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A First-in-class Phase 1 Dose-escalation Study of the Novel Oral ERK 1/2 Kinase Inhibitor
BVD-523 (ulixertinib) in Patients with Advanced Solid Tumors
Jeffrey R. Infante, Filip Janku, Anthony W. Tolcher, Manish Patel, Ryan J. Sullivan, Keith
T. Flaherty, Richard D. Carvajal, Anna M. Varghese, Deborah J. Wong, Mario Sznol, Jeffrey A. Sosman, Andrea Wang-Gillam, Howard A. Burris, Antoni Ribas, Sapna
Pradyuman Patel, Dean J. Welsch, Saurabh Saha
Disclosures ASCO 2015
Jeffrey R. Infante MD
I have no personal financial relationship to disclose
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• MAPK pathway mutations causally drive many cancers • RAF and MEK inhibitors are approved but limited by intrinsic and acquired resistance • ERK inhibition has the potential to overcome or avoid resistance from upstream mutations
dabrafenib
RTKs
vemurafenib trametinib
BVD-523
RAS RSK ERK RAF MEK
Targeting the MAPK pathway
• BVD-523 : Highly potent, selective and reversible ATP-competitive ERK1/2 inhibitor
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BVD-523 (ulixertinib): 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 BVD-523
• Tumor growth regression in BRAF and KRAS-mutant xenograft models • Single agent inhibition in patient-derived xenograft models cross-resistant to BRAFi and MEKi
4
BVD-523: Patient-derived Xenografts that Progressed on BRAF and MEK Inhibitors
0
500
1000
1500
0 7 14 21 Day
Post BRAFi-Progression
Tumors that escape BRAFi and MEKi may remain sensitive to ERKi
Vehicle
Dabrafenib
BVD-523 BVD-523 + Dabrafenib
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Tumor Volume (mm3)
RSK1/2 Phosphorylation as a BVD-523 Activity Clinical Biomarker
BVD-523
RTKs RAS RAF MEK ERK RSK
pRSK/total RSK (%Control)
10 Human PBMC Donors
EC50 ~450 nM (200 ng/mL)
6
BVD-523 inhibits RSK1/2 phosphorylation using an ex vivo human whole blood assay
BVD-523: FIH Study Objectives
Primary objective: To define the safety and tolerability of BVD-523, the maximum tolerated dose (MTD), and the recommended Phase 2 Dose (RP2D). Secondary objectives: To determine the pharmacokinetic profile of BVD-523 and selected metabolites. To investigate any preliminary clinical efficacy. Exploratory objective(s): To evaluate pharmacodynamic marker (biomarker) measures. To investigate any preliminary clinical effects on tumor response assessed by FDG-PET as indicated.
7
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
Study Design: Dose Escalation Phase
• PK collection, pre-dose through 12 hours post-dose, on Days 1 and 15 • PD collection, at pre-dose and 4 hours post-dose, on Days 1 and 15
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BVD-523: Key Eligibility
• Inclusion Criteria – Patients with metastatic or advanced-stage malignant tumor, for whom no
therapy exists that would be curative – ECOG performance status of 0 or 1 – Adequate renal, hepatic, bone marrow, and cardiac function
• Exclusion Criteria – A history or current evidence/risk of retinal vein occlusion or central serous
retinopathy – Concurrent therapy with drugs known to be strong inhibitors of CYP1A2,
CYP2D6, and CYP3A4, or strong inducers of CYP3A4
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BVD-523: Dose-Limiting Toxicity Criteria
• BVD-523 related toxicity in the first 21 days (Cycle 1) of treatment – ≥ Grade 4 hematologic toxicity > 1 day
– Grade 3 hematologic toxicity with complications – ≥ Grade 3 non-hematologic toxicity (except untreated nausea, vomiting, constipation,
pain and rash unless they persist with adequate treatment), including a doubling of AST/ALT in patients with grade 2 ALT/AST at baseline
– A treatment interruption exceeding 5 days (or > 7 days for rash, despite adequate treatment) in Cycle 1 (or inability to begin Cycle 2 for ≥ 7 days) due to BVD-523-related toxicity
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BVD-523: Patient Characteristics All Patients (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) 11
*2 Pancreatic, 1 Appendiceal, 1 NSGCT, 1 Ovarian, 3 Unknown
BVD-523: Dose Escalation and DLT
MTD defined as 600 mg po 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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* Intermediate dose
Adverse Events Possibly Related/Related to BVD-523 in ≥ 10% of Patients
Analysis cut-off date of 13 March 2015
All Patients (N=27)
All Grade (%) Grade 1/2 Grade 3/4
Blood and Lymphatic Anemia 5 (18) 3 2
Gastrointestinal Constipation 3 (11) 3 Diarrhea 14 (52) 12 2 Nausea 14 (52) 14 Vomiting 8 (30) 7 1
General Peripheral Edema 5 (18) 5 Fatigue 16 (59) 15 1 Fever 3 (11) 3
Laboratory Values Increased Creatinine 5 (18) 4 1 Increased LFTs (ALT/AST) 4 (15) 1 3
Metabolism and Nutrition Anorexia 6 (22) 3 3 Dehydration 4 (15) 2 2
Ophthamalogical Blurry/Dimmed Vision 3 (11) 3
Skin and Subcutaneous Erythema Multiforme 3 (11) 3 Rash 19 (70) 17 2 Pruritis 6 (22) 6
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GDC-0425 Cycle 1 Pharmacokinetics
EC50=200 ng/mL HWB
• BVD-523 is absorbed slowly, Tmax 2 – 4 hours post dose • Cmax and AUC generally dose related, up to 600 mg BID • Moderate accumulation in plasma (1.3 to 4.0 fold at doses >75 mg BID) • Moderate inter-patient variability.
BVD-523: Pharmacokinetics (Cycle 1 Day 15)
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1
10
100
1000
10000
0 2 4 6 8 10 12
Plasma BV
D-‐523 (ng/mL)
Time A=er Dosing (hours)
900 mg, BID
750 mg, BID
600 mg, BID
300 mg, BID
150 mg, BID
75 mg, BID
40 mg, BID
20 mg, BID
10 mg, BID
BVD-523: Pharmacodynamic inhibition of ERK substrate phosphorylation
Concentration-dependent inhibition of ERK activity in whole blood; ≥80% target inhibition at tolerated doses/exposures
0
25
50
75
100
0
1000
2000
3000
0 150 300 450 600 750 900
[BVD-523] (ng/mL)
pRSK/total RSK (% Baseline)
15
Dose (mg, BID)
Avg + Std Dev (no error bars n < 2) Day 15 Trough Data
BVD-523: Pharmacodynamic / Radiographic Response
Lesion Longest Diameter (cm)
8.8 cm 6.9 cm 5.6 cm 13.7 cm
Baseline Cycle 2 Cycle 4 Cycle 6 Cycle 8 4.7 cm
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• Metabolic response observed by FDG-PET in 5/16 evaluable patients
• Patient: 61 y/o V600E BRAF mutant melanoma • Post-vemurafenib & dabrafenib progression • Confirmed CT Partial Response on BVD-523, on-study > 500 days
BVD-523: Radiographic Response 54
33
51
23 32 86 43 56
45 298 42 85 90 175
141 772 113 93 190 86
174 101
190 506
394* -‐80
-‐60
-‐40
-‐20
0
20
40
60
80
Best % Change of SLD
from
Baseline
10 mg BID, BVD-‐523 40 mg BID, BVD-‐523 75 mg BID, BVD-‐523 150 mg BID, BVD-‐523 300 mg BID, BVD-‐523 450 mg BID, BVD-‐523 600 mg BID, BVD-‐523 750 mg BID, BVD-‐523 900 mg BID, BVD-‐523
BR
AF
KR
AS
BR
AF
NR
AS
KR
AS
BR
AF
BR
AF
BR
AF
KR
AS
BR
AF
NR
AS
BR
AF
BR
AF
ME
K1
BR
AF
BR
AF
KR
AS
BR
AF
BR
AF
BR
AF
Mel
anom
a
CR
C
Mel
anom
a
Ade
noca
rcin
oma
CR
C
Ade
noca
rcin
oma
CR
C
Mel
anom
a
Mel
anom
a
Mel
anom
a
NS
GC
T
CR
C
PTC
PTC
PTC
NS
CLC
NS
CLC
NE
T
PTC
Unk
now
n
Ova
rian
PN
ET
Mel
anom
a
Mel
anom
a
Mel
anom
a
* Evaluated with calipers
17 Note: All patients with disease measured by RECIST v1.1 who received ≥ 1 dose of study treatment and had > 1 on-treatment tumor assessment (n=25 of 27: 2 did not receive both scans of target lesions)
Analysis cut-off date of 13 March 2015
BVD-523: Duration on Study
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100 days 200 days 300 days 400 days 500 days 600 days 700 days
10 mg BID20 mg BID40 mg BID75 mg BID150 mg BID300 mg BID450 mg BID
Melanoma; BRAF V600E; Refractory 600 mg BID750 mg BID900 mg BID
Off-‐study: PDOff-‐study: otherPartial Response
Melanoma; BRAF V600K; BRAF/MEK Inhibitor naïve
Melanoma; BRAF V600E; Intolerant to other BRAF/MEK Inhibitors
NSCLC/ERCC1 Appendiceal/KRAS
Melanoma
PTC/BRAF
Ovarian/KRAS
Conclusions • BVD-523 showed manageable tolerability in 27 patients with solid tumors
• The MTD and preliminary RP2D is 600 mg BID
• PK was generally linear and dose-dependent up to 600 mg BID
• In patients’ peripheral blood, phosphorylation of the ERK substrates RSK1/2 was shown to be inhibited at doses ≥75 mg BID
• 3 PR and 7 SD >3 months
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Group 1: BRAF mutant cancers (except CRC and NSCLC), inhibitor naïve Group 2: BRAF mutant CRC, inhibitor naïve Group 3: BRAF mutant melanoma, progressed/refractory to BRAFi &/or MEKi Group 4: NRAS mutant melanoma, inhibitor naïve Group 5: MEK mutant cancers, inhibitor naïve Group 6: BRAF mutant NSCLC, inhibitor naïve
Accelerated Dose Titration
(1 patient per cohort)
FIH (10 mg, BID)
> Grade 2 Related AE
Standard “3 + 3”
Dose Escalation
Solid Tumor RP2D
Advanced Solid Tumor Protocol (NCT01781429)
BVD-523 Clinical Program Current Status
Enrollment to Date Dose Escalation n=27, complete Cohort Expansion n=21, ongoing
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Thank You to the patients and their families
Mario Sznol Harriet Kluger
Howard A Burris Todd Bauer Johanna C. Bendell Manish R. Patel Terri Peterson Michael Shearer Melissa Rivera
Anthony W. Tolcher Amita Patnaik Kyri Papadopoulos
Anna M. Varghese Richard D. Carvajal Jyothi Sreekumar Juho Whang
Jeffrey Alan Sosman Jordan Berlin Igor Puzanov
Filip Janku Sapna Patel Divya Sakamuri Goran Cabilo Anne James
Antoni Ribas Deborah Jean Wong John Glaspy Bartosz Chmielowski Christine Kivork
Keith Flaherty Ryan J. Sullivan Rebecca Heist
Andrea Wang-Gillam Craig Lockhart Rebecca Nieman
Amanda Collins, Gary DeCrescenzo, Anna Groover, Maria Miller, Saurabh Saha, Mary Varterasian,
Dean Welsch
Key Partners
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