2 tailoring secondline et

Magnitude
HR +ve patients:
Two thirds of patients in western world
Half of the patients in India
Many present with metastases, many
more develop metastases up to 10 years
since loco-regional treatment
2

MBC
Incurable
Heterogeneous
Survival ranges from months to decades

Usual first line
AI
Tamoxifen acceptable
5

My choice
So far is an AI
Likely to be:
AI with CDK4/6I
Ful 500
Ful/Ana
7
Optimal Second
Line

clinicaloptions.com/oncology
Treatment and Management Approaches in Metastatic Breast Cancer
Endocrine Resistance in ER-Positive
Breast Cancer
 Approximately 50% of hormone receptor–positive breast
cancers are de novo resistant to endocrine therapy
 Almost all patients with advanced disease will develop
acquired resistance to endocrine therapies
 The mechanisms of de novo and acquired resistance are
likely similar but are not completely understood

Second Line Hormonal
Therapy
12

Case 1
56 years. Rt MRM Feb 2012
T2N1M0, HR+, Her -2 –
3FEC/3DOCE/RT
Letrozole since Jul 2012
Asymptomatic Liver/lung/bone mets or
routine follow up
14

Case 1
What more info?
LFT normal
Repeat Biopsy?
Repeat Biopsy HR+ Her2-
15

Case 1
Options:
Combination Chemotherapy
Single agent chemotherapy
Exemastane
Fulvestrant
Exemastane/Everolimus
Tamoxifen
Tamoxifen/Everolimus
Other
17

What hormonal options do we consider at
this point?
20

PROBLEM STATEMENT
Treatment options are limited for pts who
experience disease progression after using
NSAI therapy
Two novel treatment options are among the newer
therapies approved for use in pts with HR+/HER2- ABC:
 Fulvestrant monotherapy (FUL)
 Combination therapy of everolimus and exemestane.

Indication
Fulvestrant is indicated for the treatment of HR+ MBC
in postmenopausal women with disease progression
following antiestrogen therapy.
Everolimus: postmenopausal women with advanced
hormone receptor-positive, HER2-negative breast
cancer (advanced HR+ BC) in combination with
exemestane after failure of treatment with letrozole or
anastrozole.
As a 2nd and later lines of therapy
after the failure of NSAIs

Final Analysis of Overall Survival
for the Phase III CONFIRM Trial:
Fulvestrant 500 mg versus 250 mg
Di Leo A et al.
Proc SABCS 2012;Abstract S1-4.

CONFIRM Study Design
Eligibility (N = 736)
Postmenopausal women
ER+, advanced disease
Recurred or progressed
following endocrine therapy
Fulvestrant
250 mg* + placebo*
(n = 374)
Fulvestrant
500 mg†
(n = 362)
Di Leo A et al. Proc SABCS 2012;Abstract S1-4.
* 1 injection IM; † 2 injections (250 mg each) IM
After the primary analysis:
- 50% of patients had died
- Patients on fulvestrant 250 mg were permitted to cross over to 500 mg
R

Secondary Endpoint:
Overall Survival
With permission from Di Leo A et al. Proc SABCS 2012;Abstract S1-4.

Author Conclusions
 Final OS analysis at 75% maturity shows that fulvestrant
500 mg is associated with a 4.1-month increase in
median OS and a 19% reduction in the risk of death
compared to 250 mg of fulvestrant.
 These results are consistent with previously reported PFS
and OS data (J Clin Oncol 2010;28:4594).
 Analysis of first subsequent therapies does not support
any imbalance between the study arms.
 Only 2% of patients crossed over from 250 to 500 mg.
However, activity for fulvestrant 500 mg after
pretreatment with 250 mg of fulvestrant is unknown.
 The safety results are consistent with those previously
reported for 500 mg of fulvestrant.
Di Leo A et al. Proc SABCS 2012;Abstract S1-4.

TAMRAD: Phase II Trial of Tamoxifen +
Everolimus in HR+ ABC (1/2)
61%
0
10
20
30
40
50
60
70
TAM TAM + EVE
CBR,%ofPatients
42%
Primary Endpoint – CBR
P = .045 (exploratory analysis)
EVE increased CBR
45% over TAM alone
(absolute difference
19%)
HR, hormone receptor; ABC, advanced breast cancer; PMW, postmenopausal women; ER, estrogen receptor; PgR, progesterone receptor;
HER2, human epidermal growth factor receptor 2; AI, aromatase inhibitor; CBR, clinical benefit rate; TTP, time to progression; OS, overall
survival; ORR, overall response rate; EVE, everolimus; TAM, tamoxifen.
Bachelot T, et al. J Clin Oncol. 2012;30(22):2718-2724.
TAM 20 mg/day
+ EVE 10 mg/day
TAM 20 mg/day
N = 111
PMW with ER/PgR+, HER2–
ABC previously treated with
AI in the adjuvant or
metastatic setting
Primary endpoint
CBR at 6 months
Secondary endpoints
Safety, TTP, OS,
ORR, biomarkers
27

TAM + EVE: 14.8 mo
TAM: 5.5 mo
PFS: Patients with Secondary
Hormone Resistance
HR = 0.46 (0.26-0.83), P = .0087
0.0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1.0
0 6 12 18 24 30
TTPProbability
Months
HR, hormone receptor; ABC, advanced breast cancer; PFS, progression-free survival; ITT, intent to treat; HR, hazard ratio; TTP, time to
progression; EVE, everolimus; TAM, tamoxifen; OS, overall survival; CI, confidence interval.
Bachelot T, et al. J Clin Oncol. 2012;30(22):2718-2724. Reprinted with permission. © 2012 American Society of Clinical Oncology. All rights
reserved.
OS: HR = 0.45 (95% CI of 0.24–0.81), exploratory P value of .007
Adverse events: The main toxicities associated with tamoxifen +
everolimus vs tamoxifen were: fatigue (72% vs 53%), stomatitis (56% vs
7%), rash (44% vs 7%), anorexia (43% vs 18%), and diarrhea (39% vs 11%)
HR = 0.54 (0.36-0.81)
P = .002 (exploratory analysis)
TAM + EVE: 8.6 months
TAM: 4.5 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 30 32 34
Months
TTPProbability
PFS: ITT Population
TAMRAD: Phase II Trial of Tamoxifen +
Everolimus in HR+ ABC (2/2)
28

Everolimus 10 mg/day +
Exemestane 25 mg/day
(n = 485)
Placebo +
Exemestane 25 mg/day
(n = 239)
BOLERO-2: Exemestane ± Everolimus in
Nonsteroidal AI–Refractory Advanced BC
 Refractory to therapy:
– Recurrence during or within
12 mos of end of adjuvant
treatment
– Progression during or within
1 mo after end of treatment for
advanced disease
 Stratification:
– Sensitivity to previous hormonal
therapy
– Presence of visceral disease
 No crossover allowed
 Primary endpoint: PFS
– Secondary endpoints: OS, ORR,
CBR, safety, QoL, bone markersBaselga J, et al. N Engl J Med. 2012;366:520-529.
Postmenopausal women
with HR-positive,
HER2-negative advanced
breast cancer refractory to
letrozole or anastrozole
(N = 724)

BOLERO-2: Patient Demographics, Baseline
Disease Characteristics
Characteristic
EVE + EXE
(n = 485) %
PBO + EXE
(n = 239) %
Median age, years (range) 62 (34-93) 61 (28-90)
Race
White 74 78
Asian 20 19
Black 3 1
Other 3 2
ECOG performance status 0 60 59
Visceral disease 58 59
Measurable disease* 70 68
Metastatic site
Lung 30 33
Liver 33 30
Bone 77 77
*All other patients had ≥1 mainly lytic bone lesion.
ECOG, Eastern Cooperative Oncology Group; EVE, everolimus; EXE, exemestane; PBO, placebo.
Yardley D et al. Adv Ther. 2013; 30(10):870-884. 30

BOLERO-2: Prior Therapy
Therapy
Everolimus +
Exemestane
(n = 485), %
Placebo +
Exemestane
(n = 239), %
Sensitivity to prior hormonal therapy 84 84
Last treatment: LET/ANA 74 75
Last treatment
Adjuvant 21 16
Metastatic 79 84
Prior tamoxifen 47 49
Prior fulvestrant 17 16
Prior chemotherapy for metastatic BC 26 24
Number of prior therapies: ≥3 54 53
LET = letrozole; ANA = anastrozole.
Baselga J, et al. N Engl J Med. 2012;366(6):520-529.

EVE + EXE
PBO + EXE
485 436 366 304 257 221 185 158 124 91 66 50 35 24 22 13 10 8 2 1 0
239 190 132 96 67 50 39 30 21 15 10 8 5 3 1 1 1 0 0 0 0
Patients at Risk, n
0
20
40
60
80
100
0 6 12 18 24 30 36 42 48 54 60 66 72 78 84 90 96 102 108 114 120
Censoring Times
EVE + EXE (n/N = 310/485)
PBO + EXE (n/N = 200/239)
Median PFS, Mos
EVE + EXE: 7.82
PBO + EXE: 3.19
HR: 0.45 (95% CI: 0.38-
0.54; Log-rank P < .0001)
Patients(%)
Wk
BOLERO-2: PFS at 18-Mo Follow-up
Piccart-Gebhart M, et al. ASCO 2012. Abstract 559.

BOLERO-2: PFS Subgroup Analyses (1/2)
0 0.2 0.4 0.6 0.8 1 1.2 1.4
Hazard Ratio and 95% CI
0.38 11.00 4.10
0.32 11.33 3.94
0.50 10.84 4.17
0.41 13.86 4.17
0.38 9.40 4.11
0.33 13.83 4.14
0.36 5.72 1.61
0.39 22.18 4.21
0.37 10.91 3.94
724
449
275
137
275
274
38
106
618
N
All
Local Central
Age group
<65
≥65
Region
Asia
Europe
North America
Other
Japanese patients
Japan
Non-Japan
Median PFS, mo
HR EVE + EXE PBO + EXE
0.45 7.8 3.2
0.38 8.31 2.92
0.59 6.83 4.01
0.60 8.48 4.14
0.45 7.16 2.83
0.38 8.41 2.96
0.40 4.53 1.48
0.58 8.54 4.17
0.42 7.16 2.83
Favours EVE + EXE
0.42 13.86 4.17
0.38 10.91 4.14
0.15 NA 1.45
0.39 12.45 4.21
0.35 10.91 2.79
0.43 13.14 4.14
0.37 11.01 4.11
0.27 16.59 5.82
0.46 8.31 2.89
0.43 9.56 4.07
0.19 19.52 6.51
143
547
34
435
274
184
523
318
406
573
151
Race
Asian
Caucasian
Other
Baseline ECOG performance status
0
1, 2
PgR status
Negative
Positive
Presence of visceral metastasis
No
Yes
Bone only lesions at baseline
No
Yes
0.62 8.48 4.14
0.42 7.36 2.96
0.25 6.93 1.41
0.48 8.25 4.11
0.39 6.93 2.76
0.51 6.93 2.83
0.41 8.08 3.32
0.41 9.86 4.21
0.47 6.83 2.76
0.48 6.90 2.83
0.33 12.88 5.29
Favours PBO + EXE
N
Median PFS, mo
0 0.2 0.4 0.6 0.8 1 1.2 1.4
Favours EVE + EXE Favours PBO + EXE
PFS, progression-free survival; mo, months; HR, hazard ratio; EVE, everolimus; EXE, exemestane; PBO, placebo; ECOG, Eastern
Cooperative Oncology Group; PgR, progesterone receptor; CI, confidence interval.
Yardley D et al. Adv Ther. 2013;30(10):870-884. 33

BOLERO-2: PFS Subgroup Analyses (2/2)
Median PFS, mo Median PFS, mo
0.40 10.91 4.14
0.37 11.04 4.14
0.39 10.91 4.11
0.38 15.01 6.80
0.38 10.91 4.11
0.39 17.97 7.00
0.38 11.01 4.11
0.24 11.10 6.80
114
610
620
104
653
71
691
33
Sensitivity to prior hormonal therapy
No
Yes
Only received prior adjuvant therapy
No
Yes
Only received prior adjuvant hormonal
therapy with chemotherapy
No
Yes
Only received prior adjuvant hormonal
therapy without chemotherapy
No
Yes
0.55 6.83 2.83
0.43 8.05 3.94
0.46 7.00 2.96
0.40 11.70 4.17
0.46 7.06 2.96
0.40 12.29 4.17
0.45 7.59 3.19
0.37 11.10 4.12
0 0.2 0.4 0.6 0.8 1 1.2 1.4
0.38 11.00 4.10
0.24 19.52 6.51
0.53 8.28 4.17
0.35 8.48 2.83
0.44 10.58 5.55
0.35 11.27 4.07
0.35 13.83 4.21
0.42 7.13 2.83
0.46 9.95 4.21
0.32 12.02 3.32
724
219
232
271
231
493
538
186
326
398
N
All
Number of organs involved
1
2
Prior chemotherapy
No
Yes
Prior chemotherapy
for metastatic disease
No
Yes
Prior use of hormonal therapy
other than NSAI
No
Yes
0.45 7.8 3.2
0.40 11.50 4.37
0.52 6.70 3.45
0.41 6.93 2.56
0.53 6.97 3.45
0.41 8.18 3.19
0.46 8.31 4.07
0.38 6.11 2.69
0.52 7.00 4.11
0.39 8.11 2.76
≥3
Local Central
N HR EVE + EXE PBO + EXE
0 0.2 0.4 0.6 0.8 1 1.2 1.4
All
PFS, progression-free survival; mo, months; HR, hazard ratio; EVE, everolimus; EXE, exemestane; PBO, placebo; NSAI, nonsteroidal
aromatase inhibitor; CI, confidence interval.
Yardley D et al. Adv Ther. 2013; 30(10):870-884.
Clinical benefit of EVE + EXE treatment was consistent among all prospectively
defined subgroups
34

BOLERO-2 (39-Month) Final OS Analysis
One-sided P value was obtained from the log-rank test stratified by sensitivity to prior hormonal therapy and presence of visceral
metastasis from IXRS®.
CI, confidence interval; EVE, everolimus; EXE, exemestane; HR, hazard ratio; IXRS®, Interactive Voice and Web Response System;
PBO, placebo.
Piccart M, et al. Presented at EBCC-9; 19-21 March 2014; Glasgow, Scotland. Abstract 1LBA.
35
4.4-month
difference
At 39 months’ median follow-up, 410 deaths had occurred
• 55% of patients (n = 267) in the EVE + EXE arm
• 60% of patients (n = 143) in the PBO + EXE arm
Median OS was 4.4 months longer for EVE + EXE vs PBO + EXE

Overall Survival: Hormone therapy for MBC
Months
EVE + EXE
EXE
EXE
FUL 250
EXE
FUL 250 + placebo
FUL 250 + ANA
FUL 250
FUL 500
BOLERO 2 1
EFECT 2
SOFEA 3
CONFIRM 4
1. Piccart M, et al. Presented at EBCC-9; 19-21 March 2014; Glasgow, Scotland. Abstract 1LBA. 2. Chia S J Clin Oncol 26:1664-1670.
3. Johnston S Lancet Oncol 2013; 14: 989–98 4. DiLeo A J Natl Cancer Inst 2013
100%
progressed
on NSAI
42.5%
progressed
on NSAI

Can you select the patient?
37

Eve/Exe…..effect on ‘Proliferative’ Biomarkers
 Pilot study
 Operable early BC cases (n=31)
 Eve 5 mg daily for 14 days before surgery
 Reduction in Ki67 (74%) from baseline
Macaskill EJ. Breast Cancer Res Treat 2011; 128: 725–734.
 Phase II study
 270 postmenopausal women with ABC
 Neoadj EVE (10 mg) plus letrozole (2.5 mg) for 4 mo compared with letrozole
 Response rate by clinical palpation in the everolimus arm was higher than that with
letrozole alone (ie, placebo; 68.1% v 59.1%)
 57% of everolimus pts compared with 30% in the placebo arm (P < .01) showed
defined reduction in Ki67 expression to <1% by Day 15
Baselga J. J Clin Oncol. 2009; 27(16): 2630–2637

Other agents
PIK3CA inhibitors
 Bupralisib BKM 120
 Alpelisib BYL719
 Pictilisib GDC0941
44

Key Developments: San Antonio Breast Cancer Symposium 2014
Phase II FERGI: Fulvestrant ± Pictilisib in
ER+, AI-Resistant Adv or Metastatic BC
 Primary endpoints: PFS (ITT and with PIK3CA mutation), safety
 Secondary endpoints: ORR, DOR, pharmacokinetics
Krop I, et al. SABCS 2014. Abstract S2-02.
Postmenopausal
women with ER+,
HER2-, adv or
metastatic breast
cancer, prior AI
(adjuvant or
metastatic), 0-1 prior
chemo regimens or
≤ 2 prior endocrine
therapies
(N = 168)
Fulvestrant 500 mg* +
Pictilisib (GDC-0941) 340 mg QD
(n = 89)
Fulvestrant 500 mg* +
Placebo QD
(n = 79)
PD
*28-day cycles: Days 1, 15 in cycle 1, then Day 1 thereafter.
PD
Stratified by PIK3CA mutation, PTEN loss, measurable
disease, first- vs second-degree resistance

Fulvestrant ± Pictilisib in ER+, AI-Resistant
Adv or Metastatic BC (FERGI): PFS (ITT)
100
80
60
40
20
0
PFS(%)
Mos
240 2 4 6 8 10 12 14 16 18 20 22
Placebo + Ful (n = 79)
Pictilisib + Ful (n = 89)
Pts at Risk, n
Placebo + Ful
Pictilisib + Ful
79
89
54
63
35
45
27
37
22
30
21
26
15
25
8
18
5
9
4
8
2
3
1
2
0
2
Median PFS, mos
HR
Log-rank P value
Placebo + Ful
5.1
Pictilisib + Ful
6.6
0.738
0.0959

Adv or Met BC (FERGI): PFS (ER/PR+)
100
80
60
40
20
0
PFS(%)
240 2 4 6 8 10 12 14 16 18 20 22
Placebo + Ful (n=58)
Pictilisib + Ful (n=58)
Pts at Risk, n
Placebo + Ful
Pictilisib + Ful
58
58
38
47
21
33
15
28
10
22
9
20
6
20
2
14
1
6
1
5
1
2
0
1
0
1
Mos
Median PFS, mos
HR
(95% CI)
Placebo + Ful
3.7
Pictilisib + Ful
7.4
0.440
(0.281-0.689)

Adv or Metastatic BC (FERGI): Toxicity
Adverse Event, % Fulvestrant/Pictilisib (n = 89) Fulvestrant/Placebo (n = 79)
Grade 1-4 Grade 3/4 Grade 1-4 Grade 3/4
Diarrhea 63 7 9 --
Nausea 48 3.4 19 --
Rash 43 17 6 --
Dysgeusia 35 -- -- --
Fatigue 27 6 20 --
Vomiting 20 3 4 --
Decreased appetite 19 1 6 --
Hyperglycemia 17 5 5 --
Stomatitis 16 2 2 --
Hot flash 11 -- 13 --
AST increase 11 3 8 3
Dose reduction due to AE, % 24 1
Discontinued pictilisib/placebo, % 90 87

Adv or Metastatic BC (FERGI): Conclusions
 Safety profile of fulvestrant/pictilisib consistent with
phase I experience
 GI and dermatologic toxicity resulted in significant dose
modifications and discontinuations of pictilisib
 In ITT population, addition of pictilisib produced
nonsignificant improvement in median PFS vs placebo
– 6.6 vs 5.1 mos (HR: 0.738)
 Subgroup analyses suggest activity in ER/PgR+ tumors

Investigator Commentary: Final Analysis of the Phase III
CONFIRM Trial: Fulvestrant 500 mg versus 250 mg
The CONFIRM trial compared fulvestrant at what used to be the
conventional dose of 250 mg versus 500 mg in postmenopausal women
with advanced breast cancer. The first analysis demonstrated an
improvement in progression-free survival and a nonsignificant increase
in overall survival.
This study was the final analysis of overall survival after 75% of the
events had occurred. One cannot argue with the improvement in overall
survival. The results showed a 4-month improvement in overall survival
and a 19% reduction in the risk of death.
Only 2% of the patients crossed over from the 250-mg to the 500-mg
dose. An analysis of the first subsequent therapy showed that both the
arms were similar and most of the patients went on to receive
chemotherapy. It is unlikely that imbalance between the 2 arms altered
the survival results. Based on the results of this study, I would
administer fulvestrant at 500 mg in my practice.
Interview with Lisa A Carey, MD, January 17, 2013

Meta-analysis: Chemotherapy vs
Endocrine Therapy in MBC
Methods
– Randomized trials of chemotherapy alone vs endocrine therapy alone
Results
– No significant difference for OS in 6 trials (N = 692):
HR: 0.94 (95% CI: 0.79-1.12; P = .5)
– Significant difference favoring chemotherapy for ORR in 8 trials (N = 817):
HR: 1.25 (95% CI: 1.01-1.54; P = .04)
– However, the 2 largest trials demonstrated trends in opposite directions
– Toxicity: Little information available on adverse events and QoL
– Increased toxicity with chemotherapy (nausea, vomiting, alopecia)
– 3 of 7 trials noted QoL aspects with differing results
Authors’ Conclusions
– “In women with metastatic breast cancer and where hormone receptors are
present, a policy of treating first with endocrine therapy rather than chemotherapy is
recommended except in the presence of rapidly progressive disease.”
Wilcken N, et al. Cochrane Database Syst Rev. 2003:CD002747.

1st line hormonal therapy 1st line chemotherapy
Determine sites and extent of disease & symptoms; ER status; HER2 status;
disease free & treatment-free intervals; performance status
No
Response
No life-threatening disease
Hormone-responsive
Hormone-unresponsive, or
Life-threatening disease
Response
No
Response
2nd-line hormonal therapy
2nd-line chemotherapy
Progression
Progression
Progression
Progression
3rd-line hormonal therapy
Response
No
Response
3rd-line chemotherapy
Supportive care
Algorithm for Management of Post-menopausal ER+ MBC
National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology: Breast Cancer. V3.2012
Median PFS 3-4 mo
Median PFS 12-15 mo

Traditional sequence:
1990s
Tamoxifen
MedroxyProgesterone
Megace
Premarin
Other
Post 1990s
NSAI
Tamoxifen
Fulvestrant
Steroidal AI
Other
59

The New Paradigms in First
Line Treatment
Push effective second line agent in
frontlline
Combination of hormonal agents
Combination of a hormonal agent with a
targeted agent
61

Phase II FIRST: First-line Fulvestrant vs
Anastrozole for Advanced Breast Cancer
 Primary endpoint: clinical benefit rate
Robertson JF, et al. SABCS 2014. Abstract S6-04.
Postmenopausal
women with
previously
untreated hormone
receptor–positive
advanced breast
cancer
(N = 205)
Fulvestrant 500 mg by intramuscular injection
Days 0, 14, 28, and every 28 days thereafter
(n = 102)
Anastrozole 1 mg/day orally
(n = 103)
Until disease
progression or
other event
requiring
discontinuation

First-line Fulvestrant vs Anastrozole for
Advanced Breast Cancer (FIRST): Results
 OS analysis
– Not a defined endpoint in original protocol
– Median follow-up: fulvestrant (49.6 mos), anastrozole (42.5 mos)
– Analysis conducted at 66.8% maturity (137 patients died)
Outcome Fulvestrant
500 mg
(n = 102)
Anastrozole
1 mg
(n = 103)
P Value
Clinical benefit rate, % 72.5 67.0 .386
Median time to
progression, mos
23.4 13.1 .01
Median OS, mos 54.1 48.4 .041

First-line Fulvestrant vs Anastrozole for
Adv Breast Cancer (FIRST): Conclusions
 Median OS for fulvestrant: 54.1 mos
– 5.7 mos longer than with anastrozole
– OS benefit for fulvestrant consistent across subgroups
 No new safety concerns for either fulvestrant or anastrozole
 Second randomized study showing survival advantage for fulvestrant
500 mg vs control
– Phase III CONFIRM (vs fulvestrant 250 mg, second-line therapy)
– Phase II FIRST (vs anastrozole, first-line therapy)
 Phase III FALCON study ongoing: fulvestrant vs anastrozole in
postmenopausal women with ER+ and/or PgR+ local advanced or
metastatic breast cancer, and no previous hormonal therapy

Fulvestrant first
Data exciting
Phase II study
NCCN has accepted as an option
Phase III study ongoing
I will wait
65

Line Treatment
Combination of a hormonal agent with a
targeted agent
66

FACT: Phase III Study of First-line
Anastrozole ± Fulvestrant in HR+ MBC
Fulvestrant 500 mg on Day 1, then
250 mg on Days 15, 29, then every 4th wk
Anastrozole 1 mg/day PO
(n = 258)
(n = 256)
Post- or premenopausal
women receiving GnRH
agonist, ER- or PgR-positive,
in first relapse after
treatment for localized disease
(N = 514)
Bergh J, et al. J Clin Oncol. 2012;30:1919-1925.
Primary endpoint: TTP
Secondary endpoints: ORR, TTF, DoR, clinical benefit rate, OS
Treat until progression
or undue toxicity

FACT Phase III Study of Anastrozole ±
Fulvestrant in HR+ MBC: TTP
Median TTP
Anastrozole (n = 256): 10.2 mos
Anastrozole + fulvestrant (n = 258):
10.8 mos
HR: 0.99 (95% CI: 0.81-1.20;
P = .91)
Bergh J, et al. J Clin Oncol. 2012;30:1919-1925.
ProbabilityofSurvival
WithoutProgression
Mos
1.0
0.4
0.3
0.2
0.1
0
0 30 36 42 48 54
0.9
0.8
0.7
0.6
0.5
6 12 18 24

Postmenopausal
women with HR+
MBC
(N = 707)
Anastrozole 1 mg/day PO +
Fulvestrant 500 mg on Day 1,
250 mg on Days 14 and 28,
250 mg q28 days thereafter
(n = 355)
(n = 352)
Treatment until disease
progression
Stratified by previous
adjuvant tamoxifen
Women with
progression
encouraged to
cross over to
receive
fulvestrant
SWOG S0226: Phase III Study of First-line
Anastrozole ± Fulvestrant in HR+ MBC
 Primary endpoint: PFS
 Secondary endpoints: OS, clinical benefit rate, ORR
Mehta RS, et al. N Engl J Med. 2012;367:435-444.

S0226 Study of First-line Anastrozole ±
Fulvestrant in HR+ MBC: PFS and OS
1.00
0.75
0.50
0.25
0
0 12 24 36 48 60
Anastrozole
(297 events)
Anastrozole + Fulvestrant
(268 events)
Median PFS
Combination: 15.0 mos (95% Cl: 13.2-18.4)
Anastrozole: 13.5 mos (95% Cl: 12.1-15.1)
PFS
Mos Since Randomization
HR: 0.80 (95% Cl: 0.68-0.94;
P = .007 by stratified log-rank test)
1.00
0.75
0.50
0.25
0
Anastrozole
(176 deaths)
HR: 0.81 (95% Cl: 0.65-1.00;
P = .049 by stratified log-rank test)
Anastrozole + Fulvestrant
(154 deaths)
Median OS
Combination: 47.7 mos (95% Cl: 43.4-55.7)
Anastrozole: 41.3 mos (95% Cl: 37.2-45.0)
OS
0 12 24 36 48 60 72
Mos Since Randomization

S0226: PFS and OS Overall and by
Previous Adjuvant Tamoxifen
Endpoint Anastrozole +
Fulvestrant
Anastrozole HR (95% CI) P
Value
Median PFS (n = 694), mos 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), mos 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

First-line Anastrozole ± Fulvestrant in
HR+ MBC: FACT vs SWOG S0226
FACT[1] SWOG S0226[2]
Patients, n 514 707
De novo metastatic disease, % 13 39
Prior adjuvant chemotherapy, % 45 33
Previous adjuvant endocrine
therapy (tamoxifen), %
68 40
Mean PFS range, mos 10-11 13-15
PFS benefit No Yes
1. Bergh J, et al. J Clin Oncol. 2012;30:1919-1925. 2. Mehta RS, et al. N Engl J Med. 2012;367:435-444.

First line combinations
Most (if not all) patients will have receives
adjuvany tam or AI
For de novo mets, whether Ful/Ana as per
SWOG be better than Ful 500????? - -- --
Not sure
I will rather wait
73

Line Treatment
Combination of a hormonal agent with
a targeted agent
74

LEA: Endocrine Therapy ± Bevacizumab
as First-line Treatment of MBC
 Binational, multicenter, open-label, randomized phase III trial
Endocrine Therapy
(Letrozole or Fulvestrant)* +
Bevacizumab 15 mg/kg q3 wks
(n = 191)
Endocrine Therapy
(Letrozole or Fulvestrant)*
(n = 189)
Patients with
unresectable
locally advanced
or metastatic, HR+,
HER2-
breast cancer
(N = 380)
Until disease
progression
Stratified by adjuvant AI (yes vs no), number of
lesions (1 vs multiple), measurable lesions (yes
vs no), country (Spain vs Germany)
*Letrozole: 2.5 mg/day; fulvestrant: 250 mg q28 days.
Martin M, et al. SABCS 2012. Abstract S1-7.

LEA: PFS With First-line Endocrine
Therapy ± Bevacizumab
Martin M, et al. SABCS 2012. Abstract S1-7.
Median PFS
ET + bev (n = 191): 18.4 mos
ET alone (n = 189): 13.8 mos
HR: 0.83 (95% CI: 0.65-1.06;
P = .14)
ProbabilityofSurvival
WithoutProgression
Mos
1.0
0.8
0.6
0.4
0.2
0
0 10 20 30 40 50

Ibrance® - Palbociclib
Literature Review
• Study Design (PALOMA-1/TRIO-18)
• Phase 2, randomized, open label trial
• 50 sites in 12 countries (North America, Latin
American and Europe)
• Interventions
• Palbociclib 125 mg daily (3 wks on/1 wk off)
+ Letrozole 2.5 mg daily
• Letrozole 2.5 mg daily
Finn, RS, et al., Lancet Oncol 2015;16: 25-35.

Literature Review
• Primary Endpoint:
• Progression free survival
• Secondary Endpoints:
• Objective response, clinical benefit,
duration of response, overall survival

Literature Review
Inclusion criteria Exclusion criteria
Post-menopausal
Received treatment with
Letrozole within past 12 months
Locally recurrent disease not
amenable to surgery or
metastatic disease
Any previous treatment for
advanced breast cancer
No previous treatment for
advanced disease
Brain metastasis
ER+/Her2-
Any previous treatment with CDK
inhibitor
ECOG performance status of
0 or 1

Literature Review
• Significant Adverse Events: (>20%)
Event Palbociclib+Letrozole
(n=83)
Letrozole
(n=77)
URI 31 18
Neutropenia 75 5
Leukopenia 43 3
Anemia 35 7
Stomatitis 25 7
Nausea 25 13
Diarrhea 21 10
Alopecia 22 3
Fatigue 41 23

Literature Review
• Efficacy Results: Investigator assessment
PFS Intent to Treat Population
Progression Free
Survival
Palbociclib +
Letrozole
(n=84)
Letrozole
(n=81)
Number of PFS Events (%) 41 (48.8%) 59 (72.8%)
Hazard Ratio (95% CI) 0.488 (0.319, 0.748)
Median PFS [months]
(95%CI)
20.2 (13.8, 27.5) 10.2 (5.7, 12.6)

Literature Review
• PALOMA-1/TRIO-18
• Conclusions
• Addition of palbociclib to letrozole
significantly improved progression free
survival in women with advanced ER+ and
HER2- breast cancer
• Phase 3 trial currently underway

Summary
• Only non-hormonal targeted therapy
approved for use in ER-positive, HER-2
negative advanced breast cancer
• First CDK inhibitor approved for use in
oncology
• Used in combination with letrozole
• Side effects: neutropenia / leukopenia
• Dose reduction is suggested as 1st step in tx

Prescription Information
• Dosing:
• 125 mg taken orally once daily for 21 days
followed by 7 days off treatment in 28-day
cycles
• Should be taken with food and in
combination with letrozole 2.5 mg once
daily continuously.

CDK4/6 inhibitor summary
 Palbociclib improves PFS with letrozole
– Confirmatory phase III trials ongoing
– Watch for maturing data in combination with fulvestrant or paclitaxel
 Several other CDK4/6 inhibitors in development, such as
abemaciclib and LEE011
 Many remaining questions:
– Is there an optimal endocrine, chemotherapy or targeted therapy
partner?
– How do we sequence these relative to everolimus?
– What are mechanisms of resistance?
Presented by: Tiffany A. Traina, MD

2 tailoring secondline et

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