CDC Recommendations for Skin Cancer Prevention. Systemic Therapy for Melanoma. Melanoma Incidence by Age and Gender: U.S.

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Jocelin Harvey
5 years ago
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Systemic Therapy for Melanoma Adil Daud M.D. UCSF 0.016 0.016 1:74 1:74 Lifetime Risk Risk Lifetime 0.014 0.014 0.012 0.012 1:100 1:100 0.010 0.

000 1935 1935 1960 1960 1980 1980 1985 1985 1993 1993 Melanoma Incidence by Age and Gender: U.S.

70 70 60 60 50 50 40 40 30 30 20 20 10 10 00 Male Male Female Female Under Under 65 65 Rigel DS, Carucci JA. CA Cancer J Clin. 2000;50:215 236.

Cancer Mortality Rates by State Economic Area Melanoma, White Males, 1970-94 CDC Recommendations for Skin Cancer Prevention Devesa SS et al.

1 Systemic Therapy for Melanoma Adil Daud M.D. UCSF :74 1:74 Lifetime Risk Risk Lifetime :100 1: :150 1: :250 1: :1500 1:1500 1:600 1: Melanoma Incidence by Age and Gender: U.S., Incidence Rate Rate (per (per 100,000) 100,000) Incidence Lifetime Risk of Developing Cutaneous Melanoma in the US Male Male Female Female Under Under Rigel DS, Carucci JA. CA Cancer J Clin. 2000;50: & & Over Over Ries LAG, et al, eds. SEER Cancer Statistics Review, Bethesda, MD: National Cancer Institute; 2003: Tables XVI-1 9. Cancer Mortality Rates by State Economic Area Melanoma, White Males, CDC Recommendations for Skin Cancer Prevention Devesa SS et al. Atlas of Cancer Mortality in the U.S., Washington, DC: US Govt Print Off; Avoid direct exposure to sunlight Wear a hat and protective clothing Wear sunglasses Use sunscreen Avoid sunlamps, tanning beds Perform frequent skin self examinations

Survival in Melanoma by Stage Proportion Surviving 1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.

1 0 1 2 3 4 5 6 7 8 Survival, years Stage I (n=9175) Stage II (n=5739) Stage III

Interferon α 2B Pegylated Interferon Vaccines GM CSF Chemotherapy Biochemotherapy

2001;19:3635-3648. 3648. Can vaccines actually harm patients with melanoma?

2 Survival in Melanoma by Stage Proportion Surviving Survival, years Stage I (n=9175) Stage II (n=5739) Stage III (n=1528) Stage IV (n=1158) Interferon Adjuvant Therapy Interferon α 2B Pegylated Interferon Vaccines GM CSF Chemotherapy Biochemotherapy Reproduced with permission from Balch CM, Buzaid AC, Soong SJ, et al. J Clin Oncol. 2001;19: Can vaccines actually harm patients with melanoma? EORTC Stage II melanoma (>1.5 mm) Randomized to GMK vaccine Vs observation 1314 patients Could have had SLN or not (50% each) Maybe vaccines can actually be deleterious?

GM CSF Cytokine widely used in BMT and chemotherapy related neutropenia Appears to increase DC function and immune activation in humans Phase II data in high risk melanoma in a single trial that it

3 GM CSF Cytokine widely used in BMT and chemotherapy related neutropenia Appears to increase DC function and immune activation in humans Phase II data in high risk melanoma in a single trial that it may reduce recurrence Proportion surviving Survival Curves: Overall Patient Population P<0.001 GM-CSF (n = 48) (median 37.5 mo) UAB controls (n = 48) (median 12.2 mo) Survival (mo) Spitler LE, et al. J Clin Oncol. 2000;18: Fig 1. Kaplan-Meier curves of (A) overall and (B) recurrence-free survival of the assessable cohort Fig 4. Effect of granulocyte macrophage colony-stimulating factor treatment on dendritic cells (DCs) in patients with low and high pretreatment levels of these cells Fig 5. Association between the effect of granulocyte macrophage colony-stimulating factor on dendritic cell (DC) and myeloid-derived suppressor cell (MDSC) subsets and clinical outcome Novel Therapies for metastatic Melanoma

Melanoma: Activity of commonly used regimens Some Targets in Melanoma Compound RR CNS Dacarbazine 7 %-15% No Temozolomide 10-15% + IL-2 17% ± Anti-CTLA4 10-15%? Biochemo 16%-45%?

Sorafenib Phase III Trial: PRISM Study Phase I trial as a single agent 1/37 responses Phase I in combination with paclitaxel/carboplatin 30% PR Randomized prospective 2 nd line melanoma 270 patients

4 Melanoma: Activity of commonly used regimens Some Targets in Melanoma Compound RR CNS Dacarbazine 7 %-15% No Temozolomide 10-15% + IL-2 17% ± Anti-CTLA %? Biochemo 16%-45%? Taxanes 5-15% No Gray-Schopfer Nature 445, ; Sorafenib Phase III Trial: PRISM Study Phase I trial as a single agent 1/37 responses Phase I in combination with paclitaxel/carboplatin 30% PR Randomized prospective 2 nd line melanoma 270 patients (PRISM) of Pac/carb+/ sorafenib Progressed on DTIC/TMZ No active brain metastases Measurable disease by RECIST ECOG PS 0 or 1 (N=270) Agarwala et al. Presented at ASCO 2007 R A N D O M I Z A T I O N Caboplatin AUC 6 IV Day 1 Paclitaxel 225 mg/m 2 IV Day 1 Sorafenib 400 mg PO BID Days 2-19 Caboplatin AUC 6 IV Day 1 Paclitaxel 225 mg/m2 IV Day 1 Placebo PO BID Days 2-19 Primary end point: PFS Secondary end points: TTP, ORR, Duration of response, OS BAY /11718 MELANOMA FIGURE 1 KAPLAN-MEIER CURVES FOR OVERALL SURVIVAL TIME MAY07 Survival Distribution Function Days From Randomization STRATA: treatment=placebo Censored treatment=placebo treatment=sorafenib Censored treatment=sorafenib

HDAC1 HDAC 2 HDAC3 HDAC8 IIA HDAC4 HDAC5

5 Reversing Drug Resistance Histone Deacetylase (HDAC) Inhibitors Classification of HDAC enzymes Class I Class II Class III Class IV Members HDAC1 HDAC 2 HDAC3 HDAC8 IIA HDAC4 HDAC5 HDAC7 HDAC9 IIB HDAC6 HDAC10 Sirtuins Sir2, SIR homologs HDAC11 Gallinari, et al, Cell Research17:195; 2007 VPA HDAC Pamela Munster and Doug Marchion Location Nuclear Ubiquitous Cytoplasmic Tissue specific Cytoplasmic Substrates Histones, Histones Histones Alpha Tubulin, Hsp90 Inhibitors Valproic acid Depsipeptide MGDC0103 Valproic acid Cytoplasmic/ mitochondrial Histones, Tubulin, p53, TAF Nicotinamides Nuclear Related to Rpd3 protein Depsipeptide MGDC0103

Immunotherapy in the Adjuvant Setting for Melanoma: What You Need to Know

Immunotherapy in the Adjuvant Setting for Melanoma: What You Need to Know Jeffrey Weber, MD, PhD Laura and Isaac Perlmutter Cancer Center NYU Langone Medical Center New York, New York What Is the Current