Rationale for a Cancer Target
Mechanism of Action
AxitinibRTKI includingVEGFR-1,2,3
Overview
Stage of Development
NPU00667_25cNOVEMBER 2017
Pfizer Investigational Agents for
Breast Cancer Now (BCN) Catalyst
Program
Rationale for a Cancer Target
Mechanism of Action
AxitinibRTKI includingVEGFR-1,2,3
Overview
Stage of Development
NPU00667_25cNOVEMBER 2017
AxitinibRTKI including VEGFR-1,2,3
NOVEMBER 2017
Rationale for a Cancer Target
Mechanism of Action
AxitinibRTKI includingVEGFR-1,2,3
Overview
Stage of Development
NPU00667_25cNOVEMBER 2017
Overview
Overview
INLYTA® (axitinib) (package insert). New York, New York: Pfizer Inc. September 2013.
Kania RS (Pfizer San Diego). Structure-based design and characterization of axitinib. In Li R, Stafford JA, eds.
Kinase Inhibitor Drugs (Wiley Series in Drug Discovery and Development). Hoboken, NJ: John Wiley & Sons,
Inc.; 2009: chapter 7: doi:10.1002/9780470524961.ch7.
• The vascular endothelial growth factor (VEGF)
family of proangiogenic proteins are key regulators
of many of the signaling networks contributing to
angiogenesis
• The VEGF receptors are implicated in pathologic
angiogenesis, tumor growth, and cancer
progression
• Axitinib is a small molecule substituted indazole
derivative that inhibits receptor tyrosine kinases,
including VEGFR-1, VEGFR-2, and VEGFR-3, at
therapeutic plasma concentrations
• VEGF-mediated endothelial cell proliferation and
survival were inhibited by axitinib in vitro and in
mouse models
• Axitinib was shown to inhibit tumor growth and
phosphorylation of VEGFR-2 in tumor xenograft
mouse models
Rationale for a Cancer Target
Mechanism of Action
AxitinibRTKI includingVEGFR-1,2,3
Overview
Stage of Development
NPU00667_25cNOVEMBER 2017
Stage of Development
Sponsored by SFJ Pharmaceuticals, Inc. Closed to enrollment
ClinicalTrials.gov. http://clinicaltrials.gov/. Accessed November 8, 2017
Axitinib is being investigated as a single agent or
in combination with other agent(s) in the following
tumor types. Axitinib is not approved for the uses
listed below.
Stage of Development
Adjuvant
Renal Cell
Carcinoma
(RCC)
Phase 3 *
Advanced Renal
Cell Carcinoma
(RCC)
Phase 3: Combination
Rationale for a Cancer Target
Mechanism of Action
BosutinibABL and Src Kinase Inhibitor
Overview
Stage of Development
NPU00667_25c NOVEMBER 2017
BosutinibABL and Src Kinase Inhibitor
NOVEMBER 2017
Rationale for a Cancer Target
Mechanism of Action
BosutinibABL and Src Kinase Inhibitor
Overview
Stage of Development
NPU00667_25c NOVEMBER 2017
Overview
• The Philadelphia chromosome is a reciprocal translocation
that fuses the Abl locus on chromosome 9 with the Bcr locus
on chromosome 22, resulting in overexpression of the
constitutively active protein tyrosine kinase Bcr-Abl, which is
commonly associated with chronic myeloid leukemia (CML)
• The Src family of tyrosine kinases plays a role in a variety of
normal cellular functions including proliferation, differentiation,
survival etc. and are frequently overexpressed and/or
aberrantly activated in many tumors
• Bosutinib is a synthetic quinolone derivative and kinase
inhibitor that targets both Abl and Src kinases with potential
antineoplastic activity
• Bosutinib inhibits Bcr-Abl in several CML cell lines and
transfectants, with IC50 values in the low nanomolar range and
also inhibited Bcr-Abl kinase activity in CML CD34+ cells
• Bosutinib inhibits Src in an enzyme assay with an IC50 of 1.2
nM, inhibits anchorage-independent growth of Src-transformed
fibroblasts with an IC50 of 100 nM, and inhibits Src-dependent
protein tyrosine phosphorylation
Overview
Bumbea H., et al: Journal of Medicine and Life: Volume 3, Number 2, April-June 2010.
Golas JM, Arndt K, Etienne C, et al. Cancer Res. 2003;63(2):375-381.
Konig H, Holyoake TL, Bhatia R. Blood. 2008;111(4):2329-2338.
Puttini M, Coluccia AM, Boschelli F, et al. Cancer Res. 2006;66(23):11314-11322.
Vultur A, Buettner R, Kowolik C, et al. Mol Cancer Ther. 2008;7(5):1185-1194.
Rationale for a Cancer Target
Mechanism of Action
BosutinibABL and Src Kinase Inhibitor
Overview
Stage of Development
NPU00667_25c NOVEMBER 2017
Stage of Development
ClinicalTrials.gov. http://clinicaltrials.gov. Accessed November 7, 2017.
Bosutinib is being investigated in the following
tumor type. Bosutinib is not approved for the use
listed below.
Stage of Development
Newly
Diagnosed
Chronic Phase (CP)
Chronic Myeloid
Leukemia (CML)
Phase 3*
* Closed to enrollment
Rationale for a Cancer Target
Mechanism of Action
GedatolisibPI3K/mTOR Pathway Inhibitor
Gedatolisib is an investigational compound
Overview
Stage of Development
NPU00667_25c NOVEMBER 2017
GedatolisibPI3K/mTOR Pathway Inhibitor
NOVEMBER 2017
Gedatolisib is an investigational compound
Rationale for a Cancer Target
Mechanism of Action
GedatolisibPI3K/mTOR Pathway Inhibitor
Gedatolisib is an investigational compound
Overview
Stage of Development
NPU00667_25c NOVEMBER 2017
Overview
• Phosphatidylinositol 3-kinases (PI3Ks) activate a signaling
pathway which includes the protein kinases AKT and
mTOR, leading to regulation of cell growth, cell cycle
progression, apoptosis, migration, metabolism, and
vesicular trafficking
• The PI3K/AKT/ mTOR pathway is one of the most
frequently mutated pathways in solid tumor malignancies,
resulting in activation of PI3K and its downstream targets
AKT and mTOR
• PF-05212384 is a small molecule inhibitor of the
PI3K/AKT/mTOR signaling pathway
• In vitro, PF-05212384 has demonstrated suppression of
PI3K (and mTOR) kinase activity in a diverse array of
tumor cell lines, and in vivo the compound has inhibited
tumor cell growth and induced tumor regression in human
tumor xenograft models with select gene mutations
• PF-05212384 shows antitumor activity in subcutaneous
and orthotopic human xenograft tumor models when
administered intravenously (iv) as a single agent
Overview
Arcaro A, Guerreiro AS. Curr Genomics. 2007;8(5):271-306.
Grant S. J Clin Invest. 2008;118(9):3003-3006.
Mallon RG, Feldberg LR, Lucas J, et al. Clin Cancer Res. Feb 15, 2011.
Data on file, Wyeth May 2009
Rationale for a Cancer Target
Mechanism of Action
GedatolisibPI3K/mTOR Pathway Inhibitor
Gedatolisib is an investigational compound
Overview
Stage of Development
NPU00667_25c NOVEMBER 2017
Mechanism of Action
Mechanism of Action
Adapted from Workman P, et al. Nat Biotech. 2006;24:794-796. Used with permission from AACR.
Cheng H, et al. Med. Chem. Commun. 2010;1:139-144.
Mallon RG, et al. Clin Cancer Res. Feb 15, 2011.
Rationale for a Cancer Target
Mechanism of Action
GedatolisibPI3K/mTOR Pathway Inhibitor
Gedatolisib is an investigational compound
Overview
Stage of Development
NPU00667_25c NOVEMBER 2017
Stage of Development
ClinicalTrials.gov. http://clinicaltrials.gov/. Accessed November 7, 2017
Stage of Development
Metastatic HR+
Breast Cancer
(MBC)
Phase 1 Combination
Metastatic
Triple Negative
Breast Cancer
(TNBC)
Phase 1 Combination
Rationale for a Cancer Target
Mechanism of Action
GlasdegibSmoothened (SMO) Inhibitor
Glasdegib is an investigational compound
Overview
Stage of Development
NPU00667_25c NOVEMBER 2017
GlasdegibSmoothened (SMO) Inhibitor
NOVEMBER 2017
Glasdegib is an investigational compound
Rationale for a Cancer Target
Mechanism of Action
GlasdegibSmoothened (SMO) Inhibitor
Glasdegib is an investigational compound
Overview
Stage of Development
NPU00667_25c NOVEMBER 2017
Overview
• The Hedgehog (Hh) signal transduction pathway is essential
for the patterning and development of tissues in metazoan
organisms
• The hedgehog receptor, patched homologue 1 (PTCH1),
inhibits smoothened (SMO), a key activator in the pathway
• During physiologic signaling, Hh binds to PTCH1 on neighboring
cells, thereby allowing SMO to activate hedgehog signaling.
• SMO activation results in activation of target proteins, such as GLI
transcription factors, which can cause proliferation, survival, and
differentiation of cells.
• PF-04449913 is an orally bioavailable small-molecule inhibitor
of the Hedgehog (Hh) signaling pathway with potential
antineoplastic activity
• In vivo, PF-04449913 was shown to revert multidrug
resistance (MDR) by down-regulation of ABCA2 and BCL2 on
leukemia stem cells in acute myeloid leukemia and chronic
myeloid leukemia
• PF-04449913-treated medulloblastoma allografts had reduced
levels of GLI1 gene expression and downregulation of genes
linked to the Hh signaling pathway
Overview
NCI Drug Dictionary. Accessed April 14, 2011..
Jackson-Fisher A, McMahon MJ, Lam J, et al. AACR 2011. Abstract 4504.
Papayannidis, C., Cancer Research: April 15, 2012; Volume 72, Issue 8, Supplement 1
Rationale for a Cancer Target
Mechanism of Action
GlasdegibSmoothened (SMO) Inhibitor
Glasdegib is an investigational compound
Overview
Stage of Development
NPU00667_25c NOVEMBER 2017
Mechanism of Action
• The Hedgehog pathway is expressed in all 3 germ layers
throughout embryogenesis
• The Hedgehog pathway is repressed in adult tissues but, if
aberrantly reactivated, can induce neoplasia
• Soluble Hh binds PTCH1 to release SMO and activate GLI
signaling
• Inappropriate SMO signaling is implicated in multiple human
malignancies
• The Hedgehog pathway regulates cancer stem cell maintenance
and activity
Mechanism of Action
Zhao C, Chen A , Jamieson CH, et. al. Nature. 2009;(458):776-779..
Ingham PW, et al. Genes Dev. 2001;15:3059-3087.
Xie J. Acta Biochim Biophys Sin (Shanghai). 2008;40(7):670-680.
Rationale for a Cancer Target
Mechanism of Action
GlasdegibSmoothened (SMO) Inhibitor
Glasdegib is an investigational compound
Overview
Stage of Development
NPU00667_25c NOVEMBER 2017
Stage of Development
ClinicalTrials.gov. http://clinicaltrials.gov/. Accessed November 8, 2017
Stage of Development
Acute Myeloid
Leukemia (AML)
or Myelodysplastic
Syndrome (MDS)
Phase 2 *
Myelofibrosis Phase 2
* Closed to enrollment
Myelodysplastic
Syndrome (MDS)
Acute Myeloid
Leukemia (AML) or
Chronic Myelomonocytic
Leukemia (CMML)
Phase 1b/2 Combination
LorlatinibALK/ROS1 Inhibitor
Lorlatinib is an investigational compound
Rationale for a Cancer Target
Mechanism of Action
NPU00667_25c NOVEMBER 2017
Overview
Stage of Development
LorlatinibALK/ROS1 Inhibitor
NOVEMBER 2017
Lorlatinib is an investigational compound
LorlatinibALK/ROS1 Inhibitor
Lorlatinib is an investigational compound
Rationale for a Cancer Target
Mechanism of Action
NPU00667_25c NOVEMBER 2017
Overview
Stage of Development
Overview
• A variety of human malignancies have anaplastic lymphoma kinase
(ALK) translocations, amplifications, or oncogenic mutations,
including non-small cell lung cancer (NSCLC), anaplastic large
cell lymphoma, inflammatory myofibroblastic tumors, and
neuroblastoma
• ROS1 is a receptor tyrosine kinase (RTK) implicated in tumor
progression, and the first oncogenic fusion of ROS1 (FIG-ROS1)
was discovered in glioblastoma
• Elevated ROS expression has also been observed in
cholangiocarcinoma, NSCLC, and breast cancer
• PF-06463922 is an ATP-competitive small molecule inhibitor of
both ALK and ROS1, created through structure-based drug design
(SBDD), with specific considerations such as a low efflux in cell
lines overexpressing P-glycoprotein and breast cancer resistance
protein, providing blood-brain barrier and cell penetration properties
• PF-06463922 shows antitumor activity in preclinical models which
harbor the resistant mutations ALK-G1202R and ROS1-G2032R
• Single-dose preclinical rat in vivo studies of PF-06463922 showed
oral bioavailability and CNS availability, with brain levels
approximately 30% of that in the plasma
Overview
Johnson TW, Bailey S, Burke BJ, et al. EORTC 2013 Poster 982: Is CNS availability a no-brainer? La Jolla,
CA: Pfizer Oncology.
Mossé YP, Wood A, Maris JM. Inhibition of ALK Signaling for Cancer Therapy. Clin Cancer Res.
2009;15(18):5609-5614.
Gu T, Deng X, Huang F, et al. PLoS ONE. 2010;6(1): e15640.
Rimkunas, VM, Clin Cancer Res; 18(16) August 15, 2012
LorlatinibALK/ROS1 Inhibitor
Lorlatinib is an investigational compound
Rationale for a Cancer Target
Mechanism of Action
NPU00667_25c NOVEMBER 2017
Overview
Stage of DevelopmentStage of Development
ClinicalTrials.gov. http://clinicaltrials.gov/. Accessed November 7, 2017
Stage of Development
* Closed to enrollment
ALK+
Non-Small Cell
Lung Cancer
(NSCLC)
Phase 3
ALK+ /ROS1+
Non-Small Cell
Lung Cancer
(NSCLC)
Phase 2 *
Rationale for a Cancer Target
Mechanism of Action
PalbociclibCDK 4/6 Inhibitor
Overview
Stage of Development Page 1
Page 2
NPU00667_25c NOVEMBER 2017
PalbociclibCDK 4/6 Inhibitor
NOVEMBER 2017
Rationale for a Cancer Target
Mechanism of Action
PalbociclibCDK 4/6 Inhibitor
Overview
Stage of Development Page 1
Page 2
NPU00667_25c NOVEMBER 2017
Overview
Overview
Finn RS, et al. Breast Cancer Res. 2009;11(5):R77.
Fry DW, et al. Mol Cancer Ther. 2004;3(11):1427-1438.
Knudsen ES, Wang JY. Clin Cancer Res. 2010;16(4):1094-1099.
• Cyclin-dependent kinases (CDKs) are small serine/threonine
kinases that play a key role in regulating cell cycle progression
and to a large degree govern cellular transitions from growth
phases (G1 and G2) into phases associated with DNA
replication (S) and mitosis (M)
• Progression through the G1-S phase requires phosphorylation
of the retinoblastoma (Rb) protein by CDK4 or CDK6 in
complex with their activating subunits, the D-type cyclins
• Components of this pathway, particularly cyclin D1 and Rb, are
frequently altered in sporadic human cancers to promote
deregulated cellular proliferation
• Palbociclib is an orally active inhibitor of CDK4 and CDK6
kinases. Inhibition results in decreased phosphorylation of the
CDK4/6 target retinoblastoma protein
• Blocking Rb phosphorylation prevents cell cycle progression in
sensitive cell lines
• Palbociclib has been shown, in vitro, to induce growth arrest in
the G1 phase of the cell cycle in multiple Rb+ tumor cell line
models. Palbociclib causes a specific cell cycle arrest in G1
phase and inhibits proliferation in cultured and xenografted
leukemia, myeloma, breast cancer, colon cancer, and lung
cancer cells.
Rationale for a Cancer Target
Mechanism of Action
PalbociclibCDK 4/6 Inhibitor
Overview
Stage of Development Page 1
Page 2
NPU00667_25c NOVEMBER 2017
Stage of Development Page 1
Palbociclib is being investigated as a single agent or in
combination with other agent(s) in the following tumor types.
Palbociclib is not approved for the uses listed below.
Stage of Development
HR+/HER2-
Adjuvant Breast
Cancer
Phase 3: Combination*
Phase 3: Combination** HR+/HER2 normal
Adjuvant Breast
Cancer
HR+/HER2-
Metastatic
Breast Cancer
Phase 3: Combination†
HR+/HER2+
Metastatic
Breast Cancer
Phase 3: Combination◊
* Sponsored by Alliance Foundation Trials, LLC.
For Stage II or III breast cancer patients
** Sponsored by German Breast Group.
For high risk breast cancer patients. No longer
screening
† Sponsored by Spanish Breast Cancer Group ◊ Sponsored by Alliance Foundation Trials, LLC.
ClinicalTrials.gov. http://clinicaltrials.gov/. Accessed. November 8, 2017
Rationale for a Cancer Target
Mechanism of Action
PalbociclibCDK 4/6 Inhibitor
Overview
Stage of Development Page 1
Page 2
NPU00667_25c NOVEMBER 2017
Stage of Development
Page 2
ClinicalTrials.gov. http://clinicaltrials.gov/. Accessed. November 8, 2017
Palbociclib is being investigated as a single agent or in
combination with other agent(s) in the following tumor
types. Palbociclib is not approved for the uses listed
below.
Stage of Development
Recurrent/
Metastatic
Squamous Cell
Carcinoma of the
Head & Neck (SCCHN)
Phase 2: Combination
Phase 1: Combination
Metastatic
Pancreatic Ductal
Adenocarcinoma
(PDAC)
Relapsed/
Refractory
Mantle Cell
Lymphoma
Phase 1: Combination*
* Sponsored by National Cancer Institute (NCI). Closed to enrollment
Rationale for a Cancer Target
Mechanism of Action
SunitinibMultiple RTK Inhibitor
Overview
Stage of Development
NPU00667_25cNOVEMBER 2017
SunitinibMultiple RTK Inhibitor
NOVEMBER 2017
Rationale for a Cancer Target
Mechanism of Action
SunitinibMultiple RTK Inhibitor
Overview
Stage of Development
NPU00667_25cNOVEMBER 2017
Overview
Overview
Pytel D, Sliwinski T, Poplawski T, et al. Anticancer Agents Med Chem. 2009;9(1):66-76.
SUTENT® (sunitinib malate) (package insert). New York, New York: Pfizer Inc. August 2013.
• Tyrosine kinases are enzymes which phosphorylate
tyrosine residue on targeted proteins. They stimulate
cellular pathways involved in such functions as growth,
proliferation, migration, synthesis, and apoptosis
• Sunitinib is an orally administered small molecule that
inhibits multiple receptor tyrosine kinases (RTKs), some
of which are implicated in tumor growth, pathologic
angiogenesis, and metastatic progression of cancer
• Sunitinib was identified as an inhibitor of platelet-derived
growth factor receptors (PDGFRα and PDGFRβ), vascular
endothelial growth factor receptors (VEGFR1, VEGFR2,
and VEGFR3), stem cell factor receptor (KIT), Fms-like
tyrosine kinase-3 (FLT3), colony-stimulating factor
receptor Type 1 (CSF-1R), and the glial cell-line derived
neurotrophic factor receptor (RET)
• Sunitinib inhibition of the activity of these RTKs has been
demonstrated in biochemical and cellular assays, and
inhibition of function has been demonstrated in cell
proliferation assays
Rationale for a Cancer Target
Mechanism of Action
SunitinibMultiple RTK Inhibitor
Overview
Stage of Development
NPU00667_25cNOVEMBER 2017
Stage of Development
* Closed to enrollment
ClinicalTrials.gov. http://clinicaltrials.gov/. Accessed November 8, 2017
Sunitinib is being investigated as a single agent in
the following tumor type. Sunitinib is not approved
for the use listed below.
Stage of Development
Pediatric
Advanced
Gastrointestinal
Stromal Tumor
(GIST)
Phase 2 *
Rationale for a Cancer Target
Mechanism of Action
TalazoparibPARP Inhibitor
Talazoparib is an investigational compound
Overview
Stage of Development
NPU00667_25c NOVEMBER 2017
TalazoparibPARP Inhibitor
NOVEMBER 2017
Talazoparib is an investigational compound
Rationale for a Cancer Target
Mechanism of Action
TalazoparibPARP Inhibitor
Talazoparib is an investigational compound
Overview
Stage of Development
NPU00667_25c NOVEMBER 2017
Overview
Overview
Underhill et al. Ann Oncol. 2011;22(2):268‐279
NCI Drug Dictionary. https://www.cancer.gov/publications/dictionaries/cancer-drug?cdrid=694964.
Accessed 10.23.16
Murai et al. Mol Cancer Ther. 2014;13:433-443.
https://newdrugapprovals.org/2016/02/08/talazoparib/. Accessed 10.23.16
Wainberg et al. AACR 2016 Abstract CT011.
Medivation Brochure CTSITE-MULTI-TALA-0001 03/16
• Poly (ADP-ribose) polymerase (PARP) enzymes are
associated with DNA repair, specifically base excision repair, a
key pathway in the repair of DNA single-strand breaks (SSB).
They are thought to play a role in repair of damaged DNA and
in stabilization of the genome
• Talazoparib is a dual inhibitor of the nuclear enzyme PARP
with potential antineoplastic activity
• Talazoparib is designed to inhibit PARP and trap PARP on DNA,
with the goal of preventing PARP-mediated DNA damage repair
thereby inducing tumor cell death in BRCA1/2-mutated tumor cells
• Talazoparib selectively binds to PARP and is thought to
prevent PARP mediated DNA repair of single strand DNA
breaks via the base-excision repair pathway
• This enhances the accumulation of DNA strand breaks, promotes
genomic instability and eventually leads to apoptosis. PARP
catalyzes post-translational ADP-ribosylation of nuclear proteins
that signal and recruit other proteins to repair damaged DNA and is
activated by single-strand DNA breaks
Rationale for a Cancer Target
Mechanism of Action
TalazoparibPARP Inhibitor
Talazoparib is an investigational compound
Overview
Stage of Development
NPU00667_25c NOVEMBER 2017
Mechanism of Action
Mechanism of Action
Figure adapted from Cancer Res. 2012. 72:5588-5599. Murai J et al. Trapping of PARP1 and
PARP2 by Clinical PARP Inhibitors, with permission from AACR.
Possible dual cytotoxic mechanisms of PARP inhibitors:
1: Catalytic inhibition (upper pathway) is thought to
interfere with the repair of SSBs, leading to replication fork
damage that requires homologous recombination (HR)
repair
2: Trapping of PARP-DNA complexes may also lead to
replication fork damage but utilizes additional repair
pathways including Fanconi pathway (FA), template
switching (TS), ATM, FEN1 (replicative flap endonuclease)
and polymerase β.
Rationale for a Cancer Target
Mechanism of Action
TalazoparibPARP Inhibitor
Talazoparib is an investigational compound
Overview
Stage of Development
NPU00667_25c NOVEMBER 2017
Stage of Development
ClinicalTrials.gov. http://clinicaltrials.gov/. Accessed November 7, 2017
Stage of Development
Locally Advanced
or Metastatic
Breast Cancer with
Germline
BRCA mutations
Phase 3 *
Metastatic
Castration-Resistant
Prostate Cancer
(MCRPC)
Phase 3
Locally Advanced
or Metastatic
Solid TumorsPhase 1b Combination
* Closed to enrollment