Pertuzumab en cancer de mama con sobreexpresión de.pptx

PERTUZUMAB EN CANCER DE
MAMA DE HER2 POSITIVO
Eduardo cruz
Asesor : Dr. Munive

AGENDA
• 1.características epidemiologias HER 2 +
• 2. PERTUZUMAB características generales
• Vías moleculares cancer de mama HER2+
• 3. PERTUZUMAB EN NEOADYUVANCIA
• 4. PERTUZUMAB EN ADYUVANCIA
• 5. PERTUZUMAB EN PRIMERA LINEA
• 6. TOXICIDADES
• BERENICE
• NCCN/ESMO INDICACIONES DE PERTUZUMAB
• CASO CLINICO
• 7 CONCLUSIONES

• Representa aproximadamente el 15-
20 % de todos los cánceres de
mama.
• Amplificación del gen HER2 
sobreexpresión de la proteína HER2.
• Comportamiento biológico agresivo
• Se asocia con una DFS más corta y
peores tasas OS que otros subtipos
de cáncer de mama.
CANCER DE MAMA SUBTIPO HER2 POSITIVO
Posibilidad única de utilizar un enfoque de tratamiento dirigido.

HER 2
• Receptor de TIROSINA QUINASA
perteneciente a la familia del
receptor de factor de
crecimiento epidérmico humado.
• Regulación del crecimiento
celular, la supervivencia y la
diferenciación.
La sobreexpresión de HER2 proliferación celular inhibición la apoptosis  Cancer

Representación esquemática del proceso de dimerización de los
receptores HER.

ROLE IN SIGNALING PATHWAYS
UNION DE LIGANDO ESPECIFICO
HER 2 CONFORMACION ACTIVADA DE
FORMA CONSTITUTIVA
“PAREJA DE DIMERIZACION PREFERIDA”
CON LA MAS POTENTE ACTIVIDAD
KINASA.
- HER2/HER3

HER2/
HER3
HER2/HER3
HER2/HER2
HER1/HER2
HER2/HER4

ACCION ONCOGÉNICA DE HER2
AMPLIFICACION
(Her2/neu)
SOBREEXPRESION
HETERODIMERIZA
CION
ACTIVACIÓN DE
VIAS DE
SEÑALIZACIÓN
CELULAR
CRECIMIENTO
TUMORAL Y
CANCER

PERTUZUMAB
Anticuerpo monoclonal humanizado.
Okines, F. C., & Cunningham, D. (2012). Trastuzumab: a novel standard option for patients with HER-2-positive advanced gastric or gastro-oesophageal junction cancer.
EVITA LA DIMERIZACION DE LOS RTK
DE LA FAMILIA HER 2
Mecanismo de acción complementario a
trastuzumab  sinergismo

Se une al Dominio II de la
porción extracelular de HER 2

Pertuzumab bloquea la accion del ligando
Neuregulin 1-2 e inhibe la activación de la via
de señalización PI3k/AKT/MTOR
Estimula la citotoxicidad celular dependiente
de anticuerpos

Hubalek, M., Brantner, C., & Marth, C. (2011). Role of pertuzumab in the treatment of HER2-positive breast cancer. Breast Cancer : Ta
and Therapy, 4, 65-73.

Toxicidades
• The results of a recently published meta-analysis of 14 Phase II trials, which included 598 patients, demonstrated that pertuzumab (exposure ranging from a
median of three cycles to a median of 26 cycles) was generally well tolerated.
• The incidence of LVSD was low, with most events being asymptomatic and detected at scheduled evaluations.
• The median timing of LVSD and HF was around cycle 4 (range 1–15) with 34/39 (87%) events occurring between cycles 1 and 7. Additionally, when
pertuzumab was administered in combination with trastuzumab or nonanthracycline-containing cytotoxic chemotherapy, there was no marked increase in
observed cardiac dysfunction.
• In this analysis of 598 unique atients exposed to pertuzumab, 35 (5.9%) cases of asymptomatic LVSD and four (0.7%) cases of symptomatic HF were
reported.
• Results from the completed NEOSPHERE, TRYPHAENA, and CLEOPATRA trials also indicate a low incidence of symptomatic and asymptomatic LVSD.
• Gastrointestinal toxicities (diarrhea, nausea, vomiting, and abdominal pain) and fatigue are the most frequently reported AEs associated with single-agent
therapy. Diarrhea and rash are common events that increased with pertuzumab in combination with Chemotherapy, compared with chemotherapy alone.
• The most common AEs during dual therapy with pertuzumab and trastuzumab in metastatic breast cancer (BO17929) were diarrhea, fatigue, nausea, and
rash.18 The majority of these AEs were NCI-CTC grade 1 or 2 in everity.
• The mechanisms behind diarrhea and rash are unknown, but similar side effects are observed with other agents that cause HER1 inhibition. The most
frequently occurring AEs during neoadjuvant treatment of patients with locally advanced breast cancer, using pertuzumab and trastuzumab in combination
with chemotherapy, were alopecia, neutropenia, diarrhea, nausea, fatigue, rash, and mucosal inflammation.
• Adding pertuzumab to the trastuzumab plus docetaxel regimen did not notably affect the overall afety profile, and the tolerability of pertuzumab plus
docetaxel was also broadly comparable to the triple regimen.
• Patients receiving trastuzumab and pertuzumab without ocetaxel in the neoadjuvant setting reported notably fewer AEs across most body systems,
compared to patients who received treatments containing chemotherapy.
• Serious or severe infusion- Related symptoms have been rarely observed in patients (0,1%) receiving pertuzumab.

HER2 Y CARDIO-TOXICIDAD
• PERTUZUMAB: Anticuerpo monoclonal
humanizado (IgG 1) dirigido contra el
dominio extracelular del receptor del
HER2 neu.
• Cardiotoxicidad: Tipo II  Reducción de la
contractibilidad acompañado en algunos
casos de necrosis de miocitos en pequeña
cantidad; Función ventricular se recupera
al interrumpir el tratamiento: Reversible.
Ruiz E et al, Cardio-oncología en cáncer de mama y en cáncer de próstata, 2021
Sandoo A et al, Breast cancer therapy and cardiovascular risk: focus on Trastuzumab, Vasc Health Risk Manag, 11-2015
Abbreviations: ANG II, angiotensin II; eNOS, endothelial nitric oxide synthase; HER, human epidermal
growth receptor; NO, nitric oxide; ROS, reactive oxygen species
Terapias HER2-
target

MECANISMOS DE CARDIOTOXICIDAD CON
TERAPIAS HER2-TARGET
Mecanismo Acción: Neuregulina es una
proteína producida por el endotelio
microvascular coronario y el endocardio.
Esta se une al receptor HER4, el cual se
heterodimeriza con el HER2, esta unión
favorece la fosforilación del ATP, el
acoplamiento mecánico al miocito, inhibe la
producción de ROS y disminuye la apoptosis.
El trastuzumab al bloquear HER2 en los
cardiomiocitos no permitirá que se dimerice
con el HER4, inhibiendo los efectos favorables
de la neuregulina.
Ruiz E et al, Cardio-oncología en cáncer de mama y en cáncer de próstata, 2021
PERTUZUMAB

Cardiotoxicidad con Terapias HER2-target
Kondapalli L, Cardiotoxicity: an unexpected consequence of HER2-Targeted therapies, 2016

J.ˇCelutkien ̇eet al, Imaging for cardio-oncology; European Journal of Heart Failure (2020)22,1504–1524

OPEN-LABEL PHASE II NEOSPHERE STUDY:
NEOADJUVANT TRASTUZUMAB/PERTUZUMAB
Primary endpoint: pCR (ITT)
12 semanas

NEOSPHERE: NEOADJUVANT TRASTUZUMAB/PERTUZUMAB
+ CT INCREASES PCR RATES
Gianni. Lancet Oncol. 2012;13:25.
pCR in ITT Population (Primary Endpoint)
P values vs TH: *P = .0141;
†P = .0198; ‡P = .003.
100
80
60
40
20
0
pCR
(%)
TH (n = 107) THP (n = 107) HP (n = 107) TP (n = 96)
29.0
45.8*
16.8†
24.0‡

Análisis a los 5 años del estudio NeoSphere…

Objetivo primario: Evaluar el perfil de seguridad cardiaca
1. Gianni. Lancet Oncol. 2012;13:25. 2. Schneeweiss. Ann Oncol. 2013;24:2278.
pCR assessed
at surgery
PHASE II TRYPHAENA CARDIAC SAFETY STUDY: DUAL HER2 TARGETING ±
ANTHRACYCLINE TX
6 CICLOS Q3W
A=73
C=77
B=75
Chemo-naive women
with HER2+ EBC
(operable or
LA/inflammatory);
Primary tumor > 2 cm
LVEF mayor/igual 55%
Basal
(N = 225)
Objetivo secundario: pCR (ypT0/is)
FEC + HP x 3 cycles →
THP x 3 cycles
TCHP x 6 cycles
FEC x 3 cycles →
THP x 3 cycles
Adjuvant tx
to complete
1 yr of
trastuzumab

MEDIA DE VARIACIÓN EN LA FEVI DURANTE EL TRATAMIENTO.
La media de LVEF cayo por
debajo de la línea de base
durante el tratamiento en
todos los brazos, sin embargo,
la media de caída no fue mas
de 7%.

Overall, 24 patients experienced significant LVEF declines during the study. The declines were asymptomatic in 21
of these patients.

Schneeweiss. Ann Oncol. 2013;24:2278.
FEC + HP x 3→THP x 3
(n = 73)
pCR
±
95%
CI
(%)
FEC x 3→THP x 3
(n = 75)
TCHP x 6
(n = 77)
100
80
60
40
20
0
ypT0/is and ER and PgR negative
ypT0/is and ER and/or PgR positive
46.2
79.4
48.6
65.0
50.0
83.8
A B C
57.3% 66.2
Phase II TRYPHAENA Cardiac Safety Study: Dual HER2 Targeting ± Anthracycline Tx
ypT0/is = pCR
61.6%

T: TRASTUZUMAB
P: PACLITAXEL
C: CARBOPLATINO
TRAIN-2 STUDY DESING
Phase 3 trial TRAIN-2: Neoadjuvant chemotherapy with or without anthracyclines
in the presence of dual HER2 blockade for HER2-positive breast cancer.
Primary endpoint: pCR in breast ypT0/is ypN0
N=219
N=219
*PTC: Paclitaxel/trastuzumab/carboplatino
†5FU/Epirrubicina/ciclofosfamida

Phase 3 trial TRAIN-2: Neoadjuvant chemotherapy with or without anthracyclines
in the presence of dual HER2 blockade for HER2-positive breast cancer.
67% 68%
ANTRACICLINAS
141/212 140/206
Primary endpoint: pCR in breast ypT0/is ypN0
Median follow up 19 Month

APHINITY: Study Design
• International, randomized, double-blind, placebo-controlled phase III trial[1,2]
• Primary endpoint: IDFS per modified STEEP definition[3] (excludes second primary non-BC as event)
• Secondary endpoints: IDFS per STEEP definition,[3] OS, distant recurrence-free survival, DFS, recurrence-free
interval, safety, cardiac safety, health-related QoL
Pts with HER2+ EBC, no prior invasive
BC or anticancer tx or radiotherapy,
node positive + any tumor size (no T0)
or node negative + tumor size > 1 cm,*
BL LVEF ≥ 55%
(N = 4805)
Pertuzumab + Trastuzumab + CT†
(n = 2400)
Placebo + Trastuzumab + CT†
(n = 2405)
10-yr follow-up
Surgery
Wk 52
Stratified by CT, nodal status, HR status,
geographic region, protocol version (A vs B)
*Or node negative + 1 of following: for tumors > 0.5, ≤ 1 cm, at least 1 histologic/nuclear grade 3; ER negative and PgR negative;
aged < 35 yrs. †Tx initiated ≤ 8 wks post surgery. Permitted CT: standard anthracycline or nonanthracycline regimens. Endocrine and/or
radiotherapy could be started at end of adjuvant CT.

Slide credit: clinicaloptions.com
von Minckwitz G, et al. ASCO 2017. Abstract LBA500.
APHINITY: Pt Characteristics in ITT Population
Characteristic, n (%) Pertuzumab
(n = 2400)
Placebo
(n = 2404)
Nodal status
 0 positive nodes + T ≤ 1 cm
 0 positive nodes + T > 1 cm
 1-3 positive nodes
 ≥ 4 positive nodes
90 (3.8)
807 (33.6)
907 (37.8)
596 (24.8)
84 (3.5)
818 (34.0)
900 (37.4)
602 (25.0)
Adjuvant CT regimen (randomized)
 Anthracycline containing
 Nonanthracycline containing
1865 (77.7)
535 (22.3)
1877 (78.1)
527 (21.9)
HR status (central determination)
 Negative (ER- and PgR-)
 Positive (ER+ and/or PgR+)
864 (36.0)
1536 (64.0)
858 (35.7)
1546 (64.3)
Protocol version
 A
 Amendment B*
1828 (76.2)
572 (23.8)
1827 (76.0)
577 (24.0)
*Capped node-negative enrollment in November 2012 (recruitment started November 2011); added 1000 node-positive pts and
increased sample size to 4800 pts total.

APHINITY: Interim Analysis of IDFS
• Data cutoff in December 2016 after 379 IDFS
events (median f/u: 45.4 mos)
• Most first events were visceral, distant
von Minckwitz G, et al. ASCO 2017. Abstract LBA500. Reproduced with permission.
IDFS
(%)
Mos
Pertuzumab
Placebo
Stratified HR: 0.81
(95% CI: 0.66-1.00; P = .045)
Pts at Risk, n
IDFS Event, n (%) Pertuzumab
(n = 2400)
Placebo
(n = 2404)
All pts with IDFS event 171 (7.1) 210 (8.7)
First event type
 Distant recurrence
 Locoregional recurrence
 Contralateral BC
 Death
112 (4.7)
26 (1.1)
5 (0.2)
28 (1.2)
139 (5.8)
34 (1.4)
11 (0.5)
26 (1.1)
All pts with distant recurrence 119 (5.0) 145 (6.0)
First distant recurrence site
 Lung/liver/pleural effusion
 CNS
 Other
 Bone
43 (1.8)
46 (1.9)
9 (0.4)
21 (0.9)
61 (2.5)
45 (1.9)
9 (0.4)
30 (1.2)
ITT population.
100
80
60
40
20
0
0 6 12 18 24 30 36 42 48
98.6% 96.4% 94.1% 92.3%
98.8% 95.7% 93.2% 90.6%
Pertuzumab
Placebo
2400
2404
2309
2335
2275
2312
2236
2274
2199
2215
2153
2168
2101
2108
1687
1674
879
866
(Expected: 89.2%)

APHINITY: Secondary Endpoints
3-Yr Endpoint, % Pertuzumab
(n = 2400)
Placebo
(n = 2404)
HR (95% CI)* P Value
IDFS (modified STEEP)
 Node positive
 Node negative
 HR positive
 HR negative
94.1
92.0
98.4
94.8
92.8
93.2
90.2
97.5
94.4
91.2
0.81 (0.66-1.00)
0.77 (0.62-0.96)
1.13 (0.68-1.86)
0.86 (0.66-1.13)
0.76 (0.56-1.04)
.045
.019
.644
.277
.085
IDFS (STEEP) 93.5 92.5 0.82 (0.68-0.99) .043
OS† 97.7 97.7 0.89 (0.66-1.21) .467
DRFI 95.7 95.1 0.82 (0.64-1.04) .101
ITT population.
*Stratified HR for overall IDFS, unstratified HR for IDFS subgroups.
†OS for first interim analysis at 26% of target events.

APHINITY: Safety
Outcome, n (%)
Pertuzumab
(n = 2364)
Placebo
(n = 2405)
Treatment Difference
(95% CI)
Primary cardiac endpoint
 Heart failure NYHA III/IV + LVEF drop*
 Cardiac death†
 Recovered according to LVEF
17 (0.7)
15 (0.6)
2 (0.08)
7 (0.3)
8 (0.3)
6 (0.2)
2 (0.08)
4 (0.2)
0.4% (0% to 0.8%)
Asymptomatic or mildly symptomatic LVEF drop‡ 64 (2.7) 67 (2.8) -0.1% (-1.0% to 0.9%)
Grade ≥ 3 AEs
 Neutropenia
 Febrile neutropenia
 Decreased neutrophil count
 Diarrhea
• Anthracycline CT, n/N (%)
• Nonanthracycline CT, n/N (%)
 Anemia
385 (16.3)
287 (12.1)
228 (9.6)
232 (9.8)
137/1834 (7.5)
95/528 (18.0)
163 (6.9)
377 (15.7)
266 (11.1)
230 (9.6)
90 (3.7)
59/1894 (3.1)
31/510 (6.1)
113 (4.7)
Fatal AE 18 (0.8) 20 (0.8)
*LVEF drop defined as ejection fraction decrease ≥ 10% from BL to below 50%. †Determined by Cardiac Advisory Board per
prospective definition. ‡Secondary cardiac endpoint.

APHINITY: 6-Yr Follow-up for IDFS in ITT Population
Piccart. JCO. 2021;39:1448.
Yr From Random Assignment
IDFS
(%)
3 Yr 6 Yr
100
80
60
40
20
0 1 2 3 4 5 6
94.1%
Pertuzumab
(n = 2400)
Placebo
(n = 2404)
90.6%
87.8%
93.2%
Events, n (%)
Stratified HR (95% Cl)
Median f/u, mo
221 (9.2) 287 (11.9)
0.76 (0.64-0.91)
74.1
6 yr from randomization
Difference in event-free rate, %
(95% CI for difference)
2.8
(1.0-4.6)
Patients at Risk, n
Pertuzumab
Placebo
2400 2277 2198 2122 2055 1978 1482
2404 2312 2215 2134 2039 1967 1421

APHINITY: Conclusions
• Adjuvant pertuzumab + trastuzumab + CT significantly reduced risk of recurrence events vs
placebo + trastuzumab + CT in pts with HER2+ EBC
• HR: 0.81 (95% CI: 0.66-1.00; P = .045)
• Pts with node-positive or HR-negative disease had greatest IDFS benefit
• Most recurrences to distant sites (pertuzumab: 4.7%; placebo: 5.8%)
• Investigators concluded:
• No new safety signals identified with addition of pertuzumab to trastuzumab + CT
• Low incidence of cardiac events
• No difference in fatal AE rates between arms (0.8% for both)
• Increased diarrhea incidence with pertuzumab (any-grade: 71.2% vs 45.2% with placebo)
• Ongoing follow-up important to determine long-term IDFS, safety, and OS

Phase III CLEOPATRA: Trastuzumab and
Docetaxel ± Pertuzumab in HER2+ MBC
• Primary endpoint: PFS (independently assessed)
• Secondary endpoints: PFS (investigator assessed), ORR, OS, safety
Women with
previously untreated,
HER2+ locally
recurrent/metastatic
breast cancer
(N = 808)
Trastuzumab 6 mg/kg Q3W* +
Docetaxel 75-100 mg/m2 Q3W† +
Pertuzumab 420 mg Q3W‡
(n = 402)
Trastuzumab 6 mg/kg Q3W* +
Docetaxel 75-100 mg/m2 Q3W† +
Placebo Q3W
(n = 406)
Treatment until
disease progression
or unacceptable
toxicity
Stratified by geographic region
and previous (neo)adjuvant chemotherapy
*Trastuzumab 8-mg/kg loading dose. †Minimum of 6 docetaxel cycles recommended; < 6 cycles
permitted for unacceptable toxicity or PD. ‡Pertuzumab 840-mg loading dose.
Baselga J, et al. N Engl J Med. 2012;366:109-119. Slide credit: clinicaloptions.com

Baselga J, et al. N Engl J Med. 2012;366:109-119.
Trastuzumab and Docetaxel ± Pertuzumab in HER2+
MBC (CLEOPATRA): PFS
PFS independently assessed.
100
90
80
70
60
50
40
30
20
10
0
PFS
(%)
Mos
40
0 5 10 15 20 25 30 35
HR: 0.62 (95% CI: 0.51-0.75);
P < .001)
Pertuzumab (median: 18.5 mos)
Control (median: 12.4 mos)

Trastuzumab and Docetaxel ±
Pertuzumab in HER2+ MBC
(CLEOPATRA): OS
• Second interim analysis of OS (median follow-up: 30 mos)
• Significant, confirmatory, crosses stopping boundary
Swain SM, et al. Lancet Oncol. 2013;14:461-471.
OS Pmab Placebo HR
(95% CI)
P
Value
3-yr estimated OS,
%
66 50 0.66
(0.52-0.84)
.0008
Median OS, mos Not
reached
37.6 -- --
Pertuzumab, trastuzumab, docetaxel
Placebo, trastuzumab, docetaxel
100
80
60
40
20
0
OS
(%)
Mos
55
0 5 10 20 25 30 35 40 45 50
15

Select Adverse Events (Grade ≥ 3), %
Pertuzumab
(n = 407)
Placebo
(n = 397)
Neutropenia 48.9 45.8
Febrile neutropenia 13.8 7.6
Leukopenia 12.3 14.6
Diarrhea 7.9 5.0
Peripheral neuropathy 2.7 1.8
Left ventricular systolic dysfunction 1.2 2.8
Baselga J, et al. N Engl J Med. 2012;366:109-119.
Trastuzumab and Docetaxel ± Pertuzumab in HER2+
MBC (CLEOPATRA): Safety

CLEOPATRA: Survival With Pertuzumab,
Trastuzumab, and Docetaxel in HER2+ MBC
Swain. Lancet Oncol. 2020;21:519.
Landmark OS: 37%
Events: 235 (58.5%)
Landmark OS: 23%
Events: 280 (69.0%)
HR: 0.69 (95% CI: 0.58-0.82)
P = .0001
100
80
60
40
20
0
0 10 20 30 40 50 60 70 80 90 100 110 120 130
OS
(%)
Mo
P + H + D
PBO + H + D
402
406
371
350
318
289
269
230
228
181
188
149
165
115
150
96
137
88
120
75
71
44
20
11
0
1
0
0
57.1
40.8
Median OS,
Mo
P + H + D
PBO + H + D
End-of-Study OS in ITT Population*
8 yr
Patients at Risk, n
18.7
12.4
Median PFS,
Mo
P + H + D
PBO + H + D
Landmark PFS: 16%
Events: 304 (76%)
Landmark PFS: 10%; Events: 329 (81%)
HR: 0.69 (95% CI: 0.59-0.81)
P = .0001
100
80
60
40
20
0
0 10 20 30 40 50 60 70 80 90 100 110 120
PFS
(%)
Mo
402
406
284
223
179
110
121
76
93
53
71
43
60
35
52
30
43
23
34
21
21
10
6
4
0
0
End-of-Study PFS in ITT Population*
8 yr
*Crossover patients were analyzed in the placebo arm.

Centrally confirmed HER2-
positive locally recurrent,
unresectable or metastatic
BC (mBC)
≤1 hormonal regimen
for mBC
Prior (neo)adjuvant
systemic Rx including
trastuzumab allowed if
followed by DFS ≥12 mo
Baseline LVEF ≥50%;
no CHF or LVEF <50% during
or after prior trastuzumab
Trastuzumab (T)
Docetaxel (D) (≥6 cycles recommended)
Trastuzumab
Docetaxel (≥6 cycles recommended)
Placebo (Pla)
Pertuzumab (Ptz)
1:1
N = 406
N = 402
R
Primary endpoint: Independently assessed progression-free survival (PFS)
CLEOPATRA Study Design
Baselga J et al. N Engl J Med 2012;366(2):109-19.

Independently
assessed
Ptz + T + D
(n = 402)
Pla + T + D
(n = 406)
Hazard
ratio
p-
value
Median PFS 18.5 mo 12.4 mo 0.62 <0.001
Deaths in interim
overall survival
analysis, n (%)*
69 (17.2%) 96 (23.6%) 0.64 0.005
* Not significant because analysis did not meet O’Brien-Fleming stopping
boundary; a strong trend was evident toward overall survival benefit with
pertuzumab
CLEOPATRA: Primary
Efficacy Analysis
Baselga J et al. N Engl J Med 2012;366(2):109-19.

CLEOPATRA: Overall Survival (Confirmatory
Analysis)
• Crossed O’Brien-Fleming stopping boundary and was therefore deemed statistically
significant.
• Analysis was performed after 267 deaths and 69% of the prespecified total number
of events for the final analysis had occurred.
• Median follow-up in both arms = 30 months
With permission from Swain SM et al. Proc SABCS 2012;Abstract P5-18-26.

CLEOPATRA: Overall Survival in Predefined
Subgroups

CLEOPATRA: Follow-Up Analysis — Updated
Investigator-Assessed PFS
• At the time of the data cutoff, 296 (72.9%) patients on the placebo arm and 257
(63.9%) on the pertuzumab arm had experienced a PFS event. These results
were exploratory only.
• This updated analysis of investigator-assessed PFS was consistent with the
results from the primary PFS analyses.

CLEOPATRA: Select All-Grade
Adverse Events (AEs)
AEs with ≥25% incidence or
≥5% difference between arms
Ptz + T + D
(n = 408)
Pla + T + D
(n = 396)
Diarrhea 68.1% 48.2%
Rash 36.5% 24.0%
Mucosal inflammation 27.5% 19.9%
Peripheral edema 24.8% 30.8%
Pruritus 16.7% 10.1%
Constipation 15.4% 25.5%
Febrile neutropenia 13.7% 7.6%
Dry skin 10.8% 5.8%
Swain SM et al. Proc SABCS 2012;Abstract P5-18-26.
Ptz + T + D did not increase the incidence of cardiac adverse events compared to
Pla + T + D.

CLEOPATRA: Grade ≥3 Adverse Events
Grade ≥3 adverse events
(incidence ≥5%)
Ptz + T + D
(n = 408)
Pla + T + D
(n = 396)
Neutropenia 49.0% 46.0%
Febrile neutropenia 13.7% 7.6%
Leukopenia 12.3% 14.9%
Diarrhea 9.1% 5.1%
Mucosal inflammation (Grade ≥3) was reported in 1% of patients in the placebo
arm and 1.5% of patients in the pertuzumab arm.

Author Conclusions
 At the second interim analysis, CLEOPATRA demonstrated a
statistically significant and clinically meaningful improvement in
OS with the addition of pertuzumab to trastuzumab/docetaxel as
first-line therapy for HER2-positive mBC.
– As a consequence of the statistically significant survival benefit,
patients who were still receiving study treatment on the placebo
arm were offered crossover to the pertuzumab arm.
– The final exploratory analysis of OS is event driven and will take
place when 385 events have been reached.
 No new safety signals compared to the primary analysis were
reported with 1 more year of follow-up.
 These results indicate that combined HER2 blockade and
chemotherapy with pertuzumab/trastuzumab/docetaxel can be
considered a standard first-line therapy for patients with HER2-
positive mBC.

Investigator Commentary: Confirmatory OS Analysis of
CLEOPATRA — Pertuzumab with Trastuzumab and Docetaxel as
First-Line Therapy for HER2-Positive mBC
Changes in the first-line setting for patients with mBC have been coming
along rapidly. The primary analysis of CLEOPATRA reported a significant
improvement in PFS, and, as expected, this current analysis reported an
improvement in OS. The authors confirmed little increase in toxicity
compared to dual taxane/trastuzumab therapy. This report solidifies that
the appropriate strategy is to administer a taxane in combination with
trastuzumab and pertuzumab in the first-line setting.
Recent data have shown similar efficacy with docetaxel/trastuzumab and
vinorelbine/trastuzumab but lower toxicity with the vinorelbine versus
the docetaxel combination. The results of CLEOPATRA have given us
impetus for an ongoing trial called VELVET that I have the honor of
leading. This Phase II trial is for patients who are eligible to receive first-
line therapy for HER2-positive mBC. In the first cohort, which we have
already enrolled, patients will receive pertuzumab and trastuzumab
sequentially. The second cohort will receive pertuzumab and
trastuzumab together. Vinorelbine will be given to both cohorts.
Interview with Edith A Perez, MD, January 17, 2013

*Pertuzumab is approved for N+ disease in Belgium

Tratamiento sistémico neoadyuvante
en cáncer de mama localmente
avanzado HER2 Positivo
MR Eduardo Cruz

Pertuzumab en cancer de mama con sobreexpresión de.pptx

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