10.17.09 ~ 11.50 ~ Berman ~ Non-Surgicical Approaches to Non-Melanoma Skin Cancer

10.17.09 ~ 11.50 ~ Berman ~ Non-Surgicical Approaches to Non-Melanoma Skin Cancer

Info iconThis preview shows page 1. Sign up to view the full content.

View Full Document Right Arrow Icon
This is the end of the preview. Sign up to access the rest of the document.

Unformatted text preview: New Insights into NonNon-Surgical Approaches to NMSC & Actinic Keratoses Brian Berman, M.D., Ph.D. Disclosure of Relevant Relationships with Industry Brian Berman, M.D., Ph.D. 3M 3M 3M Graceway Graceway Doak Pharmaderm Pharmaderm Peplin Neutrogena Speaker - Honoraria Consultant – Dept. compensated Investigator – Dept. compensated Speaker - Honoraria Advisory Board - Honoraria Advisory Board - Honoraria Speaker - Honoraria Advisory Board - Honoraria Advisory Board – Honoraria Speaker - Honoraria Departments of Dermatology and Medicine U i it f Mi i S h l f M di i Medical Therapies - in 20 minutes Interferon Imiquimod 5-Fluorouracil Diclofenac PDT Field cancerization: lesions at different stages of NMSC may be found near each other Photo courtesy Eggert Stockfleth, MD. Interferon (Aminolevulinic acid, MAL) Future – Ingenol mebutate – Imiquimod 3.75% cycle therapy – GDC-0449 GDC- IL Interferon-2b for SCC Open Label Baseline 34 patients SCC Bowen’s Disease [27 Invasive, 7 In-situ] In] IL IFN-2b IFN(1.5 x 106 IU) TIW x 3 wks Histological cure at 21 wks Week 21 Edwards, Berman, Rapini, et al. Arch Derm 1992; 128:1486–1489. IL Interferon-2b for SCC Imiquimod Open Label 34 patients SCC Actinic Keratoses [27 Invasive, 7 In-situ] In] IL IFN-2b IFN(1.5 x 106 IU) TIW x 3 wks Histological cure at 21 wks Immune Modification by ADOPTIVE INNATE IMIQUIMOD B Cell IgG‐2A MIP‐1 MCP‐1 TNF‐α IL‐6 IFN‐γ IFN‐α IL‐12 TH1 Cell Activation A ti ti IFN‐γ IFN‐α IL‐12 Edwards, Berman, Rapini, et al. Arch Derm 1992; 128:1486–1489. APC / PDC Chemotaxis N IP‐10 MCP‐1 N N TLR-7 PMN Chemotaxis TNF‐α MIP‐1 IFN‐α IL‐12 IMIQUIMOD APC Activation IFN‐γ O NK Cell Activation Inhibit DC cytokine production and activation IL‐10 TGF‐ IL‐4, 5, 13 TH1 Cell Chemotaxis Produce immunosuppression by direct cell contact and by IL-10 and TGF-β secretion Inhibit CD4 T cell activation and proliferation mRNA N TH2 Cell 2-3% of human T cells in PBMC express FoxP3 transcription factor, express high CD25 (high affinity IL-2 receptor), CD39, CD73 and act as Regulatory T cells IL‐8 Antigen Presenting Cell: pDC MC B‐Cell DNA NF‐κB NF B Naïve T Cell T Regulatory Cells & SCC FoxP3+ Reg T Cell Imiquimod Reduces IL-10 & TGF-β Production By T Regulatory Cells FOXP3+ T regulatory cells isolated from in vivo untreated ( ) and imiquimod-treated ( ): Normal skin (NS) and SCC Surround SCC and other tumors and suppress immune responses leading to tolerance Effects of in vivo imiquimod treatment on SCC blood vessels, immunosurveillance cells and tumor regression • Blood vessels in SCC do not express E-selectin and contain few cutaneous lymphocyte antigen (CLA)+ (CLA) T cells needed f i ll d d for immunosurveillance ill • SCC treated with imiquimod showed induction of Eselectin, recruitment of CLA+ CD8+ T cells and evidence of tumor regression Clark et al, J. Ex. Med. 2008, 205 (10):2221-2234 Clark et al, J. Ex. Med. 2008, 205 (10):2221-223 Actinic Keratosis Long Term Follow-Up (Europe) Follow- In vivo Imiquimod Effects in Cutaneous SCC Stockfleth E, et al. Arch Dermatol. 2004;140:1542-1544 2004;140:1542- 3x per week x 12 weeks (n = 25 active / n = 11 vehicle) Study Arm Complete Clearance 50 – 75 % Imiquimod 84 % 92 % Vehicle 0% 0% Follow-up Analysis: Imiquimod-Treated patients FollowImiquimod 1 Year 8 % (2/25) 18 Months 16 % (4/25) 2 Years 20 % (5/25) No patients with development of SCC Vehicle-Treated - New actinic keratoses in 90 % of (9/10) VehicleHuang (Clark), J. Invest. Dermatol. June 2009 Clinical and histological outcomes with 1 year follow-up of AK treatment with 5% imiquimod, 5% 5-FU or cryotherapy C leared Cryotherapy n=25 – Cryospray treatment (-196 °C) in one session (20-40 seconds for each lesion) – If not cleared within 2 weeks after first cryotherapy a second session performed 16% 80 40 66% 68% H istol C linical 32% 0 Clinical H istol C linical H istol NPV 86% p<.01 60% 40% 33% 20% 4% 0% 5-5-FU(n=24) FU (n=24) NPV 47% Cryosurgery (n=25) C otherapy (n=25) ry Cryosurgery (n=25) p<.01 Out of all treated patients (including in the denominator also those not cleared at end of therapy) Krawtchenko et al. Br J Dermatol 2007;157(suppl. 2):34-40 MC, Randomized, PC Study Stable liver, kidney & heart recipients >3yrs 4-10 AKs /100cm2 Imiquimod 5% or Placebo Cream (2:1) TIW x 16 wks 100% Evaluations at 24 wks 100 No evidence of graft rejection Complete Clinic and cal Histological Clearance (%) Twelve months after end of treatment 73% NPV 70% 5-FU (n=24) p=.03 for histological and p=.03 for clinical Sustained Field Clearance Rates of AKs in All Patients P tie ts ( ae n 72% 20 Histol=histological; NPV=negative predictive value of the clinical clearance based on histology Krawtchenko et al. Br J Dermatol 2007;157(suppl. 2):34-40 Krawtchenko et al. Br J Dermatol 2007;157(suppl. 2):34-40 97% Imiquimod (n=26) Follow-up: 12-months after end of treatment (EOT) Im iquim (n= od 26) Imiquimod (n=26) 32% 34% 68% 84% Evaluation performed at “test of cure” (TOC) 4-8 wks after final treatment (EOT): 80% 28% 60 – 8 weeks after last imiquimod – 4 weeks after last 5-FU – 6 weeks after last cryosurgery N C ot leared 3% 100 P atients (% s 5-FU 5% cream n=24 – 2 times/day over 4 weeks / rest up to 1 week for acute inflammation Clinical and Histological Complete Clearance of AKs 75 patients with at least 5 typical, visible, and histologically proven AK lesions in one anatomical area of up to 50 cm2 of the head, neck or décolleté randomized to: Imiquimod 5% cream n=26 – 3 times/week for 4 weeks – Rest period of 4 weeks with evaluation of clearance after 8 weeks – If lesions remained after rest period the 4 week treatment was repeated 1 case of SCC development % Change from baseline Imiquimod: -100, -70, -73 Vehicle: +167, +63, +320 90 2/2 80 65% 70 60 62.1% 62 1% 3/20 50 18/2 9 42.9% 40 Im iquim d o P lacebo 3/7 30 20 0% 0% 0% 10 0% 0/2 0/10 0/2 0/14 0 L iver K ey idn H eart A LL Ulrich et al. Brit J Dermatol 2007,157 (Suppl 2), 25- 0.5% 5-FU OD x 1, 2 & 4 Wks Mean Percent AK Lesion Reduction Effect of a 1-Week Treatment with 0.5% Topical Fluorouracil After Cryosurgery on Occurrence of Actinic Keratosis at 6 months Cryosurgery + Topical 0.5% Fluorouracil 0 5% (n=72) Patients with total clearance (%) Jorizzo J, Stewart D, Bucko A, et al. Randomized trial evaluating a new 0.5% fluorouracil formulation demonstrates efficacy after 1-, 2-, or 4-week treatment in patients with actinic keratosis. Cutis. 2002;70:335339. Weiss J, Menter A, Hevia O, et al. Effective treatment of actinic keratosis with 0.5% fluorouracil cream for 1, 2 or 4 weeks Cutis 2002;70:22-29 Rationale for Use of NSAIDs in Treatment of AK1,2,3 Ultraviolet light NSAIDs—resulting in no in PGE2 or Bcl2 Epidermis X COX-2 expression Anti apoptosis Anti-apoptosis Bcl2 cPLA2 21 Cyrosurgery +Vehicle +Vehicle (n=70) (30) 30) 5 (7.7) 7.7) P Value <.001§ <.001§ †Using Wilcoxon rank sum test §Using the Mantel-Haenszel χ2 test Jorizzo, et al, Arch Dermatol July 2004 100% Clearance Rate 1 Year follow up Diclofenac treated AKs n=47 of 52 eligible >75% Clearance Rate PGE2 Dermis Hyperplasia and angiogenesis cPLA2=calcium-dependent phospholipase A2; PGE2=prostaglandin E2 1. Goldyne ME. Prostaglandins & Other Lipid Mediators. 2000;63:15-23. 2. Zhan H, Zheng H. Am J Clin Dermatol. 2007;8:195-200. 3. Merk HF. Int J Dermatol. 2007;46:12-18. 2. Masferrer JL, et al. Cancer Res. 2000;60:1306-1311. Bilateral Comparison Efficacy & Tolerability Diclofenac 3% Gel vs 5-FU 5% Cream Single-center, bilateral, open-label, evaluator-blind study (N=29) Patients with ≥3 AKs Diclofenac gel twice daily to a on each side of y face/scalp distributed randomly selected side symmetrically Start 5-FU 5% to contralateral side Day 62 Day 90 • % Lesion reduction: 98% with 5% 5-FU vs 89% with Diclofenac 3% Gel • 66% clearance rate: 100% with 5% 5-FU vs 93% with Diclofenac 3% Gel • Severe erythema: 83% with 5% 5-FU vs 27% with Diclofenac 3% Gel • Patient-reported symptoms: 22% with 5% 5-FU vs 11% with Smith SR, et al. J Drugs Dermatol. 2006;5:156-159 Diclofenac 3% Gel Nelson & Rigel, J Clin Aesth Dermatol 2: 20-25, 2009 Bilateral Comparison Efficacy & Tolerability Diclofenac 3% Gel vs 5-FU 5% Cream Day 90 of Diclofenac 3% G l Gel Treatment Day 28 of 5% 5-FU Treatment End of Treatment Comparison Smith SR, et al. J Drugs Dermatol. 2006;5:156-159 ALAALA-PDT Phase III Registration Protocol: Topical Photodynamic Therapy for Actinic Keratoses Phase III: ALA-PDT Efficacy Results Response (%) Targeted AK Lesions: Patient Response Rate at Week (Per Protocol) 100 90 80 70 60 50 40 30 20 10 0 n=76 * n=73 * n=149 12 * L-Pts with >75% AKs Cleared L-Pts with 100% AKs Cleared V-Pts with >75% AKs Cleared n=26 n=26 n=52 V-Pts with 100% AKs Cleared CC ALA-018 n=102 ALA-019 n=99 Pooled n=201 * = P < 0.001 PDT Vehicle Touma D, Yaar M, Whitehead S et al. A trial of short incubation, broad-area photodynamic therapy for broadfacial actinic keratoses and diffuse photodamage. Arch Dermatol 2004; 140: 33-40. 33- Representative patient receiving full-face application of Levulan fullKerastick 20% for 1 hour prior to BLU-U light treatment. BLU- Baseline 1 day 1 week 1 month Levulan (aminolevulinic acid HCl) 20% (aminolevulinic solution (Kerastick®) applied to individual ( (Kerastick®) pp ) actinic keratoses for 14-18 hours followed 14by 10 J/cm2 of BLU-U® blue light delivered at BLU10 mW/cm2 in the treatment of multiple actinic keratoses of the face and scalp A trial of short incubation, broad-area photodynamic broadtherapy for facial actinic keratoses and diffuse photodamage. photodamage. Touma D, Yaar M, Whitehead S et al. Arch Dermatol 2004; 140: 33-40. 33 18 pts with photodamage & >4 AKs Levulan 20% via Kerastick applied to full face for 1, 2 or 3 hrs BLU-U BLU F/U light to10 J/cm² (16 min 40 sec) (16 sec) 1 day, 1 week, 1 month, 5 months Touma D, Yaar M, Whitehead S et al. A trial of short incubation, broad-area photodynamic broadtherapy for facial actinic keratoses and diffuse photodamage. Arch Dermatol 2004; 140: 333340. Representative patient receiving full-face application of Levulan fullKerastick 20% for 1 hour prior to BLU-U light treatment. BLU- baseline 1 day 1 month Short Incubation ALA-PDT ALAAverage AK reduction as a function of ALA incubation time Touma D, Yaar M, Whitehead S et al. A trial of short incubation, broad-area photodynamic therapy for facial actinic keratoses and diffuse photodamage. Arch Dermatol 2004; 140: 3340. Average # of AKs - With 1, 2, or 3 hr Incubation 8.0 Average # of AKs 7.0 6.0 5.0 4.0 3.0 2.0 79.2% 94.3% 1.0 90.3% 0.0 1 2 3 Incubation Intervals ( hrs) Aks Baseline BL 1 month Comparison of Levulan® & Metvix / Metvixia® For PDT of Actinic Keratoses MAL-PDT vs Vehicle Cream vs 5%-FU vs Cryotherapy for Bowen’s Disease Levulan® Metvix®/Metvixia® API Aminolevulinic acid HCl Aminolevulinic acid methyl ester Formulation Alcohol / water solution Peanut oil base ointment Strength 20% Actinic Keratosis (US) Actinic Keratosis (US, EU) BCC (EU) AK Lesion Preparation None Curetting Blue light (BLU-U®) 16.8% Approved Indications Red Light (LED) Light Activation by Efficacy (% Lesion Clearance) Safety Concerns Incubation Time Stability Price 80-90% Photosensitivity Dermatitis 14 – 18 hours label 1 hour recent articles 3 hours under occlusion 3 years at room temperature 1 year under refrigeration $104 (US) ~ 300 Euros, US pricing not known Enhanced reactivity to BCC antigen after PDT treatment of BCC CD8+ lymphocytes from 21 patients before and after BCC treatment with PDT Stimulated in vitro to HIP1, a BCC-associated tumor antigen Detected level of interferon gamma (IFN-) produced 17 / 21 patients had greater IFN- after PDT 15 / 17 > 2-fold increase Greater increase in IFN- if treated a greater area or a sBCC Kabingu E et al. Clin Cancer Res. 15:4460, 2009 Placebo-controlled, multicenter, randomized trial Compared MAL-PDT (160 mg/g; n = 96) or matching placebo cream (n = 17) with cryotherapy (n = 82), or 5-Fluorouracil (5% cream; n = 30) for treatment of BD. At 12 months, the estimated sustained lesion complete response rate with MAL-PDT was superior to that with – cryotherapy (80% vs. 67%; odds ratio, 1.77; 95% confidence interval, 1.01-3.12; P = .047) – fluorouracil (80% vs. 69%; odds ratio, 1.64; 95% confidence interval, 0.78-3.45; P = .19) 80-90% Photosensitivity 24-48 hours s/p Tx Aks Month 1 Touma et al Arch Dermatol 2004; 140: 33-40 Cosmetic outcome at 3 months was good or excellent in 94% of patients treated with MAL- PDT vs. 66% with cryotherapy and 76% with fluorouracil, and was Morton et al. Arch Dermatol. 142:729-35, maintained at 12 months 2006 Ingenol Mebutate (PEP005) Potential New Treatment for Actinic Keratosis Ingenol Mebutate (PEP005) Mechanisms of Action Euphorbia peplus European origin; Common plant; petty spurge, radium weed or milkweed Early 1800’s sap used topically to treat: – Warts – Corns – Waxy growths – Skin cancers Effective home remedy to treat skin cancers (1) 1) Australasian Journal of Dermatology, 1988 Dual mode of action Rapid removal of tumor (necrosis) and prevention of tumor relapse (immune response) – Local necrosis(1) Disruption of mitochondrial membrane f mitochondrial breakdown Cytotoxicity (necrosis) – Activation of immune system(2) Activation of adhesion molecules (e.g., Eselectin)(3) Recruitment of neutrophils (e.g., IL-8) Production of tumor-specific antibodies 1) Cancer Research 64: 2833-2899, 2004 2) J Immunol. 177: 8123-8132, 2006 3) Cancer Immunol. Immunother. 57: 1241-1251, 2008 AK Phase IIb (PEP005-015): Study Design Patient #003-002; 0.015% 3 day Randomized, multi-center, double-blind, vehiclemultidoublevehiclecontrolled, patientcontrolled, patient-applied, field-treatment field 265 pts 4-8 AKs Head (face 77% and scalp 23%) (face in a 25 cm2 area Design 6 active arms: 0.005%, 0.010% or 0.015% PEP005 for 2 or 3 days of treatment vs. vehicle for 2 or 3 days vs. Day 57 Baseline Concentration # ITT(1) Pt Group # ITT(1) Pt Vehicle 0.005% 0.01% 0.015% Endpoints Group 2 day Rx 2 day Rx 2 day Rx 2 day Rx 33 33 34 33 3 day Rx 3 day Rx 3 day Rx 3 day Rx 33 33 34 32 Primary: Complete clearance rate at day 57 Secondary: Partial clearance rate (clearance of >75% AK lesions (clearance 1) ITT = Intent to Treat within the area) PEP005-015 AK Clearance (3-Day) 3 Day Clearance Rates - Intent to Treat Day 4 Day 15 Day 8 AK Phase IIb Study (PEP005-015): Safety Composite Local Skin Response 80.0 70.0 12.0 60.0 2D Vehicle 50.0 2D 0.005% 10.0 2D 0.010% 40.0 2D 0.015% Mean Compo osite LSR 30.0 20.0 10.0 10 0 0.0 Day 29 Vehicle Low Complete clearance High strength data (0.015% x 3 days) Complete clearance rate Partial clearance rate Median % reduction* *Calculated within per protocol population, not ITT Active N=32 50.0% 71.9% 84.5% Medium High ≥75% clearance Vehicle N=33 9.0% 12.1% 0.0% P-value <0.001 <0.001 n/a 3D Vehicle 8.0 3D 0.005% 3D 0.010% 6.0 3D 0.015% 4.0 2.0 0.0 Day 1 4 8 15 29 Days 57 Ingenol mebutate Summary Next Generation Imiquimod for AKs Goals To date, approximately 1150 patients have been treated with ingenol mebutate gel in clinical trials Expand treatment area – Full face or scalp; > 25 cm2 Shorten treatment regimen – 4 or 6 weeks Simplify dosing regimen – Once daily Enhance tolerability of daily dosing – decrease concentration Maintain efficacy – 750 AK patients, 165 with NMSC, 240 healthy volunteers A favourable tolerability profile – Localized erythema flaking or scaling crusting erythema, scaling, crusting, vesicles and swelling – Peak in 3–8 days and resolve in 2–4 weeks – No long-term sequelae Competitive efficacy following 2–3 applications – Statistically significant benefit in traditionally difficult-totreat anatomical locations (arms, back of hand and chest) Imiquimod 2.5% & 3.75% daily cycle therapy Complete Clearance: Scalp Imiquimod 3.75% 2-2-2 wk cycle 2 pairs of identical studies - 969 pts 5-20 AKs full face / scalp – Each pair evaluated a different treatment regimen – Each study tested 2 investigational concentrations 2.5% and 3.75% Cycle 1 Placebo N = 159 2.5% 2 5% N = 160 3.75% N = 160 No Treatment Period 2 weeks 2 weeks 2 weeks No Treatment Period Cycle 1 Placebo N = 164 2.5% N = 164 3.75% N = 162 Cycle 2 3 weeks Cycle 2 3 weeks 3 weeks Week 0 Week 2 Week 4 Week 6 Week 14 • Final evaluation 8 weeks following final treatment Swanson N, et al. 12th World Congress on Cancers of the Skin; May 3-6, 2009; Tel-Aviv, Israel; poster. 3Tel- Subclinical Lesions Revealed & Treated Lesion Count n 30 3.75% Median lesion count 2x2x2 N = 160 AK Lesion Reduction (Median %): Pooled Data1 Study 3.75% Imiquimod 2.5% Imiquimod Placebo Pooled 2-week 81.8* 71.8* 25.0 Pooled 3-week 80.0* 66.7* 23.6 20 10 Baseline lesion count (10.6) dosing dosing 0 0 2 4 6 8 10 12 14 Study Week 85% of patients had subclinical lesions revealed •In a previous study of 5% imiquimod 2x/week for 16 weeks, the median percent reduction in AK lesions was 83.3%3 *Statistically significant from placebo 1. Swanson N, et al. 12th World Congress on Cancers of the Skin; May 3-6, 2009; Tel-Aviv, Israel; poster. 3Tel3. Lebwohl M, et al. J Am Acad Dermatol. 2004;50:714-721. Dermatol. 2004;50:714- 3.75% Imiquimod: 2-Week Cycle Regimen vs 3-Week Cycle Regimen Hedgehog Pathway & GDC-0449 in BCC Study Parameters Efficacy 90% Safety 80% 70% 60% 3.75% 2-week 3.75% 3-week 50% 40% 30% GLI1 mRNA 20% 10% 0% Complete Clearance Partial Clearance Lesion Reduction (Median) Tx-Related AEs Unscheduled Rest Periods Nl BCC Nl Mal Met Local Skin Lung BCC Cohort Inhibition of the Hedgehog Pathway in Advanced Basal Cell Carcinoma Oral GDC-0449 Treatment of Locally Aggressive BCC Before 60 yo male BCNS Before 41 yo female 5 month s 2 month s Von Hoff et al, N Engl J Med 2009;361 Von Hoff et al, N Engl J Med 2009;361 33 patients with metastatic or locally advanced basal cell carcinoma Received oral GDC-0449 daily at 150 (n=17), 270 (n=15) or 540 (n=1) mg per day Median duration of 9.8 months Tumor response assessed using Response Evaluation Criteria in Solid Tumors i T imaging & / or physical examination i h i l i ti 18 / 33 had an objective response: 2 complete response and 16 had a partial response 11 / 33 had stable disease 4 / 33 had progressive disease 8 grade 3 adverse events possibly related to the study drug in 6 patients; 1 withdrew Hedgehog signaling evident in tumors that responded to the treatment Von Hoff et al, N Engl J Med 2009;361 ...
View Full Document

This note was uploaded on 02/23/2010 for the course ENGLISH 1011 taught by Professor Thompson during the Spring '07 term at Berkeley.

Ask a homework question - tutors are online