MALIGNE MELANOOM en NIET-MELANOOM HUIDTUMOREN

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1 MALIGNE MELANOOM en NIET-MELANOOM HUIDTUMOREN POSTGRADUAAT ONCOLOGIE 3 Oktober 2012 Christine Langenaeken 1

2 OVERZICHT (1) MALIGNE MELANOOM (MM) Epidemiologie & risicofactoren Diagnostiek Staging Heelkunde & Schildwachtklier Adjuvante behandeling? Follow-up Behandeling bij herval (lokaal-in transit-nodaal) 2

3 OVERZICHT (2) MALIGNE MELANOOM (MM) Systemische behandeling BRAF inhibitie MEK inhibitie BRAF + MEK inhibitie Anti-cytotoxische T-lymfocyt antigen 4 (anti-ctla-4) antistof KIT inhibitie Angiogenese inhibitie BASAAL CEL CARCINOOM (BCC) Systemische behandeling Hedgehog inhibitie 3

4 Maligne melanoom INCIDENTIE Bron: Stichting Kankerregister 4

5 Maligne melanoom INCIDENTIE - Malignant melanoma is the 10th most frequent tumour in males (2.3%) and the 5th most frequent in females (4.2%). - Malignant melanoma is an uncommon cause of cancer death in males (1.1%) and females (1.3%). - No major differences in incidence rates are observed between the regions. - Mean age at diagnosis is 60 years in males and 55 years in females. Bron: Stichting Kankerregister 5

6 Maligne melanoom INCIDENTIE 6

7 Maligne Melanoom RISICOFACTOREN Huidtype - Bleke huid - Haarkleur: blond/hoogrood - Kleur ogen: blauw - Sproeten Door omgeving - Neiging tot zonnebrand, slecht bruinen - Voorgeschiedenis van zonnebrand met blaarvorming in jeugd - Intermittente intensieve zonblootstelling - Zonnebanken - PUVA therapie (laattijdig, > 15-20j.) Exacte golflengtespectrum verantwoordelijk voor MM (UVA/UVB) niet gekend Voorloper letsels - Dysplastische naevi: risicomerker, niet noodzakelijk voorloper - Congenitale moedervlek (vooral zeldzame zeer grote) - Lentigo maligna = melanoma in situ = altijd voorloperletsel Andere - Hoog aantal naevi - Persoonlijke antecedenten van melanoom - Familiaal voorkomen (10%), familiaal dysplastisch naevus S, xeroderma pigmentosum - Niet-melanoma huidkanker (vnl. basocellulaire carcinomen) College voor Oncologie Nationale richtlijnen

8 Moleculaire Genetica Maligne Melanoom RISICOFACTOREN Cycline-afhankelijke kinase inhibitor 2A (CDKN2A) o Tumor suppressor gen: belangrijke functie bij controle van toegang tot celcyclus en celdeling o Mutatie aangetoond in 30 % melanoom-families Cycline-afhankelijk kinase 4 (CDK4) o Melanoma-gevoeligheids-gen o Mutatie aangetoond in vijf families wereldwijd Melanocortine 1 receptor (MC1R) o Celreceptor voor produktiepad van eu-melanine (donker) en phaeo-melanine (rood) o Interactie met CDKN2A in familiaal melanoom? o Mogelijk relevant in niet-familiale melanomen? o Associatie melanoom met varianten van genen coderend voor MC1R antagonist en tyrosinase (enzym in melanine productie)? 8

9 Maligne melanoom DIAGNOSTIEK KLINISCHE DIAGNOSTIEK = Anamnese en klinisch onderzoek Volledige huidinspectie Palpatie klierstations en drainagegebied o Zeven punten-check list Verandering in grootte Verandering in vorm Verandering in kleur Ontsteking Korsten of bloeding Verandering gevoeligheid (jeuk, pijn,..) Vergroten van diameter tot > 7 mm 9

10 Maligne melanoom DIAGNOSTIEK o ABCD(EF) regel Asymmetry asymmetrie Border onregelmatige begrenzing Color kleurvariatie, inhomogeen Diameter > 6 mm Elevation verheven, vergroting, evolutie Funny niet ABCD, wel verdacht o Dermatoscopie Manueel apparaat, laat 10x vergroting huidletsel toe Correcte diagnose tot 95 % bij ervaren onderzoeker (huidartsen > huisartsen/andere specialisten) Laat toe andere huidletsels uit te sluiten en nutteloze excisies te vermijden 10

11 DIAGNOSE-KLINIEK- PATHOLOGIE DIAGNOSE KLINISCH ASPECT HISTOLOGISCH ASPECT Superficieel spreidend maligne melanoom (SSMM) (50-75%) Lentigo maligne melanoom (LMM) (5-15%) Acraal lentigineus melanoma (ALM) Nodulair melanoma (NM) (15-35%) Vrouwen > Mannen Onderste ledematen (V), rug (M) Intermittente UV expositie Geen voorkeur geslacht Chronische zonblootstelling Oudere pat met lichte huid, vrnl. gelaat en nek, traag groeiend Palmen, vingers, voetzolen, tenen (pigment uitvloei in nagelwal!) 5-10% blanken 35-90% Aziaten, afroamerikanen, hispanics Uniform donkere nodule met duidelijke rand, groeit snel en verticaal vanaf het begin Proliferatie atypische M, alleen of in nesten, alle niveaus dermis Dermale invasie (nesten, bundels) Epidermale component atypische M, alleen of in nesten, in basale laag Dermale invasie mogelijk Maligne voorloper (= in situ) Radiale groeifase met een lentigineus patroon van atypische M, deels nesten, deels alle niveaus dermis (pagetoïde spreiding) Solide dermale tumor zonder intraepidermale component van atypische M, DD metastase Varia Desmoplastisch/neurotroop Naevocytoïd melanoma Melanocytic tumor of uncertain malignant potential (MELTUMP) 11

12 Maligne melanoom APO VERSLAG Essentieel Dikte (Breslow) Anatomisch niveau (Clark) Chirurgische snedevlakken Prognostische factoren Ulceratie aantoonbaar/niet aantoonbaar Aantal mitosen per mm Regressie als aantoonbaar: zone, liefst % Vaatinvasie aantoonbaar/niet aantoonbaar Peri-neurale invasie aantoonbaar/niet aantoonbaar AJCC stadium (pt) Informatief Minimale tumorvrije marge Tumor infiltrerende lymfocyten? Microsatellieten? Immuunhistochemie 12

13 Maligne melanoom KLINISCHE STADIERING Rationale Opsporen metastasen Basisbilan, referentie voor vergelijking tijdens FU Maar Beperkte gevoeligheid van testen Ontdekken van andere pathologie Risico s van (invasieve) procedures bij verder onderzoek Welke onderzoeken? Geen consensus voorstel: in functie van stadium 1 Stadium I Niets 1 (optioneel: labo, rx thorax, echo abdomen) 2, 3 Stadium II Rx thorax 1 (optioneel: + labo, echo abdomen) 2,3 Stadium III Stadium IV CT thorax-abdomen, PET, +/- CT/MRI hersenen LDH (overige optioneel); CT thorax-abdomen, PET, +/- MRI hersenen (ifv symptomen) 1 NCCN V College voor oncologie Zorgprogramma Voorkempen 13

14 AJCC 2009 Melanoma staging & classification Tumor (T) T is Dikte Niet van toepassing Ulceratie Mitosen Niet van toepassing T 1 < 1.00 mm a: geen ulceratie EN mitosen < 1/mm² b: met ulceratie OF mitosen > 1/mm² T mm a: geen ulceratie b: met ulceratie T mm a: geen ulceratie b: met ulceratie T 4 > 4.00 mm a: geen ulceratie b: met ulceratie Balch et al. J Clin Oncol 27: ,

15 AJCC 2009 Melanoma staging & classification Lymfeklieren (N) Aantal klieren Aantasting N 0 0 Niet van toepassing N 1 1 a: micrometastase b: macrometastase N a: micrometastase b: macrometastase c: in transit metastasen/ satellietletsels zonder metastatische lymfeklieren N 3 4+ OF vlekkige aantasting OF in transit metastasen/ satellietletsels met metastatische lymfeklieren 15

16 AJCC 2009 Melanoma staging & classification Metastasen (M) Plaats LDH M 0 Geen metastasen op afstand Niet van toepassing M 1a Huid-, onderhuidse, of kliermetastasen op afstand Normaal M 1b Longmetastasen Normaal M 1c Alle andere viscerale metastasen Eender welke metastase op afstand Normaal Verhoogd 16

17 AJCC 2009 Melanoma staging & classification Clinical staging Pathologic staging T N M T N M 0 T is N0 M0 0 T is N0 M0 I A T 1a N0 M0 I A T 1a N0 M0 I B T 1b N0 M0 I B T 1b N0 M0 T 2a N0 M0 T 2a N0 M0 II A T 2b N0 M0 II A T 2b N0 M0 T 3a N0 M0 T 3a N0 M0 II B T 3b NO M0 II B T 3b N0 M0 T 4a N0 M0 T 4b N0 M0 II C T 4b N0 M0 II C T 4b N0 M0 III elke T N + M0 III A T 1 4a N 1a M0 T 1 4a N 2a M0 III B T 1 4b N 1a M0 T 1 4b N 2a M0 T 1 4a N 1b M0 T 1 4a N 2b M0 T 1 4a N 2c M0 III C T1 4b N 1b M0 T1 4b N 2b M0 T1 4b N 2c M0 elke T N 3 M0 IV elke T elke N M1 IV elke T elke N M1 17

18 Survival curves from the American Joint Committee on Cancer Melanoma Staging Database comparing (A) the different T categories and (B) the stage groupings for stages I and II melanoma. For patients with stage III disease, survival curves are shown comparing (C) the different N categories and (D) the stage groupings by American Society of Clinical Oncology Balch C M et al. JCO 2009;27:

19 Survival curves of 7,635 patients with metastatic melanomas at distant sites (stage IV) subgrouped by (A) the site of metastatic disease and (B) serum lactose dehydrogenase (LDH) levels. Balch C M et al. JCO 2009;27: by American Society of Clinical Oncology 19

20 Maligne melanoom HEELKUNDE Behandeling primaire tumor Breslow Marge Fascia < 0,5 mm 0,5 cm / 0,5 1 mm 1 cm Tot aan >1 mm OF regressie OF ulceratie 2 cm Tot aan 20

21 Maligne melanoom HEELKUNDE Schildwachtklier ( sentinel node ) Belang: pathologische stadiëring prognostische factor Overlevingsvoordeel? Multicenter selective lymphadenectomy trial-i (MSLT-I) Interim analyse bij 5 jaar follow-up: Geen verschil in melanoma-specifieke overleving (87-86%) Langere ziektevrije overleving (78-73%) Overleving wel beter in pt met klieruitruiming voor positieve sentinel versus pt in observatiegroep met klieruitruiming bij optreden van pathologische klieren (72-52%) Overleving vergelijkbaar tussen pt met negatieve sentinel en pt in observatiegroep bij wie geen pathologische klieren optraden (92%) 21

22 Maligne melanoom HEELKUNDE Indicaties voor schildwachtklierbiopsie * Tumor > 1 mm 4 mm dikte Tumor < 1 mm dikte met een risicofactor dikte < 1mm maar groter dan 0,75 mm ulceratie mitosen > 1/mm² lymfovasculaire invasie positieve diepe snijranden (regressie)? Tumor > 4 mm dikte:? Prognostische informatie Lokale controle Besluit: schildwachtklierbiopsie is aangewezen voor Hoog risico stadium I A Stadia IB II C *NCCN V3.2012, ASCO-SSO

23 Maligne melanoom HEELKUNDE APO schildwachtklier Seriële coupes Immuunhistochemie: S100, Melan A, HMB 45, Ki 67 Kapseldoorbraak? Aanwezigheid van geïsoleerde cellen is relevant (N 1a) (er is geen ondergrens om aantasting van de schildwachtklier niet te rapporteren) Combinatie van tumormassa (Rotterdam criteria) en topografie van aantasting (Dewar criteria) in sentinel klier zijn prognostisch voor de kans op aantasting van de overige klieren (niet-sentinel klier positiviteit (NSNP) en overleving* Submicrometasase (< 0,1 mm): 9% NSNP, 5j OS 91% Submicrometasase enkel subcapsulair: 2% NSNP, 5j OS 95% *van der Ploeg et al. JCO 29: (2011) 23

24 Maligne melanoom HEELKUNDE Wat doen bij een positieve schildwachtklier? Standaard volledig lymfeklierevidement Studie Multicenter Selective Lymphadenectomy Trial II Pt met tumordikte > 1.2 mm en Clark level III, of Clark level IV-V (ongeacht tumordikte) Vergelijking onmiddellijk lymfeklierevidement versus opvolging met lymfeklierevidement bij herval in regionale lymfeklieren Primair eindpunt: melanoma-specifieke overleving 24

25 Maligne melanoom HEELKUNDE Klinisch positieve klieren Lymfeklierevidement = therapie aantal aangetaste klieren is prognostisch nog behoorlijke overleving mogelijk (20-40 % op 10 j.) bij inguinale klieren: overweeg uitbreiding evidement bij + CT/PET + klier hoog-inguinaal klinisch+ klieren > 3 oppervlakkige klieren aangetast Cave morbiditeit! APO verslag Totaal aantal klieren Aantal aangetaste klieren Kapseldoorbraak Macro- en/of micrometastasen 25

26 Maligne melanoom ADJUVANTE BEHANDELING Rationale Verminderen van het risico op herval bij pt na heelkunde en vrij van aantoonbare ziekte Interferon Lage en intermediaire dosis interferon (IFN) Tegenstrijdige gegevens Soms verbetering van de ziektevrije overleving Soms trend tot betere globale overleving (niet significant) Meestal geen duidelijk effect op ziekte herval-vrije of globale overleving (RFS, OS) 26

27 Maligne melanoom ADJUVANTE BEHANDELING Hoge dosis (HD) IFN en gepegyleerd (peg) IFN ECOG 1684 Kirkwood HD IFN vs. observatie Pt met stadium IIB of III Na 6.9 jaar FU: significante verbetering in RFS en OS Na 12.6 jaar FU: verschil nog significant voor RFS, niet meer voor OS Intergroup E1690 HD IFN (ECOG 1684) vs. lage dosis IFN (WHO) vs. observatie Stadium IIB, III; bij klinisch N0 geen staging lymfeklierevidement Betere overleving voor HD IFN én observatie dan in ECOG 1684 Significante verbetering van RFS, maar geen verschil in OS voor HD IFN vs. observatie; resultaten intermediair voor lage dosis IFN vs. observatie Geen overlevingsvoordeel?: belangrijk effect van salvage behandeling (heelkunde, IFN) bij herval van pt in observatie-arm E1694 HD IFN vs. GM2-KLH vaccin Stadium IIB, III Betere RFS en OS (2j. FU) Maar EORTC voortijdig gestopt wegens significant slechtere overleving in de vaccin-arm 27

28 Maligne melanoom ADJUVANTE BEHANDELING Meta-analyses ECOG/Intergroup studies o verbetering in RFS, geen verschil in OS Meta-analyse Mocellin et al o verbetering in RFS en OS o optimaal IFN HD schema of duur van behandeling niet duidelijk Beleid? Beslissing ifv. individuele pt Rekening houden met risico op herval, co-morbiditeit, wensen pt, toxiciteit! Te bespreken met hoog risico groep: stadium IIB-IIC, stadium III Schema: o o IFN 20 MIU/m² IV 5d/week (4 wk) 10 MIU/m² SC 3/wk (11 mo.) Peg IFN 6mcg/kg/wk SC (8wk) 3 mcg/kg/wk (tot 5 jr.) 28

29 Maligne melanoom BEHANDELING Radiotherapie Indicaties Primaire setting: Indien inoperabel o o Adjuvant: bij hoog-risico pt o o Bij inoperabele tumorlokalisaties (hoofd-hals) Bij lokale recidieven, in-transit metastasen, regionale lymfeklieraantasting waar heelkunde niet mogelijk is Bij nauwe marges (hoofd-hals) Indien hoog risico op herval na lymfeklierevidement: N3 en kapseldoorbraak 29

30 Maligne melanoom FOLLOW-UP Handboek Zorgprogramma = Nationale Richtlijnen In situ melanoom: 1x/jaar dermatoloog Overige melanomen: Anamnese en klinisch onderzoek: (totale huidinspectie, volledig KO, palpatie drainagegebied, palpatie klieren): om de 3 maanden (eerste 2 jaren) om de 6 maanden (tot 5 jaren) (kans op regionaal herval) om de 12 maanden (jaarlijks, levenslang)(late recidieven, metastasen op afstand) Labo, Rx thorax, echo abdomen: om de 12 maanden (jaarlijks)(nationale Richtlijnen: geen consensus, op individ. basis Iedereen: 1x per jaar dermatoloog Bij klachten gericht onderzoek! 30

31 Maligne melanoom BEHANDELING van HERVAL Lokaal litteken herval Na onvolledige initiële excisie Staging zoals voor primair letsel Re-excisie met adequate marges (2 cm) Evt. schildwachtklierbiopsie Na vroegere volledige ruime excisie Staging om lokalisaties elders uit te sluiten Indien negatieve staging: heelkunde, marge 2 cm (doel: R0 resectie) Schildwachtklierbiopsie? Verder beleid: opvolging; studie?, adjuvant IFN??? In-transit metastasen Een of enkele letsels, lang interval Heelkunde (ruime excisie met negatieve snijranden) Indien heelkunde niet mogelijk: radiotherapie (risico voor herval binnen RTveld), laser, intralesionele therapie (BCG, IFN, imiquimod) Veel letsels, in-transit recidief na kort interval Lidmaatperfusie met chemotherapie (melphalan) 31

32 Locaal recidief en satellieten (lymfatische metastasering) na brede resectie MM + huidgreffe

33 Regionale lymfatische uitbreiding Satellieten In transit metastase Regionale klieren

34 Lidmaatperfusie

35 Maligne melanoom BEHANDELING van HERVAL Herval in regionale lymfeklieren Te doen Histologische bevestiging (biopsie) Staging onderzoeken (uitsluiten van metastasen op afstand) Behandeling Lymfeklierevidement (volledige uitruiming) Aanvullende radiotherapie bij belangrijke klieraantasting (N3) of kapseldoorbraak Metastasen op afstand Solitair, operabel, lang ziektevrij interval (> 1 jaar): R/ resectie Symptomatische, inoperabele letsels: palliatieve radiotherapie Uitgebreide metastasering: systemische behandeling 35

36 Maligne melanoom SYSTEMISCHE BEHANDELING VROEGER Chemotherapie o o DTIC (standaard) Temodal, Taxol, fotemustine Immunotherapie o o o IL-2 IFN IL-21 Combinatietherapie Combinatie chemotherapie o DTIC cisplatina (hogere respons dan DTIC mono) Bio-chemotherapie o o Chemotherapie + IFN Chemotherapie + IFN + IL-2 (meta-analyse: wel hogere respons, geen overlevingsvoordeel)* *Ives et al. JCO 2007, 25:

37 Maligne melanoom SYSTEMISCHE BEHANDELING Welkom in het tijdperk van de gerichte therapieën! Braf inhibitie (gemuteerd Braf V600) Vemurafenib (Zelboraf, Roche)(FDA, EMEA goedkeuring) Dabrafenib (GSK) Sorafenib (Nexavar, Pfizer) MEK inhibitie Trametinib (GSK ) Selumetinib (AZD6244, ARRY ) MEK 162 Braf inhibitie + MEK inhibitie Dabrafenib + trametinib (studie opgestart in KLINA september 2012) Anti-cytotoxische T-lymfocyt antigen 4 (anti-ctla-4) antistof Ipilimumab (Yervoy, Bristol-Myers Squibb)(FDA, EMEA goedkeuring) Tremelimumab (CP , Pfizer) KIT inhibitie Imatinib Inhibitie angiogenese Axitinib bevacizumab 37

38 Mitogeen geactiveerd proteïne kinase (MAPK) pad 38

39 Vemurafenib (Zelboraf ) Growth factors RTK RAS Oncogenic BRAF signalling Mutated BRAF V600 MEK Zelboraf potently inhibits oncogenic BRAF kinase ERK Leading to arrested cell proliferation Zelboraf SPC

40 BRAF inhibitie: vemurafenib Final European approval February 2012: Zelboraf is indicated in monotherapy for the treatment of adult patients with BRAF V600 mutation-positive unresectable or metastatic melanoma Based on the results of Phase II (BRIM2) in pre-treated patients Randomized phase III (BRIM3) in previously untreated patients where Zelboraf was compared to dacarbazine (DTIC) 40

41 Vemurafenib: high objective response rates (BRIM2) Sosman J et al. N Eng J Med 2012;366:

42 Vemurafenib: rapid Responses (BRIM2) Median duration of response = 6.7 months (95% CI, 5.6 to 8.6) Sosman J et al. N Eng J Med 2012;366:

43 Zelboraf efficacy in previously untreated patients - BRIM3 (cut-off Dec 2010) Overall Survival in 1L stage IIIC and IV melanoma: Zelboraf vs DTIC Median Progression-free survival tripled in Zelboraf arm (5.3 mo) vs. DTIC (1.6 mo) Overall Response Rate 9x higher in Zelboraf arm (48%) vs DTIC (5.5%) Zelboraf SPC

44 Zelboraf efficacy in previously untreated patients - BRIM3 (update ASCO, cut-off Feb 2012) Improved Overall Survival Improved Objective Response Rate in Zelboraf arm (57%) vs DTIC (8.6%) Chapman et al. Abstract 8502, J Clin Oncol 30, Oral presentation ASCO

45 Survival Data across Zelboraf Clinical Trial Program Phase I 1,5 (extension cohort) Phase II BRIM-2 2,3 Phase III BRIM-3 3,4 Population Previously treated (24) untreated (8) Previously treated (n=132) Previously untreated (n=337) ASCO 2011 cut-off Dec 10 ASCO 2012 cut-off Feb 12 (post-hoc) Median PFS (months) > Median OS (months) months survival rate 50 % 58 % - 56% 1. Flaherty KT, et al. N Engl J Med 2010;363: Sosman J et al. N Eng J Med 2012;366(8): Zelboraf (vemurafenib) Summary of Product Characteristics Feb Chapman et al. Abstract 8502, J Clin Oncol 30, oral presentation ASCO McArthur A, oral presentation ECCO ESMO Sep

46 BRAF testing Zelboraf potently inhibits the activity of different BRAF kinases with activating codon V600 mutations (BRAF V600E, K, R, D, G, M) Before taking Zelboraf, patients must have BRAF V600 mutation-positive tumour status confirmed by a validated test In BRIM 2 & 3 patients were identified using the cobas 4800 BRAF V600 Mutation Test (FDA-approved, CE-IVD labeled) cobas was designed to detect the predominant V600E mutation but also detects the less common BRAF V600D & K mutations (with lower sensitivity) Zelboraf SPC

47 Vemurafenib: posology & administration Zelboraf is an oral treatment, to be given in monotherapy. Recommended dose is 960 mg = 4 tablets of 240 mg, twice a day. First dose to be taken in the morning Second dose in the evening ± 12 hours later Each dose to be taken in the same manner i.e. either with or without a meal Tablets to be swallowed whole with water (no crushing or chewing) Patients are treated until progression or unacceptable toxicity (see dose modifications). If a dose is missed, it can be taken up to 4 hours prior to the next dose. Both doses should not be taken at the same time. In case of vomiting no additional dose should be taken. Zelboraf SPC

48 Vemurafenib: Adverse Drug Reactions Very Common 1/10 CuSCC, seborrheic keratosis, skin papilloma Decreased appetite Common 1/100 to <1/10 Folliculitis Basal cell carcinoma Uncommon 1/1000 to <1/100 Headache, dysgeusia 7 th nerve paralysis Neuropathy peripheral Uveitis Retinal vein occlusion Vasculitis Cough Diarrhoea, vomiting, nausea, constipation Photosensitivity reaction, actinic keratosis, rash, pruritus, hyperkeratosis, erythema, alopecia, dry skin, sunburn Palmar-plantar erythrodysaesthesia syndrome,erythema nodosum, keratosis pilaris Toxic epidermal necrolysis, Stevens-Johnson syndrome Arthralgia, myalgia, pain in extremity, musculoskeletal pain, back pain Fatigue, pyrexia, oedema peripheral, asthenia GGT increase Arthritis ALT, alkaline phosphatase & bilirubin increase weight decreased AST increase Zelboraf SPC

49 RAS mutations are associated with the development of cutaneous squamous cell tumors in patients treated with RAF inhibitors Model of extracellular signal regulated kinase (ERK) activation by RAF inhibitors in RAS mutant tumours. Lacouture M E et al. JCO 2012;30: by American Society of Clinical Oncology 49

50 Vemurafenib: special warnings and precautions for use Hypersensitivy reaction discontinue permanently Dermatologic reactions if severe (Steven-Johnson, toxic epiderm. necrolysis): discontinue permanently QT prolongation ECG & electrolytes (incl. Mg) must be monitored in all pts before start of treatment After 1 month After dose modification Further monitoring is recommended (esp. in pts with severe hepatic impairment) Monthly during first 3 months At least every 3 months thereafter See dose modification schedule Zelboraf SPC

51 Vemurafenib: special warnings and precautions for use Ophtalmologic reactions monitor pts routinely as serious reactions including uveitis & retinal vein occlusion have been reported Cutaneous squamous cell carcinomas (CuSCC) (including kerato-acanthoma (KA) or mixed KA subtype): median time to appearance: 7-8 weeks Dermato evaluation recommended prior to & routinely during treatment till 6 months after end of treatment. Any suspicious lesion should be excised, examined by dermatopathologist & treated as per local standard of care Monthly dermato evaluation up to 6 months after treatment for CuSCC Continue Zelboraf treatment without dose adjustment Patients should be instructed to inform their physician of any skin change Zelboraf SPC

52 Vemurafenib: special warnings and precautions Non-CuSCC Head & neck evaluation (at least visual inspection oral mucosa and lymph node palpation) recommended before, 3-monthly during and 6-monthly after end of treatment CT scan before start and 6-monthly Anal & pelvic examination before and at end of treatment New primary melanoma Reported cases were managed with excision Zelboraf treatment was continued without dose adjustment Monitoring measures as for CuSCC Zelboraf SPC

53 Vemurafenib: special warnings and precautions Liver injury Liver lab abnormalities may occur Liver enzymes & bilirubine should be monitored before and during treatment Lab abnormalities to be managed with dose reduction, treatment interruption or discontinuation Photosensitivity (mild to severe cases reported) To help patients protect from sunburn all should be advised to : avoid sun exposure whilst on treatment wear protective clothing & use broad spectrum sunscreen (SPF 30) & lipbalm As from intolerable Grade 2 toxicity, dose modifications are recommended Zelboraf SPC

54 Vemurafenib: special populations Elderly no dose adjustment required Renal impairment risk for exposure Mild/moderate: no adjustment to start dose Severe: caution, closely monitor (limited data available) Hepatic impairment Zelboraf is cleared by the liver risk for exposure Mild (e.g. due to liver mets, w/o hyperbilirubinaemia): no adjustment to start dose Moderate/severe: closely monitor especially first few weeks (!accumulation) + monthly ECG during first 3 months Paediatric, non-caucasian use no data available Zelboraf SPC

55 Effect of concomitant medication on Zelboraf Zelboraf plasma concentration might be influenced by strong inducers or inhibitors of CYP3A4 and/or transport proteins Zelboraf should be used with caution in combo with potent inhibitors of CYP3A4, glucuronidation and/or transport proteins e.g. ritonavir, saquinavir, telithromycin, ketoconazole, itraconazole, voriconazole, posaconazole, nefazodone, atazanavir Concomitant use of potent inducers of P-gp, glucuronidation, and/or CYP3A4 may lead to suboptimal exposure to Zelboraf and should be avoided e.g. rifampicin, rifabutin, carbamazepine, phenytoin or St John s Wort [hypericum perforatum] Medicines that inhibit or influence P-gp could potentially influence Zelboraf PK e.g. verapamil, clarithromycin, cyclosporine, ritonavir, quinidine, dronedarone, amiodarone, itraconazole, ranolazine Zelboraf SPC

56 BRAF inhibitie - DABRAFENIB Fase III studie (BREAK-3) Objectieve respons (OR)* Dabrafenib (3:1) 150 mg PO BID 50% (93/187 pt) (waarvan 6 pt met complete respons (CR)) DTIC 1000 mg/m² IV q3wk 6% (4/63 pt) enkel partiële respons Progressievrije overleving (PFS)* Globale overleving (OS) 6.7 maand 2.9 maand Overlevingsvoordeel (niet statistisch significant)** * Independent review committee ** HR 0.61 (95% CI ); statistisch niet significant, maar te weinig events en overschakelen van DTIC naar dabrafenib toegestaan bij progressie onder DTIC Lancet Jul 28;380(9839): Epub 2012 Jun

57 PFS: Independent reviewer-assessed (cut-off: 19 December 2011) Proportion Alive Without Progression Hazard ratio 0.35 (95% CI 0.20, 0.61) DTIC: median PFS 2.9 m Dabrafenib: median PFS 6.7 m Number at risk Time from Randomization (Months) Lancet Jul 28;380(9839): Epub 2012 Jun 25.

58 Dabrafenib (BREAK-3): treatmentrelated AEs: 5% of patients Dabrafenib, n (%) DTIC, n (%) AE All Grade 3 Grade 4 All Grade 3 Grade 4 Hyperkeratosis 95 (51) 1 (<1) 1 (<1) Skin Palmar-plantar hyperkeratosis 39 (21) 4 (2) 1 (2) SCC/KA 13 (7) 9 (5) GI Nausea 18 (10) 21 (36) Vomiting 8 (4) 12 (20) Neutropenia 2 (1) 1 (<1) 9 (15) 3 (5) 4 (7) Hematologic Thrombocytopenia 1 (<1) 1 (<1) 5 (8) 1 (2) 2 (3) Leukopenia 1 (<1) 3 (5) 1 (2) Arthralgia 30 (16) 1 (<1) Fatigue 32 (17) 2 (1) 13 (22) Other Headache 32 (17) 2 (3) Pyrexia 28 (15) 5 (3) Asthenia 26 (14) 7 (12) Photosensitivity: dabrafenib (3%), DTIC (5%) Lancet Jul 28;380(9839): Epub 2012 Jun 25.

59 DABRAFENIB Hersenmetastasen Fase II gegevens N=172 pt, asymptomatische hersenmetastasen, al dan niet voorbehandeld V600E: OR=35%, OR+SD=85%, PFS 16 wk V600K: OR=7% vs. 22% (voorbehandeld vs. 1 e lijn), OR+SD=33-50% 17 Kirkwood J, Long GV, Trefzer U, et al. BREAK-MB: A phase II study assessing overall intracranial response rate (OIRR) to dabrafenib (GSK ) in patients (pts) with BRAF V600E/k mutation-positive melanoma with brain metastases (mets) (abstract #8501). J Clin Oncol

60 MEK1/MEK 2 INHIBITIE 60

61 TRAMETINIB Krachtige, specifieke MEK1/MEK2 inhibitor Trametinib vs. chemotherapie Fase III METRIC studie N=322, 2:1 randomisatie (trametinib vs. DTIC of Taxol) Mutatiestatus: V600E (87%), V600K (13%) Vooraf chemotherapie (1/3 pt) of immunotherapie (30%) Overschakelen van chemotherapie naar trametinib toegelaten bij PD Nevenwerkingen: huiduitslag (57%), diarree (43%), oedeem (26%), troebel zicht (9%), daling ejectiefractie (7%) Trametinib 2 mg/d PO PFS 4.8 m 1.5 m OS (6 m. overleving %) 81% 67% Chemotherapie 61

62 BRAF + MEK inhibitie: rationale RAS BRAFi (dabrafenib) PFS 5.1 mo; RR 53% 1 Hyperproliferative skin AEs MEKi (trametinib) OS HR 0.54 v chemo PFS 4.8 mo; RR 22% 2 Rash AE mutbraf MEK Preclinical BRAFi +MEKi Delays BRAFi resistance Hyperproliferative skin AE perk Proliferation Survival Invasion Metastasis 1. Hauschild A, Lancet 2012; 2. Flaherty K, NEJM 2012

63 TRAMETINIB Trametinib + BRAF inhibitie Fase I/II dosis-escalatie studie N=135 (n=103 maligne melanoom met BRAF mutatie) Gunstig nevenwerkingen profiel: afzwakken BRAF toxiciteit, minder SCC Fase I - II studie* Fase I (farmacokinetiek, veiligheid): n=85;d(75/150mg BID), T ( mg OD) Fase II: n=162; D(150mg BID) + T(1-2mg OD) vs D (150mg BID) OR=76% vs. 54% PFS=9.4 m vs. 5.8 m Minder cutane SCC met combinatietherapie (7% vs. 19%) Meer koorts met combinatietherapie (71% vs. 26%) Fase III studies Opgestart (ook in AZ KLINA!) Dabrafenib + trametinib vs. Dabrafenib mono OF vs. vemurafenib *Flaherty et al. NEJM Sept 27,

64 BRAFi and MEKi Associated Adverse Events Monotherapy D (n=53) Combination D+T 150/1 (n=54) Combination D+T 150/2 (n=55) Skin papilloma 8 (15) 4 (7) 2 (4) Hyperkeratosis 16 (30) 3 (6) 5 (9) Squamous cell carcinoma/ keratoacanthoma 10 (19) 1 (2) p= (7) p=0.09 Acneiform rash 2 (4) 6 (11) 9 (16) Ejection Fraction 0 2 (4) 5 (9) Chorioretinopathy (2) *Skin toxicities include multiple terms, no cases of RVO Long et al., ESMO 2012

65 ANDERE MOLECULAIR GERICHTE THERAPIEEN Andere MEK inhibitoren MEK 162 Specifieke MEK inhibitor Activiteit in pt met gevorderd maligne melanoom Fase II studie: n=71, V600 BRAF of NRAS mutatie Fase II resultaten: PR=20%, OR + SD = 60-68% (BRAF, NRAS resp.) Selumetinib Specifieke MEK inhibitor Gerandomiseerde fase II studie vs. Temodal: n=200, BRAF mutatiestatus Resultaten: geen verschil in PFS; retrospectieve analyse: 11% respons in pt met BRAF mutatie KIT inhibitie C-kit mutaties in 15-20% van pt met acraal of mucosaal melanoom, en minder frequent in melanomen ontstaan in zones van chronische zonbeschadiging Weinig activiteit in niet-geselecteerde pt Activiteit in geselecteerde pt (c-kit mutatie of amplificatie): fase II OR=21% 65

66 ANDERE MOLECULAIR GERICHTE THERAPIEEN Angiogenese axitinib Fase II studie N=32 (n=25 voorbehandeld) Resultaten: OR=19%, PFS=2.9 m, OS=6.6 m Rol in maligne melanoom? bevacizumab Fase II gegevens in monotherapie of in combinatie (chemo, IFN) BEAM: gerandomiseerde fase II o Carboplatinum + Taxol, +/- bevacizumab (B) o Geplande analyse bij FU=13 m: trend tot betere resultaten met B o PFS: 5.6 m vs 4.2 m o OS: 12.3 m vs 8.6 m o Significant overlevingsvoordeel in groep M1c en hoog LDH Apoptose oblimersen Anti-sense oligonucleotide, onderdrukt expressie van Bcl-2 (anti-apoptose) Interessante gegevens van initiële fase III niet bevestigd in tweede studie 66

67 Ipilimumab (YERVOY TM) : werkingsmechanisme T-cel aktivatie T-cel inaktivatie T-cel aktivatie T-cel T-cel T-cel TCR MHC-II CD28 B7 TCR MHC-II CD28 CTLA 4 B7 TCR MHC-II CD28 B7 CTLA 4 YERVOY TM APC APC APC 67

68 YERVOY TM pivotal MDX trial: a large multicentre, double-blind, randomised, phase 3 trial PIVOTAL PHASE 3 MDX STUDY DESIGN Induction Follow-up Screening 676 * PATIENTS Pretreated metastatic melanoma patients with life expectancy 4 months at baseline RANDOMISE 403 PATIENTS 137 PATIENTS 136 PATIENTS YERVOY 3 mg/kg 1 dose every 3 weeks (x4) + gp100 YERVOY 3 mg/kg 1 dose every 3 weeks (x4) gp100 1 Reinduction in eligible patients 1 Reinduction in eligible patients 1 Reinduction in eligible patients Duration of follow-up ranged up to 55 months. 1 * Due to the inclusion of the gp100 peptide vaccine comparator, the study was restricted to patients with HLA-A2*0201 genotype. 1,6 Because of the minimal amount of data, re-induction is not within label. An additional four doses of treatment were offered to patients who developed progressive disease (PD) after initial clinical response (partial response [PR] or complete response [CR]) or after stable disease (SD) lasting longer than 3 months from initial tumour assessment. 1,6

69 Ipilimumab (Yervoy TM ) Fase II 1 Fase III 2 Ipi-gp100 Fase III 2 Ipi Beste respons 5.8% 5.7% 10.9% 1.5% Fase III 2 gp100 Tijd tot respons 3.3 m 3.18 m 2.74 m Ziektecontrole 27 35% 20.1% 28.5% 11% Respons verbetering na > 6m Behoud van respons >2j 3 PD -> SD 3 SD -> PR 1 PR -> CR 17.4% ( m) 2 SD -> PR 3 PR -> CR 60.6% ( m) Tijd tot progressie 2.76 m 2.86 m 2.76 m % minder kans op progressie 19% (versus gp100) 36% (versus gp100) 1-j overleving 47% 43.6% 45.6% 25.3% 2-j overleving 32% 21.6% 23.5% 13.7% Mediane overleving 10.2 m 10 m 10.1 m 6.4 m 0 1 Ann Oncol 21: , NEJM 363:8, August 19, 2010

70 Majority of responders Immunopotentiation with YERVOY TM results Potential in 4 changes distinct in tumour patterns burden with of YERVOY response TM 8 Conventional response Slow, steady decline in tumor burden Minority of responders Late response after initial progression New lesion appears and then declines along with target lesion Baseline 12 weeks First assessment Later assessments Adapted from Wolchok et al

71 New, measurable lesions (i.e., 5 x 5 mm) New, nonmeasurable lesions (i.e., <5 x 5 mm) Non-index lesions Nood aan aangepaste respons criteria Always represent PD Always represent PD WHO* Changes contribute to defining BOR of CR, PR, SD and PD irrc** Incorporated into tumor burden Do not define progression (but preclude ircr) Contribute to defining ircr (complete disappearance required) CR Disappearance of all lesions in two consecutive observations not less than 4 weeks apart Disappearance of all lesions in two consecutive observations not less than 4 wk aprt PR SD PD 50% decrease in SPD of all index lesions compared with baseline in two observations at least 4 weeks apart, in absence of new lesions or unequivocal progression of non-index lesions 50% decrease in SPD compared with baseline cannot be established nor 25% increase compared with nadir, in absence of new lesions or unequivocal progression of non-index lesions At least 25% increase in SPD compared with nadir and/or unequivocal progression of non-index lesions and/or appearance of new lesions (at any single time point) 50% decrease in tumor burden compared with baseline in two observations at least 4 weeks apart 50% decrease in tumor burden compared with baseline cannot be established nor 25% increase compared with nadir At least 25% increase in tumor burden compared with nadir (at any single time point) in two consecutive observations at least 4 weeks apart Adapted from Wolchok et al Designed to detect early effects of cytotoxic agents, and may not provide a complete assessment of immunotherapeutic agents. 8 Designed to better capture the response patterns observed with immunotherapeutic agents e.g. ipilimumab. 8 71

72 Most common irars with YERVOY TM are dermatologic or GI related Most common immune-related adverse reactions in the pivotal phase 3 MDX trial % of Patients irar YERVOY + gp100 n=380 Any grade Grade 3 Grade 4 Any grade YERVOY n=131 Grade 3 Grade 4 Any grade gp100 n=132 Grade 3 Grade 4 Any Dermatologic GI Endocrine Hepatic Other irar Death due to irar Adapted from Hodi et al For more information about safety, see YERVOY TM Summary of Product Characteristics. 2 NEJM 363:8, August 19,

73 ipilimumab - irae GASTROINTESTINAL Signs and symptoms such as: Diarrhoea Abdominal pain Blood or mucus in stool Bowel perforation Peritoneal signs Ileus SKIN Symptoms such as: Pruritus Rash NEUROLOGIC Symptoms such as: Unilateral or bilateral weakness Sensory alterations Paraesthesia ENDOCRINE Signs and symptoms such as: Fatigue Headache Mental status changes Abdominal pain Unusual bowel habits Hypotension Abnormal thyroid function tests and/or serum chemistries LIVER Signs such as: Abnormal liver function tests (e.g. elevated AST, ALT or total bilirubin) OTHER ADVERSE REACTIONS Including ocular manifestations A more exhaustive list of adverse reactions can be found on slide 62. For more information about safety, see YERVOY TM Summary of Product Characteristics. 73

74 Management of irars with YERVOY TM generally depends upon their severity and persistence 1 Three-step approach 1 Mild 1 Treat symptomatically Persistent mild or moderate 1 Treat with oral corticosteroids (prednisone 1 mg/kg daily or equivalent) Omit next dose of YERVOY TM until symptoms resolve or return to baseline. Do not replace this omitted dose Symptoms worsen, are severe, or life-threatening 1 Treat with high-dose IV corticosteroids (methylprednisolone 2 mg/kg daily or equivalent) If symptoms improve, then consider a gradual steroid taper over at least 4 weeks If symptoms do not respond within 5-7 days then consider alternative immunosuppression therapies Permanently discontinue YERVOY TM * * In skin irars: Severe grade 3: Omit treatment; Severe grade 4 Rash or Severe grade 3 Pruritus: Discontinue YERVOY TM. 1 irar management algorithms by organ system When to omit or discontinue YERVOY TM For more information about safety, see YERVOY TM Summary of Product Characteristics. Risk evaluation and mitigation strategies (REMS)

75 Hedgehog signaling is critical for embryonic development Activation of SMO or functional loss of PTCH in >90 % of BCC vismodegib Cl N HN O Cl O S O PTCH, Patched; SHH, Sonic Hedgehog; SMO, smoothened Teh MT et al. Cancer Res 2005;65:

76 SHH4476g (ERIVANCE BCC): Study design Patients with advanced BCC (n=104) n=71 with locally advanced BCC n=33 with metastatic BCC Vismodegib continuous dosing 150 mg/day Until progression, intolerable toxicity or withdrawal from study Locally advanced BCC: Inoperable Surgery inappropriate 1 cm 2 recurrences after surgery and curative resection unlikely and/or anticipated substantial morbidity and/or deformity from surgery 1. Sekulic A et al. New Engl J Med 2012;366:2171 9

77 SHH4476g (ERIVANCE BCC): Objective response rate in mbcc mbcc (n=33) IRF (1 endpoint) Primary analysis 1 INV (2 endpoint) Primary analysis 1 INV 6 month update 2 Responders, n (%) Stable disease, n (%) Progressive disease, n (%) Unevaluable/missing, n (%) 10 (30.3) 21 (63.6) 1 (3.0) 1 (3.0) 15 (45.5) 15 (45.5) 2 (6.1) 1 (3.0) 16 (48.5) 14 (42.4) 2 (6.1) 1 (3.0) 95% CI for objective response ( ) ( ) ( ) P value Median duration of response, months (range) 7.6 ( ) 12.9 ( ) 12.9 (5.55 NE) 1. Sekulic A et al. New Engl J Med 2012;366: Sekulic A et al. J Clin Oncol 2012; May 30: a8579

78 SHH4476g (ERIVANCE BCC): Objective response rate in labcc, primary analysis IRF (1 endpoint) labcc 1 (n = 63) INV (2 endpoint) Responders, n (%) Stable disease, n (%) Progressive disease, n (%) Unevaluable/missing, n (%) 27 (42.9) 24 (38.1) 8 (12.7) 4 (6.3) 38 (60.3) 15 (23.8) 6 (9.5) 4 (6.3) 95% CI for objective response ( ) ( ) P value < Median duration of response, months (range) 7.6 ( ) 7.6 ( ) 1. Sekulic A et al. New Engl J Med 2012;366: Sekulic A et al. J Clin Oncol 2012; May 30: a8579

79 SHH4476g (ERIVANCE BCC): Secondary and exploratory efficacy endpoints Median progression free survival, months [95% CI] Primary analysis, IRF 1 Primary analysis, INV 1 6 month update, INV 2 mbcc (n=33) 9.5 [7.4 NE] 9.2 [7.4 NE] 9.3 [ ] labcc (n=63) 9.5 [ ] 11.3 [ ] 12.9 [10.22 NE] Absence of residual BCC on biopsy (at week 24 or best response) 1 N/A 54% Clinical benefit rate*, n (%) 3 25 (76) 47 (75) *Clinical benefit rate = response at any time (prior to or post PD) + stable disease lasting 24 or more weeks, as assessed by independent review 1. Sekulic A et al. New Engl J Med 2012;366: Sekulic A et al. J Clin Oncol 2012; May 30: a Dirix L. ECCO ESMO 2011

80 SHH4476g (ERIVANCE BCC): Vismodegib treatment duration All treated patients (n=104) mbcc (n=33) labcc (n=71) Median duration of therapy Primary analysis, months (range) ( ) 9.7 ( ) 6 month update, months Patients remaining on treatment, n (%) Primary analysis 1 19 (57.6) 6 month update 2 11 (33.3) 32 (45.1) 26 (36.6) 1. Sekulic A et al. New Engl J Med 2012;366: Sekulic A et al. J Clin Oncol 2012; May 30: a8579

81 SHH4476g (ERIVANCE BCC): Most common adverse events, primary analysis 1 All treated patients (n=104) MedDRA preferred term All adverse events (%) Grade 1 mild (%) Grade 2 moderate (%) Grade 3 4 severe (%) Muscle spasms Alopecia Dysgeusia Weight decreased Fatigue Nausea Decreased appetite Diarrhoea Sekulic A et al. New Engl J Med 2012;366:2171 9

82 SHH4476g (ERIVANCE BCC): Serious adverse events, primary analysis 1 All treated patients (n=104) All Possibly related to vismodegib Serious events, n (%) 26 (25) 4 (4) Fatal events, n (%) 7 (7) 0 The grade 3 5 adverse event profile for the 6 month update was generally consistent with that of the primary analysis 2 No additional grade 5 adverse events were reported in the 6 month update 1. Sekulic A et al. New Engl J Med 2012;366: Sekulic A et al. J Clin Oncol 2012; May 30: a8579

83 SHH4476g (ERIVANCE BCC): Efficacy of vismodegib in locally advanced BCC Baseline Week 8 Week 20 Week 16: no BCC on biopsy 1. Sekulic A et al. New Engl J Med 2012;366:2171 9