1 / 42

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

jeroen
Télécharger la présentation

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

An Image/Link below is provided (as is) to download presentation Download Policy: Content on the Website is provided to you AS IS for your information and personal use and may not be sold / licensed / shared on other websites without getting consent from its author. Content is provided to you AS IS for your information and personal use only. Download presentation by click this link. While downloading, if for some reason you are not able to download a presentation, the publisher may have deleted the file from their server. During download, if you can't get a presentation, the file might be deleted by the publisher.

E N D

Presentation Transcript

  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

More Related