Meccanismi d’azione e indicazioni terapeutiche

(1)

Farmaci anti-HER2

- Meccanismi d’azione ed indicazioni

terapeutiche -

(2)

The HER family: therapeutic target

Slamon D et al. The Oncologist 2004;9:1-3

(3)

Mechanisms of actions of anti-HER-2 drugs:

antibodies and small molecules

Alvarez RH et al. JCO 2010;28:3366-3379

(4)

• Humanized anti-HER2 MoAb

• Targets subdomain IV of HER2

• Blocks HER2 signals

Trastuzumab

Lewis GD et al. Cancer Immunol Immun 1993;37:255-263

(5)

AKT 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 NFB

mTOR

MAPK

 apoptosis

HER2

(6)

Trastuzumab: mechanisms of action

Spector NL et al. JCO 2009;27:5838-5847

(7)

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

(8)

Trastuzumab is the standard of care in HER2-positive Breast Cancer

HERA NSABP B-31 NCCTG N9831

BCIRG 006 FinHer ECOG E2198

PHARE

Adjuvant

^5-12

1st line

^13-20

HO648g M77001 BCIRG 007

CHAT TAnDEM

RHEA HERNATA

R el ap se

S u rg er y

2nd+ lines

^21-25

NOAH MDACC GeparQuattro

Numerous phase II studies

NeoAdj

^1-4

HO649g GBG-26 BO17929 EGF104900

Numerous phase II studies

Early breast cancer Metastatic breast cancer

P ro g re ssi o 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.

(9)

HER2-positive advanced GC

(n=584)

5-FU or capecitabine

^a

+ cisplatin

(n=290) R

aChosen at investigator’s discretion GEJ, gastroesophageal junction

5-FU or capecitabine

^a

+ 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 screened

¹

810 HER2-positive (22.1%)

Trastuzumab in HER2 + Gastric Cancer

ToGA Trial - Study design

The Lancet 2010;376:687 – 697

(10)

ToGA Trial

OS (Primary Endpoint)

Bang et al. The Lancet 2010;376:687 – 697

IHC3+/FISH+

(11)

T-DM1: first chemoteraphy agents conjugated with anti HER-2 antibody

Lambert JM et al. Curr Opin Pharmacol 2005;5:543-549

(12)

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.

(13)

EMILIA trial: Study design and Results

Verma S, et al. NEJM 2012;367:1783-1791

(14)

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

(15)

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 p95

^HER2



(16)

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

(17)

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/m

²

, escalating to 100 mg/m

²

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

(18)

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

(19)

AntiHer2-related toxicities (Abstr # 533)

Ewer M, et al. ASCO 2012#533

(20)

Lapatinib

• Oral small molecule that

binds intracellular domain of EGFR and HER2 and

reversibly inhibits TK ^1-3 .

• 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.

(21)

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

(22)

EGF100151 trial

Study design

(23)

EGF 100151 trial

TIME TO PROGRESSION

(24)

AFATINIB (BIBW 2992):

mechanism of action

(25)

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.

(26)

LUX LUNG 3 trial: afatinib vs chemotherapy

PROGRESSION FREE- SURVIVAL

(27)

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.