ORAL40.05: VS-6063 & VS-5584 Exhibit Synergistic Anticancer Activity in Pre-clinical Models of Mesothelioma – Mitchell Keegan, Ph.D.

THE CANCER STEM CELL INHIBITORS VS-6063 AND VS-5584 EXHIBIT SYNERGISTIC ANTICANCER

ACTIVITY IN PRECLINICAL MODELS OF MESOTHELIOMA

Mitchell Keegan, Ph.D.Vice President of Development, Verastem, Inc.

1

ORAL40.05: VS-6063 & VS-5584 Exhibit Synergistic Anticancer Activity in Pre-clinical Models of Mesothelioma – Mitchell Keegan, Ph.D.2

Disclosure

• I am an employee and stockholder of Verastem Inc.

• I will be discussing investigational drugs

ORAL40.05: VS-6063 & VS-5584 Exhibit Synergistic Anticancer Activity in Pre-clinical Models of Mesothelioma – Mitchell Keegan, Ph.D.3

Developing potential treatment options throughout the mesothelioma patient journey

Treatment holiday4‐6 cycles Pem/Cis

Surgery

80%

20%

MPM

Neo‐adjuvant VS‐6063+VS‐5584Relapsed

Ongoing studies:

2nd line chemo or clinical trial

We want to maximize the potential treatment options for patients with mesothelioma

VS‐6063 VS‐6063

ORAL40.05: VS-6063 & VS-5584 Exhibit Synergistic Anticancer Activity in Pre-clinical Models of Mesothelioma – Mitchell Keegan, Ph.D.4

Standard‐of‐care chemotherapy enriches cancer stem cells in both mesothelioma cell lines and patient tumors

Mesothelioma CSCs in vitroH2052 cell line

Mesothelioma CSCs in vivoPaired patient biopsies

Pre‐treatment Post‐treatment

Brown = ALDH+ (cancer stem cells)

MPM cells treated with SOC chemotherapies are enriched for 

cancer stem cells

Pem/Cis

Treatment of MPM tumors with SOC chemotherapy enriches for cancer stem cells

Pre Post

Mean H Score / Patient

ORAL40.05: VS-6063 & VS-5584 Exhibit Synergistic Anticancer Activity in Pre-clinical Models of Mesothelioma – Mitchell Keegan, Ph.D.5

Profiles of VS‐6063 & VS‐5584

• Potent, selective inhibitor of FAK & PYK2 tyrosine kinases

• Preferentially targets Cancer Stem Cells (CSCs)

• Lead compound, studied in 300+ patients to date with good safety profile

• Ongoing registration‐directed trial in mesothelioma

• Orphan designation in US and EU for mesothelioma

• Potent, selective inhibitor of PI3K & mTOR kinases

• Preferentially targets Cancer Stem Cells (CSCs)

• Currently in Phase 1 with intermittent dosing schedule (3x weekly)

FAK EC50 = 15 nMPYK2 EC50 = 95 nM

VS‐6063 (defactinib)  VS‐5584

PI3K

AKT

mTORC2

AKTVS‐5584

RTKs

mTORC1

Tumor cell/CSC survival & proliferation

mTORIC50 (nM)

PI3K isoform IC50 (nM)

α β δ γ

3.4 2.6 21 3.0 2.7

ORAL40.05: VS-6063 & VS-5584 Exhibit Synergistic Anticancer Activity in Pre-clinical Models of Mesothelioma – Mitchell Keegan, Ph.D.6

Rationale: Combination of VS‐6063 (FAK) with VS‐5584 (PI3K/mTOR) for the treatment of relapsed/refractory mesothelioma

• 29 patients evaluated by GSK with their FAK inhibitor in Phase 1: Treatment resulted in median PFS of 4.5 months (vs. 6 weeks)

• 1 patient in VS‐6063 Phase 1 in Japanese subjects: Symptom improvement and PFS of 5.6 months

• PI3K/mTOR dual inhibitor GDC‐0980 showed 4 PRs among 33 mesothelioma patients in a Phase 1 study (ECCO 2013)

Both FAK & PI3K/mTOR inhibitors have shown early signs of clinical activity in mesothelioma

FAK & PI3K/mTOR inhibition may combine for more robust shut down of AKT survival signaling

Y397FAKSRC

IntegrinRTKs

Proliferation/Survival/CSC Function

mTORC1

PI3K

mTORC2 p130Cas

PAkt

ORAL40.05: VS-6063 & VS-5584 Exhibit Synergistic Anticancer Activity in Pre-clinical Models of Mesothelioma – Mitchell Keegan, Ph.D.7

VS‐6063 inhibits tumor initiation in mouse mesothelioma models

0

20

40

60

80

100

120

0 1 2 4 5 6 7 8 9 10

Tumor free

 mice, %

Weeks

Control

Pemetrexed

VS‐6063

VS‐6063 + Pem

Control

VS‐6063

PemetrexedRecovery

H28 meso cell line

Tumor initiation in vivo

VS‐6063 &Pemetrexed

ORAL40.05: VS-6063 & VS-5584 Exhibit Synergistic Anticancer Activity in Pre-clinical Models of Mesothelioma – Mitchell Keegan, Ph.D.8

Oral administration of VS‐6063 targets cancer stem cells in mesothelioma tumors grown in mouse lungs

DAPICancer Stem Cells (ALDH+)

Control VS‐6063

* p<0.05

50 mg/kg, po BID x 2 wks

VS‐6063 treatment, MM87 mesothelioma xenograft model:

ORAL40.05: VS-6063 & VS-5584 Exhibit Synergistic Anticancer Activity in Pre-clinical Models of Mesothelioma – Mitchell Keegan, Ph.D.9

VS‐5584 preferentially targets CSCs: ~ 70‐fold reduction in tumor initiating frequency in a SCLC model

VS‐5584 treatment, H841 SCLC model:

Liberase

Viable cells  Re‐implantation in limiting dilutions

CSC Assays

Tumor Initiation

****

Antitumor Efficacy SP CSC Assay

0

10

20

30

40

50

Vehicle VS‐5584

Tumor In

itiating 

Cells / 1 million

p < 0.0001

Control

VS‐5584

ORAL40.05: VS-6063 & VS-5584 Exhibit Synergistic Anticancer Activity in Pre-clinical Models of Mesothelioma – Mitchell Keegan, Ph.D.10

VS‐5584 & VS‐6063 exhibit synergistic combination activity in mesothelioma cell lines in vitro

Highest Single Agent Analysis

0.0

0.5

1.0

1.5

2.0

Combina

tion Inde

x

VS‐6063 + VS‐5584Mero‐41 mesothelioma

ED50 ED75 ED90

10.000 0.00 0.00 0.09 0.06 0.07 0.25 0.09 0.04 0.04

3.333 0.00 0.06 ‐0.01 0.07 0.08 0.23 0.08 0.05 0.04

1.111 0.00 ‐0.01 0.09 0.08 0.17 0.22 0.04 0.05 0.04

0.370 0.00 0.03 0.10 0.15 0.24 0.10 0.04 0.03 0.02

0.123 0.00 0.08 0.11 0.17 0.12 0.12 0.02 0.01 0.01

0.041 0.00 ‐0.07 0.07 0.10 0.09 0.13 0.01 0.01 0.01

0.014 0.00 ‐0.05 ‐0.08 0.20 0.15 0.08 0.00 0.00 0.01

0.005 0.00 ‐0.14 0.05 ‐0.10 0.05 ‐0.03 0.00 ‐0.01 0.01

0.002 0.00 ‐0.05 ‐0.10 0.07 ‐0.08 0.03 0.00 0.01 0.01

0.000 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00

0.001 0.002 0.005 0.014 0.041 0.123 0.370 1.111 3.333

Synergy

VS‐5584

VS‐606

3

0.0

0.5

1.0

1.5

2.0

.

Combina

tion Inde

x

VS‐6063 + VS‐5584H2052 mesothelioma

ED50 ED75 ED90

0.001 0.01 0.1 1 100.0

0.2

0.4

0.6

0.8

1.0

M

Combination Index AnalysisAn

tagonism

Syne

rgism

 

HSA Additivity ModelVS‐6063 VS‐6063 + VS‐5584

VS‐5584 + VS‐6063 @ 0.41 µMVS‐5584 + VS‐6063 @ 1.11 µM

Antagonism

Syne

rgism

 

ORAL40.05: VS-6063 & VS-5584 Exhibit Synergistic Anticancer Activity in Pre-clinical Models of Mesothelioma – Mitchell Keegan, Ph.D.11

Synergistic combination of VS‐5584 and VS‐6063 for targeting tumor initiating cells

Control

VS‐6063

VS‐5584Recovery

Meso cell line Limiting dilutions assayVS‐5584 & VS‐6063

1

10

100

1000

10000

Control VS‐5584 VS‐6063 VS‐5584 &VS‐6063

TIC pe

r 106

cells

150‐folddecrease

196‐folddecrease

∞decrease

Limiting dilution tumor initiation

Aldefluor assay

H28 cell line

Alde

fluor+ CSCs

(% of C

ontrol)

Aldefluor+ CSCsMero‐14 cell line

0.1 µM 0.3 µM

VS‐6063VS‐5584Combo

ORAL40.05: VS-6063 & VS-5584 Exhibit Synergistic Anticancer Activity in Pre-clinical Models of Mesothelioma – Mitchell Keegan, Ph.D.12

Synergistic combination of VS‐5584 and VS‐6063 for enhanced anti‐tumor efficacy compared to single agent in orthotopic meso model

0

20

40

60

80

100

Control VS‐6063 VS ‐5584 VS‐6063 + VS‐5584

% of tum

or area

p < 0.0001

p < 0.0001

Injection

MM87 mesocell line Mesothelioma tumor 

grown in lungs for 11 days

Control

VS‐6063 (BID)

VS‐5584 (M/W/F)

VS‐6063 & VS‐5584

Tumor burden 

assessment

Treatment for 2 weeks

• 2 out of 10 mice tumor free in the VS‐6063 + VS‐5584 combination group

• No tumor free mice in other groups

Tumor burden after treatment

ORAL40.05: VS-6063 & VS-5584 Exhibit Synergistic Anticancer Activity in Pre-clinical Models of Mesothelioma – Mitchell Keegan, Ph.D.13

Summary & conclusions

• VS‐6063 (defactinib) is a potent/selective FAK kinase inhibitor

• VS‐5584 is a potent/selective inhibitor of PI3K & mTORC1/2

• Both agents preferentially target CSCs and also reduce bulk tumor growth in preclinical mesothelioma models

• Synergistic activity of VS‐6063 & VS‐5584 on CSCs & bulk tumor has been observed in preclinical models

• These data support an ongoing Phase I combination study of VS‐6063 & VS‐5583 in patients with relapsed/refractory mesothelioma

– Additional study details will be presented at Poster #P2.08‐008