First-in-class oral ERK1/2 inhibitor Ulixertinib (BVD-523 ......BVD-523 (100 mg/kg, po, BID) A375...

First-in-class oral ERK1/2 inhibitor Ulixertinib (BVD-523) in patients with advanced solid

tumors: Final results of a phase I dose escalation and expansion study

Bob T. Li, Filip Janku, Manish R. Patel, Ryan J. Sullivan, Keith Flaherty, Elizabeth I. Buchbinder, Mario E. Lacouture, Anna M. Varghese, Deborah Jean Lee Wong, Mario Sznol, Jeffrey A. Sosman, Vicki L. Keedy, Andrea Wang-Gillam, Antoni

Ribas, Anthony W. Tolcher, Sapna P. Patel, Mary Varterasian, Dean Welsch, David M. Hyman, Jeffrey R. Infante

Background: Targeting the MAPK pathway

2 Presented by: Bob T. Li, MD

Background: Ulixertinib (BVD-523): A Potent & Selective ERK Inhibitor

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

4 3

BVD-523 KinomeScan @50nM ERK1 and ERK2 are only hits

Image generated using TREEspot™ So5ware Tool and reprinted with permission from KINOMEscan®, a division of DiscoveRx CorporaFon, © DISCOVERX CORPORATION 2010.

Presented by: Bob T. Li, MD

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Colo205 (BRAF-‐V600E colorectal)

Background: Targeting the MAPK pathway


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A375 (BRAF-‐V600E Melanoma)

Methods: First in Human Phase 1 Clinical Trial (NCT01781429) Study Objectives

Primary objective: To define the safety and tolerability of ulixertinib, dose limiting toxicities (DLT), the maximum tolerated dose (MTD), and the recommended phase 2 dose (RP2D). Secondary objectives: To determine the pharmacokinetic profile of ulixertinib and selected metabolites. To investigate any preliminary clinical efficacy by RECIST v1.1.

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Overall Study Design: Accelerated Dose Escalation followed by Cohort Expansion in Genetically Defined Patient Cohorts


Phase I Dose Escalation of Ulixertinib in Patients With Advanced Solid Tumors

Accelerated Dose Titration

(1 patient per cohort)

First-in-human starting dose (10 mg, BID)

> Grade 2 Related AE

Standard “3 + 3”

Dose Escalation

Recommended Phase 2 Dose

•  Establish MTD and RP2D •  Determine safety and tolerability

Advanced Solid Tumor Protocol NCT01781429

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Dose EscalaFon Data was presented at ASCO 2015 (Infante, et al.)


Dose Escalation (DLT, MTD, RP2D)

MTD and RP2D defined as 600 mg BID continuously

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

900 2/7 (29) •  Pruritis G3, elevated AST G3 •  Diarrhea G3, vomiting G3, dehydration

G3, elevated creatinine G3

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Patient Characteristics (n=27)

N (%)

Age (yr), median (range) 61 (33-86) Sex Female 13 Male 14 ECOG Performance Status (Initial)

0 10 (37) 1 17 (63)

Tumor Types Melanoma

BRAF mt Unknown

8 (30) 7 1

Colorectal Cancer 5 (18) Papillary Thyroid Cancer 4 (15) Non-small Cell Lung Cancer 2 (7) Others* 8 (30) Prior Systemic Therapy

0 1 (4) 1 2 (7)

2-3 11 (41) >3 13 (48)


Pharmacokinetics and Pharmacodynamics Are Dose-Dependent

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Dose (mg, BID)

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0 2 4 6 8 10 12 Time After Dosing (hours)

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-523

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Cycle 1 Day 15

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900 mg, BID

750 mg, BID

600 mg, BID

300 ng, BID

150 mg, BID

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40 mg, BID

20 mg, BID

10 mg, BID


Dose Escalation Duration of Treatment

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ParFal Response

Days on Study

Starting Dose*

C4D1 -‐49.6%

Pre Treatment C8D1 -‐65.7%

C48D1 -‐79.6%

BRAF V600E Melanoma PaFent, BRAFi Refractory

*Study supported intra-‐paFent dose escalaFon


Phase I Cohort Expansion of Ulixertinib in Patients With Advanced Solid Tumors

Cohort expansion in 6 molecular subgroups of patients with no approved targeted therapy

Accelerated Dose Titration

(1 patient per cohort)

First-in-human starting dose (10 mg, BID)

> Grade 2 Related AE

Standard “3 + 3”

Dose Escalation

Recommended Phase 2 Dose

BRAF Mutant Cancers (except CRC and NSCLC); inhibitor naïve

BRAF Mutant Colorectal Cancer; inhibitor naïve

BRAF Mutant Melanoma; Progressed/Refractory to BRAFi and/or MEKi

NRAS Mutant Melanoma

MEK Mutant Cancers; inhibitor naïve

BRAF Mutant Non-Small Cell Lung Cancer; inhibitor naïve

Advanced Solid Tumor Protocol

NCT01781429


Cohort Expansion Demographics

All Patients (N=108) N (%) Age (yr), median (range) 62 (21-85)

Sex

Female 39 (36)

Male 69 (64)

Race

Asian 5 (5)

African American or Black African Heritage

4 (4)

White 93 (86)

Other 6 (6)

Prior Immune Therapy

Yes 51 (47)

No 57 (53)

*PaFents were all Targeted Therapy Naïve, except for BRAF Melanoma ~Evaluable: 2 cycles on treatment and follow-‐up RECIST measurement

BRAF Other Cancer Types Glioblastoma 4

Prostate 3 Papillary Thyroid 2

Squamous Cell 2 Gallbladder 1

Small Intestine Adenocarcinoma 1 Adenoid Cystic Carcinoma 1

Angiosarcoma 1 Appendiceal 1

Cholangiocarcinoma 1 Cholangiocarcinoma/Gallbladder 1

Melanoma 1 Unknown Primary 1

Salivary Duct 1 Small Cell Lung Adenocarcinoma 1

Thyroid 1 Vaginal 1

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Cohort Recruitment BRAF Mutated Colorectal Cancer*

Total Enrollment 17 Evaluable for Efficacy~ 11

BRAF Mutated Non-Small Cell Lung Cancer* Total Enrollment 16

Evaluable for Efficacy~ 12 BRAF Mutated Melanoma

Refractory/Progressed on BRAF/MEK Inhibitors Total Enrollment 21

Evaluable for Efficacy~ 16 BRAF Mutated Cancer*


NRAS Mutated Melanoma* Total Enrollment 22

Evaluable for Efficacy~ 18 MEK Mutated Cancer*



Treatment Related Adverse Events ≥10% at RP2D 600mg BID (n=115)

Preferred Term (n=115)

Grade 1/2 (%)

Grade 3 (%)

Grand Total

GASTROINTESTINAL DISORDERS Diarrhea 42 (36) 7 (6) 49 (43) Nausea 41 (36) 2 (2) 43 (37) Vomiting 18 (16) 1 (<1) 19 (16)

GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS Fatigue 43 (37) 3 (3) 46 (40) Peripheral Edema 12 (10) 1 (<1) 13 (11)

METABOLISM AND NUTRITION DISORDERS Decreased Appetite 27 (23) 27 (23)

SKIN AND SUBCUTANEOUS TISSUE DISORDERS Dermatitis Acneiform 32 (28) 4 (3) 36 (31) Dry Skin 11 (10) 11 (10) Pruritus 27 (23) 1 (<1) 28 (24) Rash 50 (43) 17 (15) 67 (58)

No related Grade 4 or Grade 5 events occurred in this study

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*N=7 Dose EscalaFon PaFents and 108 Cohort Expansion PaFents Dosed at 600mg BID

AEs were improved in the 32% of paFents

requiring dose reducFons


Treatment Related Serious Adverse Events at RP2D 600mg BID (n=115)

Preferred Term (n=115)

Grade 1/2 (%)

Grade 3 (%)

Grand Total

BLOOD AND LYMPATIC SYSTEM DISORDERS Anemia 2 (2) 2 (2) Thrombotic Thrombocytopenic Purpura 1 (<1) 1 (<1)

CARDIAC DISORDERS Cardiac Failure 1 (<1) 1 (<1)

EYE DISORDERS Retinal Vein Occlusion 1 (<1) 1 (<1)

GASTROINTESTINAL DISORDERS Diarrhea 2 (2) 2 (2) 4 (3) Large Intestinal Ulcer 1 (<1) 1 (<1) Nausea 1 (<1) 1 (<1) Vomiting 1 (<1) 1 (<1)

GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS Peripheral Edema 1 (<1) 1 (<1)

INFECTIONS AND INFESTATIONS Escherichia Bacteremia 1 (<1) 1 (<1)

METABOLISM AND NUTRITION DISORDERS Dehydration 1 (<1) 1 (<1) Hypoalbuminemia 1 (<1) 1 (<1)

PSYCHIATRIC DISORDERS Delirium 1 (<1) 1 (<1)

RENAL AND URINARY DISORDERS Renal Failure Acute 1 (<1) 1 (<1) 2 (2)

SKIN AND SUBCUTANEOUS TISSUE DISORDERS Dermatitis Acneiform 1 (<1) 1 (<1) Rash 1 (<1) 1 (<1) Rash Maculo-Papular 2 (2) 2 (2) Swelling Face 1 (<1) 1 (<1)


Response Assessment in 101 Evaluable Patients By RECIST v1.1 Patients Dosed ≥600 mg, BID

Target Lesion % Change from

Baseline

BRAF Unspecified BRAF Atypical BRAF V600 KRAS MAP2K1 NRAS Unspecified NRAS G13 NRAS Q61 Unknown

ObjecFve responses were observed in 14 of 101 (14%) paFents

NRAS and BRAF Melanoma data was previously presented at AACR 2017


DuraFon on Study (Days)

Objective Responders Results: Time on Study

Melanoma BRAF V600E

Melanoma BRAF V600E

Melanoma BRAF V600E

Small Intestine Adenocarcinoma BRAF G469A

Gallbladder Adenocarcinoma BRAF L485W

Melanoma BRAF V600K

Glioblastoma BRAF V600E

Melanoma NRAS Q61K

Melanoma NRAS G13V

Melanoma NRAS Q61R

Squamous Cell (Head and Neck) BRAF G469A

NSCLC BRAF V600E

NSCLC BRAF L597Q

NSCLC BRAF V600E

Days on Study


Response Assessment by Group in Cohort Expansion By RECIST v1.1 Target Lesion % Change from

Baseline

BRAF Atypical BRAF V600 MAP2K1 NRAS Unspecified NRAS G13 NRAS Q61

CRC NSCLC Melanoma Others Melanoma Any

BRAF Mutant NRAS Mutant MEK Mutant



Cohort Expansion Results: Duration of Treatment

BRAF

Mutant

CRC

NSCLC

Melanom

a Others

NRA

S Mutant

Melanom

a

MEK

Mutant

Any

BRAF V600 BRAF Atypical MAP2K1 NRAS Unspecified NRAS G13 NRAS Q61

Days on Study


Response assessments in atypical (non-V600) BRAF mutations


Yao et al. Cancer Cell 2015

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Not Assessed

Response assessments in atypical (non-V600) BRAF mutations

D594G

D594N

NFIC

Fusion

D5

94N

G469A

F247L

T599

dup

K601

E

D594G

G469A

G46

6V

G469A

D594G

K6

01E

L597R

D594N

K6

01E

D594

D594G

D594G

G46

9V

L597Q

D594N

G469A

T599

dup

L597Q

L485

W

G469A

GBM

GBM

Melanom

a

Cholangio.

Small Cell Lun

g

CRC

CRC

Prostate

Vaginal

Angiosarcoma

NSCLC

Appe

ndiceal

NSCLC

Prostate

CRC

Squamou

s Cell

Prostate

Salivary Du

ct

NSCLC

NSCLC

Aden

oid CysFc

NSCLC

NSCLC

Small IntesFn

e

NSCLC

NSCLC

Gallbladd

er

Squamou

s Cell

(Head and Neck)


Yao et al. Cancer Cell 2015

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BRAF L485W Metastatic Gallbladder Adenocarcinoma

RECIST Partial Response Baseline 6 Weeks 12 Weeks


Melanoma BRAF V600E

Melanoma BRAF V600E

Melanoma BRAF V600E

Small Intestine Adenocarcinoma BRAF G469A

Gallbladder Adenocarcinoma BRAF L485W

Melanoma BRAF V600K

Glioblastoma BRAF V600E

Melanoma NRAS Q61K

Melanoma NRAS G13V

Melanoma NRAS Q61R

Squamous Cell (Head and Neck) BRAF G469A

NSCLC BRAF V600E

NSCLC BRAF L597Q

NSCLC BRAF V600E


Objective Responders Results: Time on Study

Days on Study


1 Mar 2016 8mm

Baseline 21 Jul 2016

22mm 30 Aug 2016

15mm 12 Dec 2016

9mm 14 Feb 2017

8mm

BRAF V600E Recurrent Glioblastoma Multiforme

-64% RECIST partial response


BRAF L597Q Non-Small Cell Lung Cancer


Pre-Treatment Baseline

Baseline 9 Dec 2016

2 Mar 2017

-45% RECIST partial response

Plasma ctDNA results

Conclusions •  Ulixertinib is the first-in-class ERK1/2 inhibitor that has a good safety profile 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 in this study.

•  Ulixertinib resulted in durable responses (benefit up to 3+ years) in patients who progressed on prior BRAF ± MEK inhibitor treatment or who were treatment naïve.

•  Ulixertinib resulted in durable responses in patients with BRAF (V600E/K, G469A, L485W, L597Q) and NRAS (G13V, Q61K/R) mutations, in melanoma, glioblastoma, head & neck, small bowel, gallbladder and lung cancers with clear CNS activity.

•  Further clinical development of ulixertinib is warranted, either alone or in combination with targeted or immuno-oncology agents as driven by translational science.


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

Dean Welsch

Vicki Keedy Jeffrey Sosman

James Mier

Ryan Sullivan Keith Flaherty Richard Carvajal

Harriet Kluger Mario Snzol

Andrea Wang-‐Gillam Elizabeth Buchbinder Geoffrey Shapiro

Anthony W. Tolcher Amita Patnaik Kyri Papadopoulos

Filip Janku Sapna Patel

Antoni Ribas Deborah Jean Wong

Bob T. Li Mario E. Lacouture Anna M. Varghese David M. Hyman


Key Partners:

Thank You to the paTents and their families

Jeffrey Infante

Manish Patel

First-in-class oral ERK1/2 inhibitor Ulixertinib (BVD-523 ......BVD-523 (100 mg/kg, po, BID) A375...

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