otimizando a terapia anti-her2 no câncer de mama inicial - 11h30... · consultant: abbvie, genomic...
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Otimizando a terapia anti-HER2 no câncer de mama inicial
José Bines, MD PhD
Instituto Nacional de Câncer
Clínica São Vicente
Rio de Janeiro ▪︎ Brasil
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Disclosures
Clinical study: Roche
Travel expenses: AstraZeneca, Roche
Consultant: Abbvie, Genomic Health, Libbs, Lilly, Pfizer, Roche
Personal opinion may not reflect the Instituto Nacional de Câncer orientation
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The evolution of HER2-positive breast cancer natural history
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Docetaxel Docetaxel + carboplatin
Doxorubicin + cyclophosphamide Herceptin Paclitaxel
Chemotherapy +/- sequential radiotherapy
HERA (ex-US)1,2
IHC/FISH N = 5102
Observation
1 year
2 years
NCCTG N9831 (US)4
IHC/FISH N = 1944
1 year
1 year
NSABP B-31 (US)4
IHC/FISH N = 2101
1 year
•
1. Piccart-Gebhart MJ, et al. N Engl J Med 2005; 353:1659–1672; 2. Gianni L, et al. Lancet Oncol 2011; 12:236-244; 3. Slamon D, et al. N Engl J Med 2011; 365:12731283; 4. Perez EA, et al. J Clin Oncol 2011; 29:33663373.
BCIRG-006 (global)3
FISH N = 3222 1 year
1 year
Four pivotal trials (>12,000 patients) that showed 35% reduction in the risk of death established adjuvant Trastuzumab as the SoC for HER2-positive eBC
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Failure of 3 trials of shorter Trastuzumab duration The PERSEPHONE trial still unpublished
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N %
Age, years <50 50–70 ≥70
132 233 41
33 57 10
Size of primary tumour, cm
T1a: 0.5 T1b: >0.5–1.0 T1c: >1.0–2.0 T2: >2.0–3.0
77
124 169 36
19 31 42 9
Histologic grade I: Well-differentiated II: Moderately differentiated III: Poorly differentiated
44
131 228
11 32 56
Hormone receptor status (ER and/or PR) Positive Negative
272 134
67 33
7-year analysis of APT study: Adjuvant paclitaxel and Herceptin for node-negative, HER2-positive breast cancer
APT: Patients with node-negative small tumors may receive sufficient benefit from Trastuzumab + paclitaxel
Tolaney SM, et al. ASCO 2017 (Abstract 511) Jones SE. Lancet Oncol 2013
Distant recurrence 4 (1%)
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BCIRG-006: Despite efficacy improvements with Trastuzumab, 1 in 4 patients still experience recurrence or death after 10-years follow-up
Slamon D, et al. SABCS 2015; abstract S5-04
BCIRG-006: DFS final analysis (10.3 years median follow-up)
74.6%
73.0%
67.9%
0 12 24 36 48 60 72 84 96 108 120 132
DFS
(%)
Time (months)
100
90
80
70
60
50
40
AC-T
AC-TH
TCH Trastuzumab-containing arms
25% have experienced
events at 10 years’ follow up
1 in 4 patients with
HER2-positive eBC will
still experience recurrence or
death despite 1 year of
adjuvant Herceptin +
chemotherapy
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ExteNET: Phase III trial of Neratinib in the extended ‘post-adjuvant’ showed 33% reduction in the risk of recurrence
IDFS, invasive disease-free survival; ITT, intent-to-treat. 1. Chan A, et al. Lancet Oncol 2016; 17:367–377; 2. Chan A, et al. ASCO 2015; Abstract 508; Oral presentation.
Neratinib x 1 year 240 mg/day
Placebo x 1 year
HER2-positive eBC with prior adjuvant Trastuzumab
+ chemotherapy (N = 2840)
R* 1:1
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ExteNET: Phase III trial of Neratinib in the extended ‘post-adjuvant’ showed 33% reduction in the risk of recurrence
IDFS, invasive disease-free survival; ITT, intent-to-treat. 1. Chan A, et al. Lancet Oncol 2016; 17:367–377; 2. Chan A, et al. ASCO 2015; Abstract 508; Oral presentation.
Neratinib x 1 year 240 mg/day
Placebo x 1 year
HER2-positive eBC with prior adjuvant Tratsuzumab
+ chemotherapy (N = 2840)
R* 1:1
0
50
60
70
80
90
100
0 3 6 9 12 15 18 21 24
IDFS
(%
)
Months after randomisation
Neratinib Placebo
Hormone-receptor positive (n = 1631)
4.2% HR 0.51;
95% CI 0.33–0.77; p = 0.001
97.9%
96.0%
95.4%
91.2%
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tpCR
9
5% C
I (%
)
tpCR†
NeoSphere
HT PHT PH PT 0
10
20
30
40
50
60
21.5
39.3
11.2 17.7
Benefit of dual anti-HER2 therapy with Pertuzumab plus Trastuzumab has been demonstrated in 1L mBC and neoadjuvant settings
1. Gianni L, et al. Lancet Oncol 2012; 13:25–32; 2. Schneeweiss A, et al. Ann Oncol 2013; 24:2278–2284.
0 10 20 30 40 50 60 70
0
10
20
30
40
50
60
70
80
90
100
Ove
rall
surv
ival
(%)
∆ 15.7 months
.
Swain SM, et al. N Engl J Med 2015; 372:724–734.
CLEOPATRA
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APHINITY: Phase III study to assess Pertuzumab plus Trastuzumab in the adjuvant setting showed 19% reduction in the risk of recurrence
von Minckwitz G, et al. N Engl J Med 2017; 377:122–131.
Chemotherapy* + Trastuzumab + placebo
Chemotherapy* + Trastuzumab + Pertuzumab
Randomisation and treatment within 8 weeks
of surgery
Anti-HER2 therapy for a total of 1 year (52 weeks) (concurrent with start of taxane)
Radiotherapy and/or endocrine therapy may be started at the end of adjuvant chemotherapy
Central confirmation of HER2 status
(N = 4805)
R
S U R G E R Y
Pertuzumab–Trastuzumab (n = 2400) Placebo–Trastuzumab (n = 2404)
1.0
0.9
0.8
0.7
0.0
Prop
ortio
n ev
ent-
free
0 6 12 18 24 30 36 42 48 Time (months)
93.2% 94.1%
3 years
95.7% 96.4% 98.8%
98.6%
90.6% 92.3%
4 years
1 year 2 years
0.5
0.6
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APHINITY: Subgroups with more pronounced benefit
Node-positive subgroup Hormone receptor negative subgroup
von Minckwitz G, et al. N Engl J Med 2017; 377:122–131.
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KATHERINE: T-DM1 decreased the risk of recurrence by 50% when compared with Trastuzumab among patients with residual disease after neoadjuvant treatment
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Patients that are cured without anti-HER2 treatment
More T1a, T1b being treated
Too much double blockade?
Post-neoadjuvant treatment for those that will not relapse
Are we overtreating?
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Attempts to identify biomarkers beyond HER2 Tumor infilitrating lymphocytes (TILs) may be predictive of trastuzumab benefit
Loi S. Ann. Oncol 2014.
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Standardized Uptake Value (SUV) may be predictive of pathologic complete response to pertuzumab and trastuzumab
Connoly RM. J Clin Oncol 2019
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HER2-positive early-stage breast cancer Take-Home I
T1N0 Surgery
T1N0
> T1N0
Paclitaxel + Trastuzumab
Chemotherapy + Trastuzumab OR
dual HER2-blockade
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HER2-positive early-stage breast cancer Take-Home II
> T1N0 Neoadjuvant
chemotherapy + dual HER2-blockade
Continue anti-HER2 Rx
TDM-1
PCR
No PCR
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ALLTO study: Trastuzumab + Lapatinib showed no significant increase in PFS
Moreno-Aspitia A. ASCO 2017
Surgery
Completion of all (neo)adjuvant anthracycline-
based chemotherapy
(≥4 cycles)
Design 1 no concurrent
taxane
Design 2
concurrent taxanes
(12 weeks)
Trastuzumab q3w
Lapatinib
Lapatinib
Trastuzumab qw Wash-
out
Lapatinib + Trastuzumab q3w
Ran
do
mis
atio
n
52 weeks
12 weeks 6 weeks 34 weeks*