Aktuelle Daten in der Therapie des Melanoms ein Update. ao.univ.-prof.dr. Georg Weinlich Univ.-Hautklinik Innsbruck

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1 Aktuelle Daten in der Therapie des Melanoms ein Update ao.univ.-prof.dr. Georg Weinlich Univ.-Hautklinik Innsbruck DONKO Wien 29. November 2013

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3 Monochemotherapie bei Melanom Medication Dose Response rate Dacarbazine Ringborg 1989, Middleton ;74 Chiarion Sileni, 2001, Young ; mg/m 2 i.v. daily for 5 days every 3-4 weeks mg/m 2 i.v. daily on one day every 3-4 weeks % % Temozolomide Bleehen 1995, Middleton ; mg/m 2 p.o. daily for 5 days every 4 weeks % Fotemustine Jacquillat 1990, Mornex ; mg/m 2 i.v. on days 1, 8 and 15; then 5 week pause, then repeat single dose every 3 weeks % Vindesine Nelimark 1983, Carmichael ;81 Interferon-α* Robinson 1986, Miller ;83 3 mg/m 2 i.v. every 14 day % 9-18 million IU/m 2 s.c. 3 x weekly (13-25 %) Interleukin-2* Dorval 1992, Legha 1996, Atkins ,000 IU/kg as 15 min. infusion i.v. every 8 hours for 5 days (total of 14 doses). Repeat every 2 weeks. ( %) Quelle: Diagnosis and Treatment of Melanoma. European Consensus-based Interdisciplinary Guideline, C.Garbe et al. - On behalf of the European Dermatology Forum (EDF), the European Association of Dermato-Oncology (EADO) and the European Organization for Research and Treatment of Cancer (EORTC) 07/2008

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5 Aktuelle Studien zur Melanomtherapie in Österreich Update 2013 K. Harmankaya, N. Schicher, C. Höller State of the Art SD

6 BRAF- Inhibitor

7 Wirkprinzip von Zelboraf bei Patienten mit BRAF-V600E-Mutation (ca. 40%)

8 Gesamtüberleben (%) Gesamtüberleben Chapman PB et al., ASCO Dacarbazin (n=338) Vemurafenib (n=337) Hazardrate 0.70 (95% CI: ) p< Monate PFS: 1,6 mo / 6,9 mo Vemurafenib = BRAF-Hemmer Hazardrate 0.38 Dacarbazin = Chemotherapie (95% CI: ) p<0.001

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10 An update on BREAK-3, a phase III, randomized trial: Dabrafenib (DAB) versus dacarbazine (DTIC) in patients with BRAF V600-E-positive mutation metastatic melanoma (MM). # 9013 Axel Hauschild et al. PFS: 6.9 mo OS: bei Weitergabe trotz Progress (bei 20% der Pat.)18.2 mo 25 Jun Dec 2012 OS # Deaths Median [95% CI] HR [95% CI] Dabrafenib DTIC Dabrafenib DTIC 55/187 (29%) NR [NR, NR] 0.75 [0.44, 1.29] 21/63 (33%) NR [11.3, NR] 78/187 (42%) 18.2 [16.6, NR] 0.76 [0.48, 1.21] 28/63 (44%) 15.6 [12.7, NR]

11 An update on BREAK-3, a phase III, randomized trial: Dabrafenib (DAB) versus dacarbazine (DTIC) in patients with BRAF V600-E-positive mutation metastatic melanoma (MM). # 9013 Axel Hauschild et al. PFS: 6.9 mo OS: bei Weitergabe trotz Progress (bei 20% der Pat.)18.2 mo 25 Jun Dec 2012 OS # Deaths Median [95% CI] HR [95% CI] Dabrafenib DTIC Dabrafenib DTIC 55/187 (29%) NR [NR, NR] 0.75 [0.44, 1.29] 21/63 (33%) NR [11.3, NR] 78/187 (42%) 18.2 [16.6, NR] 0.76 [0.48, 1.21] 28/63 (44%) 15.6 Crossover! [12.7, NR]

12 Kombination von BRAF- und MEK-Hemmer RAS RTK BRAF MEK BRAF-Hemmer MEK-Hemmer ERK Tumorzellwachstum

13 Dabrafenib (BRAF) in combination with Trametinib (MEK)

14 Preliminary results from a phase Ib/II, open-label, dose-escalation study of the oral BRAF inhibitor LGX818 in combination with the oral MEK1/2 inhibitor MEK162 in BRAF V600-dependent advanced solid tumors. solid tumors. # 9029 Richard Kefford et al. A complete response was observed in 1/7 (14%) BRAFi-naive melanoma patients and partial responses were observed in 5/7 (71%) BRAFi-naive melanoma patients, 2/9 (22%) BRAFi-pretreated melanoma patients BRAF inhibitor (BRAFi) dabrafenib in combination with the MEK1/2 inhibitor (MEKi) trametinib in BRAFi-naive and BRAFi-resistant patients (pts) with BRAF mutation-positive metastatic melanoma (MM). # 9005 Jeffrey Alan Sosman et al. BRAFi resistant BRAFi naive Cohort Part B Part C Part B Part C Treatment group PFS, median, months 150/2 combination N=26 Mono X-over 150/2 combination N=43 150/2 combination N= ORR, % 15% 9% 63% 76% 150/2 combination N=54

15 Dabrafenib Tafinlar (BRAF) und Trametinib - Mekinist (MEK) wurde 06 / 2013 von FDA zugelassen

16 BRAF-Inhibitoren bei Patienten mit Hirnmetastasen Response rate to vemurafenib in BRAF-positive melanoma brain metastases. # 9081 Marcin Radoslaw Dzienis et al. Vemurafenib (VEM) in patients (pts) with BRAF-mutant melanoma and brain metastases (mets). # 9060 James J. Harding et al. Conclusions: Vemurafenib resulted in 50% CNS response rate. Prospective comparison to dabrafenib may be warranted. Vemurafenib in metastatic melanoma patients with brain metastases: An open-label, single-arm, phase 2, multicenter study Kefford Richard et al. 10th International Meeting of the Society for Melanoma Research

17 Median PFS 3,7/4,0 months, median OS in both groups 6,5 months

18 BRAF-Inhibitoren bei Patienten mit Hirnmetastasen Dabrafenib in patients with Val600Glu or Val600Lys BRAF-mutant melanoma metastatic to the brain (BREAK-MB): a multicentre, openlabel, phase 2 trial. Georgina V Long et al., The Lancet Oncology, Volume 13, Issue 11, Pages , November 2012 Ansprechrate (mit oder ohne Vorbehandlung): ca. 40% OS: 32 Wo. (Verdoppelung)

19 CTLA-4 - Antikörper

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22 Immun-Checkpoint Regulatoren Programed Death

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24 Survival and long-term follow-up of safety and response in patients with advanced melanoma in a phase I trial of nivolumab (anti-pd-1; BMS ; ONO-4538) # CRA9006 Mario Sznol et al. Clinical efficacy and safety of lambrolizumab (MK-3475, Anti-PD-1 monoclonal antibody) in patients with advanced melanoma. # 9009 Antoni Ribas et al.

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26 Nivolumab: ORR 31%, Median OS 16,8 mo, OS rate 24 mo: 44%!

27 Clinical activity, safty, and biomarkers of MPDL3280A, an engineered PD-L1 antibody in Patients with locally advanced or metastatic melanoma (mm). # 9010 Omid Hamid et al. Besonderheit: Kutane Melanome, SH-Melanome, Okuläre Melanome Objektives Ansprechen bei 29% aller Patienten (PD-L1 statusabhängig) Keinerlei Ansprechen bei okulären Melanomen NW: G 3/4 in 33% 9% Hyperglykämie (PD-L1 auf Inselzellen exprimiert?) Keine Pneumonitis wie bei PD1-Ak

28 Safty and clinical activity of nivolumab (anti-pd-1, BMS , ONO-4538) in combination with ipilimumab in patients (pts) with advanced melanoma (MEL). # 9012 Jedd D. Wolchock et al. An open-label, randomized, phase II study of nivolumab (anti-pd-1, BMS , ONO-4538) given sequentially with ipilimumab in patients (pts) with advanced or metastatic melanoma (MEL). # TPS9107 F. Stephen Hodi et al.

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30 Sequential treatment with ipilimumab and BRAF inhibitors in patients with metastatic melanoma: Data from the Italian cohort of ipilimumab expanded access programme (EAP). Paolo Antonio Ascierto et al. # 9035 CA : A single-arm, open-label phase II study of vemurafenib followed by ipilimumab in patients with BRAF V600-mutated advanced melanoma (AM). F. Stephen Hodi et al. # TPS9103 Conclusions: These preliminary results suggest that, in BRAF-mutated pts, to start the sequential treatment with ipilimumab can provide a better survival than the reverse sequence.

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