use of novel combination therapies in the treatment of … · 2018-06-25 · ribociclib/...

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

©2018 Rockpointe Oncology 1Activity Slides

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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 STAGING: AJCC TNM Classification for Breast Cancer

AJCC Cancer Staging Manual, 8th Edition. Breast Cancer. The American College of Surgeons. 2018

AJCC Cancer Staging Manual, 8th Edition. Breast Cancer. The American College of Surgeons. 2018

STAGING: AJCC TNM Classification for Breast Cancer

Changing Landscape of ER-positive Metastatic Breast Cancer

Tamoxifenapproved

1970-80

Anastrozole approved

1996

Fulvestrantapproved

2002

Fulvestrant HD approved

2012

Everolimus approved

2012

Palbociclib approved

2015

Ribociclib/Abemaciclib

approved

2017

Combination therapies

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

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



Current Guidelines for Combination Therapy with Endocrine Therapy

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

PrimaryPFS

SecondaryOS

FUL + ANA n = 355

ANA n = 352 HR P value

PFS (mo) 15.0 13.5 0.80 0.007

OS (mo) median 47.7 41.3 0.81 0.049

*Crossover to fulvestrant 500 mg allowed after progression

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

PrimaryTTP

SecondaryTTF, 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

PalbociclibPD 0332991

CDK 4/6 Inhibitors Approved by the FDA

RibociclibLEE011

AbemaciclibLY2835219

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 84 67 60 47 36 28 21 13 8 5 1

LET 81 48 36 28 19 14 6 3 3 1

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-value 0.0004

PALOMA 1: Final Overall SurvivalPAL+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-value 0.281

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

PAL+LET 84 73 63 38 28 13 8

LET 81 67 52 33 21 10 3

Time (Month)Number of patients at risk



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

• Primary endpoint: PFS

• Secondary endpoints: – Response, OS, safety, biomarkers, PROs

PALOMA-2

RANDOMISE

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 excluded

n = 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 disease

n = 668

MONALEESA-2

RANDOMISE

(1:1)

PRO = patient-reported outcome; qd = once daily

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.

MONARCH 3: Study Design

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

Primary Endpoint (PFS) Met at Interim Analysis

MONALEESA-7

• Tumor assessments were performed every 8 weeks for 18 months, then every 12 weeks thereafter

• Primary analysis planned after ~329 PFS events

Stratified by:• Presence/absence of

liver/lung metastases• Prior chemotherapy for

advanced disease• Endocrine therapy partner

(tamoxifen vs NSAI)

Primary endpoint• PFS (locally assessed

per RECIST v1.1)‡

Secondary endpoints

• Overall survival (key)• Overall response rate• Clinical benefit rate• Safety• Patient-reported

outcomes

•Pre/perimenopausalwomen with HR+, HER2– ABC

•No prior endocrine therapy for advanced disease

•≤1 line of chemotherapy for advanced disease

•n=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.

Primary Endpoint: PFSInvestigator-assessed

Prob

abili

ty o

f pr

ogre

ssio

n-fr

ee s

urvi

val (

%)

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-value 0.0000000983

1086420

100

80

60

40

20

0

30282624222018161412

10

30

50

70

90

Tripathy D et al. Presented at: 2017 SABCS. Abstract GS2-05.



PFS by Endocrine Therapy PartnerInvestigator-assessed

Goserelin included in all combinations.

PFS (investigator assessment)

Tamoxifen NSAIRibociclib arm

n=87Placebo arm

n=90Ribociclib arm

n=248Placebo 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)

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-value 0.004

Time to deterioration (months)

80

90

60

50

70

40

30

20

10

0

100

1086420 282624222018161412

Even

t-fre

e pr

obab

ility

(%)

EFECTEndocrine Therapy in Hormone-refractory MBC

Prop

ortio

n o

f pat

ient

s pr

ogre

ssio

n-fre

e

MonthsAt risk:Fulvestrant

Exemestane

3.73.7Median (months)

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

Cox analysis, p=0.7021

ExemestaneFulvestrant

Fulvestrant*

Exemestane

0 3 6 9 12 15 18 21 24 270.0

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

PALOMA3 Study Design

Presented by Turner N at: 2015 ASCO Annual Meeting.

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.

*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 neoadjuvantor on/within 1 yr of adjuvant ET

− Progressed 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 PFS

Secondary endpoint: OS, Response, Clinical Benefit Rate, Safety

Stratification factors:- Metastatic site - ET resistance

(primary vs secondary)

placebo: BID (continuous schedule) fulvestrant: 500 mg

Ran

dom

izat

ion

2 :1n = 669



Primary Endpoint: PFS (ITT)

Median PFSabemaciclib + fulvestrant: 16.4 months

placebo + fulvestrant: 9.3 months

HR (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)

Cha

nge

from

bas

elin

e (%

)

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: abstract 510.

MONARCH 1Investigator Assessed Responsea 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 response

0%19.7%

Stable disease (SD) ≥ 6 mo 22.7%

Clinical Benefit Rate (ORR + SD ≥ 6 mo) 42.4 %

Acquired Resistance to Endocrine Therapy in ER+ BC

ER

Gene expression

E

EEstrogen(E)

Estrogen receptor

(ER)

Aromatase

AAndrogen(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

AKTmTOR

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

1. Bachelot T et al. J Clin Oncol. 2012;30:2718-2724; 2. Bedard PL et al. Breast Cancer Res Treat. 2008;108:307-317.

Primary Resistance to Endocrine Therapy in ER+BC

ER

Gene expression

E

EEstrogen

(E)

Estrogen receptor

(ER)

Aromatase

AAndrogen(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 ERαPost-translational modification of ERαExpression of ER cofactors

MYC amplification and overexpression

Cyclin D1 amplification or expression

PI3K

AKTmTOR

MAPK

RTK

Receptor tyrosine kinases(RTK)

Ras

1. Bachelot T, et al. J Clin Oncol. 2012;30(22):2718-2724; 2. Bedard PL, et al. Breast Cancer Res Treat. 2008;108(3):307-317

Everolimus in Hormone-refractory MBCTAM 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

0.00.10.20.30.40.50.60.70.80.91.0

Prob

abilit

y of

sur

viva

l

0 2 4 6 8 10 12 14 16 18 20 22 24 26 28Months

Time (weeks)

HR = 0.36 (95% CI: 0.27–0.47)

EVE + EXE: 10.6 MonthsPBO + EXE: 4.1 Months

Log rank P value = 3.3 x 10 -15

0 126 18 24 30 36 48 6042 54 7266 78

80

60

40

20

100

0

Prob

abilit

y of

Eve

nt (%

)

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.

Fulvestrant ± Everolimus: PFS

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



MANTA Study Design

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

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

Fulvestrant + EverolimusFulvestrant + Everolimus

• ER+, HER2- ABC

• Postmenopausal

• Measurable or evaluable disease

• Disease refractory to AI

– Relapsed on or ≤12 months from adjuvant AI, or

– Progressed on AI in the advanced setting

• Max. 1 line of chemotherapy

• ER+, HER2- ABC

• Postmenopausal

• Measurable or evaluable disease

• Disease refractory to AI

– Relapsed on or ≤12 months from adjuvant AI, or

– Progressed on AI in the advanced setting

• Max. 1 line of chemotherapy

Fulvestrant + Vistusertib(Continuous daily schedule)

Fulvestrant + Vistusertib(Continuous daily schedule)

FulvestrantFulvestrant

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 response• OS• Safety

• Fulvestrant: 500 mg i.m. injection on day 1, 15 & 29, and then q28 days• Everolimus: 10 mg orally, once daily, continuous schedule• Vistusertib (continuous): 50 mg orally, twice daily, continuous schedule• Vistusertib (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.

25

50

75

100

Prog

ress

ion-

free

Surv

ival

(%)

0 30Time (months)

12 24186

Number at risk

F+E 64 45 26 8 2 0F 66 29 14 6 1 0

F+VcontF+Vint

10195

5448

1721

68

34

00

CI = confidence interval; ITT = intent-to-treat; mths = months; PFS = progression-free survivalF = 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)


Fulvestrant + Vistusertibcont 7.6 (5.9-9.4)

Fulvestrant + Vistusertibint 8.0 (5.6-9.9)

Fulvestrant 5.4 (3.5-9.2)

Fulvestrant + Everolimus 12.3 (7.7-15.7)

Alleviation of Side Effects Associated with Best Practice

Combination Therapies

Ribociclib + Letrozolen = 334

Placebo + Letrozolen = 330

n (%)Any

GradeGrade

3Grade

4Any

GradeGrade

3Grade

4

Total331

(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)0

Nausea 178 (53.3) 8 (2.4) 0 101 (30.6) 2 (0.6) 0

Fatigue 138 (41.3) 9 (2.7) 1 (0.3) 107 (32.4) 3 (0.9) 0

Diarrhea 128 (38.3) 8 (2.4) 0 81 (24.5) 3 (0.9) 0

Alopecia 115 (34.4) 0 0 53 (16.1) 0 0

Vomiting 112 (33.5) 12 (3.6) 0 55 (16.7) 3 (0.9) 0

Arthralgia 111 (33.2) 2 (0.6) 1 (0.3) 108 (32.7) 4 (1.2) 0

Constipation 93 (27.8) 4 (1.2) 0 71 (21.5) 0 0

Headache 90 (26.9) 1 (0.3) 0 69 (20.9) 2 (0.6) 0

Hot flush 82 (24.6) 1 (0.3) 0 84 (25.5) 0 0

Back pain 81 (24.3) 10 (3.0) 0 67 (20.3) 1 (0.3) 0

Cough 77 (23.1) 0 0 70 (21.2) 0 0

Neutrophil count decreased

72 (21.6) 53 (15.9) 3 (0.9) 4 (1.2) 1 (0.3) 0

Anemia 69 (20.7) 6 (1.8) 2 (0.6) 19 (5.8) 4 (1.2) 0

Decreased appetite 69 (20.7) 5 (1.5) 0 52 (15.8) 1 (0.3) 0

Palbociclib + Letrozolen = 444

Placebo + Letrozolen =222

n (%)Any

GradeGrade

3Grade

4Any

GradeGrade

3Grade

4

Total439

(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)0 0

Fatigue 166 (37.4) 8 (1.8) 0 61 (27.5) 1 (0.5) 0

Nausea 156 (35.1) 1 (0.2) 0 58 (26.1) 4 (1.8) 0

Arthralgia 148 (33.3) 3 (0.7) 0 75 (33.8) 1 (0.5) 0

Alopecia 146 (32.9) 0 0 35 (15.8) 0 0

Diarrhea 116 (26.1) 6 (1.4) 0 43 (19.4) 3 (1.4) 0

Cough 111 (25.0) 0 0 42 (18.9) 0 0

Anemia 107 (24.1) 23 (5.2) 1 (0.2) 20 (9.0) 4 (1.8) 0

Back pain 96 (21.6) 6 (1.4) 0 48 (21.6) 0 0

Headache 95 (21.4) 1 (0.2) 0 58 (26.1) 4 (1.8) 0

Hot flush 93 (20.9) 0 0 68 (30.6) 0 0

Constipation 86 (19.4) 2 (0.5) 0 34 (15.3) 1 (0.5) 0

Rash 79 (17.8) 4 (0.9) 0 26 (11.7) 1 (0.5) 0

Asthenia 75 (16.9) 10 (2.3) 0 26 (11.7) 0 0

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

20 % in either arm, n (%) All G3 G4 All G3 G4Any 435 (98.6) 241 (54.6) 26 (5.9) 199 (89.2) 46 (20.6) 5 (2.2)

Diarrhea a 381 (86.4) 59 (13.4) 0 55 (24.7) 1 (0.4) 0

Neutropenia b 203 (46.0) 104 (23.6) 13 (2.9) 9 (4.0) 3 (1.3) 1 (0.4)

Nausea 199 (45.1) 12 (2.7) - 51 (22.9) 2 (0.9) -

Fatigue 176 (39.9) 12 (2.7) - 60 (26.9) 1 (0.4) -

Abdominal pain 156 (35.4) 11 (2.5) - 35 (15.7) 2 (0.9) -

Anemia 128 (29.0) 31 (7.0) 1 (0.2) 8 (3.6) 2 (0.9) 0

Leukopenia 125 (28.3) 38 (8.6) 1 (0.2) 4 (1.8) 0 0

Decreased appetite 117 (26.5) 5 (1.1) 0 27 (12.1) 1 (0.4) 0

Vomiting 114 (25.9) 4 (0.9) 0 23 (10.3) 4 (1.8) 0

Headache 89 (20.2) 3 (0.7) - 34 (15.2) 1 (0.4) -

Placebo + Fulvestrant

n = 223 Abemaciclib + Fulvestrant

n = 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

This presentation is the intellectual property of the author/presenter. Contact them for permission to reprint and/or distribute.

TEAE (Safety Population) SWISH Study

• Phase II single-arm trial evaluated prophylaxis with steroid mouthwash on everolimus-associated stomatitis

• Mouthwash: 10ml with dexamethasone 0.5mg/5mL (swish for 2-mins and spit) QID for 8 to 16 weeks started day 1 of exemestane and everolimus

• 92 patients enrolled with 85 evaluable

Rugo HS et al. Lancet Oncol. 2017;18:654-662.



SWISH: Effect of Steroid Mouthwash on Everolimus-associated Stomatitis

Rugo HS et al. Lancet Oncol. 2017;18:654-662.

Rare Everolimus-related Pulmonary Side Effects Grade Symptoms Management Everolimus Dose Modification

1 • Asymptomatic (radiographic findings only)

• Initiate appropriate monitoring

• No dose adjustment required

2 • Symptomatic, not interfering with ADLs

• Rule out infection• Consider treatment

with corticosteroids

• Consider interruption of therapy until symptoms improve to grade ≤1

3 • Symptomatic, interfering with ADLs; oxygen required

• Rule out infection• Consider treatment

with corticosteroids

• Reinitiate everolimus at a lower dose

• Discontinue treatment if failure to recover within 4 weeks

• Hold treatment until recovery to grade ≤1

4 • Life threatening; ventilatory support indicated

• 12 (2.7) • Consider reinitiating everolimusat a lower dose. If toxicity recurs at grade 3, consider discontinuation

• Discontinue everolimus

Based on Everolimus Package Insert.

Novel Agents and Emerging Clinical Data for HR+ Breast Cancer

Where Do We Stand Today?

First-Line Post-Progression

24.8

14.5

9.2

3.87.8

3.2

8.64.5

0

5

10

15

20

25

30

CDKi+

LET

LET EXE TAMEVE +

TAM

EVE +

EXE

CDKi+

FULV

FULV

PFS,

mon

ths

LET +/- CDK4/6iLET +/- CDK4/6i FULV +/- CDK4/6iFULV +/- CDK4/6i EXE +/- EVEEXE +/- EVE TAM +/- EVETAM +/- EVE

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 + Fulvestrant

n=576


n=571


6.9(6.8–7.8)

5.0(4.0–5.2)

HR (95% CI) 0.78 (0.67–0.89)

One-sidedP value

<0.001

Prob

abilit

y of

Pr

ogre

ssio

n-fre

e Su

rviv

al, %

Time (Months)

100

60

0

80

40

20

0 4 8 14 182 6 10 12 16 20 26 3022 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.

• 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 82 6 10 12 14 16 18 20 22 24 26Time, Months

Prob

abilit

y of

Pr

ogre

ssio

n-fre

e Su

rviv

al, %

Full Population (n=432)

Buparlisib + Fulvestrant

n=289


n=143


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.



• ER+/HER2- locally advanced or metastatic BC

• Postmenopausal • Recurrence or progression during

or after aromatase inhibitor

SANDPIPERPhase 3 Study of Taselisib in ER+ MBC

Primary Endpoint: PFS in pts with mutant tumors• Target 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.

2nd line metastatic therapy or greater

Neoadjuvant

Ongoing Trials α-specific PI3K inhibitors

NCT02077933Phase I alpelisib +everolimus

+/- exemestane

NCT02437318 (SOLAR-1)Phase III fulvestrant +/-

alpelisib

NCT02340221 (Sandpiper)Phase III Fulvestrant +/-

Taselisib

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

Buparlisib

NCT02273973 (Lorelei)Phase II Letrozole +/-

Taselisib

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

PI3K

AKT

mTOR

CCND1CDK4/6

pRb

E2F

Cell survivalProliferation

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

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

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

Letrozole + Alpelisib + RibociclibPhase Ib Study of Postmenopausal Women with ER+ MBC2

2. Juric et al. Presented at: SABCS 2015.

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 resistance• Combination of ER and FGFR inhibitors is synergistic against ER+/FGFR1-amp PDXs

Formisano and Arteaga

* 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 FGFRCompleted 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

CompletedHas 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

Activenot 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



PD-1/L1 Immunotherapy in Breast Cancer

• Immune checkpoint inhibitors are effective in a variety of solid tumors

• In the metastatic setting:– 20% ORR in TNBC 1,2

– 6–12% ORR in ER+ BC3,4

• In 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.

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 cells• This 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.

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.

Eligible:

Advanced breast cancer

ER/PR+, HER2-

Progression/no progression on prior non-steroidal AI

Exemestane plusEntinostat

Exemestane plusPlacebo

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

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 ([email protected]) for permission to reprint and/or distribute.

SNV = single nucleotide variant

n=141

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

L869RL755S

G727AR143G S653C R1153LP1074L



ESR1 Mutation Background

Presented by Turner N at 2016 ASCO Annual Meeting.

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 PCRIn the Randomized Phase III SoFEA Study

ESR1 Mutations in PALOMA-3

Presented by Turner N at the 2016 ASCO Annual Meeting.

ESR1 Mutations in PALOMA-3

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

Patient Information Brochures from CDC and Cancer.Net

• A copy has been provided with your syllabus

• Excellent tool to provide patients

• Can 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

Conclusions

• These are exciting times, as more and more (effective) therapies become available for the most common type of breast cancer

• But, 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…

use of novel combination therapies in the treatment of … · 2018-06-25 · ribociclib/...

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