Endocrine_therapy.ppt

Fulvestrant plus palbociclib versus fulvestrant plus placebo for
treatment of hormone-receptor positive, HER-2 negative
metastatic breast cancer that progressed on previous
endocrine therapy (PALOMA-3): Final analysis of the
multicenter, double-blind, phase-3 randomised controlled study
Massimo Cristofanilli, M.D., F.A.C.P.
Professor of Medicine
Associate Director of Translational Research and Precision Medicine
Robert H Comprehensive Lurie Cancer Center, Northwestern University
Chicago, USA

Treatment Approvals for HR+ Metastatic Disease Have Been Ongoing, Much Has Been Learned, and
Multiple Drugs Targeting New Pathways Are Under Development
1. Jordan VC. Steroids. 2007;72(13):829-842.2.European Medicines Agency. Assessment Report pursuant to Article 30 of Directive 2001/83/EC, as amended. http://www.ema.europa.eu/docs/en
_GB/document_library/Referrals_document/Arimidex_30/WC500109487.pdf.Accessed January 29, 2016.3.European Medicines Agency. Assessment report pursuant to Article 30 of Directive
2001/83/EC,as amended. http://www.ema.europa.eu/docs/en_GB/document_library/Referrals_document/Femara_30/WC500128493.pdf.Accessed January 29, 2016.4.European Medicines
Agency. Press Release. European Medicines Agency recommends new contraindication for Fareston (toremifene). http://www.ema.europa.eu/docs/en_GB/document_library/Press
_release/2009/11/WC500014597.pdf.Accessed January 29, 2016.5. US Food and Drug Administration. FDA-approved drug products. http://www.accessdata.fda.gov/scripts/cder/drugsatfda
/index.cfm?fuseaction= Search.DrugDetails. Accessed January 29, 2016.6.Roche. Media Release. Avastin approved in Europe for first-line treatment of patients with advanced lung cancer.
http://www.roche.com/media/store/releases/med-cor-2007-08-24.htm.Accessed January 29, 2016.7. European Medicines Agency. Assessment report for tyverb. http://www.ema.europa.eu
/docs/en_GB/document_library/EPAR_-_Public_assessment_report/human/000795/WC500044960.pdf.Accessed January 29, 2016.8. US Food and Drug Administration. Letter.
http://www.accessdata.fda.gov/drugsatfda_docs/appletter/2011/125085s0241ltr.pdf.Accessed January 29, 2016.9.US Food and Drug Administration. Letter. http://www.accessdata.fda.gov/
drugsatfda_docs/appletter/2012/022334Orig1s016ltrRepl.pdf. Accessed January 29, 2016.10.Milani A, et al. World J Clin Oncol. 2014;5:990-1001.11.Osborne CK, et al. Annu Rev Med.
2011;62:233-247.12.LangeCA, et al. Endocr Relat Cancer. 2011;18:C19-C24.13.Asghar U,et al. NatRev Drug Discov. 2015;14:130-146.14.Baselga J.Oncologist. 2011;16(suppl 1):12-19.
15.Vicier C, et al. BreastCancer Res. 2014;16:203.16.USFood and Drug Administration. Letter. http://www.accessdata.fda.gov/drugsatfda_docs/appletter/1998/20896ltr.pdf.Accessed January 29,
2016.17.US Food and Drug Administration. Letter. http://www.accessdata.fda.gov/drugsatfda_docs/appletter/2010/201532s000ltr.pdf.Accessed January 29, 2016.18.US Food and Drug
Administration. Letter http://www.accessdata.fda.gov/drugsatfda_docs/appletter/2005/021660ltr.pdf.Accessed January 29, 2016.
*Various chemotherapy agents have been approved
(capecitabine, eribulinmesylate, paclitaxel),
but do not target HR+ disease specifically16–18
CDK, cyclin-dependentkinase; ER, estrogen receptor;
HR,hormone receptor; MBC, metastaticbreast cancer;
mTOR, mammaliantarget of rapamycin;
PI3K, phosphoinositide 3-kinase
Timeline of HR+ MBC Treatments*
Understanding of estrogen, ER, and resistance11
Role of cyclin D1 and CDK4/612,13
Role of PI3K14 and mTOR15
1990 2000 2010
1995
Anastrozole EU
approval2
1996
Letrozole and
Toremifene
EU approval3,4
1999
Exemestane
US approval5
2002
Fulvestrant
US approval5
2015
Palbociclib
US approval5
2007
Bevacizumab
EU approval6
2020
1973
Tamoxifen EU
approval1
Clinical
development
of new targeted
therapies10
2012
Everolimus
US approval9
2011
Bevacizumab FDA
approval
withdrawn8
2008
Lapatinib
EU approval7
2017
Ribociclib
US approval5

04/15/2019 3
Clinical Cancer Advancement 2017

4
Overview of the CDK4/6 Inhibitor Palbociclib
• Orally active selective inhibitor of CDK4 and CDK6 kinases1,2
• Inhibits cell proliferation and cellular DNA synthesis by preventing
cell-cycle progression from G1 to S phase1
1. Fry DW, et al. Mol Cancer Ther 2004;3:1427–38
2. Menu E, et al. Cancer Res 2008;68:5519–23
3. Sutherland RL, Musgrove EA. Breast Cancer Res 2009;11:112
4. Van Arsdale T, et al. Clin Cancer Res 2015; Epub May 2
• In vitro activity in RB+ tumor cell lines and
primary tumors1
• Low nanomolar concentrations block
RB phosphorylation, inducing G1 arrest in
sensitive cell lines1
• Specific cell cycle arrest in G1 phase2,3
• Inhibits proliferation in cultured and
xenografted leukemia, myeloma, breast cancer,
colon cancer, and lung cancer cells4
Palbociclib
(PD-0332991)
N
N O
N
N
H
O
N
N
N
H2
+
S
O
O
O
OH

• Post-menopausal
• ER+, HER2– advanced breast cancer
• CCND1 amplification and/or loss of p16 (part 2 only)
• No prior treatment for advanced disease
Phase II and III Studies of Palbociclib in Endocrine-sensitive Metastatic Breast
Cancer
Phase II, PALOMA-1/TRIO 18 (1003)1
N=650
Placebo
(3/1 schedule)
+ letrozole
(2.5 mg QD)
Palbociclib (125 mg QD, 3/1 schedule)
+ letrozole
(2.5 mg QD)
Phase III, PALOMA-2
(1008)2,3
2:1
N=165
Placebo
(3/1 schedule)
+ letrozole
(2.5 mg QD)
+ letrozole
(2.5 mg QD)
1:1
RANDOMIZATION
Primary endpoint: PFS
Secondary/
exploratory endpoints:
response, OS, safety,
biomarkers, patient-
reported outcomes
Stratification factors:
both studies: disease
site, disease-free
interval; PALOMA 2
only: prior hormonal
therapy
• Post-menopausal
• ER+, HER2– advanced breast cancer
• No prior treatment for advanced disease
• AI-resistant patients excluded RANDOMIZATION
1. Finn RS, et al. Lancet Oncol 2015;16:25-35
2. clinicaltrials.govNCT01740427
3. Finn R, et al. NEJM 2016
AI, aromatase inhibitor; OS, overall survival

Phase III, PALOMA-3 (1023)1,2,4
N=348
Capecitabine
(1250 mg/m2 BID,
2/1 schedule)
+ exemestane
(25 mg QD)
• Post-menopausal
• HR+, HER2– metastatic breast cancer
• Resistant to non-steroidal AIs:
– Recurrence on or ≤12 months after end of adjuvant treatment with non-steroidal AI
– Progression on or ≤1 month after end of treatment with non-steroidal AI for advanced disease
Phase III, PEARL2,4
1:1
N=521
Placebo (3/1 schedule)
+ fulvestrant
(500 mg IM q4w)
2:1
RANDOMIZATION
Primary endpoint: PFS
Secondary/ exploratory
endpoints: response,
OS, safety, drug–drug
interactions,
biomarkers, patient-
reported outcomes
Stratification factors:
both studies: visceral
metastases, prior
sensitivity to hormonal
therapy; PALOMA 3
only: menopausal
status; PEARL only:
prior chemotherapy for
metastatic breast
cancer, country
IM, intramuscularly; q4w, every 4 weeks
aIn collaborationwith GEICAM (Spain)
Phase III Studies of Palbociclib in Endocrine-resistant Metastatic Breast
Cancer
RANDOMIZATION
+ fulvestrant
(500 mg IM q4w)
1. Turner NC, et al. N Engl J Med. 2015;373:209-219.
2. Cristofanilli M, et al, Lancet Oncology, 2016; Apr;17(4):425-39.
3. Martin M, et al. ASCO 2015 (Abstract TPS631)
4. clinicaltrials.gov NCT02028507
• HR+, HER2– metastatic breast cancer
• Premenopausal or post-menopausal
• Failure of prior hormonal treatment:
– Progressed within12 months after prior adjuvant therapy
– Progressed within1 month after prior advanced/metastatic endocrine therapy
• 1 prior chemotherapy regimen permitted

PALOMA-3: Study Design
aAll received goserelin
bMust have progressed on adjuvant tamoxifen or other prior endocrine therapy
(pre-/perimenopausal) or aromatase inhibitor therapy (postmenopausal)
cPatients randomised
dAdministered on days 1 and 15 of Cycle 1, then every 28 days
Data cut-off 5 December 2014 used for interim analysis; median follow-up 5.6 months
Data cut-off 16 March 2015 used for final analysis; median follow-up 8.9 months
Phase 3, double-blind study involving 144 centers in 17 countries (NCT01942135)
Placebo
(3 wks on/1 wk off)
+
Fulvestrantd
(500 mg IM q4w)
Palbociclib
(125 mg QD;
3 wks on/1 wk off)
+
Fulvestrantd
(500 mg IM q4w)
• Visceral metastases
• Sensitivity to prior hormonal
therapy
• Pre-/peri- vs post-
menopausal
2:1 Randomization
N=521c
Stratification:
• HR+, HER2- MBC
• Pre/perimenopausala,b or postmenopausalb
• Progressed on prior endocrine therapy:
– On or within 12 months of completion of adjuvant treatment
– On or within 1 month after treatment for MBC
• ≤1 prior chemotherapy regimen for advanced cancer
n=347
n=174
Turner NC, et al. N Engl J Med. 2015;373:209-219
Cristofanilli M, et al. Lancet Oncol 2016 [Published online
2 March 2016; http://dx.doi.org/10.1016/S1470-2045(15)00613-0]

PALOMA-3: Study Endpoints
• Primary endpoint
- Progression-free survival (PFS) by investigator assessment
• Secondary endpoints
- Overall survival
- Survival probability at 1, 2, and 3 years
- Objective response and duration of response
- Rate of clinical benefit (clinical benefit response)
- Pharmacokinetics
- Safety and tolerability
- Tumor tissue biomarkers (i.e. PIK3CA mutation status, quantitative
expression of estrogen and progesterone receptors)
- Patient-reported outcomes
Turner NC, et al. N Engl J Med. 2015;373:209-219

PALOMA-3: Analyses
• Interim analysis
- Planned after ~60% of PFS events; prespecified early stop: Haybittle-
Peto efficacy boundary (1-sided  = 0.00135)
- This was conducted with 195 events at the data cut-off of 5 December
2014 (median follow-up 5.6 months); independent data
and safety monitoring committee (IDMC) recommended early stop to
study in April 2015 1
• Blinded independent central review (BICR)
- PFS assessed by third-party core imaging laboratory in a randomly
selected sample of patients (~40%) in a BICR audit approach
• Final analysis
- Conducted with 259 events at the data cut-off of 16 March 2015
(median follow-up 8.9 months) 2
1. Turner NC, et al. N Engl J Med. 2015;373:209-219
2. Cristofanilli M, et al. Lancet Oncol 2016 [Published online

Characteristic
Intention-to-treat population
Palbociclib + fulvestrant
(n=347) Placebo + fulvestrant (n=174)
Median age, years (range) 57 (30−88) 56 (29−80)
Self-reported race, n (%)
White 252 (73) 133 (76)
Asian 74 (21) 31 (18)
Black or other 21 (6) 10 (6)
ECOG performance status, n (%)
0 206 (59) 116 (67)
1 141 (41) 58 (33)
Menopausal status, n (%)
Pre- or perimenopausal 72 (21) 36 (21)
Postmenopausal 275 (79) 138 (79)
Non-measurable disease, n (%)
Bone 75 (22) 36 (21)
Others 4 (1) 0
Measurable disease, n (%)
Any measurable disease 268 (77) 138 (79)
Visceral diseasea 206 (59) 105 (60)
Lung involvement 100 (29) 45 (26)
Liver involvement 127 (37) 81 (47)
Peritoneal involvement 2 (1) 1 (1)
Brain or pleural involvement, or both 4 (1) 2 (1)
PALOMA-3 Final Analysis: ITT Population Clinical and
Pathological Characteristics (1)
aPer protocol, visceral refers to lung, liver, brain, pleural and peritonealinvolvement, and was a study stratification factor
11

Characteristic
(n=347)
Placebo + fulvestrant (n=174)
Number of previous lines of endocrine treatment, n
(%)
1 160 (46) 91 (52)
2 140 (40) 61 (35)
≥3 47 (14) 22 (13)
Purpose of most recent treatmenta, n (%)
Adjuvant therapy 74 (21) 40 (23)
Treatment of advanced or metastatic breast
cancer 273 (79) 133 (76)
Disease-free intervalb, n (%)
Data available 233 (67) 123 (71)
>24 months 192 (82) 101 (82)
12–24 months 30 (13) 19 (15)
<12 months 11 (5) 3 (2)
Previous chemotherapy, n (%)
Neoadjuvant or adjuvant therapy onlyc 139 (40) 74 (43)
Treatment of metastatic disease (with or without
adjuvant or neoadjuvant)
113 (33) 64 (37)
aData were unavailablefor one patient in the intention-to-treatplacebo + fulvestrant group
bDefined as time from diagnosis of primarybreast cancer to first relapse in patients who received adjuvant therapy. Data were availableonly for patients who were
initiallydiagnosed with early breast cancer and then experienceddisease relapse; % are calculatedon the basis of the availabledata
cPatients did not receive chemotherapyin the context of metastatic disease
12

Characteristic
Palbociclib + fulvestrant (n=347) Placebo + fulvestrant (n=174)
Previous endocrine therapy, n (%)
Aromatase inhibitors 137 (39) 70 (40)
Tamoxifen 51 (15) 23 (13)
Aromatase inhibitors and tamoxifen 159 (46) 81 (47)
Previous sensitivity to endocrine therapya, n (%)
Yes 274 (79) 136 (78)
No 73 (21) 38 (22)
ER or PR status confirmed by central laboratory testing, n (%)
ER+ and PR+
≥Median of distribution 81 (23) 40 (23)
<Median of distribution 71 (20) 29 (17)
ER+ or PR+
≥Median of distribution 179 (52) 100 (57)
<Median of distribution 165 (48) 90 (52)
Central laboratory tested, median H-score (IQR);
mean (SD)b, n (%)
ER 110 (40–160);
107 (74)
114 (23–150);
99 (72)
PR
10 (0–100);
53 (68)
20 (0–100);
51 (62)
aPrevious sensitivity to endocrine therapy was based on randomisation
bFor classificationof receptor status (≥median of distribution,<median of distribution)the H-score was used. The median was calculated on the basis of the
number of patients who were tested by the central laboratory(250 patients in the palbociclib+ fulvestrantgroup and 130 patients in the placebo + fulvestrant
group)
13

14
PALOMA-3 Final Analysis: Treatment Summary
Treatment summary (AT population)
Palbociclib +
fulvestrant
(n=345)
Placebo +
fulvestrant
(n=172)
Dose interruption due to an AE, n (%) 187 (54) 10 (6)
Cycle delay, n (%) 123 (36) 3 (2)
Dose reductions, n (%) 117 (34) 3 (2)
Discontinuation due to AEs, n (%) 14 (4) 3 (2)
AE: adverse event; AT: as treated
• The rate of treatment discontinuation due to AEs in the palbociclib + fulvestrant group (4%) is lower
than that associated with other therapies approved for this patient population
14

PALOMA-3: Time of Onset for First and Second Dose Reductions,
Time to Dose Interruptions and Dose Delay
Verma S, et al. Oncologist. 2016 Oct;21(10):1165-1175.
*for any reasons.
†due to adverse events.
Data cut-off16 March 2015 used for final analysis; median follow-up 8.9 months
2 dose reduct i
ons
(n=22)
1 dose reduct i
on
(n=95)
Dose Interrupt i
on
(n=187†)
Dose Delay
(n=123†)
0% 10% 20% 30% 40% 50% 60%
6%
28%
54%
36%
Percent
• Time to dose reduction (125 →100):
−57 days (range: 27-293)
• Time to dose reduction (125→75):
−36 days (range: 29-85)
• Time to dose reduction (125 →100):
−34 days (range: 27-142)
• Time to dose reduction from (125→ 75):
−120 days (range: 56-392)
• Time to first dose delay† :
−64 days (range: 31-349)
• Average duration of dose delay† :
−3 days (range: 2-16)
• Time to first dose interruption*:
−18 days (range: 1-482)
• Average duration of interruption for any
reason:
−6 days (range: 1-20)

PALOMA-3 Final Analysis: Investigator-Assessed PFS (ITT Population)
PAL + FUL
(n=347)
PLACEBO + FUL
(n=174)
Median PFS, mos (95% CI) 9.5 (9.2─11.0) 4.6 (3.5─5.6)
HR (95% CI) 0.46 (0.36─0.59)
P value <0.0001
PFS
(%)
Time (months)
0
10
20
30
40
50
60
70
80
90
100
0 1 2 3 4 5 6 7 8 9 10 15
11 12 13 14
Placebo + fulvestrant
347 333 281 273 247 244 202 197 91 85 32 0
23 7 7 1
174 165 112 105 83 80 59 58 22 22 13 0
7 2 1 0
Number at risk

PALOMA-3: Updated Independent Review Committee PFS
Cristofanilli M, et al. Presented at SABCS 2015;
San Antonio, Texas, USA (Poster 4-13-01)
0
10
20
30
40
50
60
70
80
90
100
PFS
probability
(%)
Time (months)
0 1 2 3 4 5 6 7 8 9 10 15
Placebo +fulvestrant
11 12 13 14
PAL + FUL
(n=147)
PLACEBO + FUL
(n=64)
Median PFS, mos (95% CI) NE 3.8 (3.4, 9.3)
HR (95% CI) 0.37 (0.23, 0.59)
P value <0.0001

PALOMA-3 Final Analysis: PFS in Patients with No Prior Systemic Therapy
for MBC
PFS, progression-free survival; HR, hazard ratio; CI, confidenceinterval
PAL + FUL
(n=74)
PLACEBO + FUL
(n=40)
Median PFS, mos (95% CI) 9.5 (7.4–NE) 5.4 (2.1–10.9)
HR (95% CI) 0.55 (0.32–0.92)
P value 0.02
PFS
(%)
Time (months)
0
10
20
30
40
50
60
70
80
90
100
0 1 2 3 4 5 6 7 8 9 10 15
11 12 13 14
74 70 59 57 53 52 45 45 18 18 8 0
7 1 1 0
40 36 25 24 19 18 13 13 6 6 5 0
2 0 0 0
Number at risk

PALOMA-3 Final Analysis: PFS in Patients who Received ≥1 Previous Systemic
Therapy for MBC
PAL + FUL
(n=273)
PLACEBO + FUL
(n=134)
Median PFS, mos (95% CI) 9.9 (9.2–11.2) 4.2 (3.5–5.6)
HR (95% CI) 0.43 (0.33–0.57)
P value <0.0001
PFS
(%)
Time (months)
0
10
20
30
40
50
60
70
80
90
100
0 1 2 3 4 5 6 7 8 9 10 15
11 12 13 14
273 263 222 216 194 192 157 152 73 67 24 0
16 6 6 1
134 129 87 81 64 62 46 45 16 16 8 0
5 2 1 0
Number at risk

PALOMA-3: PFS in Patients with Prior Response to Endocrine Therapy
Data cut-off5 December 2014 used for interim analysis; median follow-up5.6 months
Data cut-off16 March 2015 used for final analysis; median follow-up 8.9 months
0
10
20
30
40
50
60
70
80
90
100
PFS
probability
(%)
Time (months)
0 1 2 3 4 5 6 7 8 9 10 15
Palbociclib + Fulvestrant
Placebo + Fulvestrant
11 12 13 14
PAL + FUL
(n=274)
PLACEBO + FUL
(n=136)
Median PFS, mos (95% CI) 10.2 (9.4–11.2) 4.2 (3.5–5.6)
HR (95% CI) 0.42 (0.32–0.56)
P value <0.0001

PALOMA-3: PFS in Patients Previously Treated with an Aromatase
Inhibitor
0
10
20
30
40
50
60
70
80
90
100
PFS
probability
(%)
Time (months)
0 1 2 3 4 5 6 7 8 9 10 15
11 12 13 14
PAL + FUL
(n=237)
PLACEBO + FUL
(n=119)
Median PFS, mos (95% CI) 9.5 (9.2–11.0) 3.7 (3.4–5.5)
HR (95% CI) 0.42 (0.31–0.56)
P value <0.0001

23
PALOMA-3 Final Analysis: Response Rates
Palbociclib + fulvestrant resulted in a statistically significant i
• ORR in ITT (19% vs 9%, respectively) and in patients with
• CBR in ITT (67% vs 40%) and in patients with measurable
(64% vs 36%)
Population: Intent-to-treat Measurable disease Intent-to-treat Measurable disease
Odds ratio
(95% CI)
2.47
(1.36–4.91)
2.69
(1.43–5.26)
3.05
(2.07–4.61)
3.10
(1.99–4.92)
60
50
40
30
20
10
0 Measurable
disease
Measurable
disease
Intent-to-
treat
P<0.0001
*
P=0.0019*
P=0.0012*
ORR
Intent-to-treat
CBR
P<0.0001*
Patients
(%)
70
P
R
C
R
S
D
P
R
C
R
S
D
* Two-sided exact tests stratified by the presence of visceral metastases and sensitivity
to previous hormonal therapy as per randomisationwere used to calculatep values.
ORR, objective response rate; CBR, clinicalbenefit rate; PR, partial response;
CR, completeresponse; SD, stable disease; ITT; intent-to-treat
19%
9%
25%
11%
67%
40%
64%
36%
23

PFS by menopausal status
Premenopausal
Post-
menopausal
Loiby et al., Oncologist 2017 (in
press)

PALOMA-3 Final Analysis: Response Rates in
Premenopausal women
Loiby et al., Oncologist 2017 (in
press)

Biomarkers analysis in
PALOMA-3
04/15/2019

PALOMA-3 Final Analysis: Treatment Effect by ER and PR Expression
Level
CristofanilliM, et al. Lancet Oncol 2016 [Published online
STEPP analysis to evaluate centrally assessed
ER-positive and PR-positive expression levels
Subpopulations by median progesterone-receptor H-score
HR
0.010.0 57.5 120.0 170.0
0
0.4
0.8
1.2
1.6
2.0
2.4
2.8
Subpremium HR p=0.54
131 91 94 93 53
No of patients
Subpopulations by median estrogen-receptor H-score
HR
Subpremium HR p=0.32
95 91 93 51
No of patients 92 95
0 1 50 170 215
0
0.4
0.8
1.2
1.6
2.0
2.4
2.8
140
100
• Tumor hormone receptor
expression was quantified by the
central laboratory in 250
patients
in the palbociclib + fulvestrant
group and 130 patients in the
placebo + fulvestrant group
─ Around 60% of patients in
each group provided
metastatic tissue samples
• ER and PR expression was measurable
by IHC using H-Score
• The level of hormone receptor
expression did not influence the
magnitude of PFS benefit from
palbociclib (subpremium
interaction p=0.32 for ER and
p=0.54 for PR)
ER, estrogen receptor; PR, progesterone receptor; STEPP,
subpopulation treatmenteffect pattern plot; HR, hazard ratio;
CI , confidence interval; IHC, immunohistochemistry
95% point-wise CI
HR by median ER H-score
Reference HR of 1
95% point-wise CI
HR by median PR H-score
Reference HR of 1

PIK3CA Mutation in Breast Cancer
Kalinsky K et al. Clin Cancer Res. 2009 Aug 15;15(16):5049-59.
 590 patients with primary invasive
breast cancers were assessed for
PIK3CA mutation by using
Sequenom MassARRAY
 PIK3CA mutations detected in192/590
tumor tissue = 32.5%
Gene Exon Nucleotide
Position
Nucleotide
Change
Codon
Position
Amino Acid
Change
PIK3CA 9 1624 G>A 542 E542K
PIK3CA 9 1633 G>A 545 E545K
PIK3CA 20 3140 A>G 1047 H1047R
PIK3CA 20 3140 A>T 1047 H1047L
Inostics cfDNA PIK3CA Mutation Panel
Non-QC data

PALOMA-3 Final Analysis: PFS in Patients by
PIK3CA Status (1)
•PIK3CA mutations were detected in 33% of patients who provided baseline plasma samples for
cell-free DNA (cfDNA) analysis (129/395)
• Median PFS was 5.8 months (95% CI 5.3–9.5) in patients with detectable PIK3CA mutations and
9.2 months (95% CI 7.5–10.8) in PIK3CA-negative patients (HR 1·26, 95% CI 0·94–1·68; p=0·94)
Time (months)
0 1 2 3 4 5 6 7 8 9 10 14
11 12 13
PFS
(%)
0
10
20
30
40
50
60
70
80
90
100
Negative
Positive
Number at risk
266 253 201 193 168 167 143 140 71 68 27 0
16 4 4
129 126 95 91 76 75 56 56 27 27 13 0
11 3 3
Number at risk
PIK3CA positive
PIK3CA negative
PIK3CA–
(n=266) PIK3CA+ (n=129)
Median PFS, mos (95% CI) 9.2 (7.5–10.8) 5.8 (5.3–9.5)
HR (95% CI) 1.26 (0.94─1.68)
P value 0.94

Characteristic
PIK3CA mutation analysis set
Palbociclib + fulvestrant Placebo + fulvestrant
PIK3CA positive
(n=85)
PIK3CA negative
(n=180)
PIK3CA positive
(n=44)
PIK3CA negative
(n=86)
Number of previous lines of endocrine
treatment, n (%)
1 33 (39) 73 (41) 24 (55) 46 (53)
2 19 (22) 42 (23) 4 (9) 13 (15)
≥3 13 (15) 14 (8) 6 (14) 5 (6)
Purpose of most recent treatmenta, n (%)
Adjuvant therapy 18 (21) 41 (23) 9 (20) 18 (21)
Treatment of advanced or metastatic breast
cancer 67 (79) 139 (77) 35 (80) 68 (79)
Disease-free intervalb, n (%)
Data available 56 (66) 129 (72) 32 (73) 58 (67)
>24 months 46 (82) 106 (82) 28 (88) 46 (79)
12–24 months 4 (7) 19 (15) 3 (9) 12 (21)
<12 months 6 (11) 4 (3) 1 (3) 0 (0)
Previous chemotherapy, n (%)
Neoadjuvant or adjuvant therapy onlyc 34 (40) 82 (46) 19 (43) 32 (37)
Treatment of metastatic disease (with or
without adjuvant or neoadjuvant) 23 (27) 54 (30) 15 (34) 30 (35)
PALOMA-3 Final Analysis: Patient Clinical and Pathological
Characteristics by PIK3CA Status (2)
aData were unavailablefor one patient in the intention-to-treatplacebo + fulvestrant group
bDefined as time from diagnosis of primarybreast cancer to first relapse in patients who received adjuvant therapy. Data were availableonly for patients who were
initiallydiagnosed with early breast cancer and then experienceddisease relapse; % are calculatedon the basis of the availabledata
cPatients did not receive chemotherapyin the context of metastatic disease
30

Characteristic
PIK3CA mutation analysis set
Palbociclib + fulvestrant Placebo + fulvestrant
PIK3CA positive
(n=85)
PIK3CA negative
(n=180)
PIK3CA positive
(n=44)
PIK3CA negative
(n=86)
Previous endocrine therapy, n (%)
Aromatase inhibitors 30 (35) 73 (41) 15 (34) 35 (41)
Tamoxifen 9 (11) 26 (14) 5 (11) 12 (14)
Aromatase inhibitors and tamoxifen 46 (54) 81 (45) 24 (55) 39 (45)
Previous sensitivity to endocrine therapya, n (%)
Yes 69 (81) 146 (81) 38 (86) 67 (78)
No 16 (19) 34 (19) 6 (14) 19 (22)
ER or PR status confirmed by central laboratory
testing, n (%)
ER+ and PR+
≥Median of distribution 17 (20) 44 (24) 13 (30) 19 (22)
<Median of distribution 16 (19) 38 (21) 4 (9) 18 (21)
ER+ or PR+
≥Median of distribution 48 (56) 88 (49) 29 (66) 48 (56)
<Median of distribution 46 (54) 80 (44) 20 (45) 48 (56)
Central laboratory tested, median H-score (IQR);
mean (SD)b, n (%)
ER 95 (30–145);
96 (68)
118 (43–170);
111 (77)
130 (60–160);
112 (74)
100 (10–145);
94 (74)
PR
21 (0–110);
58 (68)
10 (0–110);
56 (72)
50 (2–80);
53 (51)
10 (0–100);
52 (67)
PALOMA-3 Final Analysis: Patient Clinical and Pathological
Characteristics by PIK3CA Status (3)
aPrevious sensitivity to endocrine therapy was based on randomisation
bFor classificationof receptor status (≥median of distribution,<median of distribution)the H-score was used. The median was calculated on the basis of the number of patients
who were tested by the central laboratory(250 patients in the palbociclib+ fulvestrant group and 130 patients in the placebo + fulvestrant group)
31

PALOMA-3 Final Analysis: PFS in Patients by
PIK3CA Status (2)
PIK3CA-wild-type patients (n=266) Patients with PIK3CA mutations (n=129)
• PIK3CA status did not influence the magnitude of PFS benefit from palbociclib
(HR=0·45 for PIK3CA wild-type, HR=0·48 for PIK3CA mutation positive, Pinteraction = 0·83)
Time (months)
PFS
(%)
0 1 2 3 4 5 6 7 8 9 10 11 12 13 14
0
20
40
60
80
100
180 173 146 141 129 129 112 110 56 53 17 11 4 4 0
86 80 55 52 39 38 31 30 15 15 10 5 0 0 0
Number at risk
Palbociclib + fulvestrant(n=180)
Time (months)
PFS
(%)
0 1 2 3 4 5 6 7 8 9 10 11 12 13 14
0
20
40
60
80
100
85 82 67 64 56 55 44 44 23 23 12 10 2 2 0
44 44 28 27 20 20 12 12 4 4 1 1 1 1 0
Number at risk
Palbociclib + fulvestrant(n=85)
PAL + FUL
(n=180 )
PLACEBO + FUL
(n=86)
Median PFS,
mos (95% CI) 9.9 (9.2–13.9) 4.6 (3.4–7.3)
HR (95% CI) 0.45 (0.31–0.64)
P value <0.0001
PAL + FUL
(n=85 )
PLACEBO + FUL
(n=44)
Median PFS,
mos (95% CI) 9.5 (5.7–11.2) 3.6 (1.9–5.6)
HR (95% CI) 0.48 (0.30–0.78)
P value 0.002

PALOMA-3 Final Analysis: PFS by Patient Subgroup (1)
PFS, progression-free survival; CI, confidence interval. Full data presented in:
Palbociclib +
fulvestrant
median PFS (95%CI)
Placebo +
fulvestrant
median PFS (95%CI)
Hazard ratio
(95% CI) Pinteraction
Menopausal status at
study entry 0.89
Premenopausal or
perimenopausal 9.5 (7.4–NE) 5.6 (1.8–7.6) 0.50 (0.29–0.87)
Postmenopausal 9.9 (8.5–11.0) 3.9 (3.5–5.5) 0.45 (0.34–0.59)
Site of metastatic disease 0.82
Visceral 8.0 (7.5–9.5) 3.5 (2.0–5.3) 0.47 (0.34–0.63)
Non-visceral 11.2 (9.9–NE) 5.6 (4.6–10.9) 0.43 (0.28–0.67)
Number of disease sites 0.43
1 11.2 (9.9–NE) 9.3 (5.5–NE) 0.55 (0.34–0.90)
2 11.0 (7.5–NE) 3.6 (1.9–5.6) 0.37 (0.24–0.59)
≥3 7.6 (7.4–9.5) 3.4 (1.9–3.7) 0.40 (0.28–0.59)
Disease-free interval 0.16
≤24 months 7.2 (2.5–9.2) 5.4 (1.8–9.3) 0.83 (0.43–1.59)
>24 months 9.9 (9.3–11.2) 5.5 (3.5–7.3) 0.48 (0.35–0.68)
Favours
palbociclib plus
fulvestrant
Favours
placebo plus
fulvestrant
0.125 0.250.5 1 2 4 8

PALOMA-3 Final Analysis: PFS by Patient Subgroup (2)
PFS, progression-free survival; CI, confidence interval. Full data presented in:
Palbociclib +
fulvestrant
median PFS
(95%CI)
Placebo +
fulvestrant
median PFS (95%CI)
Hazard ratio
(95% CI) Pinteraction
Sensitivity to previous
hormonal therapy 0.13
Yes 10.2 (9.4–11.2) 4.2 (3.5–5.6) 0.42 (0.32–0.56)
No 7.4 (5.6–9.2) 5.4 (1.9–7.4) 0.64 (0.39–1.07)
The purpose of most recent
therapy 0.39
Neoadjuvant or adjuvant
treatment 9.5 (7.4–NE) 5.4 (2.1–10.9) 0.55 (0.32–0.92)
Metastatic treatment 9.9 (9.2–11.2) 3.9 (3.5–5.6) 0.43 (0.32–0.57)
Previous chemotherapy 0.22
Neoadjuvant or adjuvant
treatment only 11.0 (7.6–NE) 5.6 (3.5–9.3) 0.60 (0.40–0.88)
Metastatic treatment 7.7 (5.7–9.5) 3.5 (1.9–5.4) 0.43 (0.29–0.64)
None 10.8 (9.5–NE) 5.4 (3.4–7.3) 0.31 (0.18–0.53)
PIK3CA status 0.83
Positive 9.5 (5.7–11.2) 3.6 (1.9–5.6) 0.48 (0.30–0.78)
Favours
palbociclib plus
fulvestrant
Favours
placebo plus
fulvestrant
0.125 0.250.5 1 2 4 8

ESR1 Mutation Background
Genomic Alterations in ER+ Tumors
40
35
30
25
20
15
10
5
0
Alteration
Percentage
TP53
PIK3CA
CCND1
MCL1
MYC
FGFR1
ESR1
ERBB2
AKT1
NF1
PTEN
Primary
Metastasis
P<0.05
ESR1 mutations occur in ~20% of AI-resistant,
ER+ breast cancer
Toy et al. Nat Genet, 2013.
Robinson et al. Nat Genet, 2013.
Merenbakh-Lamin et al. Cancer Res,
2013.
Jeselsohn et al. Clin Cancer Res, 2014.
Jeselsohn et al. Nat Rev Clin Oncol,
2015.
AI=aromatase inhibitor; ER=estrogen receptor.

ESR1 Mutations in PALOMA3
D538G
Y537S
Y537N
Y537C
L536R
L536Q
L536H
L536P
S463P
E380Q
0 10 20
14.3
7.2
4.2
1.9
1.1
1.5
3.8
1.5
1.5
6
13.7
7.6
5.3
2.3
1.5
1.5
2.3
2.3
2.3
12.2
14.1
7.3
4.5
2
1.3
1.5
3.3
1.8
1.8
8.1
Column2
Pat i
ents (%)
ESR1
Amino
Acid
Change
• ESR1 mutations were
detected in 27% (106/396) of
patients with plasma samples
• Amino acid changes
P535H and V534E were
not detected
• ESR1 mutations were
polyclonal in 38% (40/106) of
mutation-positive patients

Prior Endocrine Therapy and Selection of ESR1
mutation
P
r
i
o
.
.
.
P
r
i
o
r
.
.
.
P
r
i
o
r
A
I
.
.
.
0
5
10
15
20
25
30
35
40
29.4
0
32.1
Pat
i
e
nts
with
ESR1
Mutat
i
o
AI=aromatase inhibitor; TAM=tamoxifen.
0
Prior
AI
Prior AI
and Tam
Prior
Tam
Prior Endocrine Therapy
P
r
i
o
r
S
e
n
s
E
T
N
o
p
r
i
o
r
s
e
n
s
t
o
E
T
P
r
i
o
r
S
e
n
s
A
I
N
o
P
r
i
o
r
S
e
n
s
A
I
0
10
20
30
40
30.3
12.8
Yes No
Sensitive to Prior
Endocrine Therapy
Yes No
Sensitive to Prior AI
Patients
with
ESR1
Mutation
(%)
Turner NC, et al. J Clin Oncol 2016;34(Suppl.) (Abstract 512)

PFS in All Patients
PFS
(%)
Time (months)
0
20
40
60
80
100
0 1 2 3 4 5 6 7 8 9 10 11 12 13 14
ESR1 Negative
median PFS 9.2 mo (95% CI: 7.5–10.9)
ESR1 Positive
median PFS 5.7 mo (95% CI: 3.7–9.4)
HR 1.334 (95% CI: 0.99–1.80)
P=0.0572
289 277 220 212 186 186 153 150 70 68 28 17 5 5 0
106 102 76 72 58 56 46 46 28 27 12 10 2 2 0
Negative
Number at risk:
PFS=progression-free survival.

Chadarlapaty S, et al. JAMA. 2016;2:1310-1
Copyright © 2016 American Medical Association. All right
BOLERO-2 Secondary Analysis: ESR1
Mutations Prevalence in Cell-Free DNA
Superior overall survival in patients
without mutation in ESR1 compared with
D538G and/or Y537S mutation.
Overall survival results are shown for WT
or D538G alone or Y537S alone or both
D538G and Y537S (double mutation).

PFS by ESR1 Mutation Status
ESR1 positive
0
20
40
60
80
100
0 1 2 3 4 5 6 7 8 9 10 11 12 13 14
PFS
(%)
Time (months)
median PFS 9.4 mo (95% CI: 4.1–11.2)
median PFS 4.1 mo (95% CI: 2.8–5.6)
HR 0.524 (95% CI: 0.32–0.87)
P=0.0052
67 65 49 47 39 38 35 35 23 22 10 9 1 1 0
39 37 27 25 19 18 11 11 5 5 2 1 1 1 0
Palbociclib +
Fulvestrant
Placebo +
Fulvestrant
Number at risk:
ESR1 negative
0
20
40
60
80
100
0 1 2 3 4 5 6 7 8 9 10 11 12 13 14
PFS
(%)
Time (months)
median PFS 9.5 mo (95% CI: 9.2–13.9)
median PFS 3.8 mo (95% CI: 3.4–7.4)
HR 0.438 (95% CI: 0.31–0.62)
P<0.0001
198 190 164 158 146 146 121 119 56 54 19 12 5 5 0
91 87 56 54 40 40 32 31 14 14 9 5 0
Palbociclib +
Fulvestrant
Placebo +
Fulvestrant
Number at risk:
PFS=progression-free survival. March 2015 final PFS data cut, Cristofanilli et al. Lancet Oncol, 2015.
Interaction P-values
P=0.1772 P=0.4877
Presented By Nicholas Turner at 2016 ASCO Annual Meeting

Turner N et al, SABC 2016
Treatment post-progression in women with Endocrine
Resistant HR+ Advanced Breast Cancer who recived
Fulvestrant-Palbociclib (PALOMA-3)
Updated PFS Time to next therapy

Pooled safety analysis long-term treatment
palbociclib-endocrine therapy

PALOMA-3 PRO Analysis: Global QoL – Results at Interim Analysis1
• A statistically significant difference was seen in overall change from baseline score for
global QoL with palbociclib + fulvestrant compared with placebo + fulvestrant (66.1
[95%CI 64.5–67.7] vs 63.0 [95%CI 60.6–65.3], respectively; p=0.0313)1,2
1. Harbeck N, et al. Presented at the European Cancer Congress 2015;
Vienna, Austria (P004); 2. Harbeck N, et al. Ann Oncol 2016
[Published online 30 March 2016; doi: 10.1093/annonc/mdw139].
CI, confidence interval; PRO, patient-reportedoutcome; QoL, quality of life
Global QoL: Baseline and overall scores on treatment by arm1
Baseline
0
65
60
70
Mean
Global
QoL
Score
65.9
65.3
66.1
63.0
*
Overall on
treatment
*p=0.0313 vs palbociclib + fulvestrant for
overall on-treatment score
Higher
Global
QOL

PALOMA-3 PRO Analysis: Functional Scales (QLQ-C30) – Results at
Interim Analysis1
CI, confidence interval; PRO, patient-reportedoutcome; QoL, quality of life
Estimated
Overall
Mean
Change
from
Baseline
Global
QoL
Physical
Functioning
Role
Functioning
Emotional
Functioning
Cognitive
Functioning
Social
Functioning
*
*
-10
0
10
5
-5
*Overallchange from baseline score between treatment groups statistically significant(p<0.05)
• Palbociclib + fulvestrant showed a significantly greater improvement from baseline compared with placebo + fulvestrant for
emotional functioning (2.7 [95% CI 1.1–4.3 vs −1.9 [95% CI −4.2–0.5]; p=0.0016)
Overall change from baseline EORTC QLQ-C30 scores for global QoL and functional scales
1. Harbeck N, et al. Ann Oncol 2016
[Published online 30 March 2016; doi: 10.1093/annonc/mdw139].
• Within a treatment arm, significant (based on interpretation from the 95% CIs) worsening from baseline was observed with
placebo + fulvestrant in role functioning, and for both treatment groups in cognitive functioning
Higher
level
of
functioning

CI, confidence interval; PRO, patient-reportedoutcome
PALOMA-3 PRO Analysis: QLQ-C30 Symptoms–
Results at Interim Analysis1
• Palbociclib + fulvestrant demonstrated a significant improvement from baseline in pain compared with placebo + fulvestrant
(−3.3 [95% CI −5.1−−1.5] vs 2.0 [95% CI −0.6–4.6]; p=0.0011)
• Significantly less deterioration from baseline in nausea and vomiting was seen with palbociclib + fulvestrant vs placebo +
fulvestrant (1.7 [95% CI 0.4–3.0] vs 4.2 [95% CI 2.3–6.1]; p=0.0369)
C30 Symptom Scales Estimate (95% CI)
Fatigue –1.5 (–4.5–1.5)
Nausea & vomiting (p=0.0369) –2.5 (–4.8––0.2)
Pain (p=0.0011) –5.3 (–8.5––2.1)
Dyspnea –0.5 (–3.7–2.8)
Insomnia –2.0 (–5.5–1.6)
Appetite loss –0.6 (–4.1–2.9)
Constipation 0.7 (–2.5–3.9)
Diarrhea –0.6 (–2.8–1.7)
Financial difficulties 0.3 (–3.1–3.6)
Favors placebo + fulvestrant
–10 –5 0 5 10 15 20
Estimate
Favors palbociclib + fulvestrant
Between-treatment comparison of changes in score from baseline (PRO analysis set)
1. Harbeck N, et al. Ann Oncol 2016 [Published online
30 March 2016; doi: 10.1093/annonc/mdw139].

PALOMA-3 PRO Analysis: Deterioration in QoL – Results at Interim
Analysis1
• A significantly greater delay in deterioration of QoL was observed in the palbociclib + fulvestrant group vs the
placebo + fulvestrant group (median not reached; HR 0.641; 95% CI 0.451–0.910;
1-sided p=0.0065)
1. Harbeck N, et al. Ann Oncol 2016 [Published online 30 March 2016; doi: 10.1093/annonc/mdw139].
CI, confidence interval; NE, not estimable; HR, hazard ratio; PRO, patient-reportedoutcome; TTD, time to deterioration
PALBOCICLIB +
FULVESTRANT (n=80)
PLACEBO + FULVESTRANT
(n=52)
Median TTD in QoL, mos (95%
CI) NE NE (5.7─NE)
HR (95% CI) 0.641 (0.451─0.910)
P value p=0.0065
Survival
distribution
function
Time to deterioration, mo
0
10
20
30
40
50
60
70
80
90
100
0 2 4 6 8 10 12 14
335 262 157 88 32 0
7 0
166 106 53 21 7 0
1 1
Number at risk
1. Harbeck N, et al. Ann Oncol 2016 [Published online
30 March 2016; doi: 10.1093/annonc/mdw139].

Palbociclib After CDK and Endocrine Therapy (PACE): A
Randomized Phase II Study of Fulvestrant, Palbociclib,
and Avelumab for Endocrine Pre-treated ER+/HER2-
Metastatic Breast Cancer
Palbociclib
+
Fulvestrant
+
Avelumab
Fulvestrantd
(500 mg IM q4w)
• Visceral metastases
• Sensitivity to prior hormonal
therapy
• Pre-/peri- vs post-menopausal
1:1 Randomization
N=222
Stratification:
• HR+, HER2- MBC
• Pre/perimenopausala,b or postmenopausalb
• Progression on AI + CDK4/6 inhibitor
• 0-1 prior chemo lines

Conclusions
• Palbociclib combined with fulvestrant improved PFS compared to placebo and fulvestrant in
women with HR+/HER2– advanced breast cancer whose disease had progressed on prior
endocrine therapy and benefit was demonstrated across pre-specified subgroups, including
pre-menopausal women.
• Palbociclib-Fulvestrant demonstrated activity in patients with PI3KCA or ESR1 mutations.
• Palbociclib demonstrated well tolerated, improved QOL and did not compromise further
therapeutic interventions.
• Treatment with the combination palbociclib significantly improved QOL in HR+ MBC
• Palbociclib in combination with fulvestrant represents a new standard of care for women
whose cancer progressed on prior endocrine therapy.

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