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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
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