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Keith T. Flaherty, MD Assistant Professor of Medicine Abramson Cancer Center of the

Clinical Updates Novel Agents for the Treatment of Metastatic Melanoma Future Directions: Opportunities for Targeting B-RAF and Other Targets in Melanoma Management. Keith T. Flaherty, MD Assistant Professor of Medicine Abramson Cancer Center of the University of Pennsylvania

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Keith T. Flaherty, MD Assistant Professor of Medicine Abramson Cancer Center of the

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  1. Clinical UpdatesNovel Agents for the Treatment of Metastatic MelanomaFuture Directions: Opportunities for Targeting B-RAF and Other Targets in Melanoma Management Keith T. Flaherty, MD Assistant Professor of Medicine Abramson Cancer Center of the University of Pennsylvania Philadelphia, PA

  2. Novel Cytotoxics

  3. Albumin-bound paclitaxel • Established superiority to conventional paclitaxel in metastatic breast cancer • Phase II trial in metastatic melanoma • 35 patients with chemotherapy-naïve metastatic melanoma received ABI-007 100 mg/m2 IV weekly for 3 out of 4 weeks • Objective response rate 26% • Median PFS 4 months • Phase III trial being conducted compared to dacarbazine

  4. Altering the Threshold for Chemotherapy-induced Apoptosis

  5. STA-4783 Induces Programmed Cell Death via the Intrinsic Mitochondrial Apoptotic Pathway STA-4783 induces ROS which accumulate in the mitochondria ROS elevation leads to the oxidation of cardiolipin, a mitochondrial phospholipid which holds cytochrome c in the mitochondria. Oxidation of cardiolipin leads to the release of cytochrome c STA-4783 ↑ ROS Mitochondria TARGET Cytochrome c exits the mitochondria through pores which are created by pro-apoptotic members of the Bcl2 family and are dependent upon elevated ROS Cytochrome c release Caspase 9 activation APOPTOSIS Cytochrome c activates caspase 9 which then activates caspase 3/7 leading to apoptosis

  6. Paclitaxel: 80 mg/m2 + STA-4783 213 mg/m2 (N=53) Study Population • Stage IV • 0-1 prior Chemo for Metastatic disease • ECOG 0-2 • No brain mets Primary Endpoint Progression-free Survival Randomization 2:1 (N=81) Paclitaxel: 80 mg/m2 (N=28) STA-4783 in Metastatic MelanomaStudy Design • Double-blind, randomized, controlled; 21 centers in United States • Treatment: 3 weekly treatments per each 4-week cycle, until PD • Assessment: at baseline and every other cycle thereafter (RECIST) • Cross-over for paclitaxel-alone arm after PD 1/week for 3 weeks; 1 week off Coordinating investigator: Steven O’Day, MD, The Angeles Clinic and Research Institute (81 patients were enrolled from December 2004 to September 2005)

  7. Kaplan-Meier Plot of Progression-free Survival Hazard Ratio= .583 P= 0.035* * The P-value is from a 2-sided log-rank test.

  8. 18-base DNA oligonucleotide TCTCCCAGCGTGCGCCAT Phosphorothioate backbone Selectively targets Bcl-2 RNA Decreases Bcl-2 protein Other MOAs possible B a s e O O O - O P S B a s e O O O S P - O B a s e O O O - O P S O Genasense Drug Substance (Oblimersen Sodium, G3139)

  9. Primary endpoint: overall survival Secondary endpoints: response rate, progression free survival Sample size: N = 771 Cycles every 21 days (maximum of 8): no cross-over Radiologic assessment every 2 cycles Minimum follow-up: 2 years GM301 Study Design G3139 7 mg/kg/d x 5 days  DTIC 1000 mg/m² Stratification/ Randomization DTIC 1000 mg/m²

  10. Overall Survival (24-Month)Intent-to-treat Population; N=771 1.0 0.8 0.6 Proportion Surviving 0.4 0.2 0.0 12 0 4 8 16 20 24 Months

  11. 1.0 0.8 0.6 0.4 0.2 0.0 0 2 6 10 12 14 18 20 22 24 4 8 16 Overall SurvivalBaseline LDH < 0.8 x ULN; N=274 Proportion Surviving Months

  12. AGENDA (GM307) Study Design Genasense 7 mg/kg/d CIV x 5 days  DTIC 1000 mg/m² Stratification/ Randomization Matching PCBO CIV x 5 days  DTIC 1000 mg/m² • Co-Primary Endpoints: PFS/Overall survival • Secondary endpoints: overall response rate, durable response rate, duration of response • Sample size: N = 300 • Cycles every 21 days (maximum of 8): no cross-over • Radiologic assessment every 42 days • Minimum follow-up: 2 years

  13. Signal Transduction & Angiogenesis Inhibitors

  14. B-RAF, An Oncogene in 7% of Human Cancers Mutated in 60-70% of melanoma 90% of mutations are V600E Davies et al. Nature 2002; 417:949-54 & Wan PT et al.Cell. 2004 19;116(6):855-67

  15. Response Rates & B-RAF Mutation Status Chang et al. J Transl Med. 2004 Dec 21;2(1):46.

  16. PD0325901 ARRY-142886 MAP kinase pathway inhibitors in melanoma NRAS B-RAF BAY 43-9006/sorafenib CHR-265 PLX4032 SB-590885 MEK ERK

  17. Sorafenib O C F 3 O C l N O H N N N H H Wilhelm S et al. Cancer Res. 2004;64:7099-109

  18. Sorafenib Spectrum vs. Whole Kinome Fabian, M.A. et al. Nat Biotechnol, 2005. 23(3):329-36.

  19. Single-agent Sorafenib in Melanoma • 39 patients with metastatic melanoma • 1 responder • 7 patients with stable disease at 12 weeks • 22 patients with metastatic melanoma • 1 partial response • 12 with stable disease Median progression-free survival: 3 months

  20. Sorafenib with Chemotherapy

  21. Line of therapy Randomized Trials in Metastatic Melanoma 1ST 2ND DTIC/temozolomide randomized phase II Carboplatin/paclitaxel E2603 phase III OS PFS Chemotherapy backbone

  22. Randomization (N=98) Sorafenib in Melanoma: Randomized Phase II Sorafenib + DTIC Trial Design • 1° end point: PFS • 2° end point: OS • 3° end points: TTP, tumor response rate, duration of response, EQ-5D QoL • Eligibility criteria • No prior chemotherapy, one prior immunotherapy allowed • Measurable disease by RECIST • No active brain metastases, screening brain MRI required • Stratified: • AJCC stage • Unresectable stage III • Stage IV-M1a, M1b • Stage IV-M1c • ECOG PS • 0 • 1 Group A: DTIC, 1000 mg/m2 IV q3w Sorafenib 400 mg po bid Group B: DTIC, 1000 mg/m2 IV q3w Placebo 2 tablets po bid Data on file. Bayer HealthCare.

  23. Phase II Dacarbazine ± Sorafenib ORR 24% 12% 1.00 0.75 0.50 0.25 0.00 Sorafenib + DTIC (39 events) Median: 2.7 mo. Placebo + DTIC (42 events) Median: 4.9 mo. Hazard Ratio = 0.67; P = 0.068 Progression-Free Survival Probability 0 100 200 300 400 500 600 Days From Randomization

  24. Sorafenib in Melanoma: PRISMPhase III Paclitaxel + Carboplatin ± Sorafenib RANDOMIZATION Carboplatin AUC 6 IV Day 1 Paclitaxel 225 mg/m2 IV Day 1 Sorafenib 400 mg po bid Days 2-19 Cycles repeated every 21 days Stratified by: AJCC stage: • Unresectable stage III • Stage IV – M1a, M1b • Stage IV – M1c ECOG PS: • 0 vs 1 Key Eligibility: • Progresses on DTIC/TMZ • No active brain Metastases • Measurable disease by RECIST Mandatory dose reduction after cycle 4 to paclitaxel 175 mg/m2 and carboplatin AUC 5 Carboplatin AUC 6 IV Day 1 Paclitaxel 225 mg/m2 IV Day 1 Placebo 2 tablets po bid Days 2-19 Cycles repeated every 21 days Primary endpoint: progression-free survival (by independent assessment) Secondary and tertiary endpoints: time to progression, objective response rate, duration of response, overall survival N=270 Agarwala SS, et al. Proc Am Soc Clin Oncol. 2007;25:474s. Abstract 8510.

  25. 0 14 29 43 57 71 Weeks From Randomization Phase III Carboplatin/Paclitaxel ± Sorafenib ORR 11% 10% Sorafenib + C/P (97 events) Median: 4.0 mo. Placebo + C/P (100 events) Median: 4.1 mo. 1.00 0.75 0.50 0.25 0.00 Probability of Progression-Free Survival Hazard Ratio = 0.91; P = 0.492 Agarwala SS, et al. Proc Am Soc Clin Oncol. 2007;25:474s. Abstract 8510.

  26. Paclitaxel/Carboplatin ± Sorafenib in Advanced MelanomaE2603 Phase III Trial RANDOMIZE Arm A Carboplatin AUC 6 IV Day 1 Paclitaxel 225 mg/m2 IV Day 1 Placebo 2 tablets po bid Days 2-19 Q3W Stratified by: • AJCC Stage • ECOG PS • Prior Therapy Arm B Carboplatin AUC 6 IV Day 1 Paclitaxel 225 mg/m2 IV Day 1 Sorafenib 400 mg po bid Days 2-19 Q3W 800 patients with metastatic melanoma and no prior chemotherapy; primary endpoint - OS Carboplatin and paclitaxel with or without sorafenib in treating patients with unresectable stage III or stage IV melanoma. Available at: www.clinicaltrials.gov/ct/show/NCT0010019?order=1. Accessed September 17, 2007.

  27. Tumor Regressions (N=8/group) PR / CR RAF265 Causes Tumor Regression in Xenografts of V600E B-RAF Human Melanoma MEXF 276 (B-RafV600E) 2400 0 / 0 Vehicle 2000 1600 Mean Tumor Volume (mm3)(+/- SE) 0 / 0 100 mg/kg qd Sorafenib 1200 800 1 / 0 400 10 mg/kg q2d RAF265 8 / 0 30 mg/kg q2d RAF265 8 / 0 100 mg/kg q2d RAF265 0 Courtesy of Darrin Stuart, Novartis 0 4 8 12 16 20 Days Post Staging RAF265 Sorafenib Vehicle Vehicle Vehicle 10 mg/kg 30 mg/kg 100 mg/kg Vehicle 10 mg/kg 30 mg/kg 100 mg/kg pMEK - - MEK - - Vehicle Vehicle 10 mg/kg 30 mg/kg 100 mg/kg 10 mg/kg 30 mg/kg 100 mg/kg BIM p27Kip -actin

  28. RAF-265-MEL01 Study Design 40-60 B-RAFWT Phase I MTD 40-60 B-RAFMUT Phase II expansion Serial biopsies once target drug exposure achieved • Dose escalate to MTD without regard to B-RAF status using Bayesian methodology • Assess Safety, PK, PD • Expand at MTD and stratify based on B-RAF mutation status • Assess PFS, ORR

  29. Selectivity of PLX4032 in vivo B-RafMUT N-RasMUT Lee J et al. 2006 NCI/AACR/EORTC

  30. PLX4032 Dose Escalation Study 3-6pts 6 patients with V600E+ melanoma Maximum tolerated dose Dose level 4 3-6pts Serial biopsies Dose level 3 3-6pts Target AUC 6 patients with V600E+ melanoma Dose level 2 3-6pts 3-6pts Dose level 1

  31. AZD6244 Suppresses the Growth of 1205Lu Melanoma Xenograft (B-RAF mutant) K Smalley et al, NCI/AACR/EORTC 2006

  32. Tumor pERK Suppression in Individual Patients MEK Inhibitor (PD0325901) Lorusso et al. ASCO 2005, abstract 3011

  33. Phase II Trials with MEK Inhibitors • ARRY-142886/AZ6244 (AstraZeneca) • Randomized phase II: ARRY-142886 vs. temozolomide • N = 182 • Archival, paraffin-embedded tissue collection • Sample size allows allows exploration of effect in patients with a B-RAF or N-RAS mutation • PD0325901 (Pfizer) • Single-arm phase II

  34. Single-agent Bevacizumab or Bevacizumab/IFN in Melanoma • Randomized phase II trial: • bevacizumab 15 mg/kg IV every 2 weeks vs. • bevacizumab 15 mg/kg IV every 2 weeks + 1 MIU IFNα SQ QD • 17 patients accrued as of preliminary analysis • 44% with lymph node/skin metastases (M1a) • 1 CR, 1 PR both on combination arm, both with M1a disease • 4 SD > 24 weeks (3 on bevacizumab alone) • Not published Carson W et al. ASCO 2003, abstract 2873

  35. Randomized Phase II Trial of Carboplatin/Paclitaxel ± Bevacizumab Arm A Carboplatin AUC 5 IV q 21d Paclitaxel 175 mg/m2 IV q21d Placebo R A N D O M I Z E Stratify: AJCC stage ECOG PS Arm B Carboplatin AUC 5 IV q21d Paclitaxel 175 mg/m2 IV q21d Bevacizumab 15 mg/kg IV q 21d N = 200 patients with previously untreated metastatic melanoma Primary endpoint = progression-free survival

  36. Current Phase I or II Melanoma Trials with Angiogenesis Inhibitors • AG-013736 (VEGFR & PDGFR) • Single arm phase II • CHR-258 (VEGFR & FGFR) • Phase I in melanoma • Sunitinib • Phase I with temozolomide in melanoma • Sorafenib/bevacizumab • Sorafenib/temsirolimus • Bevacizumab/temsirolimus NCI/CTEP sponsored phase II

  37. Novel Immunologics

  38. Dendritic Cell/T Cell Activating Therapies in Clinical Development PD-L1 (B7-H1) PD-1 - B7-1 (CD80) - CTLA4 T cell receptor + MHC B7-2 (CD86) CD28 Dendritic cell T cell

  39. Dendritic Cell/T Cell Activating Therapies in Clinical Development OX40L OX40 4-1BB (CD137) 4-1BBL + + CD70 + CD27 T cell receptor + MHC B7 CD28 + CD40 CD40L Dendritic cell T cell

  40. 46 responding patients out of 356 patients enrolled in 6 clinical trials Number of Patients Duration of OR (months) *Indicates patient with ongoing response, N=25. Response Duration with Ipilimumab Hamid. ASCO. 2007 (abstr 8525).

  41. Phase I Trial of CP-870,893 • 29 patients with advanced solid tumors; 15 with melanoma evaluated by RECIST • 4 Partial Responses • 7 Stable Disease • All partial responses were in patients with melanoma • Regression of lesions in liver, skin, lymph nodes, lung, muscle • All PRs at 0.2 mg/kg or 0.3 mg/kg • One melanoma patient (0.2 mg/kg) had a near CR for 18 months, then isolated LN recurrence, underwent surgery, now CR for 18 additional months UPIN 1017 (melanoma)

  42. Future Directions in Melanoma • Diverse mechanisms currently being explored in melanoma • Novel cytotoxics, signal transduction inhibitors, anti-angiogenic & novel immunotherapies • Critical for new therapies to establish which subpopulation derives the greatest benefit

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