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 ofDevelopment ofMolecularly Targeted AgentsMolecularly Targeted Agents

for Sarcomasfor Sarcomas

A Model for PersonalizedA Model for PersonalizedAnticancer Drug DevelopmentAnticancer Drug Development

OFF

Tumor Cell Growth Arrestand Cancer Regression

ONTumor CellSurvival andGrowth

Searching for Critical Switches in Sarcomas

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

Finding the Critical Switch in the Gastrointestinal Sarcoma known as GIST

Science 279:577-580, 1998.

Imatinib is a Highly EffectiveTargeted Agent in GIST

Baseline Pre-Imatinib

ON

1 month on Imatinib

OFF

Demetri GD, et al. Proc Am Soc Clin Oncol 2005; Abstract 4000.

Baseline Day 7 PET

NormalHeartandKidneys

PET after 7 days of Sunitinib

Sunitinib is an Effective Targeted Agentfor Imatinib-Resistant GIST

Targeting Pathogenic Pathwaysin Other Types of Sarcomas Besides GIST

P P P P

PDGFRA

PP P P

KIT

PI3K

AKT

mTOR

Raf

Mek

Ras

Erk

Nucleus Transcription factors

Cell adhesionCell survival

Cell proliferation

ApoptosisCell differentiation

Angiogenesis

PKCtheta

S6K

The Next Successful Application ofKinase 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

After 5 months of Imatinib

CompleteClinicalResponsesustainedandongoing> 5 years

Inhibiting PDGF-R with Imatinib inAdvanced Dermatofibrosarcoma Protuberans

(DFSP)

DFSP: Response to ImatinibDFSP: Response to Imatinib

McArthur et al. J Clin Oncol 2005; 23:866.

DecreasedCellularity

HyalineChange

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 Pathwaysin Other Sarcomas

PP P P

KIT

P P P P

PDGFRA

PI3K

AKT

mTOR

Raf

Mek

Ras

Erk

Nucleus Transcription factors

Cell adhesion Cell

survival

Cell proliferation

ApoptosisCell differentiation

Angiogenesis

PKCtheta

S6K

mTOR

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 PEComaResponding to mTOR Inhibitor

(Sirolimus)

Wagner, Morgan, Antonescu et al. 2008.

Deforolimus: a Novel mTOR Inhibitor

Non-prodrug rapamycin analog

Forms a tripartite complex with FKBP12 and mTOR

Inhibits mTOR activity at nM levels

Compatible with either i.v. or oral delivery

O

O

O O

ON

O

O

O

HO

OH

OO

O

P

O

Metcalf CA et al. Proc Am Assoc Cancer Res 2004; 45:2476.

FKBP mTOR (FRBDomain)

18 May 2004(Baseline)

08 Dec 200415 Sep 2004

Mita M, et al. Proc Eur J Cancer 2004; 40A, Abstract 409.

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)

Response to the mTOR Inhibitor Deforolimusin Chemotherapy-resistant Osteosarcoma

PET Day 1 (Baseline) PET Day 53PET Day 5

Fused CT/PET Images

Sankhala KK, et al. Proc Am Soc Clin Oncol 2005; 23: 823.

Monitoring Deforolimus Inhibition ofmTOR Activity in Blood

V. Rivera, et al. Deforolimus Study Group.

Day

1- P

re

Day

1- 4

hr

Day

2- P

re

Target ofmTOR Activity

TotalTarget

0 4 24Hrs post-dose

Phase II Deforolimus Trial:Promising Progression-Free Survival (PFS)

Sarcoma Subtype 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

Overall PFS 24% 15

• 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)

DeforolimusInactive Agents

Active Agents

No. of Patients 158 234 146

Median PFS 15 wks 7 wks 8 wks

3-month PFS 58% 21% 39%

6-month PFS 24% 8% 14%

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

Placebo (Oral)Deforolimus (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

Patient 8012: •28-year-old female •Ewing’s sarcoma with lung

metastasis •PR after 6 weeks of R1507

Restaging Week 25Dec 29, 2006

BaselineJune 19, 2006

Restaging Week 6Jan 25, 2007

BaselineDec 8, 2006

Targeting Hsp 90 in Sarcomas

Preferential targeting to cancer

Cancer cell Hsp90 is different from Cancer cell Hsp90 is different from Hsp90 in normal cellsHsp90 in normal cells

Specific chaperone function: stabilization of oncogenes in key cell signaling pathways

Wagner et al. ASCO 2008.

Activity of Hsp90 Inhibitor IPI-504 in Metastatic Liposarcoma

Baseline Cycle 9

• Prior gemcitabine/vinorelbine (13% growth after 2 cycles)

Not all Molecular Targeted Agents are Rationally Designed – but the clinical evaluation can be rational

and targeted

• 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)

Sea Tunicate, Ecteinascidia Turbinata

Ecteinascidin-743 (Trabectedin),

a tetrahydroisoquinoline alkaloid

(MW = 762)

p=0.0076HR: 0.647

Trabectedin Improves Time to Progression in AdvancedHistopathologically Confirmed Leiomyosarcomas and

Liposarcomas (Independent Review)

Grosso, Jones, Demetri, et al, Lancet Oncology 2007.

Efficacy of Trabectedin (ecteinascidin-743) in Advanced Pretreated Myxoid Liposarcomas:

a Retrospective Study

TrabectedinInduces Changes inTumor Density

Before TumorChanges in Size

0 +1 c

+5 c

+8 c

+11 c

Extrinsic and Intrinsic Apoptosis Pathways as Targets

Adapted from Ashkenazi A. Nat Rev Can 2002;2:420–430.

Intrinsicpathway

Caspase 3, 6, 7

Apoptosis

Pro-apoptotic ligand

FADD

FLIP

DR5

DR4

Extrinsicpathway

Procaspase 8, 10

p53p53

Caspase 9

Caspase 8, 10

p53

BAX, BAK

Mitochondria

SMAC/DIABLO

ChemotherapyRadiotherapy

DNA damage

PUMA, NOXA

APAF1

Cytochrome c

DNA damage

BID

IAP

BCL2, BCLXL,

MCL1

Molecularly Targeted Agents for SarcomasSummary

• Sarcomas represent a variety of clinicopathologic subtypes for discovery and development of rationally-designed 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