Download Adjuvant Chemotherapy

Breast Cancer Highlights From San Antonio
Joyce O'Shaughnessy, MD
Kimberly Blackwell, MD
Hope Rugo, MD
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Updates on Chemotherapy and Other
Novel Agents
Joyce O'Shaughnessy, MD
Adjuvant Chemotherapy
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:
Eligibility criteria:
• First ILRR
• Complete gross excision of
recurrence
• No evidence of positive
supraclavicular LNs
• No evidence of distant metastasis
Primary endpoint: DFS
Secondary endpoint: OS
(N=162)
R
A
N
D
O
M
I
Z
E
+ Endocrine therapy
for HR-positive
disease
Adjuvant
chemotherapy
+ HER2-directed
therapy (optional)
No
chemotherapy
+ Radiation therapy
(mandatory for those
with positive margins)
– Chemotherapy chosen by investigators
– Recommendation: at least 2 drugs, 3-6 months of therapy
Aebi et al., SABCS 2012; abstract S3-2
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:
Chemotherapy*
(n=85)
No chemotherapy*
(n=77)
Total failures
24
34
Local/regional
6 (25%)
9 (26%)
Distant
Soft tissue
Bone
Viscera
15 (63%)
0
8
7
22 (65%)
2
5
15
Contralateral breast
1 (4%)
1 (3%)
Secondary non-breast malignancy
1 (4%)
0
Deaths without failure
1 (4%)
2 (6%)
Site of first failure (after ILRR)
* 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.
Aebi et al., SABCS 2012; abstract S3-2
CALOR: Adjuvant Chemotherapy for Isolated
Local or Regional Recurrence
•
Efficacy results:
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
.007
5-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
.12
Survival
– 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
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:
RANDOMIZATION
(N=4391)
Standard epirubicin (E)
100
mg/m2,
Accelerated epirubicin (aE)
100 mg/m2, q2w, for 4 cycles
Pegfilgrastim 6 mg on day 2
followed by:
q3w, for 4 cycles
followed by:
CMF
Capecitabine (X)
mg/m2
600/40/600
IV bolus, days 1 & 8
or 100/40/600
mg/m2 PO, days 114, for 4 cycles
mg/m2
2500
bid,
days 1-14, for 4
cycles
CMF
Capecitabine (X)
mg/m2
600/40/600
IV bolus, days 1 & 8
or 100/40/600
mg/m2 PO, days 114, for 4 cycles
2500 mg/m2 bid,
days 1-14, for 4
cycles
Primary endpoint: TTR (time to tumor recurrence)
Secondary endpoints: DFS, OS, toxicity, QOL
Cameron et al., SABCS 2012; abstract S3-3
UK TACT2: Comparison of Standard vs
Accelerated Epirubicin in Early Breast Cancer
•
Safety results:
Standard E
Accelerated E
(n=2221)
(n=2170)
0%
0.9%
Leukopenia
3.8%
1.0%
Neutropenia
16.4%
1.7%
Febrile neutropenia
3.6%
1.4%
Grade 3/4 AEs
Hand-foot syndrome
•
Efficacy results:
Outcome
Standard E
Accelerated E
HR (95% CI)
P-value
3-year TTR
90.9%
91.0%
5-year TTR
85.2%
86.4%
0.96
(0.81-1.13)
.60
3-year OS
95.4%
94.4%
5-year OS
89.3%
88.6%
1.13
(0.93-1.37)
.23
– There were 167 breast cancer deaths in the E arm and 179 in the aE arm
Cameron et al., SABCS 2012; abstract S3-3
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:
(N=1284)
R
A
N
D
O
M
I
Z
E
epirubicin 150
q2w x 3
mg/m2
paclitaxel 225
q2w x 3
mg/m2
cyclophosphamide
2500 mg/m2
q2w x 3
+ tamoxifen
G-CSF ± epoetin alfa
+ tamoxifen
EC 90/600 mg/m2
paclitaxel 175 mg/m2
q3w x 4
q3w x 4
Primary endpoint: RFS
Moebus et al., SABCS 2012; abstract S3-4
Secondary endpoint: OS, QOL, toxicity
10-Year Follow Up of Intense Dose-Dense
Chemotherapy vs. Conventional Chemotherapy
in High-Risk Patients with ≥4 Positive LNs
•
Efficacy results:
Outcome
IDD-ETC
EC→T
HR (95% CI)
P-value
10-yr RFS
56%
47%
0.74 (0.63-0.87)
.00014
10-yr OS
4-9 positive LNs
10+ positive LNs
69%
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
– No therapy-related death or long-term toxicity was observed with iddETC
•
Transfusion results:
IDD-ETC
(n=324)
IDD-ETC +
EPO
(n=319)
P-value
--
--
< .001 (favoring +EPO arm)
Need for ≥1 transfusion
28%
13%
< .0001
Patients with venous thrombotic event
7%
13%
.029
Transfusion-related outcomes
Median hemoglobin (g/dL)
– Negative impacts of epoetin alfa on RFS and OS were not observed
Moebus et al., SABCS 2012; abstract S3-4
BEATRICE: Phase III Trial of Adjuvant
Bevacizumab in Triple-Negative Breast Cancer
•
BEATRICE study design
(N=2591)
Eligibility criteria:
• Resected triple-negative
(centrally confirmed) invasive
early breast cancer
Primary endpoint: DFS
Secondary endpoints: OS, breast
cancer-free interval, DFS, distant
DFS, safety, biomarkers
R
A
N
D
O
M
I
Z
E
4-8 cycles of standard chemotherapy
(investigator’s choice)
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)
Cameron et al., SABCS 2012; abstract S6-5
BEATRICE: Phase III Trial of Adjuvant
Bevacizumab in Triple-Negative Breast Cancer
•
Efficacy results
Outcome
3-yr invasive DFS
OS
–
•
Chemo alone
(n=1290)
Chemo + bevacizumab
(n=1301)
HR (95%CI)
P-value
82.7%
83.7%
0.87 (0.72-1.07)
.18
--
--
0.84 (0.64-1.12)
.23
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
Adverse events
Any AE
Grade ≥3 AE
Grade 5 AE
AE leading to chemo and/or bev discontinuation
AE leading to bev discontinuation
Chemo alone
(n=1271)
Chemo + bevacizumab
(n=1288)
99%
57%
0.2%
99%
72%
0.3%
2%
--
20%
18%
Cameron et al., SABCS 2012; abstract S6-5
BEATRICE: Phase III Trial of Adjuvant
Bevacizumab in Triple-Negative Breast Cancer
•
Grade ≥3 AEs of special interest by treatment phase
Chemotherapy phase
Adverse events
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%
0
<1%
0
0
<1%
<1%
0
2%
0
<1%
0
<1%
<1%
<1%
0
<1%
Gastrointestinal perforation
Proteinuria
RPLS
Wound-healing complication
–
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
Cameron et al., SABCS 2012; abstract S6-5
BEATRICE Trial: Biomarker Results
• 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
Baseline Plasma Concentration
HR*
P-Value
Median VEGF-A
High
0.81
Low
0.89
.7415
3rd Quartile VEGF-A
High
0.64
Low
0.92
.3551
Median VEGFR-2
High
.61
Low
1.24
.0291
* HR <1.0 indicates CT plus Bev better than CT alone
Carmeliet et al., SABCS 2012; abstract P3-06-34
•
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
Stage I-III breast cancer diagnosis at
NCCN (July 1997 – Dec 2008)
N=22,248
excluded
Prior history of cancer
n=1715
First diagnosis of breast cancer
n=20,533
Censored at date of
last NCCN contact
Censored at first date
of other cancer event
Died while being
followed at NCCN
Patients with
leukemia
n=16092
n=3935
n=455
n=51; 0.25%
Patients without leukemia, n=20,482
Karp et al., SABCS 2012; abstract S3-5
NCCN Analysis of Leukemia Diagnoses
in Breast Cancer Patients
*Chemotherapy
Regimens Included:
4 Cycles: AC or EC,
FA50C or FE100C, TC
6 Cycles: CMF, CAF,
TAC, FA50C or FE100C
No leukemia
Leukemia
Patient characteristic
(n=20,482)
(n=51)
P-value
Median age
53.9 years
60.2 years
.02
Race
White
African American
Other
87%
8%
5%
92%
6%
2%
.72
Surgery
Breast conservation
Mastectomy
None
57%
42%
1%
55%
45%
0
.85
Radiation therapy
After breast conservation or none
After mastectomy
None
54%
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
Karp et al., SABCS 2012; abstract S3-5
NCCN Analysis of Leukemia Diagnoses
in Breast Cancer Patients
•
•
Characteristics of leukemia cohort:
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
Hazard ratios for risk of developing leukemia:
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)
.127
Incidence of developing leukemia:
– 0.32% at 5 years
– 0.52% at 10 years
Karp et al., SABCS 2012; abstract S3-5
Metastatic Breast Cancer
Phase III Trial of Eribulin vs. Capecitabine in
Previously Treated Advanced Breast Cancer
•
Study 301 global, open-label design
(N=1102)
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
R
A
N
D
O
M
I
Z
E
Eribulin 1.4 mg/m2, days 1 & 8, q3w
Capecitabine 1250 mg/m2 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 < 1.0
Kaufman et al., SABCS 2012; abstract S6-6
Phase III Trial of Eribulin vs. Capecitabine in
Previously Treated Advanced Breast Cancer
•
Study 301 efficacy results
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
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%
---
---
3-yr OS
–
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)
Kaufman et al., SABCS 2012; abstract S6-6
Phase III Trial of Eribulin vs. Capecitabine in
Previously Treated Advanced Breast Cancer
•
Study 301 safety results
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%
Adverse events
Kaufman et al., SABCS 2012; abstract S6-6
Phase III Trial of Eribulin vs. Capecitabine in
Previously Treated Advanced Breast Cancer
•
Study 301 hematologic AEs
Eribulin
(n=544)
Hematologic AEs
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%
Kaufman et al., SABCS 2012; abstract S6-6
Phase III Trial of Eribulin vs. Capecitabine in
Previously Treated Advanced Breast Cancer
•
Study 301 non-hematologic AEs
Eribulin (n=544)
Non-hematologic AEs
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%
0
Kaufman et al., SABCS 2012; abstract S6-6
Phase II Trial of Eribulin Mesylate as FirstLine Therapy for HER2- Locally Recurrent or
Metastatic Breast Cancer
• Eribulin: 1.4 mg/m2 days 1, 8 every 3 weeks
• 48 patients enrolled
All Patients
(n=48)
ER+
(n=35)
ER-/PR-/HER2(n=10)
CR
0
0
0
PR
27%
29%
30%
ORR
27%
29%
30%
SD
48%
54%
30%
CBR *
46%
54%
30%
Median PFS
5.9 months
6.7 months
4.7 months
TTR
1.4 months
1.4 months
2.9 months
DOR
7.4 months
7.4 months
Not Evaluable
* CBR = CR + PR + durable SD
Vahdat et al., SABCS 2012; abstract P1-12-02
Retrospective Analysis of nab-Paclitaxel as FirstLine 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
42% (P=.022)
43%
23%
33%
nab-Paclitaxel (300 mg/m2 q3w)
44%
35%
nab-Paclitaxel (100 mg/m2 qw 3/4)
63%
Study CA012
nab-Paclitaxel (260 mg/m2 q3w)
Paclitaxel (175 mg/m2 q3w)
Study CA024
P=.020
52%
P<.001
nab-Paclitaxel (150 mg/m2 qw 3/4)
P=.002
76%
64%
P<.001
Docetaxel (100 mg/m2 q3w)
37%
21%
O’Shaughnessy et al., SABCS 2012; abstract P1-12-07
Retrospective Analysis of nab-Paclitaxel as FirstLine Therapy for MBC with Poor Prognostic Factors
Median PFS (months)
Visceral-Dominant
Metastases
Short DFI
nab-Paclitaxel (260 mg/m2 q3w)
5.6
5.0
Paclitaxel (175 mg/m2 q3w)
3.8
3.5
0.717 (P=.094)
0.729 (P=.220)
nab-Paclitaxel (300 mg/m2 q3w)
10.9
7.4
nab-Paclitaxel (100 mg/m2 qw 3/4)
7.5
7.3
nab-Paclitaxel (150 mg/m2 qw 3/4)
13.1
14.1
Docetaxel (100 mg/m2 q3w)
7.8
5.5
C vs D: 0.600 (P=.019)
B vs C: 1.731 (P=.010)
Overall P=.049
All NS
Study CA012
HR (P-Value)
Study CA024
HR (P-Value)
O’Shaughnessy et al., SABCS 2012; abstract P1-12-07
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
ORR
Median PFS
All Patients
n=86
BRCA1/2
Positive
n=11
BRCA1/2 WT
n=65
Unknown
n=10
30.2%
54.6%*
26.2%
30%
88 days
96 days
86 days
--
* P=.079 versus BRCA1/2 WT
• 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
Isakoff et al., SABCS 2012; abstract PD-09-03
Neoadjuvant Chemotherapy
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
prognosis3,4
– 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 patients
– Patients 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;320:474-8
4Anders et al. J Clin Oncol. 2008;26:3324-30
Loibl et al., SABCS 2012; abstract S3-1
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 triplenegative (TNBC) tumors
– For patients ≤35 years old with HR-positive, HER2negative tumors, a pCR predicted better DFS
•
pCR rate
Age ≤ 35 vs.
age ≥ 51
Overall
P = .002
HR+/HER2-
P = .013
HR+/HER2+
P = .73
HR-/HER2+
P = .61
TNBC
P = .004
Survival results:
– Very young patients had
significantly worse DFS
and LRFS, but not OS,
when compared with
either of the older age
groups
Age ≤ 35 vs.
age 36-50
Age 36-50
vs. age ≥ 51
Age ≤ 35 vs.
age ≥ 51
DFS
P = .031
P = .057
P = .022
LRFS
P = .017
P = .024
P = .00018
OS
P = .22
P = .14
P = .64
Survival
Loibl et al., SABCS 2012; abstract S3-1
Clinical Implications
• ‘Adjuvant’ chemotherapy may benefit ER-negative patients
•
•
•
•
•
with treated locoregional recurrence
Leukemia 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 response
Advances in the Treatment of
ER+ Breast Cancer
Kimberly Blackwell, MD
Adjuvant Therapy
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 S1-1
Relative Effectiveness of Letrozole vs Tamoxifen
for Lobular Cancer in BIG 1-98 Cohort
•
Ductal DFS results:
Treatment
•
5-yr DFS
8-yr DFS
HR (95% CI)
Letrozole
88%
82%
Tamoxifen
84%
75%
0.80
(0.68-0.94)
Lobular DFS results:
Treatment
•
Interaction
P-value:
.03
5-yr DFS
8-yr DFS
HR (95% CI)
Letrozole
89%
82%
Tamoxifen
75%
66%
0.48
(0.31-0.74)
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)
Filho et al., SABCS 2012; abstract S1-1
Relative Effectiveness of Letrozole vs Tamoxifen
for Lobular Cancer in BIG 1-98 Cohort
•
Multivariate analysis for DFS:
Histology
•
HR (95% CI)
Favors
Ductal Luminal A
0.95 (0.76-1.20)
--
Ductal Luminal B
0.64 (0.53-0.79)
Letrozole
Lobular Luminal A
0.49 (0.32-0.78)
Letrozole
Lobular Luminal B
0.33 (0.21-0.55)
Letrozole
Interactions:
– Treatment by histology (ductal vs. lobular): P = .006
– Treatment by subtype (Luminal A vs. Luminal B): P = .01
•
Multivariate analysis for OS:
Histology
•
HR (95% CI)
Favors
Ductal
0.69 (0.57-0.85)
Letrozole
Lobular
0.39 (0.22-0.68)
Letrozole
Interaction: treatment by histology: P = .035
Filho et al., SABCS 2012; abstract S1-1
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:
(N = 6846)
Eligibility criteria:
• ER-positive breast cancer
• Completed 5 years of
tamoxifen therapy
R
A
N
D
O
M
I
Z
E
Discontinue tamoxifen
Continue tamoxifen daily
for 5 years
1EBCTCG,
Lancet 2011;378:771-84
Davies et al., SABCS 2012; abstract S1-2
ATLAS: Effect of 10 vs 5 Years of Adjuvant
Tamoxifen in the First 2 Decades After Diagnosis
Tamoxifen Recurrence
treatment at 15 years
duration
(%)
5 years
711 (25.1%)
10 years
617 (21.4%)
Risk of
recurrence
during years 5-9
HR (95% CI)
Risk of
recurrence
during years 10+
HR (95% CI)
P-value
(all
years)
0.90
(0.79-1.02)
0.75
(0.62-0.90)
.002
Median F/u = 8 years for compliance, recurrence, death
Davies et al., SABCS 2012; abstract S1-2
ATLAS: Effect of 10 vs 5 Years of Adjuvant
Tamoxifen in the First 2 Decades After Diagnosis
•
Breast cancer mortality:
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
1.0
0.71*** (0.62-0.80)
0.71*** (0.62-0.81)
5-9
0.97 (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)
Period
(years)
*P = .0016
**P = .0001
***P < .00001
– 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
ATLAS: Effect of 10 vs 5 Years of Adjuvant
Tamoxifen in the First 2 Decades After Diagnosis
•
Mortality comparison:
Mortality cause
Due to side effects
(endometrial cancer and
pulmonary embolisms)
Due to breast cancer
10 vs 5 years
tamoxifen
(ATLAS)
5 vs 0 years
tamoxifen
(EBCTCG)
10 vs 0 years
tamoxifen (estimated
by addition)
0.2% loss
0.2% loss
0.4% loss
3% gain
9% gain
12% gain
– 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
Metastatic Breast Cancer
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:
(N = 735)
Eligibility criteria:
• Postmenopausal
• Advanced ER-positive breast
cancer
• Disease progression during or
after prior hormonal therapy
Primary endpoint: PFS
R
A
N
D
O
M
I
Z
E
Fulvestrant 500 mg
Intramuscular injections on days
0, 14, 28, and every 28 days
thereafter
Fulvestrant 250 mg
Intramuscular injections on days
0, 28, and every 28 days
thereafter (with placebo
injections on day 14)
Di Leo et al., SABCS 2012; abstract S1-4
CONFIRM: Effect of Fulvestrant 500 mg vs
250 mg on Survival in Postmenopausal Women
•
Baseline characteristics appeared well-balanced between treatment arms
•
Efficacy results:
Timing of
analysis
Fulvestrant
500 mg
Fulvestrant
250 mg
HR (95% CI)
Median PFS
First†
6.5 months
5.5 months
0.80* (0.68-0.94)
Median OS
First†
25.1 months
22.8 months
0.84** (0.69-1.03)
Median OS
Final‡
26.4 months
22.3 months
0.81*** (0.69-0.96)
Outcome
*P = .006
**P = .001
***P = .016
†First
analysis was performed at 50% maturity
analysis was performed at 75% maturity
‡ Final
– 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
CONFIRM: Effect of Fulvestrant 500 mg vs
250 mg on Survival in Postmenopausal Women
•
Safety results (reported during main trial + follow-up phase) :
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%)
Serious AEs
•
A total of 11 SAEs led to death:
Fulvestrant 500 mg
Fulvestrant 250 mg
Cardiopulmonary failure (1)
Acute myocardial infarction (1)
Cause unknown (1)
Acute renal failure
Dyspnea (2)
Aspiration
Intestinal adenocarcinoma (1)
Suicide
Hypertension
Meningitis
Di Leo et al., SABCS 2012; abstract S1-4
Phase III BOLERO-2 Trial:
Exemestane +/- Everolimus in Advanced BC
N = 724
• Postmenopausal ER+
• Unresectable locally
advanced or metastatic BC
R
2:
• Recurrence or progression 1
after letrozole or
anastrozole
Endpoints
EVE 10 mg daily
+
EXE 25 mg daily (n = 485)
Placebo
+
EXE 25 mg daily (n = 239)
Stratification: Sensitivity to prior hormone
therapy and presence of visceral
metastases
• Primary: PFS (local assessment)
• Secondary: OS, ORR, QOL, safety, bone markers, PK
Hortobagyi G et al. SABCS 2011 (Abstract #S3-7), Baselga, NEJM 2011
BOLERO-2 Trial: Final Progression-Free
Survival Analysis (18-month follow-up)
PFS (months)
Local review
EVE + EXE
PBO + EXE
HR (95% CI)
P-Value
7.8
3.2
0.45
<.0001
(95% CI, 0.38-0.54)
Central review
11.0
4.1
0.38
<.0001
(95% CI, 0.31-0.48)
w/ visceral mets
6.83
2.76
0.47
--
(95% CI, 0.37-0.60)
w/o visceral mets
9.86
4.21
0.41
--
(95% CI, 0.31-0.55)
Bone-only mets
12.88
5.29
0.33
--
(95% CI, 0.21-0.53)
Progression after
neoadj therapy
11.50
4.07
0.39
--
(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 P6-04-02
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 therapy1
– Endocrine therapy + bevacizumab has been shown to be safe and active in
phase II testing2,3
– 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:
(N = 380)
Endocrine therapy
Eligibility criteria:
R
• Postmenopausal
• Advanced HR-positive, HER2negative breast cancer
• No previous therapy for
advanced disease
Primary endpoint: PFS
A
N
D
O
M
I
Z
E
Letrozole 2.5 mg/d or
fulvestrant 250 mg q28d
Endocrine therapy + bevacizumab
Letrozole 2.5 mg/d or
fulvestrant 250 mg q28d +
bevacizumab 15 mg/kg q
1Ryden
et al. J Clin Oncol. 2005;23:4695-704
et al. Clin Breast Cancer. 2010;10(4):275-80
3Traina et al. J Clin Oncol, 2010;28(4):628-33
Martin et al., SABCS 2012; abstract S1-7
2Forero-Torres
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
Outcome
Endocrine therapy
Endocrine therapy
+ Bevacizumab
HR (95% CI)
P-value
Median PFS
13.8 months
18.4 months
0.83 (0.65-1.06)
.14
Median OS
42 months
41 months
1.18 (0.77-1.81)
.47
– 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
TRIO-18: Addition of CDK Inhibitor PD 0332991
to Letrozole for Advanced Breast Cancer
•
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
Eligibility criteria:
• ER-positive, HER2negative disease
• Locally recurrent or
metastatic
• Previously untreated
for advanced disease
• CCND1 amplification
and/or loss of p16
Primary endpoint: PFS
(N=99)
R
A
N
D
O
M
I
Z
E
PD 0332991 125 mg QD*
+ letrozole 2.5 mg QD
*3 weeks on, 1 week off
Letrozole 2.5 mg QD
1Musgrove
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
•
Second interim analysis (50% of events) efficacy results:
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
•
Second interim analysis treatment administration results:
PD 991 + letrozole
(n=83)
Letrozole
(n=77)
8.9 months
5.1 months
Dose interruptions, % of cycles
71%
22%
Cycle delays
75%
NA
Dose reductions
35%
NA
Outcome
Median duration of treatment
Finn et al., SABCS 2012; abstract S1-6
TRIO-18: Addition of CDK Inhibitor PD 0332991
to Letrozole for Advanced Breast Cancer
•
Second interim analysis most common treatment-related AE results (≥10%):
PD 991 + letrozole
(n=83)
AE
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
Finn et al., SABCS 2012; abstract S1-6
Neoadjuvant Therapy
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-07-01
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.
ORR (6 month;
Central Review)
Breast-conserving
surgery
LET
LET + ZA
P Value
54.5%
69%
.106
76%
72%
--
• 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.
Fasching et al., SABCS 2012; abstract PD-07-02
UNICANCER CARMINA 02 Trial Evaluating
Neoadjuvant Anastrozole or Fulvestrant for
Postmenopausal ER+/HER2- Breast Cancer
• Randomized Phase II Trial
– Anastrozole 1 mg/day for 4-6 months (n=59)
– Fulvestrant 500 mg days 1, 15, and 29, then q4w (n=57)
Anastrozole
Fulvestrant
Clinical Response Rate
62%
53%
Breast Conservation
64%
53%
• No grade 3/4 adverse events or SAEs reported
• Most common AEs were grade 1 hot flushes and
musculoskeletal symptoms
Lerebours et al., SABCS 2012; abstract PD-07-04
Bone-Targeted Therapies
Bone Biomarker Analysis From AZURE Study of
Zoledronic Acid Added to Standard Therapy
•
AZURE study design and primary results
(N=3360)
Eligibility criteria:
• Stage II/III breast cancer
R
A
N
D
O
M
I
Z
E
Standard therapy
Both groups were instructed to take calcium and
vitamin D supplements for 6 months; supplements
were at the discretion of the physician thereafter
Standard therapy + zoledronic acid 4 mg
First 6 months: q3-4 weeks
Next 2 years: q3 months
Next 2.5 years: q6 months
– 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
1Coleman
et al. N Engl J Med. 2011;365:1396-1405
Rathbone et al., SABCS 2012; abstract S6-4
Bone Biomarker Analysis From AZURE Study of
Zoledronic Acid Added to Standard Therapy
•
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/mL
Rathbone et al., SABCS 2012; abstract S6-4
Bone Biomarker Analysis From AZURE Study of
Zoledronic Acid Added to Standard Therapy
•
Biomarker results for overall biomarker population
–
•
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)
.05
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)
Rathbone et al., SABCS 2012; abstract S6-4
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 arms
• Renal AEs more frequent with zoledronate
• Osteonecrosis similar between arms
– 0.71% with I vs. 1.29% with Z; P = 0.28
Barrett-Lee et al., SABCS 2012; abstract PD-07-09
Clinical Implications
• The 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.
Emerging Therapies for HER2+
Breast Cancer
Hope S. Rugo, MD
Adjuvant Therapy
Questions
• What is the most appropriate
duration for adjuvant trastuzumab?
• Is the benefit of adjuvant
trastuzumab maintained with longterm follow-up?
• Does compliance with adjuvant
trastuzumab matter?
HERA Final Analysis: 2 Years vs. 1 Year of
Trastuzumab After Adjuvant Chemotherapy
•
HERA study design and previous results
(N=5102)
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%
Stratification: nodal status, adjuvant
chemotherapy regimen, HR status and
endocrine therapy, age, region
R
A
N
D
O
M
I
Z
E
1 year trastuzumab (n=1703)
8 mg/kg loading dose, 6 mg/kg
maintenance, q3w
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
Primary endpoint: DFS (1 yr vs. obs, 2 yr vs. obs)
Secondary endpoint: DFS (1 yr vs. 2 yr), OS
– 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
1Piccart-Gebhart
et al., N Engl J Med 2005;353:1659-72
Goldhirsch et al., SABCS 2012; abstract S5-2
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
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)
.63
Outcome
•
8-year median follow-up, safety results for 2 years vs. 1 year trastuzumab
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%
Outcome
Goldhirsch et al., SABCS 2012; abstract S5-2
HERA Final Analysis: 2 Years vs. 1 Year of
Trastuzumab After Adjuvant Chemotherapy
•
8-year efficacy results for 1 year trastuzumab vs. observation
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)
– 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
PHARE: Subset Analysis Comparing
6 Months vs. 12 Months of Trastuzumab as
Adjuvant Therapy
•
PHARE non-inferiority randomized study design
(N=3384)
Eligibility criteria:
• HER2-positive early breast cancer
• Tumor size ≥ 10 mm
• Received surgery + at least 4
cycles (neo)adjuvant
chemotherapy ± radiation therapy
Primary endpoint: non-inferiority of DFS
with 6 months trastuzumab
6 months
trastuzumab +
any
chemotherapy
regimen
R
A
N
D
O
M
I
Z
E
6 months trastuzumab
No further trastuzumab
Randomization was stratified by
chemotherapy /trastuzumab timing,
hormonal therapy, recruiting center
Pivot et al., SABCS 2012; abstract S5-3
PHARE: Subset Analysis Comparing
6 Months vs. 12 Months of Trastuzumab as
Adjuvant Therapy
•
DFS results, 42.5 months median follow-up
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 recurrence
6.4%
8.3%
Contralateral breast cancer
0.4%
0.7%
Second primary malignancy
1.5%
1.5%
Death
0.4%
0.5%
DFS event
– 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 requirements1
1Pivot
et al., ESMO 2012, LAB5_PR
Pivot et al., SABCS 2012; abstract S5-3
PHARE: Subset Analysis Comparing
6 Months vs. 12 Months of Trastuzumab as
Adjuvant Therapy
•
DFS subset analysis results, 42.5 months median follow-up
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)
No
Node-negative
1.33 (0.95-1.87)
No
Node-positive
1.25 (0.97-1.60)
No
< 2-cm tumor
1.02 (0.72-1.44)
No
≥2-cm tumor
1.41 (1.09-1.81)
No
Pivot et al., SABCS 2012; abstract S5-3
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
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)
No
ER-negative and
concomitant chemotherapy
1.10 (0.73-1.65)
No
ER-positive and
concomitant chemotherapy
1.23 (0.83-1.82)
No
DFS interaction
– To be considered a significant interaction, HR and CI should be > 1.15
Pivot et al., SABCS 2012; abstract S5-3
NSABP B-31 and NCCTG N9831:
Final Joint Analysis of Survival for
Adjuvant Chemotherapy ± Trastuzumab
•
NSABP B-31 study design
Control: AC→T
Arm 1
Investigational: AC→T+H
Arm 2
•
NCCTG N9831 study design
Control: AC→T
Arm A
Arm B
Arm C
Investigational: AC→T+H
= doxorubicin/cyclophosphamide (AC) 60/600 mg/m2 q3w x 4
= paclitaxel (T) 175 mg/m2 q3w x 4
= paclitaxel (T) 80 mg/m2/wk x 12
= trastuzumab (H) 4mg/kg LD + 2 mg/kg/wk x 51
Romond et al., SABCS 2012; abstract S5-5
NSABP B-31 and NCCTG N9831:
Final Joint Analysis of Survival for
Adjuvant Chemotherapy ± Trastuzumab
• Efficacy outcomes: 8.4 years of median follow-up
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)
< .0001
– 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
Romond et al., SABCS 2012; abstract S5-5
NSABP B-31 and NCCTG N9831:
Final Joint Analysis of Survival for
Adjuvant Chemotherapy ± Trastuzumab
•
First DFS events
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%
First DFS event
•
Distant recurrence by HR status
AC→T+H
Distant recurrence
AC→T
n
%
n
%
HR-positive
1110
12.7%
1105
22.3%
HR-negative
917
11.9%
911
21.5%
Romond et al., SABCS 2012; abstract S5-5
NSABP B-31 and NCCTG N9831:
Final Joint Analysis of Survival for
Adjuvant Chemotherapy ± Trastuzumab
•
OS by subgroup
OS by subgroup
HR
Significantly
favors
trastuzumab arm?
Age, years
< 40
40-49
50-59
60+
0.67
0.65
0.68
0.52
Yes
Yes
Yes
Yes
# of positive nodes
0
1-3
4-9
10+
0.94
0.59
0.72
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
Romond et al., SABCS 2012; abstract S5-5
NSABP B-31 and NCCTG N9831:
Final Joint Analysis of Survival for
Adjuvant Chemotherapy ± Trastuzumab
• Cumulative incidence of distant recurrence as
first event at 10 years
– ER and or PR positive
• 22.3 vs 12.7% (9.6% difference)
• No clear plateau in relapse
– ER and PR negative
• 21.5 vs 11.9% (9.6% difference)
• Improvement in OS increased over time
Years from
randomization
4
6
8
10
Difference in OS
2.9
5.5
7.6
8.8
Reasons for and Impact of Noncompliance With
NCCN Guidelines for Trastuzumab Use
• Rationale
– NCCN 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 P5-18-17
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:
• Small tumor size (30%)
• Baseline 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 noncompliance
– Failure to complete adjuvant trastuzumab therapy was
associated with:
• Shorter DFS (P = .03)
• Shorter OS (P = .0002)
Mullins et al., SABCS 2012; abstract P5-18-17
Metastatic Breast Cancer
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?
CLEOPATRA Biomarker Analysis: Phase III
Placebo-Controlled Study of Pertuzumab
•
CLEOPATRA study design and primary results
(N=808)
R
A
N
D
O
M
I
Z
E
Eligibility criteria:
• HER2-positive centrally confirmed
metastatic breast cancer
• First-line
Randomization was stratified by
geographic region and prior treatment
status (neo/adjuvant chemotherapy
received or not)
Placebo + trastuzumab
Docetaxel (≥6 cycles recommended)
Pertuzumab + trastuzumab
Docetaxel (≥6 cycles recommended)
Study dosing q3w until progression:
− Pertuzumab/Placebo:
− Trastuzumab:
− Docetaxel:
840 mg loading dose, 420 mg maintenance
8 mg/kg loading dose, 6 mg/kg maintenance
75 mg/m2, escalating to 100 mg/m2 if tolerated
– 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
Baselga et al., SABCS 2012; abstract S5-1
CLEOPATRA: Confirmatory Overall Survival
Analysis of Phase III Pertuzumab Study
•
Rationale
– Interim (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
Second interim
OS analysis
Pertuzumab arm
Placebo arm
HR (95% CI)
P-value
3-year estimated
66%
50%
HR =0.66 (0.52-0.84)
.0008
Not reached
37.6 months
Median OS
– 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
1Baselga
et al. N Engl J Med. 2012;366:109-19
Swain et al., SABCS 2012; abstract P5-18-26
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 patients
• 26%-31% vs. 22%-25%
– Older patients received fewer median cycles of docetaxel
• 6.0-6.5 vs. 8.0
•
Efficacy was similar
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 = .0098
Subset
1Baselga
et al. N Engl J Med. 2012;366:109-19
Miles et al., SABCS 2012; abstract P5-18-01
CLEOPATRA Biomarker Analysis: Phase III
Placebo-Controlled Study of Pertuzumab
•
Biomarker analysis study design
– Biomarkers were chosen from different parts of the HER2 signaling
pathway:
• HER2 ligands: AREG, EGF, TGFα, IGF1R, EGFR, HER2, HER3
• HER2 receptor, including soluble HER2 receptor
• Intracellular signaling components: PI3K, Akt, PTEN
• Nuclear component: c-Myc
– Biomarkers were assayed using a number of methods:
• IHC, qRT-PCR, FISH, mutational analysis, and ELISA
– Two types of correlations were investigated:
• Predictive effects
– Associations of biomarkers with pertuzumab benefit
• Prognostic effects
– Relationship of biomarker to outcome independent of treatment
arm
Baselga et al., SABCS 2012; abstract S5-1
CLEOPATRA Biomarker Analysis: Phase III
Placebo-Controlled Study of Pertuzumab
•
Biomarker predictive effects
– Pertuzumab 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 high
•
Biomarker prognostic effects
Level correlating
with better prognosis
HR (95% CI)
P-value
Serum sHER2
Low
1.23 (1.01-1.49)
.04
HER2 mRNA
High
0.77 (0.63-0.93)
.008
HER2 membrane H-score
High
0.83 (0.69-1.00)
.05
HER3 mRNA
High
0.81 (0.66-0.98)
.03
PIK3CA wildtype
High
0.63 (0.49-0.80)
.0001
Biomarker
Baselga et al., SABCS 2012; abstract S5-1
CLEOPATRA Biomarker Analysis: Phase III
Placebo-Controlled Study of Pertuzumab
•
Biomarker results: focus on PIK3CA
– PIK3CA 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
Placebo arm
Median PFS
Pertuzumab arm
Median PFS
HR (95%CI)
Mutated
8.6 months
12.5 month
0.64 (0.43-0.93)
Predictive ability
Wild-type
13.8 months
21.8 months
0.67 (0.50-0.89)
Predictive ability
PIK3CA status
Prognostic
ability
Prognostic
ability
– Mutations 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
A Phase II Study of
Pertuzumab + Trastuzumab + Weekly Paclitaxel
•
Rationale
– Evaluate 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 docetaxel1
•
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 promising
•
Results
– Of the 50 patients enrolled at the time of analysis, 33 were evaluable
– The 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;358:1663-71
Datko et al., SABCS 2012; abstract P5-18-20
A Phase II Study of Eribulin + Trastuzumab in
Advanced HER2-Positive Breast Cancer
•
Rationale
– The 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 treatment1
– 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
• Treated q3w with eribulin 1.4 mg/m2 on days 1 & 8 and trastuzumab 8 mg/kg
loading dose (6 mg/kg subsequent doses) until progression
•
Results
– 40 evaluable patients
– The median number of cycles received was 7.0 for both eribulin and trastuzumab
– Median 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%)
1Cortes
et al. Lancet. 2011;377:914-23
Vahdat et al., SABCS 2012; abstract P5-20-04
Pooled Safety Analysis: Trastuzumab Emtansine
in HER2-Positive Metastatic Breast Cancer
•
•
Rationale
– Trastuzumab emtansine (T-DM1) produced a 5.8-month
improvement in OS over lapatinib + capecitabine in patients
with HER2-positive advanced breast cancer1
– 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
1Verma
et al. N Engl J Med. 2012;367:1783-91
Dieras et al., SABCS 2012; abstract P5-18-06
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 AE
– There were 3 cases of NRH (nodular regenerative hyperplasia) and
3 patients discontinued treatment due to cardiac disorders
– Four of the 9 AEs leading to death were deemed related to
treatment:
• Hepatic failure, hepatic function abnormal, bacterial sepsis, and
metabolic encephalopathy
VITAL: Phase II Randomized Trial of Lapatinib
+ Capecitabine or Vinorelbine in MBC
•
•
Rationale
– Lapatinib is approved for use in combination with capecitabine
• Also has activity in combination with vinorelbine1-3
– Objective:
• Evaluate the efficacy and safety of lapatinib when combined with
either capecitabine or vinorelbine in women with HER2-positive
breast cancer
Study design
– Phase II, open-label, multicenter study
– Patients with HER2-positive MBC (N=112)
– Randomized to lapatinib + capecitabine or lapatinib + vinorelbine
– The primary endpoint was PFS
1Brain
et al., Br J Cancer. 2012;106:673-7
et al., SABCS 2010; abstract P3-14-18
3Bisagni et al., ESMO 2010; abstract 3529
Janni et al., SABCS 2012; abstract P5-18-21
2Lu
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:
• Palmar-plantar erythrodysesthesia, diarrhea, and rash
– The most common AEs for the vinorelbine-containing arm were:
• Neutropenia, diarrhea, rash, nausea, and fatigue
– More serious AEs were observed in the vinorelbine-containing arm
• 33% vs. 11%
Clinical Implications
• The optimal duration of adjuvant trastuzumab remains 1 year
• Long-term follow-up confirms the marked benefit of adjuvant
trastuzumab
• Pertuzumab, 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 2/22/2013
• The best chemotherapy agent to partner with lapatinib remains
capecitabine
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