Safety and Efficacy Results from the First-Time-in-Human Study of the Oral MEK 1/2 Inhibitor GSK1120212Jeffrey R. Infante1, Leslie A. Fecher3, Sujatha Nallapareddy2,  Michael S. Gordon4, Keith Flaherty3,  Donna S. Cox5, Douglas J. DeMarini5, Shannon R. Morris5, Howard A. Burris III1, Wells Messersmith2

 

1Sarah Cannon Research Institute, Nashville, TN, USA; 2University of Colorado Cancer Center, Aurora, CO, USA; 3University of Pennsylvania Abramson Cancer Center, Philadelphia, PA, USA; 4Pinnacle Oncology Hematology, Scottsdale, AZ, USA; 5GlaxoSmithKline Research and Development, Philadelphia, PA, USA

GSK1120212GSK1120212

N

N

O

O

N

O

NH

F I

NH

O

CH3

CH3

H3C .DMSO

GSK1120212 is a reversible, selective, allosteric inhibitor of

MEK1/MEK2 activation and kinase activity

IC50 (nM)MEK1 0.7

MEK2 0.9

Inhibition of pERK (nM)

SKMEL28 (B-RAFV600E) 0.92

Inhibition of proliferation

(nM)

SKMEL28 (B-RAFV600E) 2.5

Colo205 (B-RAFV600E) 1

A375P (B-RAFV600E) 1.3

HCT116 (K-RASG13N) 42

HN5 (wt RAS/RAF) 106

In Vitro Summary

Objectives

• Primary– Determine the maximum tolerated dose (MTD)

• Secondary– Characterize the pharmacokinetics (PK)– Evaluate the pharmacodynamic (PD) response

• FDG-PET • Tumor biopsies

– Measure response rate– Explore relationships between

• GSK1120212 PK, MAPK signalling, clinical endpoints

Study Design

Biopsies or FDG-PET taken at baseline and

D15Patients then treated

at RP2D

Establish MTD and RP2D

Expansion Tumor PD

Accelerated and 3+3 dose escalation

PK, tolerability

Part 1 Part 2 Part 3

1.0 mg QD

0.5 mg QD

2.0 mg QD

MTDMelanoma

Dosed at 2 mg or 2.5

mg QD

2.5 mg QD

Pancreatic

Colorectal

NSCLC

Dose Escalation

Key DLT Criteria

• Any Grade 4 hematologic toxicity or Grade 3 thrombocytopenia with bleeding

• Grade 3 or 4 non-hematologic toxicity (rash, nausea and vomiting only if uncontrolled despite supportive care)

• Treatment delay of 14 days or greater due to unresolved toxicity

• Grade 2 or greater non-hematological toxicity (at any time during treatment) that in the judgment of the investigator and GSK Medical Monitor is dose limiting

Key Eligibility Criteria• Histologically or cytologically confirmed diagnosis

of solid tumor malignancy or lymphoma

• ECOG 0-1 with adequate organ system function

• Asymptomatic treated brain metastasis– 2 week washout for Gamma knife – 4 week washout for whole brain radiation

• Eye exclusions: – History of retinal vein occlusion (RVO) or central serous retinopathy

(CSR). – Visible retinal pathology that is considered a risk factor for RVO or

CSR.– Glaucoma diagnosed within one month prior to study Day 1.– Intraocular pressure > 21mm Hg as measured by tonography.

Patient Characteristics (N=162)

Mean age, yrs 59.2

Gender, n (%) , Male 85 (52)

ECOG, n (%), 0 75 (46)

Prior lines of treatment, n (%)

01-2≥3

12 (7)56 (34)94 (58)

Tumor type, n (%)

Melanoma B-RAF-wt B-RAF-mutant B-RAF unknownPancreasColon/RectumNSCLCOther

24 (33)24 (33)24 (33)

72 (44)

26 (16)25 (15)11 (7)

28 (17)

Summary of Dose Escalation & DLTs

Dose (mg) Load D1/D2 n

3 weeks on/1 week off

0.125 2

0.25 1

0.5 2

1 2

2 3

Continuous QD dosing

2 6 mg 10

2.5 72.5 8mg 7

3.0 123.0 10 mg 4

4.0 3

MTD = 3 mg QD; RP2D = 2 mg QD

G1 rash and diarrhea

DLT = G3 rash

DLT = G3 diarrhea & G2 CSRDLT = G3 rash

DLT = G2 CSR

Most Common AEs (≥20%) Regardless of Causality at RP2D

Events 2mg QD n=46 (%)

G1-2 G3 G4

Rash 83 2 0

Diarrhea 46 2 0

Fatigue 31 7 0

Nausea 29 0 0

Vomiting 24 2 0

Peripheral Edema

26 0 0

Anemia 13 7 0

Selected AEs• Rash (2 mg QD; n=46)

– Mostly acneiform • 59% G1• 24% G2• 2% G3

• Diarrhea (2 mg QD; n=46)– Intermittent (median reported duration = 2.5 days)– Controlled with supportive care

• 33% G1• 13% G2• 2% G3

• 4 cases of grade 3 left ventricular systolic dysfunction (N=162; 2.3%)

– 1 was associated with tumor involvement of the heart

Ocular Toxicity• No retinal vein occlusion

Vitreal fluid

• Central serous retinopathy (CSR)– Blurry vision– Fluid accumulation in the macular region

between retinal pigment epithelium and

outer segment– 3 cases in 162 patients

• 2 diagnosed cycle 1 (4 mg & 10/10/3 mg)

• 1 diagnosed cycle 2 (6/6/2 mg)

– All reversible upon withholding GSK1120212Optical Coherence Tomography

(OCT)

Dose Proportionality of GSK1120212

1000

800

600

400

200

00 1 2 3 4

Dose (mg)

Day 1

5 A

UC

(n

g*h

r/m

L)

• Dose-proportional and linear

• Low variability– AUC within 3-fold range at 2 mg

dose

Without loading doseWith loading dose

2 mg (n=14) Mean CV%

AUC (ng*hr/mL) 360 31

Cmax (ng/mL) 23.3 25

• Long half-life (~4.5 days)

• Low peak/trough ratio

─ Reduces risk of Cmax-related toxicity

• Exposure profile maintains time above threshold

50

40

30

20

10

00 5 10 15 20 25

Time (hr)

Day 1

5 C

on

cen

trati

on

(n

g/m

L)

Preclinical Target (antiproliferation IC90)

1.0 mg

2.0 mg

3.0 mg

PK Profile of GSK1120212

PD Markers in B-RAF Mutant Melanoma

ppERK (H score) 99% decrease

Ki67 (% positive nuclei)

92% decrease

Pre-dose

Day 15

Dose=6/6/2 mg QD

FDG-PET Response at Day 15: B-RAF Mutant Melanoma

Dose D1-D15

SUVmax reduction at D15

Best RECISTresponse

0.5 mg QD 44% PR

Baseline Day 15

Tumor Response: B-RAF Mutant Melanoma (n=20)• 17 patients are M1c• Scans unavailable for 3 patients with clinical PD• 2 CRs and 6 PRs

─ Preliminary RR is 40% (95% CI, 19-64%)

3020100

-10-20-30-40-50-60-70-80-90

-100

3020100-10-20-30-40-50-60-70-80-90-100

PatientsComplete response

Progressive diseasePartial response

Stable disease

Maxim

um

% R

ed

ucti

on

fr

om

Baselin

e

Duration on Study: B-RAF Mutant Melanoma

Weeks

1680 24 32 40

Pati

en

ts

Time of first response

Complete response

Progressive diseasePartial response

Stable disease

*

*Previously treated with PLX4032*

Tumor Response: B-RAF Mutant Melanoma Patient

Baseline 1 month post-treatment

Dose=6/6/2 mg QD

Pre-Treatment 1 month post 4 months post

Tumor Response: B-RAF Mutant Melanoma Patient Dose=6/6/2 mg

QD

Tumor Response:B-RAF Wild-type Melanoma (n=22)

Partial response Progressive diseaseStable diseasePatients

6050403020100

-10-20-30-40-50-60-70-80-90

-100

6050403020100-10-20-30-40-50-60-70-80-90-100

Maxim

um

% R

ed

ucti

on

fr

om

Baselin

e

• Scans unavailable for 3 patients with clinical PD

Tumor Response: Pancreatic Cancer (n=17)

6050403020100

706050403020100

70

Partial response Progressive diseaseStable diseasePatients

-10-20-30-40-50-60-70-80-90

-100

-10-20-30-40-50-60-70-80-90-100M

axim

um

% R

ed

ucti

on

fr

om

Baselin

e

• Scans unavailable for 4 patients with clinical PD

Summary: GSK1120212

• Acceptable safety profile– Rash and diarrhea are common,

most cases G1-2– 3 CSRs, all reversible

• Desirable exposure profile– Long half-life– Low peak/trough ratio– Low variability

Summary: GSK1120212

• Sustained target inhibition in tumor biopsies

• Efficacy– Compelling responses in B-RAF mutant melanoma– Activity in B-RAF WT melanoma and pancreatic

cancer– Colon and NSCLC cohorts undergoing analysis

• MTD is 3 mg QD, RP2D is 2 mg QD

• Patients and families

• Sarah Cannon Research Institute– Howard A. Burris M.D.

– Johanna C. Bendell M.D.

– Suzanne Jones Pharm. D.

• University of Colorado– Wells Messersmith M.D.– Sujata Nallapareddy M.D.

– Karl Lewis M.D.

• University of Pennsylvania – Leslie Fecher M.D.

– Keith Flaherty M.D.

– Peter O’Dweyer

• Pinnacle Oncology Hematology– Michael Gordon, M.D.

– David S. Mendelson, M.D.

– Gerry Kato, M.D.

• MD Anderson– Gerald Falchook M.D.

– Razelle Kurzrock, M.D.

• Florida Cancer Specialists– Lowell Hart M.D..

• US Oncology– Nicholas Vogelzang M.D.

– Carlos Bacerra M.D.

– Carlos Alemany M.D.

– Lawrence Garbo M.D.

– Paul Conkling M.D.

– Robert Raju M.D.

• GSK MEK111054 Study Team

Acknowledgments

BACKUP SLIDES

• Does not penetrate intact blood-brain barrier• Demonstrates tumor regression and growth inhibition in

multiple xenograft animal models following oral dosing

Days Post-implantation

0

200

400

600

800

1000

1200

1400

20 30 40 50 60 70 80 90 100 110

Med

ian

Tu

mor

Volu

me,

mm

3

QD x 14QD x 25

Colo205: CRC B-RAFV600E

QD x 25

Control1 mg/kg QD x 14

1 mg/kg QD x 25 (2 series) 6PR/8

In Vivo Summary

0

10

20

30

40

50

60

70

80

90

B-RAF Mutant Ras Mutant WT Ras/Raf

Cell L

ines,

%

Solid Tumors (307 cell lines)

B-RAF and Ras Mutant Cancer Cell Lines Are More Sensitive to GSK1120212

Sensitive (gIC50<50 nM)

Less-sensitive (gIC50>50 nM, <1 µM)

Non-sensitive (gIC50>1 µM)

Mean PK Parameters at 2 mg QD in Part 2

PK Parameter Mean CV% Median Range

AUC 369.61 24 363.74 206.7-526.9

Cmax 21.18 22 20.35 12.7-27.3

• Excludes – Subjects 2103 and 2107: dose-reduced in previous tables – Subject 2303: low trough sample and poor estimate of AUC– Subject 2203: dose being withheld 12 days prior to PK sample

Characteristics of Responders:

B-RAF Mutant MelanomaDose (mg) Response Stage and lesions LDH

Priortherapie

s

2 CR M1c; nodes, liver, thigh, bone

Low 2

2 CR M1c; nodes, lung, liver, bone

High 1

2 PR M1c High 2

2 PR M1b Normal 1

2 PR M1c High ≥3

6/6/2 PR M1c Normal ≥3

10/10/3 PR M1a Normal 0

3 PR M1c Low 2

Ocular Toxicity• No retinal vein occlusion

• Visual impairment at 2 mg QD (n=46)– Incidence 7%, all G1

– All reversible with or without holding GSK1120212

Vitreal fluid

• Central serous retinopathy (CSR)– Fluid accumulation in the macular region

between retinal pigment epithelium and

outer segment

– 3 cases in 162 patients• 2 diagnosed cycle 1 (4 mg QD and 10mg LD)

• 1 diagnosed cycle 2 (6 mg, LD)

– All reversible upon withholding GSK1120212

Optical Coherence Tomography (OCT)