Farmaci anti-HER2 - AIOM€¦ · Diapositiva 1 Author: valentina sini Created Date: 3/19/2019...
Transcript of Farmaci anti-HER2 - AIOM€¦ · Diapositiva 1 Author: valentina sini Created Date: 3/19/2019...
![Page 1: Farmaci anti-HER2 - AIOM€¦ · Diapositiva 1 Author: valentina sini Created Date: 3/19/2019 6:32:51 PM ...](https://reader033.fdocumenti.com/reader033/viewer/2022051900/5feed8074a6b185680230fa3/html5/thumbnails/1.jpg)
Farmaci anti-HER2
- Meccanismi d’azione ed indicazioni terapeutiche -
![Page 2: Farmaci anti-HER2 - AIOM€¦ · Diapositiva 1 Author: valentina sini Created Date: 3/19/2019 6:32:51 PM ...](https://reader033.fdocumenti.com/reader033/viewer/2022051900/5feed8074a6b185680230fa3/html5/thumbnails/2.jpg)
The HER family: therapeutic target
Slamon D et al. The Oncologist 2004;9:1-3
![Page 3: Farmaci anti-HER2 - AIOM€¦ · Diapositiva 1 Author: valentina sini Created Date: 3/19/2019 6:32:51 PM ...](https://reader033.fdocumenti.com/reader033/viewer/2022051900/5feed8074a6b185680230fa3/html5/thumbnails/3.jpg)
Mechanisms of actions of anti-HER-2 drugs:
antibodies and small molecules
Alvarez RH et al. JCO 2010;28:3366-3379
![Page 4: Farmaci anti-HER2 - AIOM€¦ · Diapositiva 1 Author: valentina sini Created Date: 3/19/2019 6:32:51 PM ...](https://reader033.fdocumenti.com/reader033/viewer/2022051900/5feed8074a6b185680230fa3/html5/thumbnails/4.jpg)
• Humanized anti-HER2 MoAb
• Targets subdomain IV of HER2
• Blocks HER2 signals
Trastuzumab
Lewis GD et al. Cancer Immunol Immun 1993;37:255-263
![Page 5: Farmaci anti-HER2 - AIOM€¦ · Diapositiva 1 Author: valentina sini Created Date: 3/19/2019 6:32:51 PM ...](https://reader033.fdocumenti.com/reader033/viewer/2022051900/5feed8074a6b185680230fa3/html5/thumbnails/5.jpg)
AK
T
PDK1
Trastuzumab binds to subdomain IV of HER2,
continually suppresses HER2 activity and flags cells for
destruction by the immune system
cell cycle control
proliferation
survival
RAS Sos Grb2 Shc
MEK
angiogenesis
Raf AKT
PI3K
Cyclin D1
p27
BAD
GSK3
NFB mTOR
MAPK
apoptosis
HER2
HER2
![Page 6: Farmaci anti-HER2 - AIOM€¦ · Diapositiva 1 Author: valentina sini Created Date: 3/19/2019 6:32:51 PM ...](https://reader033.fdocumenti.com/reader033/viewer/2022051900/5feed8074a6b185680230fa3/html5/thumbnails/6.jpg)
Trastuzumab: mechanisms of action
Spector NL et al. JCO 2009;27:5838-5847
![Page 7: Farmaci anti-HER2 - AIOM€¦ · Diapositiva 1 Author: valentina sini Created Date: 3/19/2019 6:32:51 PM ...](https://reader033.fdocumenti.com/reader033/viewer/2022051900/5feed8074a6b185680230fa3/html5/thumbnails/7.jpg)
Trastuzumab:therapeutic indications
• As monotherapy or combination with taxanes or
vinorelbine or capecitabine or aromatase inhibitors in
HER2- positive MBC
• HER2- positive early BC
• As combination with chemotherapy in HER2
positive BC in neoadjuvant setting
• In association with capecitabine/5FU and cisplatin in
advanced or metastatic HER2- positive gastric
cancer
![Page 8: Farmaci anti-HER2 - AIOM€¦ · Diapositiva 1 Author: valentina sini Created Date: 3/19/2019 6:32:51 PM ...](https://reader033.fdocumenti.com/reader033/viewer/2022051900/5feed8074a6b185680230fa3/html5/thumbnails/8.jpg)
Trastuzumab is the standard of care in
HER2-positive Breast Cancer
HERA
NSABP B-31
NCCTG N9831
BCIRG 006
FinHer
ECOG E2198
PHARE
Adjuvant5-12 1st line13-20
HO648g
M77001
BCIRG 007
CHAT
TAnDEM
RHEA
HERNATA
Rel
apse
Su
rger
y
2nd+ lines21-25
NOAH
MDACC
GeparQuattro
Numerous
phase II studies
NeoAdj1-4
HO649g
GBG-26
BO17929
EGF104900
Numerous
phase II studies
Early breast cancer Metastatic breast cancer
Pro
gre
ssio
n
Gianni L, et al.. Lancet 2010;375: 377-384;2) Buzdar AU, et al. J CO2006;23:3676-3685; 3) Buzdar AU, et al. Clin Cancer Res 2007;13:228-233; 4) Untch M,et al.JCO 2010;28:2024-2031 5)
Piccart-Gebhart M, et al. N Engl J Med 2005;353:1659-1672; 6) Gianni L, Dafni U, et al. Lancet Oncol 2011;12:236-244; 7) Romond E, et al. N Engl J Med 2005;353:1673-1684; 8) Perez EA, et
al. J CO 2011; 29:3366-3373; 9) Slamon D, et al. N Engl J Med 2011;365:1273-1283; 10) Joensuu H, et al. N Engl J Med 2006;354:809-820; 11) Sledge GW et al. Breast Cancer Res Treat
2006;100 (S1): ab 2075; 13) Pivot X, et al. Cancer Res 2012 ;72( 24 S):S5-3; 13) Cobleigh MA, et al. JCO 1999;17:2639-2648; 14) Vogel CL, et al. JCO2002;20:719-726,; 15) Slamon DJ, et al. N
Engl J Med.2001;344:783-792; 16) Seidman AD, et al. JCO2001;19:2587–2595; 17) Robert N, et al. JCO 2006;24:2786-2792; 18) Seidman AD, et al. JCO 2008.;26:1642-1649; 19) Marty M, et al.
JCO2005;23:4265-4274; 20) Andersson M, et al. JCO 2011; 29:264-271; 21) Schaller G, et al. JCO 2005; 22) Yamamoto D, et al. Cancer Chemother Pharmacol 2008;61:509-514; 23) Bartsch R,
et al. JCO2007;25:3853-3858; 24) Blackwell KL, et al. JCO 2010;28:1124-1130; 25) Kaufman B, et al. JCO 2009;27: 5529-5537.
![Page 9: Farmaci anti-HER2 - AIOM€¦ · Diapositiva 1 Author: valentina sini Created Date: 3/19/2019 6:32:51 PM ...](https://reader033.fdocumenti.com/reader033/viewer/2022051900/5feed8074a6b185680230fa3/html5/thumbnails/9.jpg)
HER2-positive
advanced GC
(n=584)
5-FU or capecitabinea
+ cisplatin
(n=290)
R
aChosen at investigator’s discretion
GEJ, gastroesophageal junction
5-FU or capecitabinea
+ cisplatin
+ trastuzumab
(n=294)
Stratification factors − advanced vs metastatic
− GC vs GEJ
− measurable vs non-measurable
− ECOG PS 0-1 vs 2
− capecitabine vs 5-FU
Phase III, randomized, open-label, international, multicenter study
3807 patients screened1
810 HER2-positive (22.1%)
Trastuzumab in HER2 + Gastric Cancer
ToGA Trial - Study design
The Lancet 2010;376:687 – 697
![Page 10: Farmaci anti-HER2 - AIOM€¦ · Diapositiva 1 Author: valentina sini Created Date: 3/19/2019 6:32:51 PM ...](https://reader033.fdocumenti.com/reader033/viewer/2022051900/5feed8074a6b185680230fa3/html5/thumbnails/10.jpg)
ToGA Trial
OS (Primary Endpoint)
Bang et al. The Lancet 2010;376:687 – 697
IHC3+/FISH+
![Page 11: Farmaci anti-HER2 - AIOM€¦ · Diapositiva 1 Author: valentina sini Created Date: 3/19/2019 6:32:51 PM ...](https://reader033.fdocumenti.com/reader033/viewer/2022051900/5feed8074a6b185680230fa3/html5/thumbnails/11.jpg)
T-DM1: first chemoteraphy agents
conjugated with anti HER-2 antibody
Lambert JM et al. Curr Opin Pharmacol 2005;5:543-549
![Page 12: Farmaci anti-HER2 - AIOM€¦ · Diapositiva 1 Author: valentina sini Created Date: 3/19/2019 6:32:51 PM ...](https://reader033.fdocumenti.com/reader033/viewer/2022051900/5feed8074a6b185680230fa3/html5/thumbnails/12.jpg)
T-DM1: mechanisms of action
Austin CD, et al. Mol Biol Cel 2004, 15: 5268-5282; Erickson HK, et al. Cancer Res 2006;66:4426-4433.
![Page 13: Farmaci anti-HER2 - AIOM€¦ · Diapositiva 1 Author: valentina sini Created Date: 3/19/2019 6:32:51 PM ...](https://reader033.fdocumenti.com/reader033/viewer/2022051900/5feed8074a6b185680230fa3/html5/thumbnails/13.jpg)
EMILIA trial: Study design and Results
Verma S, et al. NEJM 2012;367:1783-1791
![Page 14: Farmaci anti-HER2 - AIOM€¦ · Diapositiva 1 Author: valentina sini Created Date: 3/19/2019 6:32:51 PM ...](https://reader033.fdocumenti.com/reader033/viewer/2022051900/5feed8074a6b185680230fa3/html5/thumbnails/14.jpg)
From trastuzumab to pertuzumab:
an inhibitor of HER2 dimerization
• Enterely humanized antiHER2 MoAb
• Targets subdomain II of HER2
• Inhibits HER2 dimerization
Adams Cw, et al. Cancer Immunol Immun 2006;55:717-727
![Page 15: Farmaci anti-HER2 - AIOM€¦ · Diapositiva 1 Author: valentina sini Created Date: 3/19/2019 6:32:51 PM ...](https://reader033.fdocumenti.com/reader033/viewer/2022051900/5feed8074a6b185680230fa3/html5/thumbnails/15.jpg)
Trastuzumab and Pertuzumab bind to
different regions of the HER2 receptor
Trastuzumab Pertuzumab
Subdomain IV of HER2
Dimerization domain of HER2
Trastuzumab Pertuzumab
Flags cells for destruction by the immune system
(ADCC)
Inhibits HER2 dimerization
Blocks HER2 signalling
Prevents shedding of p95HER2
![Page 16: Farmaci anti-HER2 - AIOM€¦ · Diapositiva 1 Author: valentina sini Created Date: 3/19/2019 6:32:51 PM ...](https://reader033.fdocumenti.com/reader033/viewer/2022051900/5feed8074a6b185680230fa3/html5/thumbnails/16.jpg)
Pertuzumab
08 february 2012, 15:57
Roche announced that US Food and Drug Administration (FDA) has
accepted the company’s Biologica Licence Application for pertuzumab
and granted Priority Review.
The proposed indication is Pertuzumab for use in combination with
trastuzumab and docetaxel for the treatment of patients with HER2-
positive metastatic breast cancer who have not received prior anti-
HER2 therapy or chemotherapy for metastatic disease.
The FDA confirmed the action date is june 8, 2012
![Page 17: Farmaci anti-HER2 - AIOM€¦ · Diapositiva 1 Author: valentina sini Created Date: 3/19/2019 6:32:51 PM ...](https://reader033.fdocumenti.com/reader033/viewer/2022051900/5feed8074a6b185680230fa3/html5/thumbnails/17.jpg)
CLEOPATRA
Study design
MBC, metastatic breast cancer; PD, progressive disease
Patients with
HER2-positive MBC
centrally confirmed
(N = 808)
Placebo + trastuzumab n=406
• Randomization was stratified by geographic region and prior treatment status
(neo/adjuvant chemotherapy received or not)
• 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
* <6 cycles allowed for unacceptable toxicity or PD; >6 cycles allowed at investigator discretion
Baselga J, et al. NEJM 2012;366:109-119
![Page 18: Farmaci anti-HER2 - AIOM€¦ · Diapositiva 1 Author: valentina sini Created Date: 3/19/2019 6:32:51 PM ...](https://reader033.fdocumenti.com/reader033/viewer/2022051900/5feed8074a6b185680230fa3/html5/thumbnails/18.jpg)
CLEOPATRA
Progression Free Survival
First interim analysis, at a median follow up of 19.3 mo
Baselga J, et al. NEJM 2012;366:109-119
![Page 19: Farmaci anti-HER2 - AIOM€¦ · Diapositiva 1 Author: valentina sini Created Date: 3/19/2019 6:32:51 PM ...](https://reader033.fdocumenti.com/reader033/viewer/2022051900/5feed8074a6b185680230fa3/html5/thumbnails/19.jpg)
AntiHer2-related toxicities
(Abstr # 533)
Ewer M, et al. ASCO 2012#533
![Page 20: Farmaci anti-HER2 - AIOM€¦ · Diapositiva 1 Author: valentina sini Created Date: 3/19/2019 6:32:51 PM ...](https://reader033.fdocumenti.com/reader033/viewer/2022051900/5feed8074a6b185680230fa3/html5/thumbnails/20.jpg)
Lapatinib
• Oral small molecule that
binds intracellular domain of
EGFR and HER2 and
reversibly inhibits TK1-3.
• Active also in truncated HER-
2 receptor (p95-ErbB-2)4
1 Rusnak DW, et al Mol Cancer Ther 2001;1:85-94; 2 Xia W et al Oncogene 2002;21:6255-6263; 3 Konecny GE et al. Cancer Res 2006;66:1630-
1639; 4 Xia W et al Oncogene 2004;23:646-653.
![Page 21: Farmaci anti-HER2 - AIOM€¦ · Diapositiva 1 Author: valentina sini Created Date: 3/19/2019 6:32:51 PM ...](https://reader033.fdocumenti.com/reader033/viewer/2022051900/5feed8074a6b185680230fa3/html5/thumbnails/21.jpg)
Lapatinib in HER-2 + breast cancer patients
Metastatic trials
NEOALTTO 5
GeparQuinto 6
CHERLOB 7
Holmes 8
TBCRC 006 9
Neoadjuvant trials
EGF 100151 10-11
EGF30008 12
EGF 104900 13
NOT approved in clinical
practice
5 Baselga J et al. Lancet 2012;379:633-640; 6 Untch M, et al. Lancet Oncol 2012;13:134-144; 7 Guarnieri V et al. JCO 2012;30:1989-1995; 8
Holmes FA, et al. ASCO 2011#506; 9 Chang JC et al. ASCO 2011#505 ;10 Geyer C, et al. NEJM 2006;355:2733-2743;11Cameron D, et al. Breast
Cancer Res Treat 2008;112:533-543.; 12 Johnston S et al. JCO 2009;27:5538-5546;13 Blackwell KL, et al. JCO 2012;30:2585-2593.
Approved in association with:
- capecitabine for the treatment of
patients previously treated with an
anthracycline, a taxane and
trastuzumab.
- Letrozole for metastatic HER2-
positive, ER/PgR positive MBC not
candidate to chemotherapy
![Page 22: Farmaci anti-HER2 - AIOM€¦ · Diapositiva 1 Author: valentina sini Created Date: 3/19/2019 6:32:51 PM ...](https://reader033.fdocumenti.com/reader033/viewer/2022051900/5feed8074a6b185680230fa3/html5/thumbnails/22.jpg)
EGF100151 trial
Study design
![Page 23: Farmaci anti-HER2 - AIOM€¦ · Diapositiva 1 Author: valentina sini Created Date: 3/19/2019 6:32:51 PM ...](https://reader033.fdocumenti.com/reader033/viewer/2022051900/5feed8074a6b185680230fa3/html5/thumbnails/23.jpg)
EGF 100151 trial
TIME TO PROGRESSION
![Page 24: Farmaci anti-HER2 - AIOM€¦ · Diapositiva 1 Author: valentina sini Created Date: 3/19/2019 6:32:51 PM ...](https://reader033.fdocumenti.com/reader033/viewer/2022051900/5feed8074a6b185680230fa3/html5/thumbnails/24.jpg)
AFATINIB (BIBW 2992):
mechanism of action
![Page 25: Farmaci anti-HER2 - AIOM€¦ · Diapositiva 1 Author: valentina sini Created Date: 3/19/2019 6:32:51 PM ...](https://reader033.fdocumenti.com/reader033/viewer/2022051900/5feed8074a6b185680230fa3/html5/thumbnails/25.jpg)
Afatinib in breast and lung cancer
Lung cancer
Lin NU 1
Schuler M 2
Breast cancer
LUX LUNG 1 3
LUX LUNG 2 4
LUX LUNG 3 5
NOT approved in clinical practice
1 Lin NU, et al. Breast Cancer Treat 2012;133:1057-1065; 2 Schuler M, et al. Breast Cancer Res Treat 2012;134:1149-1159; 3
Miller VA, et al. Lancet Oncol 2012;13:528-538; 17 Yang JC, et al. Lancet Oncol. 2012;13:539-548; 18 Yang JC, et al. LUX-Lung
3 ASCO 2012#LBA7500.
![Page 26: Farmaci anti-HER2 - AIOM€¦ · Diapositiva 1 Author: valentina sini Created Date: 3/19/2019 6:32:51 PM ...](https://reader033.fdocumenti.com/reader033/viewer/2022051900/5feed8074a6b185680230fa3/html5/thumbnails/26.jpg)
LUX LUNG 3 trial: afatinib vs chemotherapy
PROGRESSION FREE- SURVIVAL
![Page 27: Farmaci anti-HER2 - AIOM€¦ · Diapositiva 1 Author: valentina sini Created Date: 3/19/2019 6:32:51 PM ...](https://reader033.fdocumenti.com/reader033/viewer/2022051900/5feed8074a6b185680230fa3/html5/thumbnails/27.jpg)
Neratinib
• Small oral molecule, highly
potent irreversible TKI of
EGFR and HER2.
• Preliminary data showed
antitumor activity in patients
with trastuzumab-pretreated,
HER2-positive breast cancer.
• Mature data are awaited, and
more studies are underway on
breast and lung cancer in
monotherapy or association
with chemotherapy.
Drug unavailable in clinical practice!
Burstein HJ, et al. JCO2010;28:1301-1307.