HER2 pos. Disease Supportive care Hans Wildiers University Hospitals Leuven.
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Transcript of HER2 pos. Disease Supportive care Hans Wildiers University Hospitals Leuven.
HER2 pos. Disease
Supportive care
Hans WildiersUniversity Hospitals Leuven
• HER2 pos. Disease– Adjuvant Trastuzumab:
• HERA (2y vs 1y)• Phare (6 mo vs 1y)• NSABP B-31 and NCCTG N9831 (1y vs nil)
– Metastatic Pertuzumab: Cleopatra – HER2 Translational
• Supportive care– MDS/AML after breast cancer– Neurocognitive impact of adjuvant chemotherapy– Bone
OBSERVATIONn=1698
Women with locally determined HER2-positive invasive early breast cancer
Surgery + (neo)adjuvant CT ± RT
Centrally confirmed IHC 3+ or FISH+ and LVEF ≥ 55%
Randomization
1 year Trastuzumab8 mg/kg – 6 mg/kg3 weekly schedule
n=1703
2 years Trastuzumab8 mg/kg – 6 mg/kg3 weekly schedule
n=1701
After ASCO 2005, option of switch to Trastuzumab
HERA TRIAL UPDATE at 8 y FUP Accrual 2001 – 2005 (n=5102)
CT, chemotherapy; RT, radiotherapy
S5-2
Final analysis planned for 725 disease-free survival (DFS) events to obtain 80% power to detect a true hazard ratio of 0.80.
HER2 adjuvant
Dis
ease
-fre
e su
rviv
al (
%)
Years from randomization
89.1%
86.7%81.0%
81.6%75.8%
76.0%
DFS FOR 2 YEARS VS. 1 YEAR TRASTUZUMAB AT 8 YRS MFU
100
80
60
40
20
00 1 2 3 4 5 6 7 8 9
No. at risk
Trastuzumab 2 years 1553 1553 1442 1361 1292 1223 1153 1051 633 194
Trastuzumab 1 year 1552 1552 1413 1319 1265 1214 1180 1071 649 205
Trastuzumab 1 year
Trastuzumab 2 years
Pts Events HR (2 vs 1) 95% CI p-value
2 years 1553 367 0.99 (0.85-1.14) 0.86
1 year 1552 367
S5-2HER2 adjuvant
Hormone receptor negative2.8% received endocrine therapy
Hormone receptor positive92.6% received endocrine therapy
Years from randomization
Dis
ea
se
-fre
e s
urv
iva
l (%
)
Trastuzumab 2 years
Trastuzumab 1 year
DFS BY HORMONE RECEPTOR STATUS AT 8 YRS MFU
No. at risk
Trastuzumab 2 years 798 798 747 710 673 642 597 544 321 97
Trastuzumab 1 year 790 790 736 691 663 634 617 559 337 106
100
80
60
40
20
0
0 1 2 3 4 5 6 7 8 9
Pts Events HR (2 vs 1) 95% CI p-value
2 years 798 185 1.05 (0.85-1.29) 0.67
1 year 790 175
90.3%
89.6%
83.1%
82.9%
76.1%
77.2%
Years from randomization
Dis
ea
se
-fre
e s
urv
iva
l (%
)
Trastuzumab 2 years
Trastuzumab 1 year
100
80
60
40
20
0
0 1 2 3 4 5 6 7 8 9
Pts Events HR (2 vs 1) 95% CI p-value
2 years 755 182 0.93 (0.76-1.14) 0.51
1 year 762 192
No. at risk
Trastuzumab 2 years 755 755 695 651 619 581 556 507 312 97
Trastuzumab 1 year 762 762 677 628 602 580 563 512 312 99
87.8%
83.8%
80.1%
78.9%
75.4%
74.7%
S5-2HER2 adjuvant
Ove
rall
Su
rviv
al (
%)
Years from randomizationNo. at risk
Trastuzumab 2 years 1553 1553 1525 1485 1438 1382 1317 1193 708 208
Trastuzumab 1 year 1552 1552 1513 1461 1413 1364 1329 1218 732 225
100
80
60
40
20
00 1 2 3 4 5 6 7 8 9
OS FOR 2 YEARS VS. 1 YEAR TRASTUZUMAB AT 8 YRS MFU
97.4%
96.5%91.4%
92.6%86.4%
87.6%
Trastuzumab 1 year
Trastuzumab 2 years
Pts Events HR (2 vs 1) 95% CI p-value
2 years 1553 196 1.05 (0.86-1.28) 0.63
1 year 1552 186
S5-2HER2 adjuvant
Observation Trastuzumab Trastuzumab
Only 1 Year 2 Years
N=1744 N=1682 N=1673
≥ 1 grade 3 or 4 AE 8.2% 16.3% 20.4%
Secondary Cardiac1 0.9% 4.1% 7.2%
Primary Cardiac2 0.1% 0.8% 1.0%
Fatal adverse event 0.4% 1.1% 1.2%
ADVERSE EVENTS(SAFETY ANALYSIS POPULATION)
1 LVEF < 50% and ≥ 10% below baseline confirmed by repeat assessment, excluding patients with a primary cardiac endpoint.
2NYHA class III or IV, confirmed by a cardiologist, and LVEF < 50% and ≥ 10% below baseline, OR cardiac death.
S5-2HER2 adjuvant
Median follow-up(% follow-up time
after selective crossover)
No. of DFS events1 year trastuzumab
vs observation
127 vs 220P<0.0001
218 vs 321P<0.0001
369 vs 458P<0.0001
DFS benefit
Favours 1 year trastuzumab Favours observation0 1 2
HR (95% CI)
1 YEAR TRASTUZUMAB VS. OBSERVATION: DFS ITT ANALYSES
Extended from Gianni et al. Lancet Oncol. 2011.
2005(0%)
2006(4.3%)
2008(33.8%)
1 yr MFU
4 yrs MFU
2 yrs MFU
0.54
0.64
0.76
471 vs 570P<0.0001
2012(48.6%)
8 yrs MFU
0.76
S5-2HER2 adjuvant
Favours 1 year trastuzumab Favours observation0 1 2
HR (95% CI)
OS benefit
1 YEAR TRASTUZUMAB VS. OBSERVATION:OS ITT ANALYSES
Extended from Gianni et al. Lancet Oncol. 2011.
Median follow-up(% follow-up time
after selective crossover)
No. of deaths1 year trastuzumab
vs observation
29 vs 37P=0.26
59 vs 90P=0.0115
182 vs 213P=0.1087
2005(0%)
2006(4.1%)
2008(30.9%)
0.76
0.66
0.85
1 yr MFU
4 yrs MFU
2 yrs MFU
278 vs 350P=0.0005
2012(45.5%)
0.768 yrs MFU
S5-2HER2 adjuvant
PHARE* Trial results of subset analysis comparing 6 to 12 months of trastuzumab in
adjuvant early breast cancer
Protocol of Herceptin®
Adjuvant withReduced Exposure
*lighthouse in French
Xavier Pivot, Gilles Romieu, Marc Debled, Jean-Yves Pierga, Pierre Kerbrat, Thomas Bachelot, Alain Lortholary, Marc Espié, Pierre Fumoleau, Daniel
Serin, Jean-Philippe Jacquin, Christelle Jouannaud, Maria Rios, Sophie Abadie-
Lacourtoisie, Nicole Tubiana-Mathieu, Laurent Cany, Stéphanie Catala, David Khayat,
Iris Pauporté, Andrew Kramar.
S5-3HER2 adjuvant
Study design
trastuzumab 6 months
trastuzumab up to 12 months
stop trastuzumab
Clinical examLVEF
3
Mammography
6 9 12 15 18 21 24 30 mos
…
0
R
R: Randomization after informed consent
Up to 60 mos…
Stratification1. ER pos / neg2. Chemo: conco/
seq
S5-3HER2 adjuvant
Statistical Methods
• Non inferiority randomized trial– 2% variation in terms of absolute difference of
recurrence– The 95% CI HR margins should not cross the 1.15
boundary– 1040 DFS events required for 80% power at 5% level
or4 years of accrual and at least 2 years of follow-up
– HR were estimated from the stratified Cox model
• Accrual target: 3400 patients
S5-3HER2 adjuvant
Treatment Characteristics
12 monthsn=1690
6 monthsn=1690
Type of Chemotherapy No AnthracyclinesAnthracyclines no
taxanesAnthracyclines
and Taxanes
10.2%15.9%73.9%
11.8%15.5%72.7%
Concomitant ChemotherapySequential Chemotherapy
57.8%42.2%
57.7%42.3%
Radiotherapy 87.7% 88.2%
Hormonotherapy 50.6% 50.2%
Trastuzumab duration, mean (sd) 11.8 (2.03) 6.3 (1.46)
S5-3HER2 adjuvant
DFS Events
12 mos(n=1690)
6 mos(n=1690)
DFS Events (n=394) 10.4% 13.0%
Local RecurrenceRegional RecurrenceDistant Recurrence
Controlateral Breast Cancer2nd Primary Malignancy
Death
1.1%0.6%6.4%
0.4%1.5%
0.4%
1.4%0.5%8.3%
0.7%1.5%
0.5%
42.5mos. median Follow-up
S5-3HER2 adjuvant
0.00
0.25
0.50
0.75
1.00D
FS P
roba
bilit
y
1690 1586 1353 939 526 23T-6m1690 1613 1390 980 544 18T-12m
Trastuzumab
0 12 24 36 48 60Months
T-12m T-6m
HR (95% CI): 1.28 (1.05 - 1.56)
Disease Free Survival
* Cox model stratified by ER status and concomitant chemotherapy
95.5 91.2 87.8 84.9
97.0 93.8 90.7 87.8
Events HR 95%CI p-valueT 12m 176T 6m 219 1.28 (1.05 – 1.56) 0.29
S5-3HER2 adjuvant
Equivalent
Superior
Non Inferior
Inferior
A
B
C
D
E
.85 1 1.15 1.3 1.45 1.6
HR
Primary endpoint scenarios
PHARE trial
X Pivot et al, ESMO 2012, LBA5_PR
S5-3HER2 adjuvant
SubanalysisHR (95% CI)
ER and Chemotherapy modalities
1.57 (1.08 - 2.28)
1.25 (0.81 - 1.91)
1.10 (0.73 - 1.65)
1.23 (0.83 - 1.82)
1.28 (1.05 - 1.56)
ER - Sequential (676)
ER + Sequential (850)
ER - Concomitant (786)
ER + Concomitant (1118)
All patients (3380)
0 1.15 2 Favors 6 months Favors 12 months
S5-3HER2 adjuvant
Trastuzumab plus Adjuvant Chemotherapy for HER2-positive Breast Cancer:
Final Planned Joint Analysis of Overall Survival from NSABP B-31 and NCCTG N9831
San Antonio Breast Cancer Symposium – December 4-8, 2012 Abstract #S5-5
S5-5
Median follow-up: 8.4 years
Definitive survival analysis at 710 OS events
HER2 adjuvant
N9831/B-31 Disease-Free Survival
A P
AC P+H
N EventsAC→P 2018 680AC→P+H 2028 473
HRadj=0.60 (95% CI: 0.53-0.68) P<0.0001
62.2%
73.7%
64.9%
76.8%81.4%
San Antonio Breast Cancer Symposium, December 4-8, 2012S5-5HER2 adjuvant
B-31/N9831 Overall Survival
AC P87.0%
89.8%
79.4%84.3%
N EventsAC→P 2018 418AC→P+H 2028 286
90.3%
∆=2.9% ∆=5.5% ∆=7.6% ∆=8.8%
San Antonio Breast Cancer Symposium, December 4-8, 2012S5-5HER2 adjuvant
1. Baselga J, et al. SABCS 2011 (Abstract S5-5);2. Baselga J, et al. N Engl J Med 2012; 366: 109–119.
CLEOPATRA: update
* < 6 cycles allowed for unacceptable toxicity or PD; > 6 cycles allowed at investigator discretionHER2, human epidermal growth factor receptor 2; PD, progressive disease
Patients withHER2-positive MBCCentrally confirmed
(N = 808)
Placebo + trastuzumabn = 406
• Primary endpoint: Independently-assessed progression-free survival (PFS)
• Collection of tumor tissue (archival in >90%) and serum samples was mandatory
• Study dosing q3w:− Pertuzumab/placebo: 840 mg loading dose, 420 mg maintenance− Trastuzumab: 8 mg/kg loading dose, 6 mg/kg maintenance− Docetaxel: 75 mg/m2, escalating to 100 mg/m2 if tolerated
1:1
n = 402
Docetaxel*≥ 6 cycles recommended
PD
Pertuzumab + trastuzumab
Docetaxel*≥ 6 cycles recommended
PD
P5-18-26HER2 metastatic
CLEOPATRA: overall survival
22Stopping boundary for concluding statistical significance at this second interim analysis was p≤0.0138D, docetaxel; Pla, placebo; Ptz, pertuzumab; T, trastuzumab
0 5 10 15 20 25 30 35 40
0
10
20
30
40
50
60
70
80
90
100
n at risk
0Ptz + T + D
0Pla + T + D
Time (months)
Ove
rall
surv
ival
(%
)
45 50 55
0
0
9
4
33
22
84
67
143
128
230
198
317
285
342
324
371
350
387
383
402
406
89%
94%
1 year
2 years
69%
81% 3 years
66%
50%
Ptz + T + D: 113 events; median not reachedPla + T + D: 154 events; median 37.6 months
HR=0.6695% CI 0.52−0.84
p=0.0008
P5-18-26HER2 metastatic
CLEOPATRA: PFS
D, docetaxel; PFS, progression-free survival; Pla, placebo; Ptz, pertuzumab; T, trastuzumab
0 5 10 15 20 25 30 35 40
0
10
20
30
40
50
60
70
80
90
100
Time (months)
Pro
gre
ssio
n-f
ree
surv
ival
(%
)
45 50
0
0
0
0
8
8
34
26
67
42
108
72
178
110
218
148
284
223
341
329
402
406
Ptz + T + D: median 18.7 monthsPla + T + D: median 12.4 months
HR=0.6995% CI 0.58−0.81
∆=6.3 months
n at risk
Ptz + T + D
Pla + T + D
P5-18-26HER2 metastatic
0
10
20
30
40
50
60
70
80
90
100
0 5 10 15 20 25 30 35
Pro
gre
ssio
n-f
ree
surv
ival
(%
)
Time (months)
Ptz + T + D <65 Pla + T + D <65Ptz + T + D ≥65 Pla + T + D ≥65
CLEOPATRA PFS according to age
D, docetaxel; PFS, progression-free survival; Pla, placebo; Ptz, pertuzumab; T, trastuzumab
24
P5-18-01HER2 metastatic
CLEOPATRA PFS according to age:Exposure to docetaxel treatment
<65 years ≥65 years
Placebo+ trastuzumab
+ docetaxel(n=332)
Pertuzumab+ trastuzumab
+ docetaxel(n=346)
Placebo+ trastuzumab
+ docetaxel(n=65)
Pertuzumab+ trastuzumab
+ docetaxel(n=61)
Median number of cycles administered (range)
8.0 (1−41) 8.0 (1−35) 6.5 (1−26) 6.0 (1−16)
Median dose intensity, mg/m2/week
24.8 24.5 24.8 24.8
Dose escalation to 100 mg/m2,n (%)
53 (16.0) 41 (11.8) 8 (12.3) 7 (11.5)
Dose reduction to <75 mg/m2,n (%)
72 (21.7) 85 (24.6) 17 (26.2) 19 (31.1)
25
P5-18-01HER2 metastatic
CLEOPATRA PFS according to age: Ten most common grade ≥3 adverse events overall
<65 years ≥65 years
n (%)
Placebo+ trastuzumab
+ docetaxel(n=332)
Pertuzumab+ trastuzumab
+ docetaxel(n=346)
Placebo+ trastuzumab
+ docetaxel(n=65)
Pertuzumab+ trastuzumab
+ docetaxel(n=61)
Neutropenia 156 (47.0) 174 (50.3) 26 (40.0) 25 (41.0)Leukopenia 51 (15.4) 44 (12.7) 7 (10.8) 6 (9.8)Febrile neutropenia 26 (7.8) 51 (14.7) 4 (6.2) 5 (8.2)Diarrhea 16 (4.8) 23 (6.6) 4 (6.2) 9 (14.8)Anemia 9 (2.7) 10 (2.9) 5 (7.7) 0 (0.0)Fatigue 9 (2.7) 7 (2.0) 4 (6.2) 2 (3.3)Peripheral neuropathy 6 (1.8) 6 (1.7) 1 (1.5) 5 (8.2)LVSD 8 (2.4) 4 (1.2) 3 (4.6) 1 (1.6)Asthenia 4 (1.2) 10 (2.9) 2 (3.1) 0 (0.0)Granulocytopenia 9 (2.7) 4 (1.2) 0 (0.0) 2 (3.3)
26LVSD, left ventricular systolic dysfunction
P5-18-01HER2 metastatic
The HER2 signalling pathway Selection of biomarkers
ER
Nucleus
c-myc
Raf
MEK 1/2
MAPK
Akt
GSK3 BAD
Cell-cycleprogression
PTEN
mTOR
p27
Cyclin D1, E
FKHR
Grb2 Sos
Cell survival
Ras
Shc SosGrb2
PI3K
Cell proliferation
Y
ER
HER2EGFR HER2 HER3IGF1R
YsHER2
HER ligands
(AREG, EGF, TGFα)
NO RESULTS(except HER2)
HER2 translational S5-7
• Neosphere: associaton between pCR and immune biomarkers S6-7
• Lapatinib decreases Ki67 by 27% in HER2 neg tumors in a ‘window of opportunity’ study (mainly if also high HER3 expression) PD07-07
• New techniques for HER2 determination – Next generation sequencing is highly concordant with FISH
for HER2, and uncovers actionable genomic alterations PD02-07
– MPLA PD02-03,
– RNA scope analysis PD02-04
– AQUA: predicts trastuzumab benefit in BCIRG-005/6
PD02-01
HER2 translational
Activating HER2 mutations in HER2 Gene Amplification Negative Breast Cancers
• HER2 mutations predominantly occur in HER2 gene amplification negative patients.
• The majority of HER2 mutations are activating events that cause oncogenic transformation, thus they are highly likely to be driver events in these breast cancers.
• Neratinib is a highly potent, irreversible pan-ErbB tyrosine kinase inhibitor for all of the HER2 mutations (clinical trial has been launched)
HER2 translational S5-6
MDS/AML after BC diagnosis• Previous reports:
– NSABP trials: 0,27% after AC at 8y if RT after lumpectomy or CSF use.
– An “environmental” cancer
AML/MDS S3-5
AML/MDS S3-5
Characteristics of Leukemia cohort
AML/MDS S3-5
Cumulative incidence of Leukemia
Chemo vs no chemo: HR 2,5 p0,007
AML/MDS S3-5
Conclusions
• Adjuvant chemotherapy was associated with a cumulative 10-year incidence of leukemia of ~ 0.5%
• Almost half of the events occurred beyond year 5 • Radiation alone appears to be a risk factor, but may
not add much to patients already treated with chemotherapy
• Leukemia risk was not limited to MDS/AML, and cases of high risk lymphoid leukemia were observed
• This study highlights the challenges of studying infrequent but important clinical events
AML/MDS S3-5
Neurocognitive Impact in Adjuvant Chemotherapy for Breast Cancer Linked to
Fatigue: A Prospective Functional MRI Study
• Prospective non-randomized comparative trial
chemobrain
S6-3
n=28
n=37
n=32
• Frontal Brain Activation by group and time
chemobrain
S6-3
• Neurocognitive alterations in working memory processes and greater fatigue were evident before any adjuvant chemotherapy.
• Pre-adjuvant treatment brain alterations during working memory task predict severity of fatigue post-treatment.
• Greater fatigue across all groups was related to reduced cognitive function over time.
chemobrain S6-3Results and conclusion
Vitamin D, But Not Bone Turnover Markers, Predict Relapse In Women With Early Breast
Cancer: An AZURE Translational Study.
Bone S6-4
And 25HO VitD
Prognostic effectS6-4
only for 25HO VitD
Bone
Predictive effectS6-4
* CTX, PINP : ZOL benefit NOT predicted by higher bone turnover
* 25HO Vit D
Bone
• Population: 157 pts, 92% continued ZOLonly 37% received per label (q3-4w)
• SRE: - SRE rate 0,13 per person year during 18 month study (vs 0,13 in 18 months
before inclusion)- 83% SRE free at 18 months- persistent ZOL therapy per label ≈ lower SRE rate
(HR 0,26 p 0,009)
• Safety: - renal deterioration in 6 pts- No symptomatic hypoCa (but only 16% taking
supplements!)- Acute phase reactions 9,5%- ONJ in 7 pts (4,5%)
LOTUS trial: Prospective study of treatment pattern, effectiveness, and safety of Zoledronic acid (ZOL) beyond 2y:
subgroup analysis of pts with metastatic breast cancer.
S3-13-01Bone
• Neoadj FEC-paclitaxel +/- ZOL. PD07-05
– randomized trial (n= 182)– pCR 14,9 vs 7,9% (p 0,16)
– in postmenopauzal 18,4 vs 5,4% (p 0,15)
• iv ZOL vs po ibandronat PD09-07
– randomized trial (n=1405)– MBC with bone metastases– SRE rate per year lower for ZOL (0,44 vs 0,54, p 0,02)
BisphosphonatesBone
Conclusions HER2• HER2 adjuvant:
– HERA and NSABP B-31/NCCTG N9831 results at 8 yrs FUP show sustained and statistically significant DFS and OS benefit for 1 year trastuzumab versus observation in ITT analyses despite selective crossover. No benefit for extension to 2 years in HERA.
– PHARE failed to show that 6 months of trastuzumab is non inferior to 12 months. Subgroup analysis suggested that
• Sequential modality for ER negative tumors impacted the overall results.
• Results in other groups seemed compatible with non-inferiority hypothesis
– 1 year of trastuzumab remains the standard of care as adjuvant therapy for patients with HER2-positive early breast cancer.
• HER2 metastatic: – Addition of pertuzumab to trastuzumab and docetaxel improves OS
and PFS significantly in HER2-positive first-line without important toxicity aspects.
Conclusions supportive care
• Adjuvant chemotherapy is associated with a cumulative 10-year incidence of leukemia of ~ 0.5%
• Neurocognitive alterations in working memory processes and greater fatigue are present before any adjuvant chemotherapy.
• Low baseline VitD is associated with increased risk of bone and distant recurrence