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Slide1

Jointly provided by &

This activity is supported by educations grants from Novartis Pharmaceuticals Corporation, Pfizer, and Lilly. For further information concerning Lilly grant funding visit www.lillygrantoffice.com

Use of Novel Combination Therapies in Treatment of Advanced HR+/HER2- Breast Cancer

A CME-certified

ONCOLOGY EXCHANGE

Activity

Slide2

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Participant Survey and CME Evaluation

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Slide3

Disclosures

All relevant financial relationships with commercial interests reported by faculty speakers, steering committee members, non-faculty content contributors and/or reviewers, or their spouses/partners have been listed in your program syllabus.

Off-label Discussion Disclosure

This educational activity may contain discussion of published and/or investigational uses of agents that are not indicated by the Food and Drug Administration. PCME does not recommend the use of any agent outside of the labeled indications. Please refer to the official prescribing information for each product for discussion of approved indications, contraindications and warnings. The opinions expressed are those of the presenters and are not to be construed as those of the publisher or grantors.

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STAGING: AJCC TNM Classification for Breast Cancer

AJCC Cancer Staging Manual, 8

th

Edition.

Breast Cancer. The American College of Surgeons. 2018

Slide5

AJCC Cancer Staging Manual, 8

th

Edition.

Breast Cancer. The American College of Surgeons. 2018

STAGING: AJCC TNM Classification for Breast Cancer

Slide6

Changing Landscape of ER-positive Metastatic Breast Cancer

Tamoxifen

approved

1970-80

Anastrozole

approved

1996

Fulvestrant approved

2002

Fulvestrant

HD approved

2012

Everolimus

approved

2012

Palbociclib

approved

2015

Ribociclib

/

Abemaciclibapproved

2017

Combination therapies

Slide7

Educational Objectives

Evaluate the updated clinical guidelines for combination therapies in the treatment of HR+/HER2- advanced breast cancer patients

Integrate clinical data regarding the use of CDK 4/6 inhibitors and

mTOR

inhibitors to treat HR+/HER2- advanced breast cancer, including appropriate patient subpopulations

Mitigate toxicities associated with multi-drug treatment regimens to improve patient outcomes

Recognize potential drug-drug interactions to plan effective and safe treatment regimens for each patient

Slide8

Agenda

Welcome, Introduction, and Pre-survey

Current Guidelines for Combination Therapy with Endocrine Agents

Alleviation of Side Effects Associated with Best Practice Combination Therapies

Novel Agents and Emerging Clinical Data for HR+ Breast Cancer

Q&A Session and Concluding Remarks

Slide9

Polling Question 1Pre-activity Survey

70-year-old female presents with hip pain. Past history is significant for stage 2 breast cancer diagnosed 20 years ago, at which time she received 5-years of tamoxifen. Imaging demonstrates multiple areas consistent with probable bone metastases. Bone biopsy shows adenocarcinoma consistent with breast primary, ER-positive 95%, PR-negative, HER2-negative. She receives anastrozole and has stable disease for 24-months, at which point she develops progressive disease in her bones. All of these are reasonable second-line therapeutic options EXCEPT:TamoxifenLetrozoleFulvestrant plus palbociclib or abemaciclibExemestane plus everolimusFulvestrant

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Polling Question 2Pre-activity Survey

65-year-old post-menopausal female presents with a palpable right breast mass. Imaging confirms a mass in the right breast, as well as several enlarged lymph nodes. Breast biopsy demonstrates invasive ductal cancer, grade 1, ER-positive, PR-positive, HER2-negative. Systemic staging demonstrates enlarged nodes in the mediastinum, as well as bone metastases. She undergoes a bone biopsy that confirms metastatic breast cancer, ER-positive, PR-positive, HER2-negative. All of these are reasonable first-line therapeutic options EXCEPT:FulvestrantFulvestrant plus anastrozoleLetrozole plus a CDK inhibitorExemestane plus everolimus

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Current Guidelines for Combination Therapy with Endocrine Therapy

Slide12

SWOG S0226 Phase III Trial of Anastrozole + Fulvestrant 250 vs Anastrozole Alone

Mehta RS et al N Engl J Med. 2012;367:435-444.

FULVESTRANT 250 mg q4wk + ANASTROZOLE 1 mg PO

qday

*

ANASTROZOLE 1 mg PO

qday

*

n = 707

Post menopausal women with HR+ advanced breast cancer, untreated with HR for advanced disease

Primary

PFS

Secondary

OS

FUL + ANA n = 355

ANA n = 352

HR

P

value

PFS (mo)15.013.50.800.007OS (mo) median47.741.30.810.049

*Crossover to

fulvestrant

500 mg allowed after progression

Slide13

FACT: Phase III Study of

Anastrozole

+

Fulvestrant

250

vs

Anastrozole Alone

Bergh J et al. J Clin Oncol. 2012;30:1919-1925.

FULVESTRANT 250 mg q4wk + ANASTROZOLE 1 mg PO qday

ANASTROZOLE 1 mg PO qday

n = 514

Pre/Post menopausal women with HR+ advanced breast cancer, untreated with HR for advanced disease

Primary

TTPSecondaryTTF, ORR, CBR, Safety, OS

FUL + ANA n = 256

ANA n = 254

HR

P

value

TTP (mo)

10.8

10.2

0.72

0.91

OS (mo) median

37.8

38.2

1.00

Slide14

Palbociclib

PD 0332991

CDK 4/6 Inhibitors Approved by the FDA

Ribociclib

LEE011

Abemaciclib

LY2835219

Slide15

PALOMA 1: Progression-Free Survival

Finn R et al. Presented at: American Association for Cancer Research 2014 Congress; April 5-9, 2014; San Diego, CA. Abstract CT101.

Time (Month)

PAL+LET

8467604736282113851LET8148362819146331

Number of patients at risk

PAL + LET(n=84)LET(n=81)Number of Events (%)41 (49)59 (73)Median PFS, months(95% CI)20.2(13.8, 27.5)10.2(5.7, 12.6)Hazard Ratio(95% CI)0.488(0.319, 0.748)P-value0.0004

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PALOMA 1: Final Overall Survival

PAL+LET(n=84)LET(n=81)Patients with events, n (%)60 (71)56 (69)Median OS, months(95% CI)37.5(31.4, 47.8)34.5(27.4, 42.6)Hazard ratio (95% CI)0.897 (0.623, 1.294)P-value0.281

Finn R et al. Presented at: American Society of Clinical Oncology 2017.

PAL+LET8473633828138LET8167523321103

Time (Month)

Number of patients at risk

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PALOMA-2 and MONALEESA-2 Design of Phase III Studies

Primary endpoint: PFS Secondary endpoints: Response, OS, safety, biomarkers, PROs

PALOMA-2

RANDOMI

SE

Palbociclib (125 mg qd, 3/1 schedule) + letrozole (2.5 mg qd)

Placebo + letrozole (2.5 mg qd)

Postmenopausal ER+ HER2– advanced breast cancer with no prior treatment for advanced disease. AI-resistant patients excludedn = 666

(2:1)

Stratified by the presence/absence of liver and/or lung metastases

Ribociclib

(600 mg qd,

3 wk on/1 wk off schedule) +

letrozole (2.5 mg qd)

Placebo+ letrozole (2.5 mg qd)

Primary endpoint: PFS Secondary endpoints: OS (key), ORR, CBR, safety

Postmenopausal women with HR+/HER2– advanced breast cancer with no prior therapy for advanced diseasen = 668

MONALEESA-2

RANDOMI

SE

(1:1)

PRO = patient-reported outcome;

qd

= once daily

Slide18

PALOMA-2

Finn RS et al.

N Engl J Med

. 2016;375:1925-1936.

MONALEESA-2

PALOMA-2 & MONALEESA-2: PFS

mPFS

(months)

Ribociclib

–letrozole: 25.3Placebo–letrozole: 16.0Hazard ratio, 0.568(95% CI, 0.457-0.704)

mPFS (months)Palbociclib–letrozole: 24.8Placebo–letrozole: 14.5 Hazard ratio, 0.58(95% CI, 0.46-0.72)

Hortobagyi

GN et al.

J Clin Oncol

. 2017;35(suppl):Abstract 1038.

Slide19

MONARCH 3: Study Design

Slide20

Di Leo et al. Presented at: European Society for Medical Oncology (ESMO) 2017.

Primary Endpoint (PFS) Met at Interim Analysis

Slide21

MONALEESA-7

Tumor assessments were performed every 8 weeks for 18 months, then every 12 weeks thereafterPrimary analysis planned after ~329 PFS events

Stratified by:Presence/absence of liver/lung metastasesPrior chemotherapy for advanced diseaseEndocrine therapy partner (tamoxifen vs NSAI)

Primary endpointPFS (locally assessed per RECIST v1.1)‡Secondary endpointsOverall survival (key)Overall response rateClinical benefit rateSafetyPatient-reported outcomes

Pre/perimenopausal women with HR+, HER2– ABCNo prior endocrine therapy for advanced disease≤1 line of chemotherapy for advanced diseasen=672

Randomization

(1:1)

Ribociclib

(600 mg/day; 3-weeks-on/ 1-week-off) + tamoxifen/NSAI + goserelin* n=335

Placebo + tamoxifen/NSAI + goserelin* n=337

Phase III Placebo-controlled Study of Ribociclib and Tamoxifen/NSAI + Goserelin

NSAI = non-steroidal aromatase inhibitor; RECIST = Response Evaluation Criteria in Solid Tumors. *Tamoxifen = 20 mg/day; NSAI: anastrozole = 1 mg/ day or letrozole = 2.5 mg/day; goserelin = 3.6 mg every 28 days;

‡

PFS by Blinded Independent Review Committee conducted to support the primary endpoint.

1.

Klijn

JG et al. J

Clin Oncol.

2001;19:343-353. 2.

Mourisden

H et al.

J Clin Oncol.

2001;19:2596-2606.

Slide22

Primary Endpoint: PFS

Investigator-assessed

Probability of

progression-free survival (%)

PFS (investigator assessment)Ribociclib + tamoxifen/ NSAI (n=335)Placebo + tamoxifen/ NSAI (n=337)Number of events, n (%)131 (39.1)187 (55.5)Median PFS, months (95% CI)23.8 (19.2–NR)13.0 (11.0–16.4)Hazard ratio (95% CI)0.553 (0.441–0.694)One-sided P-value0.0000000983

10

8

6

4

2

0

100

80

60

40

20

0

30

28

26

24

22

20

18

16

14

12

10

30

50

70

90

Tripathy

D et al. Presented at: 2017 SABCS

.

Abstract GS2-05.

Slide23

PFS by Endocrine Therapy PartnerInvestigator-assessed

Goserelin included in all combinations.

PFS (investigator assessment)

Tamoxifen

NSAI

Ribociclib arm

n=87

Placebo arm

n=90

Ribociclib arm

n=248

Placebo arm

n=247

Number of events, n

39

55

92

132

Median PFS, months

(95%

CI)

22.1

(16.6–24.7)

11.0

(9.1–16.4)

27.5

(19.1–NR)

13.8

(12.6–17.4)

Hazard

ratio (95% CI)

0.585 (0.387–0.884)

0.569 (0.436–0.743)

Slide24

Patient-reported Outcomes

EORTC QLQ-C30 – Global Health Status

QoL

= quality of life.Goserelin included in all combinations.

Ribociclib

+ tamoxifen/NSAI (n=335)Placebo + tamoxifen/NSAI (n=337)Number of events, n (%)102 (30.4)115 (34.1)Median, months (95% CI)NR (22.2–NR)21.2 (15.4–23.0)Hazard ratio (95% CI)0.699 (0.533–0.916)Log-rank test P-value0.004

Time to deterioration (months)

80

90

60

50

70

40

30

20

10

0

100

10

8

6

4

2

0

28

26

24

22

20

18

16

14

12

Event-free probability (%)

Slide25

EFECT

Endocrine Therapy in Hormone-refractory MBC

Proportion of patients

progression-free

Months

At risk:FulvestrantExemestane

3.7

3.7

Median (months)

HR = 0.963, 95% CI (0.819, 1.133), p=0.6531

Cox analysis, p=0.7021

Exemestane

Fulvestrant

Fulvestrant*

Exemestane

0

3

6

9

12

15

18

21

24

27

0.0

0.2

0.4

0.6

0.8

1.0

351

195

96

50

25

12

4

2

342

190

98

41

21

12

8

6

0

1

0

0

Chia S et al.

J Clin Oncol.

2008;26:1664-1670.

*500mg D1 250mg D14, q28d

Slide26

PALOMA3 Study Design

Presented by Turner N at: 2015 ASCO Annual Meeting.

Slide27

Primary Endpoint: PFS (ITT Population)

Presented by Turner N at: 2015 ASCO Annual Meeting.

Turner NC et al.

N

Engl

J Med.

2015;373:209-219.

Slide28

*

Dose reduced by protocol amendment in all new and ongoing patients from 200 mg to 150 mg BID after 178 patients enrolled

Sledge GW Jr et al. J Clin Oncol. 2017;35:2875-2884.

MONARCH 2: Study Design

HR+/HER2- ABC

Pre/peri-  or postmenopausal

ET resistant:

Relapsed on

neoadjuvant or on/within 1 yr of adjuvant ETProgressed on first-line ET No chemo for MBC No more than 1 ET for MBC ECOG PS ≤1

abemaciclib: 150 mg * BID (continuous schedule)fulvestrant: 500 mg 

Primary endpoint:Investigator-assessed PFSSecondary endpoint: OS, Response, Clinical Benefit Rate, SafetyStratification factors:- Metastatic site - ET resistance (primary vs secondary)

placebo: BID (continuous schedule) fulvestrant: 500 mg 

Randomization

2 :1

n = 669

Slide29

Primary Endpoint: PFS (ITT)

Median PFSabemaciclib + fulvestrant: 16.4 months placebo + fulvestrant: 9.3 monthsHR (95% CI): 0.553 (0.449, 0.681)P<0.0000001

PFS benefit confirmed by blinded independent central review (HR: 0.460; 95% CI: 0.363, 0.584;

P

<0 .000001)

Slide30

Change from baseline (%)

100

0

-100

-50

-30

50

20

Previously-treated HR+/HER2− MBC

Abemaciclib

200 mg twice daily

Treatment continued until unacceptable toxicity or PD

Dickler

et al.

J Clin Oncol

.

2016;

34

:

abstr

act

510.

MONARCH

1

Investigator

Assessed

Response

a

Abemaciclib

200 mg BID (n = 132)Confirmed overall response rate (ORR; complete response + partial response) (95 % CI)19.7% (13.3-27.5)Complete responsePartial response0%19.7%Stable disease (SD) ≥ 6 mo22.7%Clinical Benefit Rate (ORR + SD ≥ 6 mo)42.4 %

Slide31

Acquired Resistance to Endocrine Therapy in ER+ BC

ER

Gene expression

E

E

Estrogen

(E)

Estrogen receptor

(ER)

Aromatase

A

Androgen

(A)

Some ways acquired resistance may occur:

Activation of growth factor signaling pathways (PI3K/ AKT/

mTOR

; MAPK/ ERK; etc.)

ER mutations

Changes in the tumor microenvironment

Acquired resistance is defined as:

PI3K

AKT

mTOR

Ras

MAPK

RTK

Receptor tyrosine kinases

(RTK)

Recurrence at least 12 months after completion of adjuvant therapy

Disease progression ≥6 months after endocrine therapy initiated in the metastatic setting

Bachelot

T et al.

J Clin Oncol

. 2012;30:2718-2724;

Bedard PL et al.

Breast Cancer Res Treat

. 2008;108:307-317.

Slide32

Primary Resistance to Endocrine Therapy in ER+BC

ER

Gene expression

E

E

Estrogen

(E)

Estrogen receptor

(ER)

Aromatase

A

Androgen

(A)

Primary resistance is defined as

Recurrence within adjuvant therapy

Disease progression < 6 months after treatment in the metastatic setting

Some ways primary resistance may occur:

FGFR amplifications

Loss of ER

α

Post-translational modification of ER

α

Expression of ER cofactors

MYC amplification and overexpression

Cyclin D1 amplification or expression

PI3K

AKT

mTOR

MAPK

RTK

Receptor tyrosine kinases

(RTK)

Ras

Bachelot

T, et al.

J

Clin

Oncol

. 2012;30(22):2718-2724;

Bedard

PL, et al.

Breast Cancer Res Treat

. 2008;108(3):307-317

Slide33

Everolimus in Hormone-refractory MBC

TAM 4.5 mo.

TAM + RAD 8.6 mo.

Hazard Ratio (HR) = 0.53 (95% CI: 0.35-0.81)Exploratory log-rank: P =0.0026

0.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

Probability of survival

0

2

4

6

8

10

12

14

16

18

20

22

24

26

28

Months

Time (weeks)

HR = 0.36 (95% CI: 0.27–0.47)

EVE + EXE: 10.6 Months

PBO + EXE: 4.1 Months

Log rank

P

value = 3.3 x 10

-15

0

12

6

18

24

30

36

48

60

42

54

72

66

78

80

60

40

20

100

0

Probability of Event (%)

Everolimus + Exemestane (E/N=114/485)

Placebo +

Exemestane

(E/N=104/239)

Baselga

J et al

.

N

Engl

J Med

.

2012;366:520-529.

Bachelot

T et al

.

J Clin Oncol

.

2012;30:2718-2724.

Slide34

Fulvestrant ± Everolimus: PFS

Presented at: San Antonio Breast Cancer Symposium, December 6-10, 2016

Slide35

MANTA Study Design

Fulvestrant + Vistusertib(intermittent schedule; 2d on 5d off)

Fulvestrant + Everolimus

ER+, HER2- ABC

Postmenopausal

Measurable or evaluable diseaseDisease refractory to AIRelapsed on or ≤12 months from adjuvant AI, or Progressed on AI in the advanced settingMax. 1 line of chemotherapy

Fulvestrant + Vistusertib(Continuous daily schedule)

Fulvestrant

R

n=90

n=90

n=60

n=60

Primary endpoint:

Investigator-assessed PFS

Secondary endpoints:Response rates (ORR)Clinical benefit rate (CBR)Duration of responseOSSafety

Fulvestrant: 500 mg i.m. injection on day 1, 15 & 29, and then q28 daysEverolimus: 10 mg orally, once daily, continuous scheduleVistusertib (continuous): 50 mg orally, twice daily, continuous scheduleVistusertib (intermittent): 125 mg orally, twice daily, day 1&2 every week

Stratification factors:Measurable Disease (vs non-measurable)Sensitivity to prior ER (sensitive vs resistant)

Sensitivity to prior ET is defined as: ≥24 months of adjuvant ET before recurrence or CR or PR or SD for ≥24 weeks with ≥1 ET for MBC

ET = endocrine therapy; ER = Estrogen Receptor, ABC = advanced breast cancer, AI = Aromatase inhibitor; PR/CR = Partial/Complete response, SD = stable disease, d = days; PFS = Progression-free survival

Trial Sponsor: Queen Mary University of London.

Slide36

25

50

75

100

Progression-free Survival (%)

0

30

Time (months)

12

24

18

6

Number at risk

F+E

64

45

26

8

2

0

F

66

29

14

6

1

0

F

+V

cont

F+V

int

101

95

54

48

17

21

6

8

3

4

0

0

CI = confidence

i

nterval;

ITT =

i

ntent-to-treat

; mths = months;

PFS = progression-free survival

F = Fulvestrant; F+E = Everolimus;

F+V(cont)

= Vistusertib, continuous

schedule;

F+V(

int

)

= Vistusertib, intermittent

schedule (2 days on, 5 days off);

San Antonio Breast Cancer Symposium, December 5-9, 2017

Primary Endpoint: PFS (ITT Population)

Median PFS,

months (95% CI)

Fulvestrant

+

Vistusertib

cont

7.6

(5.9-9.4)

Fulvestrant

+

Vistusertib

int

8.0

(5.6-9.9)

Fulvestrant

5.4

(3.5-9.2)

Fulvestrant

+

Everolimus

12.3

(7.7-15.7)

Slide37

Alleviation of Side Effects Associated with Best Practice Combination Therapies

Slide38

Polling Question 3Activity Survey

65-year-old postmenopausal woman from question above was treated with exemestane and everolimus. Twelve weeks into therapy, she complained of generalized rash and mild dyspnea on exertion. CXR showed apical changes consistent with pneumonia or pneumonitis. Treatment options would include all EXCEPT:CT chest Continue current medicationsOral antibiotics or steroidsPulmonary consult

Slide39

Polling Question 4Activity Survey

The patient received CDK4/6 inhibitor and letrozole. Three weeks into treatment she develops fever, diarrhea, and an episode of syncope. At presentation in ER, her vitals were: temp 1010F, pulse was 60/min, BP 90/60. Possible causes related to CDK4/6 inhibitor causing her symptoms include: Neutropenic feverHeart blockDiarrheaAll of the above

Slide40

Ribociclib + Letrozolen = 334Placebo + Letrozolen = 330n (%)Any GradeGrade 3Grade 4Any GradeGrade 3Grade 4Total331 (99.1)232 (69.5)56 (16.8)322 (97.6)117 (35.5)6 (1.8)Neutropenia214 (64.1)139 (41.6)29 (8.7)16 (4.8)3 (0.9)0Nausea178 (53.3)8 (2.4)0101 (30.6)2 (0.6)0Fatigue138 (41.3)9 (2.7)1 (0.3)107 (32.4)3 (0.9)0Diarrhea128 (38.3)8 (2.4)081 (24.5)3 (0.9)0Alopecia115 (34.4)0053 (16.1)00Vomiting112 (33.5)12 (3.6)055 (16.7)3 (0.9)0Arthralgia111 (33.2)2 (0.6)1 (0.3)108 (32.7)4 (1.2)0Constipation93 (27.8)4 (1.2)071 (21.5)00Headache90 (26.9)1 (0.3)069 (20.9)2 (0.6)0Hot flush82 (24.6)1 (0.3)084 (25.5)00Back pain81 (24.3)10 (3.0)067 (20.3)1 (0.3)0Cough77 (23.1)0070 (21.2)00Neutrophil count decreased72 (21.6)53 (15.9)3 (0.9)4 (1.2)1 (0.3)0Anemia69 (20.7)6 (1.8)2 (0.6)19 (5.8)4 (1.2)0Decreased appetite69 (20.7)5 (1.5)052 (15.8)1 (0.3)0

Palbociclib + Letrozolen = 444Placebo + Letrozolen =222n (%)Any GradeGrade 3Grade 4Any GradeGrade 3Grade 4Total439 (98.9)276 (62.2)60 (13.5)212 (95.5)49 (22.1)5 (2.3)Neutropenia353 (79.5)249 (56.1)46 (10.4)14 (6.3)2 (0.9)1 (0.5)Leukopenia173 (39.0)107 (24.1)3 (0.7)5 (2.3)00Fatigue166 (37.4)8 (1.8)061 (27.5)1 (0.5)0Nausea156 (35.1)1 (0.2)058 (26.1)4 (1.8)0Arthralgia148 (33.3)3 (0.7)075 (33.8)1 (0.5)0Alopecia146 (32.9)0035 (15.8)00Diarrhea116 (26.1)6 (1.4)043 (19.4)3 (1.4)0Cough111 (25.0)0042 (18.9)00Anemia107 (24.1)23 (5.2)1 (0.2)20 (9.0)4 (1.8)0Back pain96 (21.6)6 (1.4)048 (21.6)00Headache95 (21.4)1 (0.2)058 (26.1)4 (1.8)0Hot flush93 (20.9)0068 (30.6)00Constipation86 (19.4)2 (0.5)034 (15.3)1 (0.5)0Rash79 (17.8)4 (0.9)026 (11.7)1 (0.5)0Asthenia75 (16.9)10 (2.3)026 (11.7)00

Finn RS et al.

N Engl J Med

. 2016;375:1925-1936.

Hortobagyi

GN et al. J Clin Oncol. 2017;35(suppl): Abstract 1038.

PALOMA-2

MONALEESA-2

PALOMA-2 and MONALEESA-2: Toxicity

Slide41

 20 % in either arm, n (%)AllG3G4AllG3G4 Any435 (98.6)241 (54.6)26 (5.9)199 (89.2)46 (20.6)5 (2.2) Diarrhea a381 (86.4)59 (13.4)055 (24.7)1 (0.4)0 Neutropenia b203 (46.0)104 (23.6)13 (2.9)9 (4.0)3 (1.3)1 (0.4) Nausea199 (45.1)12 (2.7)-51 (22.9)2 (0.9)- Fatigue176 (39.9)12 (2.7)-60 (26.9)1 (0.4)- Abdominal pain156 (35.4)11 (2.5)-35 (15.7)2 (0.9)- Anemia128 (29.0)31 (7.0)1 (0.2)8 (3.6)2 (0.9)0 Leukopenia125 (28.3)38 (8.6)1 (0.2)4 (1.8)00 Decreased appetite117 (26.5)5 (1.1)027 (12.1)1 (0.4)0 Vomiting114 (25.9)4 (0.9)023 (10.3)4 (1.8)0 Headache89 (20.2)3 (0.7)-34 (15.2)1 (0.4)-

Placebo +

Fulvestrantn = 223

Abemaciclib + Fulvestrantn = 441

a Grade 2 diarrhea: abemaciclib + fulvestrant n = 140 (31.7 %); placebo + fulvestrant n = 11 (4.9 %). b Febrile neutropenia was uncommon [6 patients in the abemaciclib arm (1 incorrectly coded; 1 post-chemotherapy)] and was not associated with severe infection

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TEAE (Safety Population)

Slide42

SWISH Study

Phase II single-arm trial evaluated prophylaxis with steroid mouthwash on everolimus-associated stomatitisMouthwash: 10ml with dexamethasone 0.5mg/5mL (swish for 2-mins and spit) QID for 8 to 16 weeks started day 1 of exemestane and everolimus92 patients enrolled with 85 evaluable

Rugo

HS et al.

Lancet Oncol.

2017;18:654-662.

Slide43

SWISH: Effect of Steroid Mouthwash on Everolimus-associated Stomatitis

Rugo

HS et al.

Lancet Oncol.

2017;18:654-662.

Slide44

Rare Everolimus-related Pulmonary Side Effects

GradeSymptomsManagementEverolimus Dose Modification1Asymptomatic (radiographic findings only)Initiate appropriate monitoringNo dose adjustment required2Symptomatic, not interfering with ADLsRule out infectionConsider treatment with corticosteroidsConsider interruption of therapy until symptoms improve to grade ≤13Symptomatic, interfering with ADLs; oxygen requiredRule out infectionConsider treatment with corticosteroidsReinitiate everolimus at a lower doseDiscontinue treatment if failure to recover within 4 weeksHold treatment until recovery to grade ≤14Life threatening; ventilatory support indicated12 (2.7)Consider reinitiating everolimus at a lower dose. If toxicity recurs at grade 3, consider discontinuationDiscontinue everolimus

Based on

Everolimus

Package Insert.

Slide45

Novel Agents and

Emerging Clinical Data

for HR+ Breast Cancer

Slide46

Where Do We Stand Today?

First-Line

Post-Progression

CDKi

+ LET

LET

EXE

TAM

EVE +TAM

EVE + EXE

CDKi + FULV

FULV

PFS, months

LET +/- CDK4/6i

FULV +/- CDK4/6i

EXE +/- EVE

TAM +/- EVE

Slide47

BELLE 2: Addition of Buparlisib (Pan-PI3K Inhibitor) to Fulvestrant in Hormone-resistant MBC

CI = confidence interval; HR - hazard ratio; OS = overall survival; PFS = progression-free survival.

Full Population (N=1047)Buparlisib + Fulvestrantn=576Placebo + Fulvestrantn=571Median PFS, months (95% CI)6.9(6.8–7.8)5.0(4.0–5.2)HR (95% CI)0.78 (0.67–0.89)One-sided P value<0.001

Probability of Progression-free Survival, %

Time (Months)

100

60

0

80

40

20

0

4

8

14

18

2

6

10

12

16

20

26

30

22

24

28

Buparlisib + fulvestrant (n/N=349/576)

Placebo + fulvestrant (n/N=435/571)

Toxicity significant (80% grade ≥3 toxicities)

PIK3CA mutations not predictive (in tissue)

Baselga

J et al. Presented at: San Antonio Breast Cancer Symposium (SABCS) 2015.

Slide48

PFS results by independent central review were consistent with local assessment:HR 0.57 (95% CI: 0.44–0.74; one-sided P<0.001)

BELLE 3 Progression-free Survival per Investigator Assessment

CI = confidence interval; HR = hazard ratio.

6-month PFS rate:31% vs. 20%

100

80

60

40

20

0

0

4

8

2

6

10

12

14

16

18

20

22

24

26

Time, Months

Probability of

Progression-free Survival, %

Full Population (n=432)

Buparlisib + Fulvestrant

n=289

Placebo + Fulvestrant

n=143

Median PFS,

months (95%

CI)

3.9

(2.8–4.2)

1.8

(1.5–2.8)

HR (95% CI)

0.67 (0.53–0.84)

One-sided

P

-value

<0.001

Di Leo A et al.

Lancet Oncol.

2018;19:87-100.

Slide49

ER+/HER2- locally advanced or metastatic BC

Postmenopausal Recurrence or progression during or after aromatase inhibitor

SANDPIPER Phase 3 Study of Taselisib in ER+ MBC

Primary Endpoint: PFS in pts with mutant tumorsTarget HR: 0.59 (mPFS 4.5  7.6 mo) >95% power at two-sided 1% alpha level

Stratify: 1) Visceral disease 2) Endocrine sensitivity 3) Geographic region

120 Pts without PIK3CA Mutant Tumors

Taselisib 4 mg QD + Fulvestrant

Placebo QD + Fulvestrant

Taselisib 4 mg QD + Fulvestrant

Placebo QD + Fulvestrant

2:1 randomization

2:1 randomization

Treat until PD or unacceptable toxicity

No Crossover

Survival Data

480

Pts with PIK3CA Mutant Tumors

Available at: www.ClinicalTrials.gov;

NCT02340221.

Slide50

Ongoing Trials

α

-specific PI3K inhibitors

www.clinicaltrials.gov

NCT02077933

Phase I

alpelisib

+

everolimus +/- exemestane

NCT

02437318 (SOLAR-1)Phase III fulvestrant +/- alpelisib

NCT02340221 (Sandpiper)

Phase III Fulvestrant +/- Taselisib

NCT01923168 (Neo-Orb)Phase II Letrozole +/- Alpelisib or Buparlisib

NCT

02273973 (Lorelei)

Phase II

Letrozole

+/-

Taselisib

Slide51

Ribociclib (LEE011)Palbociclib (PD-0332991)Abemaciclib (LY2835219)

PI3K

AKT

mTOR

CCND1

CDK4/6

pRb

E2F

Cell survival

Proliferation

Other signals

(AMPK/ERK/p90RSK)

PI3K Inhibitor

CDK4/6 Inhibition +

α

-PI3K Inhibition Combinations Could Reverse Resistance to Endocrine Therapy as well as CDK4/6 Therapy

Slide52

1. Bardia et al. Presented at: SABCS 2015.

Exemestane + Everolimus + Ribociclib

Phase

Ib/II Study of Postmenopausal Women with AI-resistant ER+ MBC1

Letrozole + Alpelisib + Ribociclib

Phase Ib Study of Postmenopausal Women with ER+ MBC2

2.

Juric

et al. Presented at:

SABCS

2015.

Slide53

FGFR1 amplification is an independent predictor of overall survival in patients with ER+

breast cancer treated with tamoxifen

FGFR1

amplification is present in ~15% of ER+ breast cancers

Elbauomy

Elsheikh S et al. Breast Cancer Res. 2007:9:R23. Karlsson E et al. Genes Chromosomes Cancer. 2011;50:775-787. Turner N et al. Cancer Res. 2010;70:2085-2094.

Targeting FGFR

Pre-surgical

letrozole

study shows

FGFR1

amplification as a mechanism of endocrine resistanceCombination of ER and FGFR inhibitors is synergistic against ER+/FGFR1-amp PDXs

Formisano and

Arteaga

Slide54

* FGFR alteration =

FGFR1-4 amplification

Phase Ib/II trial of FGFR TKI

erdafitinib

+

fulvestrant + CDK4/6 inhibitor in endocrine-resistant ER+/HER2– metastatic breast cancer with FGF pathway alterations (Mayer, I)

Targeting FGFR

Completed

Safety and Efficacy of TK1258 in FGFR1 Amplified and Non-amplified Metastatic HER2 Negative Breast Cancer

Condition:

Metastatic Breast Cancer

Intervention:

Drug: TK1258

Completed

A Phase II Trial Testing Oral Administration of

Lucitanib

in Patients with Fibroblast Growth Factor Receptor (FGFR)1-amplified or Non-amplified Estrogen Receptor Positive Metastatic Breast Cancer

Condition:

Breast Cancer

Intervention:

Drug:

lucitanib

Completed

Has Results

Safety and Efficacy of AZD4547 in Combination with

Fulvestrant

vs.

Fulvestrant

Alone in ER+ Breast Cancer Patients

Condition:

FGFR Inhibition,

Pharmaconetics

, Biomarkers; ER+ Breast Cancer

Intervention:

Drug: AZD4547; Drug: Exemestane; Drug: Placebo; Drug:

Fulvestrant

Active

not recruiting

AZD4547 & Anastrozole or Letrozole (NSAIs) in ER + Breast Cancer Patients Who Have Progressed on NSAIs (RADICAL)

Condition:

Breast Cancer

Intervention:

Drug: AZD4547/ anastrozole or letrozole

Recruiting

Open-Label, Dose-Escalation Study of INCB054828 in Subjects with Advanced Malignancies

Condition:

Malignant Solid Tumor; Carcinoma; Non-Small-Cell-Lung; Stomach Neoplasms; Urothelial Carcinoma; Endometrial Neoplasms; Multiple Myeloma; MPN; Breast Cancer: Cholangiocarcinoma

Intervention:

Drug: INCB054828; Drug:

Gemcitabine+Cisplatin

; Drug: Pembrolizumab; Drug: Docetaxel

Recruiting

NCI-MATCH: Targeted Therapy Directed by Genetic Testing in Treating Patients With Advanced Refractory Solid Tumors, Lymphomas, or Multiple Myeloma

Condition:

Advanced Malignant Solid Neoplasm; Lymphoma; Recurrent Malignant Solid Neoplasm; Recurrent Plasma Cell Myeloma; Refractory Malignant Neoplasm; Refractory Plasma Cell Myeloma

Slide55

PD-1/L1 Immunotherapy in Breast Cancer

Immune checkpoint inhibitors are effective in a variety of solid tumorsIn the metastatic setting:20% ORR in TNBC 1,26–12% ORR in ER+ BC3,4In ER+ mBC resistant to endocrine therapy, total mutational burden increases5, but these tumors are still generally immunologically ‘cold’Immunotherapy combination strategies that increase immune recognition through enhanced antigen presentation and/or increased T cell homing may increase immunotherapy response

1Emens et al. Presented at: American Association for Cancer Research (AACR) 2015. 2Nanda et al. Presented at: AACR 2015. 3Dirix et al. JAVELIN trial. Presented at: SABCS 2015. 4Rugo et al KEYNOTE-028 trial. Prsented at: SABCS 2015. 5Lefebvre et al. PLoS Medicine. 2016;13:e1002201.

Slide56

Immunotherapy Combination Strategies in ER+ MBC – CDK4/6 Inhibition

Inhibition of CDK4/6 in ER+ breast cancer → Induction of senescence and enhanced recruitment of immune cellsThis may result in increased sensitivity checkpoint inhibitors

TCGA

CD8+ T cell marker expression correlates with expression of CXCL9 and CCL5 chemokines and high CXCL9 and CCL5 expression correlates with enhanced survival based on TCGA analysis of 1105 invasive breast cancers.

Slide57

ENCORE 301

Exemestane

±

Entinostat

in HR-positive MBC with Prior Treatment with NSAI: Overall Survival

Intent-to-treat population

Yardley et al. Presented at: ASCO Breast 2011.

www.ClinicalTrials.gov.

NCT02115282.

Slide58

Eligible:Advanced breast cancerER/PR+, HER2-Progression/no progression on prior non-steroidal AI

Exemestane plus

Entinostat

Exemestane plus

Placebo

Blood sampling: baseline, 2

wks

Treatment until progression/intolerance: exemestane 25 mg daily po AND

entinostat

/placebo 5 mg po weekly.

Proposed Schema

RANDOMIZE

n ≈ 600

ECOG 2112

A Randomized Phase III Trial of Endocrine Therapy

plus

Entinostat

/Placebo in HR-Positive Metastatic Breast Cancer

Slide59

Mutational Landscape of ER+ MBC Significant Genes with SNV and Indel Alterations

Method: “MutSig” – Lawrence et al. 2014. This presentation is the intellectual property of Ofir Cohen. Contact them at (ofirc@broadinstitute.org) for permission to reprint and/or distribute.

SNV = single nucleotide variant

n=141

Slide60

Acquired HER2 Mutations in ER+ MBC

Presented at: SABCS – December 6-10, 2016.

Kinase Domain

Acquired

(not observed in primary tumor)

Shared

(also observed in primary tumor)

Unknown

(primary tumor status unknown)

ERBB2

ERBB2 mutations in 7%

83% of ERBB2 mutations (5/6) in metastatic samples with matched primaries were acquired.

V777L

L869R

L755S

G727A

R143G

S653C

R1153L

P1074L

Slide61

ESR1 Mutation Background

Presented by Turner N at 2016 ASCO Annual Meeting.

Slide62

ESR1 Mutation Analysis by Digital PCR in the Randomized Phase III SoFEA Study

Johnston SR et al.

Lancet Oncol

. 2013;989-998. O’Leary et al. Presented at: AACR, 2016. Fribbens C et al. J Clin Oncol. 2016;34:2961-2968. Presented by Turner N at 2016 ASCO Annual Meeting.

ESR1

Mutation Analysis by Digital PCR

In the Randomized Phase III

SoFEA

Study

Slide63

ESR1 Mutations in PALOMA-3

Presented

by Turner N at the 2016 ASCO Annual Meeting.

ESR1

Mutations in PALOMA-3

Slide64

PFS by ESR1 Mutation Status

PFS = progression-free survival.

March 2015 final PFS data cut;

Cristofanilli et al. Lancet Oncol. 2016;17:425-439.Presented by Turner N at the 2016 ASCO Annual Meeting.

PFS by

ESR1

Mutation Status

Slide65

Patient Information Brochures from CDC and

Cancer.Net

A copy has been provided with your syllabusExcellent tool to provide patientsCan be shipped to your office (minimal charge for postage)Available online with additional resources at:https://www.cdc.gov/cancer/breast/https://www.cancer.net/cancer-types/breast-cancer

Slide66

Conclusions

These are exciting times, as more and more (effective) therapies become available for the most common type of breast cancerBut, are targeted therapies a must at all times? If so, how are we going to sequence (or combine) all the approved and to-be-approved targeted therapies? At what cost (side effects and financial!)?Who knows?? Need to individualize based on patient and tumor characteristics…Whatever strategy ends up making a difference in overall survival is the one likely to prevail. Anything else, becomes physician/patient preference…

Slide67

CME Credit

Post-activity Survey

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please take a moment

to answer the Post-activity Survey questions on your form

Your answers are important and will help us identify remaining educational gaps and shape future CME activities

CME

Evaluation

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ensure

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