Activity of ERK1/2 Inhibitor Ulixertinib (BVD-523) in Patients with BRAF and NRAS Mutant Melanoma

Ryan J. Sullivan, Filip Janku, Bob T. Li, Deborah Wong, Jeffrey Sosman, Vicki Keedy, Elizabeth Buchbinder, Anthony Tolcher, Anna Varghese, David M. Hyman, Keith T. Flaherty,

Antoni Ribas, Richard Carvajal, Andrea Wang-Gillam, Harriet Kluger, Manish Patel, Mary Varterasian, Dean Welsch, Jeffrey Infante

Disclosures

• Advisory Board/Consulting: I will discuss the investigational use of:• Novartis Ulixertinib• Biodesix• Amgen• Takeda

• Research Sponsorship:• Biodesix• Exosome Diagnostics• Amgen• Merck• Bristol Myers Squibb• Prometheus

Melanoma is a genetic disease with two major subtypes

Melanoma TCGA. Cell 2015

Dual BRAF plus MEK inhibition is the standard therapy for BRAF mutant melanoma…but most patient progress

1. Long et al. Lancet 20152. Robert et al. NEJM 20153. Larkin et al. NEJM 20154. Dummer et al. Soc Melanoma Res 2016 (Presented by Flaherty) Encorafenib and binimetnib4 (data not shown)

Dabrafenib and trametinib1,2

Vemurafenib and cobimetinib3

Targeting NRAS has been more challenging

NRAS

MEK

ERK

CKIT

NF1

CMET FGFR1

IGFR1

VEGFHGF

Apoptosis*

Cyclin!

D1

RAFRAF

Proliferation

Immune evasion

P13K

AKT

mTOR

PTEN

CDK4

Angiogenesis

Single-agent MEK inhibitors are active…1

MEK inhibitors are only a little better than chemo2 1. Ascierto et al. Lancet Oncol 20132. Dummer et al. Lancet Oncol 2017

The development of effective treatment for:

1. BRAF mutant melanoma following progression on a BRAF/MEK inhibitor regimen

AND

2. NRAS mutant melanoma

is sorely needed

Ulixertinib (BVD-523) is a potent inhibitor of ERK1/2

Highly potent

• ERK1 Ki < 300 pM

• ERK2 Ki = 40 pM

Highly selective

• > 1,000-fold vs CDK1, CDK2, CDK5, CDK6, GSK3b

• > 10,000-fold vs 70 other kinases

Ulixertinib has preclinical activity in both

BRAF/MEK dual inhibitor resistant melanoma andNRAS mutant melanoma

Patient derived xenograft from patient progressing

on dual BRAF/MEK inhibitor therapy

0

500

1000

1500

0 7 14 21Day

Vehicle

Dabrafenib

BVD-523

BVD-523+Dabrafenib

Tumor

Volume

(mm3)

0 2 4 6 8 10 12 14 16 18 20 220

100

200

300

400

500

600

700

800

Days

Tu

mo

r vo

ulu

me (

mm

3)

ME-010 (NRAS mutant melanoma

PDX)

Group 1: vehicle

Group 2: BVD-523 (100 mg/kg,po, bid)

NRAS Mutant

Melanoma PDX

Vehicle

BVD-523

NCT01781429: Phase I trial of ulixertinib in patients with advanced solid tumors1

Group1:BRAFmutantcancers(exceptCRCandNSCLC),inhibitornaïve

Group2:BRAFmutantCRC,inhibitornaïve

Group3:BRAFmutantmelanoma,progressed/refractorytoBRAFi &/orMEKi

Group4:NRASmutantmelanoma,inhibitornaïve

Group5:MEKmutantcancers,inhibitornaïve

Group6:BRAFmutantNSCLC,inhibitornaïve

AcceleratedDoseTitration

(1patientpercohort)

FIH(10mg,BID)

> Grade2RelatedAE

Standard“3+3”

DoseEscalation

SolidTumorRP2D

AdvancedSolidTumorProtocol

(NCT01781429)

Dose-limiting Toxicities in Cycle 1 (21 days)

Dose (mg, BID) DLT Frequency (%) DLT Description

10 0/1

20 0/1

40 0/1

75 0/1

150 0/1

300 0/4

600 1/7 (14) • Rash G3

750*2/4 (50)

• Rash G3, diarrhea G2

• Hypotension G2, elevated creatinine G2, anemia G2, delay to cycle 2 dosing

9002/7 (29)

• Pruritis G3, elevated AST G3

• Diarrhea G3, vomiting G3, dehydration G3, elevated creatinine G3

* Intermediate dose

Infante et al. ASCO 2015; manuscript in preparation

52 patients with metastatic melanoma treated

Recommended Phase II Dose:

600 mg BID

Mutation status Dose Escalation Dose Expansion

BRAF mt, no prior BRAFi

1 1

BRAF mt, prior BRAFi +/- MEKi

6 21

NRAS mt 0 22

Other/unknown 1 0

Melanoma patient characteristics

Dose Escalation (8 patients)

Dose Expansion (44 patients)

Age (median) 63.5 59

GenderMale

Female62

27 17

Pre-treatment LDHElevated

Not-elevated21

2418

Prior immune therapy 6 40

Mutation StatusBRAFNRAS

Unknown

7 01

22 22

BVD-523 Plasma Concentrations in Melanoma Patients Dosed at 600 mg, BID

Day 1Average ± SEM

N=39

Steady StateAverage ± SEM

N=28

Tmax (hours) 3.87 ± 0.38 2.82 ± 0.41

Cmax (μg/mL) 1.21 ± 0.11 2.18 ± 1.87

AUC (μg*hr/mL) 7.83 ± 0.81 18.63 ± 1.71

• Patients dosed at RP2D (600 mg, BID) had steady state plasma concentrations ranging from 2-5μM

• Blood based pRSK assay demonstrated near complete inhibition at plasma concentrations seen at 600 mg, BID

0

0.5

1

1.5

2

2.5

0 2 4 6 8 10 12

AverageConcentration±SEM(μg/m

L)

Time(h)

Day1 SteadyState

54

43

5238 44 65

41

4355

4342

42 85 4385

94

72 13292 48

12784

43 93247

97190 189 86*

43

657

42*1102

320

29

64

42 5645

42 298

Max

imu

m T

arge

t Le

sio

n C

han

ge f

rom

Bas

elin

e (

%)

* New Lesions or Non-target Lesions determined to be Progressive Disease

BRAF MT, prior therapy

BRAF MT, no prior therapy

NRAS MT

Unknown MT

~ Days on study shown with each bar ~

60

40

20

0

- 40

- 20

- 60

- 80

- 100

BVD-523 Demonstrates Efficacy in NRAS and BRAF Mutant Melanoma

BRAF MT, prior therapy

BRAF MT,no prior therapy

NRAS MT BRAF MT (NOS)

Evaluable 20 2 18 1

Best Response (RECIST1.1)

PDSD

PRCR

116

30

01

10

96

30

01

00

Partial Response

BRAF MT, prior therapy

BRAF MT, no prior therapy

NRAS MT

Unknown MT

C4D1-49.6%

Pre Treatment C8D1-65.7%

C48D1-79.6%

BRAF V600E Melanoma Patient, BRAFi Refractory

Time on Study: Example of Durable Responses to BVD-523

Days on Study

Partial Response

Pre-treatment C1D14

Days on Study

Time on Study: Example of Durable Responses to BVD-523

BRAF MT, prior therapy

BRAF MT, no prior therapy

NRAS MT

Unknown MT

Partial Response

Most common related adverse events of ulixertinib (> 20%*)

All Patients(N=52)

All Grade (%) Grade 3/4^

Rash (not acneiform) 30 (58) 7 (13)Diarrhea 29 (56) 3 (6)Fatigue 21 (40) 2 (4)Rash, acneiform 16 (31) 1 (2)Reduced appetite 14 (27) 0Ophthalmologic 11 (21) 0Anemia 8 (15) 3 (6)

*or > 1 Grade 3/4 toxicity^no Grade 4, treatment related events have occurred Updated through 01Mar17

Treatment with ulixertinib is associated with changes in ctDNA clonality in a patient with BRAFi/MEKi naïve, BRAFV600K mutant melanoma

Conclusions

• Ulixertinib is a novel ERK1/2 inhibitor that is well tolerated at the maximum tolerated dose of 600 mg BID

• The major toxicities of ulixertinib were rash, diarrhea, and fatigue; no grade 4 or 5 treatment related toxicities were seen.

• Ulixertinib resulted in responses in patients with NRAS mutant melanoma (17%)

• BRAF mutant melanoma following BRAF +/- MEK inhibitor (15%)• Received FDA Fast-Track Designation as single agent

• Likely, the optimal use of in NRAS and BRAF mutant melanoma may be in combination with other targeted agents such as BRAF inhibitors and/or CDK4/6 inhibitors, as well as with immunotherapy.

Thank You to the patients and their families

Harriet KlugerMario Snzol

Jeffrey InfanteManish R. Patel

Anthony W. TolcherAmita Patnaik

Kyri Papadopoulos

Bob LiAnna M. VargheseDavid Hyman

Vicki Keedy

Filip JankuSapna Patel

Antoni RibasDeborah Jean Wong

Ryan SullivanKeith Flaherty

Andrea Wang-Gillam

Gary DeCrescenzo, Anna Groover, Carrie Emery,Mary Varterasian, Martin Teresk, Deborah Knoerzer

Dean Welsch

Key Partners

Richard Carvajal Jeffrey Sosman Elizabeth Buchbinder