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Clinical Updates Novel Agents for the Treatment of Metastatic Melanoma

Clinical Updates Novel Agents for the Treatment of Metastatic Melanoma. David F. McDermott, MD Clinical Director, Biologic Therapy Program Beth Israel Deaconess Medical Center Assistant Professor Harvard Medical School Boston, MA. Melanoma : Epidemiology 2007.

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Clinical Updates Novel Agents for the Treatment of Metastatic Melanoma

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  1. Clinical UpdatesNovel Agents for the Treatment of Metastatic Melanoma David F. McDermott, MD Clinical Director, Biologic Therapy ProgramBeth Israel Deaconess Medical CenterAssistant Professor Harvard Medical SchoolBoston, MA

  2. Melanoma : Epidemiology 2007 Incidence: 50,700/8100 deaths 3% of all cancers 1% of all cancer deaths 12 fold increase since 1935 Lifetime risk: 1 in 75 Americans 1 in 25 Australians 9th most common malignancy, but 2nd in terms of years of potential life lost

  3. Metastatic Melanoma: Natural History “Metastatic melanoma is a bad disease.” • Median age: 45-50 • Median Survival: 6-10 months • 5-year survival: < 5% Few if any effective therapies

  4. Proposed New AJCC Staging System: Stage IV Melanoma M Status Site Serum LDH

  5. Clinical trial results appear to be influenced as much by patient selection as by treatment approach Staging Factors: Importance

  6. Metastatic Melanoma – 2008 Approved Therapies (USA)Date • DTIC 1970’s • High Dose Interleukin-2 1998 Many patients will receive both agents

  7. Single Agent DTIC Activity* • Response Rate 19% • Median Response Duration 4 mos • Median Survival 6-9 mos • 6-year survival < 2% DTIC has never been compared to observation or best supportive care *Hill et al Cancer 53:1299; 1984 (n=580)

  8. There is currently no evidence that other single agents, combination chemotherapy or the addition of tamoxifen or IFN to DTIC is superior to DTIC alone Cytotoxic Chemotherapy:Status

  9. Melanoma Therapy Good News: Many options Bad News: Many lead nowhere. Melanoma lagging behind other cancers in translating basic research discoveries into new therapies Chekov: “When many treatment options are proposed, you know the disease is incurable.”

  10. Translating Scientific Advances into Improved Therapy – Current Opportunities • Immunotherapy • Targeted therapy • B-Raf inhibition (sorafenib/chemotherapy) • Antiangiogenic therapy (STA-4783) • Novel targets

  11. F G F R B-Raf* SOS GRB2 MEK ERK ELK MEK PI3K AKT ERK BCL2 P16 Cdk4 TOR ELK Apaf1 Cyclin D Molecular Alterations in Melanoma 15% 60-70% N-RAS* GTP RAS GDP C-RAF 25-50% PTEN x

  12. Rationale for Sorafenib in Melanoma • B-Raf mutations (mostly V600E) occur in >60% of melanomas1 • Sorafenib—multikinase inhibitor targeting Raf and RTKs2 • Induces apoptosis in B-Raf wild-type and mutant melanoma cell lines • Inhibits tumor angiogenesis • Phase II single agent trial showed minimal activity3 • Phase I/II trial of sorafenib in combination with carboplatin/paclitaxel4 • Well tolerated with full doses of carboplatin and paclitaxel • Antitumor activity • One CR, PR (26%), clinical benefit (85%) • Median PFS of >8 months • Phase III randomized trials with single agent DTIC • Indicate RRs (CR + PR) between 7% and 11%5,6 • Show median PFS of 1.6 months5 1. Hingorani SR et al. Cancer Res. 2003;63:5198-5202; 2. Karasarides M et al. Oncogene. 2004; 23:6292-6298; 3. Eisen T et al. Br J Cancer. 2006;95:581-586; 4. Adapted from: Flaherty KT. Presented at: TAT; March 16-18, 2006 ; Amsterdam, The Netherlands; 5. Bedikian AY et al. J Clin Oncol. 2006;24:4378-4745; 6. Chapman PB et al. J Clin Oncol. 1999;17:2745-2751.

  13. Key Chemotherapy Trials in Melanoma *Assessable for response (N=108 for Dartmouth and N=118 for DTIC). †All patients evaluated on an intent-to-treat basis. Adapted from Atkins MB et al. Presented at: ASCO Annual Meeting; May 31- June 3, 2003; Chicago, IL. Chapman PB et al. J Clin Oncol. 1999;17:2745-2751. Middleton MR et al. J Clin Oncol. 2000;18:158-166. Bedikian AY et al. J Clin Oncol. 2006;24:4738-4745.

  14. Taxane Activity in Melanoma 1. Wiernik PH et al. J Clin Oncol. 1987:5;1232-1239.; 2. Legha SS et al. Cancer. 1990:65; 2478-2481.; 3. Einzig AI et al. Invest New Drug. 1991:9;59-64.; 4. Zimpfer-Rechner C et al. Melanoma Res. 2003:13;531-536.; 5. Aamdal S et al. Eur J Cancer. 1994:30A;1061-1064.; 6. Bedikian AY et al. J Clin Oncol. 1995:13;2895-2896.; 7. Einzig AI et al. Med Oncol. 1996:13:111-117.; 8. Hodi FS et al. Am J Clin Oncol (CCT). 2002:25;283-286.

  15. Sorafenib: Clinical Trials • Completed • Industry – Randomized Phase III Taxol/Carbo ± sorafenib in DTIC/TMZ failures-PRISM Trial • Industry – Randomized Phase II of DTIC ± sorafenib-completed • Ongoing • TMZ + sorafenib (including pts with CNS mets) – U Penn + DF/HCC • E2603 – Phase III of Taxol/Carbo ± sorafenib Will promising single institution data translate into benefit for the general melanoma population?

  16. 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 Sorafenib in Melanoma: PRISMPhase III Paclitaxel + Carboplatin ± Sorafenib 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.

  17. Sorafenib in Melanoma: PRISM Phase III Trial Patient Demographics Data on file. Bayer HealthCare.

  18. Sorafenib in Melanoma: PRISM Phase III Trial Disease Characteristics AJCC=American Joint Committee on Cancer. Data on file. Bayer HealthCare.

  19. Placebo Censored Treatment for Placebo Sorafenib Censored Treatment for Sorafenib Sorafenib in Melanoma: PRISM Phase III PFS by Independent Review 1.00 0.75 Proportion of Patients Progression-Free 0.50 0.25 0 0 100 200 300 400 500 Days From Randomization CI=confidence interval. Agarwala SS, et al. Proc Am Soc Clin Oncol. 2007;25:474s. Abstract 8510.

  20. Sorafenib in Melanoma: PRISM Phase IIIGrade 3 or Higher AEs (5% Incidence in Either Treatment Arm) Data on file. Bayer HealthCare.

  21. 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 RANDOMIZATION (N=98) 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.

  22. Sorafenib in Melanoma: Randomized Phase II Sorafenib + DTIC Patient Demographics Data on file. Bayer HealthCare.

  23. Sorafenib in Melanoma: Randomized Phase II Sorafenib + DTIC Disease Characteristics Data on file. Bayer HealthCare.

  24. 1.00 0.75 0.50 0.25 0 0 100 200 300 400 500 600 Sorafenib in Melanoma: Randomized Phase II Sorafenib + DTIC PFS (Independent Assessment) Proportion of Patients Progression-Free Sorafenib + DTIC Placebo + DTIC Censored Treatment for SorafenibCensored Treatment for Placebo Days From Randomization Data on file. Bayer HealthCare.

  25. Sorafenib in Melanoma: Randomized Phase II Sorafenib + DTIC Response Rates 71%Clinical benefit 56%Clinical benefit Data on file. Bayer HealthCare.

  26. Sorafenib in Melanoma: Randomized Phase II Sorafenib + DTIC Grade 3 or Higher AEs (5% Incidence in Either Treatment Arm) *Platelets: Grade 4 – Placebo (2%) vs Sorafenib (18%).†Neutrophils: Grade 4 – Placebo (6%) vs Sorafenib (20%). Data on file. Bayer HealthCare.

  27. 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.

  28. Sorafenib in Melanoma: Conclusions • Single agent Sorafenib • Limited activity in advanced melanoma • Sorafenib in combination • With carboplatin/paclitaxel • Did not improve PFS in a second-line patient population that failed DTIC or TMZ • With DTIC • Encouraging results in chemo-naïve patients with advanced melanoma • Strong efficacy trend toward PFS and PFS rate at 6 months vs placebo and DTIC • Generally well tolerated with carboplatin/paclitaxel and DTIC • Utility of Sorafenib + carboplatin/paclitaxel in first-line, chemo-naïve, advanced melanoma patients remains an important question • A Phase III ECOG trial (E2603) evaluating carboplatin/paclitaxel ± sorafenib in front-line patients with advanced melanoma in progress

  29. Translating Scientific Advances into Improved Therapy: Current Opportunities • Immunotherapy • Targeted therapy • B-Raf inhibition (Sorafenib/chemotherapy) • Apoptosis induction (STA-4783) • Novel targets

  30. STA-4783 in Melanoma • Novel small molecule, administered intravenously • Triggers apoptosis as single agent and sensitizes cancer cells to agents that induce cell death through mitochondria pathway • Demonstrated anti-cancer efficacy in double-blind, randomized, controlled, 21-center Phase IIb trial in metastatic melanoma • Doubled median and 6-month PFS; met primary PFS endpoint (P=0.035) • Evidence of survival advantage • Well-tolerated, with favorable safety profile • Entering pivotal, confirmatory Phase III in metastatic melanoma

  31. STA-4783: MOA

  32. 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)

  33. Apoptosis-Inducing AgentsIncreasing Oxidative Stress States STA-4783: Hsp70 inducer Phase II trial in metastatic melanoma: paclitaxel + STA-4783 vs. paclitaxel alone Phase III trial in chemotherapy-naïve patients initiated; anticipated enrollment: 600. O’Day S, et al. Proc Am Soc Clin Oncol. 2007;25:479s. Abstract 8528.

  34. Kaplan-Meier PlotProgression-free Survival (ITT) O’Day S, et al. Proc Am Soc Clin Oncol. 2007;25:479s. Abstract 8528.

  35. New Potential Targets • PI3K • IL-8 • MUC18 • CREB-ATF1 • Folded WT p53 • ABCB5 • NEDD9 • Stat 3 • NFkb • Notch 1 • BCL2 • AKT- TOR • VEGF • MITF • GSK3 • iNos Chekov: “When many treatment targets are proposed, you know the disease is incurable.”

  36. Approach to Translational Research with Targeted Therapy • Identify relevant targets • Identify drugs that hit the target • Select the population that expresses the target • Validate that the target is actually “hit” • Assess the effect of hitting the target on other proteins and pathways and on tumor regression

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