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Grand Rounds in Breast Cancer: Endocrine Therapy in Advanced Disease Lee Schwartzberg, MD, FACP Heather Greene, FNP, AOCNP®

The West Cancer Center Memphis, Tennessee

§  Dr. Schwartzberg has been a consultant for Genentech, Eisai, Helsinn, and Pfizer. In addition, he has received honoraria from Genentech and research funding from Eisai.

§  Ms. Greene has nothing to disclose.

Disclosures

§  Identify the major goals of endocrine therapy in metastatic hormone receptor–positive (HR+) breast cancer

§  Recognize the most common side effects and toxicity management strategies associated with endocrine therapies

§  Discuss the appropriate sequencing of endocrine therapies in front line and subsequent lines of therapy for HR+ metastatic breast cancer

Learning Objectives

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§  54-yr-old, postmenopausal African American female

§  Stage III (T3N0) infiltrating lobular carcinoma

§  ER+ PR+ HER2/neu-

§  S/P right mastectomy, adjuvant chemo (ACàT) and XRT to chest wall

§  Anastrozole January 2006

§  Changed to letrozole 2008

Case Study

ER = estrogen receptor; PR = progesterone receptor; XRT = x-ray therapy.

§  End of 2010: Developed diffuse body and bone aches

§  Alkaline phosphatase and ESR elevated ?inflammatory

§  January 2011: Tumor markers elevated

§  PET/CT: Diffuse bone and bone marrow uptake

Case Study (cont)

ESR = erythrocyte sedimentation rate; PET = positron emission tomography; CT = computed tomography.

A.  Start chemotherapy for metastatic disease JL510

B.  Evaluate eligibility for clinical trial JL511 C.  Send for biopsy of one of the bone lesions noted

on PET/CT JL512 D.  Start first-line endocrine therapy for metastatic

disease JL513

What would you do next?

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§  Bone/bone marrow biopsy: Metastatic carcinoma c/w breast primary

§  ER+ PR+ HER2-

Case Study (cont)

Significant Rate of Discordance Between Primary and Metastases

Amir et al. 2010; Curigliano et al, 2011; Karlsson et al, 2010; Lindstrom et al, 2010.

2010 studies comparing primary to metastasis

Amir (n ~ 270)

prospective reanalyzed

Curigliano (n ~ 250)

retrospective liver only

Karlsson (n ~ 470)

retrospective

Lindstrom (n ~ 118–459) retrospective

ER+ à ER- 12% 11% 36% 26% ER- à ER+ 14% 25% 22% 7% HER2- à HER2+ 5% 6% ND 7%

HER2+ à HER2- 12% 32% ND 3%

A.  Start first-line chemotherapy for metastatic disease JL514

B.  Evaluate eligibility for clinical trial JL515 C.  Continue with current endocrine therapy

(letrozole) JL516 D.  Change to a different endocrine therapy JL517

What would you do next?

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Therapy stratification by: §  Bone metastases §  Hormone receptor status §  HER2 status

NCCN Guidelines for HR+ Advanced Breast Cancer

National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®). Breast cancer. Version 3.2014. Available at NCCN.org

Advanced breast cancer

Bone metastases

No bone metastases

Add bone-modifying

agent

ER and/or PR+, HER2-

ER and/or PR+, HER2+

ER and/or PR + and endocrine refractory, HER2- ER/PR- or ER and/or PR+ and endocrine refractory, HER2+

NCCN Guidelines Recommend Serial Endocrine Tx for HR+, HER2- Advanced Breast Cancer Not in Visceral Crisis

NCCN Clinical Practice Guidelines in Oncology. Breast cancer, v1.2012; Osborne CK, et al. Ann Rev Med. 2011;62:233–247.

Case Study (cont)

§  Started denosumab and fulvestrant January 2011

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§  Reduce cancer-related symptoms

§  Increase progression-free survival

§  Increase time to chemotherapy

§  Improve quality of life

§  Increase overall survival

Major Goals of Endocrine Therapy in Metastatic Breast Cancer

§  Baseline §  Every 2–3 mo

–  Assessment and PE –  Labs (CBC, BMP, LFTs)

§  +/- tumor markers, CTCs

§  Every 2–6 mo –  CT CAP –  Bone scan (less often)

§  PET/CT: optional –  Frequency unclear

Disease Monitoring: Endocrine Therapy

PE = physical exam; CBC = complete blood count; BMP = basic metabolic panel; LFT = liver function test; CTC = circulating tumor cells; CAP = chest/abdomen/pelvis. National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®). Basal cell and squamous cell skin cancers. Version 3.2014. Available at NCCN.org

Treatment Options for Postmenopausal Women With ER+ Advanced Breast Cancer

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§  Disease-free interval §  Prior endocrine therapy

Clinical history radically different now than 20+ years ago with widespread use of adjuvant therapy

§  Quantitative ER expression §  Bone-only vs. visceral metastases §  HER2 expression §  PR negativity

Clinical Predictors of Outcome for ER+ Breast Cancer

Oh et al, 2006; Rakha et al, 2007; Sainsbury et al, 1987; Loi et al, 2008; Ross et al, 2008; Weigel et al, 2010; Taneja et al, 2010; Niikura et al, 2011; Kurebayashi et al, 2000.

Endocrine Agents for Postmenopausal Breast Cancer §  SERMs

•  Tamoxifen •  Toremifene •  Raloxifene

§  Estrogens •  Estradiol •  DES, EE2

§  ER downregulator •  Fulvestrant

§  Aromatase inhibitors •  Anastrozole •  Letrozole •  Exemestane

§  Progestins •  Megestrol acetate •  MPA

§  Androgens •  Fluoxymesterone

SERM = selective estrogen receptor modulator; DES = diethylstilbestrol; MPA = medroxyprogesterone acetate.

Compare Survival with Stable Disease (Clinical Benefit) to Survival With CR or PR With Anastrozole Use in ABC

0

100

0 1 2 3 4 Years From Randomization

80

60

40

20

At 2-yr

Risk Deaths Estimate

CR or PR 33 10 85%

Stable ≥24 wk 78 23 86%

Other 152 118 35%

Robertson JF, et al. Breast Cancer Res Treat. 1999;58:157–162.

Surv

ival

(%)

Clinical benefit = CR + PR + stable ≥ 24 wk

Stable disease on hormone therapy provides similar benefit as CR or PR

ABC = advanced breast cancer; clinical benefit = no prognosis for ≥ 24 wk

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Review of Trials of Hormone Therapy in First-Line Advanced Breast Cancer

§  Aromatase inhibitors (AIs) have improved efficacy compared with tamoxifen

–  TTP: Anastrzole (10.7 mo) vs. tamoxifen (6.4 mo)

–  TTP: Letrozole (9.4 mo) vs. tamoxifen (6.0 mo)

–  PFS: Exemestane (9.9 mo) vs. tamoxifen (5.8 mo)

§  Fulvestrant (250) has similar efficacy compared with tamoxifen

–  TTP: Fulvestrant (8.2 mo) vs. tamoxifen (8.3 mo)

First-Line Phase III Studies: AIs and/or Fulvestrant (250) vs. Tamoxifen

TTP = time to progression; PFS = progression-free survival. Cardoso F, et al. Breast. 2012;1–11. Epub ahead of print; Bonneterre J, et al. Cancer. 2001;92:2247–2258; Mouridsen HT. Breast Cancer Res Treat. 2007;105:19–29; Paridaens RJ, et al. J Clin Oncol. 2008;26:4883–4890; Howell A, et al. J Clin Oncol. 2004;22:1605–1613.

Letrozole vs. Tamoxifen: OS Median overall survival

Letrozole 34 mo Tamoxifen 30 mo

1.0

0.9

0.8

0.7

0.6

0.5

0.4

0.3

0.2

0.1

0.0 0 12 18 24 30 36 42 48 54 60

Kap

lan-

Mei

er E

stim

ate

Time (months)

6

Letrozole Tamoxifen Initial therapy:

p = 0.53 (log-rank test)

Mouridsen HT. Breast Cancer Res Treat. 2001;69:211, Abstract 9.

No survival difference but crossover allowed; survival favored letrozole through the first 24 mo (p = .02)

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FULVESTRANT 500 mg IM days 1, 14, 28 and q28days

thereafter

ANASTROZOLE 1 mg qd orally

FIRST: Fulvestrant (500) vs. Anastrozole (Phase II)

PMW = postmenopausal women; CBR = clinical benefit rate; ORR = overall response rate; TTP = time to progression; DoR = duration of response. Robertson JRF, et al. SABCS 2010, Abstract S1-3; Robertson JRF, et al. J Clin Oncol. 2009;27:4530–4535.

N = 205 PMW with previously

untreated HR+ advanced breast

cancer

Primary CBR defined

as CR, PR, and SD for > 24 wk

Secondary ORR, TTP,

DoR

FUL (500) n = 102

ANAS n = 103 HR p value

TTP (mo) 23.4 13.1 0.66 0.01

ORR (%) 36.0 35.5 1.02 0.947

CBR (%) 72.5 67.0 1.30 0.386

FIRST: TTP, Fulvestrant (500) vs. Anastrozole (Phase II)

Robertson JRF. SABCS 2010, Abstract S1-3.

0 6 12 18 24 30 36 42 48 0.0

0.2

0.4

0.6

0.8

1.0

Prop

ortio

n of

pat

ient

s al

ive

and

pro

gres

sion

-free

Time (months)

Fulvestrant 500 mg Anastrozole 1 mg

HR = 0.66 95% CI (0.47, 0.92)

p=0.01

Fulvestrant 500 mg n = 102 (%)

Anastrozole 1 mg n = 103 (%)

Percent with progression (%) 63 (61.8) 79 (76.7)

Median 23.4 mo 13.1 mo

             6                                        18                                    30                                    42                                    54  

1.0  

0.8  

0.6  

0.4  

0.2  

0

Time  (months)  

PFS  (%

)  

 No.  Pa>ents  At  Risk:    Anastrozole        256        148          108          57            31          16          10            5          4          1    Anastrozole        258        149          107          55            40          20            6              2          1          0  +  Fulvestrant        

Ful + Anast (n = 258)

Anast (n = 256)

No. Pts. with progression (%) 200 (77.5) 200 (78.1)

Median TTP 10.8 mo 10.2 mo

Primary TTP analysis (log-rank test) HR* (95% CI) 0.99 (0.81–1.20)

P value .91

FACT Trial: AI +/- Fulvestrant

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

Kaplan-Meier TTP and median TTP in months (full analysis set)

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Postmenopausal women with hormone

receptor–positive MBC

(N = 707)

Anastrozole 1 mg/day po + Fulvestrant 500 mg on day 1,

250 mg on days 14 and 28, 250 mg every 28 days thereafter

(n = 355)

Anastrozole 1 mg/day po (n = 352)

Treatment until disease progression

Stratified by previous adjuvant tamoxifen

Women with progression

encouraged to cross over to

receive fulvestrant

§  Primary endpoint: PFS §  Secondary endpoints: OS, safety

SWOG S0226: Study Design

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

S0226 FACT

HR: 0.81 p = .049

HR: 1.0 p = 1.00

More ET-naive pts S0226. Fulvestrant 500 mg > 250 mg – combination needed?

S0226 vis-à-vis FACT Overall Survival

San Antonio Breast Cancer Symposium. Cancer Therapy and Research Center at UT Health Science Center. December 6-10, 2011

1.00

OS

0.75

0.50

0.25

0 0 12 24 36 48 60 72

Mos Since Registration

OS in S0226 All eligible patients (n = 694)

Median OS Anastrozole: 41.3 mo (95% CI: 37.2–45.0)

Combination: 47.7 mo (95% CI: 43.4–55.7) HR: 0.81

(95% CI: 0.65–1.00; p = .049)

Anastrozole + fulvestrant (154 deaths) Anastrozole (176 deaths) Stratified log-rank p = .049

1. 0

Pro

porti

on A

live

0.7

0.5

0.2

0 0 12 24 36 42 48 54

Mos

Fulvestrant + Anastrozole

(n = 258) 102 (39.5)

37.8

30 6 18

0.6

0.4 0.3

0.1

0.8 0.9

Anastrozole (n = 256) 102 (39.8)

38.2

Kaplan-Meier Plot of OS Full Analysis Set

HR: 1.00 (95% CI: 0.76–1.32; P = 1.00)

Died, n (%) Median OS, mo

SWOG S0226: PFS and OS Overall and by Previous Adjuvant Tamoxifen

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

Endpoint Anastrozole + Fulvestrant Anastrozole HR (95% CI)

p value

Median PFS (n = 694), mo 15.0 13.5 0.80 (0.68–0.94) .007

§ No previous adjuvant tamoxifen (n = 414) 17.0 12.6 0.74

(0.59–0.92) .0055

§ Previous adjuvant tamoxifen (n = 280) 13.5 14.1 0.89

(0.69–1.15) .37

Median OS (n = 694), mo 47.7 41.3 0.81 (0.65–1.00) .049

§ No previous adjuvant tamoxifen (n = 414) 47.7 39.7 0.74

(0.56–0.98) .0362

§ Previous adjuvant tamoxifen (n = 280) 49.6 44.5 0.91

(0.65–1.28) .59

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CDK 4/6 Cell Cycle Regulation

Kedia-Mokashi NA, et al. Life Sci. 2011;88:634–643.

Growth factor signaling IGF, FGF, PDGF, HGF, EGF

MAP kinase cascade

Transcription factors

Wnt signaling

Myc

Cyclin E

Cyclin D

Cyclin G Mdm2

Tcf4

CDK2

CDK4,6

p21

p27

p53 TGF-β signaling

Block in entry in S phase

Ctnnb1

Cell-cycle arrest in G1 phase

?  

Phase II Study of Letrozole ± Palbociclib (PD-0332991) in ER+, HER2- MBC

Finn RS, et al. SABCS 2012. Abstract S1-6.

Palbociclib 125 mg QD +

Letrozole 2.5 mg QD

Letrozole 2.5 mg QD

Postmenopausal women

with ER-positive, HER2-negative

advanced breast cancer

(N = 66)

Stratified by disease site (visceral, bone only, or other); disease-free interval (> 12 vs.

≤ 12 mo from end of adjuvant to recurrence or de novo advanced disease)

Palbociclib 125 mg QD

+ Letrozole 2.5 mg QD

Letrozole 2.5 mg QD

Postmenopausal women

with ER-positive, HER2-negative

advanced breast cancer, CCND1 amp,

and/or p16 loss (N = 99)

Part 1 Part 2

All patients continued assigned treatment until disease progression, withdrawal of consent, or unacceptable toxicity with follow-up tumor assessment every 2 mo.

Stratified by disease site (visceral, bone only, or other); disease-free interval (> 12 vs. ≤ 12 mo from end of adjuvant to recurrence or de novo advanced

disease)

Finn RS, et al. SABCS 2012. Abstract S1-6.

Letrozole and Palbociclib Improves PFS in ER+ MBC

0  

0.2  

0.4  

0.6  

0.8  

1.0  

0   6   12  10   14  Months

16   20   22   28  

 PALBO+LET  (n  =  84)  21  (25)  26.1  mo  

(12.7-­‐26.1)  

PFS

Prob

abili

ty

Pts  at  risk,  n  PALBO  +  LET  LET  

84  81  

75  57  

60  38  

53  29  

43  22  

35  17  

25  11  

3  1  

1  1  

24   26  18  8  2   4  

0.3  

0.5  

0.7  

0.9  

0.1  

LET  (n  =  81)  40  (49)  7.5  mo  

(5.6-­‐12.6)  

18  6  

15  5  

14  4  

9  3  

5  3  

Events,  n  (%)  Median  PFS  (95%  CI)  HR  (95%  CI)  P  value  

0.37  (0.21-­‐0.63)  <  .001  

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Letrozole + Palbociclib

§  Filed with the FDA for approval: pending §  PALOMA-2, phase III, double-blind randomized trial, of

LET + PALBO fully accrued, results pending

§  Variety of treatment options for such patients –  Depends in part on prior adjuvant therapy

§  Premenopausal: OFS + TAM or AI §  Postmenopausal: AI, fulvestrant (HD) §  Role of combination antiestrogen therapy unclear

–  Maybe modest benefit in endocrine-naive populations

What Is the Optimal Frontline Therapy for a Patient With Advanced ER+ Breast Cancer?

OFS = ovarian function suppression NCCN, 2012.

Toxicity of Endocrine Agents

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§  Nonsteroidal: anastrozole, letrozole §  Steroidal: exemestane (+/-everolimus) §  Hot flashes, asthenia, arthralgias, osteoporosis,

nausea/vomiting, headaches, hypercholesterolemia, hypertension

§  Increased cardiovascular events in patients with preexisting ischemic heart disease

§  Monitor bone density

Aromatase Inhibitors

Arimidex [package insert]. Wilmington, DE: AstraZeneca, 2014. Aromasin [package insert]. New York, NY: Pfizer, 2013. Femara [package insert]. East Hanover, NJ: Novartis, 2014.

Fulvestrant

§  Estrogen receptor downregulator §  Hormone receptor + metastatic breast cancer

following anti-estrogen therapy §  Injection 500 mg IM days 1, 15, 29 and then

monthly §  Side effects

•  Hot flashes •  Injection site reaction

Faslodex [package insert], AstraZeneca, 2012.

Letrozole ± Palbociclib in ER+, HER2- MBC: Grade 3/4 AEs

Finn RS, et al. SABCS 2012. Abstract S1-6.

Grade 3/4 AE, % Palbociclib + LET

(n = 83) LET

(n = 77) Neutropenia 51 1 Leukopenia 14 0 Fatigue 2 1 Anemia 4 1 Nausea 2 1 Hot flush 0 0 Alopecia 0 0 Arthralgia 0 1 Diarrhea 4 0

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Case Study (cont)

§  After 1 yr on fulvestrant, PET/CT January 2012: progression in sacrum, L4, and right ovary

§  Changed to capecitabine, PET/CT: NED 6 mo later §  July 2013: CT showed 50% increase in ovarian mass

–  TAH/BSO: metastatic breast cancer ER/PR+, HER2-

NED = no evidence of disease; TAH = total abdominal hysterectomy; BSO = bilateral salpingo-oophorectomy.

A.  Change to IV chemotherapy JL518 B.  Switch to another AI JL519 C.  Switch to tamoxifen JL520 D.  Switch to exemestane + everolimus JL521 E.  Switch to fulvestrant + AI JL522

What would you do now?

Case Study

§  Exemestane/everolimus with stable disease × 8 mo §  April 2014: Routine serial CT imaging, new liver mets §  Started eribulin mesylate. September 2014 CT: Improvement in

liver mets

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What Are the Endocrine Therapy Options for Patients With Advanced or Metastatic ER+ Breast Cancer Who Progressed After Previous Lines of Therapies?

Review of Trials of Hormone Therapy in Advanced Breast Cancer After Progression on Prior Therapy

Summary: Second-Line Randomized Studies AI vs. MA

Anastrozole Letrozole Letrozole Exemestane

No. patients 263 vs. 253 199 vs. 201 174 vs. 189 366 vs. 403

Daily dosage 1 mg 2.5 mg 2.5 mg 25 mg Significant survival advantage vs. MA (mo)

Yes 26.7 vs. 22.5

(p < .025)

No 28.6 vs. 26.2

(NS)

No 25.8 vs. 21.5

(p = .15)

Yes vs. 28.4

(p = .039)

Median FU +33 mo +37 mo 45 mo 11 mo

TTP (mo) vs. MA 4.8 vs. 4.6 (NS)

3.2 vs. 3.4 (p = .99)

5.6 vs. 5.5 (p = .07)

4.7 vs. 3.9 (p = .037)

Clinical benefit (CR + PR + SD ≥ 24 wk) vs. MA (%)

42 vs. 40 (NS)

26.7% vs. 23.4 (NS)

35 vs. 32 (NS)

37 vs. 35 (NS)

Response rates (CR + PR) vs. MA (%)

12.6 vs. 12.2 (NS)

16.11 vs. 14.9 (NS)

15 vs. 12.4 (p = .04)

15 vs. 12.4 (NS)

MA = megestrol acetate Buzdar et al, 1996, 2001; Dombernowsky et al, 1998; Kaufmann et al, 2000.

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Selected Trials of Fulvestrant Use After Progression on Prior NSAI

Trial N EFECT Fulvestrant vs exemestane 693

SoFEA Fulvestrant + anastrozole vs. fulvestrant vs. exemestane

750

CONFIRM Fulvestrant high vs. fulvestrant low 736

Fulvestrant 250, loading

Fulvestrant 500

NSAI = Nonsteroidal aromatase inhibitor

FULVESTRANT 500 mg IM day 1, 250 mg day 14, 28,

monthly

EXEMESTANE 25 mg qd

EFECT: Fulvestrant (250, loading) vs. Exemestane

Chia S, et al. J Clin Oncol. 2008;26(10):1664-1670

N = 693 PMW with

advanced HR+ BC after failure of

NSAI therapy

Primary TTP

Secondary ORR, CBR, DOR, TTR,

OS, tolerability

FUL n = 351

EXE n = 342

P value

TTP (mo) 3.7 3.7 0.653 ORR (%) 7.4 6.7 0.736

Fulvestrant (250 loading) similar to exemestane

EFECT: Fulvestrant vs. Exemestane After Progression of Nonsteroidal AI

PFS  Prob

ability  

Mos  Pts  at  Risk,  n  Fulvestrant  Exemestane  

3.7  3.7  Median,  mo  

     

HR:  0.963  (95%  CI:  0.819-­‐1.133;  p  =  .6531)  

Cox  analysis,  p  =  .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.

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Fulvestrant 500 mg loading dose on day 1, then 250 mg

monthly + anastrozole 1 mg/daily

Exemestane 25 mg/daily

SoFEA: Fulvestrant (250, loading) With or Without Anastrozole vs. Exemestane

No significant differences were observed in PFS, ORR, CBR, or OS

Johnston S, et al. EBCC-8. 2012

N = 723 Post menopausal

women with advanced HR+ BC following

progression on NSAI

Primary PFS

Secondary ORR, CBR,

OS, tolerability

Fulvestrant 500 mg loading dose on day 1, then 250 mg

monthly + Placebo daily

FUL 500 n = 231

FUL + ANA n = 243

EXE

PFS (mo) 4.8 4.4 3.4

Fulvestrant 500 mg IM on days 1, 14, 28, monthly

Fulvestrant 250 mg IM monthly

CONFIRM: Fulvestrant 250 vs. 500 mg

N = 736 PMW with

advanced HR+ BC after failure of prior endocrine

therapy

Primary PFS

Secondary ORR, CBR,

DoCB, OS, Qol

Bachelot T, et al. J Clin Oncol 2012. Epub 1-7; DiLeo et al. J Clin Oncol. 2010;28:4594-4600

FUL 500 n = 362

FUL 250 n = 374 p value

PFS (mo) 6.5 5.5 .004 ORR (%) 9.1 10.2 .795 CBR (%) 45.6 39.6 .100

Mechanisms of Endocrine Resistance

Johnston SR. Clin Cancer Res. 2005;11:889s-899s

ER Target Gene Transcription

SOS

P P P P

PI3-K

Akt

P P

RAS RAF

MEK

MAPK p90RSK

ER

P p160

Basal Transcription Machinery CBP ER ER

P P P

ERE Cell growth

Plasma membrane

Cytoplasm

Nucleus

E2

SERD

AI T

IGF1R EGFR/HER2

Increased signaling through PI3-K pathway

CCI RAD

MoAb

TKI

Increased upstream signaling through EGFR and/or IGF-IR and or VEGFR

TKI

AB VEGFR

MoAb

TKI

Mechanisms of intrinsic and acquired resistance likely similar

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Selected Trials of Hormonal Therapy Including Everolimus After Progression on Prior AI* Trial N EFECT Fulvestrant (250) vs. exemestane

693

CONFIRM Fulvestrant (500) vs. fulvestrant (250)

736

SoFEA Fulvestrant + anastrozole vs. fulvestrant (250) vs exemestane

750

TAMRAD Tamoxifen ± everolimus

110

BOLERO-2 Exemestane ± everolimus

725

Fulvestrant 250

Fulvestrant 500

Everolimus combinations

*Nonsteroidal aromatase inhibitor

Tamoxifen 20 mg/day + Everolimus 10 mg/day

Tamoxifen 20 mg/day + Placebo

TAMRAD: Tamoxifen ± Everolimus (Phase II) Phase II study;

N=111 PMW with

advanced HR+ HER2- BC

Previously treated with nonsteroidal

aromatase inhibitor therapy in

adjuvant or metastatic setting

Primary CBR at 6 mo Secondary Safety, TTP,

OS, ORR

Bachelot T, et al. J Clin Oncol. 2012. Epub 1-7.

TAM+EVE n = 54

TAM n = 57 p value

CBR (6 mo) 61% 42% .045 TTP (mo) 8.6 4.5 .002

TAMRAD: Time to Progression HR = 0.53; 95% CI (0.35–0.81) Exploratory log-rank: p = .0021

TAM: 4.5 mo TAM + EVE: 8.6 mo

Months

0.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

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

Pro

babi

lity

of S

urvi

val TAM

TAM + EVE

Patients at risk TAM + RAD: n =

TAM : n = 54 57

45 44

39 30

34 24

28 22

25 13

19 11

12 6

7 1

1 0

0 0

26 16

16 7

9 2

1 0

Everolimus plus tamoxifen reduced time to progression by 47% Bachelot T, et al. J Clin Oncol. 2012. Epub 1-7

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Everolimus 10 mg/day + Exemestane 25 mg/day

(N = 485)

Placebo + Exemestane 25 mg/day

(N = 239)

BOLERO-2: Everolimus in Postmenopausal, Hormone Receptor Positive ABC

§  Stratification 1.  Sensitivity to prior hormonal therapy 2.  Presence of visceral disease

§  No crossover

Baselga J, et al. N Engl J Med. 2012;366(6):520–529.

N = 724 Postmenopausal ER+ HER2- breast

cancer pts refractory to letrozole or anastrozole

Primary PFS

Secondary OS

ORR Bone Markers

Safety PK

BOLERO-2 Primary Endpoint: PFS Central Assessment

Time (weeks)

HR = 0.36 (95% CI: 0.27–0.47)

EVE + EXE: 10.6 mo PBO + EXE: 4.1 mo

Log rank p value = 3.3 × 10-15

0 12 6 18 24 30 36 48 60 42 54 72 66 78

80

60

40

20

100

0

Prob

abili

ty o

f Eve

nt (%

)

Everolimus + Exemestane (E/N=114 / 485) Placebo + Exemestane (E/N=104 / 239)

Baselga J, et al. N Engl J Med. 2012;366(6):520–529.

Everolimus plus exemestane increased progression-free survival by 64%

PFS EVE + EXE PBO + EXE HR (95% CI) p value

Local review 7.8 mo 3.2 mo 0.45 (0.38-0.54) < .0001

Central review 11.0 mo 4.1 mo 0.38 (0.31-0.48) < .0001

With visceral mets 6.83 mo 2.76 mo 0.47

(0.37-0.60) –

Without visceral mets 9.86 mo 4.21 mo 0.41

(0.31-0.55) –

Bone-only mets 12.88 mo 5.29 mo 0.33 (0.21-0.53) –

Progression after neo/adj therapy 11.50 mo 4.07 mo 0.39

(0.25-0.62) –

BOLERO-2: Final PFS Analysis (18-mo Follow-up)

Piccart M, et al. SABCS 2012, Abstract P6-04-02.

§  OS data still not mature (HR: 0.77; 95% CI: 0.57–1.04) §  Most common grade 3/4 AEs were stomatitis (8%), hyperglycemia

(5%), fatigue (4%)

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BOLERO-2: Overall Survival

Piccart M, Ann Oncol. 2014 Sept 17 [Epub ahead of print].

Everolimus + exemestane (N = 482), %

Placebo + exemestane (N = 238), %

All grades

Grade 3

Grade 4

All grades

Grade 3

Grade 4

Stomatitis 56 8 0 11 1 0

Fatigue 33 3 <1 26 1 0

Dyspnea 18 4 0 9 1 <1

Anemia 16 5 <1 4 <1 <1

Hyperglycemia 13 4 <1 2 <1 0

AST 13 3 <1 6 1 0

Pneumonitis 12 3 0 0 0 0

BOLERO-2: Most Common Grade 3/4 AEs

Baselga J, et al. N Engl J Med. 2012;366(6):520–529.

§  Dose: 10 mg po daily with or without food §  Common side effects

–  Stomatitis (44%–86%), infections, rash, fatigue, diarrhea, edema, abdominal pain, nausea, fever, asthenia, cough, headache, and anorexia

§  Renal failure, proteinuria §  Metabolic events

–  Hyperglycemia, hyperlipidemia, hypertriglyceridemia §  Hematologic

–  Anemia, neutropenia, lymphopenia, thrombocytopenia §  Elevated serum hepatic transaminases

Dosing and Side Effects

Afinitor [package insert], Novartis, 2013; Baselga J, et al. N Engl J Med. 2012;366:520–529.

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§  Avoid acidic, spicy, hard and hot foods or liquids §  Good oral hygiene §  Use a mild toothpaste §  Avoid mouth washes containing alcohol, peroxide, iodine or

thyme (exacerbate) §  Cleansing with baking soda rinses can also be helpful

Prevention

§  Stomatitis –  Grade 1: Nonalcoholic mouth rinse or salt water –  Grade 2: Hold until grade 1, no dose change

§  If recurs at grade 2, stop again and then lower dose §  Add topical analgesic mouth rinse

–  Grade 3: Hold until grade 1, then dose-reduce §  Metabolic events (hyperglycemia, dyslipidemia) and non-

hematologic §  Hepatic impairment

Dose Modifications

Afinitor [package insert], Novartis, 2013; Baselga J, et al. N Engl J Med. 2012;366:520–529.

§  Noninfectious pneumonitis –  Grade 1, asymptomatic, radiographic changes only—no change –  Grade 2, moderate symptoms, no O2

§  Rule out infection, consider interruption, consider corticosteroids §  Reinitiate at lower dose §  Discontinue if no improvement at 4 wk

–  Grade 3, interferes with ADLs, O2 required §  Hold, rule out infection §  Consider corticosteroids §  Grade 1 à dose-reduce 50% §  If recurs at grade 3, discontinue

Dose Modifications (cont)

ADL = activities of daily living Afinitor [package insert], Novartis, 2013; Baselga J, et al. N Engl J Med. 2012;366:520–529.

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§  CYP34A substrate §  Avoid strong CYP34A inhibitors

–  Ketoconazole, clarithromycin §  Caution with mod CYP34A and/or P glycoprotein inhibitors

–  Reduce to 2.5–5 mg/day –  Aprepitant, grapefruit, diltiazem, verapamil

§  Strong CYP34A inducers may need increases in everolimus dosing –  Up to 20 mg/day in 5-mg dose increments –  Phenytoin, carbamazepine, rifampin, phenobarbital

Drug Interactions

Afinitor [package insert], Novartis, 2013; Baselga J, et al. N Engl J Med. 2012;366:520–529.

Trials in ER+, HER2+ Advanced Breast Cancer

Anastrozole 1 mg daily + Trastuzumab 4 mg/kg loading

dose ! 2 mg/kg IV qw until disease progression

ANASTROZOLE 1 mg daily until disease progression

HER2 in Intrinsic Hormone-Resistance: TANDEM Trial

N = 208 Advanced HR+, HER2+ breast

cancer

Primary PFS

Secondary CBR, ORR, TTP,

OS, 2-yr survival

Kaufman B, et al. J Clin Oncol. 2009;27:5529–5537

Crossover to receive trastuzumab was actively offered to all patients who progressed on anastrozole alone

ANAS + TRAS n = 351

ANAS n = 342 p value

PFS (mo) 4.8 2.4 .0016

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Lapatinib 1,500 mg/day po + Letrozole 2.5 mg/day po

Letrozole 2.5 mg/day po + Placebo

Letrozole ± Lapatinib in First-Line HR+ MBC

N =642 N = 219 HER2+

PMW with advanced HR+, HER2+ or -, no prior therapy for

ABC

Primary PFS in HER2+

group Secondary

ORR, CBR, OS safety

LET + LAP n = 111

LET n = 108 ORR p value

PFS (mo) 8.2 3.0 0.71 .019

ORR (%) 28 15 0.41 .021

CBR (%) 48 29 0.40 .003

Johnston S, et al. J Clin Oncol. 2009;27:5538–5546

Endocrine Therapy Beyond First Line

§  Switch to (steroidal) AI + everolimus §  Switch to different class of therapy

–  AI --> F –  AI to SERM (TAM if not previously exposed) –  Nonsteroidal AI to steroidal AI

§  Don’t forget megestrol, androgens, and estrogen §  Anti-HER2 + AI feasible and of benefit

§  AI or fulvestrant are most effective first-line single agents; fulvestrant ± AI reasonable choice for endocrine therapy–naive patients with MBC

§  Continue endocrine therapies until resistance §  mTOR inhibition with everolimus + exemestane is best second-

line therapy after progression on nonsteroidal AI §  After everolimus, back to anti-ER therapy alone

•  Multiple options •  Enhanced PI3K pathway blockade being tested

§  Addition of CDK4/6 inhibitor to first-line letrozole may become a new SOC; phase III trial under way

Endocrine Therapy Sequencing in MBC: Which Order Is Best?

SOC = standard of care

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§  Integrated model –  MD/NP or PA as a team (POD model, usually with a nurse and MA) –  Alternate seeing the patient on routine visits –  Communication through office note/email/direct

§  Walk-in model –  As part of the POD, when AP has time slots available –  As dedicated urgent care provider, for all providers

§  Satellite model –  Continuity for all patients

§  Hospital model –  NP full time at hospital during day–hospitalist role –  Rounds before and after MD –  Available for emergencies

Physician–Advanced Practitioner Interactions at the West Cancer Center