2. Breast Cancer Stats.
• Breast cancer is the most common cancer in women worldwide
• Prevalence
• Global
• More than 1.7 million new cases of breast cancer in 2012
• India
• 144,937 women were newly detected with breast cancer in 2012
• 70,218 women died of breast cancer
In India, for every 2 women newly diagnosed with breast cancer, one
lady is dying of it.
http://www.breastcancerindia.net/statistics/stat_global.html 2
3. Unmet needs in breast cancer
• Individuals with Breast cancer and TNBC *
• Management of patients with these tumor subtypes is one of the major issues in breast
cancer
• Improved understanding of drivers and poor prognostic groups are needed
• HER2þ breast cancer
• Treatment of trastuzumab-resistant disease
• Prediction of the subpopulation that will benefit from costly dual targeting interventions,
such as the combination of trastuzumab and pertuzumab.
• Advanced breast cancer
• Need for biologically driven criteria to guide treatment choice
• Identification of the optimal combinations or sequences of targeted agents
• Integration of new agents into current regimens
A. Di Leo et al. The Breast 24 (2015) 321e330
* Triple (ER/PgR/HER2) negative breast cancer
3
5. New therapeutic targets for drug treatment in breast cancer
• Agents directed at intra-tumoral targets
• Agents targeting the tumor stromal compartment
A. Di Leo et al. The Breast 24 (2015) 321e330
5
6. Agents directed at intra-tumoral targets
Molecular target Agents in development Company
Transmembrane tyrosine kinases
IGF Cixutumumab ImClone Systems Inc.
MEDI-573 MedImmune
BMS-754807 Bristol-Myers Squibb
HGF Ficlatuzumab AVEO
Rilotumumab Amgen
TAK-701 Millennium Pharmaceuticals
cMET Onartuzumab (OA5D5) Genentech
LY-2875358 Eli Lilly
Tivantinib (ARQ-197) Daiichi Sankyo
Foretinib (XL-880) Elexis
HGF, hepatocyte growth factor; IGF, insulin-like growth factor
A. Di Leo et al. The Breast 24 (2015) 321e330
6
7. Agents directed at intra-tumoral targets
Molecular target Agents in development Company
Secondary messengers
P13K/AKT/mTOR XL147 Exelixis/Sanofi-Aventis
BYL719 Novartis
BKM120 Novartis
GDC-0032 Genentech
DNA repair alterations
PARP Rucaparib Clovis
Olaparib AstraZeneca
Veliparib Abbott
MK-4827 Merck
CEP-9722 Cephalon
BMN673 Biomarin
E7016 Eisai
PARP, poly(ADP-ribose) polymerase; P13K/AKT/mTOR, phosphatidylinositol 3-kinase/serine/threonine kinase/mammalian target of rapamycin
7
8. Agents directed at intra-tumoral targets
Molecular target Agents in development Company
Others
AR Enzalutamide Medivation/Astellas
Abiraterone Janssen
Hsp90 NVP-AUY922 Novartis
Ganestespib Synta
CDK PD0332991 Pfizer
AR, androgen receptor;
CDK, cyclin-dependent kinase;
Hsp90, heat shock protein 90
A. Di Leo et al. The Breast 24 (2015) 321e330
8
9. Extracellular compartment targeted agents
Molecular target Agents in development Company
Angiogenic vascular cells
VEGF Tivozanib AVEO/Astellas
Sunitinib Pfizer
Sorafenib Bayer
Ramucirumab Eli Lilly/Imclone
Infiltrating immune cells
PD-1/PD-L1 MDX-1105-01 Bristol-Myers Squibb
AMP-514 MedImmune
MPDL3280A Genentech
CTL Ipilimumab (MDX-010) Yervoy
TAM PLX3397 Plexxikon
CTL, cytotoxic T-lymphocytes; TAM, tumor-associated macrophages; TRAIL, tumor necrosis factor-related apoptosis-inducing ligand;
VEGF, vascular endothelial growth factor.
A. Di Leo et al. The Breast 24 (2015) 321e330
9
10. Extracellular compartment targeted agents
Molecular target Agents in development Company
Cancer-associated fibroblastic cells
MMP Tanomastat (BAY 12-9566) Bayer
TRAIL Tigatuzumab Daiichi Sankyo
PRO95780 Genentech
MMP, matrix metalloproteinase; TRAIL, tumor necrosis factor-related apoptosis-inducing ligand
A. Di Leo et al. The Breast 24 (2015) 321e330
10
11. mRNA-edited form of GABRA3 suppresses GABRA3-mediated AKT
activation and breast cancer metastasis
• RNA editing
• plays critical roles in breast cancer progression, invasion and metastasis
• may be a potential therapeutic target
• Interferons upregulate the expression of ADAR1, which is responsible for GABRA3 editing in
breast cancer cells
• Recombinant interferon-b (IFN-b) has been shown in clinical trials to improve clinical
benefits and overall survival in metastatic breast cancer patients with minimal residual
disease after chemotherapy
Combination of targeting GABRA3 function and upregulating A-to-I editing of
GABRA3 mRNAs may have the potential to further improve therapeutic effects
as combination therapies.
Gumireddy et al , Nature Communications,2016
11
13. Drugs for metastatic Breast Cancer in Developmental Stage
Product Name Sponsor Development Phase*
Abemaciclib
(CDK 4/6 inhibitor)
Lilly
Indianapolis, IN
Phase II
BKM120
(PI3K inhibitor)
Novartis Pharmaceuticals
East Hanover, NJ
Phase III
BMN 673
(PARP inhibitor)
BioMarin Pharmaceutical
Novato, CA
Phase III
Cynviloq™
paclitaxel polymeric micelle
for injection
Sorrento Therapeutics
San Diego, CA
Phase III
Etirinotecan pegol
(PEGylated irinotecan)
Nektar Therapeutics
San Francisco, CA
Phase III
Medicines in Development Cancer 2014
13
14. Drugs for metastatic Breast Cancer in Developmental Stage
Product Name Sponsor Development Phase*
indoximod
(IDO pathway inhibitor)
NewLink Genetics
Ames, IA
Phase II
margetuximab
(anti-HER2 mAb)
MacroGenics
Rockville, MD
Phase II
MEDI-573
(anti-IGF mAb)
MedImmune
Gaithersburg, MD
Phase II
MLN0128
(TORC1/TORC2 inhibitor)
Millennium Pharmaceuticals
Cambridge, MA
Phase II
Myocet™
doxorubicin liposomal
Sopherion Therapeutics
East Brunswick, NJ
Phase III
SGN LIV1A
(anti-LIV-1 mAb)
Seattle Genetics
Bothell, WA
Phase I
Medicines in Development Cancer 2014
14
15. Drugs for metastatic Breast Cancer in Developmental Stage
Product Name Sponsor Development Phase*
olaparib
(PARP inhibitor)
AstraZeneca
Wilmington, DE
Phase III
palbociclib
(CDK4/6 inhibitor)
Pfizer
New York, NY
application submitted
PB272
(neratinib)
Puma Biotechnology
Los Angeles, CA
Phase III
PEG-SN38
(angiogenesis inhibitor)
Belrose Pharma
Princeton, NJ
Phase II
Perjeta®
pertuzumab
Genentech
South San Francisco, CA
Phase III
taselisib
(PI3K inhibitor)
Genentech
South San Francisco, CA
Phase I
Medicines in Development Cancer 2014
15
16. Drugs for metastatic Breast Cancer in Developmental Stage
Product Name Sponsor Indication Development Phase*
PF-05280014
(trastuzumab
biosimilar)
Pfizer
New York, NY
metastatic breast cancer Phase III
pictrelisib
(PI3K inhibitor)
Genentech
South San
Francisco, CA
ER-positive metastatic breast cancer,
metastatic HER2-negative/hormone
receptor-positive breast cancer
Phase II
PM01183
(marine-derived
alkylating agent)
Pharma Mar
Madrid, Spain
metastatic breast cancer Phase II
reparixin
(IL-8A/B receptor
antagonist)
Dompe
Milan, Italy
early-stage breast cancer
-------------------------------------
metastatic breast cancer
Phase II
-----------------------------
Phase I
Zytiga®
abiraterone acetate
Janssen Research &
Development
Raritan, NJ
Metastatic ER-positive, HER2-negative
breast cancer in postmenopausal patients
Phase II
Medicines in Development Cancer 2014
16
