Joyce OShaughnessy MD Kimberly Blackwell MD Hope Rugo MD Reminder feedback is appreciated You will be prompted at the end for your feedback Updates on Chemotherapy and Other Novel Agents ID: 528833
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Slide1
Breast Cancer Highlights From San Antonio
Joyce O'Shaughnessy, MD
Kimberly Blackwell, MD
Hope
Rugo
, MDSlide2
Reminder: feedback is appreciated. You will be prompted at the end for your feedback.Slide3
Updates on Chemotherapy and Other Novel Agents
Joyce O'Shaughnessy, MDSlide4
Adjuvant ChemotherapySlide5
CALOR: Adjuvant Chemotherapy for Isolated Local or Regional Recurrence
Rationale:Isolated local or regional recurrence (ILRR) of breast cancer has a poor prognosis
No randomized studies of adjuvant chemotherapy for ILRR have been published in the last 30 years
Objective: Evaluate the effect of adjuvant chemotherapy on patients with ILRR
CALOR study design:
Chemotherapy chosen by investigators
Recommendation: at least 2 drugs, 3-6 months of therapy
Aebi
et al., SABCS 2012; abstract S3-2
Eligibility criteria:
First ILRR
Complete gross excision of recurrence
No evidence of positive
supraclavicular
LNsNo evidence of distant metastasis
Adjuvant chemotherapy
RANDOMIZE
(N=162)
No chemotherapy
+ Endocrine therapy for HR-positive disease+ HER2-directed therapy (optional)+ Radiation therapy (mandatory for those with positive margins)
Primary endpoint: DFS
Secondary endpoint: OSSlide6
CALOR: Adjuvant Chemotherapy for Isolated Local or Regional Recurrence
Sample size:Original target was 977 patients and HR = 0.74
Amended in 2008; target was 265 patients and HR = 0.60
Actual enrollment: 162 patients
Results:
Aebi
et al., SABCS 2012; abstract S3-2
Site of first failure (after ILRR)
Chemotherapy*
(n=85)
No chemotherapy*
(n=77)
Total failures
24
34
Local/regional
6 (25%)9 (26%)
Distant Soft tissue Bone Viscera
15 (63%)
08
722 (65%)2
5
15Contralateral breast
1 (4%)
1 (3%)
Secondary non-breast malignancy
1 (4%)
0Deaths without failure1 (4%)2 (6%)
* 42% of patients in the chemotherapy arm and 32% in the no-chemotherapy arm had not received previous chemotherapy. The median time from primary surgery to ILRR was 5 and 6 years, respectively.Slide7
CALOR: Adjuvant Chemotherapy for Isolated Local or Regional Recurrence
Efficacy results:
Multivariate analysis showed treatment (chemo/no chemo) to have significant impact on both DFS (HR = 0.50;
P
= .01) and OS (HR = 0.37;
P
= .02)
Aebi
et al., SABCS 2012; abstract S3-2
Survival
Chemotherapy
No chemotherapy
HR (95% CI)
P
-value
5-yr DFS ER-positive ER-negative
69%70%67%
57%
69%35%
0.59 (0.35-0.99)
0.94 (0.47-1.89)0.32 (0.14-0.73).046
.87
.0075-yr OS ER-positive
ER-negative
88%
94%
79%
76%80%69%0.41 (0.19-0.89)
0.40 (0.12-1.28)
0.43 (0.15-1.24)
.02
.12
.12Slide8
UK TACT2: Comparison of Standard vs Accelerated Epirubicin
in Early Breast Cancer
The objective was to test the following 2 hypotheses:
Acceleration of anthracycline chemotherapy offers improved efficacy (
these results presented here
)
Capecitabine has similar efficacy but less toxicity compared with CMF
UK TACT2 Phase III trial with 2x2 factorial study design:
Cameron et al., SABCS 2012; abstract S3-3
RANDOMIZATION
(N=4391)
CMF
600/40/600 mg/m
2
IV bolus, days 1 & 8
or 100/40/600 mg/m2 PO, days 1-14, for 4 cyclesCapecitabine (X)2500 mg/m2 bid, days 1-14, for 4 cycles
Standard
epirubicin (E) 100 mg/m2, q3w, for 4 cyclesfollowed by:
CMF
600/40/600 mg/m
2IV bolus, days 1 & 8 or 100/40/600 mg/m2 PO, days 1-14, for 4 cycles
Capecitabine (X)2500 mg/m
2 bid, days 1-14, for 4 cycles
Accelerated
epirubicin
(
aE
)100 mg/m2, q2w, for 4 cyclesPegfilgrastim 6 mg on day 2followed by:Primary endpoint: TTR (time to tumor recurrence)Secondary endpoints: DFS, OS, toxicity, QOLSlide9
UK TACT2: Comparison of Standard vs Accelerated Epirubicin
in Early Breast Cancer
Safety results:
Efficacy results:
There were 167 breast cancer deaths in the E arm and 179 in the
aE
arm
Cameron et al., SABCS 2012; abstract S3-3
Grade 3/4 AEs
Standard E
(n=2221)
Accelerated
E
(n=2170)
Hand-foot syndrome0%
0.9%Leukopenia3.8%
1.0%Neutropenia
16.4%1.7%
Febrile neutropenia3.6%
1.4%OutcomeStandard E
Accelerated E
HR (95% CI)P-value
3-year TTR
90.9%
91.0%
0.96
(0.81-1.13).605-year TTR85.2%86.4%
3-year OS95.4%
94.4%
1.13
(0.93-1.37)
.23
5-year OS
89.3%
88.6%Slide10
10-Year Follow Up of Intense Dose-Dense Chemotherapy vs. Conventional Chemotherapy in High-Risk Patients with ≥4 Positive LNs
Rationale: There are no published reports of long-term survival and toxicity data with dose-dense regimens
Objective:
Confirm the Norton-Simon hypothesis of dose density and evaluate the safety of
epoetin
alfa
as primary prophylaxis
Study design:
Moebus
et al., SABCS 2012; abstract S3-4
epirubicin
150 mg/m
2
q2w x 3
paclitaxel 225 mg/m
2
q2w x 3
cyclophosphamide
2500 mg/m
2
q2w x 3
+ tamoxifen
+ tamoxifen
EC 90/600 mg/m
2
q3w x 4
paclitaxel 175 mg/m
2
q3w x 4
G-CSF ±
epoetin
alfa
RANDOMI
ZE
(N=1284)
Primary endpoint: RFS
Secondary endpoint: OS, QOL, toxicitySlide11
10-Year Follow Up of Intense Dose-Dense Chemotherapy vs. Conventional Chemotherapy in High-Risk Patients with ≥4 Positive LNs
Efficacy results:
No therapy-related death or long-term toxicity was observed with
iddETC
Transfusion results:
Negative impacts of
epoetin
alfa
on RFS and OS were not observed
Moebus
et al., SABCS 2012; abstract S3-4
Outcome
IDD-ETC
EC→T
HR (95% CI)P-value10-yr RFS56%
47%0.74 (0.63-0.87)
.00014
10-yr OS 4-9 positive LNs
10+ positive LNs69%
74%62%59%66%48%0.72 (0.60-0.87)
0.77 (0.59-1.01)0.66 (0.51-0.86)
.0007.06
.0016
Transfusion-related
outcomes
IDD-ETC
(n=324)IDD-ETC + EPO(n=319)P
-valueMedian hemoglobin (g/dL
)
--
--
< .001 (favoring
+EPO arm)
Need for
≥1
transfusion
28%
13%
< .0001
Patients with venous thrombotic event
7%
13%
.029Slide12
BEATRICE: Phase III Trial of Adjuvant Bevacizumab in Triple-Negative Breast Cancer
Cameron et al., SABCS 2012; abstract S6-5
BEATRICE study design
Eligibility criteria:
Resected triple-negative (centrally confirmed) invasive early breast cancer
4-8 cycles of standard chemotherapy (investigator’s choice)
RANDOMI
ZE
(N=2591)
4-8 cycles of standard chemotherapy (investigator’s choice) + bevacizumab 5 mg/kg/wk equivalent for 1 year duration
Chemotherapy options:
Taxane-based (≥4 cycles)
Anthracycline-based (
≥4 cycles)
Anthracycline + taxane (3-4 cycles each)
Primary endpoint: DFS
Secondary endpoints: OS, breast cancer-free interval, DFS, distant DFS, safety, biomarkersSlide13
BEATRICE: Phase III Trial of Adjuvant Bevacizumab in Triple-Negative Breast Cancer
Cameron et al., SABCS 2012; abstract S6-5
Efficacy results
None of the subgroups examined (age, baseline ECOG performance status, region, race, menopausal status, tumor size, # of positive LNs, adjuvant chemotherapy, HR status, and surgery) showed a significant effect on invasive DFS
Safety results
Outcome
Chemo alone
(n=1290)
Chemo + bevacizumab
(n=1301)
HR (95%CI)
P
-value
3-yr invasive DFS
82.7%
83.7%
0.87 (0.72-1.07)
.18
OS
--
--
0.84 (0.64-1.12)
.23
Adverse events
Chemo alone
(n=1271)
Chemo + bevacizumab
(n=1288)
Any AE
Grade ≥3 AE
Grade 5 AE
99%
57%
0.2%
99%
72%
0.3%
AE leading to chemo and/or
bev
discontinuation
AE leading to
bev
discontinuation
2%
--
20%
18%Slide14
BEATRICE: Phase III Trial of Adjuvant Bevacizumab in Triple-Negative Breast Cancer
Cameron et al., SABCS 2012; abstract S6-5
Grade ≥3 AEs
of special interest by treatment phase
5%-8% of patients taking bevacizumab + an anthracycline-based regimen experienced an LVEF decline, and ~1% experienced class III/IV CHF. Over 80% of these AEs resolved at the time of data cut-off
Adverse events
Chemotherapy
phase
Observation/
bev
only phase
Chemo
Chemo +
bev
Chemo
Chemo +
bev
All grade ≥3 AEs of special interest
3%
11%
<1%
9%
Arterial thrombotic event
<1%
<1%
<1%
<1%
Venous thromboembolic event
1%
2%
<1%
<1%
Bleeding
<1%
<1%
<1%
0
CHF/left ventricular dysfunction
<1%
<1%
<1%
2%
Hypertension
<1%
7%
<1%
5%
Fistula/abscess
<1%
0
0
<1%
Gastrointestinal
perforation
0
<1%
0
0
Proteinuria
<1%
<1%
0
2%
RPLS
0
<1%
0
<1%
Wound-healing complication
<1%
<1%
0
<1%Slide15
BEATRICE Trial: Biomarker Results
Baseline Plasma Concentration
HR*
P
-Value
Median VEGF-A
High
0.81
.7415
Low
0.89
3
rd Quartile VEGF-A
High
0.64.3551
Low0.92Median VEGFR-2High.61.0291Low1.24 Biomarker analysis performed to investigate potential predictive markers of benefit from adjuvant bevacizumab
Sub-study included 45% of total patient population Evaluated correlation of biomarkers with invasive disease-free survival
* HR <1.0 indicates CT plus Bev better than CT alone
Carmeliet et al., SABCS 2012; abstract P3-06-34Slide16
NCCN Analysis of Leukemia Diagnoses in Breast Cancer Patients
Rationale:
Adjuvant therapy provides great benefit but also infrequently causes leukemia
Objective:
Examine the incidence of leukemia among breast cancer survivors
Identify clinical characteristics of women with breast cancer who develop leukemia
Karp et al., SABCS 2012; abstract S3-5
Prior history of cancer
n=1715
First diagnosis of breast cancer
n=20,533
Stage I-III breast cancer diagnosis at NCCN (July 1997 – Dec 2008)
N=22,248
Died while being followed at NCCN
n=455
Patients with leukemia
n=51; 0.25%
Censored at first date of other cancer event
n=3935
Censored at date of last NCCN contactn=16092
Patients without leukemia, n=20,482
excludedSlide17
NCCN Analysis of Leukemia Diagnoses in Breast Cancer Patients
Karp et al., SABCS 2012; abstract S3-5
Patient characteristic
No
leukemia
(n=20,482)
Leukemia
(n=51)
P
-value
Median age
53.9 years
60.2 years
.02
Race
White
African American
Other87%8%
5%92%
6%2%
.72Surgery Breast conservation Mastectomy None
57%
42%1%
55%
45%
0
.85
Radiation therapy After breast conservation or none After mastectomy None54%17%
29%55%
24%
22%
.32
Chemotherapy “A and/ or C”*
4 cycles
6 cycles
None
or endocrine therapy only
51%
11%
38%
61%
12%
27%
.31
Local and systemic therapy
Radiation but no chemotherapy
Chemotherapy but no radiation
Chemotherapy and radiation
None
25%
16%
46%
13%
24%
18%
55%
4%
.22
*Chemotherapy Regimens Included:
4 Cycles: AC or EC, FA
50
C or FE
100
C, TC
6 Cycles: CMF, CAF, TAC, FA
50
C or FE
100
CSlide18
Characteristics of leukemia cohort:
Hazard ratios
for risk of developing leukemia:
Incidence of developing leukemia:
0.32% at 5 years
0.52% at 10 years
Karp et al., SABCS 2012; abstract S3-5
Event
n
Median time to leukemia
Leukemia
51
3.3 years
Myeloid leukemia
(with cytogenetics)
40
3.5 years
Lymphoid leukemia
7
2.0 years
NCCN Analysis of Leukemia Diagnoses
in Breast Cancer Patients
Risk factor
HR
P
-value
Radiation
vs. no radiation
1.29 (0.66-2.54)
.46
Chemotherapy
vs. no chemotherapy
2.51 (1.29-4.9)
.007
Chemotherapy
+ radiation vs. chemotherapy only or radiation only
1.59 (0.88-2.88)
.127Slide19
Metastatic Breast CancerSlide20
Phase III Trial of Eribulin vs. Capecitabine in Previously Treated Advanced Breast Cancer
Kaufman et al., SABCS 2012; abstract S6-6
S
tudy
301 global, open-label design
Eligibility criteria:
Locally advanced or metastatic breast cancer
0-3 prior chemotherapies (≤ 2 for advanced disease)
Prior anthracycline and taxane
Refractory to most recent chemotherapy
Eribulin 1.4 mg/m
2
, days 1 & 8, q3w
RANDOMI
ZE
(N=1102)
Capecitabine 1250 mg/m
2
BID PO, days 1-14, q3w
Primary endpoint: OS and PFS
Secondary endpoints: QOL, ORR, duration of response, 1-, 2-, 3-yr survival rates, tumor-related symptom assessments, safety parameters, population PK
Final analysis declared positive if
either
eribulin OS significantly better than capecitabine OS
or
eribulin PFS significantly better than capecitabine PFS and if OS HR < 1.0Slide21
Phase III Trial of Eribulin vs. Capecitabine in Previously Treated Advanced Breast Cancer
Kaufman et al., SABCS 2012; abstract S6-6
S
tudy
301 efficacy results
Pre-specified exploratory analyses
suggest that 3 subgroups may have increased therapeutic benefit with eribulin:
Triple-negative (HR 0.70, 0.55-0.91)
ER-negative (HR 0.78, 0.64-0.96)
HER2-negative (HR 0.84, 0.72-0.98)
Outcome
Eribulin
(n=554)
Capecitabine
(n=548)
HR (95%CI)
P
-value
Median PFS
(independent review)
(investigator review)
4.1 months
4.2 months
4.2 months
4.1 months
1.08 (0.93-1.25)
0.98 (0.86-1.11)
.31
.74
Median OS
15.9 months
14.5 months
0.88 (0.77-1.003)
.056
3-yr OS
17.8%
14.5%
--
.18
Objective response rate
(independent review)
(investigator review)
11%
16%
12%
20%
--
--
.85
0.10
Clinical benefit rate
(independent review)
(investigator review)
26%
33%
27%
34%
--
--
--
--Slide22
Phase III Trial of Eribulin vs. Capecitabine in Previously Treated Advanced Breast Cancer
Kaufman et al., SABCS 2012; abstract S6-6
S
tudy
301 safety results
Adverse events
Eribulin
(n=544)
Capecitabine
(n=546)
Any AEs
Treatment-related AEs
Serious AEs
94.1%
84.6%
17.5%
90.5%
77.1%
21.1%
Fatal AEs
Treatment
-related fatal AEs
4.8%
0.9%
6.6%
0.7%
Treatment-related
AEs leading to: Discontinuation of treatment Dose reduction Dose delay
5.7%31.1%
22.8%
6.2%
31.3%
29.3%Slide23
Phase III Trial of Eribulin vs. Capecitabine in Previously Treated Advanced Breast Cancer
Kaufman et al., SABCS 2012; abstract S6-6
S
tudy
301 hematologic AEs
Hematologic AEs
Eribulin
(n=544)
Capecitabine
(n=546)
All grades
Grade 3
Grade 4
All grades
Grade 3
Grade 4
Neutropenia
54%
25%
21%
16%
4%
<1%
Leukopenia
31%
13%
2%
10%
2%
<1%
Anemia
19%
2%
0
18%
<1%
<1%
Thrombocytopenia
5%
<1%
0
6%
<1%
<1%
Febrile neutropenia
2%
2%
<1%
<1%
<1%
<1%Slide24
Phase III Trial of Eribulin vs. Capecitabine in Previously Treated Advanced Breast Cancer
Kaufman et al., SABCS 2012; abstract S6-6
S
tudy
301 non-hematologic AEs
Non-hematologic AEs
Eribulin (n=544)
Capecitabine (n=546)
All grades
Grade 3
Grade 4
All grades
Grade 3
Grade 4
Hand-foot syndrome
<1%
0
0
45%
14%
0
Alopecia
35%
-
-
4%
-
-
Diarrhea
14%
1%
0
29%
5%
<1%
Nausea
22%
<1%
0
24%
2%
0
Vomiting
12%
<1%
<1%
17%
2%
0
Fatigue
17%
2%
0
15%
2%
<1%
Asthenia
15%
4%
<1%
15%
4%
0
Decreased appetite
13%
<1%
0
15%
2%
0
Peripheral sensory neuropathy
13%
4%
0
7%
<1%
0
Pyrexia
13%
<1%
0
6%
<1%
0
Headache
13%
<1%
0
10%
<1%
<1%
Dyspnea
10%
2%
<1%
11%
3%
<1%
Back pain
10%
2%
0
8%
<1%
0Slide25
Phase II Trial of Eribulin Mesylate
as First-Line Therapy for HER2- Locally Recurrent or Metastatic Breast CancerEribulin
: 1.4 mg/m
2
days 1, 8 every 3 weeks
48 patients enrolled
All Patients
(n=48)
ER+
(n=35)
ER-/PR-/HER2-
(n=10)
CR00
0PR27%
29%30%ORR
27%29%30%SD48%54%30%CBR *46%54%30%Median PFS5.9 months6.7 months4.7 monthsTTR
1.4 months1.4 months2.9 monthsDOR
7.4 months7.4 monthsNot Evaluable
Vahdat et al., SABCS 2012; abstract P1-12-02
* CBR = CR + PR + durable SDSlide26
Retrospective Analysis of nab-Paclitaxel as First-Line Therapy for MBC with Poor Prognostic Factors
Retrospective analysis of the efficacy and safety of patients with poor prognostic factors (DFI ≤ 2 years or visceral-dominant metastases) who received first-line treatment in 2 previous randomized trials.
ORR
Visceral-Dominant Metastases
Short DFI
Study CA012
nab
-Paclitaxel
(
260 mg/m
2
q3w)
42%
(P=.022)43%
Paclitaxel (175 mg/m2
q3w)23%33%Study CA024nab-Paclitaxel (300 mg/m2 q3w)44%35%nab-Paclitaxel (100 mg/m2
qw 3/4)63%52%
nab-Paclitaxel (150 mg/m2
qw 3/4)76%64%
Docetaxel (100 mg/m2 q3w)
37%21%
P
<.001
P
=.002
P
<.001
P
=.020
O’Shaughnessy et al., SABCS 2012; abstract P1-12-07Slide27
Retrospective Analysis of nab-Paclitaxel as First-Line Therapy for MBC with Poor Prognostic Factors
Median PFS (months)
Visceral-Dominant Metastases
Short DFI
Study CA012
nab
-Paclitaxel
(
260 mg/m
2
q3w)
5.6
5.0
Paclitaxel (175 mg/m2 q3w)
3.83.5
HR (P-Value)0.717 (P=.094)0.729 (P=.220)Study CA024nab-Paclitaxel (300 mg/m2 q3w)10.9
7.4nab-Paclitaxel (100 mg/m
2 qw 3/4)7.57.3
nab-Paclitaxel (150 mg/m
2 qw 3/4)13.114.1
Docetaxel (100 mg/m2 q3w)7.85.5
HR (P-Value)
C vs D: 0.600 (P=.019)
B
vs
C: 1.731 (
P
=.010)Overall P=.049All NSO’Shaughnessy et al., SABCS 2012; abstract P1-12-07Slide28
Impact of BRCA1/2 Mutation Status on Response to Platinum-Based Chemotherapy in Triple-Negative Breast Cancer in the TBCRC009 Trial
The TBCRC009 phase II trial evaluated single-agent cisplatin or carboplatin as first- or second-line therapy for metastatic TNBC
6 patients (7%) are long-term survivors who achieved durable responses and remain off all therapy (22+ - 53+ months); all of these patients are
BRCA1/2
WT (5) or unknown (1), and received platinum therapy as first-line treatment for MBC
All Patients
n=86
BRCA1/2
Positive
n=11
BRCA1/2
WTn=65
Unknown n=10
ORR30.2%54.6%*
26.2%30%Median PFS88 days96 days86 days--* P=.079 versus BRCA1/2 WTIsakoff
et al., SABCS 2012; abstract PD-09-03Slide29
Neoadjuvant ChemotherapySlide30
Neoadjuvant Chemotherapy in Breast Cancer Patients ≤ 35 Years Old
Rationale:Previous studies have shown that patients who are diagnosed with breast cancer at a young age have distinctly different disease characteristics, including pCR
rate,
1
biomarker profile,
2
and prognosis
3,4
Objective: Compare the impact of age on
pCR
(pathologic complete response) rate, DFS, LRFS (local recurrence-free survival), and OS in patients receiving neoadjuvant chemotherapy for breast cancer
Study design:A meta-analysis was performed on 8 neoadjuvant trials describing almost 9000 patientsPatients were divided into 3 age groups: ≤ 35 (n=704) 36-50 (n=4167)≥ 51 (n=4078)
1Huober et al. Breast Cancer Res Treat. 2010;124:133-40
2Colleoni et al. Ann Oncol. 2002;13:273-9
3Kroman et al. BMJ. 2000;320:474-84Anders et al. J
Clin Oncol. 2008;26:3324-30Loibl et al., SABCS 2012; abstract S3-1Slide31
Neoadjuvant Chemotherapy in Breast Cancer Patients ≤ 35 Years Old
pCR rate results:pCR
rates were significantly higher in patients ≤35 years old (23.6%) compared with those 36-50 (17.5%) and with those ≥ 51 (13.5%;
P
< .0001)
Age was an independent predictor of
pCR
for those patients with HR-positive, HER2-negative or triple-negative (TNBC) tumors
For patients ≤35 years old with HR-positive, HER2-negative tumors, a
pCR
predicted better DFS
Loibl et al., SABCS 2012; abstract S3-1
pCR
rate
Age ≤ 35 vs. age ≥ 51
OverallP = .002HR+/HER2-P = .013HR+/HER2+P = .73HR-/HER2+
P = .61TNBC
P = .004
Survival
Age ≤ 35 vs. age 36-50
Age 36-50 vs. age ≥ 51 Age ≤ 35 vs. age ≥ 51 DFSP
= .031
P = .057
P
= .022
LRFS
P
= .017P = .024P = .00018OSP
= .22P = .14
P
= .64
Survival results:
Very young patients had significantly
worse DFS and LRFS,
bu
t not OS, when compared with either of the older age groupsSlide32
Clinical Implications‘Adjuvant’ chemotherapy may benefit ER-negative patients with treated
locoregional recurrenceLeukemia risk may be 0.5% at 10 years after adjuvant anthracycline or cyclophosphamide chemotherapy
Eribulin
effective after A/T early in MBC treatment. Efficacy in TNBC promising
First-line
eribulin
is safe and active
Nab
-paclitaxel retains efficacy in poor-prognosis MBC patients
Platinum has activity in
mTNBC
and some first-line patients can have very durable responseSlide33
Advances in the Treatment of
ER+ Breast Cancer
Kimberly Blackwell, MDSlide34
Adjuvant TherapySlide35
Relative Effectiveness of Letrozole vs
Tamoxifen for Lobular Cancer in BIG 1-98 Cohort
Rationale:
Most classic lobular carcinoma is HR-positive and HER2-negative
However, limited data are available regarding the use of letrozole in classic lobular cancers
Objective: Evaluate the effectiveness of adjuvant letrozole compared with adjuvant tamoxifen in patients with lobular cancer (broken down by Luminal A and Luminal B subtypes) enrolled in the BIG 1-98 trial
Patient cohort:
Patients from BIG 1-98 with postmenopausal HR-positive disease receiving 5 years of letrozole or 5 years of tamoxifen (n=4922)
Patients eligible for this analysis with HR-positive, HER2-negative disease:
Ductal histology (n=2,599): 55.3% Luminal A, 44.7% Luminal B
Classic lobular histology (n=324): 73.1% Luminal A, 26.9% Luminal B
Filho et al., SABCS 2012; abstract S1-1Slide36
Relative Effectiveness of Letrozole vs
Tamoxifen for Lobular Cancer in BIG 1-98 Cohort
Ductal DFS results:
Lobular DFS results:
Luminal A/B DFS results:
Luminal A disease showed an interaction
P
-value of .049 for DFS
Luminal B disease was not significant for DFS (
P
= .23)
Treatment
5-yr
DFS
8-yr DFS
HR (95% CI)Letrozole88%82%0.80 (0.68-0.94)Tamoxifen84%75%
Filho et al., SABCS 2012; abstract S1-1
Treatment
5-yr
DFS8-yr DFSHR (95% CI)
Letrozole89%82%0.48
(0.31-0.74)Tamoxifen
75%66%
Interaction
P
-value:
.03Slide37
Relative Effectiveness of Letrozole vs
Tamoxifen for Lobular Cancer in BIG 1-98 Cohort
Ductal OS results:
Lobular OS results:
Treatment
5-yr
OS
8-yr OS
HR (95% CI)
Letrozole
94%
88%
0.73
(0.60-0.89)
Tamoxifen
92%84%Filho et al., SABCS 2012; abstract S1-1
Treatment
5-yr OS
8-yr OSHR (95% CI)
Letrozole96%
89%0.40 (0.23-0.69)Tamoxifen86%
74%
Interaction P
-value:
.045Slide38
Relative Effectiveness of Letrozole vs
Tamoxifen for Lobular Cancer in BIG 1-98 Cohort
Multivariate analysis for DFS:
Interactions:
Treatment by histology (ductal vs. lobular):
P
= .006
Treatment by subtype (Luminal A vs. Luminal B):
P
= .01
Multivariate analysis for OS:
Interaction:
treatment by histology:
P = .035
Histology
HR (95% CI)FavorsDuctal Luminal A0.95 (0.76-1.20)--Ductal Luminal B0.64 (0.53-0.79)Letrozole
Lobular Luminal A0.49 (0.32-0.78)
LetrozoleLobular Luminal B
0.33 (0.21-0.55)Letrozole
Filho et al., SABCS 2012; abstract S1-1
HistologyHR (95% CI)Favors
Ductal
0.69 (0.57-0.85)Letrozole
Lobular
0.39 (0.22-0.68)
LetrozoleSlide39
ATLAS: Effect of 10 vs 5 Years of Adjuvant Tamoxifen in the First 2 Decades After Diagnosis
Rationale:
An EBCTCG meta-analysis has shown that 5 years of adjuvant tamoxifen produces a lower risk of breast cancer death compared with no tamoxifen (23.6% vs. 32.7% at 15 years,
P
< .00001)
1
Treatment with 5 years of tamoxifen is currently the standard hormonal therapy for premenopausal women with early-stage, ER-positive breast cancer
Objective: Estimate the effect of 10 years of tamoxifen on ER-positive breast cancer recurrence and mortality compared with 5 years of tamoxifen
ATLAS study design:
1
EBCTCG, Lancet 2011;378:771-84
Davies et al., SABCS 2012; abstract S1-2
Eligibility criteria:
ER-positive
breast cancer Completed 5 years of tamoxifen therapyDiscontinue tamoxifenRANDOMIZE
(N = 6846)
Continue tamoxifen daily for 5 yearsSlide40
ATLAS: Effect of 10 vs 5 Years of Adjuvant Tamoxifen in the First 2 Decades After Diagnosis
Davies et al., SABCS 2012; abstract S1-2
Tamoxifen
t
reatment
duration
Recurrence at 15 years (%)
Risk of recurrence during years 5-9
HR (95% CI)
Risk of recurrence during years 10+
HR (95% CI)
P
-value
(all years)
5 years
711 (25.1%)0.90 (0.79-1.02)0.75 (0.62-0.90).00210 years 617 (21.4%)
Median F/u = 8 years for compliance, recurrence, deathSlide41
ATLAS: Effect of 10 vs 5 Years of Adjuvant Tamoxifen in the First 2 Decades After Diagnosis
Breast cancer mortality:
10 years of tamoxifen is estimated to reduce breast cancer mortality by one-third in the first decade and by one-half in the second decade
Davies et al., SABCS 2012; abstract S1-2
Period (years)
10
vs
5 years tamoxifen (ATLAS)
HR (95% CI)
5
vs
0 years tamoxifen (EBCTCG)
HR (95% CI)
10
vs
0 years tamoxifen (estimated as the product of HRs)HR (95% CI)0-4
1.00.71*** (0.62-0.80)
0.71*** (0.62-0.81)5-90.97 (0.79-1.18)
0.66*** (0.58-0.75)0.64**
(0.50-0.82)10+0.71* (0.58-0.88)
0.73** (0.62-0.86)0.52*** (0.40-0.68)*
P = .0016**P
= .0001***P < .00001Slide42
ATLAS: Effect of 10 vs 5 Years of Adjuvant Tamoxifen in the First 2 Decades After Diagnosis
Mortality comparison:
The above chart shows that the risk of death caused by tamoxifen side effects is greatly outweighed by the benefit in the reduced risk of death from breast cancer provided by 10 years of tamoxifen therapy
Davies et al., SABCS 2012; abstract S1-2
Mortality cause
10
vs
5 years tamoxifen (ATLAS)
5
vs
0 years tamoxifen (EBCTCG)
10
vs
0 years tamoxifen (estimated by addition)
Due to side effects (endometrial cancer and pulmonary embolisms)
0.2% loss0.2% loss0.4% loss
Due to breast cancer3% gain9% gain
12% gainSlide43
Metastatic Breast CancerSlide44
CONFIRM: Effect of Fulvestrant 500 mg vs
250 mg on Survival in Postmenopausal Women
Objective:
Compare fulvestrant 500 mg/month with 250 mg/month (approved dosing) for the treatment of postmenopausal women with ER-positive advanced breast cancer whose disease progressed after previous hormonal therapy
CONFIRM Phase III study design:
Di Leo et al., SABCS 2012; abstract S1-4
Eligibility criteria:
Postmenopausal
Advanced ER-positive
breast cancer
Disease progression during or after prior hormonal therapy
Fulvestrant 500 mg
Intramuscular injections on days 0, 14, 28, and every 28 days thereafter
RANDOMI
ZE
(N
=
735)
Fulvestrant 250 mgIntramuscular injections on days 0, 28, and every 28 days thereafter (with placebo injections on day 14)
Primary endpoint: PFSSlide45
Baseline characteristics appeared well-balanced between treatment armsEfficacy results:
Subsequent therapies were well-balanced between arms, with approximately 60% of patients receiving subsequent chemotherapy and approximately one-third receiving other hormonal therapy
Di Leo et al., SABCS 2012; abstract S1-4
Outcome
Timing
of analysis
Fulvestrant
500 mg
Fulvestrant
250 mg
HR (95% CI)
Median PFS
First
†
6.5 months
5.5 months0.80* (0.68-0.94)
Median OS
First†25.1 months
22.8 months0.84** (0.69-1.03)
Median OSFinal‡
26.4 months22.3 months0.81*** (0.69-0.96)*
P = .006**P
= .001***P = .016
CONFIRM: Effect of Fulvestrant 500 mg
vs
250 mg on Survival in Postmenopausal Women
†
First analysis was performed at 50% maturity
‡
Final analysis was performed at 75% maturitySlide46
Safety results (reported during main trial + follow-up phase) :
A total of 11 SAEs led to death:
Di Leo et al., SABCS 2012; abstract S1-4
Serious AEs
Fulvestrant 500 mg
n=361
Fulvestrant 250 mg
n=374
Any serious AE
35 (9.7%)
27 (7.2%)
Any causally related serious
AE
8 (2.2%)
4 (1.1%)
CONFIRM: Effect of Fulvestrant 500 mg
vs
250 mg on Survival in Postmenopausal Women
Fulvestrant 500 mg
Fulvestrant 250 mg
Cardiopulmonary failure (1)Acute myocardial infarction (1)Cause unknown (1)Acute renal failure
Dyspnea (2)
AspirationIntestinal adenocarcinoma (1)
Suicide
Hypertension
MeningitisSlide47
Phase III BOLERO-2 Trial:
Exemestane +/- Everolimus in Advanced BC
EVE 10 mg daily
+
EXE 25 mg daily (n = 485)
Placebo
+
EXE 25 mg daily (n = 239)
R
Endpoints
Primary
:
PFS (local assessment)
Secondary
:
OS, ORR, QOL, safety, bone markers, PK
2:1
N = 724
Postmenopausal ER+
Unresectable locally advanced or metastatic BC
Recurrence or progression after letrozole or anastrozole
Stratification
:
Sensitivity to prior hormone therapy and presence of visceral metastases
Hortobagyi
G et al. SABCS 2011 (Abstract #S3-7),
Baselga
, NEJM 2011Slide48
BOLERO-2 Trial: Final Progression-Free Survival Analysis (18-month follow-up)
PFS (months)
EVE + EXE
PBO + EXE
HR (95% CI)
P
-Value
Local review
7.8
3.2
0.45
(95% CI, 0.38-0.54)
<.0001
Central review11.04.1
0.38(95% CI, 0.31-0.48)
<.0001w/ visceral mets6.832.760.47(95% CI, 0.37-0.60)--w/o visceral mets9.864.210.41(95% CI, 0.31-0.55)
--Bone-only mets12.885.29
0.33(95% CI, 0.21-0.53)
--Progression after neoadj therapy11.50
4.070.39(95% CI, 0.25-0.62)
-- PFS impact consistent across all prospectively defined subgroups Overall survival data still not mature (HR=0.77; 95% CI, 0.57-1.04) Most common grade 3 or 4 AEs were
stomatitis (8%), hyperglycemia (5%), and fatigue (4%)
Swain et al., SABCS 2012; abstract P6-04-02Slide49
LEA: Effect of Adding Bevacizumab to First-Line Endocrine Therapy in Advanced Breast Cancer
Rationale:Clinical data suggest that downregulation of VEGF may overcome endocrine therapy resistance and improve efficacy to hormonal therapy
1
Endocrine therapy + bevacizumab has been shown to be safe and active in phase II testing
2,3
Objective: Determine whether bevacizumab can delay resistance to endocrine therapy in patients with HR-positive advanced breast cancer
LEA Phase III, open-label, multicenter study design:
1
Ryden et al. J
Clin
Oncol. 2005;23:4695-704
2Forero-Torres et al. Clin Breast Cancer. 2010;10(4):275-803
Traina et al. J Clin Oncol
, 2010;28(4):628-33Martin et al., SABCS 2012; abstract S1-7
Eligibility criteria: PostmenopausalAdvanced HR-positive, HER2-negative breast cancer
No previous therapy for advanced disease
Endocrine therapy Letrozole 2.5 mg/d or fulvestrant 250 mg q28d
RANDOMIZE
(N = 380)
Endocrine therapy + bevacizumabLetrozole 2.5 mg/d or fulvestrant 250 mg q28d + bevacizumab 15 mg/kg q
Primary endpoint: PFSSlide50
LEA: Effect of Adding Bevacizumab to First-Line Endocrine Therapy in Advanced Breast Cancer
Results:Baseline characteristics were well-balanced:
Approximately 80% had metastatic disease
Approximately 50% had received previous adjuvant hormonal therapy
Approximately 90% of patients received letrozole; the remainder received fulvestrant
Adverse events increased on the bevacizumab-containing arm included leukopenia and thrombocytopenia (
P
< .01); also fatigue, hypertension, hemorrhage, elevated liver enzymes, and proteinuria (
P
< .001).
Martin et al., SABCS 2012; abstract S1-7
Outcome
Endocrine therapy
Endocrine therapy +
Bevacizumab
HR (95% CI)P-valueMedian PFS13.8 months18.4 months
0.83 (0.65-1.06).14
Median OS42 months41 months
1.18 (0.77-1.81).47Slide51
Rationale:
PD 0332991 is an oral highly selective
cyclin
-dependent kinase (CDK) 4/6 inhibitor that prohibits cell cycle progression
It has been shown that PD 0332991 has synergistic activity in combination with hormonal therapy (tamoxifen)
1
A Phase I/II
study of letrozole
and PD 0332991 was initiated
The phase 1 portion has been completed and the dose of PD 0332991 selected
Phase II study design
1
Musgrove et al. Nat Rev Can. 2011;11:558-72
Finn et al., SABCS 2012; abstract S1-6
TRIO-18: Addition of CDK Inhibitor PD 0332991 to Letrozole for Advanced Breast Cancer
Eligibility criteria:
ER-positive, HER2-negative disease
Locally recurrent or metastatic
Previously untreated for advanced disease
CCND1 amplification and/or loss of p16
PD 0332991 125 mg QD* + letrozole 2.5 mg QDRANDOMIZE
(N=99)
Letrozole 2.5 mg QD
Primary endpoint: PFS
*3 weeks on, 1 week offSlide52
Second interim analysis (50% of events)
efficacy results:
Second interim analysis treatment administration results:
Finn et al., SABCS 2012; abstract S1-6
Outcome
PD 991 + letrozole
(n=84)
Letrozole
(n=81)
HR (95% CI)
P
-value
Median PFS, months
26.1
7.5
0.37 (0.21-0.63)
< .001
Objective response rate
34%
26%
--
--
Clinical benefit rate
70%
44%
----
Outcome
PD 991 + letrozole
(n=83)
Letrozole
(n=77)
Median duration of treatment
8.9 months
5.1 months
Dose interruptions, % of cycles
71%
22%
Cycle
delays
75%
NA
Dose reductions
35%
NA
TRIO-18: Addition of CDK Inhibitor PD 0332991 to Letrozole for Advanced Breast CancerSlide53
Second interim analysis most common
treatment-related
AE results (≥10%):
Finn et al., SABCS 2012; abstract S1-6
AE
PD 991 + letrozole
(n=83)
Letrozole
(n=77)
Grade 1/2
Grade
3
Grade 4
Grade 1/2
Grade
3
Grade 4
Neutropenia
19
46
5
1
1
0
Leukopenia
24
14
0
0
0
0
Anemia
19
4
1
0
0
0
Fatigue
17
2
0
13
0
0
Alopecia
18
0
0
3
0
0
Hot flush
17
0
0
10
0
0
Arthralgia
16
0
0
10
0
0
Nausea
12
2
0
1
0
0
Thrombocytopenia
11
1
0
0
0
0
TRIO-18: Addition of CDK Inhibitor PD 0332991 to Letrozole for Advanced Breast CancerSlide54
Neoadjuvant TherapySlide55
Z1031B Phase II Neoadjuvant AI Trial: Triage to Chemotherapy If Ki67 Level >10% at 2-4 Weeks
Postmenopausal patients with stage 2 or 3 ER+ breast cancer initiated preoperative AI therapy and underwent biopsy at 2-4 weeks. If Ki67 >10%: switch to NCCN-guideline chemotherapy or immediate surgery If Ki67 <10%: continue on AI for 16-18 weeks
49 patients had a Ki67 score >10%
35 received standard neoadjuvant chemotherapy
pCR
rate was only 6% and did not meet criteria for adequate activity
166 patients had a Ki67 score <10%
37% had a preoperative endocrine prognostic index (PEPI) score of 0, indicating a very low relapse risk
94% of these patients accepted a recommendation of no adjuvant chemotherapy
Ellis et al., SABCS 2012; abstract PD-07-01Slide56
FEMZONE Trial: Phase II Study of Neoadjuvant Letrozole With or Without Zoledronic Acid for Postmenopausal ER+ Breast Cancer
Postmenopausal patients with ER+/PgR+ breast cancer received 6 months of preoperative therapy with letrozole alone (n=79) or with
zoledronic
acid 4 mg q4w (n=89); accrual did not reach planned numbers.
Adverse events were consistent with known safety profiles of individual agents; no deaths or reports of osteonecrosis of the jaw; no differences in
QoL
between arms.
LET
LET + ZA
P
Value
ORR
(6 month;
Central Review)54.5%
69%.106Breast-conserving surgery
76%72%--Fasching et al., SABCS 2012; abstract PD-07-02Slide57
UNICANCER CARMINA 02 Trial Evaluating Neoadjuvant Anastrozole or Fulvestrant for Postmenopausal ER+/HER2- Breast Cancer
Randomized Phase II TrialAnastrozole 1 mg/day for 4-6 months (n=59)
Fulvestrant
500 mg days 1, 15, and 29, then q4w (n=57)
No grade 3/4 adverse events or SAEs reported
Most common AEs were grade 1 hot flushes and musculoskeletal symptoms
Anastrozole
Fulvestrant
Clinical Response Rate
62%
53%
Breast Conservation
64%
53%
Lerebours et al., SABCS 2012; abstract PD-07-04Slide58
Bone-Targeted TherapiesSlide59
Bone Biomarker Analysis From AZURE Study of Zoledronic Acid Added to Standard Therapy
1Coleman et al. N Engl
J Med. 2011;365:1396-1405
Rathbone
et al., SABCS 2012; abstract S6-4
AZURE study design and primary results
No difference in invasive DFS between groups (HR 0.98,
P
= .73), but, among postmenopausal women, invasive DFS favored zoledronic acid group (HR 0.75,
P
= .02) and OS favored zoledronic acid group (HR 0.74,
P
= .04)
1
Eligibility criteria:
Stage II/III breast cancer
Standard therapy
RANDOMI
ZE
(N=3360)
Standard therapy + zoledronic acid 4 mg
First 6 months: q3-4 weeks
Next 2 years: q3 months
Next 2.5 years: q6 months
Both groups were instructed to take calcium and vitamin D supplements for 6 months; supplements were at the discretion of the physician thereafterSlide60
Bone Biomarker Analysis From AZURE Study of Zoledronic Acid Added to Standard Therapy
Rathbone et al., SABCS 2012; abstract S6-4
AZURE biomarker study design
Goals
Identify specific prognostic factors for development of bone metastasis
Identify predictive markers for benefit from zoledronic acid treatment
Classify menopausal status using reproductive hormone levels
Biomarker population consisted of 872 patients who consented to serum storage at baseline
Biomarker population was similar to the overall population in baseline characteristics and in primary outcomes
Bone biomarkers analyzed:
PINP (measure of bone formation)
CTX (measure of bone turnover)
Vitamin D
N=766 (87.8%) had insufficient levels <30
ng
/mLSlide61
Bone Biomarker Analysis From AZURE Study of Zoledronic Acid Added to Standard Therapy
Rathbone et al., SABCS 2012; abstract S6-4
Biomarker results for overall biomarker population
Insufficient baseline vitamin D levels predict recurrence
Biomarker results among postmenopausal women (who appear to benefit from zoledronic acid, according to AZURE)
Increased bone markers
do not predict treatment benefit
High vitamin D levels predict benefit for zoledronic acid: HR 0.09 (0.01-0.82)
Biomarker
(levels at baseline)
Time to bone recurrence
Time to distant recurrence
HR (95% CI)
P
-value
HR (95% CI)
P
-value
PINP
1.15 (0.68-1.94)
.60
0.86 (0.60-1.23)
.41
CTX
1.43 (0.87-2.35)
.16
1.21 (0.87-1.70)
.26
Vitamin
D
0.11 (0.02-0.76)
.03
0.56 (0.31-1.01)
.05Slide62
ZICE Trial: Phase III Comparison of Zoledronate vs
Ibandronate for the Treatment of Bone Metastases
Patients with
histologically
confirmed breast cancer with bone metastases were randomized to 96 weeks of therapy with either:
Zoledronate
: 4 mg IV every 3-4 weeks (n=699)
Ibandronate
50 mg PO daily (n=705)
Ibandronate
failed to demonstrate non-inferiority with regard to annual skeletal event rate (0.412 for Z vs. 0.495 for I;
P=.13)Both agents similar in delaying time to first SRE (HR 1.04; P=.63)Similar median survival between armsRenal AEs more frequent with zoledronateOsteonecrosis similar between arms 0.71%
with I vs. 1.29% with Z; P = 0.28
Barrett-Lee et al., SABCS 2012; abstract PD-07-09Slide63
Clinical ImplicationsThe more endocrine-sensitive a ESBC is, the larger proportional benefit for adjuvant endocrine therapy (esp. estrogen-deprivation approaches).
Longer duration of endocrine therapy appears to have a net + survival benefit.HD Fulvestrant improves survival in MBC.Novel targeted therapies are making impact on DFS/OS in ER+ MBC.
No clear marker of benefit with adjuvant
zoledronic
acid, although relationship between low vitamin D levels and risk for recurrence.Slide64
Emerging Therapies for HER2+
Breast Cancer
Hope S.
Rugo
, MDSlide65
Adjuvant Therapy
QuestionsWhat is the most appropriate duration for adjuvant trastuzumab?
Is the benefit of adjuvant trastuzumab maintained with long-term follow-up?
Does compliance with adjuvant
trastuzumab
matter?Slide66
HERA Final Analysis: 2 Years vs. 1 Year of Trastuzumab After Adjuvant Chemotherapy
HERA study design and previous results
First interim analysis at median 2 years follow-up showed significant DFS benefit for 1 year trastuzumab over observation (HR = 0.54,
P
< .0001)
1
Eligibility criteria:
HER2-positive invasive early breast cancer
Received surgery + (neo)adjuvant chemotherapy ± radiation therapy
Then, centrally confirmed IHC 3+ or FISH+ and LVEF ≥55%
1 year trastuzumab (n=1703)
8 mg/kg loading dose, 6 mg/kg maintenance, q3w
RANDOMI
ZE
(N=5102)
2 years trastuzumab (n=1701)
8 mg/kg loading dose, 6 mg/kg maintenance, q3w
Observation (n=1698)
After ASCO 2005, patients given option to switch to trastuzumab
Stratification: nodal status, adjuvant chemotherapy regimen, HR status and endocrine therapy, age, region
1Piccart-Gebhart et al., N Engl J Med 2005;353:1659-72Goldhirsch et al., SABCS 2012; abstract S5-2
Primary endpoint: DFS (1 yr vs.
obs
, 2 yr vs.
obs
)
Secondary endpoint: DFS (1 yr vs. 2 yr), OSSlide67
HERA Final Analysis: 2 Years vs. 1 Year of Trastuzumab After Adjuvant Chemotherapy
8-year median follow-up, efficacy results for 2 years vs. 1 year trastuzumab
8-year median follow-up, safety results for 2 years vs. 1 year trastuzumab
Goldhirsch
et al., SABCS 2012; abstract S5-2
Outcome
2 years
trastuzumab
1 year trastuzumab
HR (95% CI)
P
-value
8-yr DFS
HR-positive
HR-negative
75.8%
76.1%
75.4%
76.0%77.2%
74.7%
0.99 (0.85-1.14)1.05 (0.85-1.25)0.93 (0.76-1.14)
.86.67
.51
8-yr OS
86.4%
87.6%
1.05 (0.86-1.28)
.63Outcome
2 years trastuzumab
(n=1673)
1 year trastuzumab
(n=1682)
≥ 1 grade 3/4 AE
20.4%
16.3%
Secondary cardiac event
7.2%
4.1%
Primary cardiac event
1.0%
0.8%
Fatal AE
1.2%
1.1%Slide68
HERA Final Analysis: 2 Years vs. 1 Year of Trastuzumab After Adjuvant Chemotherapy
8-year efficacy results for 1 year trastuzumab vs. observation
Results are complicated by the fact that 52.1% of the patients in the observation group crossed over to receive trastuzumab after ASCO 2005
Goldhirsch
et al., SABCS 2012; abstract S5-2
Outcome
Overall population
HR, (
P
-value)
HR-positive population
HR, (
P
-value)
HR-negative population
HR, (P
-value)DFS benefit 1 yr MFU 2 yr MFU 4 yr MFU
8 yr MFU
0.54, (<.0001)
0.64, (<.0001)
0.76, (<.0001)0.76, (<.0001)
0.60, (.003)
0.68, (.005)
0.84, (.09)
0.81,
(.03)
0.50,
(<.0001)0.62, (<.0001)0.70, (<.0001)
0.72, (<.0001)OS benefit 1 yr MFU
2 yr MFU
4 yr MFU
8 yr MFU
0.76, (.26)
0.66,
(.01)
0.85, (.11)
0.76,
(.0005)
1.67, (.21)
0.69, (.21)
1.03, (.86)
0.84, (.14)
0.47,
(.02)
0.64,
(.03)
0.75,
(.03)
0.70,
(.0007)Slide69
PHARE: Subset Analysis Comparing 6 Months vs. 12 Months of Trastuzumab as Adjuvant Therapy
PHARE non-inferiority randomized study design
Eligibility criteria:
HER2-positive early breast cancer
Tumor size ≥ 10 mm
Received surgery + at least 4 cycles (neo)adjuvant chemotherapy ± radiation therapy
6 months trastuzumab
RANDOMI
ZE
(N=3384)
No further trastuzumab
Randomization was stratified by chemotherapy /trastuzumab timing, hormonal therapy, recruiting
center
Pivot et al., SABCS 2012; abstract S5-3
Primary endpoint:
non-inferiority
of DFS with 6 months trastuzumab
6 months trastuzumab + any chemotherapy regimen Slide70
PHARE: Subset Analysis Comparing 6 Months vs. 12 Months of Trastuzumab as Adjuvant Therapy
DFS results, 42.5 months median follow-up
To be considered non-inferior, HR and CI should be between 1.0 and 1.15
DFS HR was 1.28 (1.05-1.56), which does
not
meet non-inferiority requirements
1
1
Pivot et al., ESMO 2012, LAB5_PR
Pivot et al., SABCS 2012; abstract S5-3
DFS event
12 months trastuzumab
(n=1690)
6 months trastuzumab
(n=1690)
Total events (n=394)10.4%
13.0% Local recurrence
1.1%
1.4% Regional recurrence
0.6%
0.5% Distant recurrence6.4%
8.3% Contralateral breast cancer
0.4%
0.7%
Second primary malignancy
1.5%
1.5%
Death0.4%0.5%Slide71
PHARE: Subset Analysis Comparing 6 Months vs. 12 Months of Trastuzumab as Adjuvant Therapy
DFS subset analysis results, 42.5 months median follow-up
Pivot et al., SABCS 2012; abstract S5-3
DFS subset
HR (95%CI)
Meet non-inferiority requirements?
ER-negative
1.34 (1.02-1.76)
No
ER-positive
1.23 (0.92-1.65)
No
Sequential chemotherapy
1.41 (1.06-1.86)
No
Concomitant chemotherapy
1.15 (0.87-1.53)
No
<50
years old
1.38 (1.01-1.89)No≥50 years old
1.22 (0.94-1.57)
NoNode-negative
1.33 (0.95-1.87)
No
Node-positive
1.25 (0.97-1.60)
No< 2-cm tumor1.02 (0.72-1.44)
No≥2-cm tumor
1.41 (1.09-1.81)
NoSlide72
PHARE: Subset Analysis Comparing 6 Months vs. 12 Months of Trastuzumab as Adjuvant Therapy
DFS subset analysis interaction results, 42.5 months median follow-up
To be considered a significant interaction, HR and CI should be > 1.15
Pivot et al., SABCS 2012; abstract S5-3
DFS interaction
HR (95% CI)
Meet significant
interaction
requirements?
ER-negative and sequential
chemotherapy
1.57 (1.08-2.28)
No, but almost
ER-positive and
sequential
chemotherapy
1.25 (0.81-1.91)
NoER-negative and concomitant
chemotherapy
1.10 (0.73-1.65)NoER-positive and concomitant chemotherapy
1.23 (0.83-1.82)
NoSlide73
NSABP B-31 and NCCTG N9831: Final Joint Analysis of Survival for
Adjuvant Chemotherapy ± Trastuzumab
NSABP B-31 study design
NCCTG N9831 study design
Romond
et al., SABCS 2012; abstract S5-5
Arm 1
Arm 2
Control: AC
→
T
Investigational: AC
→
T+H
= paclitaxel (T) 175 mg/m
2
q3w
x 4
= paclitaxel (T) 80 mg/m
2
/wk x 12
= trastuzumab (H) 4mg/kg LD + 2 mg/kg/wk x 51
Arm
A
Arm
B
Arm
C
=
doxorubicin/cyclophosphamide (AC) 60/600
mg/m
2
q3w
x 4
Control: AC
→
T
Investigational: AC
→
T+HSlide74
NSABP B-31 and NCCTG N9831: Final Joint Analysis of Survival for
Adjuvant Chemotherapy ± Trastuzumab
Romond
et al., SABCS 2012; abstract S5-5
Efficacy outcomes:
8.4 years of median follow-up
The results likely underestimate the treatment effect because
5%
of the women in the
AC
→T+H arm did not receive trastuzumab because of cardiac concerns
20%
of the women in the AC→T arm received trastuzumab after ASCO 2005
Outcome
AC→T+H
(n=2028)
AC→T
(n=2018)
HR (95% CI)
P
-value
10-yr
DFS
73.7%
62.2%
0.60 (0.53-0.68)
< .0001
10-yr OS
84.0%
75.2%
0.63 (0.54-0.73)
< .0001Slide75
NSABP B-31 and NCCTG N9831: Final Joint Analysis of Survival for
Adjuvant Chemotherapy ± Trastuzumab
Romond
et al., SABCS 2012; abstract S5-5
First DFS events
Distant recurrence by HR status
First DFS event
AC→T+H
(n=2028)
AC→T
(n=2018)
Distant recurrence
11.2%
19.4%
Local/regional
recurrence
4.1%
6.1%
Contralateral
breast cancer
2.3%
2.0%
Other second primary cancer
3.3%
3.7%
Death without recurrence
1.9%
1.5%
Distant recurrence
AC→T+H
AC→T
n
%
n
%
HR-positive
1110
12.7%
1105
22.3%
HR-negative
917
11.9%
911
21.5%Slide76
NSABP B-31 and NCCTG N9831: Final Joint Analysis of Survival for
Adjuvant Chemotherapy ± Trastuzumab
Romond
et al., SABCS 2012; abstract S5-5
OS
by subgroup
HR
Significantly favors trastuzumab arm?
Age, years
< 40
40-49
50-59
60+
0.67
0.65
0.680.52
YesYes
YesYes
# of positive nodes 0 1-3 4-9
10+
0.940.590.72
0.56
No
Yes
Yes
Yes
OS by subgroup
HR
Significantly favors trastuzumab arm?
HR status
Negative
Positive
0.65
0.61
Yes
Yes
Tumor size, cm
0-2
2.1-5.0
5.1+
0.51
0.68
0.58
Yes
Yes
Yes
Histologic
grade
Good
Intermediate
Poor
0.11
0.52
0.67
Yes
Yes
Yes
OS by subgroupSlide77
Cumulative incidence of distant recurrence as first event at 10 yearsER and or PR positive22.3 vs 12.7% (9.6% difference)No clear plateau in relapse
ER and PR negative21.5 vs 11.9% (9.6% difference)Improvement in OS increased over time
NSABP B-31 and NCCTG N9831:
Final Joint Analysis of Survival for
Adjuvant Chemotherapy ± Trastuzumab
Years from randomization
4
6
8
10
Difference
in OS
2.9
5.5
7.6
8.8Slide78
Reasons for and Impact of Noncompliance With NCCN Guidelines for Trastuzumab Use
RationaleNCCN guidelines recommend 1 year of adjuvant trastuzumab for patients with stage I-III HER2-positive breast cancer, but many patients fail to complete therapy
Study design
Retrospective analysis of patients from a single institution (N=331) who were eligible for adjuvant trastuzumab
Clinician-documented reasons for noncompliance with NCCN adjuvant trastuzumab guidelines were examined
Impact of noncompliance on disease-related outcomes was tested
Mullins et al., SABCS 2012; abstract P5-18-17Slide79
Reasons for and Impact of Noncompliance With NCCN Guidelines for Trastuzumab Use
Results
Median age was 53, and most patients had stage I (37%) or II (41%) disease
Physician-cited reasons for
noncompliance included:
S
mall
tumor
size (30
%)
B
aseline cardiac dysfunction (24%)Patient
refusal (16%)Advanced age (6
%)Development of metastases (6
%)Medication
toxicity (5%)Multivariate analysis identified age ≥70 (P < .001) and stage I disease (P = .001) as risk factors for noncomplianceFailure to complete adjuvant trastuzumab therapy was associated with:Shorter DFS (P = .03)Shorter OS (P = .0002)
Mullins et al., SABCS 2012; abstract P5-18-17Slide80
Metastatic Breast CancerSlide81
Metastatic: Questions
Is survival improved with the addition of pertuzumab to standard chemotherapy/trastuzumab in the CLEOPATRA Trial? Is this combination effective and safe in older patients?Do biomarkers help us to identify those who might benefit from the addition of
pertuzumab
?
Can we substitute weekly paclitaxel for
docetaxel
?
How safe is T-DM1?
Can we safely substitute
vinorelbine
for
capecitabine in combination with lapatinib?Slide82
CLEOPATRA Biomarker Analysis: Phase III Placebo-Controlled Study of Pertuzumab
CLEOPATRA study design and primary results
Significant improvements were observed in both PFS and OS with the addition of pertuzumab to trastuzumab and docetaxel for the treatment of HER2-positive metastatic breast cancer
Eligibility criteria:
HER2-positive centrally confirmed metastatic breast cancer
First-line
Placebo + trastuzumab
RANDOMI
ZE
(N=808)
Pertuzumab + trastuzumab
Docetaxel
(≥6 cycles recommended)
Docetaxel
(≥6 cycles recommended)
Study
dosing
q3w until progression:
−
Pertuzumab/Placebo:
840
mg loading dose, 420 mg maintenance
− Trastuzumab: 8 mg/kg loading dose, 6 mg/kg maintenance
− Docetaxel: 75 mg/m
2
, escalating to 100 mg/m
2 if tolerated
Randomization was stratified by geographic region and prior treatment status (neo/adjuvant chemotherapy received or not)
Baselga
et al., SABCS 2012; abstract S5-1Slide83
CLEOPATRA: Confirmatory Overall Survival Analysis of Phase III Pertuzumab Study
RationaleInterim (immature) OS results from the CLEOPATRA trial showed a trend in favor of adding pertuzumab to trastuzumab and docetaxel therapy (HR 0.64, 0.47-0.88)
1
This analysis provides confirmatory OS data using mature data
Study design
A second interim analysis of OS was performed with an additional 1 year of follow-up
Results at median follow-up of 30 months
This survival benefit was observed in nearly all subgroups analyzed
This second interim OS analysis was considered significant and confirmatory
Now crosses the O’Brien-Fleming stopping boundary
1
Baselga et al. N
Engl
J Med. 2012;366:109-19
Swain et al., SABCS 2012; abstract P5-18-26
Second interimOS analysisPertuzumab arm
Placebo arm
HR (95% CI)
P
-value
3-year estimated
66%
50%
HR =0.66 (0.52-0.84)
.0008
Median OS
Not reached
37.6
monthsSlide84
Effect of Pertuzumab Added to Trastuzumab and Docetaxel in Older Patients From CLEOPATRA
Patients were divided into 2 age groups: <65 and ≥65 Evaluates the benefit-risk ratio of adding
pertuzumab
in older patients
Of the 808 patients enrolled, 127 (15.7%) were ≥65 years old
Safety
Diarrhea, fatigue
, asthenia, decreased appetite, vomiting, and
dysgeusia
were more frequent in older patients, neutropenia and febrile neutropenia were less frequent; neuropathy was increased with pertuzumab in older patients
Dose reductions were more frequent in older patients26%-31% vs. 22%-25%Older patients received fewer median cycles of docetaxel 6.0-6.5 vs. 8.0
Efficacy was similar1
Baselga et al. N Engl J Med. 2012;366:109-19 Miles et al., SABCS 2012; abstract P5-18-01
Subset
Improvement in median PFS with pertuzumab
HR (95% CI)
P
-value
< 65 years old
4.7 months
HR =0.65 (0.53-0.80)
P
< .0001
≥ 65 years old
11.2 months
HR = 0.52 (0.31-0.86)
P
= .0098Slide85
CLEOPATRA Biomarker Analysis: Phase III Placebo-Controlled Study of Pertuzumab
Biomarker analysis study designBiomarkers were chosen from different parts of the HER2 signaling pathway:
HER2 ligands: AREG, EGF, TGF
α
, IGF1R, EGFR, HER2, HER3
HER2 receptor, including soluble HER2 receptor
Intracellular signaling components: PI3K,
Akt
, PTEN
Nuclear component:
c-
MycBiomarkers were assayed using a number of methods:IHC, qRT-PCR, FISH, mutational analysis, and ELISATwo types of correlations were investigated:
Predictive effects Associations of biomarkers with pertuzumab benefitPrognostic effects
Relationship of biomarker to outcome independent of treatment arm
Baselga
et al., SABCS 2012; abstract S5-1Slide86
CLEOPATRA Biomarker Analysis: Phase III Placebo-Controlled Study of Pertuzumab
Biomarker predictive effectsPertuzumab demonstrated PFS benefit across nearly all biomarker subgroups examined
Of 38 subgroups examined, 33 showed a significant PFS benefit for pertuzumab
The following biomarker subgroups favored pertuzumab but were not significant predictors
:
betacellulin
mRNA high, HER3 membrane H-score high, IGF1R membrane H-score high,
pAKT
cytoplasm H-score high,
pAKT
nuclear H-score highBiomarker prognostic effectsBaselga et al., SABCS 2012; abstract S5-1
Biomarker
Level correlating with better
prognosis
HR (95% CI)P-valueSerum sHER2Low
1.23 (1.01-1.49)
.04HER2 mRNA
High
0.77 (0.63-0.93).008HER2 membrane H-score
High0.83 (0.69-1.00)
.05HER3 mRNA
High
0.81 (0.66-0.98)
.03
PIK3CA
wildtype
High0.63 (0.49-0.80).0001Slide87
CLEOPATRA Biomarker Analysis: Phase III Placebo-Controlled Study of Pertuzumab
Biomarker results: focus on PIK3CAPIK3CA
mutations were associated with poorer prognosis in the placebo arm: 5.2-month reduction in median PFS
PIK3CA
mutation were associated with poorer prognosis in the
pertuzumab
arm: 9.3-month reduction in median PFS
M
utations in
PIK3CA
were not associated with resistance to
pertuzumab
Patients derived similar additional benefit from pertuzumab independent of PIK3CA mutational status
HER2 remains the best marker to predict benefit from HER2-directed therapy
Baselga et al., SABCS 2012; abstract S5-1
PIK3CA statusPlacebo armMedian PFSPertuzumab arm
Median PFS
HR (95%CI)Mutated
8.6 months12.5 month
0.64 (0.43-0.93)Wild-type
13.8 months21.8 months
0.67 (0.50-0.89)
Prognostic
ability
Prognostic
ability
Predictive ability
Predictive abilitySlide88
A Phase II Study of Pertuzumab + Trastuzumab + Weekly Paclitaxel
Rationale
E
valuate the addition of pertuzumab to a regimen similar to that used in CLEOPATRA trial in a similar patient population
Replace q3w
docetaxel
with weekly paclitaxel, which may be more tolerable than docetaxel
1
Study design
Patients with HER2-positive metastatic breast cancer
0-1 prior treatment for metastatic disease
Treated with pertuzumab (840 mg loading dose, 420 mg maintenance), trastuzumab (8 mg/kg loading dose, 6 mg/kg maintenance) q3w and paclitaxel 80 mg/m2
weekly A target 6-month PFS rate of ≥65% was considered promisingResults
Of the 50 patients enrolled at the time of analysis, 33 were evaluableThe
6-month PFS rate was 76% and the response rate was 52%No cardiac events were recorded at the time of analysis, although one woman was taken off study for an asymptomatic LVEF decline
1Sparano et al. N Engl J Med. 2008;358:1663-71Datko et al., SABCS 2012; abstract P5-18-20Slide89
A Phase II Study of Eribulin + Trastuzumab in Advanced HER2-Positive Breast Cancer
RationaleThe microtubule inhibitor eribulin was approved as monotherapy for patients with relapsed/refractory advanced breast cancer based on a 2.5-month improvement in OS over physician’s choice treatment
1
Objective: Explore the activity and safety of eribulin + trastuzumab in the first-line treatment of patients with HER2-positive advanced breast cancer
Study design
Patients with chemotherapy-naïve HER2-positive locally recurrent or metastatic breast cancer
T
reated q3w with eribulin 1.4 mg/m
2
on days 1 & 8 and t
rastuzumab
8 mg/kg loading dose (6 mg/kg subsequent doses) until progressionResults40 evaluable patients
The median number of cycles received was 7.0 for both eribulin and trastuzumabMedian PFS was 9.2 months and response rate was 55%Most common treatment-related AEs were alopecia, fatigue, neutropenia, nausea, and peripheral neuropathy. The most common grade 3/4 AE was neutropenia (35%)
1
Cortes et al. Lancet. 2011;377:914-23Vahdat
et al., SABCS 2012; abstract P5-20-04Slide90
Pooled Safety Analysis: Trastuzumab Emtansine in HER2-Positive Metastatic Breast Cancer
RationaleTrastuzumab emtansine (T-DM1) produced a 5.8-month improvement in OS over lapatinib + capecitabine in patients with HER2-positive advanced breast cancer
1
Objective:
Perform an integrated safety analysis of
882 patients
who have been treated with single-agent T-DM1 in clinical trials
Study design
Patients from 6 clinical trials and 1 extension study who received single-agent T-DM1 3.6 mg/kg q3w were included in this integrated safety analysis
1
Verma et al. N
Engl J Med. 2012;367:1783-91
Dieras et al., SABCS 2012; abstract P5-18-06Slide91
Pooled Safety Analysis: Trastuzumab Emtansine
in HER2-Positive Metastatic Breast Cancer
Results
The most common AEs
were:
Fatigue
, nausea, headache, and thrombocytopenia
With the exception of fatigue, the most common grade ≥3 AEs
were:
Thrombocytopenia, increased AST, hypokalemia, and anemia
Serious AEs were reported in 18.6% 6.2
% discontinued treatment due to an AEThere were 3 cases of NRH (nodular regenerative hyperplasia) and 3 patients discontinued treatment due
to cardiac disordersFour of the 9 AEs leading to death were deemed related to treatment:
Hepatic failure, hepatic function abnormal, bacterial sepsis, and metabolic encephalopathySlide92
VITAL: Phase II Randomized Trial of Lapatinib + Capecitabine or Vinorelbine in MBC
RationaleLapatinib is approved for use in combination with
capecitabine
Also has activity in combination with vinorelbine
1-3
Objective:
Evaluate the efficacy and safety of lapatinib when combined with either capecitabine or vinorelbine in women with HER2-positive breast cancer
Study design
P
hase II, open-label, multicenter study
P
atients with HER2-positive MBC (N=112) Randomized to lapatinib + capecitabine or lapatinib + vinorelbineThe primary endpoint was PFS
1Brain et al., Br J Cancer. 2012;106:673-7
2Lu et al., SABCS 2010; abstract P3-14-183
Bisagni et al., ESMO 2010; abstract 3529Janni et al., SABCS 2012; abstract P5-18-21Slide93
VITAL: Phase II Randomized Trial of Lapatinib + Capecitabine
or Vinorelbine in MBC
Results
Baseline characteristics were well-balanced between arms
Median PFS in both arms was 6.2 months (HR 0.84, 0.53-1.35)
The most common AEs for the
capecitabine
-containing arm
were:
P
almar-plantar
erythrodysesthesia, diarrhea, and rash
The most common AEs for the vinorelbine-containing arm were:
Neutropenia, diarrhea
, rash, nausea, and fatigueMore serious AEs were observed in the vinorelbine
-containing arm33% vs. 11%Slide94
Clinical Implications
The optimal duration of adjuvant trastuzumab remains 1 yearLong-term follow-up confirms the marked benefit of adjuvant trastuzumabPertuzumab, trastuzumab and
docetaxel
are a new standard for the first-line treatment of HER2+ metastatic breast cancer
Safe and effective in the older population
Reasonable to substitute weekly paclitaxel
HER2 remains the best predictive marker for benefit
Higher exposure to adjuvant
trastuzumab
in the US population
T-DM1 is a safe and effective therapy for metastatic HER2+ breast cancer
Approved by FDA 2/22/2013The best chemotherapy agent to partner with lapatinib remains capecitabineSlide95
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)
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