Emerging Medical Treatments and Future Directions Stefano Iacobelli Cancer Clinic & Laboratory...

Emerging Medical Treatments and

Future Directions

Stefano Iacobelli

Cancer Clinic & Laboratory of Molecular Oncology

On behalf of the Consorzio Interuniversitario Nazionale per la Bio-Oncologia (CINBO)

Breast Cancer Facts

Over 1 million new breast cancer cases are reported each year

~ 10% of new diagnosed BC patients are locally advanced or metastatic disease, and 20-60% of the remaining patients develop systemic relapse

~ 40% of the patients will die of breast cancer

Reason: Development of drug resistance in metastatic disease

Metastatic breast cancer remains an incurable disease

Gueth U et al. Oncology 2009 However…

Advances in Medical Treatment

1980 1985 1990 1995 2000 2005

Capecitabine

Bevacizumab

Paclitaxel

CMF

Gemcitabine

Albumin-Bound Paclitaxel

Trastuzumab

Lapatinib

Doxorubicin

EpirubicinMitoxantrone

Vinorelbine

Docetaxel

HER2+

Aromatase Inhibitors

Tamoxifen

ER+ or PR+

Ixabepilone

Fulvestrant

The use of newer therapeutic agents has been associated with improved

survival in MBC over time

Chia SK et al. Cancer 2007

HER-2

VEGF (R)

PARP

Three Key Clinical Advances

All In Targeted Therapies

Molecular Targets andTherapies Being Developed for Breast

Cancer

Normanno N et al. Endocr Rel Cancer 2009

However

In advanced breast cancer, primary resistance toTrastuzumab is frequent (60–70% of pts with Trastuzumabmonotherapy; 30–50% of pts with Trastuzumab pluschemotherapy)

Eventually, all advanced breast cancer patients becomeresistant to Trastuzumab within months or years

CNS is a frequent metastatic site and Trastuzumab isineffective for CNS MTS ( CSF levels 300-fold lower than inthe serum)

Trastuzumab represents the foundation of

treatment of HER2+ Breast Cancer

Altered Target Steric hindrance of receptor by cell surface proteins (MUC4)1

Truncated form of receptor (p95)2

Mutations in HER23

Increased circulating HER2 ECD

Alternativepathway signaling

IGF1R overexpression4

VEGF overexpression5

AlternativeHER signaling

HER1/HER3 heterodimers or HER1/HER1 homodimersIncreased levels of ligand (heregulin, EGF, TGFα)6

Costitutiveactivation ofdownstreameffectors

Reduced level of PTEN7

Reduced p27kip1 8

Increased AKT activity9

Molecular mechanisms of Trastuzumab resistance

9 Berns K et al. Cancer Cell 2007

1 Nagy P et al. Cancer Res 2005

2 Scaltriti M et al. J Natl Cancer Inst 2007

3 Prempree C et al. JCO 24: 611s, 2006

4 Nahta R et al. Cancer Res 2005

5 du Manoir JM et al. Clin Cancer Res 2006

6 Motoyama AB et al. Cancer Res 2002

7 Nagata Y et al. Cancer Cell 2004

8 Nahta R et al. Cancer Res 2004

Targeting HER2-beyond trastuzumab

Newer mAbs targeting the HER receptor family

- PERTUZUMAB- ERTUMAXOMAB

TKIs to HER2- receptor family- LAPATINIB- NERATINIB- JNJ-28871063

Trastuzumab-DM1

IHC 3+

FISH +

Different sites of action of various drugs acting on the HER-2 receptor signaling

pathway

Vora T et al. 2009

Pertuzumab

Humanized monoclonal antibody targeting the HER2 extracellular domain II

The combination of Pertuzumab with Trastuzumab has been shown to induce greater ADCC, receptor down-regulation and growth inhibition of tumor cells

Spiridon CI et al. Clin Cancer Res 2002

Prevents HER2 heterodimerization

Potent inhibitor of HER-mediatedsignalling pathways

Response N=66

CR 5 (7.6%)

PR 11 (16.7%)

ORR 16 (24.2%)

SD > 6 mos 17 (25.8%)

Phase II Trial of Pertuzumab and Trastuzumab in Patients With HER2–Positive Metastatic Breast

Cancer That Progressed During Prior Trastuzumab Therapy

Trastuzumab weekly (4 mg/kg loading dose, then 2 mg/kg every week) or every 3 wks (8 mg/kg loading dose, then 6 mg/kg every 3 wks)Pertuzumab every 3 weeks (840 mg loading dose, then 420 mg every 3 wks)

median PFS 5.5 months(range, 0.9 to 17.0 months)

- Grade 1 or 2 diarrhea (64%) fatigue (33%) nausea (27%)

- Only four G3 treatment-related event(2 cases of diarrhea, 1 central line infection, and 1 pruritic rash).

- no clinically significant cardiac events

Toxicities

Baselga J, J Clin Oncol 2010

CLEOPATRA: Phase III study of Trastuzumab + Pertuzumab in HER2+

MBC

1:1 randomisation

UntreatedHER2+ MBC

n=800

Herceptin + docetaxel + placebo

Herceptin + docetaxel + pertuzumab

An international Phase III randomised, double-blind, placebo-controlled study (approximately 250 sites worldwide)

End points:

Progression-free survival

Overall survival

Quality of life

Biomarker analysisExpected to be completed by March 2012

Ertumaxomab Ertumaxomab is a trifunctional, bispecific mAb targeting HER2 and CD3

It binds to HER2 positive tumor cells, T cells and fcγ receptor positive accessory immune cells (macrophages, dendritic cells and NK cells)

This tri-cell structure causes co-stimulation of T-cells resulting in the release of cytokines and lytic enzymes (e.g. perforin) and phagocytosis of tumor cells by the fcγ receptor positive cells

Zeidler RBr J Cancer 2000

Phase I Trial of the Trifunctional Anti-HER2 Anti-CD3 Antibody Ertumaxomab in MBC

Kiewe P et al. Clin Cancer Res 2006

6-h infusion

17 patients with HER2 positive MBCToxicities

Strong Th1 immune response

Doses up to 100 μg can be safely infused with close monitoring of pts. The observed clinical responses (ORR, 5/15) are encouraging and indicate antitumor efficacy

Infusion Reactions

Lapatinib inhibits EGFR and HER2

LAPATINIB GEFITINIB ERLOTINIB

ErbB1 3.0 ± 0.2* 0.4 ± 0.1* 0.7 ± 0.1*

ErbB2 13 ± 1* 870 ± 90* 1000 ± 100*

ErbB4 347 ± 16‡ 1130 ± 370‡ 1530 ± 270‡

*Kiapp (nM); ‡cKi

app (nM); gefitinib and erlotinib are ErbB1 inhibitors

N

N

O O

NH

O O

NH

S

O

N

N

NH

Cl

OO

O

F

N

O

N

N

O O

NH

Cl F

The slowoff-rate, bound EGFR structure, and dual ErbB1 and Erb2 inhibitionprofile differentiate Lapatinib from the other agent

PI3K/Akt pathwayPI3K/Akt pathwayMAPK pathway MAPK pathway (Ras/Raf/(Ras/Raf/MEK/ERK)MEK/ERK)

Lapatinib Acts Intracellularly, Directly Inhibiting Downstream Signals

Ligands

ErbB2Other ErbB

ProliferationProliferation Cell cycle, SurvivalCell cycle, Survival

PI3K/Akt pathwayMAPK pathway (Ras/Raf/MEK/ERK)

Lapatinib

Treatment continued until progression

Patients with ErbB2-positive locally advanced or metastatic breast cancer

that progressed after prior anthracycline, taxane and

trastuzumab(N=399)

RANDOMISATION

Lapatinib 1250 mg po qd continuously +

capecitabine 2000 mg/m2/d po days 1–14 q 3 wk

Capecitabine 2500 mg/m2/day

po days 1–14 q 3 wk

po = oral; qd = once daily; q 3 wk = once every 3 weeks

EGF 100151: Phase III, randomised, controlled study of lapatinib plus capecitabine vs

capecitabine alone

Cameron et al. Breast Can Res Treat 2008; Geyer et al. N Engl J Med 2006

Outcome Lapatinib +capecitabine (N=198)

Capecitabine

(N=201)

Hazard ratio(95% CI)

Odds ratio

(95% CI)

p-value

Median TTP (weeks [months])*

27.1 (6.2) 18.6 (4.3)0.57 (0.43,

0.77)– 0.00013

ORR (%) 23.7 13.9 –1.9 (1.1,

3.4)0.017

EGF 100151 study: Lapatinib plus capecitabine: significantly longer TTP in difficult to treat

population

Cameron et al. Breast Can Res Treat 2008

EGF100151 StudyMost Frequent Adverse Events All

Grades

L = Lapatinib; C = capecitabineCameron et al. Breast Can Res Treat 2008

Lapatinib inhibits p-Akt in a dose- and time-dependent manner in PTEN-null MDA-MB-468 BC cells

Low (1+) High (3+) Negative (0)

Phase II trial of Lapatinib alone in IBC

Cancer Res 2007

Scaltriti et al. J Natl Cancer Inst 2007

Lapatinib is active against tumours expressing p95ErbB2 variant

An estimated 30% of BCs overexpressing HER2 co-espress p95HER2

Preclinical evidence demonstrated that Lapatinib retains activity in models expressing p95HER2

Pedersen K et al. Mol Cell Biol 2009

EGF 104900: Randomized Study of Lapatinib Alone or in Combination With Trastuzumab in Women With ErbB2-Positive, Trastuzumab-Refractory MBC

HER2+ MBC pretreated with Trastuzumab,

Anthra, Taxane(n=296)

Lapatinib1500 mg/day

p.o.(n=148)

Lapatinib 1000 mg/day

+Trastuzumab

4 2 mg/kg IV qw(n=148)

Primary endpoint: PFS based on RECIST criteriaSecondary endpoints: ORR, CB, OS, QoL, safety Blackwell KL et al. J Clin Oncol 2010

R

Crossover if PD after4wk therapy (N = 73)

EGF 104900: Survival Analyses

The median PFS was 8.1 vs 12 wkslapatinib alone vs combination armHR 0.73 (95% CI, 0.57 to 0.93; P.008)

Improvement in PFS for the combination arm

Blackwell KL et al. J Clin Oncol 2010

Neratinib (HKI-272)

Oral, pan-HER (ie, HER1, HER2, and HER4) TKI

Rabindran SK et al. Cancer Res 2004

In a phase I study, MDT was 320 mg/day. Common AEs were diarrhea (84%), nausea (55%), asthenia (45%), anorexia (31%), and vomiting (29%)

Advanced HER2 + BC (N=136)

Neratinib 240 mgPrior trastuzumab

treatment(n = 66)

Neratinib 240 mgNo prior

trastuzumab treatment(n = 70)

Phase II study of Neratinib in pts with Advanced HER2 positive Breast Cancer

Primary end point: 16-week PFS rate

Burstein HJ et al. J Clin oncol 2010

Efficacy analysis and safety

Tumor Responses

Diarrhea was the most frequent grades 3 to 4 AE

Burstein HJ et al. J Clin oncol 2010

JNJ-28871063, A Nonquinazoline Pan-ErbB Kinase Inhibitor That Crosses the Blood-Brain BarrierBT474 ErbB2-overexpressing

breast carcinoma model

Drug plasma and tissue distribution ofJNJ-28871063 and lapatinibin nude mice bearing A431 Xenografts

L

J

N87 intracranial model5 x104 cells were injected intracranially, and animals (n=10) were treated with vehicle or 200 mg/kgJNJ-28871063 daily for 50 days

mTTP

mTTP

JNJ-28871063 significantly extended survival by 31.3%

Emanuel SL et al. Mol Pharmacol 2008

Trastuzumab-DM1 (Tmab-MCC-DM1) Immunotoxin: Ab delivery of the toxin; internalization via endocytosis induces toxin release inside the tumor

T-DM1 combines biological activity of trastuzumab with targeted delivery of DM1

DM-1: maytansine (potent microtubule destabilizing agent)

Activity in trastuzumab resistant cancer cell lines

• SK-OV-3 (Her2 2 +): ovarian carcinoma• Calu-3 (Her2 3 +): lung adenocarcinoma• BT-474-EI (Her2 3 +): breast tumor cells• MKN7 (Her2 2 +): gastric carcinoma

In a phase I study, T-DM1 was well-tolerated at the MDT of 3.6 mg/kg IV q21, with no cardiac toxicity. Grade 3-4 toxicities were thrombocytopenia and neutropenia. ORR was 44%.

Lewis Phillips GD et al. Cancer Res 2008Beeram M et al. ASCO 2008 (Abstr 1028)

Trastuzumab-DM1* q3w

ORR,safety/

Tolerability,

PFS

*3.6 mg/kg as 30- to 90-min continuous infusion.

Vukelja S, et al. SABCS 2008. Abstract 33. Vogel C, et al. ASCO 2009. Abstract 1017.

EndpointsProgression

within 60 daysof HER2-directed

therapy

Trastuzumab only

(n = 45)

Trastuzumab

+ Lapatinib

(n = 67)

HER2+

(IHC 3+ or FISH+)

MBC

(N = 112)

A phase II study of Trastuzumab-DM1in pts with HER2 positive MBC

Trastuzumab-DM1 in HER2-Positive MBC: Treatment History

Vogel C, et al. ASCO 2009. Abstract 1017.

Previous Chemotherapy and Anti-HER2 Therapy

Patients (N = 112)

Chemotherapeutic agents, median n (range)

3 (1-12)

Previous anthracycline, n (%) 78 (69.6)

Previous taxane, n (%) 94 (83.9)

Median duration of previous trastuzumab therapy, mos (range)

17.8 (1-152)

Previous lapatinib therapy, n (%) 67 (59.8)

Median duration of previous lapatinib therapy, mos (range)

6.0 (1-24)

Vogel C, et al. ASCO 2009. Abstract 1017.

Response Summary

Assessment

IRF(N = 112)

Investigator (N = 112)

Best objective response, n (%)

CR 0 3 (2.7)

PR 28 (25.0) 40 (35.7)

SD 54 (48.2) 43 (38.4)

PD 21 (18.8) 22 (19.6)

Unknown 9 (8.0) 4 (3.6)

ORR, n (%) 28 (25.0) 43 (38.4)

Clinical benefit,* n (%)

39 (34.8) 50 (44.6)

* CR, PR, or SD for ≥ 6 mos.

Trastuzumab-DM1 in HER2+ MBC:

Antitumor Activity

Response SummaryAssessment

IRF Investigator

Pts previously treated with trastuzumab and lapatinib

(n = 67) (n = 67)

ORR, n (%) 16 (23.9) 24 (35.8)

Clinical benefit,* n (%) 24 (35.8) 30 (44.8)

Pts with centrally confirmed HER2+

(n = 75) (n = 75)

ORR, n (%) 24 (32.0) 36 (48.0)

Clinical benefit,* n (%) 33 (44.0) 41 (54.7)

Subgroups analysis

Trastuzumab-DM1 in HER2-Positive MBC: PFS

Vogel C, et al. ASCO 2009. Abstract 1017.

0

0.2

0.4

0.6

0.8

1.0

0 2 4 6 8 10

Pro

po

rtio

n E

ven

t F

ree

14PFS (Mos)

IRF (N = 112) median: 4.9

INV (N = 112) median: 4.9

12

Median Follow-up 9.5 months

Trastuzumab-DM1 in HER2-Pos MBC: AEs

Any AE, n (%) Grade 1 or

2Grade 3 Grade 4 All Grades

Fatigue 72 (64.3) 5 (4.5) 0 73 (65.2)

Nausea 55 (49.1) 1 (0.9) 0 56 (50.0)

Headache 43 (38.4) 0 0 43 (38.4)

Pyrexia 39 (34.8) 1 (0.9) 0 39 (34.8)

Epistaxis 36 (32.1) 2 (1.8) 0 38 (33.9)

Thrombocytopenia NR 5 (4.5) 3 (2.7) NR

Constipation 33 (29.5) 0 0 33 (29.5)

Eye disorders 31 (27.7) 0 1 (0.9) 32 (28.6)

Cough 30 (26.8) 0 0 30 (26.8)

Diarrhea 29 (25.9) 0 0 29 (25.9)

Hypokalemia 22 (19.6) 9 (8.0) 0 27 (24.1)

Dyspnea 23 (20.5) 2 (1.8) 1 (0.9) 24 (21.4)

Pain in extremity 24 (21.4) 0 0 24 (21.4)

Vogel C, et al. ASCO 2009. Abstract 1017.

P<0.0001

Response Rates for Novel HER2-Targeting Agents after Progression

on Trastuzumab

Angiogenesis Inhibitors

Monoclonal Antibodies

- BEVACIZUMAB

Primarly antiangiogenic multitargeted TKIs

- PAZOPANIB- AXITINIB- SUNITINIB

HR = 0.51

+/- Bevacizumab 10 mg/kg q2w

First-line T herapy of MBC with Bevacizumab Added to Paclitaxel Improved PFS

Miller K et al. N Engl J Med 2007

Three prior Phase III trials (E2100, AVADO, and RIBBON-1) have established a consistent improvement in PFS with the combination of Bevacizumab with various cht as first-line treatment for MBC A previous Phase III study (AVF2119) in pts with heavily pre-treated MBC, in which bevacizumab was combined with Capecitabine, did not meet the primary end-point of PFS, but resulted in a significant increase in ORR RIBBON-2 was designed to evaluate the clinical benefit of combining Beva with various cht used to treat MBC in II line

RIBBON-2: A randomized phase III trial of Bevacizumab with cht for II line HER2neg MBC

Brufsky A et al. SABCS 2009

Bevacizumab15 mg/kg q3w or 10 mg/kg q2w

Brufsky A et al. SABCS 2009

RIBBON-2 is the first positive phase III study of bevacizumab in second-line MBC

A Phase II study of GW786034 (pazopanib) in pts with recurrent or metastatic breast cancer

Taylor SK et al. ASCO 2009Background

Pazopanib is an oral small molecule tyrosine kinase inhibitor of VEGFR1, 2, and 3, PDGFRα and β, and KIT A phase I study reached doses up 2000 mg/d DLT in 1/3 patients at 200 mg/d (grade 3 fatigue) Activity was seen with daily doses of > 800 mg

Elegibility

Metastatic or recurrent BC Up to 2 lines of cht If HER2 positive, must be trastuzumab refractory If ER+, must be hormone refractory No prior bevacizumab

Primary Endpoint- Anti-tumor efficacy: RR (RECIST)

This trial did not meet the criteria to go to stage 2 based on ORR

Pazopanib appears to have similar activity of other VEGF inhibitors in advanced pretreated breast cancer, bevacizumab and sunitinib (CBR 26%, TTP 5.3 months, vs. bevacizumab, CBR 16%, TTP 2.4 mo.; and sunitinb, CBR 17%, TTP 2.3 mo.)

These results suggest that there is minor cytotoxic as well as clear cytotoxic activity of pazopanib in advanced breast cancer, and it may be useful in studies of combination therapy

Pazopanib was well tolerated (G>3 Leuko-neutropenia; hypertension; AST, ALT)

Cobleigh et al. Semin Oncol 2003

Taylo SK et al. ASCO 2009

Burstein et al. JCO 2008

A randomized, phase II study of axitinib (AG-013736) in combination with docetaxel compared to DOC plus placebo in MBC

Rugo HS et al. ASCO 2007 Abstr 1003

Axitinib (AG-013736) a potent TKI targeting all VEGFR isoforms, PDGFR and c-KIT1

Previous phase I study identified appropriate doses of docetaxel and axitinib2 (DOC 80 mg/m2 q3w with axitinib 5 mg twice daily )

1Sloan B et al. Curr Opin Investig Drugs 2008 2Rugo HS et al. ASCO 2005 Abstr 1067

Docetaxel 80 mg/mq q3w+

Axitinib 5 mg twice dailyn=112

Docetaxel 80 mg/mq q3w+

Placebon=56

Pts with MBC not pretreated with

cht for metastatic

diseasen=168

Randomized 2:1

Primary Endpoint: TTP

Outcome

Docetaxel+

Axitinib(n=112)

Docetaxel+Placebo(n=56)

CR (%) 0.9 0

PR 39.3 23.2

SD 8.9 16.1

PD 33.9 42.9

Unknown 17 17.9

ORR, n (%) 40.2 23.2

Median TTP, mos 8.2 7

P value

0.038

0.052

Toxicities

Docetaxel and axitinib associated with a higher incidence of grade 3/4 febrile neutropenia, fatigue, stomatitis, hypertension, and thromboembolic events

Results

Axitinib has promising anti-tumor activity for pts with breast cancer

A Phase III Trial of Sunitinib (SU) Vs. Capecitabine (C) in Pts with Previously Treated HER2-Negative Advanced Breast Cancer (ABC)

HER2 negative ABC resistant to

Anthra and Taxane(n=464)

Sunitinib 37.5 mg daily(231)

Capecitabine 1250 mg/mq x2 /die d1-14 q21

(233)

Randomized 1:1

mPFS 2.8 vs. 4.2 mos for SU vs. C (p<0.001)ORR 9.1 vs. 12.9

Sunitinib is not superior to Cap given as monotherapy. Cap was better tolerated than SU. Sunitinib cannot be

recommended as monotherapy on this dosing schedule

.

Barrios C et al. SABCS 2009 Abs 46

Trial stopped for futility

Poly (ADP-ribose) polymerase (PARP)

PARP1-Inhibitors

AZD2281 Olaparib

BSI-201

PARP1 structure

PARP inhibition

and tumor-selective synthetic lethality

Peralta-Leal A et al, Free Radic. Biol. Med. 2009

CELLSURVIVAL

Tumor-selective

cytotoxicity

Phase II trial of the oral PARP inhibitor olaparib in BRCA-deficient ABC

Tutt A et al. ASCO 2009, Abst # CRA 501

Confirmed BRCA1 or BRCA2 mutationAdvanced refractory breast cancer

(stage IIIB/IIIC/IV) after failure of ≥ 1 prior chemotherapyFor advanced disease

Cohort 1 (enrolled first)

Olaparib 400 mg po bid (MDT)

28-day cycles; n = 27

Cohort 2*

Olaparib 100 mg po bid (MDT)

28-day cycles; n = 27* Following an interim review of the emerging efficacy of each cohort, patients ongoing in 100 mg bid cohort were permitted to crossover to receive the 400 mg bid dose

MDT determined during Phase I evaluation

- Median 3 prior cht treatments- In higher dose cohort, two thirds had BRCA1 mutation

Primary End-point: ORR by RECIST

ITT cohortOlaparib

400 mg bid(n=27)

Olaparib100 mg bid

(n=27)

Overall Response Rate, n (%) 11 (41)* 6 (22)*

Complete Response, n (%) 1 (4) 0

Partial Response, n (%) 10 (37) 6 (22)

Olaparib in Mutation Carriers: RESULTS

Tutt A et al. ASCO 2009, Abst # CRA 501

Phase II trial of BSI-201 in combination with gemcitabine/carboplatin in metastatic TNBC

O'Shaughnessy J et al. ASCO 2009 Abs 3Metastatic TNBC

Prior chemon = 120

RANDOMIZE

Gemcitabine 1000 mg/mq d 1, 8Carboplatin AUC 2 d 1, 8

BSI-201 5.6 mg/kg IV d 1, 4, 8, 11Gemcitabine 1000 mg/mq d1, 8Carboplatin AUC 2 d 1, 8

RESTAGINGEvery 2 cycles

* Pts randomized to gem/carbo alone could crossover to receive gem/carbo + BSI-201 at disease progression

21-daycycle

Striking early results Need confirmation in phase III trial Presumption is that PARPi interferes with chemo-induced DNA repair

O'Shaughnessy J et al. ASCO 2009 Abs 3

Resistance to PARP-Inhibitors

With the development of any active agent, resistance is sure to come

Many potential mechanisms

In a BRCA2-deficient cell line, resistance to PARP inhibition has been associated with restoration of BRCA2 function

Edwads et al, Nature 2008

Baselga J et al. SABCS 2009

Swaby et al. ASCO 2009, Abstr 1004

Phase I/II Neratinib + Trastuzumab in Trastuzumab-treated MBC

Conclusions

The list of the most promising agents in MBC is far from being complete

Novel molecules are being discovered and developed constantly

To better optimize BC therapy in the future, clinical trials testing new agents will need to meet rigorous patient selection criteria, and secure the collection of appropriate biological material.

Rationale for Targeting HER2 in Breast Cancer

Rosen LS et al. Oncologist 2010Spector NL et al. J Clin Oncol 2009Bacus SS et al. Oncogene 2002Xia W et al. Cancer Res 2006Yakes FM et al. Cancer Res 2002

20 to 25% of BCs exhibit HER2 gene amplification or protein overexpression

HER2 overexpression in BC predicts for a poor clinical outcome

It deregulates downstream signaling pathways, which impact on tumor cell growth and survival.

Concomitant up-regulation of the PI3K-AKT survival pathway and of NFkB that protects against apoptotic stimuli (eg, chemotherapy). Survivin also is regulated by HER2.

Blockage of HER2 leads to the inhibition of these survival pathway with tumor cell apoptosis