1. Jointly provided by Postgraduate Institute for Medicine and Clinical Care Options, LLC
Metastatic Breast Cancer: Experts Discuss the Impact of Therapeutic Complexity on Practice Patterns in America
This activity is supported by educational grants from Genentech and Lilly.
Image: CT757fan/Copyright©2016 iStockphoto LP. All Rights Reserved Image: VOISIN/PHANIE/Copyright©2016 Science Source. All Rights Reserved

2. Endocrine-Based Therapies for Breast Cancer
Year
Agent
Mechanism
1977
SERMs
Tamoxifen
Toremifene
Antagonizes ER in breast tissue
1990s
AIs
Anastrozole
Exemestane
Letrozole
Inhibit estrogen production in postmenopausal women
2000s
ERD
Fulvestrant
Impairs ER dimerization, increases ER degradation, and disrupts nuclear localization of ER
2010s
Combinations
Exemestane/everolimus
Letrozole/palbociclib
Fulvestrant/palbociclib
Blockade of estrogen signaling and prosurvival or cell cycle pathways
AI, aromatase inhibitor; ERD, estrogen receptor downregulator; SERM, selective estrogen receptor modulator.
Lim E, et al. Oncology (Williston Park). 2012;26:
Croxtall JD, et al. Drugs. 2011;71:
Vidula N, et al. Clin Breast Cancer. 2016;16:8-17.
Mustonen MV, et al. World J Clin Oncol. 2014;5:
Slide credit: clinicaloptions.com

3. FIRST: Results Clinical benefit rate and time to progression analyses
OS analysis
Not a defined endpoint in original protocol
Outcome
Fulvestrant 500 mg (n = 102)
Anastrozole 1 mg (n = 103)
CBR, %
72.5
67.0
mTTP, mos
23.4*
13.1
100
Fulvestrant 500 mg
Anastrozole 1 mg 80 60
OS (%)
*P = .01 40
CBR, clinical benefit rate; mTTP, median time to progression.
Median OS:
Fulvestrant 500 mg: 54.1 mos
Anastrozole 1 mg: 48.4 mos
HR: 0.70 (95% CI: ; P = .04) 20 12 24 36 48 60 72 84 96
Mos
Ellis MJ, et al. J Clin Oncol. 2015;33:
Slide credit: clinicaloptions.com

4. PALOMA-1: PFS Median follow-up: 29.6 mos 100 80 60 PFS (%) 40 20 4 8
Median PFS:
Palbociclib plus letrozole (n = 84): 20.2 mos (95% CI: ) Letrozole (n = 81): 10.2 mos (95% CI: ) 80 60
PFS (%) 40 20
HR: (95% CI: ; 1-sided P = .0004) 4 8 12 16 20 24 28 32 36 40
Mos
Median follow-up: 29.6 mos
Slide credit: clinicaloptions.com
Finn RS, et al. Lancet Oncol. 2015;16:25-35.

5. Phase III PALOMA-2: Study Design
Palbociclib 125 mg QD
3 wks on/1 wk off +
Letrozole 2.5 mg QD
(n ≈ 325)
Postmenopausal women with ER+/HER2- advanced BC and no prior systemic therapy
(N ≈ 650)
Tx to objective tumor progression, death, toxicity, or study withdrawal
Placebo QD
3 wks on/1 wk off +
Letrozole 2.5 mg QD
(n ≈ 325)
BC, breast cancer; DoR, duration of response; Tx, treatment; QoL, quality of life.
Primary endpoint: PFS
Secondary endpoints including: OS, ORR, DoR, QoL, and safety
Slide credit: clinicaloptions.com
ClinicalTrials.gov. NCT

6. PALOMA-3: PFS in Overall Population and Specific Pt Subgroups
Median follow-up: 8.9 mos
Median PFS generally favored the palbociclib combination in all pt subgroups analyzed
100
Median PFS:
Fulvestrant plus palbociclib (n = 347): 9.5 mos (95% CI: ) Fulvestrant plus placebo (n= 174): 4.6 mos (95% CI: ) 80 60
PFS (%) 40
AI, aromatase inhibitor; ITT, intent to treat; NE, not evaluable. 20
HR: 0.46 (95% CI: ; P = .0001) 2 4 6 8 10 12 14
Mos
Slide credit: clinicaloptions.com
Cristofanilli M, et al. Lancet Oncol. 2016;17:

7. BOLERO-2: PFS at 18-Mo Follow-up
1.0
Median PFS:
EVE + EXE: 7.8 mos
PBO + EXE: 3.2 mos
0.8
0.6
HR: 0.45 (95% CI: ;
P < .0001)
PFS (Probability)
0.4
0.2
EVE, everolimus; EXE, exemestane; PBO, placebo. 2 4 6 8 10 12 14 16 18 20 22 24 26 28
Mos
Yardley D, et al. Adv Ther. 2013;30:
Slide credit: clinicaloptions.com

8. PALOMA-3: Adverse Events
Grade 3/4 Hematologic Event,
n (%)
Palbociclib + Fulvestrant
(n = 345)
Placebo + Fulvestrant
(n = 172)
Neutropenia
223 (65)
1 (< 1)
Anemia
10 (3)
3 (2)
Leukopenia
95 (28)
2 (1)
Thrombocytopenia
8 (2)
Febrile neutropenia was uncommon in both groups (3 pts vs 1 pt, respectively)
The most common nonhematologic AEs included infections, fatigue, nausea, headache, and diarrhea
Incidence of grade 3/4 AEs was comparable between arms, with no more than 2% of pts experiencing grade 3/4 toxicities
Discontinuations due to AEs were similar with palbociclib + fulvestrant and placebo + fulvestrant (4% vs 2%, respectively)
AE, adverse event.
Slide credit: clinicaloptions.com
Cristofanilli M, et al. Lancet Oncol. 2016;17:

9. Phase III MONARCH 2 & 3: Abemaciclib in Combination With Other Agents
Postmenopausal women with HR+, HER2- locally advanced or metastatic BC with no prior systemic therapy in this setting
Abemaciclib 150 mg BID PO + Fulvestrant 250 mg IM injection x 2 Day 1, 15, cycle 1; Day 1 every 28 days
(n ≈ 420)
MONARCH 2:
abemaciclib + fulvestrant
(N ≈ 630)
Primary endpoint: PFS
Placebo BID PO +
Fulvestrant 250 mg IM injection x 2 Day 1, 15, cycle 1; Day 1 every 28 days
(n ≈ 210)
Abemaciclib 150 mg BID PO + Anastrozole 1 mg/day or Letrozole 2.5 mg/day, PO
(n ≈ 300)
BC, breast cancer; NSAI, nonsteroidal aromatase inhibitor.
MONARCH 3: abemaciclib + NSAI
(N ≈ 450)
Primary endpoint: PFS
Placebo BID PO +
Anastrozole 1 mg/day or Letrozole 2.5 mg/day, PO
(n ≈ 150)
Slide credit: clinicaloptions.com
1. ClinicalTrials.gov. NCT ClinicalTrials.gov. NCT

10. BELLE-2: Buparlisib Efficacy and Safety
PFS significantly longer with use of buparlisib + fulvestrant
Median PFS, Mos
(95% CI)
Buparlisib + Fulvestrant
(n = 576)
Placebo + Fulvestrant
(n = 571) HR
P Value
Overall population
6.9 ( )
5.0 ( )
0.78 ( )
< .001
PI3K-activated pts*
6.8 ( )
4.0 ( )
0.76 ( )
.014†
ctDNA PIK3CA mutant‡
7.0 ( )
3.2 ( )
0.56 ( )
ctDNA PIK3CA nonmutant§
6.8 ( )
6.8 ( )
1.05 ( )
.642
*N = 372 (n = 188 buparlisib + fulvestrant; n = 184 placebo + fulvestrant). †Not statistically significant based on a threshold of P = .01 for this subpopulation. ‡n = 200 (n = 87 buparlisib + fulvestrant; n = 113 placebo + fulvestrant). §n = 387 (n = 199 buparlisib + fulvestrant; n = 188 placebo + fulvestrant).
AE, adverse event; ALT, alanine aminotransferase; AST, aspartate aminotransferase; PI3K, phosphatidylinositol 3-kinase.
Grade 3/4 AEs were significantly higher for buparlisib (63.2%/14.1%) vs placebo (27.4%/4.6%)
Buparlisib associated with liver toxicities (ie, increased ALT/AST)
Slide credit: clinicaloptions.com
Baselga J, et al. SABCS Abstract S6-01.

11. ENCORE301: PFS and OS PFS OS
1.0
Exemestane + entinostat: median, 4.28 mos
Exemestane + placebo: median, 2.27 mos
1.0
Exemestane + entinostat: median, mos
Exemestane + placebo: median, mos
0.8
HR: 0.73 (95% CI: ); P = .055
0.8
0.6
0.6
PFS (Probability)
OS (Probability)
0.4
0.4
0.2
0.2
HR: 0.59 (95% CI: ); P = .036 4 8 12 16 20 24 28 6 12 18 24 30 36 42
Mos
Mos
AE, adverse event.
Entinostat significantly improved PFS and OS
Most common grade 3/4 AEs: neutropenia (15% entinostat vs 0% placebo) and fatigue (13% entinostat vs 3% placebo)
Protein hyperacetylation in entinostat-treated pts associated with prolonged PFS for all cell types tested (B and T cells, monocytes)
Slide credit: clinicaloptions.com
Yardley DA, et al. J Clin Oncol. 2013;31:

12. Phase III E2112: Exemestane ± Entinostat in Advanced Breast Cancer
Entinostat: oral, histone deacetylase inhibitor
Primary endpoints: OS, PFS
Secondary endpoints: ORR (CR or PR), TTD, toxicity
Other outcomes: adherence, QoL, protein lysine acetylation
Pre/peri/postmenopausal women and men with HR+/HER2-, inoperable, locally advanced or metastatic BC, with progression on/after NSAI therapy
(N ≈ 600)
Entinostat PO Days 1, 8, 15, 22 +
Exemestane PO QD Days 1-28
(n ≈ 300)
Until disease progression or unacceptable toxicity
Placebo PO Days 1, 8, 15, 22 +
Exemestane PO QD Days 1-28
(n ≈ 300)
*Pre/perimenopausal female and all male pts receive goserelin acetate SC Day 1.
BC, breast cancer; HR, hormone receptor; NSAI, nonsteroidal aromatase inhibitor; QoL, quality of life; TTD, time to deterioration.
Slide credit: clinicaloptions.com
ClinicalTrials.gov. NCT

13. Trastuzumab and Docetaxel ± Pertuzumab in HER2+ MBC (CLEOPATRA): PFS
100
Pertuzumab (median: 18.5 mos) Control (median: 12.4 mos) 90
HR: 0.62 (95% CI: );
P < .001) 80 70 60
PFS (%) 50 40
MBC, metastatic breast cancer. 30 20 10 5 10 15 20 25 30 35 40
Mos
PFS independently assessed.
Baselga J, et al. N Engl J Med. 2012;366:
Slide credit: clinicaloptions.com

14. Trastuzumab and Docetaxel ± Pertuzumab in HER2+ MBC (CLEOPATRA): OS
Second interim analysis of OS (median follow-up: 30 mos)
Significant, confirmatory, crosses stopping boundary
100
Pertuzumab, trastuzumab, docetaxel Placebo, trastuzumab, docetaxel 90 80 70 60
OS (%) 50
MBC, metastatic breast cancer; Pmab, pertuzumab. 40 OS
Pmab
Placebo
HR (95% CI)
P Value
3-yr estimated OS, % 66 50
0.66 ( )
.0008
Median OS, mos
Not reached
37.6 -- 30 20 10 5 10 15 20 25 30 35 40 45 50 55
Mos
Swain SM, et al. Lancet Oncol. 2013;14:
Slide credit: clinicaloptions.com

15. Trastuzumab and Docetaxel ± Pertuzumab in HER2+ MBC (CLEOPATRA): Safety
Select Adverse Events (Grade ≥ 3), %
Pertuzumab
(n = 407)
Placebo
(n = 397)
Neutropenia
48.9
45.8
Febrile neutropenia
13.8
7.6
Leukopenia
12.3
14.6
Diarrhea
7.9
5.0
Peripheral neuropathy
2.7
1.8
Left ventricular systolic dysfunction
1.2
2.8
MBC, metastatic breast cancer.
Baselga J, et al. N Engl J Med. 2012;366:
Slide credit: clinicaloptions.com

16. EMILIA Study of T-DM1 vs Lapatinib/ Capecitabine in HER2+ MBC: PFS (IRC)
100 80 60 40 20
Events, n
265
304
Median Mos, n
9.6
6.4
T-DM1
Lapatinib/capecitabine
Stratified HR: 0.65
(95% CI: ); P < .001
PFS (%)
IRC, independent review committee; MBC, metastatic breast cancer; T-DM1, ado-trastuzumab emtansine. 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30
Mos
Verma S, et al. N Engl J Med. 2012;367:
Slide credit: clinicaloptions.com

17. EMILIA Study of T-DM1 vs Lapatinib/ Capecitabine in HER2+ MBC: OS
Median Mos, n
30.9
25.1
85.2% (95% CI: )
T-DM1
Lapatinib/capecitabine 60 40 20
64.7% (95% CI: )
Stratified HR: 0.68
(95% CI: ); P < .001
78.4% (95% CI: )
OS (%)
51.8% (95% CI: )
MBC, metastatic breast cancer; T-DM1, ado-trastuzumab emtansine.
Mos
Verma S, et al. N Engl J Med. 2012;367:
Slide credit: clinicaloptions.com

18. TH3RESA: Final OS Analysis
Median OS significantly improved with use of T-DM1 vs physician-selected therapy in pretreated pts with HER2+ MBC despite substantial crossover
Disposition: discontinuation occurred in 67.1% T-DM1 arm vs 79.3 TPC arm
44.9% of TPC arm pts received T-DM1 crossover therapy
Median OS, Mos
TPC
(n = 198)
T-DM1
(n = 404)
Stratified HR (95% CI)
P Value
All pts
15.8
22.7
0.68 ( )*
.0007
Sensitivity analysis (pts censored at crossover to T-DM1)
15.6
0.58 ( )
.0002
*Prespecified crossing boundary = HR: < (P < .012).
MBC, metastatic breast cancer; T-DM1, trastuzumab emtansine; TPC, treatment of physician’s choice.
Slide credit: clinicaloptions.com
Wildiers H, et al. SABCS Abstract S5-05.

19. TNT: Overall Response Rate90
Carboplatin Docetaxel Crossover 80
P = .03 70
68.0% 60 50
P = .44
P = .16
Response at Cycle 3 or 6 (%) 40
35.6%
36.6%
31.4%
P = .73
33.3% 30
25.6%
28.1%
22.8% 20
C→D, carboplatin followed by docetaxel; D→C, docetaxel followed by carboplatin. 10
All Pts (n = 376)
C→D D→C Crossover* (All pts; n = 182)
BRCA1/2 Mutation (n = 43)
No BRCA1/2 Mutation (n = 273)
*Excludes those with no first progression or not starting crossover treatment.
Slide credit: clinicaloptions.com
Tutt A, et al. SABCS Abstract S3-01.

20. TNBC: Classifications
Mesenchymal-like TNBC
(ML-TNBC) IM
Immune-associated (IM) TNBC
Immune
signature
Angiogenesis M
Claudin-
Low
EMT signature:
cell motility
growth factor signaling
(TFG6, Notch,
Wnt/β-catenin, Hedgehog)
BL1
Cell cycle
DNA damage
MSL
Growth
signaling
(EGF,
IGF)
BL2 BL
cytokeratine
Normal
Basal-like (BL) TNBC BL
Low
proliferation
LA/LB
PI3K
mutations
AR, androgen receptor, EGF, epidermal growth factor; EMT, epithelial-mesenchymal transition; IGF, insulin-like growth factor; PI3K, phosphoinositide 3-kinase; TNBC, triple-negative breast cancer.
HER2e
Luminal/apocrine (LA) TNBC AR
Pathway
HER2-enriched (HER2e) TNBC
LAR
Lehmann's classification
PAM50/claudin-low classification
Le Du F. Oncotarget. 2015;6: This work is licensed under a Creative Commons Attribution 3.0 Unreported License.
Slide credit: clinicaloptions.com

21. KEYNOTE-012: Pembrolizumab in Advanced TNBC: Tumor Regression
Individual Evaluable Pts (n = 23)
100
Confirmed CR (nodal disease)
Confirmed PR SD PD 80 60 40 20
Change From Baseline in Sum of Longest Diameter of Target Lesion (%)
-20
DoR, duration of response; PD, progressive disease; SD, stable disease; TNBC, triple-negative breast cancer.
ORR: 18.5%
Durable responses
Median DoR: not reached (range: wks)
3 of 5 responding pts for ≥ 11 mos
-40
-60
-80
-100
Nanda R, et al. SABCS Abstract S1-09.
Slide credit: clinicaloptions.com