Transcript No Slide Title

Overcoming Treatment Challenges in
Sarcomas:
Promising Novel Targeted Agents
George D. Demetri, MD
Center for Sarcoma and Bone Oncology
Dana-Farber Cancer Institute
Ludwig Center at Dana-Farber / Harvard
Boston, Massachusetts
Development of
Molecularly Targeted Agents
for Sarcomas
A Model for Personalized
Anticancer Drug Development
Searching for Critical Switches in Sarcomas
ON
OFF
Tumor Cell
Survival and
Growth
Tumor Cell
Growth Arrest
and Cancer
Regression
Finding the Critical Switch in the
Gastrointestinal Sarcoma known as GIST
Gain-of-Function Mutations of c-kit in Human
Gastrointestinal Stromal Tumors
Seiichi Hirota, Koji Isozaki, Yasuhiro Moriyama, Koji Hashimoto,
Toshirou Nishida, Shingo Ishiguro, Kiyoshi Kawano, Masato Hanada,
Akihiko Kurata, Masashi Takeda, Ghulam Muhammad Tunio, Yuji Matsuzawa,
Yuzuru Kanakura, Yasuhisa Shinomura, Yukihiko Kitamura
Science 279:577-580, 1998.
Imatinib is a Highly Effective
Targeted Agent in GIST
Baseline PreImatinib
ON
1 month on
Imatinib
OFF
Sunitinib is an Effective Targeted Agent
for Imatinib-Resistant GIST
PET after 7
days of
Sunitinib
Normal
Heart
and
Kidneys
Baseline
Day 7 PET
Demetri GD, et al. Proc Am Soc Clin Oncol 2005; Abstract 4000.
Targeting Pathogenic Pathways
in Other Types of Sarcomas Besides GIST
KIT
PDGFRA
P
P
P
P
P
P
P
P
Ras
PI3K
PKCtheta
Raf
AKT
Mek
mTOR
Erk
S6K
Nucleus
Transcription factors
Cell proliferation
Angiogenesis
Cell adhesion
Cell differentiation
Apoptosis
Cell survival
The Next Successful Application of
Kinase Inhibition to Sarcoma Therapy
• Dermatofibrosarcoma Protuberans (DFSP)
– Balanced translocation - t(17;22) - leads to uncontrolled
production of PDGF ligand
– This induces autocrine activation of the wild-type PDGF-receptor
system
– Imatinib and Sunitinib also block PDGF-receptors
Inhibiting PDGF-R with Imatinib in
Advanced Dermatofibrosarcoma Protuberans
(DFSP)
After 5 months of Imatinib
Complete
Clinical
Response
sustained
and
ongoing
> 5 years
DFSP: Response to Imatinib
Decreased
Cellularity
Hyaline
Change
McArthur et al. J Clin Oncol 2005; 23:866.
Testing Kinase Inhibitors as Therapy
for Other Sarcoma Subtypes
• Imatinib
– Occasional activity in desmoid tumors (SARC)
• Sorafenib
– Some activity in vascular sarcomas (MSKCC)
• Sunitinib
– Some activity in vascular sarcomas and desmoplastic small
round cell tumor (MSKCC and DFCI)
• Dasatinib
– SARC trial ongoing
Testing Kinase Inhibitors as Therapy for
Other Sarcoma Subtypes
• Pazopanib
– Oral Tyrosine Kinase Inhibitor with activity against VEGF-R,
PDGFR, and KIT, tested by EORTC
– Activity demonstrated in several subtypes including
leiomyosarcomas and synovial sarcoma
– Phase III clinical trial to begin soon with EORTC and other
international collaborations
Targeting Pathogenic Pathways
in Other Sarcomas
KIT
PDGFRA
P
P
P
P
P
P
P
P
Ras
PI3K
PKCtheta
Raf
AKT
Mek
mTOR
mTOR
Erk
S6K
Nucleus
Transcription factors
Cell
proliferation
Angiogenesis
Cell
adhesion
Apoptosis
Cell
survival
Cell
differentiation
mTOR-driven Sarcomas
• LAM and PEComa family of tumors
– Lymphangioleiomyomatosis (LAM)
– Angiomyolipoma (AML)
– Perivascular Epitheliod Cell-oma (PEComa)
• LAM/AML can be associated with Tuberous Sclerosis
Complex or sporadic
Patient with Metastatic PEComa
Responding to mTOR Inhibitor
(Sirolimus)
Wagner, Morgan, Antonescu et al. 2008.
Deforolimus: a Novel mTOR Inhibitor
O
P


Non-prodrug rapamycin analog
Forms a tripartite complex with
FKBP12 and mTOR
O
O
O
O
O
O
HO
O


O
OH
N
O
O
O
Inhibits mTOR activity at nM
levels
Compatible with either i.v. or
oral delivery
FKBP
mTOR
(FRB
Domain
)
Metcalf CA et al. Proc Am Assoc Cancer Res 2004; 45:2476.
Phase I Deforolimus Trial: Objective Response
in Chemotherapy-resistant Ewing’s Sarcoma
• 20-year old patient with metastatic Ewing’s sarcoma
progressing despite nine prior anti-cancer regimens
• Daily dosing with Deforolimus, 15 mg (IV)
18 May 2004
(Baseline)
15 Sep 2004
08 Dec 2004
Mita M, et al. Proc Eur J Cancer 2004; 40A, Abstract 409.
Response to the mTOR Inhibitor Deforolimus
in Chemotherapy-resistant Osteosarcoma
PET Day 1 (Baseline)
PET Day 5
PET Day 53
Fused CT/PET Images
Sankhala KK, et al. Proc Am Soc Clin Oncol 2005; 23: 823.
Monitoring Deforolimus Inhibition of
mTOR Activity in Blood
Target of
mTOR Activity
Total
Target
Hrs post-dose
0
4
24
V. Rivera, et al. Deforolimus Study Group.
Phase II Deforolimus Trial:
Promising Progression-Free Survival (PFS)
6-Month Rate
Median (wks)
Bone Sarcoma
25%
16
Soft-tissue Sarcomas
24%
15
• Leiomyosarcoma
22%
16
• Liposarcoma
30%
16
• Other soft-tissue
sarcomas
23%
15
24%
15
Sarcoma Subtype
Overall PFS
• Benefits observed across all sarcoma subtypes
Historical Context for Promising Disease
Control with Deforolimus in Sarcomas
Progression-free Survival (PFS) Compared with Historical Data
from EORTC
Historical Data (EORTC)
Deforolimus
Inactive
Agents
Active Agents
158
234
146
Median PFS
15 wks
7 wks
8 wks
3-month PFS
58%
21%
39%
6-month PFS
24%
8%
14%
No. of Patients
Phase II Activity of Deforolimus in
Sarcomas
• Promising activity of Deforolimus in patients with a broad
range of advanced soft-tissue and bone sarcomas
– Achieved primary endpoint of ≥ 25% Clinical Benefit Response
in each histologic subgroup of advanced sarcomas
• No significant differences among the 4 sub-groups
– 29% overall CBR rate despite low incidence of tumor shrinkage
– PFS more than double that of historical control (EORTC)
• 24% 6-month PFS rate (vs. 8%)
• 15-week median PFS (vs. 7 weeks)
• Well-tolerated with manageable side-effects
• A solid foundation upon which a definitive phase III trial
has been developed to test the activity of deforolimus
Phase III Trial (“SUCCEED”): Deforolimus
vs. Placebo to Maintain Clinical Benefit from
Prior Chemotherapy in Sarcomas
Primary Endpoint
• Progression-Free Survival
Secondary Endpoints
• Overall Survival
• Objective Response Rate
• Improvement in Symptoms
• Safety and Tolerability of Deforolimus
Confirmed Favorable Outcome (PR, CR, SD)
After Prior Chemotherapy
(< 1 year on therapy)
1:1 Randomization
Deforolimus
(Oral)
Placebo (Oral)
IGF1 and IGF1-R Signaling
is a Promising Target for Sarcomas
Nat Rev Cancer © 2004 Nature Publishing Group.
Anti-IGF1R Monoclonal Antibody R1507: Responses
in Ewing Sarcomas- Phase I Clinical Study
Patient 7002:
• 27-year-old male
• Ewing’s sarcoma with lung metastasis
• Partial Response (PR) after 25 weeks of R1507
Baseline
June 19, 2006
Restaging Week 25
Dec 29, 2006
Baseline
Dec 8, 2006
Restaging Week 6
Jan 25, 2007
Patient 8012:
• 28-year-old female
• Ewing’s sarcoma with lung metastasis
• PR after 6 weeks of R1507
Targeting Hsp 90 in Sarcomas
Preferential targeting to cancer
Cancer cell Hsp90 is different from
Hsp90 in normal cells
Specific chaperone function:
stabilization of oncogenes in key cell
signaling pathways
Activity of Hsp90 Inhibitor IPI-504
in Metastatic Liposarcoma
Baseline
Cycle 9
• Prior gemcitabine/vinorelbine (13% growth after 2 cycles)
Wagner et al. ASCO 2008.
Not all Molecular Targeted Agents are Rationally
Designed – but the clinical evaluation can be rational
and targeted
Sea Tunicate, Ecteinascidia
Turbinata
• Binds to DNA minor groove,
bending the helix
• Interacts with transcription factors
and other DNA binding proteins
• Major activity in myxoid/round cell
liposarcoma with TLS/CHOP
fusion oncoprotein (DNA binding
protein)
Ecteinascidin-743
(Trabectedin),
a tetrahydroisoquinoline
alkaloid
(MW = 762)
Trabectedin Improves Time to Progression in Advanced
Histopathologically Confirmed Leiomyosarcomas and
Liposarcomas (Independent Review)
p=0.0076
HR: 0.647
Efficacy of Trabectedin (ecteinascidin-743)
in Advanced Pretreated Myxoid Liposarcomas:
a Retrospective Study
0
+1
c
Trabectedin
Induces Changes in
Tumor Density
+5
c
+8
c
Before Tumor
Changes in Size
+11 c
Grosso, Jones, Demetri, et al, Lancet Oncology 2007.
Extrinsic and Intrinsic Apoptosis Pathways
as Targets
Extrinsic
pathway
Pro-apoptotic ligand
DR5
Chemotherapy
Radiotherapy
DR4
DNA damage
Intrinsic
pathway
p53
FADD
FLIP
PUMA, NOXA
BID
BAX, BAK
BCL2, BCLXL,
MCL1
Procaspase 8, 10
Mitochondria
Caspase 8, 10
Cytochrome c
Caspase 9
Caspase 3, 6, 7
APAF1
IAP
SMAC/DIABL
O
p53
Apoptosis
DNA damage
Adapted from Ashkenazi A. Nat Rev Can 2002;2:420–430.
Molecularly Targeted Agents for Sarcomas
Summary
• Sarcomas represent a variety of clinicopathologic
subtypes for discovery and development of rationallydesigned drugs to target specific molecular pathways
• Inhibition of a single pathway (KIT signaling) has proven
effective for GIST
• Inhibition of multiple pathways will likely provide the best
results over time