her2. dr
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Dr. Luis M. Zetina ToacheCancer Consultants GTTRANSCRIPT
CANCER DE MAMAHER 2+
Dr. Luis Miguel Zetina Toache
Cancer Consultants GT
Burstein HJ, et al. N Engl J Med. 2005;353:1652-1654.
Trastuzumab:
Copyright © 2005 Massachusetts Medical Society. All rights reserved.
Novel anti-HER2 therapies:
Baselga J Ann Oncol 2010;21:vii36-vii40
HER pathways are of critical importance in cancer
“Beginning with benign hyperplasia and extending through invasive metastasis, a number of studies demonstrate that [HER family] receptor activation can play a major role in all aspects of cancer development.”
— Sliwkowski MX, “Alterations in the ErbB Signaling Network in Breast Cancer”1
1. Sliwkowski MX. In: Harris JR, Lippman ME, Morrow M, Osborne CK, eds. Diseases of the Breast. 3rd ed. Philadelphia, PA: Lippincott Williams & Wilkins; 2004:415-426.
Structure of a HER family receptor1
HER family receptors exist on the surface of cells and contain
extracellular, transmembrane,
and tyrosine kinase domains.
Each of these domains is responsible for a different
aspect of HER signaling pathways1
1. Burgess AW, Cho HS, Eigenbrot C, et al. Mol Cell. 2003;12:541-542.
Components of HER family receptors
Activation of HER receptors has numerous cellular effects and is a complex process
Receptor activation is a complex, multistep process
1. Ménard S, Tagliabue E, Campiglio M, Pupa SM. J Cell Phys. 2000;182:150-162. 2. Sliwkowski MX. In: Harris JR, Lippman ME, Morrow M, Osborne CK, eds. Diseases of the Breast. 3rd ed. Philadelphia, PA: Lippincott Williams & Wilkins; 2004:415-426. 3. Olayioye MA, Neve RM, Lane HA, Hynes NE. EMBO J. 2000;19:3159-3167.
Role of HER2 gene expression in breast carcinoma. Ménard S, Tagliabue E, Campiglio M, Pupa SM. Copyright © 2000 J Cell Phys; Reprinted with permission of Wiley-Liss, Inc., a subsidiary of John Wiley & Sons, Inc.
Signal Transduction by the HER Family Promotes Proliferation, Survival, and Invasiveness
Adapted from Hudis. N Engl J Med. 2007;357:39
Akt
SOS
RAS
RAF
MEK
VEGF
MAPK
P
P
PP
Receptor specificligands HER1, HER2,
HER3*, or HER4HER2
HER1(EGFR)
HER2HER4
HER3
Tyrosine kinasedomains
Plasmamembrane
PI3K
Cell proliferationCell survivalCell mobility and invasiveness
Cytoplasm
NucleusTranscription
Receptor regulation through internalization
Receptor internalization is an important regulator of HER family signaling in normal
cells, and is retained in cancerous cells1
: 1. Sliwkowski MX. In: Harris JR, Lippman ME, Morrow M, Osborne CK, eds. Diseases of the Breast. 3rd ed. Philadelphia, PA: Lippincott Williams & Wilkins; 2004:415-426.
Adapted with permission from Lippincott Williams & Wilkins. Sliwkowski MX. In: Harris JR, Lippman ME, Morrow M, Osborne CK, eds. Diseases of the Breast. 3rd ed. Philadelphia, PA: Lippincott Williams & Wilkins; 2004:415-426.
Normal (1x)~ 25,000-50,000 HER2
receptors
Overexpressed HER2 (10-100x)
up to ~ 2,000,000 HER2 receptors
Excessive cellular division
HER2 Overexpression in Breast Cancer
Pegram MD, et al. Cancer Treat Res. 2000;103:57-75. Ross JS, et al. Am J Clin Pathol. 1999;112(suppl 1):S53-S71. Slamon DJ, et al. Science. 1987;235:177-182.
HER2 is overexpressed in ~ 25% of breast cancers
HER2 Overexpression Shortens Survival
HER2 oncogeneamplification
HER2 oncoproteinoverexpression
Shortened survival
Median Survival From First Diagnosis
HER2 overexpressing 3 years HER2 normal 6-7 years
Slamon DJ, et al. Science. 1987;235:177-182. Slamon DJ, et al. Science. 1989;244:707-712.
TRATAMIENTO DE CÁNCER DE MAMA
HER 2 POSITIVO
Estimación de las recurrencias prevenidas por el uso de trastuzumab en EBC en USA
(M Danese; SABCS 08 poster 2107)
• Los datos del SEER estiman que Trastuzumab adyuvante previene 2,800 recurrencias en 1 año en USA
• Extrapolado en un período de 25 años podría prevenir más de 50,000 recurrencias
• Estos resultados son consistentes con los europeos de Weisgerber-Kriegl presentados en ASCO 2008
PILAR DE TRATAMIENTO PARA PTES HER 2 POSITIVAS
clinicaloptions.com/oncologyNew Directions in the Treatment of Patients With HER2-Positive Breast Cancer
Burstein HJ, et al. N Engl J Med. 2005;353:1652-1654.
Trastuzumab: Mecanismo de accion
Copyright © 2005 Massachusetts Medical Society. All rights reserved.
Estudios de Herceptin en Adyuvancia:>13,000 pacientes tratados
NCCTG N9831 (USA)
HERA (ex-USA) BCIRG 006 (global)
NSABP B-31 (USA)
Piccart-Gebhart et al 2005; Romond et al 2005; Slamon et al 2006FISH, hibridización fluorescente in situ
IHC / FISH (n=5090)
Observación
1 año
2 años
IHC / FISH (n=3505)
1 año
1 año
FISH(n=3222)
1 año
1 año
IHC / FISH (n=2030)
1 año
DocetaxelDocetaxel + carboplatino
Doxorubicina + ciclofosfamida Herceptin
Quimioterapia
estándar Paclitaxel
Análisis combinado de NCCTG N9831 actualizado / NSABP B-31: Beneficio de DFS*
Perez et al 2007
Pacientes (%)
73.1%
86.4%
0 1 2 3 4 5 6 7
Años desde larandomización
77.6%
85.9%92.3%
87.9%
Seguimiento medio: 2.9 años
HR=0.48; p0.00001
ACPHACP
Eventos222397
n19891979
18541800
13471235
868753
522460
202168
48
No.at risk
*Eventos intención de tratamiento: enfermedad recurrente, cáncer de mama contralateral, muerte por 2ndo primario. DFS: sobrevida libre de enfermedad
0
20
40
60
80
100
52%
Actualización de NCCTG N9831 / NSABP B-31 – análisis combinado: beneficio de OS*
89.4%95.9%
92.7%
92.6%97.5% 94.6%
0
20
40
60
80
100
0 1 2 3 4 5
Años desde larandomización
HR=0.65; p=0.0007
ACPHACP
n19891979
18861863
14191376
938898
570562
217211
No.at risk
*Eventos intención de tratamiento: enfermedad recurrente, cáncer de mama contralateral, 2ndo primario, muerte Perez et al 2007
Pacientes (%)
35%
Estudios de Herceptin adyuvante:beneficio en DFS probado
Joensuu et al 2006; Perez et al 2007;Slamon et al 2006; Smith et al 2007
B-31 / N9831 ACPH 4
3BCIRG 006 ACDH
HERA H 1 año 2
V, vinorelbinaaSobrevida libre de recaída
0 1 2Favorece aHerceptin
No favorecea Herceptin
HR
Seguimiento medio a 2 años
BCIRG 006 DCarboH 3
FinHer VH / DHa 3
0 1 2Favorece aHerceptin
No favorece aHerceptin
HR
Estudios de Herceptin adyuvante:beneficio de OS probado
B-31 / N9831 ACPH
BCIRG 006 ACDH
HERA H 1 año
BCIRG 006 DCarboH
FinHer VH / DHa
4
3
2
Seguimiento medio en años
3
Joensuu et al 2006; Perez et al 2007;Slamon et al 2006; Smith et al 2007
3
Conclusions:The addition of 1 year of adjuvant trastuzumab significantly improved disease-free and overall survival among women with HER2-positive breast cancer. The risk–benefit ratio favored the nonanthracycline TCH regimen over AC-T plus trastuzumab, given its similar efficacy, fewer acute toxic effects, and lower risks of cardiotoxicity and leukemia. (Funded by Sanofi-Aventis and Genentech; BCIRG-006 ClinicalTrials .gov number, NCT00021255.)
Table 2. Therapeutic Index for Critical Clinical Events.* AC-T plus Clinical Event AC-T Trastuzumab TCH number of eventsTotal events 201 146 149Distant breast-cancer recurrence 188 124 144Grade 3 or 4 congestive heart failure 7 21 4Acute leukemia 6 1 1†
D. Slamon New England Journal of Medicine october 6, 2011 vol. 365
no. 14
APc3s x 3 ciclos
Pc3s x 4 ciclos
CMFc4s x 3 ciclos
APc3s x 3 ciclos
Pc3s x 4 ciclos
CMFc4s x 3 ciclos
Cirugía seguida deradioterapiaa
Cirugía seguida de radioterapiaa
Cirugía seguida de radioterapiaa
H + APc3s x 3 ciclos
H + P c3s x 4 ciclos
H c3s x 4 ciclos+ CMF c4s x 3 ciclos
H continuada c3shasta la semana 52
Estudio internacional, fase III, randomizado en CMLA: NOAH
AP, doxorubicina (60 mg/m2), paclitaxel (150 mg/m2); CMF, ciclofosfamida, metotrexate, fluorouracilo; H, Herceptin (8 mg/kg dosis de carga, luego 6 mg/kg);CMLA: cáncer de mama localmente avanzadolocally; P, paclitaxel (175 mg/m2); aPacientes positivos por receptor hormonal recibirán tamoxifeno adyuvante
CMLA HER2-positivo(IHC 3+ or FISH+)
CMLA HER2-negativo(IHC 0/1+)
n=115 n=113 n=99
Gianni et al 2007
Herceptin neoadyuvante duplica la tasa de respuesta patológica
0
10
20
30
40
50
Con H Sin H HER2 negativo
Con H Sin H HER2 negativo
Pacientes (%)
HER2 positivo HER2 positivo
pCR tpCR
43
23
17
38
2016
p=0.29
p=0.002p=0.003
p=0.43
tpCR: total pCR en mama y ganglios Gianni et al 2007
HER2-positive (%) HER2-negative (%) P value
5-yr RFS 77 94 <0.001
High Risk of Recurrence for Breast Cancer Patients with HER2-Positive Node Negative Tumors 1 cm or Smaller
Gonzalez-Angulo AM, et al. J Clin Oncol 2009;27(34):5700-6
Y los tumores menores de 2 cms, ganglios (-) ?
clinicaloptions.com/oncologyNew Directions in the Treatment of Patients With HER2-Positive Breast Cancer
Case 1: Woman With MBC and No Previous Trastuzumab Presentation: 58-yr-old woman was found to have
architectural distortion in the right breast, upper outer quadrant, on routine screening mammography
– Core needle biopsy confirmed invasive ductal carcinoma, estimated by imaging to be a T1 lesion
Treatment: She underwent lumpectomy/SLNB that revealed a 0.9-cm intermediate-grade invasive ductal carcinoma that was ER+/PgR+/HER2+ by FISH, with a Ki-67 value of 30%
– 2 sentinel nodes were removed and found to be uninvolved by cancer
T1 NO MO G2 ER/PR+ HER2+
clinicaloptions.com/oncologyNew Directions in the Treatment of Patients With HER2-Positive Breast Cancer
Case 1: Woman With MBC and No Previous Trastuzumab Follow-up: She received adjuvant radiation therapy followed by
letrozole for 1 yr, at which time she was seen by her oncologist for new cough and mild shortness of breath
– CT scan of the chest revealed a mild right pleural effusion and several nodules up to 1 cm in size in the right, middle, and lower lobes
– Biopsy revealed adenocarcinoma that was ER+/PgR-/HER2 3+ by IHC, consistent with breast primary
– No other metastases were detected by CT or bone scan
There are no clinical trials available at your center for which she is eligible. You review multiple treatment options with her and she tells you she would like to take the treatment that has the highest chance of leading to a response and to a prolonged survival, as she recently found out her daughter is pregnant with her first grandchild
clinicaloptions.com/oncologyNew Directions in the Treatment of Patients With HER2-Positive Breast Cancer
Case 1: Woman With MBC and No Previous Trastuzumab
What treatment option would you recommend at this time?
A. Trastuzumab plus chemotherapy
B. Trastuzumab plus aromatase inhibitor
C. Lapatinib plus capecitabine
D. Single-agent aromatase inhibitor
E. Trastuzumab single agent
clinicaloptions.com/oncologyNew Directions in the Treatment of Patients With HER2-Positive Breast Cancer
clinicaloptions.com/oncologyNew Directions in the Treatment of Patients With HER2-Positive Breast Cancer
Case 1: Woman With MBC and No Previous TrastuzumabWhat treatment option would you recommend at this time?
A. Trastuzumab plus chemotherapy (preferred choice)
B. Trastuzumab plus aromatase inhibitor
C. Lapatinib plus capecitabine
D. Single-agent aromatase inhibitor
E. Trastuzumab single agent
Single-Agent Trastuzumab in First-line Treatment of HER2+ MBC
Patients Response Rate, %
Median Time to Progression, Mos
HER2+ by IHC(N = 111)
26 3.5
HER2+ by FISH (n = 79)
34 4.9
Vogel CL, et al. J Clin Oncol. 2002; 20:719-726.
Herceptin Combinations as First-line Therapy for MBC: Pivotal Phase III Trial
Patients with HER2+ (IHC 2+/3+) MBC, no previous
chemotherapy, measurable
disease, KPS ≥ 60%
(N = 469)No previous
adjuvantAC
Paclitaxel(n = 96)
Herceptin+ Paclitaxel
(n = 92)
AC(n = 138)
Herceptin+ AC
(n = 143)
Previousadjuvant
AC
Slamon DJ, et al. N Engl J Med. 2001;344:783-792.
Herceptin in MBC: The Pivotal Trial
Treatment ObjectiveResponse Rate, %
Median TTP, Mos Median OS, Mos
Chemo 32 4.6 20.3
Chemo +Herceptin
50 7.4 25.1
Slamon DJ, et al. N Engl J Med. 2001;344:783-792.
P < .001 for all 3 comparisons.Despite crossover at TTP
Herceptin in Triple-Combination Regimens: Response Rates
ORR (%)
H + Carbo + T
H + V + T
H + E90 + C
H + E60 + C
H + Carbo + T
H + V + X
H + G + P
H + G + Carbo
H + G + P
H + E + T
H + Carbo + P every 3 wks
H + Carbo + P every wk
H + TLC D-99 + P
H + Carbo + T
H + Carbo + T
H + Cisplatin + T
H + Carbo + P
H + X + T
Forbes et al, 2006 (N = 130)
Wardley et al, 2006 (N = 111)
Robert et al, 2006 (N = 92)
Pegram et al, 2004 (N = 62)
Pegram et al, 2004 (N = 59)
Yardley et al, 2002 (N = 61)
Cortes et al, 2004 (N = 54)
Perez et al, 2005 (N = 48)
Perez et al, 2005 (N = 43)
Venturini et al, 2006 (N = 45)
Miller et al, 2002 (N = 45)
Yardley et al, 2006 (N = 41)
Fountzilas et al, 2004 (N = 40)
Chan et al, 2007 (N = 34)
Dirix et al, 2006 (N = 34)
Untch et al, 2004 (N = 26)
Untch et al, 2004 (N = 25)
Yardley et al, 2004 (N = 24)
0 10 20 30 40 50 60 70 80 90 100
Herceptin in Recommended First-line Combinations for HER2+ MBC
HER2+ disease without previous Herceptin: Herceptin plus
• Paclitaxel ± carboplatin
• Docetaxel
• Vinorelbine
• Capecitabine
HER2+ disease with previous Herceptin: Herceptin plus
• Other first-line agents
• Capecitabine
• Lapatinib (without cytotoxic therapy)
NCCN. Clinical practice guidelines in oncology: breast cancer. v2.2011.
SOSRAS
RAF
BasalTranscription
Machineryp160
Cross-talk Between Signal Transduction and Endocrine Pathways
Adapted from Johnston SRD. Clin Cancer Res. 2005;11:889s-899s.
ERE ER Target Gene Transcription
ER CBPPP P P
ER
Pp90RSK
AktP
MAPKP
CellSurvival
Cytoplasm
Nucleus
ER
P13-KP
P
PPP
P
CellGrowth
MEKP
PlasmaMembrane
AI
MoAb
EGFR/HER2
IGFRGrowth FactorEstrogen
Cross-talk between signal transduction pathways and ER signaling in endocrine-resistant breast cancer, with opportunities for targeted intervention.
Johnston S R Clin Cancer Res 2010;16:1979-1987
©2010 by American Association for Cancer Research
Hormonal Therapy in HER2+ MBC
Regimen ORR, % PFS, Mos
Trastuzumab (N = 79)[1] 26 3.5-3.8
Anastrozole + trastuzumab (N = 103)[2] 20 4.8
Anastrozole (N = 104)[2] 7 2.4
Lapatinib + letrozole (N = 642)[3] 28 8.2
Letrozole (N = 644)[3] 15 3.0
Lapatinib (N = 138)[4] 24 NA
1. Vogel C, et al. J Clin Oncol. 2002;20:719-726.2. Mackey JR, et al. SABCS 2006. Abstract 3.3. Johnston S, et al. J Clin Oncol. 2009;27:5538-5546.4. Gomez HL, et al. J Clin Oncol. 2008;26:2999-3005.
clinicaloptions.com/oncologyNew Directions in the Treatment of Patients With HER2-Positive Breast Cancer
Lapatinib Blocks Signaling Through Multiple Receptor Combinations
Downstream signaling cascade
Downstream signaling cascade
1 + 11 + 1 2 + 22 + 2 1 + 21 + 2 Blocks signaling throughErbB1 and ErbB2 homodimers and heterodimers
Might also prevent signaling through heterodimers between these receptors and other ErbB family members
Potentially blocks multiple ErbB signaling pathways
Lapatinib is indicated in MBC only for patients with progression after trastuzumab, anthracycline, and taxane treatment
Lapatinib is indicated in MBC only for patients with progression after trastuzumab, anthracycline, and taxane treatment
clinicaloptions.com/oncologyNew Directions in the Treatment of Patients With HER2-Positive Breast Cancer
Patients (N = 138) randomized to 2 schedules of lapatinib monotherapy
Median time to response (all patients): 7.9 wks; median duration of response (all patients): 28.4 wks
Safety: only grade 1/2 asymptomatic cardiac adverse events (4 patients)
Lapatinib as First-line Treatment for HER2-Amplified LABC or MBC
Endpoint Lapatinib1500 mg/day
(n = 69)
Lapatinib500 mg BID
(n = 69)
All Patients(N = 138)
Response rate, n (%) 15 (22) 18 (26) 33 (24)
Clinical benefit rate, n (%) 20 (29) 23 (33) 43 (31)
6-mo PFS, % 41 45 43
Gomez HL, et al. J Clin Oncol. 2008;26:2999-3005.
Herceptin +Chemotherapy
Current therapeutic cascade in HER2+ MBC
HER2+ /ER + MBC
Good performance statusVisceral disease
Rapidly progressing
Poor performance statusNon visceral disease
Slow progression
Herceptinmonotherapy
Herceptin +Aromatase
Inhibitor
Prior A.I.?
YES NO
Tratamiento mas allá de progresión
clinicaloptions.com/oncologyNew Directions in the Treatment of Patients With HER2-Positive Breast Cancer
Case 2: Woman With HER2+ MBC and Progression Following Trastuzumab Background: 39-yr-old woman diagnosed with stage IIA, breast cancer
in 2004. T2 N0 MO
– 2.6-cm tumor
– ER+/PgR-/HER2+
Treatment: TAC for 6 cycles plus radiation therapy and tamoxifen
Follow-up: 1 yr after end of chemotherapy, she is found to have bone and lymph node metastases
– Lymph node biopsy reveals the tumor is negative for hormone receptors (ER/PgR) and continues to overexpress HER2
Treatment: she receives 6 cycles of TCH and achieves CR
– She continues on maintenance single-agent trastuzumab without progression for almost 2 yrs
clinicaloptions.com/oncologyNew Directions in the Treatment of Patients With HER2-Positive Breast Cancer
Case 2: Woman With HER2+ MBC and Progression Following TrastuzumabScans reveal new liver metastases, and vinorelbine is added to trastuzumab. She has another CR that lasts 9 mos, at which time scans reveal progressive disease in the liver and bones.
What treatment option would you recommend at this time?
A. Switch to lapatinib/capecitabine
B. Switch to lapatinib/trastuzumab
C. Switch to trastuzumab and new chemotherapy
D. Start chemotherapy without HER2-targeted therapy
E. Switch to lapatinib alone
clinicaloptions.com/oncologyNew Directions in the Treatment of Patients With HER2-Positive Breast Cancer
Case 2: Woman With HER2+ MBC and Progression Following TrastuzumabScans reveal new liver metastases, and vinorelbine is added to trastuzumab. She has another CR that lasts 9 mos, at which time scans reveal progressive disease in the liver and bones.
What treatment option would you recommend at this time?
A. Switch to lapatinib/capecitabine (preferred choice)
B. Switch to lapatinib/trastuzumab (reasonable)
C. Switch to trastuzumab and new chemotherapy
D. Start chemotherapy without HER2-targeted therapy
E. Switch to lapatinib alone
clinicaloptions.com/oncologyNew Directions in the Treatment of Patients With HER2-Positive Breast Cancer
1 2
Downstream signaling pathways
Cell proliferation Cell survival
21 1 2
TrastuzumabT
LapatinibL L L L L L
Erb receptors
Mechanism of Action of LapatinibCompared to Trastuzumab
clinicaloptions.com/oncologyNew Directions in the Treatment of Patients With HER2-Positive Breast Cancer
Patients with HER2+ progressive MBC or
stage IIIB/IIIC LABC with T4 lesion and unlimited
previous therapies*
Primary endpoint: TTP
Secondary endpoints: OS, PFS, ORR
Primary endpoint: TTP
Secondary endpoints: OS, PFS, ORR
Lapatinib1250 mg/day PO +
Capecitabine 2000 mg/m2/day on
Days 1-14 every 21 days
Lapatinib1250 mg/day PO +
Capecitabine 2000 mg/m2/day on
Days 1-14 every 21 days
Capecitabine2500 mg/m2/day on
Days 1-14 every 21 days
Capecitabine2500 mg/m2/day on
Days 1-14 every 21 days
*No previous capecitabine and must have included trastuzumab (MBC) or anthracycline/taxane (MBC or adjuvant).
Geyer C, et al. N Engl J Med. 2006;355:2733-2743.
EGF100151 Phase III Study: Lapatinib + Capecitabine in Advanced Breast Cancer
clinicaloptions.com/oncologyNew Directions in the Treatment of Patients With HER2-Positive Breast Cancer
Lapatinib + Capecitabine in HER2+ MBC:TTP
Cameron D, et al. Oncologist. 2010;15:924-934.
TTP With 1 Previous Trastuzumab Regimen TTP With > 1 Previous Trastuzumab Regimen
CapecitabineLapatinib + capecitabine
Cu
mu
lati
ve P
rog
ress
ion
Fre
e (%
)
100
80
60
40
20
00 20 40 60 80
Wks
100
80
60
40
20
00 20 40 60 80
WksC
um
ula
tive
Pro
gre
ssio
n F
ree
(%)
CapecitabineLapatinib + capecitabine
Reproduced with permission of The Oncologist, from Lapatinib plus capecitabine in women with HER-2–positive advanced breast cancer: Final survival analysis of a phase III randomized trial, Cameron D, et al., Vol 15, 2010; permission conveyed through Copyright Clearance Center, Inc.
clinicaloptions.com/oncologyNew Directions in the Treatment of Patients With HER2-Positive Breast Cancer
Result Capecitabine(n = 201)
Capecitabine + Lapatinib(n = 207†)
HR P Value
Median TTP, wks[1] 18.6 31.3 0.50 < .001
OS, wks[1] 56.6 71.4 0.79 .077
ORR, %[2] 13.9 23.7 -- .017
Brain mets as site of first progression,* n (%)[2]
13 (6) 4 (2) -- .045
† n=198 in 2008 study.*Exploratory analysis.
1. Cameron D, et al. Oncologist. 2010;15:924-9342. Cameron D, et al. Breast Cancer Res Treat. 2008;112:533-543.
Lapatinib + Capecitabine in HER2+ MBC: Efficacy
clinicaloptions.com/oncologyNew Directions in the Treatment of Patients With HER2-Positive Breast Cancer
Combining Lapatinib and Trastuzumab Increases Antitumor Activity
Scaltriti M, et al. Oncogene. 2009;28:803-814. Konecny GE, et al. Cancer Res. 2006;66:1630-1639. Xia W, et al. Oncogene. 2004;23:646-653.
Tum
or
Vo
lum
e (
mm
3 )
1600
1400
1200
1000
800
600
400
200
013 16 19 21 23
Days After Injection*P < .05; †P < .01 vs control; ‡P < .05 vs trastuzumab; §P < .01 vs both lapatinib and trastuzumab.
ControlTrastuzumabLapatinibTrastuzumab + lapatinib*
*†‡ †
†
§
Reprinted by permission from Macmillan Publishers Ltd: Oncogene; Scaltriti, et al. 28:803-814, copyright 2009.
Treatment with lapatinib plus trastuzumab resulted in complete tumor remission in mouse model
– Effect was durable: no tumor relapse observed at 8 mos after treatment
Lapatinib induced accumulation of inactive HER2 at plasma membrane
– Trastuzumab-mediated cytotoxicity was higher with the addition of lapatinib in MCF7/HER2 cells
In vivo activity was consistent with in vitro data demonstrating the combination as synergistic
Blackwell KL, et al. J ClinOncol. 2010;28:1124-1130.
Patients with HER2+ (FISH/IHC3+) MBC and
progression on anthracycline, taxane, and
Herceptin
Lapatinib 1500 mg/day PO(n = 148)
Lapatinib 1000 mg/day PO + Herceptin 4 mg/kg → 2 mg/kg IV weekly
(n = 148)
Objetivo primario: supervivencia libre de progresión
Objetivos secundarios: Supervivencia global, respuesta, beneficio clínico
EGF104900 Estudio fase III: Bloqueo dual de Her2 en CMM
Supervivencia L (n = 145)
L + T (n = 146)
Muertes, n (%) 113 (78) 105 (72)
Mediana (m) 9.5 14
HR (95% CI) 0.74 (0.57-0.97)
Log-rank P value .026
6 meses SG
80%
70%
12 meses SG
56%
41%
Blackwell KL, et al. SABCS 2009. Abstract 61.
Su
pe
rviv
enci
a g
lob
al
Pacientes en riesgo, n148148
LL + T
121102
8865
6447
4328
2513
0
20
40
60
80
100
0 5 10 15 20 25 35Meses desde la aleatorización
1
30
LL + T
EGF104900 Estudiofase III: Bloqueo dual de Her2 en CMM
Nuevas terapias anti Her2
clinicaloptions.com/oncologyNew Directions in the Treatment of Patients With HER2-Positive Breast Cancer
Case 3: Woman With HER2+ MBC and Relapse Following Trastuzumab/Lapatinib Presentation: 56-yr-old woman was diagnosed with stage III ER+/
PgR-/HER2+ breast cancer
– Treatment: doxorubicin/cyclophosphamide and docetaxel/trastuzumab
Follow-up: 3 yrs after completing maintenance trastuzumab, she was diagnosed with bone and lung metastases
– Treatment: docetaxel/trastuzumab
Follow-up: after achieving PR that lasted for 9 mos, she developed liver metastases
– Treatment: lapatinib/capecitabine
Follow-up: she achieved SD for 6 mos, after which she developed lung and lymph node metastases
clinicaloptions.com/oncologyNew Directions in the Treatment of Patients With HER2-Positive Breast Cancer
Case 3: Woman With HER2+ MBC and Relapse Following Trastuzumab/LapatinibWhat treatment options do you feel are appropriate to consider for this patient at this time?
A. Lapatinib/trastuzumab
B. Enrollment in a trial evaluating a new agent for HER2+ breast cancer
C. Trastuzumab plus bevacizumab
D. Lapatinib/trastuzumab/chemotherapy
E. Trastuzumab plus chemotherapy
clinicaloptions.com/oncologyNew Directions in the Treatment of Patients With HER2-Positive Breast Cancer
Case 3: Woman With HER2+ MBC and Relapse Following Trastuzumab/LapatinibWhat treatment options do you feel are appropriate to consider for this patient at this time?
A. Lapatinib/trastuzumab (reasonable)
B. Enrollment in a trial evaluating a new agent for HER2+ breast cancer (preferred choice)
C. Trastuzumab plus bevacizumab
D. Lapatinib/trastuzumab/chemotherapy
E. Trastuzumab plus chemotherapy (reasonable)
Can we further optimise the treatment of HER2-positive MBC in the future?
Despite the proven efficacy of the standard of care, Herceptin plus chemotherapy, a proportion of patients with HER2-
positive breast cancer will not respond, while the majority of patients with MBC will progress within 1 year1
1. Slamon et al. New Eng J Med 2001; 344:783–792
MBC = metastatic breast cancer
Pertuzumab
Mechanism of action
There are four receptors in the HER family
• Receptors are able to homo- and heterodimerise• HER2 does not appear to have a direct ligand and HER3 lacks
kinase activity• However, HER2 and HER3 are highly complementary to each other
HER2HER1/EGFR HER4HER3
Yarden & Sliwkowski. Nat Rev Mol Cell Biol 2001;2:127–137EGFR = epidermal growth factor receptor
Homodimers Heterodimers
HER2:HER3 dimers initiate the strongest mitogenic signalling
HER1:HER1HER2:HER2
HER3:HER3HER4:HER4
HER1:HER2 HER1:HER3HER1:HER4
HER2:HER4HER3:HER4
Tzahar et al. Mol Cell Biol 1996;16:5276–5287; Citri et al. Exp Cell Res 2003;284:54–65; Huang et al. Cancer Res 2010;70:1204–1214.
Signalling activity
+ + ++ + + + ++ + + ++ + + +
+
HER2:HER3
HER2 dimerises preferentially with HER3 to drive downstream signalling
Phosphorylation of the HER3 intracellular domain by HER2 initiates a signalling cascade
Ligand-activatedHER2:HER3 dimer
Baselga, Swain. Nat Rev Cancer 2009;9:463–475; Yarden, Sliwkowski. Nat Rev Mol Cell Biol 2001;2:127–137; Graus-Porta et al. EMBO J 1997;1647–1655; Tzahar et al. Mol Cell Biol 1996;16:5276–5287;
Lee-Hoeflich et al. Cancer Res 2008;68:5878–5887.
HER2 HER3
PP
P P
Akt
Shc
HER2:HER3 dimerisation initiates multiple signalling pathways, including increased tumour cell proliferation
Downstream PI3K/Akt signalling is
mainly mediated by HER3 after
transphosphorylation by HER2
Yarden, Sliwokowski. Nat Rev Mol Cell Biol 2001;2:127–137; Olayioye et al. EMBO J 2000;19:3159–3167; Kim et al. J Biol Chem 1994;269:24747–24755; Soltoff et al. Mol Cell Biol 1994;14:3550–3558;Baselga, Swain. Nat Rev Cancer 2009;9:463–475; Rowinsky. Annu Rev Med 2004;55:433–457;
HER2 HER3
GRb2
SosRAS
PI3KPP
PP PDK
1
PP P
RAF
MEK
MAPKP
P
mTOR
Cyclin 01
GSK36NF
BBADp2
7
Angiogenesis Proliferation
Cell cyclecontrol
Apoptosis
Survival
Pertuzumab is the first in a new class of targeted anticancer therapeutic agents called HER2 Dimerisation Inhibitors
• By blocking HER2 dimerisation, pertuzumab inhibits key HER signalling pathways that mediate cancer cell proliferation and survival1–4
• Pertuzumab prevents the formation of HER2:HER3 receptor pairs1,5
HER2
Dimerisationdomain
1. Agus et al. Cancer Cell 2002;2:127–137; 2. Baselga. Cancer Cell 2002;2:93–95; 3. Citri et al. Exp Cell Res 2003;284:54–65. 4. Franklin et al. Cancer Cell 2004;5:317–328;
5. Hughes et al. Mol Cancer Ther 2009;8:1885–1892
Pertuzumab
HER3
Herceptin and pertuzumab bind to different epitopes on HER2 and show complementary mechanism of actions
HER2
Dimerisationdomain
Cho et al. Nature 2003;421:756–760; Fendly et al. Cancer Res 1990;50:1550–1558; Franklin et al. Cancer Cell 2004;5:317–328;Nahta et al. Cancer Res 2004;64:2343–2346; Scheuer et al. Cancer Res 2009;69:9330–9336
Pertuzumab
HER3
Herceptin
Subdomain IV• Herceptin does not inhibit ligand-
activated HER2 dimerisation• Herceptin prevents HER2 activation
by extracellular domain shedding• Herceptin inhibits ligand-
independent HER2 signalling and flags cells for destruction by the immune system
• Pertuzumab inhibits ligand-activated HER2 dimerisation
• Pertuzumab flags cells for destruction by the immune system
• Pertuzumab suppresses multiple HER signalling pathways, leading to a more comprehensive blockade of HER2-driven signalling
Pertuzumab
HER2-positive MBC combination studies
Summary of pertuzumab combination trials in HER2-positive breast cancer
EBC(Neo-
adjuvant)
First-line MBC Third-line MBCSecond-line MBC
BO17929 cohorts 1+2 (n=66)
P+TBO17929 cohort 3 (n=29)
P mono then P+T
NCI study (n=11)
P+T
CLEOPATRA (n=800)D+T±P
PHEREXA (n=450)
Capecitabine+T±P
NEOSPHERE (n=400)
D+T vs D+T+P vsT+P vs D+P
TRYPHAENA (n=225)
D+FEC+T+P vscarboplatin+D+T+P
Enrolling
Enrolment complete
Data on file. Genentech USA, Inc., CA, USA andF Hoffmann-La Roche Ltd., Basel, Switzerland
D = docetaxel; EBC = early-stage breast cancer;FEC = 5-fluorouracil, epirubicin, cyclophosphamide; MBC = metastatic breast cancer;P = pertuzumab; T = Herceptin
74
Providing greater efficacy and better tolerability than Herceptin plus chemotherapy
as single agent or in combination with a biologic
“… replacing Herceptin plus chemotherapy”
Aim for paradigm shift in treatment of breast cancer
Trastuzumab-DM1 (T-DM1) is a first-in-class antibody drug-conjugate (ADC)
75
Anatomy of T-DM1
T-DM1 selectively delivers a highly toxic payload to HER2-positive tumor cells
Receptor-T-DM1 complex is internalized into HER2-positive cancer cell
Potent antimicrotubule agent is released once inside the HER2-positivetumor cell
T-DM1 binds to the HER2 protein on cancer cells
• Trastuzumab-like activity by binding to HER2• Targeted intracellular delivery of a potent antimicrotubule
agent, DM1
TDM4450g: ongoing Phase II study of T-DM1 vs trastuzumab + docetaxel in first-line HER2-positive MBC
Primary endpoints• PFS (independent
assessment)• Safety
Secondary endpoints• OS• ORR• DoR • CBR• Pharmacokinetic
properties• Time to symptom
progression
HER2-positive MBCNo prior chemotherapy for MBC
(n=137)
T-DM1 Trastuzumab + docetaxel
Fully recruited, results to be presented later this year
Clinicaltrials.govPI: Edith Perez
• Se observó una mejora significativa de la SSP en las pacientes del grupo de trastuzumab emtansina (n= 67) en comparación con el grupo de Herceptin + quimioterapia (n = 70), (mediana de SSP: 14,2meses frente a 9,2; HR: 0,59; p: 0,035).• La TRO fue mayor en el grupo de trastuzumab emtansina que en el de Herceptin + quimioterapia(64,2% frente al 58,0%).• Los eventos adversos (EA) frecuentes y graves (grado 3 o superior) disminuyeron significativamenteen el grupo de trastuzumab emtansina en comparación con el grupo de Herceptin + quimioterapia:Los EA más frecuentes en el grupo de trastuzumab emtansina fueron fatiga (49,3%), náuseas (47,8%),un aumento de las cifras de una enzima específica secretada por el hígado y otros órganos (aspartatoaminotransferasa o AST, 39,1%) y fiebre (39,1%). Los EA más frecuentes en el grupo de Herceptin +quimioterapia fueron pérdida de cabello (66,7%), una cifra reducida de un tipo específico deleucocitos (neutropenia, 63,6%), diarrea (45,5%) y fatiga (45,5%). Coincidiendo con resultados yapublicados, EA graves (grado 3 o superior) se notificaron con menor frecuencia en el grupo detrastuzumab emtansina que en el de Herceptin + quimioterapia (46,4% frente a 89,4%), al igual quesuspensiones del tratamiento por EA (7,2% frente a 28,8%). Los EA graves más frecuentes en el grupode trastuzumab emtansina consistieron en una cifra aumentada de dos enzimas hepáticas diferentes(ALT y AST) y una cifra baja de plaquetas (8,7%). Los EA graves más frecuentes en el grupo de3/5Herceptin + quimioterapia consistieron en una cifra reducida de un tipo específico de leucocitos(neutropenia, 60,6%), una cifra total reducida de leucocitos (leucocitopenia, 25,8%) y fiebre asociadacon una cifra reducida de un tipo específico de leucocitos (neutropenia febril, 13,6%).• Los datos de la supervivencia global no están maduros en este momento. El número de fallecimientosen cada grupo del estudio fue idéntico. Según los investigadores, ninguna muerte estaba relacionadacon el tratamiento (trastuzumab emtansina o Herceptin + quimioterapia).
TDM4370g (EMILIA): ongoing Phase III study of T-DM1 vs capecitabine + lapatinib in the second-line setting
Primary endpoints● PFS (independent assessment)● SafetySecondary endpoints● OS● PFS (investigator assessment)● ORR● CBR ● DoR● Quality of life● TTF
n=319 as of June 4, 2010200 sites
FPI: February 27 2009
HER2-positive incurable locally advanced breast cancer or MBC
Prior trastuzumab and / or taxane(n=580)
T-DM1 Capecitabine + lapatinib
Clinicaltrials.govTTF, time to treatment failureFPI, first patient in
TDM4788g/BO22589 (MARIANNE): first-line T-DM1 + pertuzumab vs trastuzumab + docetaxel
Clinicaltrials.gov
Primary endpoints● PFS (independent assessment)● SafetySecondary endpoints● ORR (independent assessment)● OS● 1-year survival● PFS● ORR (investigator assessment)● CBR● TTF● DoR● Safety and tolerability
HER2-positive MBCNo prior chemotherapy
(n=1092)
Trastuzumab + taxane
T-DM1 + placebo
T-DM1 +pertuzumab
Global study starts summer 2010332 centers in 40 countries
T-DM1 and Pertuzumab: Binding to HER2
Diéras V, et al. SABCS 2010. Abstract P3-14-01.
Pertuzumab-HER2 Complex Herceptin/T-DM1-HER2 Complex
Pertuzumab
Dimerization domain
Herceptin/T-DM1
IV IV
III
II
I
III
II
I
T-DM1 and Pertuzumab: Mechanism of Action
Diéras V, et al. SABCS 2010. Abstract P3-14-01.
Pertuzumab
HER2
HER2 DimerT-DM1
DM1
Lysosome
Nucleus
clinicaloptions.com/oncologyNew Directions in the Treatment of Patients With HER2-Positive Breast Cancer
Widakowich C, et al. Anticancer Agents Med Chem. 2008;8:488-496.Miller TW, et al. Clin Cancer Res. 2009;15:7266-7276.
mTOR
AKT
AMPKTSC1 TSC2
PTENLKB1
PI3K
RHEB
IGF-1R EGFR/HER2Increased signaling through IGF-1R
Constitutive PI3K/AKT activation
Elevated AKT or pAKT
Absent or low PTEN
Truncated HER2
Nutrients
mTOR inhibitorGrowth &
proliferation
Angiogenesis Cellmetabolism
Downstream inhibition with mTOR inhibitor counters these resistance mechanisms
Synergy of mTOR inhibition and trastuzumab in vitro and in vivo
mTOR Inhibition May Overcome Trastuzumab Resistance
clinicaloptions.com/oncologyNew Directions in the Treatment of Patients With HER2-Positive Breast Cancer
Angiogenesis in MCF-7 Spheroids: Day 14
MCF-7 Neo:3.5 x mag.
Mature vasculature No vessel buds
Development stopped
MCF-7 Neo:3.5 x mag.
Mature vasculature No vessel buds
Development stopped
MCF-7 HER-2/neu:10 x mag.
High number mature vessels Vessel buds in center of tumor
Vasculature still growing
MCF-7 HER-2/neu:10 x mag.
High number mature vessels Vessel buds in center of tumor
Vasculature still growing
clinicaloptions.com/oncologyNew Directions in the Treatment of Patients With HER2-Positive Breast Cancer
P
P
P
P
Cell growth, proliferation, survival, metastasis, angiogenesis
Akt/PKB
mTOR
S6K1
PI3-K
Lapatinibphase III
Gefitinibphase II
Everolimusphase III
EGFR HER2
4E-BP1
elF-4E
Protein synthesis
Neratinibphase III
Pertuzumabphase III
Trastuzumab
T-DM1 phase III
P
P
P
P
PTEN
VEGFRSunitinibphase II
Bevacizumabphase III VEGF
Targeted Agents for HER2+ Breast Cancer
Muchisimas Gracias
Dr. Luis Miguel Zetina Toache
Cancer Consultants GT