novedades en la terapia her2 · 2017-01-20 · novedades en la terapia her2 javier cortes, ramon y...
TRANSCRIPT
NOVEDADES EN LA TERAPIA HER2
Javier Cortes,
Ramon y Cajal University Hospital, Madrid, Spain
Vall d´Hebron Institute of Oncology (VHIO),
Barcelona, Spain
News SABCS 2016 1. Is everolimus active in aromatase inhibitor resistant breast cancer?
2. Come listen to the latest phase III clinical trials on the extended use of aromatase inhibitors, DATA, NSABP B42
and BOOG 2006-05) and Dr…. discussing these pivotal clinical trials
3. The latest results on the role of the immune system in all breast cancer subtypes will be presented at SABCS
this year
4. Randomized PARP inhibitor clinical trial, somatic BRCA1/2 mutations in breast cancer and other abstracts will be
presented that will change the landscape of treating breast cancer
5. The PERTAIN trial will be presented evaluating for the first time the role of trastuzumab, pertuzumab and an
aromatase inhibitor combination in the metastatic seeting. The NSABP B52 will evaluate the role of combination
of antiHER2 and endocrine therapy in the neoadjuvant setting.
6. Can PAM50 predict pathologic complete response? Find out the first results of the PAMELA clinical trial at
SABCS this year
7. How does radiotherapy impact the cosmetic outcomes of reconstruction? A prospective multicenter clinical trial will provide the answer
8. A novel BRD4 inhibitor can circumvent endocrine resistance
9. BELLE-3: the results of the first phase III randomized clinical trial with a PI3K inhibitor in metastatic breast
cancer will be presented at SABCS.
10.What is the impact of low fat diet and exercise on breast cancer outcomes? SABCS will have the answer.
11.Can a bisphosphonate, ibandronate, improve outcomes in early stage breast cancer? The TEAM IIB trial will
provide the answer.
HER2-POSITIVE PRIMARY BREAST
CANCER
0 1 2 3 4 5
P=0.016
% E
vent
-Fre
e
60
40
20
0
100
80
Years from Randomization
HR=0.64 (95% CI: 0.44-0.93)
Neoadjuvant NOAH
Event-Free Survival
L. Gianni et al, ASCO Annual Meeting 2013. Roche data on file.
HR=0.76 (95% CI: 0.67-0.86)
% E
vent
-Fre
e
60
40
20
0 0 2 4 6 8 10
P<0.0001
100
80
Years from Randomization
Adjuvant HERA
Disease-Free Survival
Without T With T Without T With T
Trastuzumab Improves Outcomes in HER2+ EBC
HR=0.76 (95% CI: 0.67-0.86)
% E
vent
-Fre
e
60
40
20
0 0 2 4 6 8 10
P<0.0001
0 1 2 3 4 5
P=0.016
Without T With T
100
80 41.9%
28.8%
% E
vent
-Fre
e
60
40
20
0
100
80
Years from Randomization
HR=0.64 (95% CI: 0.44-0.93)
Without T With T
Years from Randomization
Neoadjuvant NOAH
Event-Free Survival
L. Gianni et al, ASCO Annual Meeting 2013
Adjuvant HERA
Disease-Free Survival
Unmet Medical Need Remains in HER2+ EBC
Roche data on file.
NeoSphere – Study Design NeoSphere
S
U
R
G
E
R
Y
Study dosing: q3w x 4
TH (n=107) docetaxel (75100 mg/m2) trastuzumab (86 mg/kg)
THP (n=107) docetaxel (75100 mg/m2) trastuzumab (86 mg/kg) pertuzumab (840420 mg)
HP (n=107) trastuzumab (86 mg/kg) pertuzumab (840420 mg)
TP (n=96) docetaxel (75100 mg/m2) pertuzumab (840420 mg)
FEC q3w x 3
FEC q3w x 3
Docetaxel q3w x 3 FEC q3w x 3
FEC q3w x 3
Trastuzumab q3w cycles 5 - 17
Trastuzumab q3w cycles 5 - 17
Trastuzumab q3w cycles 5 - 17
Trastuzumab q3w cycles 5 - 21
Identical chemotherapy backbone and identical adjuvant trastuzumab
= any improvement in long-term outcomes can be attributed solely to the neoadjuvant therapy
FEC; 5-fluorouracil, epirubicin and cyclophosphamide Gianni L. et al. Lancet Oncol 2012
Pathological Complete Response in
Breast (ypT0/is) NeoSphere
H, trastuzumab; P, pertuzumab; T, docetaxel p values from Cochran-Mantel-Haenszel test and adjusted for multiplicity
p=0.0198
TH THP HP TP
p=0.0141 50
40
30
20
10
0
pC
R, %
9
5%
CI
p=0.003
29.0
45.8
16.8
24.0
N=107 N=107 N=107 N=96
Gianni L. et al. Lancet Oncol 2012
• Part of the German Phase II/III ADAPT umbrella study, designed to:
– Identify early molecular or imagining markers predictive of response
– Determine whether patients with eBC can be spared traditional chemotherapies
• WSG-ADAPT HER2+/HR– study design:
WSG-ADAPT HER2+/HR–: 12 weeks of neoadjuvant trastuzumab +
pertuzumab ± weekly paclitaxel in HER2-positive/HR-negative eBC
U Nitz, et al. Poster presentation and discussion, Abstract 518
Week 3: Ki67, cellularity
PH
PH + pac
R
2.5:1
S
U
R
G
E
R
Y
HER2-positive
hormone receptor-
negative eBC
(N = 134)
12 weeks of neoadjuvant therapy
Initial prognostic biopsy:
baseline Ki67, HR and
HER2 status
Primary objective:
• Non-inferiority of tpCR (ypT0/is ypN0): PH responders vs all
PH + pac patients
Secondary objectives:
• Evaluation of dynamic testing
• EFS
• OS
• Safety
WSG-ADAPT HER2+/HR–: Efficacy
U Nitz, et al. Poster presentation and discussion, Abstract 518
34,4
90,5
24,4
78,6
0
10
20
30
40
50
60
70
80
90
100
PH (n = 92)
PH + pac (n = 42)
pC
R/t
pC
R r
ate
, %
tpCR (ypT0/is, ypN0) pCR (ypT0, ypN0)
8,3
44,7
4,2
31,6
0
10
20
30
40
50
60
70
80
90
100
PH: no early response
PH: early response
pC
R/t
pC
R r
ate
, %
tpCR (ypT0/is, ypN0) pCR (ypT0, ypN0)
pCR/tpCR pCR/tpCR: responders vs. non-responders (PH group)
WSG-ADAPT HER2+/HR–: Safety
U Nitz, et al. Poster presentation and discussion, Abstract 518
AE, adverse event; SAE, serious adverse event
• Most AEs were grade 1 or 2
• Rates of grade 3–4 AEs were similar between arms
• There were five SAEs per arm
AE, n (%) PH (n = 62) PH + pac (n = 40) p-value
Anaemia 0 11 (26.8) < 0.001
Cardiac disorders 1 (1.1) 3 (7.3) 0.09
Ear/labyrinth disorders 1 (1.1) 3 (7.3) 0.09
Eye disorders 1 (1.1) 4 (9.8) 0.03
Gastrointestinal disorders
Diarrhoea
Vomiting
33 (36.7)
26 (28.9)
2 (2.2)
25 (61.0)
19 (46.3)
1 (2.4)
0.01
0.07
1.0
Fatigue 15 (16.7) 15 (36.6) 0.01
Infections/infestations 10 (11.1) 13 (31.7) 0.01
Decreased appetite 0 4 (9.8) 0.01
Nervous system disorders 14 (15.6) 23 (56.1) < 0.01
Skin disorders 16 (17.8) 26 (63.4) < 0.001
Respiratory disorders 8 (8.9) 16 (39.0) < 0.001
• Studies such as NeoSphere and TRYPHAENA have demonstrated high pCR rates with
pertuzumab- and trastuzumab-containing regimens (PHT, FEC-PHT and TCHP)
– However, there are currently no data for the combination of PH with dose-dense AC, an
anthracycline regimen commonly used in the US
• This was a single-centre retrospective analysis of 80 patients with Stage II–III HER2-positive breast
cancer treated with a neoadjuvant pertuzumab-containing regimen or AC-TH (2011–2015)
• pCR rates were highest with AC-PHT and TCHP (but not statistically significant vs. AC-TH), but toxicity
was also higher than with the other regimens
– One symptomatic LVEF decrease was reported in a patient receiving AC-PHT
Neoadjuvant pertuzumab-containing regimens vs. AC-TH for
HER2-positive localised breast cancer
L Spring, et al. Poster presentation, Abstract 586
AC-PHT
(n = 31)
TCHP
(n = 15)
PHT
(n = 17)
AC-TH
(n = 17)
pCR, % 64.5 60.0 41.8 41.2
Planned cycles completed, % 71 73 94 65
• T-DM1 has demonstrated significant improvements in survival compared with lapatinib and
capecitabine in HER2-positive second-line mBC, and pertuzumab has proven efficacy in both
eBC and mBC
– The combination of the two agents offers a potential for a traditional chemotherapy-free treatment regimen
• KRISTINE is a randomised, multicentre, open-label Phase III study of neoadjuvant T-DM1 plus
pertuzumab vs. TCHP in HER2-positive eBC
– Primary endpoint: pCR rate (ypT0/is, ypN0)
KRISTINE: pCR rates after neoadjuvant T-DM1 + P vs. TCHP in
patients with HER2-positive eBC
SA Hurvitz, et al. Oral presentation, Abstract 500
HER2-positive,
operable, locally advanced or
inflammatory
eBC (>2 cm)
N = 444
Docetaxel
+ carboplatin
+ pertuzumab
+ trastuzumab
T-DM1 + pertuzumab
Su
rge
ry
Pertuzumab +
trastuzumab
T-DM1
+ pertuzumab
Fo
llow
-up
6 cycles of neoadjuvant therapy
KRISTINE: Efficacy and HRQoL results
SA Hurvitz, et al. Oral presentation, Abstract 500
* Time to a ≥10-point decrease from baseline
ITT population TCHP
(n = 221)
KP
(n = 223) p-value
pCR rate
Overall, % (95% CI) 55.7 (48.8–62.3) 44.4 (37.8–51.2) 0.0155
ER+, % 43.8 35.1
ER–, % 73.2 54.2
BCS rate, % 52.6 41.7 0.0228
HRQoL
Median time to deterioration
in HRQoL, months* 3.0 4.6
Median time to deterioration
in physical function, months* 2.8 4.9
KRISTINE: Safety and conclusions
SA Hurvitz, et al. Oral presentation, Abstract 500
• KRISTINE did not meet its primary endpoint of superior pCR with KP vs. TCHP; the safety profile of the KP
arm was better than the TCHP arm, with fewer SAEs and grade ≥3 AEs
Safety population TCHP
(n = 219)
KP
(n = 223)
SAE, % 28.8 4.9
Grade ≥3 AE, % 64.4 13.0
Selected grade ≥3 AEs, %
Neutropenia 25.1 0.4
Diarrhoea 15.1 0.9
Febrile neutropenia 15.1 0
Anaemia 9.6 0.9
Neutrophil count decreased 9.1 0
Platelet count decreased 5.0 1.3
Fatigue 3.2 1.3
LVEF <50% and ≥10% points decrease from BL 0.5 0.4
• Lapatinib is indicated for use in second-line HER2-positive mBC, but it is not currently
approved for use in eBC
• NSABP B-41 is a Phase III open-label, randomised trial
– Primary endpoint: pCR
• pCR results were previously reported: 52.5% with Hpac, 53.2% with Lpac, 62.0% with HLpac
5-year outcomes of NSABP protocol B-41: Lapatinib as part of
a neoadjuvant treatment regimen in HER2-positive eBC
A Robidoux, et al. Oral presentation, Abstract 501
HER2-positive
eBC
N = 529
AC lapatinib + paclitaxel
AC trastuzumab + paclitaxel
Su
rge
ry
Trastuzumab to
complete 1 year HER2-
targeted therapy AC lapatinib +
trastuzumab + paclitaxel
NSABP B-41 5-year outcomes: Results
A Robidoux, et al. Oral presentation, Abstract 501
• In a subgroup analysis of RFI, the combination of the two HER2-targeted agents was favoured in most groups
compared with the trastuzumab regimen and trastuzumab was favoured over lapatinib across the same subgroups
RFI OS
N Events HR (vs T) P value (vs T)
AC→WP+T 177 23 1 NA
AC→WP+L 171 31 1.27 (0.74, 2.2) 0.14
AC→WP+T+L 171 16 0.66 (0.34, 1.25) 0.33
N Events HR (vs T) P value (vs T)
AC→WP+T 179 10 1 NA
AC→WP+L 171 17 1.52 (0.69, 3.35) 0.11
AC→WP+T+L 172 7 0.63 (0.24, 1.67) 0.55
1.0
0.8
0.6
0.4
0.2
0
Pro
po
rtio
n o
f re
cu
rre
nce
-fre
e
0 1.0 2.0 3.0 4.0 5.0
Time (years)
Overall log-rank test: P=0.049
90% 86.9%
80.7%
1.0
0.8
0.6
0.4
0.2
0
Ove
rall
su
rviv
al
0 1.0 2.0 3.0 4.0 5.0
Time (years)
Overall log-rank test: P=0.07
95.7% 94.5%
89.4%
Trastuzumab 6 mg/kg every 3
weeks
Lapatinib 1000 mg/day
+ Letrozole or Tamoxifen if HR+
HER2+ Breast
Cancer
stage I-IIIA
N=150 S
U
R
G
E
R
Y
18 weeks
Baseline PAM50
Week 2 PAM50
Week 6 Ultrasound
PAMELA trial schema Prat A, et al. SABCS 2016
Trastuzumab 6 mg/kg every 3 weeks
Lapatinib 750 mg/day
Paclitaxel 80 mg/m2 weekly x 12
PD
*
*, defined as any increase in tumor size.
Adjuvant systemic
treatment was at
the discretion of
the treating
physician
PAMELA trial objectives
• Primary objective:
o To evaluate the ability of the HER2-E subtype to predict
pathological complete response (pCR) in the breast (ypT0-is) in
all patients (ITT population) at the time of surgery.
• Secondary objectives included:
o pCR in the breast and axilla (ypT0-isN0).
o Association of subtype at baseline with pCR beyond HR status.
o Changes in subtype calling at baseline vs. week 2.
o Association of subtypes identified at week 2 with pCR.
o Safety.
Intrinsic subtype at baseline vs. pCR in the breast
0%
20%
40%
60%
80%
100%
pCR breast pCR breast/axilla
Baseline samples (N=151)
10.0%
∆=30.6%
pC
R r
ate
40.6%
∆=24.7%
34.7%
10.0%
pCR
Intrinsic subtype at baseline vs. pCR in the breast
0%
20%
40%
60%
80%
100%
pCR breast pCR breast/axilla
Baseline samples (N=151)
10.0%
∆=30.6%
pC
R r
ate
40.6%
∆=24.7%
34.7%
10.0%
pCR
0%
20%
40%
60%
80%
100%
HER2-E(n=101)
LumA(n=22)
LumB(n=16)
Basal-like(n=9)
Normal-like(n=3)
12.5%
40.6%
0%
11.1%
pCR breast
66.7%
Intrinsic subtype at baseline vs. pCR in the breast
Signatures NBreast
pCR rateOR
Lower
95%
Upper
95%p-value OR
Lower
95%
Upper
95%p-value
HR status
HR+ 77 18.2% 1 - - - 1 - - -
HR-negative 74 43.2% 3.4 1.64 7.2 0.001 2.3 1.05 5.05 0.038
Intrinsic subtype
nonHER2-E 50 10.0% 1 - - - 1 - - -
HER2-E 101 40.6% 6.2 2.25 16.81 <0.001 4.5 1.6 12.94 0.005
Univariate Bivariate
Intrinsic subtype at baseline vs. pCR in the breast
Signatures NBreast
pCR rateOR
Lower
95%
Upper
95%p-value OR
Lower
95%
Upper
95%p-value
HR status
HR+ 77 18.2% 1 - - - 1 - - -
HR-negative 74 43.2% 3.4 1.64 7.2 0.001 2.3 1.05 5.05 0.038
Intrinsic subtype
nonHER2-E 50 10.0% 1 - - - 1 - - -
HER2-E 101 40.6% 6.2 2.25 16.81 <0.001 4.5 1.6 12.94 0.005
Univariate Bivariate
• No other clinical-pathological variable was found associated with pCR.
Intrinsic subtype at baseline vs. pCR in the breast
Signatures NBreast
pCR rateOR
Lower
95%
Upper
95%p-value OR
Lower
95%
Upper
95%p-value
HR status
HR+ 77 18.2% 1 - - - 1 - - -
HR-negative 74 43.2% 3.4 1.64 7.2 0.001 2.3 1.05 5.05 0.038
Intrinsic subtype
nonHER2-E 50 10.0% 1 - - - 1 - - -
HER2-E 101 40.6% 6.2 2.25 16.81 <0.001 4.5 1.6 12.94 0.005
Univariate Bivariate
• No other clinical-pathological variable was found associated with pCR.
HER2-POSITIVE METASTATIC BREAST
CANCER
Pertuzumab in MBC: 1st Line
Baselga J, et al. NEJM 2012; Swain S, et al. NEJM 2015
HER2+ MBC: Still an unmet need...
100
80
60
40
20
0
0 12 24 36 48 60
Time From Diagnosis, months
Pro
bab
ility
of
Su
rviv
al, %
• PHEREXA is a multi-centre, open-label, randomised Phase III trial of H + capecitabine ± P (PHX) in
patients who progressed during/after H-based first-line treatment for HER2-positive mBC
• Primary endpoint: Independent Review Facility (IRF) PFS
• Key secondary endpoints: OS and safety
PHEREXA (Phase III): Trastuzumab + capecitabine ±
pertuzumab for second-line treatment of HER2-positive mBC
A Urruticoechea, et al. Oral presentation, Abstract 504
Patients with
HER2-positive mBC, who received
prior taxane and progressed after 1L H
N = 452
Trastuzumab + capecitabine (HX)
Pertuzumab + trastuzumab + capecitabine
(PHX)
PHEREXA: Efficacy
A Urruticoechea, et al. Oral presentation, Abstract 504
* Stratified
0 10 20 30 40 50 60 70 80 0.0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1.0
Time (months)
Pro
po
rtio
n s
urv
ivin
g
HX
PHX
224 190 130 51 19 6 0 0 0
228 205 162 66 31 12 1 0 0
HX (n = 224)
PHX
(n = 228)
Events, n (%) 115 (51) 98 (43)
mOS, months 28.1 36.1
∆, months 8.0
HR (95% CI)* 0.68 (0.51–0.90)
mFU, months 29.5 29.3
HX
(n = 224)
PHX
(n = 228)
Events, n (%) 158 (71) 168 (74)
mPFS, months 9.0 11.1
∆, months 2.1
HR (95% CI)* 0.82 (0.65–1.02)
Log-rank p-value* 0.07
mFU, months 28.6 25.3
224 142 74 38 26 21 11 5 3 2 1 0 0 0
228 165 99 58 39 23 9 5 4 3 2 1 0 0
0 5 10 15 20 25 30 35 40 45 50 55 60 65 0.0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1.0
Time (months)
Pro
po
rtio
n p
rog
res
sio
n-f
ree
HX
PHX
• PHEREXA did not meet its primary endpoint of IRF PFS
PFS (IRF) OS
• The PHEREXA study did not meet its primary PFS endpoint, as the addition of pertuzumab to
trastuzumab and capecitabine did not significantly improve PFS compared with trastuzumab and
capecitabine
– There was an absolute improvement seen in OS (of 8 months to 26.1 months); however, this was
not statistically significant because of the hierarchical testing design of the study
• No new safety signals were identified when pertuzumab was used in combination with trastuzumab
and capecitabine
PHEREXA: Conclusions
A Urruticoechea, et al. Oral presentation, Abstract 504
• HERMYL-1401O trastuzumab was developed as a biosimilar antibody to Herceptin
• HERiTAge is a Phase III study designed to test the bioequivalence of HERMYL-1401O trastuzumab
to the originator product, Herceptin
• Primary endpoint: overall response rate
– Key secondary endpoints: time to progression, overall survival, duration of response
HERiTAge (Phase III): Safety and efficacy of the proposed
trastuzumab biosimilar MYL-1401O vs. Herceptin
HS Rugo, et al. Oral presentation, Abstract LBA503
HER2-positive mBC
(first-line)
N = 600
Herceptin + taxane
HERMYL-1401O trastuzumab + taxane
• ORR results fell within the pre-defined equivalence margin
• PFS at 24 weeks n (%): MYL-1401O – 41 (17.8); Herceptin: 48 (21.1); p = 0.303
• Unstratified HR (95% CI): 0.8 (0.529–1.218); p = 0.302
HERiTAge: Efficacy
HS Rugo, et al. Oral presentation, Abstract LBA503
71,2 67,1
0
20
40
60
80
100
MYL-1401O Herceptin
OR
R a
t 2
4 w
ee
ks, %
71.2 (65.21, 77.13) 67.1 (60.87, 73.39)
N=230 N=228
HERiTAge: Safety, immunogenicity and PK summary
HS Rugo, et al. Oral presentation, Abstract LBA503
MYL-1401O
n = 247
Herceptin
n = 246
≥1 SAEs, n (%) 94 (38.1) 89 (36.2)
Neutropenia, n (%) 68 (27.5) 62 (25.2)
Febrile neutropenia, n (%) 11 (4.5) 10 (4.1)
Leukopenia, n (%) 4 (1.6) 12 (4.9)
Pneumonia, n (%) 4 (1.6) 5 (2.0)
Treatment-related deaths, n (%) 4 (1.6) 4 (1.6)
64 63 63,5 63 63 63
0
10
20
30
40
50
60
70
80
Baseline Cycle 5 Cycle 9
%
% LVEF (Median)
MYL-1401O Herceptin
246 212 209 148 244 140
• Immunogenicity was low, similar between the two products and
consistent with published Herceptin data
• Similar overall ADA rate
• MYL-1401O: 2.4%; Herceptin: 2.8%
• PK was similar for both products
MYL-1401O had equivalent efficacy and safety
to trastuzumab and has low immunogenicity
Clinical Quality Attribute Evaluation
(>100 analytical attributes – eg amino
acid sequence glycosylation etc)
Non-clinical and pre-clinical studies
(eg PK, PD toxicology binding antibody, immunogenicity)
Clinical equivalence study
(PK, immunogenicity and primary clinical
endpoint)
Biosimilarity – what does it take?
Clinical Quality Attribute Evaluation
(>100 analytical attributes – eg amino
acid sequence glycosylation etc)
Non-clinical and pre-clinical studies
(eg PK, PD toxicology binding antibody, immunogenicity)
Clinical equivalence study
(PK, immunogenicity and primary clinical
endpoint)
Is MYL-1401O a biosimilar?
(?) (Yes) (Yes)
• Analysis of registry data suggests that patients with HER2-positive mBC have a worse
prognosis if they have CNS metastases (CNS+) than if they do not
• ONT-380-004 is a Phase Ib study of T-DM1 plus escalating doses of ONT-380 in
HER2-positive mBC, including patients with previously treated (stable or progressive)
or untreated CNS lesions
– Data presented are for all patients treated at the recommended Phase II dose of ONT-380
CNS-penetrant TKI (ONT-380) + T-DM1 in HER2-positive mBC,
including patients with brain metastases
VF Borges, et al. Poster presentation and discussion, Abstract 513
* Including patients with previously treated CNS lesions (stable or progressive) or untreated
asymptomatic CNS lesions
HER2-positive mBC, prior trastuzumab and
a taxane*
Recommended Phase II dose
ONT-380 (300 mg BID) & T-DM1
(3.6 mg/kg IV q3w)
n = 50
Dose escalation and
cohort expansion
ONT-380 + T-DM1 in HER2-positive mBC: Results &
conclusions
VF Borges, et al. Poster presentation and discussion, Abstract 513
* In patients with measurable disease
• Clinical benefit was similar whether patients had CNS metastases or not and regardless of the number of
prior HER2-containing regimens they had received for their disease
• The safety profile was similar for patients both with and without CNS metastases, and was in line with
previously reported safety findings
• Encouraging efficacy and tolerability suggest further investigation of this combination is warranted
Overall
N = 50
With CNS mets
n = 30
Without CNS mets
n = 20
ORR, % 47* NR NR
RR in CNS, % NR 36* N/A
Median PFS, mo
(95% CI)
8.2
(5.1–10.2)
6.7
(5.1–9.2)
8.2
(3.1–N/A)
San Antonio Breast Cancer Symposium, December 6–10, 2016
This presentation is the intellectual property of the author/presenter. Contact them at [email protected] for permission to reprint and/or distribute 55
Primary analysis of PERTAIN: A randomized, two-arm, open-label, multicenter phase II trial
assessing the efficacy and safety of pertuzumab given in combination with trastuzumab plus an
aromatase inhibitor in first-line patients with HER2-positive and hormone receptor-positive metastatic or locally advanced breast cancer
Mothaffar Rimawi,1 Jean-Marc Ferrero,2 Juan de la Haba-Rodriguez,3
Valerie Easton,4 Christine Schuhmacher,4 Eleonora Restuccia,4 and Grazia Arpino5
1Dan L. Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, TX; 2Département d'Oncologie Médicale, Centre Antoine Lacassagne, Nice, France;
3Oncology Department, Maimonides Institute of Biomedical Research, Reina Sofía Hospital, University of Córdoba, Córdoba, Spain; 4F. Hoffmann-La Roche Ltd, Basel, Switzerland;
5Department of Clinical Medicine and Surgery, Università degli Studi di Napoli Federico II, Naples, Italy
S3-04
San Antonio Breast Cancer Symposium, December 6–10, 2016
This presentation is the intellectual property of the author/presenter. Contact them at [email protected] for permission to reprint and/or distribute 56
PERTAIN Study Design (Phase II Trial)
Postmenopausal patients
with HER2-positive and
hormone receptor-
positive LA/MBC, not
previously treated with
systemic non-hormonal
anticancer therapy in the
advanced setting
(N = 258)*
Stratification factors:
• Chemotherapy (yes/no)
• Time since adjuvant hormone therapy
(<12 months/≥12 months/no prior therapy)
Pertuzumab + Trastuzumab
Trastuzumab
* 165 events to detect significant improvement in PFS from 7 months to 10.8 months (i.e. HR 0.645) with 80% power and a 2-sided log-rank test at an alpha level of 0.05. † Choice of chemotherapy must be specified before randomization; administered per product labelling. LA, locally advanced; R, randomization.
+
Aromatase Inhibitor
Docetaxel or Paclitaxel Aromatase Inhibitor (18–24 weeks)†
OR
+
Aromatase Inhibitor
Docetaxel or Paclitaxel Aromatase Inhibitor (18–24 weeks)†
OR
R
Choice of
chemotherapy
must be
specified
before
randomization
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Study Endpoints
CBR, clinical benefit rate; DoR, duration of response; ORR, overall response rate; QoL, quality of life.
Primary endpoint
• PFS
• Event-driven analysis
• 165 events needed; 166 events observed; median follow-up 31 months
Secondary endpoints
• OS
• Final analysis after a minimum follow-up of 60 months for all patients
• ORR
• CBR
• DoR
• Time to response
• Safety and tolerability
• QoL
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Primary Progression-Free Survival Analysis (Stratified, ITT Population)
Analysis based upon Kaplan–Meier approach including stratification factors from IXRS. HR from a stratified Cox proportional hazards model including stratification factors from IXRS.
Median time of follow-up: 31 months. CI, confidence interval; HR, hazard ratio.
Pertuzumab + Trastuzumab + AI
(n = 129)
Trastuzumab + AI
(n = 129)
Events, n (%) 74 (57.4) 92 (71.3)
Median, months 18.89 15.80
(95% CI) (14.09, 27.66) (11.04, 18.56)
∆, months 3.09
HR (95% CI) 0.65 (0.48, 0.89)
p-value 0.0070
129 123 121 116 114 107 102 91 89 84 81 77 74 71 69 65 62 58 57 56 55 53 48 46 43 39 37 36 33 28 28 26 21 16 13 13 12 10 7 5 4 3 1 1 0
129 122 116 108 104 93 90 81 80 75 73 67 64 61 60 56 54 47 47 39 39 36 33 32 29 26 26 23 18 15 14 12 10 9 8 6 5 3 2 2 1 1 1 1 0 N at risk
Months
Event-
free P
robabili
ty (
%)
44 43 42 41 40 39 38 37 36 35 34 33 32 31 30 29 28 27 26 25 24 23 22 21 20 19 18 17 16 15 14 13 12 11 10 9 8 7 6 5 4 3 2 1 0
100
90
80
70
60
50
40
30
20
10
0
Median
Pertuzumab + Trastuzumab + AI
Trastuzumab + AI
San Antonio Breast Cancer Symposium, December 6–10, 2016
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Progression-Free Survival by Stratification Subgroups
0.2 0.4 0.6 0.8 1.0 1.2 1.4 1.6
* HR for pertuzumab arm vs. control arm (control arm, reference category) from an unstratified Cox model.
ITT population 258 166 0.66 (0.48, 0.89)
Chosen to receive induction chemotherapy
Yes 148 94 0.75 (0.50, 1.13)
No 110 72 0.55 (0.34, 0.88)
Time since adjuvant hormone therapy
<12 months 48 37 0.79 (0.42, 1.52)
≥12 months 84 45 0.50 (0.27, 0.91)
No prior hormone therapy
126 84 0.71 (0.46, 1.09)
Subgroup n Events HR* (95% CI) Pertuzumab
arm better Control arm better
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Progression-Free Survival by Baseline Subgroups
* HR for pertuzumab arm vs. control arm (control arm, reference category) from an unstratified Cox model. † Includes treatment in the neoadjuvant, adjuvant, and other settings.
ITT population 258 166 0.66 (0.48, 0.89)
Prior (neo)adjuvant treatment with trastuzumab Yes 59 40 0.68 (0.37, 1.27)
No 199 126 0.64 (0.45, 0.92)
Prior (neo) adjuvant chemotherapy Yes 115 71 0.64 (0.40, 1.02)
No 143 95 0.67 (0.44, 1.02)
Prior hormone therapy†
Yes 110 70 0.64 (0.40, 1.02)
No 148 96 0.67 (0.44, 1.00)
Age category <65 years 172 108 0.66 (0.45, 0.97)
≥65 years 86 58 0.66 (0.39, 1.12)
Disease type at screening
Visceral 182 118 0.67 (0.47, 0.97)
Non-visceral 76 48 0.65 (0.36, 1.16)
Subgroup n Events HR* (95% CI)
0.2 0.4 0.6 0.8 1.0 1.2 1.4 1.6
Pertuzumab arm better
Control arm better
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Overall Response Rate (ITT Population with Measurable Disease at Baseline)
Based on best overall response according to RECIST Version 1.1. NE: Patients who did not have any evaluable post-baseline assessments.
95% CIs were computed using the Clopper–Pearson approach. 95% difference in ORR between treatment arms with associated 95% CIs calculated using the Hauck–Anderson approach.
CR, complete response; NE, not evaluable; PR, partial response; SD, stable disease.
63,3
55,7
7,3
0,9
56,0 54,7
26,6 27,4
5,5
12,3
4,6 4,7
0
10
20
30
40
50
60
70
Pertuzumab + Trastuzumab + AI (n = 109)
Trastuzumab + AI (n = 106)
Pa
tie
nts
, %
Δ ORR = 7.6% (95% CI –6.0, 21.3)
Chi-squared p = 0.2537
ORR CR PR SD PD NE ORR CR PR SD PD NE
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Most Common Adverse Events (Incidence ≥20%; Safety Population)
Pertuzumab + Trastuzumab + AI
(n = 127)
Trastuzumab + AI
(n = 124)
Diarrhea 70 (55.1) 45 (36.3)
Alopecia 36 (28.3) 40 (32.3)
Nausea 41 (32.3) 32 (25.8)
Asthenia 39 (30.7) 31 (25.0)
Arthralgia 37 (29.1) 29 (23.4)
Edema peripheral 31 (24.4) 22 (17.7)
Vomiting 29 (22.8) 22 (17.7)
Anemia 26 (20.5) 18 (14.5)
Data are number of patients, n (%).
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Worst LVEF While on Treatment (Safety Population)
Data are number of patients, n (%).
Local assessment by ECHO or MUGA; change from baseline was only calculated where the type of scan was the same as at baseline.
* Seven patients had an LVEF of exactly 45%.
† Eight patients discontinued before post-baseline LVEF assessment was due, two patients discontinued and left the study before LVEF was completed,
one patient discontinued and a post-baseline assessment was not done (site error).
LVEF Pertuzumab + Trastuzumab + AI
(n = 127)
Trastuzumab + AI
(n = 124)
>45% 110 (86.6) 112 (90.3)
40–45% and ≥10% fall
from baseline* 6 (4.7) 4 (3.2)
<40% 5 (3.9) 3 (2.4)
No LVEF measurement
on treatment† 6 (4.7) 5 (4.0)
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Conclusions
• PERTAIN met its primary PFS objective:
Pertuzumab + Trastuzumab + AI was superior to Trastuzumab +
AI in postmenopausal women with HER2-positive/hormone
receptor-positive LA/MBC
• Secondary efficacy endpoints (ORR and DoR) supported the primary
PFS analysis
• Subgroup analyses were generally consistent with the primary analysis
• Pertuzumab + Trastuzumab + AI was well tolerated and no new safety signals
were identified
Conclusions
HER2+ MBC: Still an unmet need...
100
80
60
40
20
0
0 12 24 36 48 60
Time From Diagnosis, months
Pro
bab
ility
of
Su
rviv
al, %