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GSK1120212

Safety and Efficacy Results from the First-Time-in-Human Study of the Oral MEK 1/2 Inhibitor GSK1120212.

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GSK1120212

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  1. Safety and Efficacy Results from the First-Time-in-Human Study of the Oral MEK 1/2 Inhibitor GSK1120212 Jeffrey 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 GSK1120212

  2. In Vitro Summary GSK1120212 is a reversible, selective, allosteric inhibitor of MEK1/MEK2 activation and kinase activity

  3. 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

  4. Study Design Tumor PD Dose Escalation Expansion Part 3 Part 2 Part 1 Melanoma 2.5 mg QD MTD PK, tolerability Pancreatic 2.0 mg QD Accelerated and 3+3 dose escalation Colorectal 1.0 mg QD NSCLC 0.5 mg QD Biopsies or FDG-PET taken at baseline and D15 Patients then treated at RP2D Dosed at 2 mg or 2.5 mg QD Establish MTD and RP2D

  5. 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

  6. 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.

  7. Patient Characteristics (N=162)

  8. Summary of Dose Escalation & DLTs G1 rash and diarrhea DLT = G3 rash DLT = G3 diarrhea & G2 CSR DLT = G3 rash DLT = G2 CSR MTD = 3 mg QD; RP2D = 2 mg QD

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

  10. 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

  11. Ocular Toxicity • No retinal vein occlusion • 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 GSK1120212 Vitreal fluid Optical Coherence Tomography (OCT)

  12. Dose Proportionality of GSK1120212 1000 • Dose-proportional and linear • Low variability • AUC within 3-fold range at 2 mg dose 800 600 Day 15 AUC (ng*hr/mL) 400 200 0 0 1 2 3 4 Dose (mg) With loading dose Without loading dose

  13. PK Profile of GSK1120212 • Long half-life (~4.5 days) • Low peak/trough ratio • Reduces risk of Cmax-related toxicity • Exposure profile maintains time above threshold 50 1.0 mg 2.0 mg 40 3.0 mg 30 Day 15 Concentration (ng/mL) 20 10 Preclinical Target (antiproliferation IC90) 0 0 5 10 15 20 25 Time (hr)

  14. 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

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

  16. 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%) 30 20 10 0 -10 -20 -30 30 -40 20 -50 10 -60 0 -70 -10 -80 Maximum % Reduction from Baseline -20 -90 -30 -100 -40 -50 -60 -70 -80 -90 -100 Patients Complete response Stable disease Partial response Progressive disease

  17. Duration on Study: B-RAF Mutant Melanoma Time of first response * Previously treated with PLX4032 * Patients * Complete response Stable disease Partial response Progressive disease 8 0 16 24 32 40 Weeks

  18. Tumor Response: B-RAF Mutant Melanoma Patient Dose=6/6/2 mg QD 1 month post-treatment Baseline

  19. Tumor Response: B-RAF Mutant Melanoma Patient Dose=6/6/2 mg QD Pre-Treatment 1 month post 4 months post

  20. Tumor Response:B-RAF Wild-type Melanoma (n=22) • Scans unavailable for 3 patients with clinical PD 60 60 Partial response Progressive disease 50 50 40 40 Stable disease 30 30 20 20 10 10 0 0 -10 -10 -20 -20 -30 -30 Maximum % Reduction from Baseline -40 -40 -50 -50 -60 -60 -70 -70 -80 -80 -90 -90 -100 -100 Patients

  21. Tumor Response: Pancreatic Cancer (n=17) • Scans unavailable for 4 patients with clinical PD 70 70 60 60 50 50 40 40 30 30 20 20 10 10 0 0 -10 -10 Maximum % Reduction from Baseline -20 -20 -30 -30 -40 -40 -50 -50 -60 -60 -70 -70 -80 -80 -90 -90 -100 -100 Patients Partial response Stable disease Progressive disease

  22. 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

  23. 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

  24. Acknowledgments • Pinnacle Oncology Hematology • Michael Gordon, M.D. • David S. Mendelson, M.D. • Gerry Kato, M.D. • MD Anderson • Gerald Falchook M.D. • RazelleKurzrock, 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 • 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

  25. BACKUP SLIDES

  26. In Vivo Summary • Does not penetrate intact blood-brain barrier • Demonstrates tumor regression and growth inhibition in multiple xenograft animal models following oral dosing 1400 Control 1200 1 mg/kg QD x 14 1 mg/kg QD x 25 (2 series) 6PR/8 1000 800 Median Tumor Volume, mm3 Colo205: CRC B-RAFV600E 600 400 200 0 20 30 40 50 60 70 80 90 100 110 Days Post-implantation QD x 14 QD x 25 QD x 25

  27. B-RAF and Ras Mutant Cancer Cell Lines Are More Sensitive to GSK1120212 Sensitive (gIC50<50 nM) 90 Less-sensitive (gIC50>50 nM, <1 µM) 80 Non-sensitive (gIC50>1 µM) 70 60 50 Cell Lines, % 40 30 20 10 0 B-RAF Mutant Ras Mutant WT Ras/Raf Solid Tumors (307 cell lines)

  28. Mean PK Parameters at 2 mg QD in Part 2 • 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

  29. Characteristics of Responders: B-RAF Mutant Melanoma

  30. Ocular Toxicity • No retinal vein occlusion • 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 Vitreal fluid • Visual impairment at 2 mg QD (n=46) • Incidence 7%, all G1 • All reversible with or without holding GSK1120212 Optical Coherence Tomography (OCT)

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