial peak and sustained concentrations of active topoisomerase-1inhibitor

1

Xie

et al.

J

Clin

Oncol

. 2002;20:3293-3301

2

Jameson

et al.

Clin Cancer

Res

. 2013;19:268-78

Slide19

Etirinotecan Pegol Demonstrated Excellent Activity in Breast Cancer ModelMCF-7 tumor were grown subcutaneously in nude mice

Dose

Control

Irinotecan 40 mg/kg

Etirinotecan pegol 40 mg/kg

Etirinotecan pegol 20 mg/kg

MCF-7 tumor were grown subcutaneously in nude mice.

Slide20

Single Agent Chemotherapy Outcomes in Refractory MBCA = Adriamycin T = Taxane C = Capecitabine

AuthorAgentPrior Therapy

RR

PFS

(mo.)

A

T

C

Perez

JCO 2007

Ixabepilone

x

x

x

11%

3.1

CortesJCO 2010Eribulinxxx9%2.6CortesLancet 2011Eribulinxxx / ‒13%3.7AwadaLancet Oncology 2013etirinotecan pegol(q14d + q21d)xxx / ‒29%4.7etirinotecan pegol(q21d only)xxx / ‒29%5.620

Slide21

Locally recurrent or metastatic breast cancer (n=852) Prior treatment with anthracycline, a taxane,

and capecitabine ECOG PS 0-1 2-5 prior chemotherapies for advanced disease Stable brain metastases allowedBEACON Phase 3 Study Design

Single-AgentEtirinotecan

Pegol145 mg/m

2

every 3 weeks

(n=429)

Single-Agent Treatment of Physician’s Choice (TPC)

Docetaxel

,

eribulin

, gemcitabine,

ixabepilone

,

nab

-paclitaxel, paclitaxel or

vinorelbine(n=423)RStratification:Geographic region Prior eribulin useReceptor status135 centers in US, Canada, Belgium, France, Germany, Italy, Korea, Russia, Spain, The Netherlands, UKEnrollment: Dec 2011 – Aug 2013Event cutoff: Dec 2014Primary EndpointOverall SurvivalSecondary EndpointsPFS, ORR, CBR, DoR, HRQoLExploratory EndpointsPD Markers in CTC, othersPerez E, et al. Lancet Oncol 2015

Slide22

Baseline CharacteristicsCharacteristic, n (%)Etirinotecan

Pegol(n=429)TPC(n=423)

Age, years, median (range)

55 (28-84)

55 (32-80)

ECOG PS

0

175 (41%)

134 (32%)

1

252 (59%)

285 (67%)

≥ 2

2 (<1%)

4 (1%)

Median time since initial diagnosis of BC (yr)

5.85.4Median time since diagnosis of ABC (yr)2.52.5Brain metastasis (history and/or stable)36 (8%)31 (7%)Liver metastasis 229 (53%)227 (54%)Lung metastasis 155 (36%)168 (40%)ECOG PS, Eastern Cooperative Oncology Group performance status; ABC, advanced breast cancer; TPC, treatment of physicians’ choice.Perez E, et al. Lancet Oncol 2015

Slide23

40%

23%

18%

8%

4%

4%

3%

Patients, %

Eribulin

Vinorelbine

Gemcitabine

nab

-Paclitaxel

Paclitaxel

Ixabepilone

Docetaxel

Chemotherapy AgentBreakdown of TPC Agents UsedPatients on TPC Received ChemotherapyPerez E, et al. Lancet Oncol 2015

Slide24

Primary Efficacy Endpoint: Overall Survival

1.00.8

0.6

0.4

0.2

0.0

0

3

6

9

12

15

18

21

24

27

30429423392371

331

301

276

229

219

177

161

142

91

93

53

52

25

25

10

9

3

2

Number at Risk:

Months from Randomization

Survival Probability

Events OS (95% CI)

Etirinotecan Pegol (n=429) 318 12.4 mo (11.0-13.6)

TPC (n=423) 329 10.3 mo (9.0-11.3)

HR (95% CI): 0.872 (0.747-1.019)

Log-rank P-value = 0.0835

Perez E, et al. Lancet Oncol 2015

Slide25

Secondary Efficacy EndpointsEndpointEtirinotecan Pegol

(n=429)TPC(n=423)Progression-free survival, median

mo

(95% CI)

2.4

(2.1-3.5)

2.8

(2.1-3.5)

Objective response rate, n (%)

1

(95% CI)

58 (16%)

(12.7-20.7)

61 (17%)

(

13.3-21.3)Duration of response, median mo1(95% CI)3.9 (3.5-5.1)3.7(2.1-3.9)Clinical benefit rate, n (%)2(95% CI)88 (21%)(16.8-24.6)83 (20%)(15.9-23.7)Analyzed for patients with measurable disease by RECIST v1.1 at baseline1In patients with measurable disease at baseline (n=354 [EP]; n=358 [TPC])2CR+PR+SD ≥ 6 monthsCI, confidence interval; CR, complete response; HR, hazard ratio; PR, partial response; SD, stable disease; TPC, treatment of physicians’ choice.Perez E, et al. Lancet Oncol 2015

Slide26

Adverse Events: Grade ≥ 3Etirinotecan Pegol (n=425)

TPC(n=406)Grade ≥ 3 Toxicity Regardless of Causality(≥ 3% Difference)

48%

63%

1

More Common on

Etirinotecan

Pegol

Grade 3

Grade 4

Grade 3

Grade 4

Diarrhea

10%

01%0More Common on TPC Neutropenia28%2%20%11% Peripheral neuropathy3 <1%<1%4%0 1P < 0.0012Neutropenia=neutropenia, neutrophil count decreased, febrile neutropenia, neutropenic sepsis 3Peripheral neuropathy is a combination of 12 Preferred TermsPerez E, et al. Lancet Oncol 2015

Slide27

Global Health Status5 Functional Scales: Physical Role

Emotional Cognitive SocialHealth-Related Quality of Life (EORTC QLQ-C301)

Estimated using a mixed-effects model repeated measures from baseline scores over 32 weeks

1. Fayers P, et al. EORTC Monograph. 1998.

+10

+5

0

-5

Favors Etirinotecan Pegol

Treatment Difference

(95% CI)

P-value

4.1 (

0.68-7.43

)

0.0185

4.1 (0.89-7.36)0.01252.9 (-1.14-6.85)0.16112.8 (-0.38-5.99)0.08362.4 (-0.54-5.32)0.10921.9 (-1.91-5.79)0.3217Change from BaselineDifference in Mean Scores Over 32 Weeks

Perez E, et al. Lancet Oncol 2015

Slide28

Pre-planned OS Subgroup AnalysesSubgroup EP N # Events

TPC N # EventsPrior Eribulin Y

71 59

72 60

N

259

351 269

TNBC

119 102

117 97

HER2+

30 19

32 22

HR+

208

290 221

Prior Regimens ≥ 5 91 94 75 4 101153 117 ≤ 3170 126 176 137 Liver Metastasis229 179 227 197 Lung Metastasis155 121 168 132 Brain Metastasis 36 31 31 29 Sites Involved > 2201 158 202 178 ≤ 2228 160 221 151HR (95% CI)EPMedianTPCMedian 0.87 (0.60, 1.25)11.0 8.00.87 (0.73, 1.03)12.810.91.00 (0.76, 1.32) 9.8

8.8

0.96 (0.52,

1.78)

8.6

11.6

0.83 (0.69,

1.00)

13.6

11.0

0.82 (0.60,

1.11)

11.9

9.7

0.82 (0.63,

1.07)

13.6

9.7

0.92

(0.72, 1.17)

12.1

11.5

0.73 (0.59,

0.89)

10.9

8.3

0.93 (0.73,

1.20)

12.0

10.4

0.51 (0.30,

0.86)

10.0

4.8

0.77 (0.62,

0.95)

10.6

8.6

0.98 (0.78,

1.22)

13.3

12.6

0.1

0.5

1

1.5

2

3

4

5

Favoring

Etirinotecan

Pegol

Perez E, et al. Lancet Oncol 2015

Slide29

Pre-planned OS Subgroup AnalysesSubgroup EP N # Events

TPC N # EventsPrior Eribulin

Y

71 59

72 60

N

259

351 269

TNBC

119 102

117 97

HER2+

30 19

32 22

HR+

208

290 221 Prior Regimens ≥ 5 91 94 75 4 101153 117 ≤ 3170 126 176 137 Liver Metastasis229 179 227 197 Lung Metastasis155 121 168 132 Brain Metastasis 36 31 31 29 Sites Involved > 2201 158 202 178 ≤ 2228 160 221 151HR (95% CI)EPMedianTPCMedian 0.87 (0.60, 1.25)11.0 8.00.87 (0.73, 1.03)12.810.91.00 (0.76, 1.32)

9.8

8.8

0.96 (0.52,

1.78)

8.6

11.6

0.83 (0.69,

1.00)

13.6

11.0

0.82 (0.60,

1.11)

11.9

9.7

0.82 (0.63,

1.07)

13.6

9.7

0.92

(0.72, 1.17)

12.1

11.5

0.73 (0.59,

0.89)

10.9

8.3

0.93 (0.73,

1.20)

12.0

10.4

0.51 (0.30,

0.86)

10.0

4.8

0.77 (0.62,

0.95)

10.6

8.6

0.98 (0.78,

1.22)

13.3

12.6

0.1

0.5

1

1.5

2

3

4

5

Favoring

Etirinotecan

Pegol

Perez E, et al. Lancet

Oncol

2015

Slide30

30

Events OS (95% CI)Etirinotecan Pegol (n=36) 31 10.0 mo (7.8-15.7)TPC (n=31) 29 4.8 mo (3.7-7.3)

HR (95% CI): 0.511 (0.304-0.858)

Log-rank P-value = 0.0099

1.0

0.8

0.6

0.4

0.2

0.0

0

3

9

12

15

18

212427

30

36

31

33

27

22

7

16

6

13

4

4

2

3

2

2

1

1

0

0

Months from Randomization

Survival Probability

26

14

Number at Risk:

6

Overall Survival in Patients With History of Brain Metastases (n=67)

Perez E, et al.

L

ancet

Oncol

2015

Slide31

31

Events OS (95% CI)Etirinotecan Pegol (n=36) 31 10.0 mo (7.8-15.7)TPC (n=31) 29 4.8 mo (3.7-7.3)

HR (95% CI): 0.511 (0.304-0.858)

Log-rank P-value = 0.0099

1.0

0.8

0.6

0.4

0.2

0.0

0

3

9

12

15

18

212427

30

36

31

33

27

22

7

16

6

13

4

4

2

3

2

2

1

1

0

0

Months from Randomization

Survival Probability

26

14

Number at Risk:

6

72.2%

(54.5-84.0)

45.2%

(27.4-61.4)

44.4%

(28.0-59.6)

19.4%

(7.9-34.6)

Overall Survival in Patients With History of Brain Metastases (n=67)

Perez E, et al.

L

ancet

Oncol

2015

Slide32

32

Events OS (95% CI)Etirinotecan Pegol (n=36) 31 10.0 mo (7.8-15.7)

TPC (n=31) 29 4.8 mo (3.7-7.3)

HR (95% CI): 0.511 (0.304-0.858)

Log-rank P-value = 0.0099

1.0

0.8

0.6

0.4

0.2

0.0

0

3

9

12

15

18212427

30

36

31

33

27

22

7

16

6

13

4

4

2

3

2

2

1

1

0

0

Months from Randomization

Survival Probability

26

14

Number at Risk:

6

72.2%

(54.5-84.0)

45.2%

(27.4-61.4)

44.4%

(28.0-59.6)

19.4%

(7.9-34.6)

Overall Survival in Patients With History of Brain Metastases (n=67)

Perez E, et al.

L

ancet

Oncol

2015

IS THIS REAL OR FAKE NEWS?

Slide33

Systemic treatment for BC BM: New options and future directionsThe challenge of BC BMEtirinotecan pegolThe BEACON study Patients with BC BMSupporting evidenceConclusions

Slide34

Etirinotecan Pegol Achieves Higher & Sustained SN38 in Brain Tumors vs Irinotecan100x higher SN38 concentrationsafter etirinotecan pegolHoch et al.  Etirinotecan pegol prolongs survival in an experimental model of brain metastasis of human triple negative breast cancer.  Presented at European Cancer Congress 2013, Abstract 1915

34

SN38 from etirinotecan pegol

etirinotecan pegol

IV Dose

50 mg/kg

SN38 from Irinotecan

Mice with intracranial MDA-MB-231Br tumors; single dose once tumor reach ~20 mg; brain tumor harvested at indicated times (n=5/time point) and analyzed for SN38 by LC-MS/MS.

Slide35

Etirinotecan Pegol Prolongs Survival of Animals with TNBC Brain Metastases

End of Study

5/10 animals survived largely tumor free

35

Treatment Start

(21 days post tumor cell injection)

End of Study

Median

Survival

(Days)

Vehicle

(n=18)

21.5

Irinotecan

50 mg/kg

(n=10)

21Etirinotecan pegol50 mg/kg(n=10)60Intracardiac injection of MDA-MB-231Br cells in mice; treatment start after brain metastases are established (21 days after tumor injection); IV dosing q7d for duration of study Hoch et al.  Etirinotecan pegol prolongs survival in an experimental model of brain metastasis of human triple negative breast cancer.  Presented at European Cancer Congress 2013, Abstract 1915

Slide36

EP Prolongs Survival of Animals with TNBC Brain Metastases vs TPCMedian Survival (Days)Vehicle

38EP (50 mg/kg) 86Eribulin (1.5 mg/kg)

40

Docetaxel

(10 mg/kg)

39

Vinorelbine

(10 mg/kg)

43

Gemcitabine (60 mg/kg)

48

40% Survival

V

E

V

D

GIntracardiac injection of MDA-MB-231Br cells in mice; treatment start after brain metastases are established (21 days after tumor injection); EP, docetaxel, vinorelbine: IV dosing q7d; eribulin, gemcitabine: IP dosing q4d

Slide37

BEACON: Brain eventsAt baseline, - 795 patients were NOT known to have brain metastasesEtirenotecan pegol: 20/393 (5.1%) developed brain metastases TPC: 29/392 (7.4%) developed brain metastases 20HR for OS = 0.63

Slide38

BEACON: Brain eventsAt baseline, - 795 patients were NOT known to have brain metastasesEtirenotecan pegol: 20/393 (5.1%) developed brain metastases TPC: 29/392 (7.4%) developed brain metastasesHR for OS = 0.63- 67 patients WERE known to have brain metastases; censoring extracranial progression eventsEtirenotecan pegol: PFS 7.6 monthsTPC: PFS 3.7 monthsHR for censored PFS = 0.62

Slide39

BEACON: Brain eventsAt baseline, - 795 patients were NOT known to have brain metastasesEtirenotecan pegol: 20/393 (5.1%) developed brain metastases TPC: 29/392 (7.4%) developed brain metastasesHR for OS = 0.63- 67 patients WERE known to have brain metastases; censoring extracranial progression eventsEtirenotecan pegol: PFS 7.6 monthsTPC: PFS 3.7 monthsHR for censored PFS = 0.62

UNPUBLISHED

Slide40

40

Nagpal et al., J Neurooncol. 2015; 123(2): 277–282Durable Response in Patients with Glioblastoma (GBM)

45 weeks

5.28 x 7.87 mm

-72% change in tumor area

Baseline

8.69 x 17.38

mm

Prospective, single-arm phase 2

study in adults

with

recurrent high grade

glioma after

bevacizumab

Had

undergone

optimal resection, standard chemo-radiation or stereotactic radiosurgery concurrent with chemotherapy, and a KPS > 503/18 (16.7%) of GBM patients had partial imaging response (by RANO criteria); 5 (28%) additional patients had stable disease confirmed at 1st and 2nd MRI

Slide41

41Confirmatory Onzeald

trialPrimary EndpointKey Secondary EndpointsCompare overall survival of patients who receive EP to patients who receive TPCORR & DoR per RECIST 1.1PFS per RECIST 1.1 & RANO-BMClinical Benefit & Quality of Life

Patients with metastatic breast cancer who have stable brain metastases

Previously treated with an

anthracycline

,

taxane

&

capecitabine

(N=350)

Randomized

1:1

Single agent

etirinotecan

pegol

(EP)145 mg/m2 Q21 dayTreatment of Physician’s Choice (TPC)Single agent eribulin, ixabepilone, vinorelbine, gemcitabine, paclitaxel, docetaxel, nab-paclitaxelArm AArm BSurvival Follow-upQ 12 weeksTumor Assessment by RECIST 1.1 & RANO-BM Q8 weeks

Slide42

Systemic treatment for BC BM: New options and future directionsThe challenge of BC BMEtirinotecan pegolThe BEACON study Patients with BC BMSupporting evidenceConclusions

Slide43

The Blood Brain Barrier and the Blood Tumour Barrier

Capillary in Healthy BrainCapillary in Brain Metastasis

43

HYPOTHESIS

It

is

appears

that

molecules are

able to penetrate the leaky brain tumor

vasculature

but their

cytoxicity

may be limited if they are extrusion pump

substratesps

MRI with Enhancing Brain Metastasis

Slide44

The Blood Brain Barrier and the Blood Tumour Barrier

Capillary in Healthy BrainCapillary in Brain Metastasis

44

Extrusion pumps e.g. P

Gp

protect the brain from natural toxins that evade the BBB but not drugs that aren’t substrates

Extrusion pumps

HYPOTHESIS

It

is

appears

that

molecules are

able to penetrate the leaky brain tumor

vasculature

but their

cytoxicity may be limited if they are extrusion pump substratesps

Slide45

Conclusions

Breast cancer brain metastases represent an increasing clinical challengeThere have been improvements in local treatments but to date no effective, specific systemic treatments approvedEtirinotecan pegol (Onzeald) & T-DM1 (Kadcyla) appear to improve OS for those with history of brain metastasesWe need to challenge assumptions about the BBB and drug delivery to intracranial cancers

Slide46

Thank you for your attention

c.j.twelves@leeds.ac.uk

Slide47

Blood Brain Barrier is NOT the same as the Blood Tumour Barrier

Capillary in Healthy BrainCapillary in Brain Metastasis

47

It is

appears

that

macromolecule are

able to penetrate the leaky brain tumor vasculature through the fenestrae to allow

drug into

tumor tissue

MRI with Enhancing Brain Metastasis

Slide48

48Confirmatory Onzeald

trial (ATTAIN)Primary EndpointKey Secondary EndpointsCompare overall survival of patients who receive EP to patients who receive TPCORR & DoR per RECIST 1.1PFS per RECIST 1.1 & RANO-BMClinical Benefit & Quality of Life

Patients with metastatic breast cancer who have stable brain metastases

Previously treated with an

anthracycline

,

taxane

&

capecitabine

(N=350)

Randomized

1:1

Single agent

etirinotecan

pegol

(EP)145 mg/m2 Q21 dayTreatment of Physician’s Choice (TPC)Single agent eribulin, ixabepilone, vinorelbine, gemcitabine, paclitaxel, docetaxel, nab-paclitaxelArm AArm BSurvival Follow-upQ 12 weeksTumor Assessment by RECIST 1.1 & RANO-BM Q8 weeks

Slide49

Chemotherapy for MBC

ER +ve(HER2 –ve)

HER 2 +

ve

Triple negative

Luminal A

Luminal B

HER 2 enriched

Luminal-HER 2

Basal

Basal/normal

BRCA

1

Hormones, then

chemotherapy

Anti-HER2 therapy plus

chemotherapyChemotherapy

Slide50

Loco-regional management of MBC brain metastases: Surgery followed by RT

Patchell et al, NEJM 1990, 322, 494-50016, 46, 80-88

Surgery preferred treatment for better prognosis patients with a limited number of accessible lesionsIn 2 of 3 randomized trials OS improved with surgery + WBRT versus WBRT alone

Overall survival

was significantly longer in the surgical group (median, 40 weeks vs. 15 weeks in the radiation group; P<0.01), and

they remained

functionally independent longer (median, 38 weeks vs. 8

weeks;

P<0.005).

Slide51

The challenge of heavily pre-treated MBC

After an anthracycline and a taxane…Current guidelines recognise the lack of proven standards of care and proven treatment options in heavily pre-treated MBC1,2In a 2009 systematic review, no randomised controlled trial showed any significant differences between the commonly prescribed regimens in terms of overall survival2Eribulin is the only cytotoxic proven to improve OS in this setting 3

New, effective and well tolerated therapies are needed in this population 2

1.Cardoso F et al Ann Oncol 2010,21

suppl

5: v15-9

2. Janssen J et al

Eur

J Cancer

2009:45:2749-58

3. Cortes J et al Lancet Oncology 2011,377,914-23

Slide52

Slide53

Presentation, imaging and pathology of metastatic breast cancer brain metastases

Slide54

Presented By Paul Brown at 2015 ASCO Annual Meeting

Brain Metastases: Radiotherapy

Slide55

MBC with Brain Metastases:Surgery or radiotherapy

Factors in favor of neurosurgery: Histological verification e.g. after a long recurrence-free interval Need for immediate decompression, life-threatening symptoms Tumor size not allowing stereotactic radiotherapyFactors in favor of primary radiotherapy: No need for rapid decompression or histological verification Tumor location poorly amenable to surgery More than two lesions

Slide56

Systemic Therapies for Brain Metastases from Breast Cancer1.Venur VA et al. Int. J. Mol. Sci. 2016, 17, 1543 2. Swain SM et al. Annals of Oncology 25: 1116–1121, 2014

How effective are targeted therapies for the treatment of BM in BC?

Prof. Twelves: are there any trials you would remove/add to this table? Do you feel that the patient populations are suitable for this table?We’ve added the Cleopatra trial – although this trial was in patients who progressed to brain mets. Let us know which ones you wish include/remove given the time constraints of the discussion

Swain et al Pertuzumab

Trastuzumab

Phase III with pertuzumab/

trastuzumab/docetaxel 402 -- 15.0 34.4

compared to

trastuzumab/docetaxel 406 -- 11.9 26.3

Time to CNS metastases

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Brain Metastases:HER2 targeted therapy

Slide58

Baseline Characteristics (cont’d)CharacteristicEtirinotecan Pegol

(n=429)TPC(n=423)Receptor status (n, %)

Hormone receptor positive

295 (69%)

290 (69%)

Triple negative

119 (28%)

117 (28%)

HER2 positive

30 (7%)

32 (8%)

Stage IV disease at initial diagnosis (n, %)

70 (16%)

75 (18%)

Visceral disease at enrollment

(n, %)

319 (74%)324 (77%) Prior regimens for metastatic disease (median, range)3 (1-6)3 (1-6)Prior chemotherapy exposure (n, %) Prior anthracycline410 (96%)406 (96%) Prior taxane 429 (100%) 423 (100%) Prior capecitabine 429 (100%) 423 (100%) Prior eribulin 71 (17%) 72 (17%)Perez E, et al. Lancet Oncol 2015

Slide59

59

SN38: 7-Ethyl-10-hydroxy-camptothecin; NPC: 7-ethyl-10-(4-amino-1-piperidino) carbonyloxycamptothecin;APC: 7-ethyl-10-[4-N-(5-aminopentanoic acid)-1-piperidino]carbonyloxycamptothecin

HYDROLYSIS

(SLOW)

TUMOR,

TISSUE,

PLASMA

HYDROLYSIS

(SLOW)

TUMOR,

TISSUE,

PLASMA

APC, NPC

(inactive)

SN38 -GLUC

(inactive)

LIVERCYP3A4OXIDATIONLIVERUGT1A1ESTERASES(FAST)LIVER,PLASMACompared to generic irinotecanSN38irinotecanEtirinotecanpegolEtirinotecan pegol: Metabolic Pathway

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Challenge of Metastatic Breast Cancer With Brain MetastasesBreast cancer is the 2nd most common solid tumor for brain metastasesUp to 50% of HER2+ subtypeFrom 25-46% of TNBC subtypeAutopsies show brain metastases in up to 36% of patients with MBCAlmost 20% of asymptomatic patients with MBC screened for CEREBRAL trial had brain metastases

Nancy Lin Breast cancer brain metastases: new directions in systemic therapyecancer medicalscience 2013-see references 4,6-8 for incidence and 14-19 for survivalBrufsky et al Clin Cancer Res 2011, 17, 4834-43Pivot et al SABCS 2011

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Challenge of Metastatic Breast Cancer With Brain MetastasesRising incidence most likely due toLonger natural history of MBC (especially HER2 +ve)Better imagingLower threshold for imaging (and trial screening)Limited survival upon diagnosis of brain metastases:10-23 months for HER2+ 3-7 months for TNBC

Nancy Lin Breast cancer brain metastases: new directions in systemic therapyecancer medicalscience 2013-see references 4,6-8 for incidence and 14-19 for survival

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Hazard Ratio by Receptor Status in Patients With History of BM (n=67)62Receptor StatusNKTR-102N=36TPCN=31TotalOSHR

Triple Negative10 (27.8%)8 (25.8%)18 (26.9%)0.547HER2 Positive4 (11.1%)5 (16.1%)9 (13.4%)0.266Other

22 (61.1%)18 (58.1%)

40 (59.7%)

0.469