SAMO Swiss Academy of Multidisciplinary Oncology Masterclass, Saturday, September 19th, 2015, Bern

Transkript

1 SAMO Swiss Academy of Multidisciplinary Oncology Masterclass, Saturday, September 19th, 2015, Bern Dr. med. Simone M. Goldinger FMH Dermatologie und Venerologie FMH Pharmazeutische Medizin UniversitätsSpital Zürich

2 Overview Key issues on the diagnosis and treatment: Melanoma with mutations Melanoma wildtype Targeted Therapy Immunotherapy Clinical Trials

3 Disclosures Dr. Goldinger Advisory Board Participation at Roche, Novartis, BMS, MSD Research funding from University Hospital of Zurich Fellowship funding from Paul Janssen / SAKK Travel support by Roche, Novartis, BMS, MSD

4 Q 1: Which statement about sentinel node biopsy is correct? 1. Sentinel node biopsies should be offered in every surgical department 2. Sentinel node biopsy has an impact of the long term survival of the patient 3. Sentinel node biopsy is indicated in a patient with a ulcerated pt1b; tumor thickness 0,5 mm 4. Sentinel node biopsy is indicated in a young patient with a tumor thickness of 0,8 mm with a mitotic activity (pt1b) 4

5 Q 2: Which treatment is mainly indicated in a metastatic melanoma patient Stage IV, BRAF mut? 1. Irradiation therapy 2. Pegylated interferon 3. Treatment with BRAF- and MEK- inhibitors 4. Treatment with BRAF-inhibitor alone 5. Therapy with Dacarbazine 6. Therapy with Ipilimumab and/or Anti-PD-1 antibodies 7. None of the above

6 Suspicious Lesions: ABCD Rule A = Asymmetry B = Border Irregularities C = Color D = Dynamics (or evolution):

7 Ugly Duckling sign

8 Dermoscopy

9 Total body photography

10 Self-inspection

11 10 Year- Survival of Melanoma patients Survivalin % Thin primary tumors Thick primary tumors Lymph node metastases distant metastases Months Häffner et al., Br J Cancer 1992

12 Melanoma Breslow tumor thickness < 0.76mm: 100% 5y survival Breslow tumor thickness > 3mm: 50% 5y survival

13 Melanoma: Treatment of localized disease Wide excision of primary tumors: 0.5 cm for in situ melanomas 1 cm for tumors with thickness of up to 2 mm 2 cm for thicker tumors (> 2mm) Sentinel lymphnode dissection: primary tumors with Breslow tumor thickness >1 mm (and/or >0.75 mm with additional risk factors such as ulceration or mitotic rate (pt1b)) Lymphnode dissection: Should be discussed with patient if SLN is positive? Adjuvant treatment: peg-interferon in ulcerated primaries with micromet clinical trial Thompson JF et al. Cutaneous melanoma. Lancet 2005; 365: Han D et al. Clinicopathologic predictors of SLN metastasis in thin melanoma. J Clin Oncol 2013; 31: Morton DL et al. Sentinel-node biopsy or nodalobservation in melanoma. N Engl J Med 2006; 355: Eggermont AM et al. Long-term results of the randomized phase III trial EORTC J Clin Oncol 2012; 30:

14 The melanomas?

15 2011

16 Epithelium associated Site High UV Low UV Glabro us Mucos a Subtype Desmopl. melanoma CS D Non-CSD melanom a Spitzoid melanom a Acral melanom a Mucosal melanom a Mutational Processes 100 Age 50 Mutations Rearrangements Bastian BC Annu Rev Pathol. 2014

17 Landscape of oncogenic driver mutations

18 Melanoma: Treatment locoregional disease Surgery Radiotherapy: cave no impact on PFS or OS Electrochemotherapy Intralesional Therapy: replicating herpes virus T-Vec Isolated limb perfusion Burmeister BH et al. Adjuvant RT vs. Obs alone after lymphadenectomy for melanoma. Lancet Oncol 2012; 13: Hong A et al. Role of radiation therapy in cutaneous melanoma. Cancer J 2012; 18: Campana LG et al. Treatment of metastatic melanoma with electrochemotherapy. J Surg Oncol 2014; 109: Andtbacka RH et al. T-Vec improves durable RR in pts with advanced melanoma. J Clin Oncol 2015 [Epub ahead of print].

19 Catharanthus roseus

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21 Treatment options for advanced melanoma Immunotherapy Targeted Therapy Chemotherapy Radiotherapy

22 Registered in CH Pipeline Outlook Vemurafenib (Zelboraf ) Encorafenib Combinations: how? Dabrafenib (Tafinlar ) Trametinib Adjuvant treatment? Cobimetinib (Cotellic )* Binimetinib Brain metastasis? Selumetinib Schedules? Ipilimumab (Yervoy ) Nivolumab Combination? Pembrolizumab (Keytruda )** Indication? * Swissmedic approval on Aug 27th, 2015 ** Swissmedic approval on Sept 11th, 2015

23 Treatment Indication Interdisciplinary Tumorboard Dermatooncologists Plastic surgeons Radiooncologists Oncologists Researchers Pschooncologists ENTs Pathologists

24 EWS-ATF1 MITF ETR GNAQ/11* GNAQ/11 mutation: ~50% ocular mels Nucleus EWS-ATF1 transl: clear cell sarcoma MITF amp: ~30-40% mels NRAS mutation: ~20% of cut mels BRAF mutation: 50-60% of cut mels TFs Salirasib NF-1 NRAS* BRAF* MEK1/2 ERK1/2 RTK* KIT mutation/amp: ~40% acral, muc mels Vemurafenib Dabrafenib Encorafenib Trametinib Cobimetinib Binimetinib Selumetinib Imatinib Sunitinib Nilotinib PI3-K AKT* PTEN* AKT3 activation/amp: ~60% mels Survival vs. apoptosis PTEN mutation: ~10% mels

25 Vemurafenib BRAF Inhibition: Comparison Day 0 Day 17 URB, Female, 1948

26 WBRT Vemurafenib 3 months

27 RR & PFS in BRAFmut Metastatic Melanoma Inhibitor CR+ PR% median PFS Reference Vemurafenib (phase III) Chapman et al., New Engl J Med 2011 Dabrafenib (phase III) Hauschild et al., Lancet 2012 Trametinib (phase III) Flaherty et al., New Engl J Med 2012 Binimetinib (phase II) * Ascierto et al., Lancet Oncol 2013 Combos Vemurafenib + Cobimetinib vs Vemurafenib (phase III) Larkin et al., New Engl J Med 2014 Dabrafenib + Trametinib Flaherty et al., New Engl J Med 2012 Dabrafenib+Trametinib vs D Long G. et al., New Engl J Med 2014 Dabrafenib+Trametinib vs V Robert et al., New Engl J Med 2014 DTIC + Selumetinib (phase II) Robert et al., Lancet Oncol 2013 * Some patients pretreated with BRAF inhibitor.

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29 EWS-ATF1 MITF ETR GNAQ/11* GNAQ/11 mutation: ~50% ocular mels Nucleus EWS-ATF1 transl: clear cell sarcoma MITF amp: ~30-40% mels CDK NRAS mutation: ~20% of cut mels BRAF mutation: 50-60% of cut mels TFs Salirasib NF-1 NRAS* BRAF* MEK1/2 ERK1/2 RTK* KIT mutation/amp: ~40% acral, muc mels Vemurafenib Dabrafenib Encorafenib Trametinib Cobimetinib Binimetinib Selumetinib Imatinib Sunitinib Nilotinib PI3-K AKT* PTEN* AKT3 activation/amp: ~60% mels Survival vs. apoptosis PTEN mutation: ~10% mels

30 1st biopsy LOGIC II: A Phase II rational combination study Primary endpoint: ORR BRAF V600 melanoma LGX818 + MEK Relapse/ PD BRAF V600 melanoma LGX818 + MEK + PI3Ki BKM120 Biopsy 2nd biopsy Biopsy + FGFRi BGJ398 Define mechanism of resistance at relapse Analyze select panel of genes within 15 days + cmeti INC280 + CDK4i LEE001

31 The cancer immunity cycle T Vec Other intralesional? Release of tumour-specific antigens Killing of tumour cells 1 Tumour-specific 2 antigen presentation 7 Priming and 3 activation of T cells Pembrolizumab Nivolumab Recognition of tumour cells by T cells Ipilimumab 6 Trafficking of 4 T cells to tumours 5 Infiltration of T cells into tumours Adapted from Chen DS, Mellman I. Immunity 2013;39:1 10;and Raaijmakers et al. Immunobiology 2014

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33 Primary Endpoint: Overall Survival Patients Surviving (%) Patients at Risk 210 Nivolumab208 Dacarbazine HR 0.42 (99.79% CI, ; P < ) (Boundary for statistical significance ) NR=not reached. Based on 5 August 2014 database lock Months yr OS 73% 1-yr OS 42% 8 3 Nivolumab (N=210) Dacarbazine (N=208) Follow-up since randomization: months

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36 RR & PFS Immunotherapy in Met Melanoma Inhibitor CR+ PR% median OS Reference Ipilimumab (phase III) Hodi et al, New Engl J Med 2010 Ipi vs. DTIC (phase III) Robert et al, New Engl J Med 2011 Pembrolizumab (phase I) Hamid et al, New Engl J Med 2013 Pembro (Ipi refract) (ph I) 26 N/A Robert et al, Lancet 2014 Pembro vs. Chemo (Ipi refract) (phase II) 38 N/A Ribas et al, Lancet Oncol 2015 Pembro vs. Ipi (phase III) 32.9 N/A Robert et al, New Engl J Med 2015 Nivolumab (phase I) 28 N/A Topalian et al, J Clin Oncol 2014 Nivo (Ipi refract) (phase I) 25 N/A Weber et al, Lancet Oncol 2015 Nivo in untreated pts (ph III) 40 NR Robert et al, New Engl J Med 2015 Combos median PFS Ipi + Nivo (phase I) 53 NA Wolchok et al, New Engl J Med 2013 Ipi + Nivo vs. Ipi (phase II) 61 NR Postow et al. New Engl J Med 2015 Ipi + Nivo vs. Nivo vs. Ipi (phase III) 57.7 vs vs. 6.9 Larkin et al, New Engl J Med 2015

37 Timepoint of Occurence Goldinger SM, Romano E, Michielin O, Dummer R. Management und Beurteilung des Ansprechens von Ipilimumab bei Patienten mit Melanom. Swiss Med Forum 2012;12(44):

38 Vitiligo like depigmentation- frequent during anti PD1 therapy

39 Toxic epidermal Nekrolysis (Lyell)

40 Melanoma treatment 2015 Zurich/Switzerland Stage II T(2-4)b N0M0 EORTC Phase III, randomisiert: pegyliertes Interferon-alpha 2b (Cylatron) 3mcg/kg subkutan für 2 Jahre versus Beobachtung bei primär ulzeriertem Melanom Stage III A (komplett reseziert) Interferon (keine Studie) Pegyliertes Interferon-alpha 2b (Cylatron ) 1x/Woche s.c. oder Interferon-alpha 2b (Intron A ) 3x/Woche s.c. nach Erhalt der Kostengutsprache für mindestens 1 Jahr Stage III B/C or Stage IV (completey resected) CA Studie: Ipilimumab vs. Nivolumab Adjuvante Studie für komplett reseziertes Melanom Stadium IIIB/C oder IV zur Untersuchung der Immuntherapie Ipilimumab vs. Nivolumab Voraussichtlich Mai 2015 offen Stage III B/C or Stage IV (not resected ) Stage IIIc (inoperable), Stage IV (distant metastases) Amgen : Neoadjuvant T-VEC + Operation vs. Operation Adjuvante Studie für Melanompatienten im Stadium IIIB IV M1a mit resezierbaren Metastasen Amgen Offene Phase 1b/2-Studie zu T-VEC mit MK-3475 zur Behandlung des Melanoms im Stadium IIIB bis IVM1c (adjuvante RT, Immuntherapie und IFN erlaubt)

41 Metastatic Melanoma treatment 2015 Stage IV 1 st Line BRAF indip +Hautläsion Keine Läsion BRAF wt BRAF mut +Biopsie Amgen Offene Phase 1b/2-Studie zu T-VEC mit MK-3475 zur Behandlung des Melanoms im Stadium IIIB bis IVM1c (adjuvante RT, Immuntherapie und IFN erlaubt) Ipilimumab (keine Studie) Über die Krankenkasse beantragte Behandlung mit Ipilimumab (Yervoy ) 3mg/kg iv alle 3 Wochen für insgesamt 4 Infusionen CLGX818X2109 LOGIC 2 Trial Eine multizentrische, unverblindete Phase-II-Studie zur sequentiellen LGX818/MEK162- Kombination, gefolgt von einer rationalen Kombination mit zielgerichteten Wirkstoffen nach der Progression zur Überwindung der Resistenz bei erwachsenen Patienten mit lokal fortgeschrittenem oder metastasiertem Melanom mit einer BRAF-V600-Mutation BRAF mut CMEK162B2301 COLUMBUS Trial Phase III, randomisiert, dreiarmig, IIIB-IV: LGX818 + MEK162 versus LGX818- Monotherapie versus Vemurafenib-Monotherapie Stage IV 2 nd Line BRAF mut BRAF mut BRAF indip CMEK162X2110 Triple Combo Trial Phase II, multizentrisch, offen, IIIB-IV: LGX818 in Kombination mit MEK162 und LEE011. Patienten können mit Immuntherapie oder mit BRAFi vorbehandelt sein (Progredienz oder Intoleranz) BRAF Inhibitor Vemurafenib oder Dabrafenib (keine Studie) Über die Krankenkasse beantragte Behandlung mit Vemurafenib (Zelboraf ) oder Dabrafenib (Tafinlar ) po täglich Nivolumab oder Pembrolizumab Anti-PD1-Antikörper zur Behandlung von fortgeschrittenem Melanom, wo die therapeutischen Möglichkeiten ausgeschöpft sind Stage IV 2 nd Line p53 wt CCGM097X2101 HDM2 Inhibitor Trial Phase I, multizentrisch, Dosiseskalationsstudie: oral verabreichtes p53/hdm2 Interaktions-inhibitors CGM097 bei erwachsenen Patienten mit bestimmten, fortgeschrittenen, soliden Tumoren

42 Melanoma treatment: Outlook Adjuvant treatment in melanoma? Treatment Combinations? Treatment Schedules? Patients with brain metastasis?.. Patients should be treated in controlled clinical trials evaluating systematically new treatment approaches

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45 Q 1: Which statement about sentinel node biopsy is correct? 1. Sentinel node biopsies should be offered in every surgical department 2. Sentinel node biopsy has an impact of the long term survival of the patient 3. Sentinel node biopsy is indicated in a patient with a ulcerated pt1b; tumor thickness 0,5 mm 4. Sentinel node biopsy is indicated in a young patient with a tumor thickness of 0,8 mm with a mitotic activity (pt1b) 45

46 Q 1: Which statement about sentinel node biopsy is correct? 1. Sentinel node biopsies should be offered in every surgical department 2. Sentinel node biopsy has an impact of the long term survival of the patient 3. Sentinel node biopsy is indicated in a patient with a ulcerated pt1b; tumor thickness 0,5 mm 4. Sentinel node biopsy is indicated in a young patient with a tumor thickness of 0,8 mm with a mitotic activity (pt1b) 46

47 Q 2: Which treatment is mainly indicated in a metastatic melanoma patient Stage IV, BRAF mut? 1. Irradiation therapy 2. Pegylated interferon 3. Treatment with BRAF- and MEK- inhibitors 4. Treatment with BRAF-inhibitor alone 5. Therapy with Dacarbazine 6. Therapy with Ipilimumab and/or Anti-PD-1 antibodies 7. None of the above

48 Q 2: Which treatment is mainly indicated in a metastatic melanoma patient Stage IV, BRAF mut? 1. Irradiation therapy 2. Pegylated interferon 3. Treatment with BRAF- and MEK- inhibitors 4. Treatment with BRAF-inhibitor alone 5. Therapy with Dacarbazine 6. Therapy with Ipilimumab and/or Anti-PD-1 antibodies 7. None of the above