first-in-class oral erk1/2 inhibitor ulixertinib (bvd-523 ......bvd-523 (100 mg/kg, po, bid) a375...
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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
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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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BVD-523 (75 mg/kg, po, BID)
BVD-523 (50 mg/kg, po, BID)
BVD-523 (25 mg/kg, po, BID)
Colo205 (BRAF-‐V600E colorectal)
Background: Targeting the MAPK pathway
4 Presented by: Bob T. Li, MD
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BVD-523 (75 mg/kg, BID)BVD-523 (50 mg/kg, BID)BVD-523 (25 mg/kg, BID)
BVD-523 (100 mg/kg, BID)
BVD-523 (10 mg/kg, BID)
MIAPaCa2 (KRAS-‐G12C pancreaFc) 0 4 8 12 16 20
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BVD-523 (25 mg/kg, po, BID)
BVD-523 (50 mg/kg, po, BID)
BVD-523 (100 mg/kg, po, BID)
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
Presented by: Bob T. Li, MD
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
6
Dose EscalaFon Data was presented at ASCO 2015 (Infante, et al.)
Presented by: Bob T. Li, MD
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
12
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)
7 Presented by: Bob T. Li, MD
Pharmacokinetics and Pharmacodynamics Are Dose-Dependent
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[BVD
-523
] (n
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pRSK
/total RSK
(%
Baseline)
Dose (mg, BID)
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0 2 4 6 8 10 12 Time After Dosing (hours)
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BVD
-523
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Cycle 1 Day 15
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sma
BV
D-5
23 (µ
g*hr
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Dose Level (mg, BID)
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Pla
sma
BV
D-5
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g*hr
/mL)
Dose Level (mg, BID)
Cycle 1 Day 1
Cycle 1 Day 15
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0 2 4 6 8 10 12 Time After Dosing (hours)
900 mg, BID
750 mg, BID
600 mg, BID
300 ng, BID
150 mg, BID
75 mg, BID
40 mg, BID
20 mg, BID
10 mg, BID
Presented by: Bob T. Li, MD
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
Presented by: Bob T. Li, MD
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
10 Presented by: Bob T. Li, MD
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*
Total Enrollment 24 Evaluable for Efficacy~ 22
NRAS Mutated Melanoma* Total Enrollment 22
Evaluable for Efficacy~ 18 MEK Mutated Cancer*
Total Enrollment 8 Evaluable for Efficacy~ 4
Presented by: Bob T. Li, MD
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
Presented by: Bob T. Li, MD
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)
13 Presented by: Bob T. Li, MD
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
14 Presented by: Bob T. Li, MD
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
15 Presented by: Bob T. Li, MD
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
16 Presented by: Bob T. Li, MD
DuraFon on Study (Days)
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
17 Presented by: Bob T. Li, MD
Response assessments in atypical (non-V600) BRAF mutations
Presented by: Bob T. Li, MD
Yao et al. Cancer Cell 2015
18
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)
Presented by: Bob T. Li, MD
Yao et al. Cancer Cell 2015
19
BRAF L485W Metastatic Gallbladder Adenocarcinoma
RECIST Partial Response Baseline 6 Weeks 12 Weeks
20 Presented by: Bob T. Li, MD
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
DuraFon on Study (Days)
Objective Responders Results: Time on Study
Days on Study
21 Presented by: Bob T. Li, MD
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
22 Presented by: Bob T. Li, MD
BRAF L597Q Non-Small Cell Lung Cancer
23 Presented by: Bob T. Li, MD
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.
24 Presented by: Bob T. Li, MD
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
Presented by: Bob T. Li, MD
Key Partners:
Thank You to the paTents and their families
Jeffrey Infante
Manish Patel