Optimal Treatment Strategy for ER-positive, HER2- negative MBCgbcc.kr/upload/Hiroji Iwata.pdf ·...

Optimal Treatment Strategy for ER-positive, HER2-negative MBC

-Implications from the Clinical Trial and Experience-

Hiroji Iwata

Aichi Cancer Center Hospital

2018GBCC 2018.4.6

AstraZeneca does not, under any circumstances, promote its products for off-label or unapproved use

HR+ HER2-74%

HR+ HER2+10%

HR- HER2+6%

HR- HER2-10%

subtype classification

HR+ HER2- HR+ HER2+ HR- HER2+ HR- HER2-

Registration data in JBCS 2013

Distribution of age

age

case

s

Overall survival of

each cancer type in Japan（1999-2002)

Breast Cancer5 year ：88.7%

10year：80.4%

Clinical characteristics in ER+ve MBC

500 thousand pts data registered EBCTCG

74,194 cases:after surgery

62,923 cases: complete 5Yendocrine therapy after surgery

4% until 10Y, 13% until 20Y after surgeryfor T1N0 without recurrence at 5Y

20% until 10Y, 41% until 20Y after surgery for T2N4-9 without recurrence at 5Y

Risk of Distant Recurrence

The timing of recurrence by ER status1771cases（1998～2003)

23.6% (47/199): later 5

years after surgery

0

5

10

15

20

25

30

35

40

45

50

HR+(199)

0

5

10

15

20

25

30

35

40

45

50

HR-(112)

7.1% (9/112): later 5 years after surgery

0 1 2 3 4 5 6 7 8 9 10 0 1 2 3 4 5 6 7 8 9 10 (Y)(Y)

Hato Y, et al, Jpn J Breast Cancer 2012; 27(2):153-158

Distant organs Local/regional

ER PgR HER2 bone Lung Liver Brain local regional others

+ + +5

(33.3）3

(20.0)1

(6.7)1

(6.7)3

(20.0)5

(33.3)3

+ + -22

(42.3)12

(23.1)4

(7.7)9

(17.3)8

(15.4)6

+ - +4

(36.4)5

(45.5)1

(9.1)1

(9.1)2

+ - -11

(44.0)5

(20.0)3

(12.0)1

(4.0)4

(16.0)5

(20.0)4

- + + 1

- + -

- - +1

(6.3)5

(31.3)2

(12.5)5

(31.3)3

(18.8)5

- - -4

(15.4)9

(34.6)2

(7.7)2

(7.7)5

(19.2)6

(23.1)

Initial recurrent sites（by subtypes）（Aichi Cancer Center 2002～2007）

Time to BM according to subtype

Luminal

Luminal-HER2

HER2

TN

Luminal

Luminal-HER2

HER2

TN

From diagnosis Breast cancer From diagnosis Metastases

Niikura et al. Breast Cancer Res Treat. 2014 Aug;147(1):103-12

Subtype Number of Pt Median Survival

95% CI

Luminal 343 9.3 (7.2 – 11.3)

Luminal-HER2 162 16.5 (11.9 -21.1)

HER2 270 11.5 (9.1 – 13.8)

TN 337 4.9 (3.9 – 5.9)

Overall Survival according to subtype

Niikura et al. Breast Cancer Res Treat. 2014 Aug;147(1):103-12

From diagnosis Brain Metastases

The characteristics for MBC with ER positive

• Late recurrence

• Bone mets

• Long time until brain mets after initial mets but similar OS (median 1Y) with other subtypes after brain mets

Three Purpose of treatment for MBC

Palliate symptomsPrevent symptomsProlong survival

Endocrine therapy for ER+ MBC

Strategy for ER+MBC

• Continues endocrine therapy as long as possible.

• Endocrine monotherapy or combination with targeting therapy

• Adaptive timing to change the chemotherapy

Which factors do you consider to determine to use drug as 1st line endocrine therapy？

• DFS（from surgery to recurrence)

• Adjuvant therapy（AI or TAM or LH-Rha+TAM)

• Condition of recurrence（± visceral）

• Symptomatic or not

• Menopausal status

• Evidence for candidate drugs

1st line endocrine therapy for MBC with ER+

J Clin Oncol. 2016 Sep 1;34(25):3069-103 AstraZeneca does not, under any circumstances, promote its products for off-label or unapproved use

Therapeutic indicationsMonotherapy

This medicine is indicated for the treatment of hormone receptor positive, HER2 negative, locally advanced or metastatic breast cancer in postmenopausal

women.

Combination therapy

This medicine is indicated in combination with palbociclib for the treatment of hormone receptor (HR)-positive, human epidermal growth factor receptor 2

(HER2)-negative locally advanced or metastatic breast cancer in women who have received prior endocrine therapy

https://www.ncbi.nlm.nih.gov/pubmed/?term=Endocrine+Therapy+for+Hormone+Receptor%E2%80%93Positive+Metastatic+Breast+Cancer:+American+Society+of+Clinical+Oncology+Guideline

AI is better than TAM as 1st line for ER+ MBC

Which is better, AI or Fulvestrant?

esmo.org

FALCON: A PHASE III RANDOMISED TRIAL OF FULVESTRANT 500 MG VS. ANASTROZOLE FOR HORMONE RECEPTOR-POSITIVE ADVANCED BREAST CANCERMatthew J Ellis,1 Igor M Bondarenko,2 Ekaterina Trishkina,3 Mikhail Dvorkin,4 Lawrence Panasci,5

Alexey Manikhas,6 Yaroslav Shparyk,7 Servando Cardona-Huerta,8 Kwok-Leung Cheung,9

Manuel Jesus Philco-Salas,10 Manuel Ruiz-Borrego,11 Zhimin Shao,12 Shinzaburo Noguchi,13

Lynda M Grinsted,14 Mehdi Fazal,15 Mary Stuart,16 John FR Robertson9

1Lester and Sue Smith Breast Center, Baylor College of Medicine, Houston, Texas, USA; 2Oncology Department, Dnipropetrovsk State Medical

Academy, Dnipropetrovsk, Ukraine; 3Leningrad Regional Oncology Dispensary, St Petersburg, Russia; 4Clinical Oncology Dispensary, Omsk,

Russia; 5Department of Oncology, Jewish General Hospital, Montreal, Canada; 6City Clinical Oncology Dispensary, St Petersburg, Russia; 7Lviv State Oncology Regional Treatment and Diagnostic Centre, Lviv, Ukraine; 8Breast Cancer Center, Tecnológico de Monterrey, Monterrey,

Mexico; 9Division of Medical Sciences and Graduate Entry Medicine, University of Nottingham, Royal Derby Hospital Centre, Derby, UK; 10Unidad de Investigación, Instituto Oncológico de Lima, Lima, Peru; 11Hospital Universitario Virgen del Rocío, Seville, Spain; 12Fudan University

Shanghai Cancer Center, Shanghai, China; 13Department of Breast and Endocrine Surgery, Osaka University Graduate School of Medicine,

Osaka, Japan; 14AstraZeneca, Cambridge, UK; 15AstraZeneca, Gaithersburg, MD, USA; 16AstraZeneca, Alderley Park, Macclesfield, UK

LBA14_PR

permission obtained

FALCON: PHASE III STUDY DESIGN

Randomised, double-blind, parallel-group, international, multicentre study

Follow-up for disease progression and survival

Randomisation of 450 patients was planned to achieve 306 progression events; if the true PFS HR was 0.69 this

would provide 90% power for statistical significance at the 5% two-sided level (log-rank test)

Stratification factors: prior chemotherapy for advanced disease (yes / no); measurable vs. non-measurable

disease (at baseline); locally advanced vs. metastatic disease

Subgroup analysis of PFS for pre-defined baseline covariates

aAssessed via RECIST 1.1, surgery / radiotherapy for disease worsening, or death; bInterim analysis at the time of PFS analysis

EDoCB, expected duration of clinical benefit; EDoR, expected duration of response; FACT-B, Functional Assessment of Cancer Therapy –

Breast;

TOI, Trial Outcome Index

• Postmenopausal women

• Locally advanced or

metastatic breast cancer

• ER+ and / or PgR+

• HER2-

• Endocrine therapy-naïve

Fulvestrant 500 mg(500 mg IM on Days 0, 14 and 28, then every 28 days)

+ placebo to anastrozole

Anastrozole 1 mg (daily PO)

+ placebo to fulvestrant

Primary endpoint: PFSa

Secondary endpoints1:1 • OSb

• ORR

• CBR

• DoR, EDoR

• DoCB, EDoCB

• HRQoL (FACT-B

total and TOI)

• Safety

permission obtained

FALCON: BACKGROUND

First-line treatment recommendations for postmenopausal women with hormone receptor-positive

advanced / metastatic breast cancer include endocrine therapy with a third-generation aromatase

inhibitor (including anastrozole) or tamoxifen

Fulvestrant is a selective estrogen receptor degrader (SERD) approved for hormone receptor-positive

advanced breast cancer and disease progression following prior anti-estrogen therapy

In the Phase II, open-label FIRST study (first-line treatment for locally advanced or metastatic breast

cancer), fulvestrant 500 mg was at least as effective as anastrozole:

CBR (primary endpoint): 72.5% vs. 67.0%; odds ratio 1.30 (95% CI 0.72, 2.38; p=0.386)1

TTP: 23.4 vs. 13.1 months; HR 0.66 (95% CI 0.47, 0.92; p=0.01)2

OS: 54.1 vs. 48.4 months; HR 0.70 (95% CI 0.50, 0.98; p=0.04)3

The objective of the FALCON study (NCT01602380) was to confirm the PFS (TTP) superiority of

fulvestrant over anastrozole in postmenopausal patients with hormone receptor-positive locally

advanced / metastatic breast cancer who had not received prior endocrine therapy

1Robertson et al. J Clin Oncol 2009; 27: 4530–45352Robertson et al. Breast Cancer Res Treat 2012; 136: 503–511

3Ellis et al. J Clin Oncol 2015; 33: 3781–3787TTP in FIRST and PFS in FALCON had equivalent definitionspermission obtained

Clinical benefit of fulvestrant 500 mg

CONFIRM (NCT00099437): study design1

23

Fulvestrant 250 mg (n=374)

250 mg im every

28 days


500 mg im on days 0,

14 and 28, and every

28 days thereafter

Post-menopausal women with HR+ advanced breast cancer

progressing or relapsing after one prior endocrine therapy

Randomised, double-blind, parallel-group, multicentre, phase III study

Primary endpoint: PFS

Secondary endpoints: ORR, DoR, CBR, DoCB, OS, tolerability, QoL

Follow-up until disease

progression

1. Di Leo A, et al. J Clin Oncol 2010;28:4594-4600.

＊Fulvestrant 250mg is not approved in Japan

CONFIRM: PFS (primary endpoint)1

24

1. Di Leo A, et al. J Clin Oncol 2010;28:4594–4600. Erratum in: J Clin Oncol 2011;29:2293.


1.0

0.8

0.6

0.4

0.2

0 4 8 12 16 20 24 28 32 36 40 44 48

Pro

po

rtio

n p

ati

en

ts p

rog

res

sio

n-f

ree

Time (months)

216

199

163

144

113

85

90

60

54

35

37

25

19

12

12

4

7

3

3

1

2

1

0

0

362

374

Patients at risk:

500 mg

250 mg

Hazard ratio = 0.80; 95% CI: 0.68–0.94;

P=0.006

Median PFS

Fulvestrant 500 mg: 6.5 months

Fulvestrant 250 mg: 5.5 months

0.0

Fulvestrant 500 mg

Fulvestrant 250 mg

Fulvestrant 500 mg significantly prolongs PFS compared

with fulvestrant 250 mg

CONFIRM: PFS by pre-defined covariates1

25

0.40 0.60 0.80 1.00 1.25 1.50

Receptor status ER+ and PgR+ER+ and PgR- or unknown

NoYes

Visceral involvement

Response to last endocrine

therapy prior to fulvestrant

ResponsivePoorly responsive or unknown

NoYes

Measurable disease

<65≥65

Age, years

Last endocrine therapy

prior to fulvestrant

AIAnti-oestrogen

All patients

Hazard ratio (fulvestrant 500 mg vs fulvestrant 250 mg) and 95% CI

Favours

fulvestrant 500 mg

Favours

fulvestrant 250 mg

Fulvestrant 500 mg significantly prolongs PFS across all

subgroups compared with fulvestrant 250 mg



CONFIRM: DoCB1†

Median DoCB was 16.6 and 13.9 months for fulvestrant 500 mg and 250 mg, respectively

0 5 10 15 20

Time (months)

13.9

16.6

Fulvestrant

250 mg

Fulvestrant

500 mg

†Clinical benefit = CR+PR+SD ≥24 weeks

26

Median DoCB was not significantly different for

fulvestrant 500 mg vs fulvestrant 250 mg



CONFIRM: OS (final analysis 75%, FAS)1

27

0.1

0

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

0 4 8 12 16 20 24 28 32 36 40 44 48 52 56 60 64 68 72 76 80

Fulvestrant 500 mg

Fulvestrant 250 mg

362 333 288 254 227 202 178 163 141 123 114 98 81 64 47 30 26 15 8 1 0500 mg

374 338 299 261 223 191 164 137 112 96 87 74 64 48 37 22 14 8 3 2 0250 mg

Time (months)Patients at risk:

†Nominal value, cannot be claimed as significant as no adjustments were made for multiplicity

Median OS (months)

Fulvestrant 500 mg 26.4

Fulvestrant 250 mg 22.3

Hazard ratio = 0.81; 95% CI: 0.69–0.96;

P=0.02†

1. Di Leo A, et al. J Natl Cancer Inst 2014:106:djt337.

＊Fulvestrant 250mg is not approved in Japan。

Pro

po

rtio

n o

f p

ati

en

ts a

live

Fulvestrant 500 mg is associated with a 4.1-month difference in median

OS compared with fulvestrant 250 mg

FALCON: BACKGROUND

First-line treatment recommendations for postmenopausal women with hormone receptor-

positive

advanced / metastatic breast cancer include endocrine therapy with a third-generation

aromatase inhibitor (including anastrozole) or tamoxifen

Fulvestrant is a selective estrogen receptor degrader (SERD) approved for hormone receptor-

positive advanced breast cancer and disease progression following prior anti-estrogen

therapy

In the Phase II, open-label FIRST study (first-line treatment for locally advanced or metastatic

breast cancer), fulvestrant 500 mg was at least as effective as anastrozole:

- CBR (primary endpoint): 72.5% vs. 67.0%; odds ratio 1.30 (95% CI 0.72, 2.38; p=0.386)1

- TTP: 23.4 vs. 13.1 months; HR 0.66 (95% CI 0.47, 0.92; p=0.01)2

- OS: 54.1 vs. 48.4 months; HR 0.70 (95% CI 0.50, 0.98; p=0.04)3

The objective of the FALCON study (NCT01602380) was to confirm the PFS (TTP) superiority

of fulvestrant over anastrozole in postmenopausal patients with hormone receptor-positive

locally advanced / metastatic breast cancer who had not received prior endocrine therapy

1Robertson et al. J Clin Oncol 2009; 27: 4530–45352Robertson et al. Breast Cancer Res Treat 2012; 136: 503–511

3Ellis et al. J Clin Oncol 2015; 33: 3781–3787TTP in FIRST and PFS in FALCON had equivalent definitionspermission obtained

29

Phase II FIRST study design

Robertson JFR et al. J Clin Oncol 2009;27: 4530-5

Anastrozole 1mg(1 mg p.o. daily)

n=103

Progression

Follow-up

Fulvestrant 500mg(500 mg i.m. on Days 0, 14 and

28 and every 28 days thereafter)

n=102

Progression

Follow-up

Open-label, randomised (1:1), first line, phase II trial

in estrogen receptor-positive postmenopausal

women with ABC (n=205) Clinical benefit rate, the primary endpoint of the study

was met (fulvestrant 72.5% versus anastrozole 67.0%).

Secondary endpoints include:

• Time to progression

• Objective response rate

• Safety

30

Fulvestrant 500mg was associated with improved time to progression

Robertson JFR et al. Breast Cancer Res Treat 2012;136:503-11

Time (months)

102 74 65 52 45 34 20 6 0

103 69 55 39 30 21 8 2 0

Fulvestrant 500mg

Anastrozole mg

Patients at risk:

Pro

po

rtio

n o

f p

ati

en

ts a

live

an

d p

rog

res

sio

n-f

ree

0 6 12 18 24 30 36 42 48

0.0

0.2

0.4

0.8

1.0

HR=0.66; 95% CI: 0.47, 0.92;

p=0.01

0.6

Anastrozole 1mg (n=103)

Fulvestrant 500mg (n=102)

Median TTP: Fulvestrant 23.4 months versus anastrozole 13.1 months

31

Fulvestrant 500mg was associated with improved overall survival

Ellis MJ et al. J Clin Oncol 2015:1-9

HR=0.70; 95% CI 0.50, 0.98;

p=0.04

102 90 84 77 57 47 31 24

103 90 80 72 49 39 21 14

0 6 12 18 24 30 36 42 1080.0

0.2

0.4

0.6

0.8

1.0

Pro

po

rtio

n o

f

pa

tie

nts

alive

Time (months)

48 54 60 66 72 78 84 90 96 102

Months

Fulvestrant 500mg

Anastrozole 1mg

Patients at risk:

4

2

39

29

Median OS: Fulvestrant 54.1 months vs. anastrozole 48.4 months

Anastrozole 1mg (n=103)

Fulvestrant 500mg (n=102)

32

Responses to subsequent systemic therapy were recorded for

133 patients


Fulvestrant 500mg

N (%)

Anastrozole 1mg

N (%)

Number receiving subsequent systemic

therapy64 69

Clinical benefit rate 43.8 46.4

Category of subsequent therapy

Endocrine therapy 34 50

Of these 133 patients, 84 received subsequent endocrine therapy

33

Responses to subsequent endocrine therapy was similar in both arms


8.8

14.0

32.4

28.0

0

10

20

30

40

50

60

Fulvestrant Anastrozole

Complete response Partial Response Stable Disease ≥24 weeks

n=34 n=50

%

Total CBR: 41.2% Total CBR: 42.0%


Randomised, double-blind, parallel-group, international, multicentre study

Follow-up for disease progression and survival

Randomisation of 450 patients was planned to achieve 306 progression events; if the true PFS HR was 0.69 this

would provide 90% power for statistical significance at the 5% two-sided level (log-rank test)

Stratification factors: prior chemotherapy for advanced disease (yes / no); measurable vs. non-measurable

disease (at baseline); locally advanced vs. metastatic disease

Subgroup analysis of PFS for pre-defined baseline covariates

aAssessed via RECIST 1.1, surgery / radiotherapy for disease worsening, or death; bInterim analysis at the time of PFS analysis

EDoCB, expected duration of clinical benefit; EDoR, expected duration of response; FACT-B, Functional Assessment of Cancer Therapy –

Breast;

TOI, Trial Outcome Index





• HER2-






Primary endpoint: PFSa

Secondary endpoints1:1 • OSb

• ORR

• CBR

• DoR, EDoR

• DoCB, EDoCB

• HRQoL (FACT-B

total and TOI)

• Safety

permission obtained

FALCON: KEY INCLUSION / EXCLUSION CRITERIA

Postmenopausal women with histologically confirmed ER+ and / or PgR+, HER2-

locally advanced or metastatic breast cancer

WHO performance status 0–2

≥1 measurable and / or non-measurable lesion(s)

Key exclusion criteria:

Prior endocrine treatment for breast cancer

Systemic estrogen-containing hormone-replacement therapy use ≤6 months prior to

randomisation

Presence of life-threatening metastatic visceral disease

Prior systemic treatment for breast cancer except one line of chemotherapy, radiotherapy

completed ≤28 days prior to randomisation (except radiotherapy for control of bone pain)

permission obtained

FALCON: BASELINE PATIENT CHARACTERISTICS

Fulvestrant (N=230) Anastrozole (N=232)

Median age, years (range) 64.0 (38–87) 62.0 (36–90)

Race, n (%)

White 175 (76.1) 174 (75.0)

Any prior chemotherapy, n (%) 79 (34.3) 81 (34.9)

Advanced disease 36 (15.7) 43 (18.5)

Adjuvant / neoadjuvant 35 / 11 (15.2 / 4.8) 27 / 16 (11.6 / 6.9)

WHO performance status, n (%)

0 / 1 / 2 117 / 106 / 7 (50.9 / 46.1 / 3.0) 115 / 105 / 12 (49.6 / 45.3 / 5.2)

Receptor status, n (%)

ER+ / PgR+ 175 (76.1) 179 (77.2)

ER+ / PgR- 44 (19.1) 43 (18.5)

ER+ / PgR unknown 10 (4.3) 7 (3.0)

ER- / PgR+ 1 (0.4) 3 (1.3)

ER- / PgR- 0 0

Overall disease classification, n (%)

Locally advanced disease 28 (12.2) 32 (13.8)

Metastatic disease 202 (87.8) 200 (86.2)

Visceral disease, n (%) 135 (58.7) 119 (51.3)

Measurable disease, n (%) 193 (83.9) 196 (84.5)

permission obtained

FALCON: PRIMARY ENDPOINT, PFS

A circle represents a censored observation

HR 0.797 (95% CI 0.637, 0.999); p=0.0486

Median PFS

Fulvestrant: 16.6 months

Anastrozole: 13.8 months

Number of patients at risk:Fulvestrant

Anastrozole230

232

187

194

171

162

150

139

124

120

110

102

96

84

81

60

63

45

44

31

24

22

11

10

2

0

0

0

Pro

po

rtio

n o

f p

atie

nts

aliv

e an

d

pro

gre

ssio

n f

ree

Time (months)

0.9

1.0

0.7

0.8

0.5

0.6

0.3

0.4

0.1

0.00 3 6 9 12 15 18 21 24 27 30 3633 39

0.2

Fulvestrant (n=230)

Anastrozole (n=232)

permission obtained

FALCON: FOREST PLOT FOR PFS BY PATIENT SUBGROUP

Global interaction test p=0.106

NC, not calculable

All patients

Breast cancer type

Locally advanced

Metastatic

Prior chemotherapy

Yes

No

Geographic region

US and Canada

Non-US or Canada

Asia

Non-Asia

Measurable disease

Measurable

Non-measurable

ER+ and PgR+ at baseline

Yes

No

Prior systemic estrogen containing HRT

Yes

No

Bisphosphonate use at baseline

Yes

No

Visceral disease

Yes

No

143 / 230 (62.2%)

11 / 28 (39.3%)

132 / 202 (65.3%)

31 / 36 (86.1%)

112 / 194 (57.7%)

16 / 25 (64.0%)

127 / 205 (62.0%)

19 / 34 (55.9%)

124 / 196 (63.3%)

124 / 193 (64.2%)

19 / 37 (51.4%)

103 / 175 (58.9%)

40 / 55 (72.7%)

3 / 3 (100.0%)

140 / 227 (61.7%)

44 / 61 (72.1%)

99 / 169 (58.6%)

92 / 135 (68.1%)

51 / 95 (53.7%)

166 / 232 (71.6%)

14 / 32 (43.8%)

152 / 200 (76.0%)

33 / 43 (76.7%)

133 / 189 (70.4%)

19 / 24 (79.2%)

147 / 208 (70.7%)

22 / 33 (66.7%)

144 / 199 (72.4%)

143 / 196 (73.0%)

23 / 36 (63.9%)

127 / 179 (70.9%)

39 / 53 (73.6%)

3 / 5 (60.0%)

163 / 227 (71.8%)

53 / 62 (85.5%)

113 / 170 (66.5%)

87 / 119 (73.1%)

79 / 113 (69.9%)

Number of patients with event

Fulvestrant Anastrozole

0.25 0.5 1 1.5 2HR (95% CI)

0.797 (0.637, 0.999)

0.790 (0.360, 1.731)

0.784 (0.621, 0.991)

1.081 (0.659, 1.771)

0.752 (0.585, 0.967)

0.664 (0.338, 1.304)

0.811 (0.640, 1.029)

0.811 (0.438, 1.501)

0.791 (0.622, 1.005)

0.763 (0.599, 0.971)

0.985 (0.534, 1.818)

0.728 (0.561, 0.944)

1.041 (0.669, 1.621)

NC

0.779 (0.622, 0.977)

0.685 (0.455, 1.032)

0.820 (0.626, 1.073)

0.993 (0.740, 1.331)

0.592 (0.419, 0.837)

HR (95% CI)

permission obtained

FALCON: PFS IN PATIENTS WITH OR WITHOUT VISCERAL DISEASE

Post hoc interaction test p<0.01


Without visceral disease With visceral disease

HR 0.59 (95% CI 0.42, 0.84)

Median PFS


Anastrozole: 13.8 monthsPro

po

rtio

n o

f p

atie

nts

aliv

e an

d p

rog

ress

ion

-fre

e

Time (months)

0.9

1.0

0.7

0.8

0.5

0.6

0.3

0.4

0.1

0.0

0.2

Pro

po

rtio

n o

f p

atie

nts

aliv

e an

d p

rog

ress

ion

-fre

e

Time (months)

0.9

1.0

0.7

0.8

0.5

0.6

0.3

0.4

0.1

0.0

0 5 10 15 20 25 30 35 40

0.2

0 5 10 15 20 25 30 35 40

HR 0.99 (95% CI 0.74, 1.33)

Median PFS


Anastrozole: 15.9 months

Fulvestrant (n=135)

Anastrozole (n=119)

Fulvestrant (n=95)

Anastrozole (n=113)

permission obtained

FALCON: OS (31% MATURITY)

Median follow up 25.0 months


0 6 21

Time (months)

Fulvestrant (N=230)

Anastrozole (N=232)

3 9 12 15 18 24 27 30 33 36 39

0.9

1.0

0.7

0.8

0.6

0.5

0.4

0.3

0.2

0.1

0.0

Pro

po

rtio

n o

f p

atie

nts

aliv

e

HR 0.88 (95% CI 0.63, 1.22); p=0.428

Number of patients at risk:

FulvestrantAnastrozole

230232

221223

208213

200197

188186

180175

168164

153155

129122

9294

5761

3137

1718

00

permission obtained

FALCON: SECONDARY ENDPOINTS

aIn patients with measurable disease at baseline

Endpoint Fulvestrant (N=230) Anastrozole (N=232)

ORRa 46.1%

(89 / 193)

44.9%

(88 / 196)

Odds ratio (95% CI)

1.07 (0.72, 1.61); p=0.729

CBR78.3%

(180 / 230)

74.1%

(172 / 232)

Odds ratio (95% CI)

1.25 (0.82, 1.93); p=0.305

Median DoR 20.0 months 13.2 months -

Median DoCB 22.1 months 19.1 months -

EDoR 11.4 months 7.5 monthsRatio (95% CI)

1.52 (1.23, 1.89); p<0.001

EDoCB 21.9 months 17.5 monthsRatio (95% CI)

1.26 (1.13, 1.39); p<0.001

Median time to

deterioration in FACT-B

total score

13.8 months 11.1 monthsHR (95% CI)

0.84 (0.66, 1.07); p=0.159

permission obtained

FALCON: MOST COMMON AEs

(FREQUENCY >5%; SAFETY ANALYSIS POPULATION)

MedDRA preferred termNumber (%) of patients


Patients with any AE 166 (72.8) 173 (74.6)

Arthralgia 38 (16.7) 24 (10.3)

Hot flush 26 (11.4) 24 (10.3)

Nausea 24 (10.5) 24 (10.3)

Fatigue 26 (11.4) 16 (6.9)

Hypertension 15 (6.6) 21 (9.1)

Back pain 21 (9.2) 14 (6.0)

Anaemia 9 (3.9) 20 (8.6)

Insomnia 15 (6.6) 13 (5.6)

Diarrhoea 14 (6.1) 13 (5.6)

Constipation 13 (5.7) 11 (4.7)

Myalgia 16 (7.0) 8 (3.4)

ALT increased 16 (7.0) 7 (3.0)

Pain in extremity 13 (5.7) 10 (4.3)

Dyspnoea 9 (3.9) 13 (5.6)

Oedema peripheral 9 (3.9) 13 (5.6)

AST increased 12 (5.3) 8 (3.4)

Cough 12 (5.3) 8 (3.4)

permission obtained

식품의약품안전처. 온라인의약도서관: 의약품상세정보-파슬로덱스[Accessed on 19 October 2017]. Available from: http://drug.mfds.go.kr/html/bxsSearchDrugProduct.jsp?item_Seq=200711211;



FALCON: AEs IN ANY CATEGORY

(SAFETY ANALYSIS POPULATION)

AE category

Number (%) of patients


SAEs 30 (13.2) 31 (13.4)

Considered related to treatment 4 (1.8) 3 (1.3)

Discontinuations due to AEs 16 (7.0) 11 (4.7)

AEs Grade 3 or worse 51 (22.4) 41 (17.7)

Deaths due to AEs 6 (2.6) 7 (3.0)

Considered related to treatment 0 0

permission obtained

FALCON: CONCLUSIONS

The Phase III FALCON study met its primary endpoint

Statistically significant improvement in PFS for fulvestrant vs. anastrozole

The primary analysis was supported by secondary efficacy endpoints

Treatment effects were largely consistent across pre-specified patient subgroups,

with the largest treatment effect seen in patients without visceral disease

The AE profile was generally consistent with known profiles

Overall, HRQoL was maintained and was similar in both treatment groups

These results are consistent with data from the FIRST study and confirm that

fulvestrant is more efficacious than anastrozole in postmenopausal women with

hormone receptor-positive locally advanced or metastatic breast cancer who have

not received prior endocrine therapy

permission obtained

1st line endocrine therapy for MBC with ER+


Therapeutic indicationsMonotherapy

This medicine is indicated for the treatment of hormone receptor positive, HER2 negative, locally advanced or metastatic breast cancer in postmenopausal

women.

Combination therapy

This medicine is indicated in combination with palbociclib for the treatment of hormone receptor (HR)-positive, human epidermal growth factor receptor 2

(HER2)-negative locally advanced or metastatic breast cancer in women who have received prior endocrine therapy


Which is better, Fulvestrant or AI + CDK inhibitor?

CDK inhibitors

Drug name Pharmacy Study name

Palbociclib Pfizer PALOMA-1,2,3

Abemaciclib Lilly MONARCH-1,2,3

Ribociclib Novartis MONALEESA-2

This slide contains information about unapproved products by MFDS and AstraZeneca does not, under any circumstances, promote its products for off-label or unapproved uses

Presented By Cynthia Ma at 2016 ASCO Annual Meeting

permission obtained, This slide contains information about unapproved products by MFDS and AstraZeneca does not, under any circumstances, promote its products for off-label or unapproved uses

Fulvestrant or combination with CDKiWithout visceral disease

HR 0.59 (95% CI 0.42, 0.84)

Median PFS Fulvestrant: 22.3 monthsAnastrozole: 13.8 monthsP

rop

ort

ion

of

pat

ien

ts a

live

and

pro

gre

ssio

n-f

ree

Time (months)

0.9

1.0

0.7

0.8

0.5

0.6

0.3

0.4

0.1

0.0

0.2

0 5 10 15 20 25 30 35 40

Fulvestrant (n=95)

Anastrozole (n=113)

HR:0.58 HR:0.59Robertson JFR, et al, Lancet 2016; 388: 2997-3005Finn RS, et al. N Engl J Med 2016; 375: 1925-1936

Phase II FIRST study design

Anastrozole 1mg(1 mg p.o. daily)

n=103

Progression

Follow-up

Fulvestrant 500mg(500 mg i.m. on Days 0, 14 and

28 and every 28 days thereafter)

n=102

Progression

Follow-up

Open-label, randomised (1:1), first line, phase II trial

in estrogen receptor-positive postmenopausal

women with ABC (n=205)






• HER2-






1:1


250 mg im every

28 days


500 mg im on days 0,

14 and 28, and every

28 days thereafter

Post-menopausal women with HR+ advanced

breast cancer progressing or relapsing after

one prior endocrine therapy

CONFIRM study design

Robertson JFR, San Antonio Breast Cancer Symposium 2017, PD5-09

• FALCON - Robertson JFR, et al. Lancet. 2016 Dec 17;388(10063):2997-3005.• CONFIRM - Di Leo A, et al. J Clin Oncol 2010;28:4594-4600.• FIRST – Ellis MJ et al. J Clin Oncol. 2015 Nov 10;33(32):3781-7

Robertson JFR, San Antonio Breast Cancer Symposium 2017, PD5-09* FALCON - Robertson JFR, et al. Lancet. 2016 Dec 17;388(10063):2997-3005 *CONFIRM - Di Leo A, et al. J Clin Oncol 2010;28:4594-4600 *FIRST – Ellis MJ et al. J Clin Oncol. 2015 Nov 10;33(32):3781-7

ER+ MBC with non-visceral disease

Fulvestrant = Palbocilcib + AI

Which do you recommend?

The difference of medical support among each countries

•Indication

•Insurance

•Real world

Indication of Everolimus and Palbociclib in Japan

Accepted to combine with any endocrine drugsAccepted to use at any lines for MBC

Japan is a special country around the world

Only: Recurrent and metastatic breast cancer with ER+

KOREA ?

The difference of medical support between Japan and US

Japan US

Insurance Universal health insurance70% covered by public

Private insurancePublic (medicare and Medicaid)

High cost medical system

determine the limit cost payed by herself(＄440～1,000/month)

none

Real world data about agents used by line of therapy for MBC in US

Swallow E, et al. SABCS2014 Abst #P1-13-08

100

（%）

0Line 1 Line 2 Line 3

Anastrozole

n=11,545

（100%）n=3,021

（26%）n=821

（7%）

Letrozole

40

60

20

80

Tamoxifen

Exemestane

Fulvestrant

MegestrolOther

38%

27%

12%

7%

7%

6%

18%

18%

14%

20%

18%

10%

14%

13%

19%

20%

19%

13%

HR+/ HER2- mBC

n=49,527

Index ET

n=11,545

Patients with mBC

n=107,295

Post-menopausal females

n=36,823

Pre-index enrollment

n=19,120

- This slide contains information about unapproved products by MFDS and AstraZeneca does not, under any circumstances, promote its products for off-label or unapproved uses)

The schematic illustration showing the main differences Japan and other countries to care relapses in HR-positive breast cancer over time

Japan

Other countries

Death

1st line

2nd line

~4th lineChemoX

1st line 2nd line ChemoX

effect on mortality?

Developing

Cancer

Endocrine therapy

Endocrine therapy

X

X

XCancer

detectedBeginning

of drug therapy

Death

surgery

X

X

intensive follow up

during adjuvant therapy

BOLERO-2 (Phase 3): Everolimus in Advanced BC

EVE 10 mg daily+

EXE 25 mg daily (n = 485)

Placebo+

EXE 25 mg daily (n = 239)

Endpoints• Primary: PFS (local assessment)

• Secondary: OS, ORR, QoL, safety, bone markers, PK

R2:1

N = 724• Postmenopausal HR+

(ER or PgR) BC

• Unresectable, locally

advanced or metastatic BC

• Recurrence or progression

after letrozole or

anastrozole Stratification: Sensitivity to prior hormone therapy and presence of visceral metastases

Abbreviations: BC, breast cancer; ER, estrogen receptor; EVE, everolimus; EXE, exemestane; ORR, overall response rate; OS, overall survival; PFS, progression-free survival; PgR, progesterone receptor; PK, pharmacokinetics; QoL, quality of life.

Data from Baselga J, et al. New Engl J Med. 2012;366(6):520-529.

Gnant M, et al. Presented at: 2012 CIBD Annual Meeting; November 15-17, 2012; Lyon, France. Abstract: S43

BOLERO-2 PFS at 18-Months’ Follow-Up in Overall Patient Population

PFS –local assessment (N = 724)

Abbreviations: CI, confidence interval; EVE, everolimus; EXE, exemestane; HR, hazard ratio; PBO, placebo.

Piccart M, et al. ASCO 2012, Abstract 559.

EVE 10 mg + EXE

PBO + EXE

0

20

40

60

80

100

Time, wk

0 6 12 18 24 30 36 42 48 54 60 66 72 78 84 90 96 102 108 114 120

485 436 366 304 257 221 185 158 124 91 66 50 35 24 22 13 10 8 2 1 0

239 190 132 96 67 50 39 30 21 15 10 8 5 3 1 1 1 0 0 0 0

Pro

bab

ility

of

Eve

nt,

%

HR = 0.45 (95% CI, 0.38-0.54)Log-rank P < .0001

Kaplan-Meier mediansEVE 10 mg + EXE: 7.8 moPBO + EXE: 3.2 mo

Censoring times

EVE 10 mg + EXE (n/N = 310/485)PBO + EXE (n/N = 200/239)

Patients at risk

63

ALL Japan

OS (EXE) 26.6(22.6-33.1) 38.5 (24.7-NA)

OS (EXE +EVE) 31.0(28.0-34.6) 35.1(28.1-NA)

Gnant M, et al. Presented at: 2012 CIBD Annual Meeting; November 15-17, 2012; Lyon, France. Abstract: S43

JCOG1204 study shema

High risk primary breast cancer patients after surgery

・ER+, more than 4 LN+, more than 1LN+ after neoadjuvant chemo

・TN, HER2+: more than 1LN+, non-pCR after neoadjuvant chemo

Rnadomized

Stratification factors (site, subtype, neoadjuvant chemo)

A groups：standard follow up

・MMG：annual

・tumor marker: annual

B groups ：intensive follow up

・MMG：annual

・tumor marker: 4times /year until 3 Y,

2times /year after 3Y

・chest CT, abdormal CT, bone scinti.

PET/CT, Brain MRI et al.

The difference of OS after recurrence between Japan and outside Japan

•About 1 year

Would you recommend the AI + palbociclibfor every MBC with ER+ ?

Nonon-visceral, Asymptomatic : Fulvestrant monotherapy

Which drugs do you used after 2nd line endocrine therapy？

• Effect of previous treatment

• Change the drug of different mechanism

• Condition of cancer (speed, location et al)

• Asymptomatic or not

• evidence

Endocrine therapy after 2nd line for MBC with ER+

fulvestrant AI + Palbociclib

Sequential Endocrine monotherapy

EXE+EVE (AI + palbociclib)

No data

EXE + EVE

Beyond CDK inhibitor

Endocrine monotherapy

Placebo

(3 wks on/ 1wk off)

+

Fulvestrantd

(500 mg IM q4w)

Palbociclib

(125 mg QD;

3 wks on/1 wk off)

+

Fulvestrantd

(500 mg IM q4w)

aAll received goserelin.bMust have progressed on prior endocrine therapy (pre-/perimenopausal) or aromatase inhibitor therapy

(postmenopausal).cPatients randomized.dAdministered on Days 1 and 15 of Cycle 1, then every 28 d.

• Visceral metastases

• Sensitivity to prior hormonal

therapy

• Pre-/peri- vs post-menopausal

PALOMA3 Study Design

Turner et al. N Engl J Med. E-pub June 1, 2015

2:1 Randomization

N=521c

Stratification:

• HR+, HER2– ABC

• Pre-/peri-a,b or postmenopausalb

• Progressed on prior endocrine

therapy:

– On or within 12 mo adjuvant

– On therapy for ABC

• ≤1 prior chemotherapy regimen

for advanced cancer

● Phase 3, double-blind study involving 144 centers in 17 countries (NCT01942135)

● This analysis includes patients enrolled in Korea and Japan.

n=347

n=174

Turner NC, et al, N Engl J Med 2015; 373: 209-219Cristofanilli M, et al, Lancet Oncol. 2016; 17: 425-439

Patients characteristics is Paloma-3 Asian population

Characteristic

Asian

(n=105) Non-Asian (n=416)

Median (range) age, y 52 (34‒82) 58 (29‒88)

<65 y, n (%) 86 (82) 306 (74)

≥65 y, n (%) 19 (18) 110 (26)

Race, n (%)

White 0 385 (93)

Asian 105 (100) 0

Black or other 0 29 (7)

Ethnicity, n (%)

Hispanic/Latino 0 28 (7)

Not Hispanic/Latino 105 (100) 385 (93)

Median (range) weight, kg 56 (31‒83) 72 (43‒142)

Median (range) height, cm 155 (140‒174) 163 (122‒183)

ECOG performance status, n (%)

0 73 (70) 249 (60)

1 32 (31) 167 (40)

Measurable disease present, n (%) 87 (83) 319 (77)

Documented sensitivity to prior hormonal therapy, n (%) 65 (62) 326 (78)

Menopausal status

Pre-/peri- 44 (42) 64 (15)

Post- 61 (58) 352 (85)

Iwata H, et al, J Glob Oncol. 2017; 3: 289-303

*1-sided P value from the log-rank test stratified by the presence of visceral metastases and sensitivity to prior hormonal therapy per randomization.

CI=confidence interval; FUL=fulvestrant;

HR=hazard ratio; PAL=palbociclib

Primary Endpoint: Progression Free Survival (PFS)

Asian

Palbociclib +

Fulvestrant

n=74

Placebo +

Fulvestrant

n=31

HR (95% CI) 0.53 (0.29, 0.95)

1-sided P value 0.016*

Non-Asian

Palbociclib +

Fulvestrant

n=273

Placebo +

Fulvestrant

n=143

HR (95% CI) 0.44 (0.34‒0.59)

1-sided P value <0.000001*

0

20

40

60

80

100

0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15

Pro

gre

ss

ion

Fre

e S

urv

iva

l P

rob

ab

ilit

y (

%)

Time (Month)

Number of Patients at Risk:

273

143

261

135

219

87

212

80

192

64

189

61

158

44

154

43

71

16

65

16

27

10

19

5

7

2

74

31

72

30

62

25

61

25

55

19

55

19

44

15

43

15

20

6

20

6

5

3

4

2

0

0

7

1

1

0

0

Asian

Non-Asian

Secondary Endpoints: Response Assessment

Asian Non-Asian

Response, n (%)

Palbociclib +

Fulvestrant

(n=74)

Placebo +

Fulvestrant

(n=31)

Palbociclib +

Fulvestrant

(n=273)

Placebo +

Fulvestrant

(n=143)

CBR=CR+PR+SD≥24

wks52 (70) 16 (52) 179 (66) 53 (37)

CR 0 1 (3) 0 3 (2)

PR 14 (19) 3 (10) 52 (19) 8 (6)

SD ≥24 wks 38 (51) 12 (39) 127 (47) 42 (29)

SD <24 wks 9 (12) 9 (29) 39 (14) 31 (22)

Objective progression 12 (16) 6 (19) 46 (17) 51 (36)

CBR=clinical benefit response rate; CR complete response;

PR=partial response; SD=stable disease.Iwata H, et al, J Glob Oncol. 2017; 3: 289-303

Effectiveness of fulvestrant in advanced or metastatic breast cancer patients in the real world: A multi-center cohort study

with 1,072 patients （JBCRG-C06; Safari）.

Hidetoshi Kawaguchia, Norikazu Masudab, Takahiro Nakayamac, Kenjiro Aogid, Keisei Anane,

Yoshinori Itof, Shoichiro Ohtanig, Nobuaki Satoh, Shigehira Sajii, Eriko Tokunagaj, Seigo Nakamurak,

Yoshie Hasegawal, Masaya Hattorim, Tomomi Fujisawan, Satoshi Moritao, Miki Yamaguchip,

Toshinari Yamashitaq, Yutaka Yamamotor, Shinji Ohnos, Masakazu Toit

aDepartment of Breast Surgery, Matsuyama Red Cross Hospital, Matsuyama, Japan. bDepartment of Surgery, Breast Oncology, NHO Osaka

National Hospital, Osaka, Japan. cDepartment of Breast and Endocrine Surgery, Osaka Medical Center for Cancer and Cardiovascular Diseases,

Osaka, Japan. dDepartment of Breast Oncology, Shikoku Cancer Center, Matsuyama, Japan. eDepartment of Surgery, Kitakyushu Municipal Medical

Center, Kitakyushu, Japan. fBreast Medical Oncology Department and sBreast Oncology Center, The Cancer Institute Hospital Of JFCR, Tokyo,

Japan. gDepartment of Breast Surgery, Hiroshima City Hiroshima Citizens Hospital, Hiroshima, Japan. hDepartment of Breast Oncology, Niigata

Cancer Center Hospital, Niigata, Japan. iDepartment of Medical Oncology, Fukushima Medical University, Fukushima, Japan. jDepartment of Breast

Oncology, Kyushu Cancer Center, Fukuoka, Japan. kDepartment of Surgery, Division of Breast Surgical Oncology, Showa University School of

Medicine, Tokyo, Japan. lDepartment of Breast Surgery, Hirosaki Municipal Hospital, Hirosaki, Japan. mDepartment of Breast Oncology, Aichi

Cancer Center Hospital, Nagoya, Japan. nDepartment of Breast Oncology, Gunma Prefectural Cancer Center, Ohta, Japan. oDepartment of

Biomedical Statistics and Bioinformatics, tDepartment of Breast Surgery,Kyoto University Graduate School of Medicine, Kyoto, Japan. pDepartment

of Breast Surgery, JCHO Kurume General Hospital, Kurume, Japan. qDepartment of Breast Surgery, Tokyo Metropolitan Cancer and Infectious

Diseases Center Komagome Hospital, Tokyo, Japan. rDepartment of Breast and Endocrine Surgery, Kumamoto University, Graduate School of

Medical Sciencies, Kumamoto, Japan.

Kawaguchi H, et al, Beast Cancer Res Treat 2017; 163: 545-554

77

CONSORT diagram

A total of 1,072 patients were recruited from 16 centers in Japan. Of

those, 1,031 patients were evaluated for efficacy （41 patients were

excluded owing to the use of combination therapy or ER status）.

＊with chemotherapy or with new investigational drugs

Enrolled （N=1,072）

Safety Analysis （n=1,072）

Efficacy Analysis （n=1,031）

Combined therapy ＊（n=37）ER（-）（n=4）


78

Patient characteristics （Efficacy data set, n=1,031）

CharacteristicsAll

（n=1,031）Advanced

（n=222）Recurrent

（n=809）

Age （F500 start）

Median （Range）, years 64 （33-96） 64 （35-92） 64 （33-96）

<65, n （%） 526 （51.0） 120 （54.1） 406 （50.2）

≥65, n （%） 505 （49.0） 102 （45.9） 403 （49.8）

Treatment lines, n （%）

1st 21 （2.0） 5 （2.3） 16 （2.0）

2nd 234 （22.7） 55 （24.8） 179 （22.1）

3rd 275 （26.7） 59 （26.6） 216 （26.7）

≥4th 501 （48.6） 103 （46.4） 398 （49.2）

Period from AMBC

diagnosis

to F500 use

Median （Range）, years 3.4 （0-26.9） 3 （0-18.2） 3.5 （0-26.9）

<3, n （%） 473 （45.9） 113 （50.9） 360 （44.5）

≥3, n （%） 557 （54.0） 109 （49.1） 448 （55.4）

Missing, n（%） 1 （0.1） 0 1 （0.1）

DFI

Median （Range）, years NA NA 5.6 （0-31.8）

<2, n （%） NA NA 102 （12.6）

≥2, n （%） NA NA 706 （87.3）

Missing, n （%） NA NA 1 （0.1）

Visceral metastasis, n （%）No 697 （67.6） 208 （93.7） 489 （60.4）

Yes 334 （32.4） 14 （6.3） 320 （39.6）


79

TTF：All patients （n=1,031）

TT

F

00.00

0.20

0.40

0.60

0.80

1.00

48

Months

Median TTF: 5.4 months

6 18 3012 24 36 42


SOLAR-1 Study design

N = 560 patients

N = 340

N = 220

PIK3CA

mutant

PIK3CA

non-mutant

Stratify by:

• Lung/Liver

metastases

• Prior

CDK4/6i

BYL719 + fulvestrant N = 170

Placebo + fulvestrant N = 170

BYL719 + fulvestrant N = 110

Placebo + fulvestrant N = 110

R

A

N

D

O

M

I

Z

A

T

I

O

N

1:1

1:1

Patient Population:

Men & Post-menopausal women•HR+/HER2- locally advanced/MBC

•AI pretreated•Tumor tissue for PI3K pathway activation testing

Cycle 1 Day 1

RANDOMIZ.FOLLOW UP PHASE

SAFETYEFFICACYSURVIVAL

EOT

PIK3CA status by Novartis designated central lab.

All eligibility criteria verified

Day -35* Day -1SCREENING PHASE

Cycle of 28+/- 3 daysRANDOMIZED TREATMENT PHASE

Cycle 1 Day 15

Cycle nDay 1

BYL719 + Fulvestrant

Endpoints

• Secondary• PFS (in PIK3CA non-

mutant cohort)• OS (in PIK3CA non-mutant

cohort)• PFS by Central• ORR, CBR (in each cohort)• Safety• BYL719 PK • QOL (in each cohort)• ECOG (in each cohort)• PI3K status based on

ctDNA vs PFS (in each cohort)

• Exploratory• Biomarkers• PK/safety - efficacy

relationship• QOL• HRU

• Primary (by local)• PFS (in PIK3CA mutant

cohort)• Key secondary

• OS (in PIK3CA mutant cohort)

Including many Asian countries

- This slide contains information about unapproved products by MFDS and AstraZeneca does not, under any circumstances, promote its products for off-label or unapproved uses

Key points for MBC with ER+

• Endocrine monotherapy or combined therapy with targeting therapy (Everolimus or CDK inhibitor)

• Time to chemotherapy

The purpose of treatment for MBC

Prolong survival with better QoL

1. Cases without symptom by cancer progress

avoid the severe AE by treatment

2. Symptomatic cases by cancer progress (pain, tumor, cough, appetite loss, dyspnea et al)

improve the symptom by treatment

Acknowledgement

Staff:

Masaya HattoriMasataka SawakiAkiyo YoshimuraYayoi AdachiHaruru KotaniNaomi Gondo

Resident:

Ayumi kataokaSakura OnishiMadoka IwaseKayoko SuginoNanae HorisawaMakiko MoriMistuo Terada

Thank you for your attention

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