A Scientific Overview of VS-6766: An Investigational Backbone of Therapy in RAS-Driven CancersExecutive Summary

August 13, 2021

2

Scientific Pillars Overview 1. The full therapeutic potential of targeting the RAS pathway has not yet

been realized - RAS is the most frequently mutated oncogene in human cancers and is associated with a high disease burden and a worse prognosis

2. VS-6766 is a novel dual RAF/MEK inhibitor - VS-6766 achieves vertical blockade of the RAS pathway with a single drug through dual RAF/MEK inhibition

3. Defactinib is a selective FAK inhibitor - Defactinib addresses the compensatory pFAK activation that occurs upon RAS pathway blockade

4. VS-6766 has the potential to become a backbone of therapy for RAS pathway-driven tumors - Due to its dual RAF/MEK blockade and its improved safety profile, VS-6766 may be an ideal combination partner with agents targeting the RAS pathway or parallel signaling pathways

3

RAS is the Most Frequently Mutated Oncogene in Human Cancers and is Associated with a High Disease Burden and a Worse Prognosis

Breadth of potential opportunity

• ~30% of all human cancers are driven by mutations of the

RAS family of genes

Executive Summary

NSCLCIncidence3,5:

194K

ColorectalIncidence5:

105K

PancreaticIncidence5:

58K

UterineEndometrioid

Incidence4,5: 59K

MelanomaIncidence5:

108K

Multiple MyelomaIncidence5:

32K

MelanomaIncidence5:

108K

OvarianIncidence5:

22K

Papillary ThyroidIncidence5,6:

42K

OvarianIncidence5:

22K

KRAS-mutant Cancers1

31% 45%98% 21%

NRAS-mutant Cancers1

28%

BRAF-mutant Cancers2

60% 35–60% 30–80%

20%

5%

Established prognostic significance

• Data (at right) derived from pan-cancer meta-analyses show

patients with alterations in KRAS, NRAS, or HRAS had worse

prognosis than those without alterations

1 Cox et al. Nature Reviews 13: 828 (2014); 2 Turski et al. Mol Cancer Ther 15: 533 (2016);3 85% of lung cancer is NSCLC (Lu et al. Cancer Manag Res. (2019)); 4 90% of all uterine cancers are of the endometrial type (ACS); 5 Cancer Statistics (2020), Siegel et al. CA Cancer J

Clin (2020);70:7-30; 6 8 out of 10 thyroid cancers are of the papillary type (ACS)

Sources: McCormick F. Clin Cancer Res (15April2015); Adderley H et al. E Bio Medicine (01Mar2019); Papke B et al. Science (17Mar2017); Ryan M et al. Nature Reviews Clinical Oncology (01Oct2018); NIH cancer.gov/research/key-initiatives/ras; Gimple RC, Wang X. Front Oncol. 9:965 https://www.frontiersin.org/articles/10.3389/fonc.2019.00965/full.

4

VS-6766 is a Unique Small Molecule RAF/MEK Inhibitor

• VS-6766 inhibits both MEK & RAF kinase activities

• MEK inhibitors paradoxically induce MEK phosphorylation (pMEK) by relieving ERK-dependent feedback inhibition of RAF

• By inhibiting RAF phosphorylation of MEK, VS-6766 has advantage of not inducing pMEK

• VS-6766 inhibits ERK signaling more completely; may confer enhanced therapeutic activity

Executive Summary

RTK

Growth factors

VS-6766

Tumor Growth

RAF

MEK

ERK

RAS

VS-6766 (RAF/MEKi) mirdametinib (MEKi)

Reference: Ishii et al. Cancer Research, 2013; Lito et al. Cancer Cell, 2014

5

VS-6766 Achieves Vertical Blockade of RAS Pathway through Dual RAF/MEK Inhibition

Executive Summary

• Current Challenges

• Blocking any single target in the pathway is insufficient for

maximum depth and duration of anti-tumor efficacy (e.g., SHP2i,

KRAS G12Ci, RAFi, MEKi, ERKi)

• Vertical blockade concept is now well established

• Necessary to block more than one target in the pathway

• Many single target agents (e.g., SHP2i, MEKi) have poor

tolerability as monotherapy

• Solutions offered by VS-6766

• Vertical pharmacological blockade through dual RAF/MEK inhibition

• Favorable tolerability with established twice weekly dosing regimen

should enable safe and tolerable combinations with a variety of

anti-tumor agents

• Compelling synergy data (preclinical) emerging for VS-6766

combinations (e.g., with KRAS G12C inhibitors)

RTK

Growth factors

EGFRi

FGFRi

G12Ci

RAFi

MEKi

ERKi

VS-6766

SHP2i

SOS1i

Tumor Growth

RAF

MEK

ERK

RAS

6

Combination of RAF and MEK Inhibition Has Shown Better Efficacy and Overall Safety, Supporting a Dual RAF/MEK Inhibition Approach

Executive Summary

16

mo

19

mo

25

mo

mOS

+34%

Best Response by RECIST & mOS with

BRAFi/MEKi Monotherapy or Combination Regimens in Metastatic

BRAF V600 E/K Melanoma

Comparison of Safety Profiles with

BRAFi/MEKi Monotherapy or Combination Regimens

59

45

2918 19

2622 17

3728

169

27 3139

9

25 22

Peripheral EdemaHypertensionRash diarrhoea Fatigue Alopecia

-54%

-31% +34%

-50% +32%-15%

Trametinib (MEKi) Dabrafenib (BRAFi) Dabrafenib (BRAFi) + Trametinib (MEKi)41%

53%

69%

ORR

+30%

Trametinib (MEKi)

Dabrafenib (BRAFi)

Dabrafenib (BRAFi) + Trametinib (MEKi)

Also, frequencies of key secondary lesions due to BRAFi monotherapy

decreases when given in combo with MEKi

7 7

22

35

4 2 27

HyperkeratosisSkin PapillomacSCC/ Keratoacanthoma

Basal Cell Carcinoma

-43% -71%

-91%

-80%

Sources: Long, G. V. et al. Ann. Oncol. (2017); Robert, C. et al. Eur. J. Cancer (2019)

7

Optimization of Novel Intermittent Dosing Regimen for Improved Safety While Maintaining Clinical Efficacy

Executive Summary

Treatment-Related Adverse EventVS-6766 monotherapy

Daily at MTD

N=6

28-day cycle1

RP2D

VS-6766 monotherapy

4mg twice weekly

N=26

28-day cycle1

RP2D

(VS-6766 3.2mg twice

weekly + defactinib

200mg twice daily)

N=38

21 days of 28-day cycle2

Common Terminology Criteria for Adverse

Events (CTCAE) Grade

Grade ≥3 Grade ≥3 Grade ≥3

Rash 3 (50%) 5 (19%) 2 (5%)

CK elevation (Creatine phosphokinase) 1 (17%) 2 (8%) 2 (5%)

1 Chenard-Poirier, et al. ASCO 2017; 2 Banerji, Q4 2020 report; Data on file;

RP2D: recommended phase 2 dosing;

MTD: maximum tolerated dose

8

VS-6766 Monotherapy Demonstrates Activity in Refractory KRAS Mutant NSCLC Adenocarcinoma for Patients with KRAS G12V or G12R Mutations

Executive Summary

0 10 20 30 40 50 60 70 80

Time on Treatment (Weeks)

KR

AS

mu

tN

SC

LC

24 55

Best Response by RECIST v1.1 Duration of Treatment

19 5 0 0

-8

-14

-22

-38

-44

-68

-80

-60

-40

-20

0

20

Be

st

Re

sp

on

se

% C

ha

nge

fro

m B

ase

lin

e

G12D

A146V G12V G12V G12V G12D G12D G12V G12R G12V

KRASmut NSCLC

Best ResponsePartial ResponseStable Disease

G12V

G12V

G12D

G12R

G12V

G12V

G12D

G12D

G12V

A146V

210

Source: Guo, et al. Lancet Oncology (2020)

9

0 5 10 15 20 25 30 35 40 45 50

Uterine sarcoma

Clear cell ovarian

Endometrial

LGSOC

LGSOC

Duration of Treatment (Weeks)

24

VS-6766 Monotherapy Shows Activity Across RAS Pathway Mutations in Refractory Gynecologic Cancers

Executive Summary

Best Response by RECIST v1.1 Duration of Treatment

4 1

-30

-48

-65

-80

-60

-40

-20

0

20

Clear cell

ovarian

Uterine

sarcoma

LGSOC Endometrial LGSOC

Be

st

Re

sp

on

se

% C

ha

nge

fro

m B

ase

lin

e

BRAF V600E KRAS G12V KRAS G12D

Best ResponsePartial ResponseStable Disease

Sources: Guo, et al. Lancet Oncology (2020); Data on File

KRAS G12D

BRAF V600E

KRAS G12V

KRAS G12D

KRAS G12V

KRAS G12VKRAS G12D

10

Blockade of RAF and/or MEK induces Compensatory Signaling through FAK Which May Limit Anti-tumor Efficacy

Executive Summary

RTK

RAS

RAF

MEK

ERK YAP

Growth factors

βα

Y397

Integrin

FAK

Extracellular Matrix

SRC

RhoA

Tumor Growth

P

= Feedback Reactivation

1 Chen. Mol Cancer Res (2018); 2 Banerji, BTOG Dublin (Jan 23, 2019)

• FAK activation may be a resistance mechanism to RAS pathway inhibition

• Blockade of RAF or MEK activates FAK as a potential resistance mechanism in preclinical models

• Clinically, dual blockade of RAF and MEK with VS-6766 activates FAK in patients’ tumors

• FAK activation can drive tumor growth through activation of AKT, YAP and RhoA pathways to bypass the anti-tumor efficacy of RAS pathway blockade

• Combination of VS-6766 with defactinib may therefore confer deeper and more durable anti-tumor efficacy

AKT

11

Combination of VS-6766 with a FAK Inhibitor Leads to More Robust Anti-Tumor Efficacy in vivo

Executive Summary

KRASmut Ovarian TOV-21G in vivo Model1 KRASmut NSCLC H358 in vivo Model2

0 5 10 15

0

100

200

300

400

500

Tumor growthVS-4718 + CH5126766

Days on treatment

Tu

mo

r vo

lum

e

(mm

3 +

/- S

EM

)

Vehicle

Trametinib 1.5 mg/kg QD

FAKi 50 mg/kg BID

VS-6766 1.5 mg/kg QD

VS-6766 + FAKi

1 Coma AACR 2021; 2 Krebs AACR 2021

0 5 10 15 20

0

200

400

600

Tumor growth

Days on treatment

Tu

mo

r vo

lum

e

(mm

3 +

/- S

EM

)

Vehicle

Trametinib 0.3 mg/kg QD

FAKi 50 mg/kg BID

VS-6766 0.3 mg/kg QD

VS-6766 + FAKi

12

Defactinib (VS-6063) is a Selective FAK Inhibitor

Executive Summary

pF

AK

(Y

39

7;

H S

co

re)

Day 1

Day 1

0

0

5 0

1 0 0

1 5 0

Pre-treatment Post-treatment

pFA

K (

Y3

97

; H

-Sco

re)

* 03-315

Ovarian Cancer: Tumor Biopsies

Mesothelioma: Tumor Biopsies

FAK EC50 = 15 nM

Defactinib

Defactinib µM

0.0001 0.001 0.01 0.1 1 10

0

25

50

75

100

% C

ellu

lar

Au

top

ho

sp

ho

ryla

tio

n

Dosage: Oral, 400mg BID

• Studied in 500+ patients

with good safety profile

observed to date

• Dose-limiting toxicity not

reached

• Early signs of clinical

efficacy

• Well-established safety

profile as a single agent

and in combination:

• RAF/MEK, PD-1,

Chemotherapy

13

• Low-Grade Serous Ovarian Cancer (LGSOC) is a type of ovarian cancer that disproportionately affects younger women

• 1,000 to 2,000 patients in the U.S. and 15,000 to 30,000 worldwide diagnosed with LGSOC each year

• A slow growing cancer that has a median survival of almost 10 years, so patients remain in treatment for a long time (10-yr prevalence, ~80,000 worldwide, ~6,000 US)

• Patients often experience significant pain and suffering from their disease over time

• Most prior research has focused on high-grade serous ovarian cancer (HGSOC); However, LGSOC is clinically, histologically and molecularly unique from HGSOC with limited treatments available

Executive Summary

KRAS mutant, 30%

NRAS, BRAF,

ARAF mutant,

20%

Other RAS-associated

gene mutations,

20%

Non-RAS-

associated, 30%

~30% of LGSOC Patients have KRAS mutation~70% of LGSOC shows RAS pathway-associated mutations

Source: AACR Project GENIE Cohort v9.0-public and Verastem unpublished analysis

Sources: Monk, Randall, Grisham. “The Evolving Landscape of Chemotherapy in Newly Diagnosed Advanced Epithelial Ovarian Cancer.” Am Soc Clin Oncol Educ Book (2019); Slomovitz, Gourley, Carey, Malpica, Shih, Huntsman, Fader, Grisham et al. “Low-Grade Serous Ovarian Cancer: State of the Science.” Gynecol Oncol (2020);

Grisham, Iyer. “Low-Grade Serous Ovarian Cancer: Current Treatment Paradigms and Future Directions.” Curr Treat Options Oncology (2018).

RAS Pathway Mutations Are Present in the Majority of LGSOC Patients

14

VS-6766 in Combination with Defactinib Shows Robust ORR with Durability in Refractory LGSOC with Expanded Number of Patients (n=17)

Executive Summary

-70

-60

-50

-40

-30

-20

-10

0

10

20

0 3.7 7.5 11.2 14.9 18.7 22.4 26.1

Response by RECIST

Time (months)

Continuing treatment

Time on Treatment (months)

* G12A

G12V

WT

* WT

* WT

* # G12D

WT

G12D

* G12D

* D33E, I24N

* Undocumented

* WT

* # WT

G12D

G12D

G12D

G12V

0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 3432

*

# Approaching PR

Previous MEK inhibitor treatment

Partial response

Stable disease

Time to response

Continuing on treatment

• KRAS G12C mutations ORR = 56% (5/9); data still maturing

• Current ORR = 41% (7/17); data still maturing

• PRs observed in patients who previously progressed on MEKi1

• 9/17 (53%) still on study2

• 3 patients on treatment for ~2 years or more

1 Patients came off prior MEKi treatment primarily for progression;

Source: Banerji, RAS-Targeted Drug Development, September 2020

Re

sp

on

se

(% c

ha

nge

fro

m b

ase

lin

e)

Time on Treatment (months)

2 Data cutoff date August 17, 2020

15

In an Updated Dec. 2020 Read-out (n=24), ORR Data Has Continued to Strengthen, in Both KRAS Mutant and KRAS Wild-Type Patients, with a Consistent Safety Profile

• Overall response rate (ORR) is 52% (11 of 21 response evaluable patients)

• KRAS mutant ORR at 70% (7 of 10 response evaluable patients)

• KRAS wild-type ORR at 44% (4 of 9 response evaluable patients)

• KRAS status undetermined ORR at 0% (0 of 2 response evaluable patients)

• As reported previously, the most common side effects seen in the study were rash, creatine kinase elevation, nausea, hyperbilirubinemia and diarrhea, most being NCI CTC Grade 1/2 and all were reversible

• Additional data is anticipated to be shared at a medical meeting in 2H 2021

Executive Summary

May 2021: FDA granted Breakthrough Therapy designation for VS-6766 + defactinib

for treatment of patients with recurrent low-grade serous ovarian cancer (LGSOC) after

one or more prior lines of therapy, including platinum-based chemotherapy

16

NSCLC Continues to be a Cancer with

High Unmet Needs Due to Multiple

Driver Mutations

Lung cancer is the single leading cause of cancer deaths in the US and worldwide. NSCLC accounts for 80-95% of all lung cancers1. There are 3 subtypes: adenocarcinoma (47%), squamous cell carcinoma (35%), and large cell carcinomas (18%)2

There will be an estimated 228,820 new cases (116,300 men and 112,520 women) and 137,720 deaths in 2020 in the US1

More than half of newly diagnosed patients have advanced disease at initial diagnosis. The 5-year OS rate is 24% (16% for men, 23% for women)3

NSCLC is a molecularly heterogenous disease with multiple driver mutations: EGFR, KRAS, LKB-1, ROS1, BRAF and ALK4

Executive Summary

1 ACS. Cancer Facts and Figures 2020; https://www.cancer.org/content/dam/cancer-org/research/cancer-facts-and-statistics/annual-cancer-facts-and-figures/2020/cancer-facts-and-figures-2020.pdf.2 Lung Cancer Foundation of America (https://lcfamerica.org/lung-cancer-info/types-lung-cancer/)

3 Cancer.Net. Lung Cancer - Non-Small Cell: Statistics (2020); https://www.cancer.net/cancer-types/lung-cancer-non-small-cell/statistics.4 Grosse et al. “Analysis of the frequency of oncogenic driver mutations and correlation with clinicopathological characteristics in patients with lung adenocarcinoma from Northeastern Switzerland.” Diagn Pathology

(2019):14:18

17%

7%

4%

3%

3%

30%

25%

EGFR-sensitizing

ALK

EGFR other

MET

>1 mutation

HER2

ROS1

BRAF

RET

NTRK1

PIK3CA

MEK1

Unknown oncogenic driver detected

KRAS

Frequency of molecule aberrations in driver oncogenes in lung adenocarcinomas

17

G12V Mutation Occurs Frequently in KRAS-Mutant NSCLC

Executive Summary

0

2

4

6

8

10

12

14

G12C G12V G12D G12A G13C G12S G13D

KRAS Mutation

% o

f P

ati

en

ts

US Annual Incidence1,2: 92K

WW Annual Incidence1,2: 836K

NSCLC Adenocarcinoma3

1 GLOBOCAN (2018); 2 https://www.ncbi.nlm.nih.gov/books/NBK519578/; 3 Riely, G et al. ‘Association of outcomes and co-occurring genomic alterations in patients with KRAS-mutant non-small cell lung cancer.’ Journal of Clinical Oncology, vol. 34(15) (2016): p 9019

G12V is same size as

ALK market

18

VS-6766 Inhibits CRAF - The Key Driver of KRAS G12V Mutant NSCLC

A Precision Approach to KRAS G12V Driven NSCLC

Executive Summary

KRAS G12V

CRAF BRAF PI3K

MEK/ERK AKT/mTOR

Tumor Growth

KRAS G12V signals mainly through RAF/MEK in contrast to other variants, such as KRAS G12D, which signal more through PI3K/AKT

KRAS G12V models are especially dependent on CRAFCRAF, but not BRAF, ablation improves survival of mice with KRAS G12V induced lung cancer in vivo

CRAF Drives KRAS G12V NSCLC1

+83% OS

1 Blasco, R. B. et al. Cancer Cell (2011); 2 Ishii et al. Cancer Res (2013);

Sources: Ihle et al. JNCI (2012); Cespedes et al. Carcinogenesis (2006); Sanclemente, M. et al. Cancer Cell (2018)

2

CRAF KO Shows Strong Efficacy

BRAF KO Has No Effect

19

VS-6766 +/- FAKi Induces Significant Tumor Regression in KRAS G12V

Mutant NSCLC in vivo Model, with Clear Differentiation from Trametinib

Executive Summary

Doses Tested

Trametinib: 0.1 mg/kg QD (5 days/week)

VS-6766: 0.1 mg/kg QD (5 days/week)

FAKi: 50 mg/kg BID (5 days/week)

KRAS G12V Mutant; Trp53 KO NSCLCSame KRAS G12V NSCLC Model as Previous Slide

• VS-6766 monotherapy caused tumor regression

• VS-6766 + FAKi showed stronger regression

• No significant anti-tumor effect of trametinib at same dose level Source: Coma et al, AACR 2021

Veh

icle

Tram

etin

ib

VS-6

766

FAKi

VS-6

766

+ FA

Ki

0

1

2

3

4

5

6

7

812

13

Tu

mo

r v

olu

me

fo

ld c

ha

ng

e

(me

an

)

Veh

icle

Tram

etin

ib

VS-6

766

FAKi

VS-6

766

+ FA

Ki

0

1

2

3

4

5 T

um

or

vo

lum

e f

old

ch

an

ge

(Me

an

SE

M)

ns

****

***

20

0 10 20 30 40 50 60 70

Mono

Combo

Mono

Mono

Mono

Combo

Mono

180 200 220

216216

7070

5858

2020

1919

1818

1414

Time on Treatment (weeks)

Continuing on treatment

Time on Treatment

24

Mono: VS-6766 monotherapy

Combo: VS-6766 + Defactinib

*

*

4.0 mg VS-6766/200 mg defactinib++

Mono Mono Mono Mono Combo Mono Combo-80

-70

-60

-50

-40

-30

-20

-10

0

10

Be

st

Re

sp

on

se

(% c

ha

ng

e f

rom

ba

se

lin

e)

4.0 mg VS-6766/200 mg defactinib

Best response by RECIST

0

-8

-38

-46

-68 -70

0

Mono: VS-6766 monotherapy

Combo: VS-6766 + Defactinib

Continuing on treatment*

*

+

+

VS-6766 ± Defactinib Showed a Strong Signal in KRAS G12V NSCLC to be Further Validated

Executive Summary

Best Response by RECIST in KRAS G12V NSCLC Time on Treatment for KRAS G12V NSCLC

VS-6766 ± Defactinib Has a Confirmed 57% ORR in KRAS G12V NSCLC in Integrated Analysis

1 Guo, et al. Lancet Oncology (2020); 2 Krebs, AACR VM 2, April 9, 2021

• Activity of VS-6766 as a single agent or in combination with defactinib in KRAS G12V mutant NSCLC

Weeks on treatment

21

VS-6766 has Potential to Become a Backbone of Therapy for RAS Pathway-Driven Cancers: Vertical Blockade and Parallel Inhibition

Current Challenges

• Blocking RAS pathway can be circumvented through parallel pathways (e.g., PI3K/AKT/mTOR, FAK, RhoA, YAP)

• Combinations of MEKi + AKTi have shown poor tolerability

Solutions offered with VS-6766 in combination with parallel pathway inhibitors

• Good tolerability with twice weekly VS-6766 opens up intermittent dosing options for combinations

• Compelling preclinical synergy data with VS-6766 in combination with FAKi and inhibitors of PI3K/AKT/mTOR pathway (i.e., everolimus)

• RP2D established for VS-6766 + defactinib and for VS-6766 + mTORi (i.e., everolimus) with twice weekly regimen (Udai Banerji, 3Q20)

Executive Summary

βα

Integrin

Extracellular Matrix

P

AKTi

mTORi

FAKi

RTK

Growth factors

G12Ci

RAFi

MEKi

ERKi

VS-6766

SHP2i

SOS1i

Tumor Growth

EGFRi

FGFRi

RhoA, YAP, etc.

A. VERTICAL BLOCKADE B. PARALLEL INHIBITION

RAS

RAF

MEK

ERK mTOR

AKT

PI3K

FAK

SRC

22

Vertical Blockade: Preclinical Synergy of VS-6766 in Combination with Drugs Targeting Other Nodes in the RAS Pathway

Potential VS-6766 combinations for clinical assessment:

• VS-6766 + G12Ci

• VS-6766 + SHP2i, SOS1i

• VS-6766 + ERK1/2i

Executive Summary

Source: Coma et al, AACR 2021

H2

122

SW

837

H1

373

SW

15

73

H3

58

H2

030

MIA

PA

CA

2

0

10

20

30

40

50

VS-6766 + AMG 510

Co

mb

ined

Sy

nerg

y S

co

re

NSCLC

Panc

Synergy

Antagonism

Indication

CRC

H2

122

H1

373

MIA

PA

CA

2

H3

58

SW

15

73

HP

AC

AS

PC

1

A4

27

HP

AF

II

SK

LU

1

PA

NC

03

27

H2

291

CF

PA

C1

H2

444

CA

PA

N2

H4

41

-20

0

20

40

VS-6766 + Afatinib

Co

mb

ined

Sy

nerg

y S

co

re

KRASG12C

KRASG12D

KRASG12V

80% (4/5) 100% (6/6)100% (5/5)

Indication

NSCLC

PDAC

Synergy

Antagonism

H2

122

SW

15

73

H1

373

MIA

PA

CA

2

H3

58

AS

PC

1

HP

AF

II

A4

27

HP

AC

SK

LU

1

CA

PA

N2

CF

PA

C1

H2

291

PA

NC

03

27

H2

444

H4

41

-20

-10

0

10

20

30

40

VS-6766 + LY-3214996

Co

mb

ined

Sy

nerg

y S

co

re

NSCLC

PDAC

Synergy

Antagonism

100% (5/5) 66% (4/6)60% (3/5)

KRASG12C

KRASG12D

KRASG12V

Indication

H2

122

MIA

PA

CA

2

H3

58

H1

373

SW

15

73

A4

27

HP

AC

HP

AF

II

SK

LU

1

AS

PC

1

PA

NC

03

27

CF

PA

C1

H2

444

H2

291

CA

PA

N2

H4

41

-20

0

20

40

VS-6766 + BI-3406

Co

mb

ined

Sy

nerg

y S

co

re

KRASG12C

KRASG12D

KRASG12V

100% (5/5) 83% (5/6)60% (3/5)

Indication

NSCLC

PDAC

Synergy

Antagonism

H2

122

SW

837

H1

373

SW

15

73

H3

58

H2

030

MIA

PA

CA

2

0

10

20

30

40

50

VS-6766 + AMG 510

Co

mb

ined

Sy

nerg

y S

co

re

NSCLC

Panc

Synergy

Antagonism

Indication

CRC

H2

122

SW

837

SW

15

73

H3

58

MIA

PA

CA

2

H1

373

0

10

20

30

40

50

VS-6766 + MRTX849

Co

mb

ined

Sy

nerg

y S

co

re

NSCLC

PDAC

Synergy

Antagonism

Indication

CRC

VS-6766 + pan-HERi (afatinib) VS-6766 + SHP2i (RMC-4550) VS-6766 + SOS1i (BI-3406)

VS-6766 + G12Ci (AMG 510) VS-6766 + G12i (MRXT849) VS-6766 + ERK1/2i (LY-3214996)

23

Preclinical Synergy of VS-6766 + G12C Inhibitors in KRAS G12C mt Models

Executive Summary

Synergy of VS-6766 + G12C inhibitor AMG 510 across

G12C Mutant NSCLC, CRC & Pancreatic Cancer Cell Lines

Doses Tested

Trametinib: 0.3 mg/kg QD

VS-6766: 0.3 mg/kg QD

FAKi: 50 mg/kg BID

AMG 510: 30 mg/kg QD

-100

0

100

200

300

400

Response at Day 10

Resp

on

se

(% c

ha

ng

e f

rom

base

lin

e)

Vehicle

VS-6766 0.3mg/kg QD

AMG 510 30mg/kg QD

VS-6766 + AMG 510

VS-4718 50mg/kg BID

VS-6766 + VS-4718

AMG 510 + VS-4718

VS-6766 + AMG 510 + VS-4718

Trametinib 0.3mg/kg QD

Trametinib + AMG 510

Vehicl

e

Tram

etin

ib

10 PR

VS-676

6FAKi

AMG51

0

AMG51

0 +

Tra

met

inib

AMG51

0 +

VS-676

6

AMG51

0 +

FAKi

VS-676

6 +

FAKi

AMG51

0 +

VS-676

6 +

FAKi

-30

20

1 SD

2 SD

1 SD

1 SD

1 SD

1 PR8 SD

2 PR 4 SD

3 PR 2 SD

4 PR

VS-6766 & FAKi Potentiate AMG 510 Efficacy in KRAS G12C Mutant

NSCLC in vivo; Tumor Regression in All Mice with Triple Combination

VS-6766 + AMG 510 Yields Deeper and More

Sustained Inhibition of ERK Signaling Pathway

H2122 KRAS G12C Mutant NSCLC

ND: not determined

Re

sp

on

se

@ D

ay

10

AMG 510

VS-6766

4h 48h

p-ERK

Actin

Total ERK

-

-

+

-

-

+

+

+

-

-

+

-

-

+

+

+H2122 KRAS G12C mutant NSCLC

Concentrations Tested

AMG 510: 100 nM

VS-6766: 100 nM

Combined Synergy Score

Cell line IndicationSensitivity to G12C

inhibitors

VS-6766 +

AMG 510

VS-6766 +

MRTX849

H2122 NSCLC Moderately sensitive 44.7 44.6

H1373 NSCLC Sensitive 10.0 3.4

SW1573 NSCLC Insensitive 8.6 12.0

H358 NSCLC Sensitive 6.9 5.4

H2030 NSCLC Moderately sensitive 5.1 ND

SW837 CRC Sensitive 16.1 18.5

MIAPACA2 Panc Sensitive 2.3 5.3

0 5 10 15 20 25 30

0

500

1000

1500

2000

Tumor growth

Days after cell inoculation

Tu

mo

r vo

lum

e

(mm

3 +

/- S

EM

)

Vehicle

AMG510

AMG510 + FAKi

AMG510 + VS-6766

AMG510 + VS-6766 + FAKi

VS-6766

Source: Coma et al, AACR 2021

24

Parallel Inhibition: Two Synergistic Combinations with VS-6766 Currently in Clinical Evaluation

Synergistic VS-6766 combinations currently in clinical evaluation:

• VS-6766 + defactinib (FAKi)

• VS-6766 + everolimus (mTORi)

Potential VS-6766 combination for clinical assessment:

• VS-6766 + CDK4/6i

Executive Summary

Presented at RAS-Targeted Drug Discovery (February 23–25, 2021)

SW

15

73

H1

373

H3

58

MIA

PA

CA

2

H2

122

A4

27

SK

LU

1

HP

AF

II

AS

PC

1

HP

AC

H2

291

H2

444

CA

PA

N2

H4

41

PA

NC

03

27

CF

PA

C1

-40

-20

0

20

40

VS-6766 + M2698

Co

mb

ined

Sy

nerg

y S

co

re

NSCLC

Panc

Synergy

Antagonism

80% (4/5) 66% (4/6)80% (4/5)

KRASG12C

KRASG12D

KRASG12V

Indication

MIA

PA

CA

2

H3

58

H1

373

SW

15

73

H2

122

HP

AC

A4

27

AS

PC

1

HP

AF

II

SK

LU

1

CF

PA

C1

H2

291

H4

41

H2

444

PA

NC

03

27

CA

PA

N2

-20

-10

0

10

20

VS-6766 + Defactinib

Co

mb

ined

Sy

nerg

y S

co

re

KRASG12C

KRASG12D

KRASG12V

40% (2/5) 83% (5/6)20% (1/5)

Indication

NSCLC

PDAC

Synergy

Antagonism

H2

122

MIA

PA

CA

2

H1

373

H3

58

SW

15

73

A4

27

HP

AC

AS

PC

1

HP

AF

II

SK

LU

1

CF

PA

C1

CA

PA

N2

H2

291

PA

NC

03

27

H4

41

H2

444

-20

-10

0

10

20

30

40

VS-6766 + Palbociclib

Co

mb

ined

Sy

nerg

y S

co

re

KRASG12C

KRASG12D

KRASG12V

100% (5/5) 50% (3/6)100% (5/5)

Indication

NSCLC

PDAC

Synergy

Antagonism

SW

15

73

H1

373

H3

58

MIA

PA

CA

2

H2

122

A4

27

SK

LU

1

HP

AF

II

AS

PC

1

HP

AC

H2

291

H2

444

CA

PA

N2

H4

41

PA

NC

03

27

CF

PA

C1

-40

-20

0

20

40

VS-6766 + M2698

Co

mb

ined

Sy

nerg

y S

co

re

NSCLC

Panc

Synergy

Antagonism

80% (4/5) 66% (4/6)80% (4/5)

KRASG12C

KRASG12D

KRASG12V

Indication

VS-6766 + AKTi (M2698) VS-6766 + mTORi (everolimus)

VS-6766 + FAKi (defactinib) VS-6766 + CDK4/6i (palbociclib)

THANK YOU